Note: Descriptions are shown in the official language in which they were submitted.
2~~w"~~~
-1-
4-18700 A
Pharmacolo~icallv active hydrazine derivatives and processes for the
preparation thereof
The invention relates to a novel class of non-hydrolysable analogues of
peptides that are
cleavable by aspartate proteases, namely hydrazine derivatives, to processes
for the
preparation thereof, to pharmaceutical compositions that comprise those
peptide
analogues, and to the use thereof as medicaments or for the preparation of
pharmaceutical
compositions for contaalling virus-dependent diseases, and to novel
intermediates for the
preparation of those compounds.
The immune deficiency syndrome AIDS ("Acquired Immunodeficiency Syndrome") is
a
fatal disease. The disease is becoming increasingly widespread throughout the
world
primarily within certain risk groups, but it is also spreading beyond those
risk groups. The
disease already affects millions of people and the conx~ol of its causes is
one of the most
important aims of modern medicine. Hitherto the retrovimses HI:V-1 and HIV-2
(HIV
representing "Human Immunodeficiency Virus") have been identified as a cause
of the
disease and they have been characterised by moleculaz~ biology. From the point
of view of
treatment, in addition to previous ways of mitigating the symptoms of AIDS and
certain
preventive measures, there is particular interest in the search for
compositions that inter-
fere with the reproduction of the virus itself but do not damage the intact
cells and tissues
of the patient.
Compounds that appear especially promising are those which suppress the
,processing of
the protein building blocks of the virus that are biosynthesised in human
cells, and thus
suppress the correct assembly of those building blocks to form complete,
infectious
virions.
HIV-1 and HIV-2 each have in their genome a region that codes for a "gag-
protease". That
"gag-protease" is responsible fox the correct proteolytic cleavage of the
precursor proteins
that are produced from the genome regions coding for the "Group Specific
Antigens"
(gag). During the cleavage, the structural proteins of the virus core are
liberated. The
"gag-protease" itself is a component of a precursor protein encoded by the pal-
genome
region of HIV-1 and HIV-2, which protein also contains the regions for the
"reverse
-2-
transcriptase" and the "integrase" and is thought to be cleaved by
autoproteolysis.
The "gag-protease" cleaves the major core protein p24 of HIV-1 and HIV-2
preferentially
h1-terminally of proline residues, for example in the divalent residues Phe-
Pro, Leu-Pro or
Tyr-Pro. It is a protease having a catalytically active aspartate residue in
the active centre>
a so-called aspartate protease.
If the action of the "gag-protease" could be suppressed, the proteins
necessary for the
assembly of the virus core would no longer be available to the virus. This
would result in
the limitation or even the suppression of the reproduction of the virus. There
is therefore a
need for inhibitory substances for the "gag-protease" for use as antiviral
compositions
against AmS and other retroviral diseases.
A number of "gag-protease" inhibitors containing central groups that axe not
proteo-
lytically cleavable peptide isosters have already been synthesised. Despite
intensive
research, however, it has not been possible hitherto for aspartate protease
inhibitors
suitable for use in humans to be used for the control of A>DS in a majority of
infected
patients, pharmacodynamic problems being the main determining factor in this
regard. In
addition, most of the "gag-protease" inhibitors known hitherto have more than
two
asymmetric carbon atoms in the said central building block, and this
necessitates relatively
expensive stereospecific syntheses or isomer separation methods. The object of
this patent
application is, therefore, to provide a novel class of inhibitory substances
fox viral
aspartate proteases having a novel central building block. Furthermore, it
should be
possible to synthesise that central building block in a sterically simple
manner. In
addition, the novel central building blacks have amino groups at both ends, so
that if
suitable substituents are selected, then, far example, structures analogous to
retro-inverso-
peptides are present.
The compounds according to the invention are compounds of formula
R2
R~
R Ra
N ~/
R~ \~~~~N\N/~
R3 R4
Ra
CA 02072785 2003-04-17
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3
wherein Rl and R9 are each independently of the other
hydrogen; acyl; unsubstituted or substituted alkyl., alkenyl
o:r alkynyl; heterocyclyl; sulfo; sulfon~vl substituted by
unsubstituted or substituted alkyl, aryl., t.eterocyclyl,
alkoxy, which is unsubst.ituted or substituted, or by
a:ryloxy; sulfamoyl that :is un substitut;ed or substitui~ed at
the nitrogen atom; or phosphoryl substituted by or.~e or two
radicals, which may be identical or different, selecl~ed from
unsubstituted or substituted alkyl, frorr~ unsubstit.utE~d or
substituted cycloalkyl, :from aryl, from hydroxy, from
unsubstituted or substituted alkoxy, from cycloalkoxy and
from aryloxy; with the proviso that not more than one of the
radicals R1 and R9 is hydrogen; and Rx and R~ are each
independently of the other hydrogen or crone of the radicals
mentioned above for R1 and R9; or the pairs of substituents
R1 and RZ, and RB and R9, each independently of the other, may
form together with the nitrogen atom t:o which they are
bonded a heterocyclic ring consisting of the bonding
nitrogen atom together with a radical selected from
ethylene, trimethylene, tetramet.hylene and pentamethylene in
which a carbon atom may :have been replaced by nitz:ogen,
oxygen, sulfur or by sulfur mono- or di--substituted by
oxygen and which may beunsaturated, or one of those
radicals with an oxo substituent at each of the two carbon
atoms linked to the bonding carbon atom and with or without
a fused-on benzene or naphthalene ring; R3 a.nd R~ are each
independently of the other hydrogen, unsubstituted or
substituted alkyl or cycloalkyl; aryl;: heterocyclyl; or
unsubstituted or substituted alkenyl; or R3 and R~ together
form unsubstituted or substituted alkylene, alkylidene or
benzo-fused alkylene; RS is hydroxy; R6 is hydrogen;
or RS and R6 together are oxo;
CA 02072785 2003-04-17
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3 ~.r
and R~ is unsukast.itr.~t~ed or subst:,.tuted alkyl or
cycloalkyl; aryl; hetero~~ycly:L; or un:-xux_:~st:.i.t..uted or
substituted alkenyl;
and salts of -t:~e rnecr~.ianed c:cac~~rpouzuds where salt-
farming groups are pr_ese~t.
According to ore as~JC::ct of t:he: i n~~~~ention, there is
provided a compound of formul<~
R~ Rs ,Rs R7
I ,, ,
R1~N~,~: ,~ t. ,N_,,,N,...Rg (z),
R3, .F~a I
R~
wherein R1 and R~ are each independent_Ly ~.~t the ot:..her
hydrogen; C1-Czsacyl; subst:ituteci alkana~,;~l, a:~l.kaxy carbonyl,
carbamoyl, or an acyl_ radi.c:al ~.:at- an arninc, a<,.id;
unsubstituted or substituted ,--C;,salky:zp ~.,,-~:::zsalk:e:rlyl or
Cl-Czsalkynyl; Cz-C:zsheterac:ycly::l.; sulfc:a; .ult:onyl :>ubstituted
by unsubstituted ar substi.t~utec: r:x:Lky:L, F.:r-~:~r aryl,
Cz-Czsheterocyclyl, C~-Czsalkoxy, whi.c:ln ~> unsubstit:uted or
substituted, or by Cf;-Czzarylo.xy; sul. f<r.rn~:}y1 ~:shat is
unsubstituted or substituted at the rnit.ac>gecn atom;; a
monovalent residue of (L) -~;ral ire=. :bond~:3c.~ W a the carbaxy
group and acylated benzyl oxy~~,arborfyl. ~~.r:
thiomorpholinocarbonyl at r_he ~:~rnino nitrr_>gerl atom; or
phosphory:l substituted by one ~:~.r twc> :rar~:a_c:ats, which may be
identical or different, selected from r~c~ru.bstitu.tE=_d or
substituted C~_-Czsalkyl, from unsubsti-tur~r>~~~ ar su.b~stituted
C3-Czscycloalkyl, from C~-Cizary~..., fr:am P~z~~.~xo~y, from
u.nsubstituted or substituted C:~--Gz,alko;~~~, f:ram
C'n-Czsc~yclaal.koxy and fram cJ~;-~;_».~~ry:l..oxy; w ~ th the proviso
that not more than one c~f thc: r:adi.a~_s R., sa~~::a Ry .LS hydrogen;
a.nd R~. and R~ are each indeper~dentl y of th~a c>the r hydrogen or
CA 02072785 2003-04-17
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3b
one of the radicals mentioned above for R1 and Ra,; or the
pairs of R,, and Rz, and R8 and Rg, each independently of the
other, may form together with the nitrogen. atom to which
they are bonded a saturated or unsaturated Lxeterocyc:Lic ring
consisting of the bonding nitrogen atom together with a
radical selected from ethylene, trimethylene, tetramethylene
and pentamethylene in which a carbon atom may be rep:Laced by
nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted by oxygen or naphthalene-1,8-dicarbonylimido; R3
and R4 are each independently of the other hydrogen;
unsubstituted or substituted Cl-Czsalkyl or c~:3-C25cycloalkyl;
Ch-Czzaryl; Cz-Czsheterocyclyl; or unsubstituted or
substituted C1-Czsalkenyl; or R~ arid R~ together form
unsubstituted or substituted ~~~-Czsalkylene, C2-C~,Salky:lidene
or benzo-fused C,,-Czsalkylene; RS is hydroxy; R~ i.s hydrogen;
or RS and R6 together are oxo; and R~ is u.nsubstituted or
substituted C1-Czsalkyl o:r C3-Czscycloalkyl; c~'~-Czzax:yl;
Cz-Czsheterocyclyl; or unsubstituted or substituted
C~-Czsalkenyl; or a salt of the compound where salt:-forming
groups are present; with the exception ~:~f tLie compound of
formula T wherein R1, Rz , R3 , R,~ , R~ and R~k are eacYx hydrogen,
Rs is hydroxyl, R~ is a radical of the formula -C'Hz- (C=0) -NH-
(1~-CH3) -CHz-C'.OOH, and R9 is tent-butoxycarbonyl.
In the description of this invention, the term
"lower" used in the definition of groups or radicals, for
example lower alkyl, lower alkoxy, lower alkanoyl etc.,
means that, unless expressly otherwise cLefined, the groups
or radicals so defined contain up to and including 7, and
preferably up to and including 4, carbon atoms.
Unless indicated to the contrary, the radicals R1,
Rz, R3, R4, R~, RB and/'or R9 may be mono- to 'poly-substituted,
CA 02072785 2003-04-17
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3c
especially mono- to tri-substituted, for example mono-
substituted, by identical or different substituents.
The carbon atoms in compounds of formula T
substituted by R3 and R4 and by R~ and R~;
2~'~~~~a
-4-
may, if they are asymmetric, be in the (R)-, (S)- or (R,S)-configuration, as
may also any
other asymmetric carbon atoms present. Accordingly, the present compounds may
be in
the form of isomeric mixtures or in the form of pure isomers, especially in
the form of dia-
stereoisomeric mixtures, pairs of enantiomers or pure enantiomers. Preferred
compounds
of formula I are those wherein the carbon atom substituted by R3 or by hydroxy
RS has
the (S)-configuration and any other asymmetric carbon atoms that may be
present are,
independently of one another, in the (R)-, (S)- or (R,S)-configuration.
The general terms and names used in the description of this invention
preferably have the
following meanings, and within the different levels of meanings of the
radicals listed
hereinbefore arid hereinbelow it is possible to use any combinations or
individual radicals
instead of the general definitions:
Acyl R1, R2, Rg or R~ has, for example, up to 25, preferably up to 19, carbon
atoms and
is especially the acyl group of a carboxylic acid, of a semiester of carbonic
acid, of an un-
substituted or N-substituted carbamic acid, of an unsubstituted or N-
substituted oxalamide
or of an unsubstituted or substituted amino acid, it being possible for there
to be thio-
carbonyl groups instead of carbonyl groups in each of the acyl radicals
mentioned.
Preferably not more than one of the radicals R1 and R,2 and not more than one
of the
radicals Rg and R9 is acylated.
Preferred acyl groups R1, R2, Rg and R9 of a carboxylic acid are unsubstituted
or substi-
tuted allcanoyl having up to 19 carbon atoms, for example n-decanoyl, or
preferably
lower alkanoyl, such as formyl, acetyl, propionyl, butyryl or pivaloyl, or
substituted
lower alkanoyl, especially in the form of
cycloalkyl-lower alkanoyl wherein cycloalkyl has, for example, fram 3 to 7
carbon
atoms and lower alkanoyl is as defined above, for example cycloalkylcarbonyl,
especially
having a total of from 4 to 8 carbon atoms, such as cyclopropyl-, cyclobutyl-,
cyclopentyl-
or cyclohexyl-carbonyl, or 2-cyclohexyl- or 2-cyclopentyl-acetyl,
cycloalkenyl-lower alkanoyl wherein cycloalkenyl has, for example, from 3 to 7
carbon
atoms, such as cycloalkenylcarbonyl, preferably having from 4 to 8 carbon
atoms, such as
1-cyclohexenylcarbonyl, 1,4-cyclohexadienylcarbonyl or 1-cyclohexenylacetyl or
1,4-
cyclohexadienylacetyl,
bicycloalkyl-lower alkanoyl wherein bicycloalkyi contains, for example, from 5
to 10
carbon atoms, for example bicycloalkylcarbonyl, preferably having from 8 to 11
carbon
atoms, such as decahydronaphthyl-2-carbonyl, endo- or exo-norbornyl-2-
carbonyl,
-5-
bicyclo[2.2.2]oct-2-ylcarbonyl or bicyclo[3.3.1]non-9-ylcarbonyl, and also
bicyclo-hexyl-,
-heptyl-, -octyl-, -nonyl- or -decyl-acetyl or -3-propionyl, such as
bicyclo[3.1.0]hex-1-, -2-
or -3-yl-, bicyclo[4.1.0]hept-1- or -7-yl-, bicyclo[2.2.1]kept-2-yl-, such as
endo- or exo-
norbornyl-, bicyclo[3.2.1]oct-2-yl-, bicyclo[3.3.0]oct-3-yl- or
bicyclo[3.3.1]non-9-yl-, and
also a- or ~i-decahydronaphthyl-acetyl or -3-propionyl,
bicycloalkenylcarbonyl, preferably having from 8 to 12 carbon atoms, such as 5-
norbornen-2-ylcarbonyl or bicyclo[2.2.2]octen-2-ylcarbonyl,
tricycloalkyl-lower alkanoyl wherein tricycloalkyl contains, for example, from
8 to 10
carbon atoms, fox example tricycloalkylcarbonyl, preferably having from 8 to
11 carbon
atoms, such as 1- or 2-adamantylcarbonyl, and also tricyclo[5.2.1.02~]dec-8-yl-
or
adamantyl-acetyl, such as 1-adamantyl-acetyl,
aryl-lower alkanoyl wherein aryl has from 6 to 14 carbon atoms, such as in
phenyl,
indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl,
and may be
unsubstituted or especially mono- to tri-substituted by lower alkyl, for
example methyl,
ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or
2-naphthyl,
hydroxy, lower alkoxy, for example methoxy, carbamoyl-lower alkoxy, N-lower
alkyl-
carbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino,
mono- or
di-lower alkylamino, lower alkanoylamino, for example pivaloylamino, halogen,
fox
example fluorine, chlorine or bromine, carboxy, .lower alkoxycarbonyl, such as
tert-
butoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such as
benzyloxy-
carbonyl, lower alkanoyl, sulfo, lower allcylsulfonyl, for example
rnethylsulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl,
carbamoyl,
mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower
alkylaminosulfonyl,
nitro and/or by cyano, wherein phenyl may be present up to three times, for
example in
Biphenyl-, dibenzyl- or triphenyl-lower alkanoyl, such as Biphenyl-, dibenzyl-
or tri-
phenyl-acetyl, and wherein lower allcanoyl may be unsubstituted or
substituted, for
example by lower alkyl, far example methyl, heterocyclyl selected from
pyrrolyl, furyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, indolyl,
quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a benzo-fused,
cyclopenta-, cyclo-
hexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or partially
saturated, hydroxy, lower alkoxy, lower alkanoyloxy, for example acetoxy,
propionyloxy,
butyroxy, isobutyroxy or pivaloyloxy, acetoacetoxy, amino- or
benzyloxycarbonylamino-
lower alkanoyloxy, for example 2-amina- or 2-benzyloxycarbonylamino-2-methyl-
propionyloxy, aryl-lower alkanoyloxy when°ein aryl has from 6 to 10
carbon atoms, for
example in benzoyloxy, phenylacetoxy, 1- or 2-naphthoyloxy, lower
alkoxycarbonyloxy,
for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy-,
sec-
-s-
butoxy-, tart-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, tart-
pentyloxy-,
n-hexyloxy-, isohexyloxy- or n-heptyloxy-carbonyloxy, mono- or di-lower
aLkylamino-
carbonyloxy, for example ethylaminocarbonyloxy or diethylaminocarbonyloxy,
aryloxy-
carbonyloxy wherein aryl has from 6 to 10 carbon atoms, for example
phenoxycarbonyl-
oxy or 1- or 2-naphthyloxycarbonyloxy, aryl-lower alkoxycarbonyloxy wherein
aryl has
from 6 to 14 carbon atoms, especially phenyl-lower alkoxycarbonyloxy, for
example
benzyloxycarbonyloxy, and also 1- or 2-naphthylmethoxycarbonyloxy or 9-
fluorenyl-
methoxycarbonyloxy, sulfonyloxy, lower allcylsulfonyloxy, for example methyl-,
ethyl-,
propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tart-butyl-, n-pentyl-,
isopentyl-,
neopentyl-, tart-pentyl-, n-hexyl-, isohexyl- or n-heptyl-sulfonyloxy,
phenylsulfonyloxy,
2- or 4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy, carboxy, esterified
carboxy
selected from lower alkoxycarbonyl, for example methoxy-, ethoxy-, n-propoxy-,
isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tart-butoxy-, n-pentyloxy-,
isopentyloxy-,
neopentyloxy-, tart-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-
carbonyl, aryl-
oxycarbonyl wherein aryl has from 6 to 10 carbon atoms, for example
phenoxycarbonyl or
1- or 2-naphthyloxycarbonyl, aryl-lower alkoxycarbonyl wherein aryl has from 6
to 12
carbon atoms, for example benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl
or 2-
fluorenylmethoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, for example
methyl- or
tart-butyl-sulfonyl, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxyphosphoryl,
carbarnoyl, carbamoyl substituted by one or two radicals selected from lower
alkyl, such
as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, spec-butyl, ten-butyl,
n-pentyl,
isopentyl, neopentyl, tart-pentyl, n-hexyl, isohexyl or n-heptyl, for example
in N-methyl-
carbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, from carboxy-lower
alkyl or
lower alkoxycarbonyl-lower alkyl, for example in the form of
carboxymethylcarbamoyl
(glyci~tylcarbonyl) or in the form of tart-butoxycarbonylmethylcarbamoyl, from
di-lower
alkylamino-lower alkyl, for example 2-dimethylaminoethyl, aminacarboxy-lower
alkyl,
for example 5-amino-5-carboxypentyl, from hydroxy-lower alkyl, for example
hydroxy-
methyl or hydroxyethyl, and from di-lower alkoxy-lower allcyl, for example 2-
(2,2-
dimethoxyethyl), or carbamoyl substituted by one radical selected from
ethylene, tri-
methylene, tetramethylene and pentamethylene in which a carbon atom may have
been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, such as piperidin-1-yl-, pyrazin-1-yl-, piperazin-1-
yl-,
pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomarpholino- or S,~-
dioxothio-
morpholino-carbonyl; sulfamoyl, phosphono, benzofuranyl, oxo and/or by cyano
and is
unbranched or branched, for example selected from benzoyl that is
unsubstituted or mono-
or poly-substituted by lower alkyl, for example methyl, phenyl, halogen, for
example
fluorine or chlorine, hydroxy, lower alkoxy, for example methoxy, and/or by
vitro, such as
4-chloro-, 4-methoxy- or 4-vitro-benzoyl, naphthylcarbonyl, such as a- or ~i-
naphthyl-
carbonyl or 1,8-naphthalenedicarbonyl bonded to the amino group via both
carbonyl
groups, indenylcarbonyl, such as'1-, 2- or 3-indenylcarbonyl, indanylcarbanyl,
such as f-
or 2-indanylcarbonyl, phenanthrenylcarbonyl, such as 9-phenanthrenylcarbonyl,
phenyl-
acetyl, a-naphthylacetyl, (3-naphthylacetyl, lower alkylphenylacetyl, such as
4-methyl-
phenylacetyl, lower alkoxyphenylacetyl, such as 4-methoxyphenylacetyl, 3-
phenyl-
propionyl, 3-(p-hydroxyphenyl)-propionyl, diphenylacetyl, di-(4-methoxyphenyl)-
acetyl,
triphenylacetyl, 2,2-dibenzylacetyl, anilinophenylacetyl substituted in the
phenyl radical
by one or two radicals selected from lower alkyl, for example methyl or ethyl,
hydroxy,
lower alkoxy, for example methoxy, amino, mono- or di-lower alkylamino, for
example
ethylamino or dimethylamino, halogen, for example fluorine or chlorine,
carboxy, sulfo,
carbamoyl, sulfamoyl and cyano and/or at the amino group by one or two
radicals selected
from lower alkyl and benzyl, such as 2-(o,o-dichloroanilino)-phenylacetyl or 2-
(0,0-
dichloro-N-benzylanilino)-phenylacetyl, 3-a- or 3-~3-naphthylpropionyl, 2-
benzyl-3-(1-
pyrazolyl)-propionyl, 3-phenyl- or 3-a-naphthyl-2-hydroxypropionyl, 3-phenyl-
or 3-a-
naphthyl-2-lower alkoxypropionyl, such as 3-phenyl- or 3-a-naphthyl-2-
neopentyloxy-
propionyl, 3-phenyl- or 3-a-naphthyl-2-lower alkanoyloxypropionyl, such as 3-
phenyl-2-
pivaloyloxy- or -2-acetoxy-propionyl, 2-benzyl- or 1- or 2-naphthyl-3-(N-
methoxy-N-
methylamino)-propionyl, 3-a-naphthyl-2-acetoacetoxypropionyl, 3-a-naphthyl-2-
ethyl-
aminocarbonyloxy-propionyl or 3-a-naphthyl-2-(2-amino- or 2-benzyloxycarbonyl-
amino-2-methylpropionyloxy)-propionyl, 3-phenyl- or 3-a-naphthyl-2-
carboxymethyl-
propionyl, 3-phenyl- or 3-a-naphthyl-2-lower alkoxycarbonyl-propionyl, such as
3-a-
naphthyl-2-ethoxycarbonyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-
benzyloxycarbonyl-
methyl-propionyl, 2-(S)benzyl-3-tert-butylsulfonyipropionyl, 3-phenyl-2-
phosphono- or
-phosphonomethylpropionyl, 3-phenyl-2-dimethoxyphosphoryl- or -dimethoxy-
phosphorylmethyl-propionyl, 3-phenyl-2-diethoxyphosphoryl- or -
diethoxyphosphoryl-
methyl-propionyl, 3-phenyl-2-ethoxy- or -methoxy-hydroxyphosphorylpropionyl,
phenyl-
lower alkanoyl wherein the lower alkanoyi radical is substituted by carbamoyl,
such as
2(R,S)-carbamoyl-3-phenylpropionyl, 3-phenyl- or 3-a-naphthyl-2-
carbamoylpropionyl,
3-phenyl- or 3-a-naphthyl-2-tert-butylcarbamoyl-propionyl, 3-phenyl- or 3-a-
naphthyl-
2-(2-dimethylaminoethyl)carbarnoylpropionyl, 3-a-naphthyl-2-(carboxy- ar ten-
butoxy-
carbonyl)methylcarbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-(3-hydroxy-2-
propyl)-
carbamoyl-prapionyl, 3-phenyl- or 3-a-naphthyl-2-(2,2-dimethoxyethyl)carbamoyl-
propionyl, 3-phenyl- or 3-a-naphthyl-2-(5-amino-5-carboxypentyl)-
carbamoylpropionyl,
3-phenyl- or 3-a-naphthyl-2-cyanopropionyl, 3-phenyl- or 3-a-naphthyl-2-
cyanomethyl-
5.
~~~~F~r~~~
_g_
propionyl, 3-phenyl- or 3-a-naphthyl-2-acetonyl-prapionyl, 4-
hydroxyphenylbutyryl,
4-phenyl- or 4-a-naphthyl-3-carboxybutyryl, 4-phenyl- or 4-a-naphthyl-3-
benzyloxy-
carbonyl-butyryl, 2-benzyl- or 2-a-naphthylmethyl-4-cyanobutyryl, 2-benzyl-4-
(2-benzo-
furanyl)-4-oxobutyryl, 2-benzyl- br 2-a-naphthylmethyl-5-dimethylamino-
pentanoyl,
2-benzyl- or 2-a-naphthylmethyl-4-oxapentanoyl, 2-benzyl- or 2-a-
naphthylmethyl-4,4-
dimethyl-3-oxo-pentanoyl, 2-benzyl- or 2-a-naphthylmethyl-5-dimethylamino-4-
oxo-
pentanoyl, and 2-benzyl- or 2-a-naphthylmethyl-5,5-dimethyl-4-oxo-hexanoyl,
especially
phenyl-lower alkanoyl, such as phenylacetyl, or phenyl-lower alkanoyl wherein
the lower
alkanoyl radical is substituted by carbamoyl, such as 2(R,S)-carbamoyl-3-
phenyl-
propionyl,
phenyl-lower alkenoyl, such as (3-phenylacryloyl or (3-phenylvinylacetyl,
heterocyclyl-lower alkanoyl wherein lower alkanoyl is unsubstituted or
substituted as
defined above under aryl-lower alkanoyl Rt, R2, R8 and R9 and wherein
heterocyclyl is
preferably a single or double ring system having from 3 to 1D ring atoms, is
bonded via a
carbon atom or, especially, via a nitrogen atom and contains up to 3 further
hetero atoms
selected from oxygen, nitrogen, sulfur, selenium, and sulfur linked to 1 or 2
oxygen atoms,
the mentioned ring system may also be fused with 1 or 2 phenyl or naphthyl
radicals, it
being possible for naphthyl also to be fused-on on both sides, or with 1 or 2
cycloalkyl
z~adicals, cycloalkyl preferably having from 5 to 7 ring atoms; and may be
unsaturated or
partially or fully saturated, for example thienyl-, furyl-, pyranyl-, pyrrolyl-
, imidazolyl-,
pyrazolyl-, oxazolyl-, isoxazolyl-, thiazolyl-, furazanyl-, tetrazolyl-,
pyridyl-, pyrazinyi-,
pyrimidinyl-, pyridazinyl-, azepinyl-, indolyl-, benzimidazolyl-, 1H-indazolyl-
, quinolyl-,
isoquinolyl-, quinoxalinyl-, quinazolinyl-, cinnolyl-, purinyl-, pteridinyl-,
naphthyridinyl-,
4H-quinolizinyl-, 3,1-benzofuranyl-, benz[e]indolyl-, 4,1-benzoxazinyl-, 4,1-
benzo-
thiazinyl-, carbazolyl-, (3-carbolinyl-, phenazinyl-, phenanthridyl-,
acridinyl-, phen-
oxazinyl-, phenothiazinyl-, 1-azaacenaphthenyl-, cyclohexa[b]pyrrolyl-,
cyclohepta[b]-
pyrrolyl-, cyclohexa[d]pyrazolyl-, cyclohexa[b]pyridyl-, cyclohexa[b]pyrazinyl-
, cyclo-
hexa[b]pyrimidinyl-, cyclohexa[b]-1,4-oxazinyl-, cyclohexa[b]-1,4-thiazinyl-,
pyrrolidinyl-, pyrrolinyl-, imidazolidyl-, 2-imidazolinyl-, 2,3-dihydropyridyl-
, piperidyl-,
piperazinyl-, 2,3,5,6-tetrahydropyrazinyl-, morpholinyl-, thiomorpholinyl-,
S,S-dioxo-thio-
morpholinyl-, indolinyl-, isoindolinyl-, 4,5,6,7-tetrahydroindolyl-, 1,2,3,4-
tetrahydro-
quinolyl-, 1,2,3,4-tetrahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4-
tetrahydro-
3,1-benzodiazinyl-, 3,4-dihydro-3H-4,1-benzoxazinyl-, 3,4-dihydra-3H-4,1-benzo-
thiazinyl-, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl- or 5,6-
dihydrophenanthridinyl-lower
alkanoyl, the mentioned heterocyclyl radicals being unsubstituted or
substituted by lower
alkyl, fax example methyl, phenyl, 1- or 2-naphthyl, phenyl-lower alkyl, for
example
-9-
benzyl, hydroxy-Iower alkyl, for example hydroxymethyl or 2-hydroxyethyl,
lower
alkoxy-lower alkyl, for example methoxymethyl or 2-methoxyethyl, phenoxy- or
naphthyloxy-Iower alkyl, for example 2-phenoxyethyl, 1- or 2-
naphthyloxymethyl,
phenyl-lower alkoxy- or naphthyl-lower alkoxy-lower alkyl, for example
benzyloxy-lower
alkyl, lower allcanoyloxy-lower alkyl, for example acetoxymethyl, phenyl- or
naphthyl-
lower alkanoyloxy-lower alkyl, for example benzoyloxy-, phenylacetoxy- or 1-
or 2-
naphthoyloxy-methyl, -2-ethyl or -2-(2,2-dimethylethyl), lower
alkoxycarbonyloxy-lower
alkyl, for example tent-butoxycarbonyloxy-lower alkyl, phenyl-, naphthyl- or
fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-
benzyloxycarbonyloxy-
ethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for example
aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy-lower alkyl, for example
carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or
ethoxy,
phenyl- or naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-
naphthyloxy, amino,
lower alkylamino, for example methyl-, ethyl- or tert-butyl-amino, di-Iower
alkylamino,
for example dimethyl- or diethyl-amino, carboxy, lower alkoxycarbonyl, for
example
methoxy-, isopropoxy-, sec-butoxy- or ten-butoxy-carbonyl, phenyl- or naphthyl-
lower
alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for example fluorine,
chlorine,
bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example
acetyl or
pivaloyl, lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl or dialkoxyphosphoryl, for example dimethoxy-
or
diethoxy-phosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, for example
N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, hydroxy- or
carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-methylcarbamoyl
or
hydroxy- or carboxy-ethylcarbamoyl, sulfamoyl, vitro, oxo andlor by cyano,
with hetero-
cyclyl-lower alkanoyl being selected especially from pyrrolylcarbonyl that is
unsubstituted
or substituted by lower alkyl or by phenyl, for example 2- or 3-
pyrrolylcarbonyl, ~- or
5-methylpyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl,
thienylcarbonyl, such as
2-thienylcarbonyl, furylcarbonyl, such as 2-furylcarbonyl, pyridylcarbonyl,
such as 2-, 3-
or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, indolylcarbonyl that is
unsubstituted or
substituted by lower alkyl, such as methyl, phenyl-lower alkyl, such as
benzyl, lower
alkoxy, such as methoxy, phenyl-lower alkoxy, such as benzyloxy, or by
halogen, such as
chlorine, such as 2-, 3~ or 5-indolylcarbonyl, 1-methyl-, 5-methyl-, 5-methoxy-
,
5-benzyloxy-, 5-chloro- or 4.,5-dimethyl-indolyl-2-carbonyl, 1-benzylindolyl-2-
or -3-
carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, unsubstituted or hydroxy-
substituted
quinolyl-lower alkanoyl, for example quinolylcarbonyl, such as 2-, 3- or ~-
quinolyl-
carbonyl or 4-hydroxyquinolyl-2-carbonyl, unsubstituted or hydroxy-substituted
iso-
- 10-
quinolylcarbonyl, such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-
dihydroiso-
quinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-(3,1-benzofuranyl)-carbonyl,
Benz[e]indolyl-2-carbonyl, (3-carbolinyl-3-carbonyl, cyclohepta[b]pyrrolyl-5-
carbonyl, '
3-chromanylcarbonyl, 3-thiochromanylcarbonyl, pyrrolidinyl-3-carbanyl, hydroxy-
pyrrolidinylcarbonyl, such as 3- or 4-hydroxypyrrolidinyl-2-carbonyl,
oxopyrrolidinyl-
carbonyl, such as 5-oxopyrrolidinyl-2-carbonyl, piperidylcarbonyl, such as
piperidino-
carbonyl or 2-, 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such as pyrazin-
1-ylcarbonyl,
piperazinylcarbonyl, such as piperazin-1-ylcarbonyl, morpholinyl-lower
alkanoyl, for
example morpholinylcarbonyl, such as morpholinocarbonyl, thiomoapholinyl-lower
alkanoyl, for example thiomorpholinylcarbonyl, such as thiomorpholinocarbonyl,
S,S-
dioxothiomorpholinylcarbonyl, such as S,S-dioxothiomorpholinocarbonyl,
indolinylcarbonyl, such as 2- or 3-indolinylcarbonyl, 1,2,3,4-
tetrahydroquinolylcarbonyl,
such as 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-
tetrahydroisoquinolyl-
carbonyl, such as 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl or 1-
oxo-1,2,3,4-
tetrahydroisoquinolyl-3-carbonyl, tetrazolyl-lower alkanoyl, such as 3-
(tetrazol-1-yl)-
propionyl, and pyridyl-lower alkanoyl, for example pyridylacetyl, such as 2-,
3- or
4-pyridylacetyl, heterocyclyl-lower alkanoyl being selected more especially
from
rnorpholinocarbonyl, thiomorpholinocarbonyl, S,S-dloxothiomorpholinocarbonyl,
pyridyl-
acetyl, indolylacetyl, benzofuranylacetyl, 4-pyrrolidinylacetyl, 1-
imidazolylacetyl,
quinolin-2-ylacetyl, indol-2-ylacetyl, 2-morpholino-2-isopropylacetyl and 2-
(S,S-dioxo-
thiomorpholino)-2-isopropylacetyl, most especially morpholinocarbonyl,
thiomorpholino-
carbonyl, quinolin-2-ylcarbonyl, 3-(tetrazol-1-yl)-propionyl or 2- or 3-
pyridylacetyl,
heterocyclyl-lower alkenoyl wherein heterocyclyl is selected especially from
pyrrolyl,
furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl,
indolyl, quinolyl, isoquinolyl, quinoxalinyl, ~i-caxbolinyl and a benzo-fused,
cyclopenta-,
cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or
partially saturated, for example pyrrolidyl-lower alkenoyl, such as IV-
pyrrolidylacryloyl,
hydroxy-lower alkanoyl, such as 3-hydroxypropionyl or 2-hydroxy-2-
methylpentanoyl,
hydroxy-lower alkoxy-lower alkanoyl, such as 3-hydroxy-n-propoxycarbonyl,
lower allcoxy-lower alkanoyl, for example lower alkoxyacetyl or lower
alkoxypropionyl,
such as methoxyacetyl, ethoxyacetyl or 3-methoxypropionyl,
lower alkoxy-lower alkoxy-lower alkanoyl, such as 2-methoxymethoxy-3-methyl-
pentanoyl,
phenoxy-Iower alkanoyl or nitrophenoxy-lower alkanoyl, such as phenoxyacetyl
or 4-
nitrophenoxyacetyl,
naphthyloxy-lower alkanoyl, such as cx- or Li-naphthyloxyacetyl,
2~'~~'~3
-11-
lower alkanoyloxy-lower alkanoyl wherein lower alkanoyloxy is, far example,
~acetoxy,
propionyloxy, butyroxy, isobutyroxy or pivaloyloxy, such as acetoxyacetyl or 3-
acetoxy
propionyl, ' '
acetoacetoxy-lower alkanoyl, such as 3-acetoacetoxy-propionyl
amino- or benzyloxycarbonylamino-lower alkanoyloxy-lower alkanoyl, for example
2-
amino- or 2-benzyloxycarbonylamino-2-methylpropionyloxy-lower alkanoyl, such
as
-acetyl or -3-propionyl, .
aryl-lower alkanoyloxy-lower alkanoyl wherein aryl has from 6 to 10 carbon
atoms,
such as in benzoyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxy-lower alkanoyl,
lower alkoxycarbonyloxy-lower alkanoyl, for example methoxy-, ethoxy-, n-
propoxy-,
isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tent-butoxy-, n-pentyloxy-,
isopentyloxy-,
neopentyloxy-, tart-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-
carbonyloxy-
-lower alkanoyl, such as -acetyl or -3-propionyl,
mono- or di-lower alkyl-aminocarbonyloxy-lower alkanoyl, for example
ethylamino-
carbonyloxy-lower alkanoyl or diethylaminocarbonyloxy-lower alkanoy.l, such as
-acetyl
or -3-propionyl,
aryloxycarbonyloxy-lower alkanoyl wherein aryl has from 6 to 10 carbon atoms,
for
example phenoxycarbonyloxy- or 1- or 2-naphthyloxycarbonyloxy-lower alkanoyl,
such
as -acetyl or -3-propionyl,
aryl-lower alkoxycarbonyloxy-lower alkanoyl wherein aryl has from 6 to 12
carbon
atoms, for example phenyl-lower alkoxycarbonyloxy-lower alkanoyl, such as
benzyloxy-
carbonyloxy-acetyl or -3-propionyl, and also 1- or 2-
naphthylmethoxycarbonyloxy-lower
alkanoyl or 9-fluorenylmethoxycarbonyloxy-lower allcanoyl, such as -acetyl or
-3-propionyl,
sulfonyloxy-lower alkanoyl, such as -acetyl or -3-propionyl,
lower alkylsulfonyloxy-lower alkanoyl, for example methyl-, ethyl-, propyl-,
isopropyl-,
n-butyl-, isobutyl-, sec-butyl-, tart-butyl-, n-pentyl-, isopentyl-, neopentyl-
, tart-pentyl-,
n-hexyl-, isohexyl- or n-heptyl-sulfonyloxy-lower alkanoyl, such as -acetyl or
-3-propionyl,
phenylsulfonyloxy-, 2- or 4-toluenesulfonyloxy- or 1- or 2-naphthylsulfonyloxy-
lower
alkanoyl,
arylmercapto-lower alkanoyl wherein aryl has from 6 to 10 carbon atoms and is
preferably phenyl or naphthyl, for example phenylmercapto-lower alkanoyl, such
as
-acetyl or -3-propionyl,
amino-lower alkanoyl wherein the amino group is not in the in a- or (3-
position, such as
5-aminopentanoyl,
~"~r~'~~
-12-
lower alkanoylamino-lower alkanoyl wherein the amino group is not in the a- or
(3-
position of the lower alkanoyl radical, such as 5-amino-pentanoyl,
lower alkoxycarbonylamino-lower alkanoyl wherein the amino group is not in the
a- of
(3-position of the lower alkanoyl radical, such as 5-(tert-
butoxycarbonylamino)-pentanayl,
phenyl-lower alkoxycarbonylamino-lower alkanoyl wherein the amino group is not
in
the a- or (3-position of the lower alkanoyl radical, such as 5-
benzyloxycarbonylamino-
pentanoyl or 6-benzyloxycarbonylaminohexanoyl,
amino-lower alkanoyl substituted at the amino nitrogen atom by heterocyclyl-
lower
alkanoyl as defined above for heterocyclyl-lower alkanayl Rl, R2, Rg or Rg,
especially by
N-morpholino- or N-thiomorpholino-carbonyl, for example N-morpholino- or N-
thio-
rnorpholino-carbonylamino-lower alkanoyl, such as N-morpholino- or N-
thiornorpholino-
carbonylamino-acetyl,
halo-lower alkanoyl preferably containing up to 3 halogen atoms, for example a-
halo-
acetyl, such as a-fluoro-, a-chloro-, a-bromo-, a-iodo-, a,a,a-trifluoro- or
a,a,a-tri-
chloro-acetyl, or halopropionyl, such as B-chloro- or );-bromo-propionyl,
caxboxy-lower alkanoyl, for example cwboxyacetyl or 13-carboxypropionyl,
lower alkoxycarbonyl-lower alkanoyl, for example lower alkoxycarbonylacetyl or
lower
alkoxycarbonylpropionyl, such as methoxycarbonylacetyl, 3-
methoxycarbonylpropionyl,
ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl or ;3-tent-
butoxycarbonylpropionyl, '
lower alkylcarbonyl-halo-lower alkanoyl, such as 3-ethoxycarbonyl-2-
difluoramethyl-
propionyl,
2-halo-lower alkoxycarbonyl-lower alkanoyl, such as 2-chloro-, 2-bramo-, 2-
iodo- or
2,2,2-trichloro-ethoxycarbanyl-acetyl or -3-propionyl,
phenyl- or naphthyl-lower alkoxycarbonyl-lower alkanayl, for example benzyloxy-
carbonyl-lower alkanoyl, such as 3-benzyloxycarbonyl-2,2-dimethylpropionyl,
heterocyclyl-lower alkoxycarbonyl-lower alkanoyl wherein heterocyclyl is
preferably
selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl and 13-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicals, it
also being possible for the mentioned radicals to be fully or partially
saturated, such as in
4-pyridylmefhoxycarbonyl-acetyl or -3-propionyl or 2-morpholinocarbonyloxy-4-
methyl-
pentanoyl,
sulfonyl-lower alkanoyl, such as 3-sulfonylpropionyl,
lower alkylsulfonyl-lower alkanoyl, such as 2-ethylsulfonyl- or 2-tert-
butylsulfanyl-
acetyl,
arylsulfonyl-lower alkanoyl wherein aryl preferably has from 6 to 10 carbon
atoms, for
-13-
example phenyl or naphthyl, such as phenylsulfoacetyl,
carbamoyl-lower alkanoyl, such as carbamoylacetyl or 3-carbamoylpropionyl,
lower alkylcarbamoyl-lower allcanoyl, for example lower alkylcarbamoylacetyl
or
methylcarbamoyl-lower alkanoyl, such as methylcarbamoylacetyl,
di-lower alkylcarbamoyl-lower alkanoyl, for example di-lower
alkylcarbamoylacetyl or
dimethylcarbamoyl-lower alkanoyl, such as dirnethylcarbamoylacetyl,
hydroxy-lower alkylcarbamoyl- or di(hydroxy-lower alkyl)carbamoyl-lower
alkanoyl,
such as hydroxyrnethylcarbamoyl- or di(hydroxymethyl)carbamoyl-acetyl or -
propionyl,
N-lower alkoxy-lower alkoxy-lower alkylcarbamoyl-lower alkanoyl, such as 2-
isobutyl-
3-(2-(2-methoxyethoxy)ethylaminocarbonyl)-propionyl,
carboxy-lower alkylcarbamoyl- or di(carboxy-lower alkyl)carbamoyl-lower
alkanoyl,
such as carboxymethyl- or di(carboxymethyl)carbamoyl-acetyl or -propionyl,
carbamoyl-lower alkanoyl substituted at the nitrogen atom by a radical
selected from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted by
oxygen, it also being possible for the radical so formed to be fully or
partially unsaturated,
for example in the form of piperidino-, pyrazin-1-yl-, piperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
carbonyl-lower alkanoyl, such as in morpholinocarbonyl-acetyl, 3-(morpholino-
carbanyl)-propionyl or 3-(morpholinocarbonyl)-2-isobutyl-propionyl,
N-heterocyclyl-lower alkylcarbamoyl-lower alkanoyl or N-lower alkyl-N-
heterocyclyl-
lower alkylcarbamoyl-lower alkanoyl wherein heterocyclyl is preferably
selected from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl,
pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxatinyl, f3-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals,
which may also
be fully or partially saturated, from morpholinyl and thiomorpholinyl, such as
N-methyl-
2-(N-2-pyridylmethyl)-carbamoylacetyl, 2-(N-morpholino-lower alkylcarbamoyl)-
lower
alkanoyl, such as 2(R,S)-(N-(2-morpholinoethyl)-carbamoyl-3-methyl-butyryl or
2-(N-
(pyridyl-lower alkyl)-carbamoyl)-lower alkanoyl, such as (2(R,S)-(N-(2-
pyridylmethyl)-
carbamoyl)-3-methyl)-butyryl,
sulfamoyl-lower alkanoyl, such as 2-sulfamoylacetyl,
N-(phenyl- or naphthyl-lower alkyl)sulfamoyl-lower alkanoyl, such as 3-
benzylamino-
sulfonyl-2-isopropyl-propionyl,
sulfarnoyl-lower alkanoyl substituted at the nitrogen atom by a radical
selected from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, lower alkyl-substituted, such as methyl-
substituted,
-14-
nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen, it
also being
possible for the radical so formed to be fully ar partially unsaturated, for
example in the
form of piperidino-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl,
pyrimi-
din-1-yl-, pyridazin-1-yl-, mozpholino-, thiomorpholino- or S,S-
dioxothiomoapholino-
sulfonyl-lower alkanoyl, such as 3-(4-methylpiperazinylsulfonyl)-2-
isopropylpropionyl or
3-(morpholinosulfonyl)-2-isopropyl-propionyl,
oxo-lower alkanoyl, such as acetoacetyl or propionylacetyl,
cyano-lower alkanoyl, such as cyanoacetyl, 2- or 3-cyanopropionyl or 2-, 3- or
4-cyano-
butyryl,
hydroxy-carboxy-lower alkanoyl, such as 2-hydroxy-2-carboxy-acetyl or 2-
hydroxy-3-
carboxypropionyl,
a-naphthyloxy-carboxy-lower alkanoyl, such as 2-a-naphthyloxy-4-carboxy-
butyryl,
hydroxy-lower alkoxycarbonyl-lower allcanoyl, for example hydroxy-lower alkoxy-
carbonyl-acetyl or -propionyl or hydroxy-ethoxy- or hydroxy-methoxy-caxbonyl-
lower
alkanoyl, such as 2-hydroxy-2-ethaxy- or -methoxy-carbanylacetyl or 2-hydroxy-
3-eth-
oxy- or -methoxy-carbonyl-propionyl,
a-naphthyloxy-lower alkoxycarbonyl-lower alkanoyl, for example a-naphthyloxy-
lower
alkoxycarbonyl-acetyl, -propionyl or -butyryl or a-naphthyloxy-ethoxycarbonyl-
lower
allcanoyl, such as a-naphthyloxy-ethoxycarbonylacetyl, 2-a-naphthyloxy-3-
ethoxy-
carbonylpropionyl or 2-a-naphthyloxy-4-tert-butoxycaxbanylbutyryl,
a-naphthyloxy-benzyloxycarbonyl-lower alkanoyl, such as 2-a-naphthyloxy-3-
benzyloxycarbonyl-propionyl,
esterified hydroxy-lower alkoxycarbonyl-lower alkanoyl wherein the hydroxy
group is
esterified by lower alkanoyl, for example acetyl, propionyl or pivaloyl; by
cycloalkyl-
lower alkanoyl wherein cycloalkyl has from 3 to 7 carbon atoms and lower
alkanoyl is
preferably as last defined, for example cyclohexylcarbonyl or 2-eyclohexyl- or
2-cyclo-
pentyl-acetyl; by bicycloalkyl-lower alkanoyl wherein bicycloalkyl has, for
example, fi~ozn
to 10, especially from 6 to 9, carbon atoms, such as in bicyclohexyl-, -heptyl-
, -octyl-,
-nonyl- or -decyl-acetyl or -3-propionyl, for example bicyclo[3.1.0]hex-1-, -2-
or -3-yl-,
bicyclo[4.1.0]hept-1- or -7-yl-, bicyclo[2.2.1]hept-2-yl-, such as endo- or
exo-norbornyl-,
bicyclo[3.2.1]oct-2-yl-, bicyclo[3.3.0]oct-3-yl- or bicyclo[3.3.1]non-9-yl-,
and also a- or
13-decahydronaphthyl-acetyl or -3-propionyl; by tricycloalkyl-lower alkanoyl
wherein
tricycloalkyl has, far example, from 8 to 10 carbon atoms, for example in
tricyclo-
[5.2.1.02~6]dec-8-yl- or adamantyl-, such as i-adamantyl-acetyl; by aryl-lower
alkanoyl
wherein aryl has from 6 to 14 carbon atoms, for example phenyl, indenyl,
indanyl,
naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, which may be
unsubstituted or
-15-
mono- to tri-substituted by lower alkyl, such as isopropyl, halo-lower alkyl,
such~as tri-
fluaromethyl, hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower
alkylcarbamoyl-
lower allcoxy or N,N-di-lower alkylcarbaznoyl-lower alkoxy, amino, mono- or di-
lower
alkylamino, halogen, such as fluorine, chlorine or bromine, carboxy, lower
alkoxy-
carbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower
alkanoyl, lower
alkylsulfonyl, for example methylsulfonyl, phosphono, hydroxy-lower
alkoxyphosphoryl
or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower
alkylaminocarbamoyl,
sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano; by lower
alkoxy-
carbonyl, for example tert-butoxycarbonyl; by 2-halo-lower alkoxycarbonyl as
defined
above; or by phenyl- or fluorenyl-lower alkoxycarbonyl, for example
benzyloxycarbonyl
or 9-fluorenylmethoxycarbonyl, such as a-acetoxy-a-methoxycarbonyl-acetyl, a-
benzoyl-
oxy-, a-(1- or 2-naphthoyloxy)-, a-(phenyl-2-acetoxy)-, a-(1- or 2-naphthyl-2-
acetoxy)-,
a-(4-methylphenyl-2-acetoxy)-, a-(4-methoxyphenyl-2-acetoxy)- or a-(2-(o,o-
dichloro-
phenyl)-2-acetoxy)-a-methoxycarbonyl-acetyl,
dihydroxy-carboxy-lower alkanoyl, such as 2,3-dihydroxy-3-carboxy-propionyl,
dihydroxy-lower alkoxycarbonyl-lower alkanoyl, such as 2,3-dihydroxy-3-ethoxy-
or
-methoxy-carbonyl-propionyl,
dihydroxy-lower alkoxycarbonyl-lower alkanoyl esterified by lower alkanoyl,
such as
acetyl, pxopionyl or butyryl, lower alkoxycarbonyl, far example tert-
butoxycarbonyl,
phenyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl or 9-
fluorenyl-
methoxycarbonyl, lower alkylsulfonyl or by toluenesulfonyl, for example di-
lower
alkanoyloxy-lower alkoxy-propionyl, such as 2,3-diacetoxy-3-methoxycarbonyl-
propionyl,
a-naphthyloxy-di-lower alkylamino-lower alkanoyl, such as 2-a-naphthyloxy-5-
dimethylamino-pentanoyl;
a-naphthyioxy-carbamoyl-lower alkanoyl, such as 2-a-naphthyloxy-
4-carbamoyl-butyryl,
a-naphthyloxy-oxo-lower alkanoyl, such as 2-a-naphthyloxy-4-oxo-pentanoyl,
a-naphthyloxy-cyano-lower alkanoyl, such as a-naphthyloxy-cyano-acetyl or 2-a-
naphthyloxy-4-cyanabutyryl,
lower alkenoyl having from 3 to 7 carbon atoms, preferably having 3 or 4
carbon atoms,
lower alkenoyl being unsubstituted or substituted by the same substituents as
lower
alkanoyl, especially by phenyl, hydroxy, lower alkoxy, such as methoxy, phenyl-
lower
alkoxy, such as benzyloxy, lower alkanoyloxy, such as acetoxy, lower
alkanoylamino,
such as acetylamino, lower allcoxycarbonyloxy, such as tent-butoxycarbonyloxy,
phenyl-
or naphthyl-lower alkoxycarbonyloxy, such as benzyloxycarbonyloxy, carboxy,
lower
~~~r~/w~~~
-16-
alkoxycarbonyl, such as tart-butoxycarbonyl, phenyl- or naphthyl-lower
alkoxycarbonyi,
halogen, such as chlorine or bromine, carbamoyl and/or by mono- or di-lower
alkyl-
carbamoyl, such as in acryloyl, vinylacetyl, crotonoyl or 3- or 4-pentenoyl, 3-
phenyl-
acryioyl, 3-phenylvinyiacetyl or 5-phenyl-4-acetylaminopenten-2-oyl,
cycloalkyl-lower alkenoyl wherein cycloallcyl preferably has from 3 to 7
carbon atoms,
for example cyclohexylacryloyl, or
lower allcynoyl having. from 3 to 7, preferably 3 or 4, carbon atoms, for
example
propioloyl or 2- or 3-butynoyl.
Prefezred acyl groups R1, R2, Rg and R9 of a semiester of carbonic acid are
lower alkoxycarbonyl, for example methoxy-, ethoxy-, isopropoxy-, isobutoxy-
or
tart-lower alkoxy-carbonyl, such as tart-butoxycarbonyl or isobutoxycarbonyl,
2-halo-lower alkoxycarbonyl, such as 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-
trichloro-
ethoxycarbonyl,
aryloxycarbonyl wherein aryl has from 6 to 14 carbon atoms and is, for
example, phenyl,
biphenylyl, 1- or 2-naphthyl, fluorenyl, or phenyl mono- or poly-substituted
by lower
alkyl, for example methyl or tart-butyl, hydroxy, lower alkoxy, for example
methoxy,
ethoxy or tart-butoxy, halogen, fox example chlorine or bromine, and/or by
nitro, such as
phenoxycarbonyl,
aryl-lower allcoxycarbonyl, for example arylmethoxy-carbonyl, wherein aryl has
from 6
to 14 carbon atoms and is, for example, phenyl, biphenylyl, 1- or 2-naphthyl,
fluorenyl, or
phenyl mono- or poly-substituted by lower alkyl, for example methyl or tent-
butyl,
hydroxy, lower alkoxy, for example methoxy, ethoxy or tent-butoxy, halogen,
for example
chlorine or bromine, and/or by nitro, for example phenyl-lower alkoxycarbonyl,
such as
benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
diphenyl-
lower alkoxycarbonyl, such as diphenylmethoxycarbonyl, di-(4-methoxyphenyl)-
methoxy-
carbonyl, trityloxycarbonyl or fluorenyl-lower alkoxycarbonyl, such as 9-
fluorenyl-
methoxycarbonyl, especially benzyloxycarbonyl,
heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is preferably selected
from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl, pyri-
midinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,13-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals,
which may also
be fully or partially saturated, from morpholinyl and from thiomorpholinyl and
may be
unsubstituted or substituted, especially by lower alkyl, such as methyl, such
as 1-methyl-
pyrrolidin-2-yl-methoxycarbonyl, 2-furylmethoxycarbonyl, 2-tetrahydrofuranyl-
lower
alkoxycarbonyl, such as 2-tetrahydrofuranyl-methoxycarbonyl, 1-methyl-2-
piperidyl-
i J
-17-
methoxycarbonyl or 2-morpholino-ethoxycarbonyl, or 2-, 3- or 4-
pyridylmethoxycarbonyl,
2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-
trimethylsilyloxyearbonyl, or
2-triarylsilyl-lower alkoxycarbonyl wherein aryl is phenyl or 1- or 2-
naphthyl, such as
triphenylsiiylethoxycarbonyl.
Preferred acyl groups Rl, R2, Rg and Rg of an unsubstituted or substituted
carbamic acid,
in addition to suitable radicals already mentioned as preferred aryl groups
R1, R2, Rg and
R9, are
carbamoyl or
unsubstituted or substituted N-alkyl- or N,N-dialkylcarbamoyl wherein the
alkyl radical
has up to 12 carbon atoms, preferably unsubstituted or substituted lower alkyl-
or di-lower
alkyl-carbamoyl, such as methyl-, ethyl-, propyl-, tent-butyl-, dimethyl-,
diethyl- or di-n-
propyl-carbamoyl, the substituents being selected from phenyl, for example in
benzyl-
carbamoyl, N-phenyl-lower alkyl-N-lower alkylcarbamoyl, such as N-benzyl-N-
methyl-
carbamoyl, or dibenzylcarbamoyl, heterocyclyl as defined under heterocyclyl-
lower
alkanoyl R1, R2, Rg and R9, preferably selected from thienyl, furyl, pyranyl,
pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl,
pyrazinyl,
pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimida;aolyl, 1H-indazolyl,
quinolyl,
isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl,
naphthyridinyl, 4H-
quinolizinyl, 3,1-benzofuranyl, bent[e]indolyl, 4,1-benzoxazinyl, 4,1-
benzothiazinyl,
carbazolyl, (3-carbolinyl, phenazinyl, phenanthridyl, ac:ridyl, phenoxazinyl,
phenothiazinyl,
1-azaacenaphthenyl, cyclohexa[b]pyrrolyl, cyclohepta[b]pyrrolyl,
cyclohexa[d]pyrazolyl,
cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl,
cyclohexa[b]-1,4-
oxazinyi, cyclohexa[b]-1,4-thiazinyl, pyrrolidinyl, pyrrolinyl,
imidazolidinyl, 2-
imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6-
tetrahydropyrazinyl,
morpholinyl, thiomorpholinyl, S,S-dioxothiomorpholinyl, indolinyl,
isoindolinyl, 4,5,6,7-
tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl,
chromanyl,
thiochromanyl, 1,2,3,4-tetrahydro-3,1-benzodiazinyl, 3,4-dihydro-3H-4,1-
benzoxazinyl,
3,4-dihydro-3H-4,1-benzothiazinyl, 2,3,4,~-tetrahydro--1H-5,1-benzazepinyl and
5,6-
dihydrophenanthridinyl, the mentioned radicals being unsubstituted or
substituted by
lower alkyl, for example methyl, phenyl, 1- or 2-naphthyl, phenyl-lower alkyl,
for
example benzyl, hydroxy-lower alkyl, far example hydroxymethyl or 2-
hydroxyethyl,
lower alkoxy-lower alkyl, for example methoxymethyl or 2-methoxyethyl, phenoxy-
or
naphthyloxy-lower alkyl, for example 2-phenoxyethyl, 1- or 2-
naphthyloxymethyl,
phenyl-lower alkoxy- or naphthyl-lower alkoxy-lower alkyl, for example
benzyloxy-lower
alkyl, lower alkanoyloxy-lower alkyl, for example acetoxyrnethyl, phenyl- or
naphthyl-
~~ ~~~~a
-18-
lower alkanoyloxy-lower alkyl, for example benzoyloxy-, phenylacetoxy- or 1-
or
2-naphthoyloxy-metbyl, -2-ethyl or -2-(2,2-dimethylethyl), lower
alkoxycarbonyloxy-
lower alkyl, for example tert-butoxycarbo~nyloxy-lower alkyl, phenyl-,
naphthyl- or '
fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-benzyloxycarbonyl-
oxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for example
aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy-lower alkyl, for example
carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or
etboxy,
phenyl- or naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-
naphthylmethoxy,
amino, lower alkylamino, for example methyl-, ethyl- or tert-butyl-amino, di-
lower allcyl-
amino, for example dimetbyl- or diethyl-amino, carboxy, lower alkoxycarbonyl,
for
example methoxy-, isopropoxy-, sec-butoxy- or tent-butoxy-carbonyl, phenyl- or
naphthyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for
example
fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower
alkanoyl, for
example acetyl or pivalayl, lower alkylsulfonyl, for example methyl- or ethyl-
sulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or dialkoxy-phosphoryl, for example
dimethoxy- or diethoxy-phosphoryl, carbamoyl, mono- or di-lower
alkylcarbamoyl, for
example N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl,
hydroxy-
or carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-
methylcarbamayl or
hydroxy- or carboxy-ethylcarbamoyl, sulfamoyl, nitro, oxo and/or by cyana,
especially
pyridyl, such as 2-, 3- or 4-pyridyl, more especially in N-heterocyclyl-lower
alkyl-N-lower
alkylcarbamoyl, for example N-pyridyl-lower alkyl-N-lower alkylcarbamoyl, such
as
N-(2-, 3- or 4-pyridylmethyl)-N-methyl-carbamoyl, or in N-heterocyclyl-lower
alkyl-
carbamoyl, for example 2- or 3-pyridyl-lower alkylaminocarbonyl, such as 2- or
3-pyridylmethylaminocarbonyl, hydroxy, for example in hydroxymethyl, 2-
hydroxyethyl,
3-hydroxypropyl, 2-hydroxypropyl, N-dihydroxy-lower alkyl, such as 2,3-
dihydroxy-n-
propyl or 2-hydroxy-2,2-dimethylethyl, lower allcoxy, preferably in lower
alkoxy-lower
alkyl, for example methoxymethyl or 2-methoxyethyl, lower alkanoyloxy,
preferably in
lower alkanoyloxy-lawer alkyl, for example lower alkanoyloxymethyl or lower
alkanoyloxyethyl, such as acetoxymethyl, 2-acetoxyethyl, 3-propionyloxymethyl,
2-propionyloxyethyl, 4-butyroxymethyl or 2-butyroxyethyl, aryloxy or aryloxy
and
hydroxy wherein aryl has from 6 to 14 carbon atoms, such as phenyl, naphthyl
or
fluorenyl, preferably in aryloxy-lower alkyl or aryloxyhydroxy-lower alkyl,
such as
phenoxymethyl, 2-phenoxyethyl, 1- or 2-naphthyloxymethyl or 1- or 2-
naphthyloxyethyl,
or 2-phenyl-2-hydroxyethyl, aryl being unsubstituted or mono- or di-
substituted, for
example by lower alkyl, for example methyl, ethyl, propyl, isopropyl, butyl,
sec-butyl or
tert-butyl, by hydroxy, by lower alkoxy, for example methoxy, ethoxy, propoxy,
CA 02072785 2003-04-17
-19-
isopropoxy, butoxy, sec-butoxy or tert-butaxy, by carboxy, by lower
alkoxycarbonyl, for
example isopropoxycarbonyl, sec-trutoxycarb~>nyl or tert-butoxycarbonyl, or by
carbamoyl, lower alkyl- or di-lower alkyl=carbamoyl andjcar by mono- or di-
(hydroxy- or~
carboxy-lower alkyl)carbamoyl and it being possible for the rr~entioned
substituents to be
present in different ring positions, for example in the faun of 4-
rnethylphenoxy, 2,4,x-tri-
methylphenoxy, 4-hydroxyphenoxy, 4-methoxyphenaxy, 3,~-ciimethoxyphenoxy,
2.-carboxyphenoxy, 2-tert-butaxycarbanylphenoxy, 2- or 4-carbamoylphenaxy,
carbamoyl,
carboxy-lower allkylcarbamoyl or hydroxy-lower alkylcarbamcayl, such as in
4-carbamoyl-n-butyl, 7-carbamoyl-:n-heptyl, :.~-hydroxyethylcarbamoyl-n-butyl
or
4-(tris[hydroxymethyl]methyl)-carbamoyl-n-butyl, and also ar~nino, for example
in
2-aminoethyl or 3-aminoprapyl, lav~er alkylamino, fo~° example in
methyl- or ethyl-
aminomethyl, di-lower alkylamino, fc~r example in dimethylanair~omethyl,
halogen,
especially fluorine, chlorine or bromine, for example in 2,~,~;-
tric~hloroethyl, sulfo, for
example in sulfomethyl or 4-sulfobutylarnina, and sulfamoyl, for example in ~-
sulfamoyl-
ethyl.
Preferred acyl groups R1, R2, Rg and Rg of an unsubstituted or substituted N-
substituted
oxalamide are oxamoyl or lower alkyloxamovl, such as methyt- or ethyl-oxamoyl.
Preferred acyl groups R1, R2, Rg and Rg of an unsubstituted or substituted
amino acid are
farmed by the amino acid residues of an a- or (i-amine acid, especially
a natural a-amino acid having the h-configuration, such as those normally
occurring in
proteins, or an epimer of such an amino acid, that is to say having the
unnatura D-
configuration, or a D,L-isomeric mi;cture thereof, a homologue of such an
amino acid, far
example wherein the amino acid side chain has been lengthened or shortened by
one or
two methylene groups, wherein the amino group is in the (3-position and/or
wherein a
methyl group has been replaced by hydrogen, a substituted aromatic amino acid
wherein
the aromatic radical has from 6 to 14 carbon atoms, for example a substituted
phenyl-
alanine ar phenylglycine wherein the phenyl may be mono- or poly-substituted
by lower
alkyl, for example methyl, hydroxy, lower alkuxy, far example methoxy, lower
alkanoyl-
oxy, for example acetoxy, amine, lower alkylamina, far ex;~mple methylamino,
di-lower
alkylamino, for example dimethylamino, lower alkanoylamino, fc~r example
acetylamino
or pivaloylamino, lower alkoxycarbonylamina, for example. teat-
lautoxycarbonylamino,
arylmethoxycarbonylamino wherein aryl preferably has from 6 to 14 carbon
atoms, for
example benzyloxycarbonylamino or 9-lluorenylmethoxycarbanylamina, halogen,
for
example fluorine, chlorine, bromine or iodine, carboxy and/or by nitro, a
benzo-fused
CA 02072785 2003-04-17
_2p~.
phenylalanine or phenylglycine, such as a-naphthylalanine, or a hydrogenated
phenyl-
alanine or phenylglycine, such as cyclohexylalanine or cyclohexylglycine.
7.'hose amino acids can be substituted at free amino or hydroxy functions,
preferably at a
free amino function, by one of the radicals mentioned abo~re under aryl R.I as
the acyl.
group of a carboxylic acid, a semiester of carbonic acid, art unsubstituted or
N-substituted
carbamic acid or an unsubstituted or N-substituted oxalamide or by one of the
radicals
mentioned below under unsubstituted or substituted alkyl; aryl-lower alkyl;
heterocyclyl;
heterocyclyl-lower alkyl; sulfa; sulfonyl substituted by alkyl, w r I, aryl-
lower alkyl,
heterocyclyl-lower alkyl, alkoxy, aryloxy, aryl-lower alkoxy or by
heteroc:yclyl-lower
alkoxy; phosphoryl R 1, R2, Rg or Rc~ substituted by one or two identical or
different
radicals selected from alkyl, cycloal.kyl, cyc:lraalkyl-lower alkyd,
~~r°yl, aryl-lower alkyl,
h:ydroxy, alkoxy, cycloalkaxy, uyclaalkyl-Iower alkaxy, ~~ryloxy and aryl-
lower alkoxy;
and sulfamoyl R1, R2, Rg or R9, which is unsubstituted or substituted at the
nitrogen
atom; or by one of the radicals mentioned as protecting groups in the section
relating to
processes.
Especially preferred is the radical, bonded via a carboxy group, of an amino
acid selected
from glycine (H-Crly-OH), alarrine (;l;I-Ala-()I-l), saline (1-i-"'Val-OI-I),
norvaline: (a-amino-
vaeric acid), leucine (H-Leu-OH), isoleucine (H-Ile-OH), r~orleucine (a-
aminohexanoic
arid, H-Nle-OH), serine (H-Ser-OH), hamoserine (a-aminC>-y-hydroxybutyric
acid),
threonine (H-Thr-OH), methionine (1-1-Met-OH), cysteine (kI-(:'ys-OH),
praline.
(I-1-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanig~e (H-Phe-OH),
tyrosine
(H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalan ine, 4-
~,arboxyphenylalanine,
I3-phenylserine (B-hydroxyphenylala:nine), phenylglycirte:, cx,-
naphthylalanine (H-Nal-OH),
cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (1-i-Trp-OI-i),
indoline-
2-carboxylic acid, 1,2,3,4-tetrahydroisoduinoline-3-carboxylic acid, aspartic
acid
(H-Asp-OH), asparagine (H-Asn-Ol-1), aminornalonic acid, aminornalonic acid
mono-
arnide, glutamic acid (H-Glu-OI-I), glutamine (lv-Gln-Ol-l), hiistwdine (H-His-
OH), arginine
(H-Arg-OH), lysine (H-Lys-OH), 8-hydroxylysine, arnithine (a,8-diaminovaleric
acid)"
3-a.minopropanoic acid, a,y-diaminobutyric acid and a,li-diaminopropionic
acid,
especially preferably the radical of an aliphatic amino acid selecaed from
valine, alanine,
leucine and isoleucine, or an amino acid selected from glycine, glutamic acid
and
asparagine, it being possible for each of the mentioned amino acids (with the
exception of
gly~cine) to be in the D-, L- or (D,L)-form, preferably in the L-fc~rr~n (with
the exception of
Val which may also be in the (D)- or (U,L)-form), and wherein
~~~r~~~a
-21-
the a-amino group may be unsubstituted or mono- or di-N-alkylated, far example
by
lower alkyl, such as methyl or n-propyl, by amino-lower alkyl, such as 3-
aminopropyl, by
phenyl- or naphthyl-amino-lower alkyl, such as 3-phenylaminopropyl, or by
piperazinyl-'
carbonyl-lower alkyl substituted at the nitrogen atom by lower alkyl, such as
methyl, such
as 4-methylpiperazinylcarbonylmethyl, or may be N-acylated, for example by
lower
alkanoyl, such as acetyl; by aryl-lower alkanoyl wherein aryl is selected from
phenyl,
indenyl, indanyi, naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl
and may be
unsubstituted or especially mono- to tri-substituted by lower alkyl, for
example methyl,
ethyl or propyl, halo-lower alkyl, for example trifluoromethyl, phenyl, 1- or
2-naphthyl,
hydroxy, lower alkoxy, for example methoxy, carbamoyl-lower alkoxy, N-lower
alkyl-
carbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower alkoxy, amino,
mono- or
di-lower alkylamino, lower alkanoylamino, for example pivaloylamino, halogen,
for
example fluorine, chlorine or bromine, carbaxy, lower alkoxycarbonyl, such as
tert-
butoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, such as
benzyloxy-
carbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, for example
methylsulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl,
caxbamoyl,
mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower
alkylaminosulfonyl,
vitro and/or by cyano, wherein phenyl may be present up to three times, for
example in
diphenyl-, dibenzyl- or triphenyl-lower alkanoyl, such as diphenyl-, dibenzyl-
or
triphenyl-acetyl, and wherein lower alkanoyl may be unsubstituted or
substituted, for
example by lower alkyl, for example methyl, heterocyclyl selected from
pyrrolyl, furyl>
thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyndyl, pyrazinyl,
pyrimidinyl, indolyl,
quinolyl, isoguinolyl, quinoxalinyl, f3-carbolinyl and a benzo-, cyclopenta-,
cyclohexa- or
cyclohepta-fused derivative of those radicals, which may also be fully or
partially
saturated, hydroxy, lower alkoxy, lower alkanoyloxy, for example acetoxy,
propionyloxy,
butyroxy, isobutyroxy or pivaloyloxy, acetoacetoxy, amino- or
benzyloxycarbonylamino-
lower alkanoyloxy, for example 2-amino- or 2-benzyloxycarbonylamino-2-
methylpro-
pionyloxy, aryl-lower alkanoyloxy wherein aryl has from 6 to 10 carbon atoms,
for
example in benzoyloxy, phenylacetoxy, 1- or 2-naphthoyloxy, lower
alkoxycarbonyloxy,
for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-, isobutoxy-,
sec-
butoxy-, tent-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-, tert-
pentyloxy-,
n-hexyloxy-, isohexyloxy- or n-heptyloxy-carbonyloxy, mono- or di-lower alkyl-
amino-
carbonyloxy, for example ethylaminocarbonyloxy or diethylaminocarbonyloxy,
aryloxy-
carbonyloxy wherein aryl has from 6 to 10 carbon atoms, for example
phenoxycarbonyl-
oxy or 1- or 2-naphthyloxycarbonyloxy, aryl-lower alkoxycarbonyloxy wherein
aryl has
from 6 to 14 carbon atoms, especially phenyl-lower alkoxycarbonyloxy, for
example
-22-
benzyloxycarbonyloxy, and also 1- or 2-naphthylmethoxycarbonyloxy or 9-
fluorenyl-
methoxycarbonyloxy, sulfonyloxy, lower allcylsulfonyloxy, for example methyl-,
ethyl-,
propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tert-butyl-, n-pentyl-,
isopentyl-,
neopentyl-, tent-pentyl-, n-hexyl-, isohexyl- or n-heptyl-sulfonyloxy, or
phenylsulfonyl- ,
oxy, 2- or 4-toluenesulfonyloxy or 1- or 2-naphthylsnlfonyloxy, carboxy,
esterified
carboxy selected from lower alkoxycarbonyl, for example methoxy-, ethoxy-, n-
propoxy-,
isopropoxy-, n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-,
isopentyloxy-,
neopentyloxy-, tent-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-
carbonyl,
aryloxycarbonyl wherein aryl has from 6 to 10 carbon atoms, for example
phenoxy-
carbonyl or 1- or 2-naphthyloxycarbonyl, aryl-lower alkoxycarbonyl wherein
aryl has
from 6 to 12 carbon atoms, for example benzyloxycarbonyl, 1- or 2-
naphthylmethoxy-
carbonyl or 9-fluorenylmethoxycarbonyl, lower alkanoyl, lower alkylsulfonyl,
for example
methyl- or tent-butyl-sulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower
alkoxy-
phosphoryl, carbamoyl, carbamoyl substituted by one or two radicals selected
from lower
alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl,
tent-butyl, n-
pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or n-heptyl, for
example in
N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, from carboxy-
lower
alkyl or lower alkoxycarbonyl-lower alkyl, for example in the form of
carboxymethyl-
carbamoyl (glycinylcarbonyl) or tert-butoxycarbonylrnethylcarbamoyl, from di-
lower
alkylamino-lower alkyl, for example 2-dimethylaminoethyl, aminocarboxy-lower
alkyl,
for example 5-amino-5-carboxypentyl, from hydroxy-lower alkyl, for example
hydroxy-
methyl or hydroxyethyl, and from di-lower alkoxy-lower alkyl, for example 2-
(2,2-
dimethoxyethyl), or carbamoyl substituted by one radical selected from
ethylene, tri-
methylene, tetramethylene and pentamethylene in which a carbon atom may have
been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, for example in the form of piperidino-, pyrazin-1-yl-
, piper-
azin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, marpholino-, thiomorpholino- or
S,S-dioxo-
thiomorpholino-carbonyl; sulfamoyl, phosphono, benzofuranyl, oxo and/or by
cyano and
is unbranched or branched, preferably by aryl-lower alkanoyl wherein aryl has
from 6 to
14 carbon atoms and is unsubstituted or substituted, for example by lower
alkanoyl, such
as in 2-benzyl-3-pivaloylpropionyl, or by lower alkylsulfonyl, such as in 2-
benzyl-3-tert-
butylsulfonylpropionyl, with phenyl-lower alkanoyl, for example phenylacetyl,
being
especially preferred; by heterocyclyl-lower alkanoyl selected from thienyl-y
furyl-,
pyranyl-, pyaolyl-, imidazolyl-, pyrazolyl-, oxazolyl-, isoxazolyl-, thiazolyl-
, furazanyl-,
tetrazolyl-, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-, azepinyl-,
indolyl-, benz-
imidazolyl-, 1H-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-,
quinazolinyl-, cinnolyl-,
2fl~1?~~
-23-
purinyl-, pteridinyl-, naphthyridinyl-, 4H-quinolizinyl-, 3,1-benzofuranyl-,
benz[e]-
indolyl-, 4,1-benzoxazinyl-, 4,1-benzothiazinyl-, carbazolyl-, (3-carbolinyl-,
phenazinyl-,
phenanthridyl-, acridyl-, phenoxazinyl-, phenothiazinyl-, 1-azaacenaphthenyl-,
cyclohexa-
[b]pyrrolyl-, cyclohepta(b]pyrrolyl-, cyclohexa[d]pyrazolyi-,
cyclohexa(b]pyridyl-, cyclo-
hexa[b]pyrazinyl-, cyclohexa[b]pyrimidinyl-, cyclohexa[b]-1,4-oxazinyl-,
cyclohexa[b]-
1,4-thiazinyl-, pyrrolidinyl-, pyrrolinyl-, imidazolidinyl-, 2-imidazolinyl-,
2,3-dihydro-
pyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyrazinyl-, morpholinyl-
, thio-
morpholinyl-, S,S-dioxothiomorpholinyl-, indolinyl-, isoindolinyl-, 4,5,6,7-
tetrahydro-
indolyl-, 1,2,3,4-tetrahydroquinolyl-, 1,2,3,4-tetrahydroisoquinolyl-,
chromanyl-, thio-
chromanyl-, 1,2,3,4-tetrahydro-3,1-benzodiazinyl-, 3,4-dihydro-3H-4,1-
benzoxazinyl-,
3,4-dihydro-3H-4,1-benzothiazinyl-, 2,3,4,5-tetrahydro-1H-S,1-benzazepinyl-
and S,6-
dihydrophenanthridinyl-lower alkanoyl, the mentioned heterocyclyl radicals
being
unsubstituted or substituted by lower alkyl, for example methyl, phenyl, 1- or
2-naphthyl,
phenyl-lower alkyl, for example benzyl, hydroxy-lower alkyl, for example
hydroxymethyl
or 2-hydroxyethyl, lower alkoxy-lower alkyl, for example methoxymethyl or 2-
methoxy-
ethyl, phenoxy- or naphthyloxy-lower alkyl, for example 2-phenoxyethyl, 1- or
2-naphthyloxymethyl, phenyl-lower alkoxy- or naphthyl-lower alkoxy-lowex
alkyl, for
example benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, for example
acetoxy-
methyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, fox example
benzoyloxy-,
phenylacetoxy- or 1- or 2-naphthoyloxy-methyl, -2-ethyl or -2-(2,2-
dimethylethyl), lower
alkoxycarbonyloxy-lower alkyl, for example tert-buto:Kycarbonyloxy-lower
alkyl, phenyl-,
naphthyl- or fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-
benzyloxy-
carbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for
example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy-lower alkyl, for
example
carboxymethyl or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or
ethoxy,
phenyl- or naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-
naphthylmethoxy,
amino, lower alkylarnino, for example methyl-, ethyl- or tert-butyl-amino, di-
lower alkyl-
amino, for example dimethyl- or diethyl-amino, carboxy, lower alkoxycarbonyl,
for
example methoxy-, isopropoxy-, sec-butoxy- or tent-butoxy-carbonyl, phenyl- or
naphthyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for
example
fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower
alkanoyl, for
example acetyl or pivaloyl, lower alkylsulfonyl, for example methyl- or ethyl-
sulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or dialkoxy-phosphoryl, for example
dimethoxy- or diethoxy-phosphoryl, carbamoyl, mono- or di-lower
alkylcarbamoyl, for
example N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl,
hydroxy-
or carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-
methylcarbamoyl or
-24-
hydroxy- or carboxy-ethylcarbamoyl, sulfamoyl, nitro, axo and/or by cyano, for
example
pyridylcarbonyl, such as 2-, 3- or 4-pyridylcarbonyl, 3,4-
dihydroxypyrrolidinylcarbonyl,
N-benzyloxycaxbonyl-piperidin-4-ylcarbonyl, 1-methylpiperazin-4-ylcarbonyl,
morpholinocarbonyl, thiomorpholinocarbonyl, S,S-dioxothiomorphalinocarbonyl,
indol-2-ylcarbonyl, quinol-2-ylcarbonyl, pyridyiacetyl, such as 2- or 3-
pyridylacetyl,
imidazolylacetyl, such as imidazol-1-ylacetyl, morpholinylacetyl, such as
morpholino-
acetyl, pyridylpropionyl, such as 3-(2- or 3-pyridyl)propionyl,
pyrrolidinylpropionyl, such
as 3-(4-pyrrolidinyl)propionyl, morpholinylpropionyl, such as 3-
morpholinopropionyl, or
tetrazolylpropionyl, such as 3-(tetrazol-1-yl)-propionyl; by heterocyclyl-
lower alkenoyl
wherein heterocyclyl is selected especially from pyrrolyl, furyl, thienyl,
imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl, iso-
quinolyl, quinoxalinyl,13-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa-
or
cyclohepta-fused derivative of those radicals, which may also be fully or
partially
saturated, for example pyrrolidyl-lower alkenoyl, such as N-pyrrolidyl-
acryloyl, halo-
lower alkanoyl containing up to 3 halogen atoms, for example a-haloacetyl,
such as
a-fluoro-, a-chloro-, a-bromo-, a-iodo-, a,a,a-trifluoro- or a,a,a-trichloro-
acetyl, or
halopropionyl, such as f3-chloro- or 13-bromo-propionyl; by lower
alkoxycarbonyl, such as
tert-butoxycarbonyl; by aryl-lower alkoxycarbonyl whexein aryl has from 6 to
14 carbon
atoms and is selected, for example, from phenyl, naphthyl and fluorenyl, far
example
phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, or 9-fluorenylmethoxy-
carbonyl; by heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is
selected
especially from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, axazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, !3-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicals,
which may also be fully or partially saturated and unsubstituted or
substituted especially
by lower alkyl, such as methyl, for example 1-methylpyrrolidin-2-yl-
methoxycarbonyl,
2-furylmethoxycarbonyl, tetrahydrofuranyl-lower alkoxycarbonyl, such as 2-
tetrahydro-
furanyl-methoxycarbonyl, 1-methyl-2-piperidyl-methoxycarbonyl or 2-morpholino-
ethoxycarbonyl; by carboxy-lower alkanoyl, such as 3-carboxypropionyl, 5-
carboxy-
pentanoyl or 6-carboxyhexanoyl; by lower alkoxycarbonyl-lower alkanoyl, such
as
5-methoxycarbonylpentanoyl or 6-methoxycarbonylhexanoyl; by hydroxy-lower
alkoxy-
lower alkanoyl, such as 3-hydroxy-n-propoxycarbonyl; by amino-lower alkanoyl
wherein
the amino group is not in the a- or (3-position of the lower alkanayl radical,
such as 5-
aminopentanoyl; by phenyl-lower alkoxycarbonylamino-lower alkanoyl wherein the
amino group is not in the a- or (3-position of the lower alkanoyl radical,
such as 5-benzyi-
oxycarbonylaminopentanoyl or 6-benzyloxycarbonylaminohexanoyl;
_25_
by amino-lower alkanoyl substituted at the amino nitrogen atom by heteracyclyl-
lower
alkanoyl, preferably as defined above for heterocyclyl-lower alkanoyl Rl, R2,
Rg or Rg,
especially by N-morpholino- or N-thiomorpholino-carbonyl, for example N-
morpholino-
or N-thiomorpholino-carbonylamino-lower alkanoyl, such as N-morpholino- or N-
thio-
morpholino-carbonylamino-acetyl;
by carbamoyl; by phenyl-lower alkylaminocarbonyl, such as benzylaminocarbonyl;
by
N-di-lower alkylamino-lower alkyl-N-lower alkylaminocarbonyl, such as N-(2-
dimethyl-
amino)ethyl-N-methylaminocarbonyl; by N-dihydroxy-lower alkyl-N-lower
alkylamino-
carbonyl, such as N-(2,3-dihydroxy-n-propyl)-N-methylaminocarbonyl; by N-
hetero-
cyclyl-lower alkyl-N-lower alkylcarbamoyl wherein heterocyclyl is selected
from thienyl,
furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,
thiazolyl, furazanyl,
pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl, indolyl,
benzimidazolyl,
1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl, quinazolinyl, cinnolyl,
purinyl,
pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1-benzofuranyl, benz[e]indolyl,
4,1-benz-
oxazinyl, 4,1-benzothiazinyl, carbazolyl, [i-carbolinyl, phenazinyl,
phenanthridyl, acridyl,
phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl, cyclohexa[b]pyrrolyl,
cyclohepta[b]-
pyrrolyl, cyclohexa[d]pyrazolyl, cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl,
cyclohexa-
[b]pyrimidinyl, cyclohexa[b]-1,4-oxazinyl, cyclohexa[b]-1,4-thiazinyl,
pyrrolidinyl,
pyrrolinyl, imidazolidinyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl,
piperazinyl,
2,3,5,6-tetrahydxopyrazinyl, morpholinyl, thiomorpholinyl, S,S-
dioxothiomorpholinyl,
indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2"3,4-
tetrahydroquinolyl, 1,2,3,4-tetra-
hydroisoquinolyl, chromanyl, thiochromanyl, 1,2,3,4-tetrahydro-3,1-
benzodiazinyl, 3>4-
dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-benzothiazinyl, 2,3,4,5-
tetrahydro-1H-
5,1-benzazepinyl and 5,6-dihydrophenanthridinyl, the mentioned radicals being
nnsubsti-
tuted or substituted by lower alkyl, for example methyl, phenyl, 1- or 2-
naphthyl, phenyl-
-lower alkyl, for example benzyl, hydroxy-lower alkyl, for example
hydroxyrnethyl or
2-hydroxyethyl, lower alkoxy-lower alkyl, fox example methoxymethyl or 2-
methoxy-
ethyl, phenoxy- or naphthyloxy-lower alkyl, for example 2-phenoxyethyl, 1- or
2-naphthyloxymethyl, phenyl-lower alkoxy- or naphthyl-lower aikoxy-lower
alkyl, for
example benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, for example
acetoxy-
methyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, for example
benzoyloxy-,
phenylacetoxy- or 1- or 2-naphthoyloxy-methyl, -2-ethyl or -2-(2,2-
dimethylethyl), lower
alkoxycarbonyloxy-lower alkyl, for example tent-butoxycarbonyloxy-lower alkyl,
phenyl-,
naphthyl- or fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-
benzyloxy-
carbonyloxyethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for
example aminomethyl, 2-aminoethyl or 2-aminopropyl, carboxy-lower alkyl, for
example
~~'~~'~8~~
-26-
carboxymethyl or 2-carboxyethyl, hydroxy, lower allcoxy, for example methoxy
or ethoxy,
phenyl- or naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-
naphthylmethoxy,
amino, lower alkylamino, for example methyl-, ethyl- or tent-butyl-amino, di-
lower alkyl=
amino, for example dimethyl- or diethyl-amino, carboxy, lower alkoxycarbonyl,
for
example methoxy-, isopropoxy-, sec-butoxy- or tent-butoxy-carbonyl, phenyl- or
naphthyl-lower alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for
example
fluorine, chlorine, bromine or iodine, especially chlorine or bromine, lower
alkanoyl, for
example acetyl or pivaloyl, lower alkylsulfonyl, for example methyl- or ethyl-
sulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or dialkoxy-phosphoryl, for example
di-
methoxy- or diethoxy-phosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl,
for
example N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl,
hydroxy-
or carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-
methylcarbamoyl or
hydroxy- or carboxy-ethylcarbarnoyl, sulfamoyl, nitro, oxo and/or by cyano,
especially
pyridyl, such as 2-, 3- or 4-pyridyl, for example 2- or 3-pyridyl-lower
alkylaminocarbonyl,
such as 2- or 3-pyridylmethylaminocarbonyl; by N-2-, N-3- or N-~1-pyridyl-
lower
alkyl-N-lower alkylaminocarbonyl, such as N-2-, N-3- or N-4-pyridylmethyl-N-
methyl-
aminocarbonyl;
by heterocyclyl-lower alkylcarbamoyl-lower alkanoyl, such as defined above for
hetero-
cyclyl-lower alkylcarbamoyl-lower alkanoyl Rl, R2, Rg or R~, for example 2-(N-
morpholino-lower alkylcarbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(2-
morpholino-
ethyl)-carbaznoyl)-3-methyl-butyryl, or 2-(N-(pyridyl-lower alkyl)-carbamoyl)-
lower
alkanoyl, such as (2(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-3-methyl)-butyryl;
by sulfonyl; by lower alkylsulfonyl, such as methyl- or ethyl-sulfonyl; by
arylsulfonyl
wherein aryl has from 6 to 10 carbon atoms and, for example, is selected from
phenyl and
naphthyl and is unsubstituted or especially substituted by lower alkyl, such
as methyl, or
by lower alkoxy, such as methoxy, such as p-toluenesulfonyl; by
heterocyclylsulfonyl
wherein heterocyclyl is preferably selected from pyrrolyl, furyl, thienyl,
imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl, iso-
quinolyl, quinoxalinyl,13-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa-
or
cyclohepta-fused derivative of those radicals, which may also be fully or
partially
saturated, from morpholinyl and from thiomorpholinyl and may be unsubstituted
or substi-
tuted, especially by lower alkyl, such as methyl, such as morpholinosulfonyl,
thio-
morpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or
piperazino-
sulfonyl (heterocyclylsulfonyl not being a substituent in preferred forms); by
sulfamoyl or
by sulfamoyl substituted by heterocyclyl-lower alkyl, wherein heterocyclyl is
as last
defined, and/or by lower alkyl, such as N-2-pyridylmethyl-N-
methylaminosulfonyl,
-27-
a carboxy group of the side chain is present in esterified or amidated form,
for example
in the form of a lower alkyl ester group, such as methoxycarbonyl or tart-
butoxycarbonyl,
an aryl ester group or an aryl-lower alkyl 'ester group, aryl being phenyl, 4-
nitrophenyl, '
naphthyl or biphenylyl, for example in the form of a 4-nitrophenoxycarbonyl,
benzyloxy-
carbonyl or 9-fluorenylmethoxycarbonyl group, or in the form of a carbamoyl, a
lower
alkylcarbamoyl, such as methylcarbamoyl, a di-lower alkylaminocarbamoyl, such
as
dimethylcarbamoyl, a mono- or di-(hydroxy-lower alkyl)carbamoyl, such as
hydroxy-
methylcarbamoyl ar di(hydroxymethyl)carbamoyl, or mono- or di-(carboxy-lower
alkyl)-
carbamoyl group, such as a carboxymethylcarbamoyl or di-
(carboxymethyl)carbamoyl
group,
an amino group of the side chain is present in alkylated form, for example in
the form of
mono- or di-lower alkylamino, such as n-butylamino or dimethylamino, or in
acylated
form, for example in the form of lower allcanoylamino, such as acetylamino or
pivaloyl-
amino, amino-lower alkanoylamino, such as 3-amino-3,3-dimethylpropionylamino,
aryl-
lower alkanoylamino wherein aryl has from 6 to 14 carbon atoms, for example
phenyl,
naphthyl or fluorenyl, and is unsubstituted or substituted by lower alkyl,
hydroxy, lower
alkoxy, carboxy, carbamoyl or by sulfamoyl, such as 4-hydroxyphenylbutyryl,
lower
alkoxycarbonylamino, such as tent-butoxycarbonylamino,
arylmethoxycarbonylamino
wherein aryl has from 6 to 14 carbon atoms, such as benzyloxycarbonylamino or
9-fluorenylmethoxycarbonylamino, piperidyl-1-carbonyl, morpholinocarbonyl,
thio-
morpholinocarbonyl or S,S-dioxothiomotpholinocarbonyl, and/or
a hydroxy group of the side chain is present in etheiified or esterified form,
for example
in the form of a lower alkoxy, such as methoxy or tart-butoxy, aryl-lower
alkoxy, such as
benzyloxy, lower alkanoyioxy, such as acetoxy, or lower alkoxycarbonyloxy
group, for
example a tent-butoxycarbonyloxy group.
Special preference is given to acyl groups Rl, R2, Rg and R9 of an
unsubstituted or
substituted amino acid selected from phenylalanine, N-(benzyloxycarbonyl)-
phenyl-
alanine, N-(2(R,S)-benzyl-3-pivaloyl-propionyl)-phenylalanine, N-(9-
fluorenylmethoxy-
carbonyl)-phenylalanine, tyrosine, N-propyltyrosine, tyrosine-O-methyl ether,
N-(3-
amino-3,3-dimethylpropionyl)-tyrosine-O-methyl ether, N-(2(S)-benzyl-3-tart-
butyl-
sulfonylpropionyl)-tyrosine-O-tart-butyl ether, N-(9-fluorenylmethoxycarbonyl)-
tyrosine-
O-methyl ether, N-(9-fluorenylmethoxycarbonyl)-tyrosine-O-tart-butyl ether, N-
morpholinocarbonyl-glycine, N-(N-(2-, 3- or 4-pyridyl)methyl-N-
methylaminocarbonyl)-
glycine, valine, N-(3-phenylaminopropyl)-valine, N-(4-
methylpiperazinylcarbonyl-
methyl)-valine, N-(trilluoroacetyl)-valine, N-phenylacetyl-valine, N-acetyl-
valine, N-(3-
-28-
phenylpropionyl)-valine, N-(2(R;S)- or -(~S)-benzyl-3-pivaloyl-propianyl)-
valine, N-(2-
carbamoyl-3-phenyl-propionyl)-valine, N-(2(S)-benzyl-3-tert-
butylsulfonylpropionyl)-
valine, N-(2(R,S)-carbamoyl-3-phenyl-propionyl)-valine, N-(2-, 3- or 4-
pyridylcarbonyl)-
valine, N-(1-imidazolylacetyl)-valine, N-(2- or 3-pyridylacetyl)-valine, N-
(morpholino-
acetyl)-valine, N-(3-(2- or 3-pyridyl)-propionyl)-valine, N-(3-(4-
pyrrolidinyl)-propionyl)-
valine, N-(3-(morpholino)-propionyl)-valine, N-(N-benzyloxycarbonylpiperidin-4-
yl-
carbonyl)-valine, N-tetrahydrofurylmethoxycarbonyl-valine, N-3-(tetrazol-1-yl)-
propionyl-valine, N-(indol-2-ylcarbonyl)-valine, N-(quinoline-2-carbonyl)-
valine,
N-(1-methylpiperazin-4-ylcarbonyl)-valine, N-(3,4-
dihydroxypyrrolidinylcarbonyl)-
valine, N-methoxycarbonyl-valine, N-isobutoxycarbonyl-valine, N-tert-
butoxycarbonyl-
valine, N-benzyloxycarbonyl-valine, N-(2-furylmethoxycarbonyl)-valine, N-(1-
methyl-
pyrrolidin-2-yl-methoxycarbonyl)-valine, N-(1-methyl-2-
piperidylmethoxycaxbonyl)-
valine, N-(1-methyl-3-piperidyl-methoxycarbonyl)-valine, N-(2-
(morpholino)ethoxy-
carbonyl)-valine, N-(3-carboxypropionyl)-valine, N-(5-carboxypentanoyl)-
valine, N-(6-
carboxyhexanoyl)-valine, N-(5-methoxycarbonylpentanoyl)-valine, N-(6-methoxy-
carbonylhexanoyl)-valine, N-(3-aminopropionyl)-valine, N-(4-aminobutyryl)-
valine,
N-(5-benzyloxycarbonylaminopentanoyl)-valine, N-(6-benzyloxycarbonylamino-
hexanoyl)-valine, N-(morpholinocarbonyl)-valine, N-(thiomorpholinocarbonyl)-
valine,
N-(S,S-dioxothiomorpholinocarbonyl)-valine, N-(N-benzylaminocaxbonyl)-valine,
N-
(N-2-pyridylmethyl-N-methylaminocarbonyl)-valine, N-(N-3-pyridylmethyl-amino-
carbonyl)-valine, N-(N-2-pyridylmethyl-aminocarbonyl)-valine, N-morpholino-
carbonyl-
amino-acetyl-vzline, N-(2-pyrrolidylacryloyl)-valine, N-methylsulfonyl-valine,
N-morpholinosulfonyl-valine, N-(p-toluenesulfonyl)-valine, N-(4-
methylpiperazinyl-
sulfonyl)-valine, N-(N-(2-pyridylmethyl)-N-methyl-sulfamoyl)-valine, N-(N-2-
pyridyl-
methyl-N-methyl-aminocarbonyl)-valine, N-(3-aminopropyl)-leucine, N-acetyl-
leucine,
N-(3-aminopropionyl)-leucine, N-(2(R,S)- or N-(2S)-benzyl-3-pivaloyl-
propionyl)-
leucine, N-(2(S)-benzyl-3-tert-butylsulfonylpropionyl)-leucine, N-(2-, 3- or 4-
pyridyl-
carbonyl)-leucine, N-(4-thiomorpholinocarbonyl)-leucine, N-(4-(S,S-dioxothio-
morpholino)carbonyl)-leucine, N-(4-aminobutyryl)-leucine, N-(3-hydroxy-n-
propoxy-
carbonyl)-leucine, N-(benzyloxycarbonyl)-leucine, N-(N-(2-
(dimethylamino)ethyl)-
N-methyl-aminocarbonyl)-leucine, N-(N-(2,3-dihydroxy-n-propyl)-N-methyl-amino-
carbonyl)-leucine, N-acetyl-isoleucine, N-propionyl-isoleucine, N-
(benzyloxycarbonyl)-
isoleucine, N-(2(R,S)-benzyl-3-pivaloyi-propionyl)-norleucine, N-(2(S)-benzyl-
3-tert-
butylsulfonylpropionyl)-norleucine, N-(tert-butoxycarbonyl)-norleucine, N-
(tert-butoxy-
carbonyl)-serine, N-(benzyloxycarbonyl)-serine, N-acetyl-serine O-methyl
ether,
N-(benzyloxycarbonyl)-serine O-methyl ether, N-(2(R,S)-benzyl-3-pivaloyl-
propionyl)-
~~"~~'~
-29-
serine, N-benzyloxycarbonyl-glutamic acid, asparagine, N-benzyloxycarbonyl-
asparagine,
quinoline-2-carbonyl-asparagine, and N-(rnorpholinocarbonyl)-asparagine, the
amino acid
residues preferably being in the (L)- or (D,L)-form, and in the case of valine
also in the
(D)-form. ~ .-
Unsubstituted or substituted alkyl R1, R2, Rg or R9 contains an alkyl radical
having from
1 to 20, preferably up to.10, carbon atoms, is branched or unbranched, may
contain instead
of a methylene group a hetero atom selected from thia, aza and selena and is,
for example,
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl,
n-pentyl,
isopentyl, neopentyl, tart-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl, n-
nonyl or n-decyl.
Preference is given to lower alkyl, for example methyl, ethyi, n-propyl,
isopropyl, n-butyl,
isobutyl, sec-butyl, tent-butyl, n-pentyl, isopentyl, neopentyl, tent-pentyl,
n-hexyl, isohexyl
or n-heptyl, which is unsubstituted or substituted.
Radicals suitable as substituents in substituted alkyl, preferably substituted
lower alkyl,
are the radicals mentioned for lower alkanoyl R1, R2, Rg and R9.
Substituted lower alkyl is preferably
cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms and
lower alkyl
is as defined above, fox example cycloalkyl-methyl or -ethyl, preferably
having a total of
from 4 to 13 caxbon atoms, for example cyclopropyl-, cyclobutyl-, cyclopentyl-
or cyclo-
hexyl-lower alkyl, such as -methyl or -ethyl,
cycloalkenyl-lower alkyl, for example cycloalkenylmethyl, wherein cycloalkyl
preferably has from 4 to 8 carbon atoms, such as 1-cyclohexenylmethyl, 1,4-
cyclohexa-
dienylmethyl or 1-cyclohexenylethyl or 1,4-cyclohexadienylethyl,
bicycloalkyl-lower alkyl wherein bicycloalkyl has, fox example, from 5 to 10
carbon
atoms, for example bicycloalkyl-methyl or -ethyl, preferably having from 8 to
11 carbon
atoms, such as decahydronaphthyl-2-methyl, endo- or exo-norbornyl-2-methyl,
bicyclo-
[2.2.2]oct-2-ylmethyl or bicycla[3.3.1]non-9-ylmethyl, and also bicyclo-hexyl-
, -heptyl-,
-octyl-, -nonyl- or -decyl-ethyl or -3-propyl, for example bicyclo[3.1.0]hex-1-
, -2- or
-3-yl-, bicyclo[4.1.0]kept-1- or -7-yl-, bicyclo[2.2.1]kept-2-yl-, for example
endo- or
-exo-norbornyl-, bicyclo[3.2.1]oct-2-yl-, bicyclo[3.3.0]oct-3-yl- or
bicyclo[3.3.1]-
non-9-yl-, and also a- or 13-decahydronaphthyl-ethyl or -3-propyl,
tricycloallcyl-lower alkyl wherein tricycloallcyl contains, for example, from
8 to 10
carbon atoms, for example tricycloalkyl-methyl or -ethyl, preferably having
from 8 to I 1
carbon atoms, such as I- or 2-adamantylmethyl, and also
tricyclo[5.2.1.02~6Jdec-8-yl- or
-30-
adamantyl-, such as 1-adarnantyl-ethyl, ,
aryl-lower alkyl wherein especially
- aryl has from 6 to 14 carbon atoms, such as in phenyl, indenyl, indanyl,
naphthyl,
anthryl, phenanthryl, acenaphthyl or fluorenyl, which may be unsubstituted or
especially
mono- to tri-substituted by lower allcyl, for example methyl, ethyl or
isopropyl, halo-lower
alkyl, such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower
alkoxy, for
example methoxy, carbamoyl-lower alkoxy, N-lower alkyicarbamoyl-lower allcoxy
or
N,N-di-lower alkylcaxbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
lower
alkanoylamino, for example pivaloylamino, halogen, for example fluorine or
chlorine,
carboxy, lower alkoxycarbonyl, benzyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl,
lower alkanayl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower alkoxy-
phosphoryl
or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylearbamoyl,
sulfamoyl,
mono- or di-lower alkylsulfamoyl, nitro and/or by cyano, wherein phenyl may be
present
up to three times, such as in diphenyl-, dibenzyl- or triphenyl-lower alkyl,
for example
Biphenyl-, dibenzyl- or triphenyl-2-ethyl, and
wherein lower alkyl is unsubstituted or substituted, for example by lower
alkyl, such as
methyl, heterocyclyl selected from pyrrolyl, furyl, thienyl, imidazolyl,
pyrazolyl, oxazolyl,
thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl,
quinoxalinyl,
13-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused
derivative of
those radicals, which may also be fully or partially saturated, hydroxy, lower
alkoxy,
lower alkanoyloxy, such as acetoxy, propionyloxy, ba~tyroxy, isobutyroxy or
pivaloyloxy,
acetoacetoxy, amino- or benzyloxycarbonylamino-louver alkanoyloxy, such as Z-
amino- or
2-benzyloxycarbonylamino-2-methylpropionyloxy> aryl-lower alkanoyloxy wherein
aryl
has from 6 to 10 carbon atoms, such as in benzoyloxy, phenylacetoxy, 1- or 2-
naphthoyl-
oxy, lower alkoxycarbonyloxy, for example methoxy-, ethoxy-, n-propoxy-,
isopropoxy-,
n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-,
neopentyl-
oxy-, tent-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-carbonyloxy,
mono- or
di-lower alkyl-aminocarbonyloxy, such as ethylaminocarbonyloxy or diethylamino-
carbonyloxy, aryloxycarbonyloxy wherein aryl has from 6 to 10 carbon atoms,
for
example phenoxycarbonyloxy or 1- or 2-naphthyloxycarbonyloxy, aryl-lower
alkoxy-
carbonyloxy wherein aryl has from 6 to 12 carbon atoms, for example phenyl-
lower
alkoxycarbonyloxy, such as benzyloxycarbonyloxy, and also 1- or 2-
naphthylmethoxy-
carbonyloxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, lower
alkylsulfonyloxy, for
example methyl-, ethyl-, propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-,
tert-butyl-,
n-pentyl-, isopentyl-, neopentyl-, tert-pentyl-, n-hexyl-, isohexyl- or n-
heptyl-sulfonyloxy,
phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy,
amino,
~'~ ~f~a
-31-
mono- or di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, such as N-
methoxy-
N-methylamino, mono- or di-(phenyl- or -naphthyl-lower alkyl)amino, such as
benzyl-
amino, lower alkanoylamino, such as pivaloylamino, carboxy, esterified carboxy
selected
from lower alkoxycarbonyl, for example methoxy-, ethoxy-, n-propoxy-,
isopropoxy-,
n-butoxy-, isobutoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-,
neo-
pentyloxy-, tent-pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-
carbonyl, aiyloxy-
carbonyl wherein aryl has from 6 to 10 carbon atoms, for example
phenoxycarbonyl or f-
or 2-naphthyloxycarbonyl, aryl-lower alkoxycarbonyl wherein aryl has from 6 to
12
carbon atoms, for example benzyloxycarbonyl, 1- or 2-naphthylmethoxycarbonyl
or
9-fluorenylmethoxycarbonyl, lower alkanoyl, such as pivaloyl or acetyl, lower
alkyl-
sulfonyl, such as tert-butylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-
lower
alkoxyphosphoryl, carbamoyl, carbamoyl substituted by one or two radicals
selected from
lower alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl,
sec-butyl,
tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, n-hexyl, isohexyl or
n-heptyl, such as
in N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, from
carboxy-
lower alkyl or lower alkoxycarbonyl-lower alkyl, for f;xample in the form of
carboxy-
methylcarbamoyl (glycinylcarbonyl) or tent-butoxycarbonylmethylcarbamoyl, from
di-
lower alkylamino-lower alkyl, for example 2-dimethylaminoethyl, from
aminocarboxy-
lower alkyl, such as 5-amino-5-carboxypentyl, from hydroxy-lower alkyl, far
example
hydroxymethyl or hydroxyethyl, and from di-lower al;koxy-lower alkyl, for
example
2-(2,2-dimethoxyethyl), or carbamoyl substituted by one radical selected from
ethylene,
trimethylene, tetramethylene and pentamethylene in which a carbon atom may
have been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, for example in the form of piperidino-, pyrazin-1-yl-
,
piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino-
or S,S-di-
oxothiomorpholino-carbonyl; sulfamoyl, phosphono, benzfuranyl, oxo (which is
not
present at the carbon atom bonded to the amino nitrogen atom linked to Rl, R2,
Rg or R~)
and/or by cyano and is unbranched or branched, is especially selected from
phenyl-lower
alkyl, such as benzyl that is unsubstituted or mono- or poly-substituted in
the benzyl
radical by lower alkyl, for example methyl, phenyl, hydroxy, lower alkoxy, for
example
methoxy, halogen, for example chlorine, vitro, and/or by cyano, such as 4-
methoxy-,
4-fluoro-, 4-chloro-, 4-vitro- or 4-cyano-benzyl, naphthylmethyl, such as a-
or 1i-naphthyl-
methyl, indenylmethyl, for example 1-, 2- or 3-indenylmethyl, indanylmethyl,
such as f-
or 2-indanylmethyl, and phenanthrenylmethyl, such as 9-phenanthrenylmethyl, 2-
phenyl-
ethyl, 2-a-naphthylethyl, 2-13-naphthylethyl, 2-lower alkylphenyl-ethyl, such
as 2-(4-
methylphenyl)ethyl, 2-lower alkoxyphenylethyl, such as 2-(4-
methoxyphenyl)ethyl, 2,2-
-32-
diphenylethyl, 2,2-di(4-methoxyphenyl)ethyl, 2,2,2-triphenylethyl and 2,2-
dibenzylethyl,
from phenyl-lower alkyl substituted in the 2- and p-positions by two radicals
selected from
phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, and lower
alkanoylamino, such
as pivaloylamino, such as 2,p-dibenzyloxycarbonylamino-phenylethyl or 2-
pivaloyl-
amino-p-benzyloxycarbonylamino-phenylethyl, 2,p-diamino-phenylethyl, 3-
phenylpropyl,
3-(p-hydroxyphenyl)-propyl, 3-a- or 3-~i-naphthylpropyl, 2-benzyl-3-(1-
pyrazolyl)-propyl,
3-phenyl- or 3-a-naphthyl-2-hydroxy-propyl, 3-phenyl- or 3-a-naphthyl-2-lower
alkoxy-
propyl, such as 3-phenyl- or 3-a-naphthyl-2-neopentyloxy-propyl, 3-phenyl- or
3-a-
naphthyl-2-lower alkanoyloxy-propyl, such as 3-phenyl-2-pivaloyloxy- or -2-
acetoxy-
propyl, 2-benzyl- or 1- or 2-naphthyl-3-(N-methoxyl-N-methylamino)-propyl, 3-
phenyl-
or 3-a-naphthyl-2-dimethylaminomethyl-propyl, 3-a-naphthyl-2-pivaloyloxy- or
-2-acetoxy-propyl, 3-a-naphthyl-2-acetoacetoxy-propyl, 3-a-naphthyl-2-
ethylamino-
carbonyloxy-propyl or 3-a-naphthyl-2-((2-amino- or 2-benzyloxycarbonylamino)-
2-methylpropionyloxy)-propyl, 3-phenyl- or 3-a-naphthyl-2-carboxymethylpropyl,
3-phenyl- or 3-a-naphthyl-2-lower alkoxycarbonyl-propyl, such as 3-a-naphthyl-
2-
ethoxycarbonyl-propyl, 3-phenyl- or 3-a-naphthyl-2-benzyloxycaxbonylmethyl-
propyl,
2-(S)-benzyl-3-tert-butylsulfonyl-propyl, 3-phenyl-2-phosphono- or -
phosphonomethyl-
propyl, 3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethyl-propyl,
3-phenyl-2-diethoxyphosphoryl- or -diethoxyphosphorylmethyl-propyl, 3-phenyl-
2-ethoxy- or -methoxyhydroxyphosphoryl-propyl, 3-phenyl- or 3-a-naphthyl-2-
carbamoyl-propyl, 3-phenyl- or 3-a-naphthyl-2-tert-butylcarbamoyl-propyl, 3-
phenyl- or
3-a-naphthyl-2-(2-dimethylaminoethyl)carbamoyl-propyl, 3-a-naphthyl-2-(carboxy-
or
tent-butoxycarbonyl)methylcarbamoyl-propyl, 3-phenyl- or 3-a-naphthyl-2-(3-
hydroxy-
2-propyl)carbarnoyl-propyl, 3-phenyl- or 3-a-naphthyl-2-(2,2-dimethoxyethyl)-
carbamoylpropyl, 3-phenyl- or 3-a-naphthyl-2-(5-amino-5-carboxypentyl)-
carbamoyl-
propyl, 3-phenyl- or 3-a-naphthyl-2-cyano-propyl, 3-phenyl- or 3-a-naphthyl-2-
cyano-
methyl-propyl, 3-phenyl- or 3-a-naphthyl-2-acetonyl-propyl, 4-
hydroxyphenylbutyl,
4-phenyl- or 4-a-naphthyl-3-carboxy-butyl, 4-phenyl- or 4-a-naphthyl-3-
benzyloxy-
carbonyl-butyl, 2-benzyl-4-(2-benzofuranyl)-4-oxobutyl, 2-benzyl- or 2-a-
naphthyl-
methyl-4-cyano-butyl, 2-benzyl- or 2-a-naphthylmethyl-5-dimethylamino-pentyl,
2-benzyl- or 2-a-naphthylmethyl-4-oxo-pentyl, 2-benzyl- or 2-a-naphthylmethyl-
4,4-
dimethyl-3-oxo-pentyl, 2-benzyl- or 2-a-naphthyimethyl-5-dimethylamino-4-oxo-
pentyl
or 2-benzyl- or 2-a-naphthylmethyl-5,5-dimethyl-4-oxo-hexyl, preferably phenyl-
lower
alkyl, such as benzyl, 2-phenylethyl or 3-phenylpxopyl, 4-hydroxybenzyl, 1- or
2-naphthyimethyl or 1- or 2-naphthyl-2-ethyl, especially phenyl-lower alkyl as
last
defined,
-33-
heterocyclyl-lower alkyl containing especially unsubstituted or substituted
heterocyclyl
as mentioned under heterocyclyl-lower alkanoyl Rly R2, Rg and R9 and lower
alkyl that
is unsubstituted or substituted in the same manner as lower alkanoyl in
heterocyclyl-lower
alkanoyl R1, R2, Rg and R9 (oxo not being present at the carbon atom bonded to
the
nitrogen atom carrying the .radical R1, R2, Rg or R9), for example methyl, 2-
ethyl or
3-propyl bonded to unsubstituted or lower alkyl- or phenyl-substituted
pyrrolyl, such as 2-
or 3-pyrrolyl, 4- or 5-methylpyrrolyl or 4- or 5-phenylpyrrolyl, thienyl, such
as 2-thienyl,
furyl, such as 2-furyl, pyrazolyl, such as 1-pyrazolyl, tetrazolyl, such as
tetrazol-1-yl,
pyridyl, such as 2-, 3- or 4-pyridyl, indolyl that is unsubstituted or
substituted by lower
alkyl, for example methyl, phenyl-lower alkyl, for example benzyl, lower
alkoxy, for
example methoxy, phenyl-lower alkoxy, for example benzyloxy, or by halogen,
for
example by chlorine, such as 2-, 3- or 5-indolyl, 1-methyl-, 2-methyl-, 5-
methoxy-,
5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indol-2-yl, 1-benzylindol-2-yl or -3-
yl, 4,5,6,7-
tetrahydroindol-2-yl, cyclohepta[b]pyrrol-5-yl, unsubstituted or hydroxy-
substituted
quinolyl, such as 2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl, unsubstituted
or hydroxy-
substituted isoquinolyl, such as 1-, 3- or 4-isoquinolyl or 1-oxo-1,2-
dihydroisoquinol-3-yl,
2-quinoxalinyl, 3,1-benzfuran-2-yl, benz[e]indol-2-yl, (3-casbolin-3-yl, 3-
chromanyl,
3-thiochromanyl, 3-pyrrolidinyl, hydroxypyrrolidinyl, such as 3- or 4-
hydroxypyrrolidin-
2-yl, oxopyrrolidinyl, such as 5-oxopyrrolidin-2-yl, piperidinyl, such as 2-,
3- or 4-piperi-
dinyl, morpholinyl, such as 2- or 3-morpholinyl, thiomorpholinyl, such as 2-
or 3-thio-
morpholinyl, S,S-dioxothiomorpholinyl, such as S,S-dioxothiomorpholin-2- or -3-
yl,
indolinyl, such as 2- or 3-indolinyl, 1,2,3,4-tetrahydroquinolyl, such as
1,2,3,4-tetrahydro-
quinol-2-, -3- or -4-yl, 1,2,3,4-tetrahydroisoquinolyl, such as 1,2,3,4-
tetrahydroiso-
quinol-1-, -2- or -3-yl, or 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl, or 4-
pyrrolidinylmethyl
or 1-imidazolylmethyl,
hydroxy-lower alkyl, such as 3-hydroxypropyl or 2-hydroxy-3-methylpentyl,
lower alkoxy-lower alkyl, for example lower alkoxyethyl or lower alkoxypropyl,
such as
2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl,
lower alkoxy-lower alkoxy-lower alkyl, such as 2-methoxymethoxy-3-methyl-
pentyl,
phenoxy-lower alkyl or nitrophenoxy-lower alkyl, such as phenoxyrnethyl,
phenoxyethyl
or 4-nitrophenoxymethyl,
naphthyloxy-lower alkyl, for example a- or 13-naphthyloxyethyl,
lower alkanoyloxy-lower alkyl, for example lower alkanoyloxyethyl or lower
alkanoyl-
oxypropyl, such as acetoxyethyl or 3-acetoxypropyl,
acetoacetoxy-lower alkyl,
arylmercapto-lower alkyl wherein aryl has from 6 to 10 carbon atoms, for
example
~~'~~'~~
-34-
phenyl or naphthyl, such as phenylmercaptomethyl,
amino-lower alkyl, such as 3-aminopropyl or 5-aminopentyl,
mono- or di-lower alkylamino-lower alkyl, such as dimethylaminoethyl or 2-
dimethyl-'
amino-2-isopropylethyl,
phenyl- or naphthyl-amino-lower alkyl, such as 3-phenylaminopropyl,
lower alkanoylamino-lower alkyl, such as 4-acetylaminopentyl,
piperazinylcarbonyl-lower alkyl substituted at the nitrogen atom by lower
alkyl, such as
methyl, such as 4-methylpiperazinylcarbonylmethyl,
lower alkoxycarbonylamino-lower alkyl, such as 5-(tent-butoxycarbonylamino)-
pentyl or
3-ethoxycarbonylamino-2-isobutyl-propyl,
phenyl-lower alkoxycarbonylamino-lower alkyl, such as 5-
(benzyloxycarbonylamino)-
pentyl,
aminocarbonylamino-lower alkyl, such as aminocarbonylamino-ethyl,
N-phenyl-lower alkyl-N-lower allcylaminocarbonylamino-lower alkyl, for example
2-
isobutyl-3-(N-benzyl-N-methylaminocarbonylamino)propyl,
halo-lower alkyl, for example 2-haloethyl, such as 2-fluoro-, 2-chloro-, 2-
bromo-,
2-iodo-, 2,2,2-trifluoro- or 2,2,2-trichloro-ethyl, trifluoro-lower alkyl,
such as trifluoro-
methyl, or halopropyl, such as 3-chloro- or 3-bromopropyl,
carboxy-lower alkyl, for example carboxyethyl or 3-carboxypropyl,
lower alkoxycarbonyl-lower alkyl, for example lower alkoxycarbonylethyl or
lower
alkoxycarbonylpropyl, such as methoxycarbonylethyl, 3-methoxycarbonylpropyl,
ethoxy-
carbonylethyl or 3-ethoxycarbonylpropyl,
2-halo-lower alkoxycarbonyl-lower alkyl, such as 2-chloro-, 2-bromo-, 2-iodo-
or 2,2,2-
trichloro-ethoxycarbonyl-2-ethyl or -3-propyl,
phenyl- or naphthyl-lower alkoxycarbonyl-lower alkyl, for example benzyloxy-
carbonyl-lower alkyl, such as 3-benzyloxycarbonyl-2,2-dimethylpropyl,
heterocyclyl-lower alkoxycarbonyl-lower alkyl wherein heterocyclyl is
preferably
selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,13-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicals, it
also being possible for the mentioned radicals to be fully or partially
saturated, such as in
4-pyridylmethoxycarbonyl-2-ethyl or -3-propyl or 2-rnorpholinocarbonyloxy-4-
methyl-
pentyl,
lower alkylsulfonyl-lower alkyl, such as 2-ethylsulfonyl- or 2-tert-
butylsulfonyl-methyl,
arylsulfonyl-lower alkyl wherein aryl preferably has from 6 to 10 carbon
atoms, for
example phenyl or naphthyl, such as phenylsulfonylmethyl,
2~~'~ ~"~~~
-35-
carbamoyl-lower alkyl, such as carbamoylethyl or 3-carbamoylpropyi,
lower alkylcarbamoyl-lower alkyl, for example lower alkylcarbamoylethyl or
methyl-
carbamoyl-lower alkyl, such as 2-methylcarbamoylethyl,
di-lower alkylcarbamoyl-lower'alkyl, for example 2-di-lower
alkylcarbamoylethyl or
dimethylcarbamoyl-lower alkyl, such as 2-dimethylcarbamoylethyl,
hydroxy-lower alkylcarbamoyl- or di(hydroxy-lower alkyl)carbamoyl-lower alkyl,
such
as 2-hydroxymethylcarbamoyl- or di(hydroxymethyl)carbamoyl-2-ethyl or -3-
propyl,
N-lower alkoxy-lower alkoxy-lower alkylcarbamoyl-lower alkyl, such as 2-
isobutyl-3-
(2-(2-methoxyethoxy)ethylaminocarbonyl)-propyl,
carboxy-lower alkylcarbamoyl- or di(carboxy-lower alkyl)carbamoyl-lower alkyl,
such
as carboxymethyl- or di(carboxymethyl)carbamoyl-2-ethyl or -3-propyl,
carbamoyl-lower alkyl substituted at the nitrogen atom by a radical selected
from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, oxygen, sulfi~r or by sulfur mono- or di-
substituted by
oxygen, it being possible for the radical so formed also to be fully or
partially unsaturated,
for example in the form of piperidino-, pyrazin-1-yl-, piperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomozpholino-
carbonyl-
lower alkyl, such as in 2-morpholinocarbonyl-ethyl, 3-(morpholinocarbonyl)-
propyl or 3-
(morpholinocarbonyl)-2-isobutyl-propyl,
N-lower alkyl-N-heterocyclyl-lower alkylcarbamoya-lower alkyl wherein
heterocyclyl is
preferably selected from pyrrolyl, furyi, thienyl, imidazolyi, pyrazolyl,
oxazolyl, thiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoduinolyl, quinoxalinyl,
Ci-carbolinyl
and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of
those
radicals, which may also be .fully or partially saturated, such as 2-(N-2-
pyridylmethyl)-
N-methylcarbamoyl-ethyl,
suifamoyl-lower alkyl, such as 2-sulfamoylethyl,
N-(phenyl- or naphthyl-lower alkyl)sulfamoyl-lower alkyl, such as 3-
benzylamino-
sulfonyl-2-isopropyl-propyl, or
sulfamoyl-lower allcyl substituted at the nitrogen atom by a radical selected
from
ethylene, trimethylene, tetramethylene and pentameihylene wherein a carbon
atom may
have been replaced by nitrogen, lower alkyl-substituted, such as methyl-
substituted,
nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen, it
being possible
for the radical so formed also to be fully or partially unsaturated, for
example in the form
of piperidino-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
sulfonyl-lower
alkyl, such as 3-(4-methylpiperazinylsulfonyl)-2-isopropyl-propyl or 3-(4-
morpholiny-
- 36 -
sulfonyl)-2-isopropyl-propyl,
oxo-lower alkyl (wherein oxo is not present at the carbon atom bonded to the
nitrogen
atom carrying the radical R1, R2, Rg or Rg), such as 3-oxo-n-butyl or 3-oxo-n-
pentyl,
cyano-lower alkanoyl, such as cyanomethyl, 2-cyanoethyl, 2- or 3-cyano-n-
propyl or 2-,
3- or 4-cyano-n-butyl,
hydroxy-carboxy-lower alkyl, such as 2-hydroxy-2-carboxy-ethyl or 2-hydroxy-
3-carboxypropyl,
a-naphthyloxy-carboxy-lower alkyl, such as 2-a-naphthyloxy-4-carboxy-n-butyl,
hydroxy-lower alkoxycarbonyl-lower alkyl, for example 2-hydroxy-2-lower alkoxy-
carbonyl-ethyl or -propyl or hydroxy-ethoxy- or hydroxy-methoxy-carbonyl-lower
alkyl,
such as 2-hydroxy-2-ethoxy- or -methoxy-carbonylethyl or 2-hydroxy-3-ethoxy-
or
-methoxy-carbonylpropyl,
a-naphthyloxy-lower alkoxycarbonyl-lower alkyl, for example a-naphthyloxy-
lower
alkoxycarbonyl-2-ethyl, -2-propyl or -2-butyryl or a-naphthyloxyethoxycarbonyl-
lower
allcyl, such as a-naphthyloxy-ethoxycarbonyl-2-ethyl, 2-a-naphthyloxy-3-
ethoxycarbonyl-
propyl or 2-a-naphthyloxy-4-tent-butoxycarbonylbutyl,
a-naphthyloxy-benzyloxycarbonyl-lower alkyl, such as 2-a-naphthyloxy-3-
benzyloxy-
carbonyl-propyl,
esterified hydroxy-lower alkoxycarbonyl-lower alkyl wherein the hydroxy group
is
esterified by lower alkanoyl, for example acetyl, prop:ionyl or pivaloyl,
cycloalkyl-lower
alkanoyl wherein cyclo~dkyl has from 3 to 7 carbon atoms and lower alkanoyl is
as last
defined, for example cyclohexylcarbonyl or 2-cyclohexyl- or 2-cyclopentyl-
acetyl,
bicycloalkyl-lower alkanoyl wherein bicycloalkyl has, for example from 5 to
10,
especially from 6 to 9, carbon atoms, such as in bicyclo-hexyl-, -heptyl-, -
octyl-, -nonyl-
or -decyl-acetyl or -3-propionyl, fox example bicyclo[3.1.0]hex-1-, -2- or -3-
yl-, bicyclo-
[4.1.0]hept-1- or -7-yl-, bicyclo[2.2.1]kept-2-yl-, for example endo- or exo-
norbornyl-,
bicyclo[3.2.1]oct-2-yl-, bicyclo[3.3.0]oct-3-yl- or bicyclo[3.3.1]non-9-yl-,
and also a- or
13-decahydronaphthyl-acetyl or -3-propianyl, tricycloalkyl-lower alkanoyl
wherein tri-
cycloalkyl contains, for example, from 8 to 10 carbon atoms, for example m
tricyclo-
[5.2.1.02~6]dec-8-yl- or adamantyl-, such as 1-adamantyl-acetyl, aryl-lower
alkanoyl
wherein aryl has from 6 to 14 carbon atoms, for example phenyl, indenyl,
indanyl,
naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, which may be
unsubstituted or
mono- to tri-substituted by lower alkyl, hydroxy, lower alkoxy, carbamoyl-
lower allcoxy,
N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower
alkoxy,
amino, mono- or di-lower alkylamino, halogen, such as fluorine, chlorine or
bromine,
carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl,
-37-
lower alkanoyl, lower alkylsulfonyl, for example methylsulfonyl, phosphono,
hydroxy-
lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, sx~lfamoyl,
nitro and/or
by cyano, lower alkoxycarbonyl, for example tent-butoxycarbonyl, 2-halo-lower
alkoxy-
carbonyl as defined above, or by phenyl- or fluorenyl-lower alkoxycarbonyl,
far example
benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, such as 2-acetoxy-2-methoxy-
carbonyl-ethyl, 2-benzoyloxy-, 2-(1- or 2-naphthoyloxy)-, 2-(phenyl-2-acetoxy)-
, 2-(1- or
2-naphthyl-2-acetoxy)-, 2-(4-methylphenyl-2-acetoxy)-, 2-(4-methoxyphenyl-2-
acetoxy)-
or 2-(2-(o,o-dichlorophenyl)2-acetoxy)-2-methoxycarbonyl-ethyl or -3-propyl,
dihydroxy-carboxy-lower alkyl, such as 2,3-dihydroxy-3-carboxy-propyl,
dihydroxy-lower alkoxycarbonyl-lower alkyl, such as 2,3-dihydroxy-3-ethoxy- or
-methoxy-carbonyl-propyl,
dihydroxy-lower alkoxycarbonyl-lower alkyl esterified by lower alkanoyl, such
as
acetyl, propionyl or butyryl, lower alkoxycarbonyl, for example tert-
butoxycarbonyl,
phenyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl or 9-
fluorenyl-
methoxycarbonyl, lower alkylsulfonyl or by toluenesulfonyl, for example di-
lower
alkanoyloxy-lower alkoxy-propyl, such as 2,3-diacetoxy-3-methoxycarbonyl-
propyl,
a-naphthyloxy-di-lower alkylamino-lower alkyl, such as 2-a-naphthyloxy-5-
dimethyl-
aminopentyl,
a-naphthyloxy-carbamoyl-lower alkyl, such as 2-a-naphthyloxy-4-carbamoyl-
butyl,
a-naphthyloxy-oxo-lower alkyl (wherein oxo is nol: present at the carbon atom
bonded to
the nitrogen atom carrying the radical R1, R2, Rg or 1(t9), such as 2-a-
naphthyloxy-4-oxo-
pentyl, or
a-naphthyloxy-cyano-lower alkyl, such as 2-a-naphthyloxy-cyano-ethyl or 2-a-
naphthyloxy-4-cyanobutyl.
Lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or
tert-butyl, is
especially preferred.
Alkenyl Rt, R2, Rg or Ry preferably contains from 2 to 10 carbon atoms, is
preferably
lower alkenyl having from 2 to 7, especially from 2 to 4, carbon atoms and is,
for example,
vinyl, allyl or 2- or 3-butenyl. Lower alkenyl Rt, R2, R8 or R9 may be
substituted by the
same substituents as may lower alkyl, for example by cycloalkyl, as defined in
the case of
cycloalkyl-lower alkanoyl Rt, R.,, R8 or R9, that is unsubstituted or mono- to
tri-substi-
tuted by lower alkyl, such as isopropyl, halo-lower alkyl, such as
trifluoromethyl, hydroxy,
lower alkoxy, earbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or
N,N-di-
lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
halogen, such
2~"~~"~~~
-38-
as fluorine, chlorine or bromine, carboxy, lower alkoxycarbonyl, phenyl-,
naphthyl- or
fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, for
example methyl-
sulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxyphosphoryl,
carbamoyl, mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower
alkyl-
sulfamoyl, nitro and/or by cyano and is bonded, especially at the terminal
carbon atom, to
lower alkenyl, such as in cyclobutyl-, cyclopentyl-, cyclohexyl- or
cycloheptyl-methyl-2-
vinyl, -2- or -3-allyl or -2-, -3- or -4-but-2-enyl; aryl, as defined under
aryl-lower alkanoyl
Rl, R2, R8 or R9, that is unsubstituted or substituted and is bonded,
preferably terminally,
to lower alkenyl, such as in styryl, 3-phenylallyl (cinnamyl), 2-(a-naphthyl)-
vinyl or 2-
((3-naphthyl)-vinyl; unsubstituted or substituted heterocyclyl, as defined
under hetero-
cyclyl-lower alkanoyl Rt, R2, Rg or R9, preferably selected from pyrrolyl,
furyl, thienyl,
imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
indolyl,
quinolyl, isoquinolyl, quinoxalinyl, ~-carbolinyl and a benzo-, cyclopenta-,
cyclohexa- or
cyclohepta-fused derivative of those radicals, which may also be fully or
partially
saturated and are unsubstituted or substituted as indicated above and are
bonded via a
nitrogen or carbon atom to lower alkenyl, preferably to the terminal carbon
atom of the
lower alkenyl radical, which is selected, for example, from vinyl, allyl and 2-
or 3-butenyl,
for example in the form of pyrimidin-1-yl-, piperidino-, pyrazin-1-yl-,
piperazin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-~dioxothiomorphalino-
lower alkenyl,
such as in 2-morpholino-vinyl, 3-mozvpholino-allyl or 4-morpholino-2- or -3-
butenyl,
pyrrolyl-lower alkenyl that is unsubstituted or substituted by lower alkyl or
by phenyl,
such as 2- or 3-pyrrolyl-vinyl or -allyl, 4- or 5-methylpyrrolyl-vinyl or -
allyl or 4- or
5-phenylpyrrolyl-vinyl or -allyl, thienyl-lower alkenyl, such as 2-thienyl-
vinyl or -allyl,
furyl-lower alkenyl, such as 2-furyl-vinyl or -allyl, pyridyl-lower alkenyl,
such as 2-, 3- or
4.-pyridyl-vinyl or -allyl, indolyl-lower alkenyl that is unsubstituted or
substituted by lower
alkyl, for example methyl, phenyl-lower alkyl, for example benzyl, lower
alkoxy, for
example methoxy, phenyl-lower alkoxy, for example benzyloxy, or by halogen,
for
example chlorine, such as 2-, 3- or 5-indolyl-vinyl or -allyl, 1-methyl-, 2-
methyl-,
5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indol-2-yl-, 1-benzylindol-
2-yl- or
-3-yl-vinyl or -allyl, 4,5,6,7-tetrahydroindol-2-yl-methyl, -ethyl or -n-
propyl, cyclohepta-
[b]pyrrol-5-yl-vinyl or -allyl, unsubstituted or hydroxy-substituted quinolyl-
lower alkenyl,
for example 2-, 3- or 4-quinolyl- or 4-hydroxyquinol-2-yl-vinyl or -allyl,
unsubstituted or
hydroxy-substituted isoquinolyl-lower alkenyl, such as 1-, 3- or 4-isoquinolyl-
or 1-oxo-
1,2-dihydroisoquinol-3-yl-vinyl or -allyi, 2-quinoxalinyl-vinyl or -allyl, 3,1-
benzo-
furan-2-yl-vinyl or -allyl, bent[e]indol-2-yl-vinyl or -allyl, (3-carbolin-3-
yl-vinyl or -allyl,
3-chromanyl-vinyl or -allyl, 3-thiochromanyl-vinyl or -allyl, 3-pyrrolidinyl-
vinyl or -allyl,
-39-
hydroxypyrrolidinyl-lower alkenyl, such as 3- or 4-hydroxypyrrolidin-2-yl-
vinyl or -allyl,
oxopyrrolidinyl-lower alkenyl, such as 5-oxopyrrolidin-2-yl-vinyl or.-allyl,
piperidinyl-
lower alkenyl, such as 2-, 3- or 4-piperidinyl-vinyl- or -allyl, morpholinyl-
lower alkenyl,
such as 2- or 3-morpholinyl-vinyl or -allyi, thiomorpholinyl-lower alkenyl,
such as 2- or
3-thiomorpholinyl-vinyl or -allyl, S,S-dioxothiomorpholinyl-lower alkenyl,
such as S,S-
dioxothiornorpholin-2- or -3-yl-vinyl or -allyl, indolinyl-lower alkenyl, such
as 2- or
3-indolinyl-vinyl or -allyl, 1,2,3,4-tetrahydroquinolyl-lower alkenyl, such as
1,2,3,4-tetra-
hydroquinol-2-, -3- or -4-yl-vinyl or -allyl, 1,2,3,4-tetrahydroisoquinolyl-
lower alkenyl,
such as 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl-vinyl or -allyl, or 1-oxo-
1,2,3,4-tetra-
hydroisoquinol-3-yl-vinyl or -allyl; also hydroxy; etherified hydroxy selected
from lower
alkoxy, such as methoxy or ethoxy, phenoxy or naphthyloxy, phenyl- or naphthyl-
lower
alkoxy, such as benzyloxy, and heterocyclyl-lower alkoxy wherein heterocyclyl
is
preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,
ø-carbolinyl
and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of
those
radicals, which may also be fully or partially saturated, for example 4-
pyrrolidinyl-
methoxy, 1-imidazolylmethoxy, 2-pyridylmethoxy, 3-pyridylmethoxy, quinolin-2-
yl-
methoxy or indol-2-ylmethoxy; esterifted hydroxy selected from lower
alkanoyloxy, such
as acetoxy, propionyloxy, butyroxy, isobutyroxy or pivaloyloxy, acetoacetoxy,
amino- or
benzyloxycarbonylamino-lower alkanoyloxy, such as 2-amino- or 2-
benzyloxycarbonyl-
amino-2-methylpropionyloxy, aryl-lower alkanoyloxy wherein aryl contains from
6 to 10
carbon atoms, such as in benzoyloxy, phenylacetoxy, 1- or 2-naphthoyloxy,
lower alkoxy-
carbonyloxy, for example methoxy-, ethoxy-, n-propoxy-, isopropoxy-, n-butoxy-
, iso-
butoxy-, sec-butoxy-, tert-butoxy-, n-pentyloxy-, isopentyloxy-, neopentyloxy-
, tert-
pentyloxy-, n-hexyloxy-, isohexyloxy- or n-heptyloxy-carbonyloxy, mono- or di-
lower
alkylaminocarbonyloxy, such as ethylaminocarbonyloxy or
diethylaminocarbonyloxy,
aryloxyearbonyloxy wherein aryl contains from 6 to 10 carbon atoms, for
example
phenoxycarbonyloxy or 1- or 2-naphthyloxycarbonyloxy, aryl-lower
alkoxycarbonyloxy
wherein aryl contains from 6 to 12 carbon atoms, for example phenyl-lower
alkoxy-
carbonyloxy, such as benzyloxycarbonyloxy, and also 1- or 2-
naphthylmethoxycarbonyl-
oxy or 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, lower alkylsulfonyloxy, for
example
methyl-, ethyl-, propyl-, isopropyl-, n-butyl-, isobutyl-, sec-butyl-, tent-
butyl-, n-pentyl-,
isopentyl-, neopentyl-, tent-pentyl-, n-hexyl-, isohexyl- or n-heptyl-
sulfonyloxy, phenyl-
sulfonyloxy, 2- or 4-toluenesulfonyloxy and 1- or 2-naphthylsulfonyloxy;
halogen, for
example chlorine or bromine; carboxy; esterified carboxy selected from lower
alkoxy-
carbonyl, such as methoxycarbonyl, ethoxycarbonyl and ten-butoxycarbonyl, 2-
halo-
~'~~~1
-40-
lower allcoxycarbonyl, for example 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-
trichloro-ethoxy-
carbonyl, phenyl- or naphthyl-lower alkoxycarbonyl, for example
benzyloxycarbonyl, and
heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is preferably selected
from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl,
pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, it
also being
possible for the mentioned radicals to be fully or partially saturated, for
example in
4-pyridylmethoxycarbonyl; or amidated carboxy selected from carbamoyl, lower
alkyl-
carbamoyl, such as methylcarbamoyl, di-lower allylcarbamoyl, such as dimethyl-
carbamoyl, hydroxy-lower alkylcarbamoyl or di(hydroxy-lower alkyl)carbamoyl,
such as
hydroxymethylcarbamoyl or di(hydroxymethyl)carbamoyl, N-lower alkoxy-lower
alkoxy-lower alkylcarbamoyl, such as 2-(2-methoxyethoxy)ethylaminocarbonyl,
carboxy-
lower alkylcarbamoyl or di(carboxy-lower alkyl)carbamoyl, for example
carboxymethyl-
or di(carboxymethyl)-carbamoyl, and from carbarnoyl substituted at the
nitrogen atom by
a radical selected from ethylene, trimethylene, tetramethylene and
pentamethylene
wherein a carbon atom may have been replaced by nitrogen, oxygen, sulfur or by
sulfur
mono- or di-substituted by oxygen, it also being possible for the radical so
formed to be
fully or partially unsaturated, for example in the form of piperidino-,
pyrazin-1-yl-,
piperazin-1-yl-, pyrimidin-1-yl-, pyridazin-1-yl-, mot~pholino-,
thiomorpholino- or S,S-
dioxothiomorpholino-carbonyl, N-lower alkyl-N-heterocyclyl-lower
alkylcarbamoyl
wherein heterocyclyl is preferably selected from pyrrolyl, furyl, thienyl,
imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrirnidinyl, indolyl,
quinolyl, iso-
quinolyl, quinoxalinyl, (3-carbolinyl and a benzo-fused, cyclopenta-,
cyclohexa- or cyclo-
hepta-fused derivative of those radicals, which may also be fully or partially
saturated, for
example N-2-pyridyhnethyl-N-methylcarbamoyl.
Alkynyl Rt, R2, Rg or R9 contains especially from 2 to 10, preferably, as
lower alkynyl,
from 2 to 7, especially from 2 to 4, carbon atoms, and is, for example,
ethynyl, 1-.propynyl
or 2-propynyl, it being possible for the mentioned radicals to be
unsubsrituted or substi-
tuted by the radicals menrioned for lower alkenyl Rl, Rz, Rg or Rg,
~Ieterocyclyl Rl, R2, R8 and R9 is bonded via a carbon atom and contains
especially an
unsubstituted or substituted heterocyclyl mentioned under heterocyclyl-lower
alkanoyl Rt,
R2, Rg and R9 and is preferably pyrrolyl that is unsubstituted or substituted
by lower alkyl
or by phenyl, such as 2- or 3-pyrrolyl, 4- or 5-methylpyrrolyl or 4- or 5-
phenylpyrrolyl,
thienyl, such as 2-thienyl, furyl, such as 2-furyl, pyridyl, such as 2-, 3- or
~4-pyridyi,
2"d?'~~3
-41-
indolyl that is unsubstituted or substituted by lawer alkyl, for example
methyl, phenyl-
lower alkyl, for example benzyl, lower alkoxy, for example methoxy" phenyl-
lower
alkoxy, for example benzyloxy, or by halogen, for example chlorine, such as 2-
, 3- or
5-indolyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-
dimethyl-
indol-2-yl, 1-benzylindol-2-yl or -3-yl, 4,5,6,7-tetrahydroindol-2-yl,
unsubstituted or
hydroxy-substituted quinolyl, such as 2-, 3- or 4-quinolyl or 4-hydroxyquinol-
2-yl,
unsubstituted or hydroxy-substituted isoquinolyl, such as 1-, 3- or 4-
isoquinolyl or 1-oxo-
1,2-dihydroisoquinol-3-yl, 2-quinoxalinyl, 3,1-benzofuran-2-yl, benz[e]indol-2-
yl,
(3-carbolin-3-yl, cyclohepta[b]pyrrol-5-yl, 3-chromanyl, 3-thiochromanyl, 3-
pyrrolidinyl,
hydroxypyrrolidinyl, such as 3- or 4-hydroxypyrrolidin-2-yl, oxopyrrolidinyl,
such as
5-oxopyrrolidin-2-yl, piperidyl, such as 2-, 3- or 4-piperidyl, mozpholinyl,
such as 2- or
3-morpholinyl, thiomorpholinyl, such as 2- or 3-thiomorpholinyl, S,S-dioxothio-
morpholinyl, such as S,S-dioxothiomorpholin-2- or -3-yl, indolinyl, such as 2-
or
3-indolinyl, 1,2,3,4-tetrahydroquinolyl, such as 1,2,3,4-tetrahydroquinol-2-, -
3- or -4-yl,
1,2,3,4-tetrahydroisoquinolyl, such as 1,2,3,4-tetxahydroisoquinol-1-, -2- or -
3-yl, or
1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl.
Alkyl-substituted sulfonyl Rt, R2, Rg and R9 preferably contains an
unsubstituted or
substituted alkyl radical mentioned under alkyl Rt, R,;, R8 and R9 and is
especially
lower alkylsulfonyl, such as methylsulfonyl, ethylsu:lfonyl, n-propylsulfonyl
or tert-butyl-
sulfonyl,
aryl-lower alkyl-substituted sulfonyl that contains, for example, an
unsubstituted or
substituted radical mentioned under aryl-lower alkyl Rl, R2, R$ and R9 and is
selected
especially from the radicals benzyl-, 4-chloro-, 4-methoxy- or 4-nitro-benzyl-
, naphthyl-
methyl-, for example a- or (3-naphthylmethyl-, 2-phenylethyl-, 2-a-
naphthylethyl-, 2-(3-
naphthylethyl-, 2-(4-methylphenyl)ethyl-, 2-(4-methoxyphenyl)ethyl-, 3-
phenylpropyl-,
3-(p-hydroxyphenyl)-propyl-, 2,2-diphenylethyl- and 2,2-di(4-methoxyphenyl)-
ethyl-
sulfonyl, or
heterocyclyl-lower alkyl-substituted sulfonyl that contains, for example, an
unsubsdtuted
or substituted radical mentioned under heterocyclyl-lower alkyl Rz, R2, Rg and
R9 and is
selected especially from radicals such as 2- or 3-pyrrolyl-, 2-thienyl-, 2-
furyl-,
1-pyrazolyl-, 2-, 3- or 4-pyridyl-, 2-, 3- or 5-indolyl-, (1-methyl-, 2-methyl-
, 5-methoxy-,
5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indol-2-yl)-, (1-benzylindol-2-yl or -
3-yl)-,
4,5,6,?-tetrahydroindol-2-yl-, (2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl)-
, (1-, 3- or
4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl)-, 3-pyrrolidinyl-, (3- or 4-
hydroxy-
pyrrolidin-2-yl)-, S-oxopyrrolidin-2-yl-, (2- or 3-morpholinyl)-, (2- or 3-
thiomorphalinyl)-,
~~~~~'~~3
-42-
(S,S-dioxothiomorpholin-2- or -3-yl)-, (2- or 3-indolinyl)-, (1,2,3,4-
tetrahydroquinol-2-,
-3- or -4-yl)- and (1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl)-methyl-
sulfonyl.
Aryl-substituted sulfonyl Rl, R2,'Rg and Rg preferably contains an
unsubstituted or substi-
tuted aryl radical mentioned under aryl-lower alkanoyl Rt, R2, Rs and Rg and
is especially
phenyl- or 1- or 2-naphthyl-sulfonyl that is unsubstituted or mono- or di-
substituted by
lower alkyl, such as phenylsulfonyl, 2- or 4-toluenesulfonyl or 1- or 2-
naphthylsulfonyl.
Heterocyclyl-substituted sulfonyl Rt, R2, Rs and Rg preferably contains
heterocyclyl that
is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, (3-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicals,
which may also be fully or partially saturated, from morpholinyl and from
thiomorpho-
linyl and may be unsubstituted or substituted, especially by lower alkyl, such
as methyl,
such as morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-
methyl-
piperazinylsulfonyl or piperazinosulfonyl. In especially preferred forms of
the invention,
heterocyclylsulfonyl as substituent may be absent.
Alkoxy-substituted sulfonyl Rt, R2, R8 and Rg preferably contains an
unsubstituted or
substituted alkyl radical mentioned under alkyl Rt, R,Z, R$ and Rg and is
selected
especially from
lower alkoxy-, such as methoxy-, ethoxy- or tert-butoxy-sulfonyl,
heterocyclyl-lower alkoxysulfonyl that contains, for example, an unsubstituted
or substi-
tuted heterocyclyl-lower alkyl radical mentioned under heterocyclyl-lower
alkyl Ri, R2,
R8 and Rg and is selected especially from 2- or 3-pyrrolyl-, 2-thienyi-, 2-
furyl-,
1-pyrazolyl-, 2-, 3- or 4-pyridyl-, 2-, 3- or 5-indolyl-, (1-methyl-, 2-methyl-
, 5-methoxy-,
5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indol-2-yl)-, (1-benzylindol-2-yl or -
3-yl)-,
4,5,6,7-tetrahydroindol-2-yl-, (2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl)-
, (1-, 3- or
4-isoquinolyl or 1-oxo-1,2-dihydroisoquinol-3-yl)-, 3-pyrrolidinyl-, (3- or 4-
hydroxy-
pyrrolidin-2-yl)-, 5-oxopyrrolidin-2-yl-, (2- or 3-morpholinyl)-, (2- or 3-
thiomorpholinyl)-,
(S,S-dioxothiomorpholin-2- or -3-yl)-, (2- or 3-indolinyl)-, (1,2,3,4-
tetrahydroquinol-2-,
-3- or -4-yl)- and (1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl)-
methoxysulfonyl or
-ethoxysulfonyl,
aryl-lower alkoxysulfonyl that contains, for example, an unsubstituted or
substituted
aryl-lower alkyl radical mentioned under aryl-lower alkyl Rl, Rz, R8 and Rg,
such as
benzyloxysulfonyl,
~~~~~t~.7~
-43-
hydroxy-lower alkoxy-, such as 3-hydroxypropoxy- or 2-hydroxy-3-
methylpentyloxy-
sulfonyl, ,
lower alkoxy-lower alkoxy-, for example lower alkoxyethoxy- or lower
alkoxypropoxy-,
such as methoxyethoxy- or 3-mechoxypropoxy-sulfonyl,
lower alkoxy-lower alkoxy-lower alkoxy-, such as 2-methoxymethoxy-3-
methylpentyl-
oxy-sulfonyl,
phenoxy-lower alkoxy- or nitrophenoxy-lower alkoxy-, such as phenoxymethoxy-,
phenoxyethoxy- or 4-nitrophenoxymethoxy-sulfonyl,
naphthyloxy-lower alkoxy-, such as a- or ~3-naphthyloxyethoxy-sulfonyl,
lower alkanoyloxy-lower alkoxy-, for example lower alkanoyloxyethoxy- or lower
alkanoyloxypropoxy-, such as acetoxyethoxy- or 3-acetoxypropoxy-sulfonyl,
amino-lower alkoxy-, such as 5-aminopentyloxy-sulfonyl,
mono- or di-lower alkylamino-lower allcoxy-, such as dimethylaminoethoxy- or
2-dirnethylamino-2-isopropylethoxy-sulfonyl,
lower alkanoylamino-lower alkoxy-, such as 4-acetylaminopentyloxy-sulfonyl,
lower alkoxycarbonylainino-lower alkoxy-, such as 5-(tert-butoxycarbonylamino)-
pentyloxy- or 3-ethoxycarbonylamino-2-isobutyl-pro;poxy-sulfonyl,
phenyl-lower alkoxycarbonylamino-lower alkoxy-, such as 5-(benzyloxycarbonyl-
amino)-pentyloxy-sulfonyl,
acetoacetoxy-sulfonyl,
aminocarbonylamino-lower alkoxy-, such as aminocarbonylamino-ethoxy-sulfonyl,
N-phenyl-lower alkyl-N-lower alkyl-aminocarbonylamino-lower alkoxy-, for
example
2-isobutyl-3-(N-benzyl-N-methylaminocarbonylamino)propoxy-sulfony1,
halo-lower alkoxy-, for example 2-haloethoxy-, such as (2-chloro-, 2-bromo-, 2-
iodo- or
2,2,2-trichloro-ethoxy)-, or halopropoxy-, such as (3-chloro- or 3-bromo-
propoxy)-
sulfonyl,
carboxy-lower alkoxy-, such as carboxyethoxy- or 3-carboxypropoxy-sulfonyl,
lower alkoxycarbonyl-lower alkoxy-, for example lower alkoxycarbonylethoxy- or
lower
alkoxycarbonylpropoxy-, such as methoxycarbonylethoxy-, 3-
methoxycarbonylpropoxy-,
ethoxycarbonylethoxy- or 3-ethoxycarbonylpropoxy-sulfonyl,
2-halo-lower alkoxycarbonyl-lower alkoxy-, such as (2-chloro-, 2-bromo-, 2-
iodo- or
2,2,2-trichloro-ethoxycarbonyl-2-ethoxy or 3-propoxy)-sulfonyl,
lower alkylsulfonyl-lower alkoxy-, such as (2-ethylsulfonyl- or 2-tert-
butylsulfonyl-
methoxy)-sulfonyl,
carbamoyl-lower alkoxy-, such as carbamoylethoxy- or 3-carbamoylpropoxy-
sulfonyl,
and
-44-
carbamoyl-lower alkoxysulfonyl substituted at the nitrogen atom by a radical
selected
from ethylene, trimethylene, tetramethylene and pentamethylene whe~°ein
a carbon atom
may have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted
by oxygen, it also being possible for the radical so formed to be fully or
partially unsatur-
ated, for example in the form of (piperidino-, pyrazin-1-yl-, piperazin-1-yl-,
pyrimidin-
1-yl-, pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-
dioxothiomorpholino-
carbonyl-lower alkoxy)-, such as in 2-morpholinocarbonyl-ethoxy-, 3-
(morpholino-
carbonyl)-propoxy- ar 3-(morpholinocarbonyl)-2-isobutyl-propoxy-sulfonyl.
Aryloxy-substituted sulfonyl Rt, R2, R8 and R9 preferably contains an
unsubstituted or
substituted aryl radical mentioned under aryl-lower alkanoyl Rt, R2, Rs and R9
and is
selected especially from benzylaxysulfonyl and 1- or 2-naphthyloxysulfonyh
Sulfamoyl Rt, R2, R8 and R9 substituted at the nitrogen atom may be
substituted
preferably by the same radicals as may carbamoyl in carbamoyl-lower al.kanoyl
Rt, R2, R8
and R9 and is selected especially from mono- or di-lower alkylsulfamoyl, such
as N,N-
dimethylsulfamoyl, N-(phenyl- or naphthyl-lower alkyl)sulfamoyl, such as 3-
benzyl-
sulfamoyl, and sulfamoyl substituted at the nitrogen atom by a radical
selected from
ethylene, trimethylene, tetramethylene or pentamethylene wherein a carbon atom
may
have been replaced by nitrogen, lower alkyl-substituted, such as methyl-
substituted,
nitrogen, oxygen, sulfur or by sulfiu mono- or di-substituted by oxygen, it
also being
possible for the radical so formed to be fully or partially unsaturated, for
example in the
form of piperidino-, pyrazin-1-yl-, piperazin-1-yl-, methylpiperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
sulfonyl, such
as 4-methylpiperazinylsulfonyl or morpholinosulfonyl-2-isopropyl-propyl.
Phosphoryl Rt, R2, Rg and R9 substituted by one or two identical or different
radicals
selected from alkyl, cycloalkyl, cycloalkyl-lower alkyl, aryl, aryl-lower
alkyl, hydroxy,
alkoxy, cycloalkoxy, cycloalkyl-lower alkoxy, aryloxy and aryl-lower alkoxy
preferably
contains
as unsubstituted ar substituted alkyl one or two of the unsubstituted or
substituted
radicals mentioned under alkyl, especially lower alkyl Rt, R2, Rg and R9, for
example
lower alkyl, such as methyl, ethyl, n-propyl, isopropyl, n-butyl and tent-
butyl,
- cycloalkyl-lower alkyl that is a lower alkyl radical substituted especially
terminally by
one of the cycloalkyl radicals mentioned under cycloalkyl-lower alkanoyl Rt,
R2, R8 and
R9, such as cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, 2-
cyclopentylethyl,
- ~5 -
3-cyclopentylpropyl, cyclohexylrnethyl, 2-cyclohexylethyl or 3-
cyclohexylpropyl,
- aryl-lower alkyl, as defined under aryl-lower allcyl Rl, R2, R8 or R9,
especially benzyl,
unsubstituted, mono- or poly-substituted preferably by lower alkyl, for
example methyl,
phenyl, hydroxy, lower alkoxy, for example methoxy, halogen, for example
chlorine,
and/or by nitro, such as 4-methoxy-, 4-chloro- or 4-nitro-benzyl,
naphthylmethyl, such as
a- or (3-naphthylmethyl, 2-phenylethyl, 2-a-naphthylethyl, 2-(3-naphthylethyl,
2-lower
alkylphenylethyl, such as 2-(4-methylphenyl)ethyl, 2-lower alkoxyphenylethyl,
such as
2-(4-methoxyphenyl)ethyl, 2,2-diphenylethyl, 2,2-di(4-methoxyphenyl)-ethyl,
2,2,2-tri-
phenylethyl, 2,2-dibenzylethyl, 2,p-diamino-phenylethyl, or phenyl-lower alkyl
substi-
tuted in the 2- and p-positions by two radicals selected from phenyl-lower
alkoxycarbonyl,
for example benzyloxycarbonyl, and lower alkanoylamino, for example
pivaloylamino,
such as Z,p-dibenzyloxycarbonylamino-phenylethyl or 2-pivaloylamino-p-
benzyloxy-
carbonylamino-phenylethyl, 3-phenylpropyl, 3-(p-hydroxyphenyl)-propyl, 3-a- or
3-(3-
naphthylpropyl, 2-benzyl-3-(1-pyrazolyl)-propyl, 3-phenyl- or 3-a-naphthyl-2-
hydroxy-
propyl, 3-phenyl- or 3-a-naphthyl-2-lower alkoxy-propyl, such as 3-phenyl- or
3-a-
naphthyl-2-neopentyloxy-propyl, 3-phenyl- or 3-a-naphthyl-2-lower alkanoyloxy-
propyl,
such as 3-phenyl- or 3-a-naphthyl-2-pivaloyloxy- or -2-acetoxy-propyl, 2-
benzyl- or 1- or
2-naphthyl-3-(N-methoxy-N-methylamino)-propyl, 3-phenyl- or 3-a-naphthyl-2-
dimethyl-
aminomethyl-propyl, 3-a-naphthyl-2-acetoacetoxy-propyl, 3-a-naphthyl-2-
ethylamino-
carbonyloxy-propyl or 3-a-naphthyl-2-(2-amino- or 2-benzyloxycarbonylamino-2-
methyl-
propionyloxy)-propyl, 3-phenyl- or 3-a-naphthyl-2-carboxymethyl-propyl, 3-
phenyl- or
3-a-naphthyl-2-lower alkoxycarbonyl-propyl, such as 3-a-naphthyl-2-
ethoxycarbonyl-
propyl, ~-phenyl- or 3-a-naphthyl-2-benzyloxycarbonylmethyl-propyl, 2-(S)-
benzyl-
3-tent-butylsulfonyl-propyl, 3-phenyl-2-phosphono- or -phosphonomethyl-propyl,
3-phenyl-2-dimethoxyphosphoryl- or -dimethoxyphosphorylmethyl-propyl, 3-phenyl-
2-
diethoxyphosphoryl- or -diethoxyphosphorylmethyl-propyl, 3-phenyl-2-ethoxy- or
-methoxy-hydroxyphosphorylpropyl, 3-phenyl- or 3-a-naphthyl-2-carbamoyl-
propyl,
3-phenyl- or 3-a-naphthyl-2-tert-butylcarbamoyl-propyl, 3-phenyl- or 3-a-
naphthyl-2-(2-
dimethylaminoethyl)carbamoyl-propyl, 3-a-naphthyl-2-(carboxy- or tent-
butoxycarbonyl)-
methylcarbamoyl-propyl, 3-phenyl- or 3-a-naphthyl-2-(3-hydroxy-2-propyl)-
carbamoyl-
propyl, 3-phenyl- or 3-a-naphthyl-2-(2,2-dimethoxyethyl)-carbamoyl-propyl, 3-
phenyl- or
3-a-naphthyl-2-(5-amino-5-carboxypentyl)-carbamoyl-propyl, 3-phenyl- or 3-a-
naphthyl-
2-cyano-propyl, 3-phenyl- or 3-a-naphthyl-2-cyanomethyl-propyl, 3-phenyl- or 3-
a-
naphthyl-2-acetonyl-propyl, 4-hydroxyphenylbutyl, 4-phenyl- or 4-a-naphthyl-3-
carboxy-
butyl, 4-phenyl- or 4-a-naphthyl-3-benzyloxycarbonyl-butyl, 2-benzyl- or 2-a-
naphthyl-
methyl-4-cyano-butyl, 2-benzyl-4-(2-benzofuranyl)-4-oxobutyl, 2-benzyl- or 2-a-
-46-
naphthylmethyl-5-dimethylamino-pentyl, 2-benzyl- or 2-a-naphthylmethyl-4-oxo-
pentyl,
2-benzyl- or 2-a-naphthylmethyl-4,4-dimethyl-3-oxa-pentyl, 2-benzyl- or 2-a-
naphthyl-
methyl-5-dimethylamino-4-oxo-pentyl, or 2-benzyl- or 2-a-naphthylmethyl-5,5-
dimethyl-
4-oxo-hexyl,
as cycloalkyl one of the radicals mentioned under cycloalkyl-lower allcanoyl
Rt, RZ, Rg
and Rg, especially cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl,
as aryl one of the unsubstituted or substituted radicals mentioned under aryl-
lower
alkanoyl Rl, R2, R8 and Rg, preferably phenyl, unsubstituted, mono- or poly-
substituted by
lower alkyl, for example methyl, halo-lower alkyl, for example
trifluoromethyl, phenyl,
hydroxy, lower alkoxy, for example methoxy, halogen, for example fluorine or
chlorine,
and/or by nitro, such as 4-methyl-, 3-hydroxy-, 4-methoxy-, 4-chloro- or 4-
nitro-phenyl,
naphthyl, such as a- or (3-naphthyl, or anilinophenyl substituted in the
phenyl radical by
one or two radicals selected from lower alkyl, such as methyl or ethyl,
hydroxy, lower
alkoxy, such as methoxy, amino, mono- or di-lower alkylamino, such as
ethylamino or
dimethylamino, halogen, such as fluorine or chlorine, carboxy, sulfo,
carbarnoyl,
sulfamoyl and cyano, and/or at the amino group by one or two radicals selected
from
lower alkyl and benzyl, such as 2-(o,o-dichloroanilino)-phenyl or 2-(o,o-
dichloro-
N-benzylanilino)-phenyl,
as alkoxy one of the unsubstituted or substituted radicals mentioned in the
case of
alkoxy-substituted sulfonyl Rt, R2, R8 and Rg, especially lower alkoxy, such
as methoxy,
ethoxy or tent-butoxy, cycloalkyl-lower alkoxy with one of the radicals
mentioned under
phosphoryl Rl, R2, Rg and R9 substituted by cycloalkyl-lower alkyl, bonded via
oxygen,
such as cyclapropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, 2-
cyclopentyl-
ethoxy, 3-cyclopentylpropoxy, cyclohexylmethoxy, 2-cyclohexylethoxy or 3-
cyclohexyl-
propoxy, aryl-lower allcoxy with one of the radicals mentioned under sulfonyl
Rl, R2, R8
and Rg substituted by aryl-lower alkoxy, bonded via oxygen, especially
benzyloxy,
hydroxy-lower alkoxy, such as 3-hydroxypropoxy or 2-hydroxy-3-methylpentyloxy,
lower
alkoxy-lower alkoxy, for example lower alkoxyethoxy or lower alkoxypropoxy,
such as
methoxyethoxy or 3-methoxypropoxy, lower alkaxy-lower alkoxy-lower alkoxy,
such as
2-methoxymethoxy-3-methylpentyloxy, phenoxy-lower alkoxy or nitrophenoxy-lower
alkoxy, such as phenoxymethoxy, phenaxyethoxy or 4-nitrophenoxymethoxy,
naphthyl-
oxy-lower alkoxy, such as a- or (3-naphthyloxyethoxy, lower alkanoyloxy-lower
alkoxy,
such as lower alkanoyloxyethoxy or lower alkanoyloxyprapoxy, such as
acetoxyethoxy or
3-acetoxypropoxy, amino-lower alkoxy, such as 5-aminopentyloxy, mono- or di-
lower
alkylamino-lower alkoxy, such as dimethylaminoethoxy or 2-dimethylamino-2-
isopropyl-
ethoxy, lower all:anoylamino-lower alkoxy, such as 4-acetylaminopentyloxy,
lower
2~~~ ~~'~
-47-
alkoxycarbonylamino-lower alkoxy, such as 5-(tent-butoxycarbonylamino)-
pentyloxy or
3-ethoxycarbonylamino-2-isobutyl-propoxy, phenyl-lower alkoxycarbonylamino-
lower
alkoxy, such as 5-(benzyloxycarbonylamino)-pentyloxy, aminocarbonylamino-lower
alkoxy, such as aminocarbonylamino-ethoxy, N-phenyl-lawer alkyl-N-lower alkyl-
amino-
caxbonylamino-lower alkoxy, such as 2-isobutyl-3-(N-benzyl-N-
methylaminocarbonyl-
amino)propoxy, hula-lower alkoxy, for example 2-haloethoxy, such as 2-chloro-,
2-bromo-, 2-iodo- or 2,2,2-trichloro-ethoxy, or halopropoxy, such as 3-chloro-
or
3-bromo-propoxy, carboxy-lower alkoxy, such as carboxyethoxy or 3-
carboxypropoxy,
lower alkoxycarbonyl-lower alkoxy, for example lower alkoxycarbonylethoxy or
lower
alkoxycarbonylpropoxy, such as methoxycarbonylethoxy, 3-
methoxycarbonylpropoxy,
ethoxycarbonylethoxy or 3-ethoxycarbonylpropoxy, 2-halo-lower alkoxycarbonyl-
lower
alkoxy, such as 2-chloro-, 2-bromo-, 2-iodo- or 2,2,2-trichloro-ethoxycarbonyl-
2-ethoxy or
-3-propoxy, lower alkylsulfonyl-lower alkoxy, such as 2-ethylsulfonyl- or 2-
tent-butyl-
sulfonyl-methoxy, carbamoyl-lower alkoxy, such as carbamoylethoxy or 3-
carbamoyl-
propoxy, or carbamoyl-lower alkoxy substituted at the nitrogen atom by a
radical selected
from ethylene, trimethylene, tetramethylene and pentamethylene wherein a
carbon atom
may have been replaced by nitrogen, oxygen, sulfur ox by sulfur mono- or di-
substituted
by oxygen, it also being possible for the ring formed to be fully or partially
unsaturated,
for example in the form of (piperidino-, pyrazin-1-yl-, piperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
carbonyl)-
lower alkoxy, such as in 2-morpholinocarbonyl-ethox;y, 3-(morpholinocarbonyl)-
propoxy
or 3~(morpholinocarbonyl)-2-isobutyl-propoxy,
as cycloalkoxy one of the cycloalkyl radicals mentioned under cycloalkyl-lower
alkanoyl
Rl, R2, R8 and R9, bonded via oxygen, such as cyclobutoxy, cyclopentyloxy or
cyclo-
hexyloxy, or
as aryloxy one of the radicals mentioned under aryloxy-substituted sulfonyl
Rl, R2, R8
and R9, especially benzyloxy or 1- or 2-naphthyloxy,
and is especially preferably lower alkylphosphoryl, such as tert-
butylphosphoryl,
hydroxy-lower alkoxyphosphoryl, such as hydroxy-methoxy-phosphoryl ox hydroxy-
ethoxy-phosphoryl, or di-lower alkoxyphosphoryl, such as dimethoxy-phosphoryl
or
diethoxy-phosphoryl.
The phosphono radicals and the individual definitions of the radicals Rt, R2,
R8 and R9
mentioned for substituted phosphoryl may also, independently of one another,
be omitted
from the definition of the radicals Rt, R2, Rs and R9 in the compounds of
formula I.
_~s-
Preferably not more than one of the radicals Rt and R2 and of the radicals R$
and R9 is
defined by the radicals mentioned under acyl, sulfo, substituted sulfo,
phosphono or
substituted phosphoryl, while the other radical is selected from the remaining
substituents
mentioned.
A heterocyclic ring formed by the pairs of substituents Rt and R2, and Rg and
R9,
independently of one another, together with the nitrogen atom to which they
are bonded,
and comprising the bonding nitrogen atom together with a radical selected from
ethylene,
trimethylene, tetramethylene and pentamethylene in which a carbon atom may
have been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, or one of those radicals with an oxo substituent at
each of the
two carbon atoms linked to the bonding carbon atom and with or without a fused-
on
benzene or naphthalene ring, is preferably piperidino, pyrazin-1-yl, piperazin-
1-yl,
pyrimidin-1-yl, pyridazin-1-yl, morpholino, thiomorpholino, S,S-
dioxothiomorpholino,
succinimido, malimido, oxalimido, maleimido, phthalimido or naphthalene-1,8-
dicarbonylimido, preferably only one of the pairs of substituents Rt and R2 or
R8 and R~
forming one of the said heterocyclic rings.
Unsubstituted or substituted alkyl R~, Rq, or R~ is preferably one of the
unsubstituted or
substituted radicals mentioned under alkyl Rl y R2, R8 and R9 and is selected
especially
from
lower alkyl, for example methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl
or tent-butyl,
cycloalkyl-lower alkyl that contains, for example, the cycloalkyl radicals
mentioned
under cycloalkyl-lower alkanoyl Rl, R2, Rg or R~, such as cyclopropyl,
cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl, cycloalkyl being unsubstituted or mono-
to tri-
substituted by lower alkyl, such as isopropyl, halo-lower alkyl, such as
trifluoromethyl,
hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower
allcoxy or
N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
halogen, such as fluorine, chlorine or bromine, carboxy, lower alkoxycarbonyl,
phenyl-,
naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower
alkylsulfonyl, far
example methylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylaminocarbamoyl, sulfamoyl,
mano-
or di-lower alkylsulfamoyl, nitro and/or by cyano and being bonded, preferably
terminally,
to lower alkyl, especially methyl, ethyl, n-propyl, isopropyl, n-butyl,
isobutyl or tert-butyl,
such as cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-lower alkyl,
such as -methyl
2~~ ~'~
-49-
or -ethyl, especially preferably cyclohexyl-lower alkyl, such as
cyclohexylmethyl,
bicycloalkyl-lower alkyl wherein bicycloalkyl contains, for example, from 5 to
10,
especially from 6 to 9, carbon atoms, for example bicycloalkyl-methyl or -
ethyl,
preferably having from 8 to 11 carbon atoms, such as decahydronaphthyl-2-
methyl, endo-
or exo-norbornyl-2-methyl, bicyclo[2.2.2]oct-2-ylmethyl or bicyclo[3.3.1]non-9-
ylmethyl,
and also bicyclo-hexyl-, -heptyl-, -octyl-, -nonyl- or -decyl-ethyl or -3-
propyl, for example
bicyclo[3.1.0]hex-1-, -2- or -3-yl-, bicyclo[4.1.0]hept-1- or -7-yl-,
bicyclo[2.2.1]hept-2-yl-,
for example endo- or exo-norbornyl-, bicyclo[3.2.1]oct-2-yl-,
bicyclo[3.3.0]oct-3-yl- or
bicyclo[3.3.1]non-9-yl-, and also a- or (3-decahydronaphthyl-ethyl or -3-
propyl,
tricycloalkyl-lower allcyl, wherein tricycloalkyl contains, for example, from
8 to 10
carbon atoms, for example tricycloalkyl-methyl or -ethyl, preferably having
from 8 to 11
carbon atoms, such as 1- or 2-adamantylmethyl, and also
tricyclo[5.2.1.02>b]dec-8-yl- or
adamantyl-, such as 1-adamantyl-ethyl,
aryl-lower alkyl, for example as defined under aryl-lower alkyl R1, R2, Rg or
Rc~, that is
unsubstituted or substituted as defined there, for example phenyl-lower alkyl,
such as
benzyl, 2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano-, 4-methoxy- or 4-
hydroxy-
benzyl, or 1- or 2-naphthyl-methyl or -2-ethyl, especially phenyl-lower alkyl,
as last
defined,
heterocyclyl-lower alkyl, for example as defined under heterocyclyl-lower
alkyl R1, R2,
Rg or R9, that is unsubstituted or substituted as defined there and is
selected especially
from pyrimidin-1-yl-, piperidino-, pyrazin-1-yl-, piperazin-1-yl-, pyridazin-1-
yl-, morpho-
lino-, thiomorpholino- or S,S-dioxothiomorpholino-lower alkyl, such as in 2-
morpholino-
ethyl, 3-morpholino-propyl or 3-morpholino-2-isobutyl-propyl, unsubstituted or
lower
alkyl- or phenyl-substituted pyrrolyl-lower alkyl, such as 2- or 3-pyrrolyl-
methyl, -ethyl or
-n-propyl, 4- or 5-methylpyrrolyl-methyl, -ethyl or -n-propyl or 4- or 5-
phenylpyrrolyl-
methyl, -ethyl or -n-propyl, thienyl-lower alkyl, such as 2-thienyl-methyl, -
ethyl or
-n-propyl, 1-imidazolylmethyl, furyl-lower alkyl, such as 2-furyl-methyl, -
ethyl or
-n-propyl, pyridyl-lower alkyl, such as 2-, 3- or 4-pyridyl-methyl, -ethyl or -
n-propyl,'
indolyl-lower alkyl that is unsubstituted or substituted by lower alkyl, for
example methyl,
phenyl-lawer alkyl, for example benzyl, lower alkoxy, for example methoxy,
phenyl-
lower alkoxy, for example benzyloxy, or by halogen, for example chlorine, such
as 2-, 3-
or 5-indolyl-methyl, -ethyl or -n-propyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-
benzyloxy-,
5-chloro- or 4,5-dimethyl-indol-2-yl-, 1-benzylindol-2-yl- or -3-yl-methyl, -
ethyl or
-n-propyl, 4,5,6,7-tetrahydroindol-2-yl-methyl, -ethyl or -n-propyl,
cyclohepta[b]pyrrol-
5-yl-methyl, -ethyl or -n-propyl, unsubstituted or hydroxy-substituted
quinolyl-lower
alkyl, for example 2-, 3- or 4-quinolyl- or 4-hydroxyquinol-2-yl-methyl, -
ethyl or
-s~-
-n-propyl, unsubstituted or hydroxy-substituted isoquinolyl-lower alkyl, such
as 1-, 3- or
4-isoquinolyl- or 1-oxo-1,2-dihydroisoquinol-3-yl-methyl, -ethyl or -n-propyl,
2-quinoxa-
linyl-methyl, -ethyl or -n-propyl, 3,1-benzofuran-2-yl-methyl, -ethyl or -n-
propyl, bent[e~-
indol-2-yl-methyl, -ethyl or -n-propyl, (3-carbolin-3-yl-methyl, -ethyl or -n-
propyl, 3-
chromanyl-methyl, -ethyl or -n-propyl, 3-thiachromanyl-methyl, -ethyl or -n-
propyl, 3- or
4-pyrrolidinyl-methyl, -ethyl or -n-propyl, hydroxypyrrolidinyl-lower alkyl,
such as 3- or
4-hydroxypyrrolidin-2-yl-methyl, -ethyl or -n-propyl, oxopyrrolidinyl-lower
alkyl, such as
5-oxopyrrolidin-2-yl-methyl, -ethyl or -n-propyl, piperidinyl-lower alkyl,
such as 2-, 3- or
4-piperidinyl-methyl, -ethyl or -n-propyl, morpholinyl-lower alkyl, such as 2-
or
3-morpholinyl-methyl, -ethyl or -n-propyl, thiomorpholinyl-lower alkyl, such
as 2- ar
3-thiomorpholinyl-methyl, -ethyl or -n-propyl, S,S-dioxothiomorpholinyl-lower
alkyl,
such as S,S-dioxothiomorpholin-2- or -3-yl-methyl, -ethyl or -n-propyl,
indolinyl-lower
alkyl, such as 2- or 3-indolinyl-methyl, -ethyl or -n-propyl, 1,2,3,4-
tetrahydroquinolyl-
lower alkyl, such as 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl-methyl, -ethyl
or -n-propyl,
1,2,3,4-tetrahydroisoquinolyl-lower alkyl, such as 1,2,3,4-tetrahydroisoquinol-
1-, -2- or
-3-yl-methyl, -ethyl ox -n-propyl, and 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl-
methyl,
-ethyl or -n-propyl,
hydroxy-lower alkyl, such as 3-hydroxypropyl or 2-hydroxy-3-methylpentyl,
lower alkoxy-lower alkyl, for example lower alkoxyethyl or lower alkoxypropyl,
such as
2-methoxyethyl, 2-ethoxyethyl or 3-methoxypropyl,
phenoxy-lower alkyl or nitxophertoxy-lower alkyl, such as phenoxymethyl,
phenoxyethyl
or 4-nitrophenoxymethyl,
naphthyloxy-lower alkyl, such as a- or (3-naphthyloxyethyl,
lower alkanoyloxy-lower alkyl, for example lower alkanoyloxyethyi or lower
alkanoyl-
oxypropyl, such as acetoxyethyl or 3-acetoxypropyl,
acetoacetoxy-lower alkanoyl,
arylmercapto-lower alkyl wherein aryl contains from 6 to 10 carbon atoms, for
example
phenyl or naphthyl, such as phenylmercaptomethyl,
amino-lower alkyl, such as 5-aminopentyl,
mono- or di-lower alkylamino-lower alkyl, such as dimethylaminoethyl or 2-
dimethyl-
amino-2-isopropylethyl,
phenyl- or naphthyl-amino-lower alkyl, such as 3-phenylaminopropyl,
lower alkanoylamino-lower alkyl, such as 4-acetylaminopentyl,
piperazinylcarbamoyl-lower alkyl substituted at the nitrogen atom by lower
alkyl, such
as methyl, such as 4-methylpiperazinylcarbonylmethyl,
lower alkoxycarbonylamino-lower alkyl, such as 5-(tert-butoxycarbonylamino)-
pentyl or
-51-
3-ethoxycarbonylamino-2-isobutyl-propyl,
phenyl-lower alkoxycarbonylamino-lower alkyl, such as 5-
(benzyloxycarbonylamino)-
pentyl,
aminocarbonylamino-lower alkyl, such as 2-aminocarbonylamino-ethyl,
N-phenyl-lower alkyl-N-lower alkylaminocarbonylamino-lower alkyl, such as 2-
isobutyl-3-(N-benzyl-N-methylaminocarbonylamino)propyl,
halo-lower alkyl wherein halogen is selected from fluorine, chlorine, bromine
and
iodine, for example 2-haloethyl, such as 2-fluoro-, 2-chloro-, 2-bromo-, 2-
iodo-,
2,2,2-trifluoro- or 2,2,2-trichloro-ethyl, trifluoro-lower alkyl, such as
trifluoromethyl, or
halopropyl, such as 3-fluoro-, 3-chloro- or 3-bromo-propyl,
carboxy-lower alkyl, such as carboxyethyl or 3-carboxypropyl,
lower alkoxycarbonyl-lower alkyl, for example lower alkoxycarbonylethyl or
lower
alkoxycarbonylpropyl, such as methoxycarbonylethyl, 3-methoxycarbonylpropyl,
ethoxy-
carbonylethyl or 3-ethoxycarbonylpropyl,
2-halo-lower alkoxycarbonyl-lower alkyl, such as 2-chloro-, 2-bromo-, 2-iodo-
or 2,2,2-
trichloro-ethoxycarbonyl-2-ethyl or -3-propyl,
phenyl- or naphthyl-lower alkoxycarbonyl-lower alkyl, for example
benzyloxycarbonyl-
lower alkyl, such as 3-benzyloxycarbonyl-2,2-dimethylpropyl,
heterocyclyl-lower alkoxycarbonyl-lower alkyl wherein heterocyclyl is
preferably
selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, (3-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicais, it
also being possible for the mentioned radicals to be fully or partially
saturated, such as in
4-pyridylmethyloxycarbonyl-2-ethyl or -3-propyl or 2-morpholinocarbonyloxy-4-
methyl-
pentyi,
lower alkylsulfonyl-lower alkyl, for example 2-ethylsulfonyl- or 2-tent-
butylsulfonyl-
methyl,
arylsulfonyl-lower alkyl wherein aryl preferably contains from 6 to 10 carbon
atoms, for
example phenyl or naphthyl, such as phenylsulfomethyl,
carbamoyl-lower alkyl, such as carbamoylethyl or 3-carbamoylpropyl,
lower alkylcarbamoyl-lower alkyl, for example lower alkylcarbamoylethyl or
methyl-
carbamoyl-lower alkyl, such as 2-methylcarbamoylethyl,
di-lower alkylcarbamoyl-lower alkyl, for example 2-di-lower
alkylcarbamoylethyl or di-
methylcarbamoyl-lower alkyl, such as 2-dimethylcarbamoylethyl,
hydroxy-lower alkylcarbamoyl- or di(hydroxy-lower alkyl)carbamoyl-lower alkyl,
Sllch
as 2-hydroxymethylcarbamoyl- or di(hydroxymethyl)carbamoyl-2-ethyl or -3-
propyl,
-52-
N-lower alkoxy-lower alkoxy-lower alkylcarbamoyl-lower alkyl, such as 2-
isobutyl-3-
(2-(2-rnethoxyethoxy)ethylaminocarbonyl)-propyl,
carboxy-lower alkylcarbamoyl- or di(carboxy-lower alkyl)carbamoyl-lower alkyl,
for '
example carboxymethyl- or di(carboxymethyl)-carbamoyl-2-ethyl or -3-propyl,
carbamoyl-lower alkyl substituted at the nitrogen atom by a radical selected
from
ethylene, trimethylene, terramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted by
oxygen, it also being possible for the radical so formed to be fully or
partially unsaturated,
for example in the form of piperidino-, pyrazin-1-yl-, piperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
carbonyl-
lower alkyl, such as in 2-morpholinocarbonyl-ethyl, 3-(morpholinocarbonyl)-
propyl or 3-
(morpholinocarbonyl)-2-isobutyl-propyl,
N-lower alkyl-N-heterocyclyl-lower alkylcarbamoyl-lower alkyl wherein
heterocyclyl is
preferably selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,
(3-carbolinyl
and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of
those
radicals, which may also be fully or partially saturated, such as 2-(N-2-
pyridylrnethyl)-N-
methylcarbamoyl-ethyl,
sulfamoyl-lower alkyl, such as 2-sulfamoylethyl,
N-(phenyl- or naphthyl-lower alkyl)sulfamoyl-lower alkyl, such as 3-
benzylamino-
sulfonyl-2-isopropyl-propyl, or
sulfamoyl-lower alkyl substituted at the nitrogen atom by a radical selected
from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been xepiaced by nitrogen, nitrogen substituted by lower alkyl, such as
methyl,
oxygen, sulfur or by sulfur mono- or di-substituted by oxygen, it also being
possible for
the radical so formed to be fully or partially unsaturated, for example in the
form of
piperidino-, pyrazin-1-yl-, piperazin-1-yl-, 4-methylpiperazin-1-yl-,
pyrimidin-1-yl-,
pyridazin-1-yl-, morpholino-, thiomorpholino- or S,S-dioxothiomorpholino-
sulfonyl-lower
alkyl, for example 3-(4-methylpiperazinylsulfonyl)-2-isopropyl-propyl or 3-
(morpholino-
sulfonyl)-2-isopropyl-propyl,
oxo-lower alkyl (wherein oxo is not present at the carbon atom that is bonded
to the
nitrogen atam carrying the radical R~), such as 3-oxo-n-butyl or 3-oxo-n-
pentyl,
cyano-lower alkyl, such as cyanomethyl, 2-cyanoethyl, 2- or 3-cyano-n-propyl
or 2-, 3-
or 4-cyano-n-butyl,
hydroxy-carboxy-lower alkyl, such as 2-hydroxy-2-carboxyethyl or 2-hydroxy-
3-carboxypropyl,
~~~~~?'~~
-S3-
a-naphthyloxy-carboxy-lower alkyl, such as 2-a-naphthyloxy-4-carboxy-n-butyl,
hydroxy-lower alkoxycarbonyl-lower alkyl, for example 2-hydroxy-2-lower alkoxy-
carbonyl-ethyl or -propyl or hydroxy-ethoxy- or hydroxy-methoxy-carbonyl-lower
alkyl,'
such as 2-hydroxy-2-ethoxy- or -methoxy-carbonylethyl or 2-hydroxy-3-ethoxy-
or
-methoxy-carbonyl-propyl,
a-naphthyloxy-lower alkoxycarbonyl-lower alkyl, for example a-naphthyloxy-
lawer
alkoxycarbonyl-2-ethyl,,-2-propyl or -2-butyryl or a-naphthyloxyethoxycarbonyl-
lower
alkyl, such as a-naphthyloxyethoxycarbonyl-2-ethyl, 2-a-naphthyloxy-3-
ethoxycarbonyl-
propyl or 2-a-naphthyloxy-4-tent-butoxycarbonylbutyl,
lower alkylcarbonylhalo-lower alkyl, such as 3-ethoxycarbonyl-2-
difluoromethyl,
a-naphthyloxy-benzyloxycarbonyl-lower alkyl, such as 2-a-naphthyloxy-3-
benzyloxy-
carbonyl-propyl,
esterified hydroxy-lower alkoxycarbonyl-lower alkyl wherein the hydroxy group
is
esterified by lower allcanoyl, for example acetyl, propionyl or pivaloyl,
cycloalkyl-lower
alkanoyl wherein cycloallcyl contains from 3 to 7 carbon atoms and lower
alkanoyl is as
last defined, for example cyclohexylcarbonyl or 2-cyclohexyl- or 2-cyclopentyl-
acetyl,
bicycloalkyl-lower alkanoyl wherein bicycloallcyl contains, for example, from
S to 10,
especially from 6 to 9, carbon atoms, such as in bicyclo-hexyl-, -heptyl-, -
octyl-, -nonyl-
or -decyl-acetyl or -3-propionyl, for example bicyclo[3.1.0]hex-1-, -2- or -3-
yl-, bicyclo-
[4.1.0]hept-1- or -7-yl-, bicyclo[2.2.1]hept-2-yl-, for example endo- or exo-
norbornyl-,
bicyclo[3.2.1]oct-2-yl-, bicyclo[3.3.0]oct-3-yl- or bicyclo[3.3.1]non-9-yl-,
and also a- or
(~-decahydronaphthyl-acetyl or -3-propionyl, tricycloalkyl-lower alkanoyl
wherein
tricycloalkyl contains, for example, from 8 to 10 carbon atoms, for example in
tricyclo-
[5.2.1.02~6]dec-8-yl- or adamantyl-, such as 1-adamantyl-acetyl, aryl-Iower
allcanoyl
wherein aryl contains from 6 to 14 carbon atoms, for example phenyl, indenyl,
indanyl,
naphihyl, anthryl, phenanthryl, acenaphthyl or fluorenyl, and may be
unsubstituted or
mono- to tri-substituted by lower alkyl, hydroxy, lower alkoxy, carbamoyl-
lower alkoxy,
N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower
alkoxy,
amino, mono- or di-lawer alkylamino, halogen, such as fluorine, chlorine ox
bromine,
carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl,
lower alkanoyl, lower alkylsulfonyl, for example methylsulfonyl, phosphono,
hydroxy-
lower alkoxyphospharyl, di-lower alkoxyphosphoryl, carbamoyl, sulfamoyl, nitro
and/or
by cyano, lower alkoxycarbonyl, for example ten-butoxycarbonyl, 2-halo-lower
alkoxy-
carbonyl, as defined above, or by phenyl- or fluorenyl-lower alkoxycarbonyl,
for example
benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, such as 2-acetoxy-2-methoxy-
carbonyl-ethyl, 2-benzoyloxy-, 2-(1- or 2-naphthoyloxy)-, 2-(phenyl-2-acetoxy)-
, 2-(1- or
2~~~'l?p~~
-s~-
2-naphthyl-2-acetoxy)-, 2-(4-methylphenyl-2-acetoxy)-, 2-(4-methoxyphenyl-2-
acetoxy)-
or 2-(2-(o,o-dichlorophenyl)-2-acetoxy)-2-methoxycarbonyl-ethyl or,-3-propyl,
dihydroxy-carboxy-lower alkyl, such as 2,3-dihydroxy-3-carboxy-propyl,
dihydroxy-lower alkoxycarbonyl-lower alkyl, such as 2,3-dihydroxy-3-ethoxy- or
-methoxy-carbonyl-propyl,
dihydroxy-lower alkaxycarbonyl-lower alkyl esterified by lower alkanoyl, such
as acetyl,
propionyl or butyryl, lower alkoxycarbonyl, for example tert-butoxycarbonyl,
phenyl- or
fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl or 9-
fluorenylmethoxy-
carbonyl, lower alkylsulfonyl or by toluenesulfonyl, for example di-lower
alkanoyloxy-
lower alkoxy-propyl, such as 2,3-diacetoxy-3-meihoxycarbonyl-propyl,
a-naphthyloxy-di-lower alkylamino-lower alkyl, such as 2-a-naphthyloxy-s-
dimethyl-
amino-pentyl,
a-naphthyloxy-caxbamoyl-lower alkyl, such as 2-a-naphthyloxy-4-carbamoyl-
butyl,
a-naphthyloxy-oxo-lower alkyl (wherein oxo is not present at the carbon atom
that is
bonded to the nitrogen atom carrying the radical R~), such as 2-a-naphthyloxy-
4-
oxo-pentyl, or
a-naphthyloxy-cyano-lower alkyl, such as 2-a-naphthyloxy-cyano-ethyl or 2-a-
naphthyl-
oxy-4-cyano-butyl.
Lower alkyl that is unsubstituted or mono- or poly-substituted by hydroxy,
lower alkoxy,
amino, mono- or di-lower alkylamino, fluorine, chlorine or by cyano is
preferred, and
lower alkyl, such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl or
tent-butyl, is very
especially preferred.
Cycloalkyl R3, R4 or R7 is preferably as defined under cyeloalkyl-lower
alkanoyl Rl,
R2, Rg or Rg, for example cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or
cyclo-
heptyl, cycloallcyl being unsubstituted or mono- to tri-substituted by lower
alkyl, such as
isopropyl, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy,
carbamoyl-
lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy ~r N,N-di-lower
alkylcarbamoyl-
lower alkoxy, amino, mono- or di-lower alkylamino, halogen, such as fluorine,
chlorine or
bromine, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxy-
carbanyl, lower alkanoyl, lower alkylsulfonyl, for example methylsulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono-
or di-
lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, vitro
and/or by
cyano, such as cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl, especially
cyclohexyl.
~~~~s~"'~~
-ss-
Aryl R3, R4 or R7 is preferably one of the unsubstituted or substituted aryl
radicals
mentioned under aryl-lawer alkanoyl R1, R2, Rg or R~ and is especially phenyl,
naphthyl
or fluorenyl that is unsubstituted or mono- to tri-substituted by lower alkyl,
such as
isopropyl, halo-lower alkyl, such ~as trifluoromethyl, hydroxy, lower alkoxy,
carbamoyl-
lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower
alkylcarbamoyl-
lower alkoxy, amino, mono- or di-lower alkylamino, halogen, such as fluorine,
chlorine or
bromine, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxy-
carbonyl, lower alkanoyl, lower alkylsulfonyl, for example methylsulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono-
or di-
lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, vitro
and/or by
cyano, such as phenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-nitrophenyl, 4-
cyanophenyl or
1- or 2-naphthyl.
lHeterocyclyl R3, R4 or R7 is preferably as defined under heterocyclyl Rl, R2,
Rg or R9,
which is unsubstituted or substituted as defined there, and is selected
especially from 2- or
3-pyrrolyl, 4- or 5-methylpyrrolyl or 4- or 5-phenylpyrrolyl, 2-thienyl, 2-
furyl, 2-, 3- or
4-pyridyl, 2-, 3- or 5-indolyl, 1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-
, 5-chloro-
or 4,5-dimethyl-indol-2-yl, 1-benzylindol-2- or -3-yl, 4,5,6,7-tetrahydroindol-
2-yl, cyclo-
hepta[b]pyrrol-5-yl, 2-, 3- or 4-quinolyl or 4-hydroxyquinol-2-yl, 1-, 3- or 4-
isoquinolyl,
1-oxo-1,2-dihydroisoquinol-3-yl, 2-quinoxalinyl, 3,1-benzofuran-2-yl,
benz[e]indol-2-yl,
(3-carbolin-3-yl, 3-chromanyl, 3-thiochromanyl, 3-pyrrolidinyl, 3- or 4-
hydroxypyrrolidin-
2-yl, such as 5-oxopyrrolidin-2-yl, 2-, 3- or 4-piperidinyl, 2- or 3-
morpholinyl, 2- or
3-thiomorpholinyl, S,S-dioxothiomorpholin-2- or -3-y.l, 2- or 3-indolinyl,
1,2,3,4-tetra-
hydroquinol-2-, -3- or -4-yl, 1,2,3,4-tetrahydroisoquinol-1-, -2- or -3-yl, or
1-oxo-1,2,3,4-
tetrahydroisoquinol-3-yl.
Unsubstituted or substituted alkenyl R3, R4 or R7 is preferably as defined
under alkenyl
R1, R2, Rg or R9, especially lower alkenyl that is unsubstituted or
substituted as defined
there, for example
lower alkenyl, such as vinyl, allyl or 2- or 3-butenyl,
cycloalkyl-lower alkenyl wherein cycloalkyl is as defined in the case of
cycloalkyl-lower
alkanoyl Rl, R2, Rg or R9 and is unsubstituted or mono- to tri-substituted by
lower alkyl,
such as isopropyl, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower
alkoxy,
carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lawer
alkyl-
carbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, such as
fluorine,
chlorine or bromine, cttrboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or
fluorenyl-lower
-56-
alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, for example
methylsulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl ar di-lower aikoxypho~phoryi,
carbamoyl,
mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower
alkylsulfamoyl,
nitro and/or by cyano and is banded especially to the terminal carbon atom of
lower
alkenyl, such as cyclobutyl-, cyclopentyl-, cyclohexyl- or cycloheptyl-methyl-
2-vinyl, -2-
or -3-allyl or -2-, -3- or -4-but-2-enyl,
aryl-lower alkenyl having an unsubstituted or substituted aryl radical defined
under aryl
R3 or Rq. that is banded, preferably terminally, to lower alkenyl, and having
a lower
alkenyl radical defined under lower allcenyl R1, R2, Rg or R9, such as styryl,
3-phenyl-
allyl (cinnamyl), 2-(a-naphthyl)-vinyl or 2-((i-naphthyl)-vinyl, or
unsubstituted ar substituted heteracyclyl-lower alkenyl that contains, for
example, an
unsubstituted or substituted lower alkenyl radical mentioned under alkenyl Rl,
R2, Rg or
Rc~, for example vinyl, allyl or 2- or 3-butenyl, that is substituted,
preferably at the
terminal carbon atom, by an unsubstituted or substituted heterocyclyl radical
mentioned
under heterocyclyl R1, R2, Rg or R9, for example in the form of pyrimidin-1-yl-
, piper-
idino-, pyrazin-1-yl-, piperazin-1-yl-, pyri.dazin-1-yl-, morpholino-,
thiomorpholino- or
S,S-dioxothiomorpholino-lower alkenyl, such as in 2-morpholino-vinyl, 3-
morpholino-
allyl or ~-morpholino-2- or -3-butenyl, unsubstituted or lower alkyl- or
phenyl-substituted
pyrrolyl-lower alkenyl, such as 2- or 3-pyrrolyl-vinyl or -allyl, ~.- or 5-
methylpyrrolyl-
vinyl or -allyl or 4- or 5-phenylpyrrolyl-vinyl or -allyl, thienyl-lower
alkenyl, such as
2-thienyl-vinyl or -allyl, furyl-lower alkenyl, such as 2-furyl-vinyl or -
allyl, pyridyl-lower
alkenyl, such as 2-, 3- or 4-pyridyl-vinyl ar -aiiyl, indalyl-lower alkenyi
that is unsubsti-
tuted or substituted by lower alkyl, for example methyl, phenyl-lower alkyl,
for example
benzyl, lower alkoxy, for example methoxy, phenyl-lower allcoxy, far example
benzyloxy,
or by halogen, for example chlorine, such as 2-, 3- or 5-indolyl-vinyl or -
allyl, 1-methyl-,
2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indol-2-yl-, 1-
benzyl-
indol-2-yl- or -3-yl-vinyl or -allyl, 4,5,6,7-tetrahydroindol-2-yl-methyl, -
ethyl or -n-propyl,
cycloheptajb]pyrrol-5-yl-vinyl or -allyl, unsubstituted or hydroxy-substituted
quinolyl-
lower alkenyl, for example 2-, 3- or 4-quinolyl- or 4-hydroxyquinol-2-yl-vinyl
or -allyl,
unsubstituted or hydroxy-substituted isoquinolyl-lower alkenyl, such as 1-, 3-
or
4-isoquinolyl- or 1-oxo-1,2-dihydroisoquinol-3-yl-vinyl or -allyl, 2-
quinoxalinyl-vinyl or
-allyl, 3,1-benzofuran-2-yl-vinyl or -allyl, benz[e]indol2-yl-vinyl or -allyl,
~i-carbolin-
3-yl-vinyl or -allyl, 3-chromanyl-vinyl or -allyl, 3-thiochromanyl-vinyl or -
allyl, 3-pyrrol-
idinyl-vinyl or -allyl, hydroxypyrrolidinyl-lower alkenyl, such as 3- or 4-
hydroxy-
pyrrolidin-2-yl-vinyl or -allyl, oxopyrrolidinyl-lower alkenyl, such as 5-
oxopyrrolidin-
2-yl-vinyl or -allyl, piperidinyl-lower alkenyl, such as 2-, 3- or 4-
piperidinyl-vinyl or
c
-57-
-allyl, morpholinyl-lower alkenyl, such as 2- or 3-morpholinyl-vinyl or -
allyl, thiomorpho-
linyl-lower alkenyl, such as 2- or 3-thiomorphalinyl-vinyl or -allyl, S,S-
dioxothio-
morpholinyl-lower alkenyl, such as S,S-dioxothiomorpholin-2- or -3-yl-vinyl or
-allyl,
indolinyl-lower alkenyl, such as 2- or 3-indolinyl-vinyl or -allyl, 1,2,3,4-
tetrahydro-
quinolyl-lower alkenyl, such as 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl-
vinyl or -allyl,
1,2,3,4-tetrahydroisoquinolyl-lower alkenyl, such as 1,2,3,4-
tetrahydroisoquinol-1-, -2- or
-3-yl-vinyl or -allyl, or 1-oxo-1,2,3,4-tetrahydroisoquinol-3-yl-vinyl or -
allyl.
Unsubstituted or substituted alkylene formed by R3 and R4 together contains
especially an
alkylene radical having up to 20 carbon atoms, it also being possible for the
mentioned
radicals to contain one or more double bonds, preferably lower alkylene, for
example
ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene or hepta-
methylene, that is unsubstituted or substituted, especially by unsubstituted
or substituted
aryl, as defined under aryl-lower alkanoyl R1, R2, Rg or Rc~, preferably by
phenyl,
indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl,
which are
unsubstituted or mono- to tri-substituted by radicals such as lower alkyl, for
example
methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl,
phenyl, 1- or
2-naphthyl, hydroxy, lower alkoxy, for example methoxy, carbamoyl-lower
alkoxy,
N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower allcylcarbamoyl-lower
alkoxy,
amino, mano- or di-lower alkylamino, lower alkanoylamino, for example
pivaloylamino,
halogen, for example fluorine, chlorine or bromine, cauboxy, lower
alkoxycarbonyl,
phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, sulfo,
lower alkyl-
sulfonyl, for example methylsulfonyl, phosphono> hydroxy-lower
alkoxyphosphoryl or di-
lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl,
sulfamoyl, mono-
or di-lower alkylaminosulfonyl, nitro and/or cyano, and/or is substituted in
the same
manner as lower alkanoyl in aryl-lower alkanoyl R1, R2, Rg or R9, especially
by lower
alkyl, for example methyl, hydroxy, lower alkoxy, for example methoxy or
ethoxy, lower
alkanoyloxy, for example acetoxy or propionyloxy, benzoyloxy, phenylacetoxy or
1- or
2-naphthoyloxy, lower alkoxycarbonyloxy, for example isopropoxycarbonyloxy or
tert-
butoxycarbonyloxy, phenyl-lower alkoxycarbonyloxy, for example benzyloxy-
carbonyloxy, 9-fluorenylmethoxycarbonyloxy, sulfonyloxy, lower
alkylsulfonyloxy, for
example methyl- or ethyl-sulfonyloxy, phenylsulfonyloxy, 2- or 4-
toluenesulfonyloxy,
amino, mono- or di-lower alkylamino, for example mono- or di-methylamino or -
ethyl-
amino, lower alkanoylamino, for example acetylamino or pivaloylamino, carboxy,
lower
alkoxycarbonyl, for example isopropoxy- or tert-butoxy-carbonyl,
benzyloxycarbonyl,
9-fluorenylmethoxycarbonyl, lower alkanoyl, for example acetyl or propionyl,
lower
-58-
alkylsulfonyl, such as methylsulfanyl or tent-butylsulfonyl, phosphono,
carbamoyl, mono-
or di-lower alkylcarbamoyl, for example N-methylcarbamoyl or
N,N;dimethylcarbamoyl,
piperidino, pyrazin-1-yl, pyrimidin-1-yl, pyridazin-1-yl, morpholino,
thiomorpholino or
S,S-dioxothiomorpholino, sulfambyl, oxo and/or by cyano, such as ethylene,
ethyl-
ethylene, trimethylene, propylene or tetramethylene.
Unsubstituted or substituted alkylidene formed by R3 and R4 together contains
up to 20
carbon atoms and no double bonds or one or more double bonds in addition to
the linking
double bond, and is preferably lower alkylidene, for example methylene,
ethylidene,
propylidene, butylidene or pentylidene, that is unsubstituted or substituted
especially by
cycloalkyl, such as mentioned under cycloalkyl-lower alkanoyl Rl, R2, Rg or
R~, for
example cyclopropyl, cyclobutyl, cyclopenryl or cyclohexyl, cycloalkenyl, such
as
mentioned under cycloalkenyl-lower alkanoyl Rl, R2, Rg or R9, for example
cyclo-
hexen-1-yl or 1,4-cyclohexadienyl, unsubstituted or substituted aryl, such as
defined under
aryl-lower alkanoyl Rl, R2, Rg or R9, preferably by phenyl, indenyl, indanyl,
naphthyl,
anthryl, phenanthryl, acenaphthyl or fluorenyl, which are unsubstituted or
mono- to tri-
substituted by radicals such as lower alkyl, for example methyl, ethyl or
propyl, halo-
lower alkyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy,
lower alkoxy,
far example methoxy, cwbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower
alkoxy or
N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
lower
alkanoylamino, for example pivaloylamino, halogen, for example fluorine,
chlorine or
bromine, carboxy, lower alkoxycarbonyl, phenyl-, na;phthyl- or fluorenyl-lower
alkoxy-
carbonyl, lower alkanoyl, sulfo, lower aL~Cylsulfonyl, :fox example
methylsulfonyl,
phosphono, hydroxy-lower alkoxyphosphoryl or di-lower aLkoxyphosphoryl,
carbamoyl,
mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower
alkylaminosulfonyl,
nitro and/or cyano, and/or is substituted in the same manner as lower alkanoyl
in aryl-
lower alkanoyl R1, R2, Rg or R9, especially by lower alkyl, for example
methyl, hydroxy,
lower alkoxy, for example methoxy or ethoxy, lower alkanoyloxy, for example
acetoxy or
prapionyloxy, benzoyloxy, phenylacetoxy or 1- or 2-naphthoyloxy, lower
alkoxycarbonyl-
oxy, for example isopropoxycarbonyloxy or tert-butoxycarbonyloxy, phenyl-lower
alkoxy-
carbonyloxy, for example benzylaxycarbonyloxy, 9-fluorenylmethoxycarbonyloxy,
sulfonyloxy, lower alkylsulfonyloxy, for example methyl- or ethyl-sulfonyloxy,
phenyl-
sulfonyloxy, 2- or 4-toluenesulfonyloxy, amino, mono- or di-lower alkylamino,
for
example mono- or di-methyl-amino or -ethyl-amino, lower alkanoylamino, for
example
acetylamino or pivaloylamino, carboxy, lower alkoxycarbonyl, for example
isopropoxy-
or tert-butoxy-carbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, lower
alkanoyl,
X07 ~~
-59-
for example acetyl or propionyl, lower alkylsulfonyl, such as methylsulfonyl
or tent-butyl-
sulfonyl, phosphono, carbamoyl, mono- or di-lower alkylcarbamoyl, for example
N-methylcarbamoyl or N,N-dimethylcarbamoyl, piperidino, pyrazin-1-yl,
pyrimidin-1-yl;
pyridazin-1-yl, morpholino, thiomorpholino or S,S-dioxothiomorpholino,
sulfamoyl, oxo
and/or by cyano, such as ethylidene, propylidene, butylidene, benzylidene or
cinnamylidene.
Unsubstituted or substituted benzo-fused alkylene formed by R3 and Rq.
together contains
up to 20 carbon atoms and is preferably lower alkylene, for example ethylene,
trimethyl-
ene, tetramethylene, pentamethylene, hexamethylene or heptamethylene, anto
which a
benzene ring has been fused, and is unsubstituted or substituted especially by
unsubsti-
tuted or substituted aryl, as deFtned under aryl-lower alkanoyl Rl, R2, Rg or
R9,
preferably by phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl,
acenaphthyl or
fluorenyl, which are unsubstituted or mono- to tri-substituted by radicals
such as lower
alkyl, for example methyl, ethyl or propyl, halo-lower alkyl, for example
trifluoromethyl,
phenyl, 1- or 2-naphthyl, hydroxy, lower alkoxy, for example methoxy,
carbamoyl-lower
alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-
lower
alkoxy, amino, mono- or di-lower alkylamino, lower alkanoylamino, for example
pivaloylamino, halogen, for example fluorine, chlorine or bromine, carboxy,
lower alkoxy-
carbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower
alkanoyl, sulfo,
lower alkylsulfonyl, fox example methylsulfonyl, phosphono, hydroxy-lower
alkoxy-
phosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower
alkylcarbamoyl,
sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitro and/or cyano, and may
also be
substituted by lower alkyl, for example methyl, hydroxy, lower alkoxy, for
example
methoxy or ethoxy, lower alkanoyloxy, for example acetoxy or propionyloxy,
benzoyloxy,
phenylacetoxy or 1- or 2-naphthoyloxy, lower alkoxycarbonyloxy> for example
iso-
propoxycarbonyloxy or tart-butoxycarbonyloxy, phenyl-lower alkoxycaxbonyloxy,
for
example benzyloxycarbonyloxy, 9-fluorenylmethoxycarbonyloxy, sulfonyloxy,
lower
alkylsulfonyloxy, for example methyl- or ethyl-sulfonyloxy, phenylsulfonyloxy,
2- or 4-
toluenesulfonyloxy, amino, mono- or di-lower alkylamino, for example mono- or
di-
methyl-amino or -ethyl-amino, lower alkanoylamino, for example acetylamino or
pivaloylamino, carboxy> lower alkoxycarbonyl, for example isopropoxy- or tent-
butoxy-
carbonyl, benzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, lower alkanoyl, for
example
acetyl or propionyl, lower alkylsulfonyl, such as methylsulfonyl or tert-
butylsulfotryl,
phosphono, carbamoyl, mono- or di-lower alkylcarbamoyl, for example N-methyl-
carbamoyl or N,N-dimethylcarbamoyl, piperidino, pyrazin-1-yl, pyrimidin-1-yl,
pyrid-
~?~~
-60-
azin-1-yl, moaphoiino, thiomorpholino or S,S-dioxothiomorpholino, sulfamoyl,
oxo and/or
by cyano, such as ortho-phenylene. ,
When, in the compounds of formula I substituted by the mentioned radicals,
nitrogen
atoms having free hydrogen and/or hydroxy groups are vicinal with respect to
double or
triple bonds (as in the case of unsubstituted or substituted alkenyl or
alkynyl R1, R2, Rg or
R9), the corresponding tautomeric imino and oxo compounds are always also
included.
Salts of compounds of formula I are especially acid addition salts, salts with
bases or,
where several salt-forming groups are present, can also be mixed salts or
internal salts.
Salts are especially the pharmaceutically acceptable, non-toxic salts of
compounds of
formula I.
Such salts are formed, for example, from compounds of formula I having an acid
group,
for example a carboxy group, a sulfo group, or a phosphoryl group substituted
by one or
two hydroxy groups, and are, for example, salts thereof with suitable bases,
such as
non-toxic metal salts derived from metals of groups Ia, Ib, lIa and IIb of the
Periodic
Table of the Elements, especially suitable alkali metal salts, for example
lithium, sodium
or potassium salts, or alkaline earth metal salts, for example magnesium or
calcium salts,
also zinc salts or ammonium salts, as well as salts fozrned with organic
amines, such as
unsubstituted or hydroxy-substituted mono-, dl- or tri-alkylamines, especially
mono-, di-
or tri-lower alkylamines, or with quaternary ammonium compounds, for example
with
N-methyl-N-ethylamine, diethylamine, triethylamine, mono-, bis- or tris-(2-
hydroxy-lower
alkyl)amines, such as mono-, bis- or tris-(2-hydroxyethyl)amine, 2-hydroxy-
tert-butyl-
amine or tris(hydroxymethyl)methylamine, N,N-di-lower alkyl-N-(hydroxy-lower
alkyi)-
amines, such as N,N-dimethyl-N-(2-hydroxyethyl)-amine or tri-(2-hydroxyethyl)-
amine,
N-methyl-D-glucamine, or quaternary ammonium salts, such as tetrabutyiammonium
salts. The compounds of formula I having a basic group, for example an amino
group, can
form acid addition salts, for example with inorganic acids, for example
hydrohalic acids,
such as hydrochloric acid, sulfuric acid or phosphoric acid, or with organic
carboxylic,
sulfonic, sulfo or phospho acids or N-substituted sulfamic acids, for example
acetic acid,
propionic acid, giycolic acid, succinic acid, malefic acid, hydroxymaleic
acid, methyl-
maleic acid, fumaric acid, malic acid, tartaric acid, gluconic acid, glucaric
acid, glucuronic
acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, salicylic acid,
4-aminosali-
cyiic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, embonic acid,
nicotinic acid or
a
-61-
isonicotinic acid, as well as with amino acids, for example the a-amino acids
mentioned
hereinbefore, especially glutamic acid and aspartic acid, and with
methanesulfonic acid,
ethanesulfonic acid, 2-hydroxyethanesulfonic acid, ethane-1,2-disulfonic acid,
benzene-
sulfonic acid, 4-methylbenzenesuJfonic acid, naphthalene-2-sulfonic acid, 2-
or
3-phosphoglycerate, glucose-6-phosphate, N-cyciohexylsulfamic acid (forming
cycla-
mates) or with other acidic organic compounds, such as ascorbic acid.
Compounds of
formula I having acid and basic groups can also form internal salts.
For isolation or purification purposes, it is also possible to use
pharmaceutically unaccept-
able salts.
The compounds of the present invention have an inhibiting effect on viral
aspartate
proteases, especially a gag-protease-inhibiting effect. In the tests described
below, at
concentrations of 10-6 to 10-9 mol/1 they inhibit especially the action of the
gag-protease
of HIV-1 and HIV-2 and are therefore suitable as agents against diseases
caused by those
viruses or by related retroviruses, fox example against EI.mS.
The ability of the compounds of formula I to inhibit the proteolytic activity
of, fox
example, HIV-1 protease can be demonstrated, for example, by the method
described by J.
I-Iansen et al., The EMBO Journal 7, 1785-1791 (1988). In that method, the
inhibition of
the action of the gag-protease is measured on a substrate that is a fusion
protein of the
gag-precursor protein and MS-2, expressed in E. coli. The substrate and its
cleavage
products are separated by polyacrylamide gel electrophoresis and made visible
by
immunoblotting using monoclonal antibodies to MS-2.
In a test that is even simpler to carry out and that gives precise
quantitative results, there is
used as substrate for the gag-protease a synthetic peptide that corresponds to
the cleavage
site of the gag-precursor protein. That substrate and its cleavage products
can be analysed
by high-pressure liquid chromatography (HPLC).
For example, there is used as substrate for a recombinant HIV-1 protease
(preparation in
accordance with Billich, S. et al., J. Biol. Chem. 263(34), 17905 - 17908
(1990)) a
synthetic chromophoric peptide (for example HT~ARVL[N02]FEANleS (Sachem, Switz-
erland) or an icosapeptide such as RRSNQVSQNYPIVQNIQGRR (prepared by peptide
synthesis using known methods) that corresponds to one of the cleavage sites
of the gag-
precursor protein. That substrate and its cleavage products can be analysed by
high-
0~
-62-
pressure liquid chromatography (HPLC).
For that purpose an inhibitor of formula I to be tested is dissolved in
dimethyl sulfoxide;
the enzyme assay is carried out by adding suitable dilutions of the inhibitor
in 20 mM
~i-morpholinoethanesulfonic acid (MES) buffer, pH 6.0, to the assay mix of
67.2 ~.M of
the above-mentioned chromophoric peptide in 0.3M sodium acetate, 0.1M NaCI, pH
7.4,
or 122 ~.M of the above-mentioned icosapeptide in 20 mM MES buffer, pH 6Ø
The size
of the batches is 100 ~1. The reaction is started by the addition of, in the
first case, 2 ~.1
and, in the second case, 10 ~.1 of HIV-1 protease and is stopped in the first
case after
15 min by the addition of 100 ~1 of 0.3M HC104 and in the second case after
incubation
for one hour at 37°C by the addition of 10 ~.1 of 0.3M HC104. After
centrifugation of the
sample for 5 min at 10 000 x g in 100 ~.1 (batch with chromophoric peptide) or
20 ~.1
(icosapeptide batch) of the resulting supernatant and application to a 125 x
4.6 mm
Nucleosil~ C18-5~, I-IPLC column (Macherey & Nagel, Diiren) and elution, the
reaction
products are quantified by reference to the peak height of the cleavage
product at 280
(batch with chromophoric peptide) or at 215 nm (batch with icosapeptide),
gradient:
100 % eluant 1-> 50 % eluant 1/50 % eluant 2 (eluant 1: 75 % acetonitrile, 90
% H20,
0.1 % trifluoroacetic acid (TFA); eluant 2: 75 % acetonitrile, 25 % H20, 0.08
% TFA) in
the course of 15 min; throughput rate 1 ml/min.
In this test, there are preferably obtained ICSp values (ICSp = the
concentration that
reduces the activity of HIV-1 protease by 50 % compared with a control without
an
inhibitor) of approximately from 10-6 to 10-9M, especially from approximately
10-7 to
approximately 10-8M, for compounds of formula I.
In a further test it can be shown that the compounds of the present invention
protect cells
that normally become infected by HIV from such infection or at least slow down
such
infection. In that test the human T-cell leukaemia cell line MT-2 (Science
229, 563
(1985)), which is extremely sensitive to the cytopathogenic effect of HIV, is
incubated
with HIV alone or with HIV in the presence of the compounds of the invention
and after a
few days the viability of the cells thus treated is assessed.
For that purpose the MT-2 cells are kept at 37°C in humid air with 5 %
C02 in RPMI
1640 medium (Gibco, Switzerland; RPMI 1640 comprises an amino acid mixture
without
L-Gln) supplemented with 10 % heat-inactivated foetal calf serum, L-glutamine,
hepes
(2-(4-(2-hydroxyethyl)-1-piperazino]-ethanesulfonic acid) and standard
antibiotics. 50 ~.1
CA 02072785 2003-04-17
21489-8495
fy~ ..
of the particular test compound in culture medium and 10(9 p.1 of HIV-1 in
culture medium
(800 TCID50/ml) (TCID50 = Tisscre Culture Infectious Dose '_i0 = dose drat
infects 50 %
of the MT-2 cells) axe added to 4x103 exponentially growing MT-2 cells in 50
wl of
culture medium per well on 9fi-well microtitre, plates. Parallel batches on a
further micro-
titxe plate with cells and test compound receive 1t~0 ~.l of culture medium
without virus.
After incubation for 4 days, the reverse transcriptase (RT) activity is
determined in 10 p.l
of cell supernatant. The RT activity is determined in 50 mM of Iris (a,a,a-
izis(hydroxy-
rnethyl)methylamine, ultra pure, Merck, Federal Republic of Clermany) pH 7.8;
75 mM of
KCI, 2 mM of dithiothreitol, 5 mM of MgCl2; 0.05 % Nonidet P-40 (detergent;
Sigma,
Switzerland); 50 ~.g/ml of polyaderaylic acid (F'harmacia, Sweden); 1.6 p.g/ml
of dT(12-18)
TM
(Sigma, Switzerland). The mixture is filtered through a 0.45 a Acrodisc filter
(Gellman
Science Inc, Ann Arbor) and stored at -20°C. 0. I % (;v/v) [alpha-
32P]dTTP is added to
aliquots of that solution in order to achieve a final radioactive activity of
10 p.Ci/ml. 10 ltl
of the culture supernatant are transferred to a new 96-well microtitre plate
and. 30 ~1 of the
mentioned RT cocktail are added thereto. After mixing, the plate is incubated
for from 1.5
TM
to 3 hours at 37°C. 5 p.l of that reaction mixture are transferred to
Whatman DE81 paper
(Whatman). The dried filters are washed three times for 5 minutes with 300 mM
of
NaCI/25 mM of trisodium citrate and once with 95 °lo ethanol and again
air-dried. Eval-
r
nation is effected in a Matrix packard 9b-well counter (Packard). The ED90
values are
calculated and defined as the lowest concentration of the p~.rticular test
compound that
reduces the RT activity by 90 %'o in comparison with cell batches not treated
with the test
compound. The RT activity is a measure of the reproduction c~f HIV-1.
In that test, the campounds of the invention exhibit an ED90 of approximately
from 10-5
to 10-8M, preferably approximately from 5 x 10-7 to 5 x 10-BM.
In the groups of compounds of formula I mentioned below" it may be
advantageous, for
example in order to replace rather general definitions with more specific
definitions, to use
definitions of radicals from the above-mentioned general defrrritions or t:o
insert or omit
definitions from the other groups.
Preference is given to a corrrpcaund of formula 1 according tc~ claim 1
wherein
R 1 and R9 are each independently of the other hydrogen; lower alkanoyl" such
as formyl,
acetyl, propionyi, butyryl or pivaloyl, especially acetyl; aryl-tower
alkarroyl wherein aryl
is preferably as defined above under the general clef"initiorzs c~f ~ary~l-
lower alkanoyl and is
unsubstituted or substituted as defined them:, i.e. aryl k~as from ~ to 14
carbon atoms, as in
_6q_
phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or
fluorenyl, and
may be unsubstituted or especially mono- to tri-substituted by lower alkyl,
for example
methyl, ethyl or propyl, halo-lower alkyl, for example trifluoromethyl,
phenyl, 1- or
2-naphthyl, hydroxy, lower alkox~y, for example methoxy, carbamoyl-lower
alkoxy,
N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-lower
allcoxy,
amino, mono- or di-lower alkylamino, lower alkanoylamino, for example
pivaloylamino,
halogen, for example fluorine, chlorine or bromine, carboxy, lower
alkoxycarbonyl, such
as tent-butoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl,
such as
benzyloxycarbonyl, lower aLkanoyl, sulfo, lower alkylsulfonyl, for example
methyl-
sulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxyphosphoryl,
carbamoyl, mono- or di-lower alkylcarbamoyl, sulfamoyl, mono- or di-lower
alkylamino-
sulfonyl, nitro and/or by cyano, wherein phenyl may be present up to three
times, for
example in diphenyl-, dibenzyl- or triphenyl-lower alkanoyl, such as diphenyl-
, dibenzyl-
or triphenyl-acetyl, and wherein lower alkanoyl is unsubstituted or
substituted by carba-
rnoyl or by carbamoyl substituted at the nitrogen atom by one or two xadicals
selected
from lower alkyl, carboxy-lower alkyl, lower alkoxycarbonyl-lower alkyl, di-
lower alkyl-
amino-lower alkyl, aminocarboxy-lower alkyl, hydroxy-lower alkyl and di-lower
alkoxy-
lower alkyl, preferably as described under aryl-lower alkanoyl above in the
general defini-
tions, for example 4-chloro-, 4-methoxy- or 4-nitro-bt:nzoyl,
naphthylcarbonyl, such as a-
or 13-naphthylcarbonyl, or 1,8-naphthalene-dicarbonyl bonded to the amino
group via both
carbonyl groups, indenylcarbonyl, such as I-, 2- or 3-indenylcarbonyl,
indanylcarbonyl,
such as 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, such as 9-
phenanthrenylcarbonyl,
phenyl-lower alkanoyl, such as phenylacetyl or 3-phenylpropionyl, a-
naphthylacetyl,
13-naphthylacetyl, lower alkylphenylacetyl, such as 4-methylphenylacetyl,
lower alkoxy-
phenylacetyl, such as 4-methoxyphenylacetyl, 3-phenylpropionyl, 3-(p-
hydroxyphenyl)-
pxopionyl, diphenylacetyl, di(4-methoxyphenyl)acetyl, triphenylacetyl, 2,2-
dibenzylacetyl,
3-a- or 3-~i-naphthylpropionyl, phenyl-lower alkanoyl wherein the lower
alkanoyl radical
is substituted by carbamoyl, such as 2(R,S)-carbamoyl-3-phenylpropionyl, 3-
phenyl- or
3-a-naphthyl-2-carbamoylpropionyl, 3-phenyl- or 3-a-naphthyl-2-tert-
butylcarbamoyl-
propionyl, 3-phenyl- or 3-a-naphthyl-2-(2-
dimethylaminoethyl)carbamoylpropionyl,
3-a-naphthyl-2-(carboxy- or tert-butoxycarbonyl)methylcarbamoylpropionyl, 3-
phenyl- or
3-a-naphthyl-2-(3-hydroxy-2-propyl)carbamoylpropionyl, 3-phenyl- or 3-a-
naphthyl-2-
(2,2-dimethoxyethyl)-carbamoylpropionyl, 3-phenyl- or 3-a-naphthyl-2-(5-amino-
5-carboxypentyl)-carbamoylpropionyl, especially phenyl-lower alkanayl, such as
phenyl-
acetyl, or phenyl-lower alkanoyl wherein the lower alkanoyl radical is
substituted by carb-
amoyl, such as 2(R,S)-carbamoyl-3-phenylpropionyl; heterocyclyl-lower alkanoyl
that is
-65-
preferably as defined above for heteroaryl-lower alkanoyl R1, R2, Rg and R9,
especially
heterocyclyl-lower alkanoyl wherein lower alkanoyl is unsubstituted and
wherein hetero-
cyclyl is preferably a single or a double ring system having from 3 to 10 ring
atoms, is
bonded via a carbon atom or, especially, via a nitrogen atom, contains up to
three further
hetero atoms selected from oxygen, nitrogen, sulfur, selenium, and sulfur
linked to 1 or 2
oxygen atoms, and may be unsaturated or partially or fully saturated, for
example thienyl-,
furyl-, pyranyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, oxazolyl-, isoxazolyl-,
thiazolyl-,
furazanyl-, tetrazolyl-, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-,
azepinyl-, indolyl-,
benzimidazolyl-, 1H-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-,
quinazolinyl-,
cinnolyl-, purinyl-, pteridinyl-, naphthyridinyl-, 4H-quinolizinyl-, 3,1-
benzofuranyl-,
4,1-benzoxazinyl-, 4,1-benzothiazinyl-, cyclohexa[b]pyrrolyl-,
cyclohepta[b]pyrrolyl-,
cyclohexa[d]pyrazolyl-, cyclohexa[b]pyzidyl-, cyclohexa[b]pyrazinyl-,
cyclohexa[b]~-
pyrimidinyl-, cyclohexa[b]-1,4-oxazinyl-, cyclohexa[b]-1,4-thiazinyl-,
pyrrolidinyl-,
pyrrolinyl-, irnidazolidyl-, 2-imidazolinyl-, 2,3-dihydropyridyl-, piperidyl-,
piperazinyl-,
2,3,5,6-tetrahydropyrazinyl-, morpholinyl-, thiomorpholinyl-, S,S-dioxo-
thiomorpholinyl-,
indolinyl-, isoindolinyl-, 4,5,6,7-tetrahydroindolyl-, 1,2,3,4-
tetrahydroquinolyl-, 1,2,3,4-te-
trahydroisoquinolyl-, chromanyl-, thiochromanyl-, 1,2,3,4-tetrahydro-3,1-
benzodiazinyl-,
3,4-dihydro-3H-4,1-benzoxazinyl- or 3,4-dihydro-3H-4,1-benzothiazinyl-lower
alkanoyl,
the mentioned heterocyclyl radicals being unsubstitutf;d or substituted by
lower alkyl, for
example rnetlryl, phenyl, 1- or 2-naphthyl, phenyl-lower alkyl, for example
benzyl,
hydroxy-lower alkyl, for example hydroxymethyl or 2-hydroxyethyl, lower alkoxy-
lower
alkyl, for example methoxymethyl or 2-methoxyethyl, phenoxy- or naphthyloxy-
lower
alkyl, for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl-lower
alkoxy- or
naphthyl-lower alkoxy-lower alkyl, for example benzyloxy-lower alkyl, lower
alkanoyl-
oxy-lower alkyl, for example acetoxymethyl, phenyl- or naphthyl-lower
alkanoyloxy-
lower alkyl, for example benzoyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxy-
methyl,
-2-ethyl or -2-(2,2-dimethylethyl), lower alkoxycarbonyloxy-lower alkyl, for
example
tent-butoxycarbonyloxy-lower alkyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxy-
carbonyloxy-lower alkyl, for example 2-benzyloxycarbonyiaxyethyl or 9-
fluorenyl-
methoxycarbonyloxyethyl, amino-lower alkyl, for example aminomethyl, 2-
aminoethyl or
2-aminopropyl, carboxy-lower alkyl, for example carboxymethyl or 2-
caxboxyethyl,
hydroxy, lower alkoxy, for example methoxy or ethaxy, phenyl- or naphthyl-
lower atkoxy,
for example benzyloxy or 1- or 2-naphthyloxy, amino, lower alkylamino, for
example
methyl-, ethyl- or tent-butyl-amino, di-lower alkylamino, for example dimethyl-
or
diethyl-amino, carboxy, lower alkoxycarbonyl, for example methoxy-, isopropoxy-
,
sec-butoxy- or tert-butoxy-carbonyl, phenyl- or naphthyl-lower alkoxycarbonyl,
for
zz7~
-66-
example benzyloxycarbonyl, halogen, for example fluorine, chlorine, bromine
or.iodine,
especially chlorine or bromine, lower alkanoyl, for example acetyl or
pivaloyl, lower
alkylsulfonyl, for example methyl- or ethyl-sulfonyl, phosphono, hydroxy-lower
alkoxy-'
phosphoryl or dialkoxyphosphoryl, for example dimethoxy- or diethoxy-
phosphoryl,
carbamoyl, mono- or di-lower alkylcarbamoyl, for example N-methylcarbamoyl,
N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, hydroxy- or carboxy-lower alkyl-
carbamoyl, for example.hydroxy- or carboxy-methylcarbamoyl or hydroxy- or
carboxy-
ethylcarbamoyl, sulfamoyl, nitro, oxo and/or by cyano, with heterocyclyl-lower
alkanoyl
being selected especially from pyrrolylcarbonyl that is unsubstituted or
substituted by
lower alkyl or by phenyl, for example 2- or 3-pyrrolylcarbonyl, 4- or
5-methylpyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl,
thienylcarbonyl, such as
2-thienylcarbonyl, furylcarbonyl, such as 2-furylcarbonyl, pyridylcarbonyl,
such as 2-, 3-
or 4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, indolylcarbonyl that is
unsubstituted or
substituted by lower allcyl, such as methyl, phenyl-lower alkyl, such as
benzyl, lower
alkoxy, such as methoxy, phenyl-lower alkoxy, such as benzyloxy, or by
halogen, such as
chlorine, such as 2-, 3- or 5-indolylcarbonyl, 1-methyl-, 5-methyl-, 5-methoxy-
,
5-benzyloxy-, 5-chloro- or 4,5-dimethyl-indolyl-2-carbonyl, 1-benzyl-indolyl-2-
or
-3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, unsubstituted or hydroxy-
substituted
quinolyl-lower alkanoyl, for example quinolylcarbonyl, such as 2-, 3- or 4-
quinolyl-
carbonyl or 4-hydroxyquinolyl-2-carbonyl, unsubstituted or hydroxy-substituted
isoquin-
olylcarbonyl, such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-
dihydroisoquinolyl-
3-carbonyl, 2-quinoxalinylcarbonyl, 2-(3,1-benzofuranyl)carbonyl,
cyclohepta[b]-
pyrrolyl-5-carbonyl, 3-chromanylcarbonyl, 3-thiochrornanylcarbonyl,
pyrrolidinyl-3-carb-
onyl, hydroxypyrrolidinylcarbonyl, such as 3- or 4-hydroxypyrrolidinyl-2-
carbonyl, oxo-
pyrrolidinylcarbonyl, such as 5-oxopyrrolidinyl-2-carbonyl, piperidylcarbonyl,
such as
piperidinocarbonyl or 2-, 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such
as pyrazin-1-
ylcarbonyl, piperazinylcarbonyl, such as piperazin-1-ylcarbonyl, morpholinyl-
lower
alkanayl, for example morpholinylcarbonyl, such as morpholinocarbonyl,
thiomorpho-
linyl-lower alkanoyl, for example thiomorpholinylcarbonyl, such as
thiomorpholino-
carbonyl, S,S-dioxothiomorpholinylcarbonyl, such as S,S-
dioxothiomorpholinocarbonyl,
indolinylcarbonyl, such as 2- or 3-indolinylcarbonyl, 1,2,3,4-
tetrahydroquinolylcarbonyl,
such as 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-
tetrahydroisoquinolyl-
carbonyl, such as 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl or 1-
oxo-1,2,3,4-
tetrahydroisoquinolyl-3-carbonyl, tetrazolyl-lower alkanoyl, such as 3-
(tetrazol-1-yl)-
propionyl, and pyridyl-lower alkanoyl, for example pyridylacetyl, such as 2-,
3- or
4-pyridylacetyl, heterocyclyl-lower alkanoyl being selected more especially
from rnorpho-
27
lino-lower alkanoyl, such as morpholinocarbonyl, thiomorpholino-lower
alkanoyl, such as
thiomorpholinocarbonyl, pyridyl-lower alkanoyl, such as 2-, 3- or 4-
pyridylacetyl, quino-
linyl-lower alkanoyl, such as quinoline-2_carbonyl, and tetrazolyl-lower
alkanoyl, such a's
3-tetrazol-1-ylpropionyl; amino-lower alkanoyl substituted at the amino
nitrogen atom by .
heterocyclyl-lower alkanoyl wherein heterocyclyl-lower alkanoyl is as defined
above for
heterocyclyl-lower alkanoyl Rl, R2, Rg or R9, preferably as defined for
heterocyclyl-
lower alkanoyl R1 and R9, especially amino-lower alkanoyl substituted at the
amino
nitrogen atom by N-morpholino- or by N-thiomorpholino-carbonyl, more
especially
N-morpholino- or N-thiomorpholino-carbonylamino-lower alkanoyl, such as N-
morpho-
lino- or N-thiomorpholino-carbonylamino-acetyl; halo-lower alkanoyl containing
up to
three halogen atoms, especially a-haloacetyl, such as a-fluoro-, a-chloro-, a-
bromo-,
a-iodo-, a,a,a-trifluoro- or a,a,a-trichloro-acetyl, or halopropionyl, such as
B-chloro- or
Li-bromo-propionyl, especially trifluoroacetyl; (N-heterocyclyl-lower
alkylcarbamoyl)-
lower alkanoyl wherein heterocyclyl is preferably selected from pyrrolyl,
furyl, thienyl,
imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl,
indolyl,
quinolyl, isoquinolyl, quinoxalinyl, b-carbolinyl and a benzo-fused,
cyclopenta-, cyclo-
hexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or partially
saturated, from morpholinyl and from thiomorpholinyl, especially 2-(N-
morpholino-lower
alkylcarbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(~;-morpholinoethyl)-
carbamoyl)-
3-methylbutyryl, or 2-(N-(pyridyl-lower alkyl)-carbaraoyl)-lower alkanoyl,
such as
~(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-3-methylbutyryl; lower alkoxycarbonyl,
especially methoxy-, ethoxy-, isopropoxy-, isobutoxy- or tent-lower alkoxy-
caxbonyl, for
example methoxycarbonyl, tert-butoxycarbonyl or isobutoxycarbonyl; aryl-lower
alkoxy-
carbonyl wherein aryl preferably has from 6 to 14 carbon atoms and is, for
example,
phenyl, biphenylyl, 1- or 2-naphthyl, fluorenyl, or phenyl that is mono- or
poly-substituted
by lower alkyl, for example methyl or tert-butyl, hydroxy, lower allcoxy, for
example
methoxy, ethoxy or tert-butoxy, halogen, for example chlorine or bromine,
and/or by vitro,
for example phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, 4-
methoxybenzyl-
oxycarbonyl, 4-nitrobenzyloxycarbonyl or fluorenyl-lower alkoxycarbonyl, such
as
9-fluorenylmethoxycarbonyl, especially phenyl-lower alkoxycarbonyl, such as
benzyloxy- .
carbonyl; heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is preferably
selected
from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl,
pyridyl, pyrazinyl,
pyrimidinyl, indolyl, quinolyl, isaquinolyl, quinoxalinyl,13-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals,
which may also
be fully or partially saturated, and from morpholinyl and from thiomorpholinyl
and is
unsubstituted or substituted, especially by lower alkyl, such as by methyl,
for example
_68_
1-methylpyrrolidin-2-ylmethoxycarbonyl, 2-furylmethoxycarbonyl, 2-
tetrahydrofuranyl-
lower alkoxycarbonyl, such as 2-tetrahydrofurylmethoxycarbonyl, 1-methyl-2-
piperidyl-
methoxycarbonyl or 2-morpholinoethoxycarbonyl, or 2-, 3- or 4-
pyridylmethoxycaxbony~,
especially tetrahydrofuranyl-lower alkoxycarbonyl, such as 2(R,S)-
tetrahydrofuranyl-
methoxycarbonyl; lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl,
such as
methylsulfonyl; heterocyclylsulfonyl wherein heterocyclyl is preferably
selected from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl, pyri-
midinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,13-carbolinyl and a
benzo-fused,
cyclopenta-, cyclahexa- or cyclohepta-fused derivative of those radicals,
which may also
be fully or partially satuxated, from morpholinyl and from thiomorpholinyl and
may be
unsubstituted or substituted, especially by lower alkyl, such as methyl, such
as morpho-
linosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-
methylpiperazinylsulfonyl or
piperazinosulfonyl; N-heterocyclyl-lower alkyl-N-lower alkylcarbamoyl that is
as defined
above under unsubstituted or substituted N-alkyl- or N,N-dialkyl-carbamoyl Rl,
R2, Rg or
R~, wherein heterocyclyl is preferably selected from thienyl, furyl, pyranyl,
pyrrolyl,
imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, furazanyl, pyridyl,
pyrazinyl,
pyrimidinyl, pyridazinyl, azepinyl, indolyl, benzimidazolyl, 1H-indazolyl,
quinolyl, iso-
quinolyl, quinoxalinyl, quinazolinyl, cinnolyl, purinyl, pteridinyl,
naphthyridinyl,
4H-quinolizinyl, 3,1-benzofuranyl, benz[e]indolyl, 4,1-benzoxazinyl, 4,1-
benzothiazinyl,
carbazolyl, (3-carbolinyl, phenazinyl, phenanthridyl, acridyl, phenoxazinyl,
phenothiazinyl,
1-azaacenaphthenyl, cyclohexa[b]pyrrolyl, cyclohept<i[b]pyrrolyl,
cyclohexa[d]pyrazolyl,
cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl, cyclohexa[b]pyrimidinyl,
cyclohexa[b]-1,4-
oxazinyl, cyclohexa[b]-1,4-thiazinyl, pyrrolidinyl, pysrolinyl,
imidazolidinyl, 2-imidazo-
linyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6-
tetrahydropyrazinyl, morpholinyl,
thiomorpholinyl, S,S-dioxothiomorpholinyl, indolinyl, isoindolinyl, 4,5,6,7-
tetrahydro-
indolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-tetrahydroisoquinolyl, chromanyl,
thiochrom-
anyl, 1,2,3,4-tetrahydro-3,1-benzodiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl,
3,4-di-
hydro-3H-4,1-benzothiazinyl, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl and 5,6-
dihydro-
phenanthridinyl, the mentioned radicals being unsubstituted or substituted by
lower alkyl,
for example methyl, phenyl, 1- or 2-naphthyl, phenyl-lower alkyl, for example
benzyl,
hydroxy-lower alkyl, for example hydroxymethyl or 2-hydroxyethyl, lower
allcoxy-lower
alkyl, for example methoxymethyl or 2-methoxyethyl, phenoxy- or naphthyloxy-
lower
alkyl, for example 2-phenoxyethyl, 1- or 2-naphthyloxymethyl, phenyl-lower
alkoxy- or
naphthyl-lower alkoxy-lower alkyl, for example benzyloxy-lower alkyl, lower
alkanoyl-
oxy-lower alkyl, for example acetoxymethyl, phenyl- or naphthyl-lower
allcanoyloxy-
lower alkyl, for example benzoyloxy-, phenylacetoxy- or 1- or 2-naphthoyloxy-
methyl,
-69-
-2-ethyl or -2-(2,2-dimethylethyl), lower alkoxycarbonyloxy-lawer alkyl, for
exarrtple
tert-butoxycarbonyloxy-lower alkyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxy-
carbonyloxy-lower alkyl, for example 2-benzyloxycarbonyloxyethyl or 9-
fluorenyl-
methoxycarbonyloxyethyl, amino-lower alkyl, for example aminomethyl, 2-
aminoethyl or
2-aminopropyl, carboxy-lower alkyl, for example carboxymethyl or 2-
carboxyethyl,
hydroxy, lower alkoxy, for example methoxy or ethoxy, phenyl- or naphthyl-
lower alkoxy,
for example benzyloxy or 1- or 2-naphthylmethoxy, amino, lower alkylamino, for
example
methyl-, ethyl- or tert-butyl-amino, di-lower alkylamino, for example dimethyl-
or
diethyl-amino, carboxy, lower alkoxycarbonyl, for example methoxy-, isopropoxy-
,
sec-butoxy- or tert-butoxy-carbonyl, phenyl- or naphthyl-lower alkaxycarbonyl,
for
example benzyloxycarbonyl, halogen, for example fluorine, chlorine, bromine or
iodine,
especially Chlorine or bromine, lower alkanoyl, for example acetyl or
pivalayl, lower
alkylsulfonyl, for example methyl- or ethyl-sulfonyl, phosphono, hydroxy-lower
alkoxy-
phosphoryl or dialkoxyphosphoryl, for example dimethoxy- or diethoxy-
phosphoryl,
carbatnoyl, mono- or di-lowex alkylcarbamoyl, for example N-methylcarbamoyl,
N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, hydroxy- or carboxy-lower alkyl-
carbamoyl, for example hydroxy- or carboxy-methylcarbamoyl or hydroxy- or
carboxy-
ethylcarbamoyl, sulfamoyl, vitro, oxo and/or by cyano, and is especially
pyridyl, such as
2-, 3- or 4-pyridyl, more especially N-pyridyl-lower alkyl-N-lower
alkylcarbamoyl, such
as N-(2-,3- or 4-pyridylmethyl)-N-methylcarbamoyl; or an acyl radical of an
amino acid
the amino function of which is free or acylated by one: of the other radicals
mentioned
hitherto for R1 and Rg, the amino acid radicals, each ;independently of the
athers,
preferably being as defined fox unsubstituted or substituted amino acids as
acyl R1, R2, Rg
and Rg, especially the radical of a natural a-amino acid having the L-
configuration, such
as those normally occurring in proteins, or an epimer of such an amino acid,
i.e. having the
unnatural D-configuration, or the D,L-isomeric mixture thereof, a homologue of
such an
amino acid, for example wherein the amino acid side Chain has bean lengthened
or
shortened by one or two methylene groups, wherein the amino group is in the (3-
position
and/or wherein a methyl group has been replaced by hydrogen, a substituted
aromatic
amino acid wherein the aromatic radical has from 6 to 14 carbon atoms, for
example a
substituted phenylalanine or phenylglycine wherein phenyl may be mono- or poly-
substituted by lower alkyl, for example methyl, hydroxy, lower alkoxy, for
example
methoxy, lower alkanoyloxy, for example acetoxy, amino, lower alkylamino, for
example
methylamino, di-lower alkylamino, for example dimethylamino, lower
alkanoylamino, for
example acetylamino or pivaloylamino, lower alkoxycarbonylamino, for example
tert-butoxycarbonylamino, arylmethoxycarbonylamino wherein aryl preferably has
from 6
_7p_
to 14 carbon atoms, for example benzyloxycarbonylamino or 9-fluorenylmethoxy-
carbonylamino, halogen, for example fluorine, chlorine, bromine or iodine,
carboxy and/or
by nitro, a benzo-fused phenylalanine or phenylglycine, such as a-
naphthylalanine, or a
hydrogenated phenylalanine or phenylglycine, such as a cyclohexylalanine or
cyclohexyl-
glycine, especially the radical, bonded via a carboxy group, of an amino acid
selected
from glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), norvaline (a-
amino-
valer~ic acid), leucine (I~-Leu-OH), isoleucine (H-Ile-OH), norleucine (a-
aminohexanoic
acid, H-Nle-OH), serine (H-Ser-OH), homosezine (a-amino-y-hydroxybutyric
acid),
threonine (H-Thr-OH), methionine (I-I-lVfet-OH), cysteine (H-Cys-OH), proline
(H-Pro-OH), trans-3- and trans-4-hydroxyproline, phenylalanine (H-Phe-OH),
tyrosine
(H-Tyr-OH), 4-aminophenylalanine, 4-chlorophenylalanine, 4-
carboxyphenylalanine,
B-phenylserine (B-hydroxyphenylalanine), phenylglycine, a-naphthylalanine (H-
Nal-OH),
cyclohexylalanine (H-Cha-OH), cyclohexylglycine, tryptophan (H-Trp-OH),
indoline-2-
caxboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic
acid
(I3-Asp-OH), asparagine (H-Asn-OI-I), aminomalonic acid, aminomalonic acid
monoamide, glutarnic acid (H-Glu-OH), glutamine (I-I-Gln-OH), histidine (I-I-
His-OH),
arginine (H-Arg-OI-I), lysine (H-Lys-OH), b-hydroxylysine, ornithine (a,b-
diaminovaleric
acid), 3-aminopropanoic acid, a,y-diaminobutyric acid and a,B-diaminopropionic
acid,
more especially the radical of an amino acid selected from valine, alanine,
leucine,
isoleucine, glycine, glutamic acid and asparagine, whf;rein each of the
mentioned amino
acids (with the exception of glycine) may be in the I~-, L- or (D,L)-form,
preferably (with
the exception of Val, which may also be in the (D)- or (D,L)-form) in the L-
form, the
a-amino group is unsubstituted or N-acylated by one of the radicals mentioned
above fox
R~ and R9, especially by lower alkanoyl, phenyl-lower alkanoyl, such as
phenylacetyl,
phenyl-lower alkanoyl wherein the lower alkanoyl radical is substituted by
carbamoyl,
such as 2(R,S)-carbamoyl-3-phenylpropionyl, morpholino-lower allcanoyl, such
as
morpholinocarbonyl, thiomorpholino-lower allcanoyl, such as
thiomorpholinacarbonyl,
pyridyl-lower alkanoyl, such as 2-, 3- or 4-pyridylacetyl, quinolinyl-lower
alkanoyl, such
as quinoline-2-carbonyl, tetrazolyl-lower alkanoyl, such as 3-tetrazol-1-
ylpropionyl,
amino-lower alkanoyl substituted at the amino nitrogen atom by N-morpholino-
or
N-thiomorpholino-carbonyl, for example N-morpholino- or N-thiomozpholino-
carbonyl-
amino-lower alkanoyl, such as N-morpholino- or N-thiomorpholino-
carbonylaminoacetyl,
halo-lower alkanoyl containing up to three halogen atoms, for example a-
haloacetyl, such
as a-fluoro-, a-chloro-, a-bromo- a-iodo-, a,a,a-trifluoro- or a,a,a-trichloro-
acetyl, or
halopropionyl, such as ~-chloro- or (3-bramo-propionyl, especially tr-
ifluoroacetyl,
2-(N-morpholino-lower alkylcarbamoyl)-lower alkanoyl, such as
0'~
-
2(R,S)-(N-(2-morpholinoethyl)-carbamoyl-3-methylbutyryl, 2-(N-(pyridyl-lower
alkyl)-carbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(2-pyridylmethyl)-
carbamoyl)-lower
alkanoyl, lower alkoxycarbonyl, phenyl-lower alkoxycarbonyl, tetrahydrofmanyl-
lower
alkoxycarbonyl, such as 2(R,S)-tetrahydrofuranylmethoxycarbonyl, lower
alkylsulfonyl,
morpholinosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl,
4-methylpiperazinylsulfonyl or piperazinosulfonyl or N-pyridyl-lower alkyl-N-
lower
alkylcarbamoyl, such as. N-(2-, 3- or 4-pyridylmethyl)-N-methylcarbamoyl,
special prefer-
ence being given to N-morpholinocarbonyl-glycine, N-(N-(2-, ~- or 4-
pyridyl)methyl-
N-methylaminocarbonyl)-glycine, valine, N-(trifluoroacetyl)-valine, N-
phenylacetyl-
valine, N-(2- or 3-pyridyl)-acetyl-valine, N-acetyl-valine, N-(2-carbamoyl-3-
phenyl-
propionyl)-valine, N-(2(R,S)-carbamoyl-3-phenylpropionyl)-valine, N-(~- or 3-
pyridyl-
acetyl)-valine, N-2-tetrahydrofurylmethoxycarbonyl-valine, N-(3-(tetrazol-1-
yl)-
propionyl)-valine, N-(quinoline-2-carbonyl)-valine, N-methoxycarbonyl-valine,
N-isobutoxycarbonyl-valine, N-tert-butoxycarbonyl-valine, N-benzyloxycarbonyl-
valine,
N-(mozpholinocarbonyl)-valine, N-(thiomorpholinocarbonyl)-valine, N-(S,S-
dioxothio-
morpholinocarbonyl)-valine, N-(N-2-pyridylmethyl-N-methylaminocarbonyl)-
valine,
N-morpholinocarbonylaminoacetyl-valine, N-methylsulfonyl-valine, N-acetyl-
isoleucine,
N-,propionyl-isoleucine, N-(benzyloxycarbonyl)-isoleucine, N-benzyloxycarbonyl-
glutamic acid, asparagine, N-benzyloxycarbonyl-asparagine or quinoline-2-
carbonyl-
asparagine, the mentioned amino acid radicals preferably being in the (L)- or
(D,L)-form,
and in the case of valine also in the (D)-form, with the proviso that not more
than one of
the two radicals Rl and R9 rnay be hydrogen,
R2, R~, R6 and Rs are hydrogen,
R~ is lower alkyl, such as isobutyl or n-butyl; cycloalkyl-lower alkyl as
defined above for
cycloalkyl-lower alkyl R3, R4 and R~, wherein, preferably, cycloalkyl has from
3 to 7
carbon atoms and is unsubstituted or mono- to tri-substituted by lower alkyl,
such as
isopropyl, halo-lower alkyl, such as trifluoromethyl, hydroxy, lower alkoxy,
carbamoyl-
lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower
alkylcarbamoyl-
lower alkoxy, amino, mono- or di-lower alkylamino, halogen, such as fluorine,
chlorine or
bromine, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower
alkoxy-
carbonyl, lower alkanoyl, lower alkylsulfonyl, for example methylsulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono-
or di-
lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro
and/or by
cyano and is bonded, preferably terminally, to lower alkyl, especially methyl,
ethyl,
n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as cyclobutyl-,
cyclopentyl-,
cyclohexyl- or cycloheptyl-lower alkyl, such as -methyl or -ethyl, especially
cyclohexyl-
o~z~~
-72-
lower alkyl, most especially cyclohexylmethyl; or is aryl-lower alkyl that is
preferably as
defined under aryl-lower alkyl R3, R4 and R~, wherein aryl contains especially
from 6 to
14 carbon atoms, such as in phenyl, indenyl, indanyl, naphthyl, anthryl,
phenanthryl,
acenaphthyl or fluorenyl, and is unsubstituted or substituted, and may be,
especially,
mono- to tri-substituted by lower alkyl, for example methyl, ethyl or
isopropyl, halo-lower
alkyl, such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy, lower
alkoxy, for
example methoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy
or
N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
lower
alkanoylamino, for example pivaloylamino, halogen, for example fluorine or
chlorine,
carboxy, lower alkoxycarbonyl, benzyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl,
lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower
alkoxyphosphoryl
or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl,
sulfamoyl,
mono- or di-lower alkylsulfamoyl, vitro and/or by cyano, wherein phenyl may be
present
up to three times, such as in diphenyl-, dibenzyl- or triphenyl-lower alkyl,
for example
diphenyl-, dibenzyl- or triphenyl-2-ethyl, especially phenyl-lower alkyl that
is
unsubstituted or substituted by the mentioned substituents, especially benzyl,
2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano-, 4-methoxy- ar 4-hydroxy-
benzyl,
RS is hydroxy, and
R~ is unsubstituted or substituted lower alkyl, preferably unsubstituted or
substituted as
described above for unsubstituted or substituted alkyl R3, R~ or R~,
especially lawer alkyl,
more especially isobutyl or n-butyl, cycloalkyl-lower alkyl, as last described
for cyclo-
alkyl-lower alkyl R3, especially cyclohexyl-lower alkyl, such as
cyclohexylmethyl, or
aryl-lower alkyl, as last described for aryl-lower alkyl R3, especially phenyl-
lower alkyl
that is unsubstituted or substituted by the mentioned substituents, such as
benzyl,
2-phenylethyl, 3-phenylpropyl, 4-fluoro-, 4-cyano-, 4-methoxy- or 4-hydroxy-
benzyl,
or a salt thereof where a salt-forming group is present.
Of the last-mentioned compounds of formula I, special preference is given to
those
wherein
Rt and R9 are each independently of the other hydrogen; lower alkanoyl; aryl-
lower
alkanoyl wherein the lower alkanoyl radical is unsubstituted or substituted by
carbamoyl
or by carbamoyl substituted at the nitrogen atom by one or two radicals
selected from
lover alkyl, carboxy-lower alkyl, lower allcoxycarbonyl-lower alkyl, di-lower
alkyl-
amino-lower alkyl, aminocarboxy-lower alkyl, hydroxy-lower alkyl or by di-
lower
alkoxy-lower alkyl, and wherein azyl contains from 6 to 14 carbon atoms;
heterocyclyl-
-73-
lower alkanoyl wherein heterocyclyl contains from 3 to 10 ring atoms and up to
4 hetero
atoms selected from O, N, S, Se, and S linked to I or 2 oxygen atoms (S=O,
O=S=O);
halo-lower alkanoyl having from 1 to 3 halogen atoms; N-heterocyclyl-lower
alkyl-
carbamoyl-lower alkanoyl; lower alkoxycarbonyl; aryl-lower alkoxycarbonyl
wherein aryl
contains from 6 to I4 carbon atoms; heterocyclyl-lower alkoxycarbonyl wherein
hetero-
cyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,
(3-carbolinyl
and a benzo-fused, cyelopenta-, cyclohexa- or cyclohepta-fused derivative of
those
radicals, which may also be fully or partially saturated;
lower alkylsulfonyl; N-(heterocyclyl-lower alkyl)-carbamoyl-N-lower
alkylcarbamoyl; or
the radical, bonded via the carboxy group, of an amino acid selected from
glycine, alanine,
valine, norvaline, leucine, isoleucine, norleucine, serine, homoserine,
threonine,
methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline,
phenylalanine,
tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine,
(3-hydroxyphenylalanine, phenylglycine, a-naphthylalanine, cyclohexylalanine,
cyclo-
hexylglycine, tryptophan, aspartic acid, asparagine, aminomalonic acid,
aminomalonic
acid monoamide, glutamic acid, glutamine, histidine, arginine, lysine, 8-
hydroxylysine,
ornithine, a,y-diaminobutyric acid or a,~3-diaminopropionic acid, the amino
acid radicals
being unsubstituted or substituted by one of the mentioned radicals Rt or R9
with the
exception of the radical of one of the amino acids itself;
R2, R4, R6 and R9 are hydrogen,
R3 is cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms,
or is aryl-
lower alkyl wherein aryl has from 6 to 14 carbon atoms,
RS is hydroxy, and
R~ is lower alkyl, cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7
carbon
atoms, or is aryl-lower alkyl wherein aryl has from 6 to I4 carbon atoms,
and salts of such compounds having salt-forming groups, the general
expressions and
definitions preferably having the meanings mentioned as preferred in the
previous para-
graph.
Preference is likewise given to the compounds mentioned in the penultimate
section above
in which the substituents have all the meanings mentioned with the exception
of morpho-
linosulfonyl, thiomorpholinosulfonyl, piperidinosulfonyl, 4-
methylpiperazinylsulfonyl or
piperazinosulfonyl as Rl and/or R9.
Preference is given also to the compounds of formula I wherein Rt and R9 are
each
-74-
independently of the other .
- hydrogen,
- lower alkoxycarbonyl,
- 2-halo-lower alkoxycarbonyl,
- aryloxycarbonyl wherein aryl has from 6 to 14 carbon atoms,
- aryl-lower alkoxycarbonyl wherein aryl has from 6 to 14 carbon atoms,
- heterocyclyl-lower alkoxycarbonyl wherein heterocyclyl is selected from
pyrrolyl, furyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, indolyl,
quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a benzo-fused,
cyclopenta-, cyclo-
hexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or partially
saturated,
- 2-tri-lower alkylsilyl-lower alkoxycarbonyl,
- 2-triarylsilyl-lower alkoxycarbonyl wherein aryl is phenyl or 1- or 2-
naphthyl,
- the radical, bonded via the carboxy group, of an amino acid selected from
glycine,
alanine, valine, norvaline, leucine, isoleucine, norleucine, serine,
homoserine, threonine,
methionine, cysteine, proline, trans-3- and trans-4-hydroxyproline,
phenylalanine,
tyrosine, 4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine,
(3-phenylserine, phenylglycine, a-naphthylalanine, cyclohexylalanine,
cyclohexylglycine,
tryptophan, indoline-2-carboxylic acid, 1,2,3,4-tetrahydroisoquinoline-3-
carboxylic acid,
aspartic acid, asparagine, aminomalonic acid, aminornalonic acid monoamide,
glut<lmic
acid, glutamine, histidine, arginine, lysine, S-hydroxy'.lysine, ornithine,
a,y-diaminobutyric
acid and a,~i-diaminopropionic acid, it being possible for each of those amino
acids to be
in the D-, L- or (D,L)-form, preferably in the L-form, and wherein
the a-amino group may be unsubstituted or mono- or di-N-alkylated by lower
alkyl, by
amino-lower alkyl, by phenyl- or naphthyl-amino-lower alkyl, or by
piperazinylcarbonyl-
lower alkyl substituted at the nitrogen atom by lower alkyl, or may be N-
acylated by lower
alkanoyl; by aryl-lower alkanoyl wherein aryl is selected from phenyl,
indenyl, indanyl,
naphthyl, anthryl, phenanthryl, acenaphthyl and fluorenyl and may be
unsubstituted or
mono- to tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-
naphthyl,
hydroxy, lower alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower
alkoxy or
N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
lower
alkanoylamino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or
fluorenyl-
lower alkoxycarbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono,
hydroxy-
lower alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-
lower
alkylcarbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitro and/or
by cyano,
wherein phenyl may be present up to three times, and wherein lower alkanoyl
may be
2~°~~~
-75-
unsubstituted or substituted by lower alkyl, heterocyclyl selected from
pyrrolyl, furyl,
thienyl, imidazolyl, pyxazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, indolyl,
quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a benzo-, cyclopenta-,
Cyclohexa- oz
cyclohepta-fused derivative of those radicals, which may also be fully or
partially
sari~rated, hydroxy, lower allcoxy, lower alkanoyloxy, acetoacetoxy, amino- or
benzyloxy-
carbonylamino-lower aikanoyloxy, aryl-lower alkanoyloxy wherein aryl has from
6 to 10
carbon atoms, lower alkoxycarbonyloxy, mono- or di-lower
alkylaminocarbonyloxy,
aryloxycarbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower
alkoxy-
carbonyloxy wherein aryl has from 6 to 14 carbon atoms, sulfonyloxy, lower
alkyl-
sulfonyloxy, phenylsulfonyloxy, 2- or 4-toluenesulfonyloxy or 1- or 2-
naphthylsulfonyl-
oxy, carboxy, esterified carboxy selected from lower alkoxycarbonyl,
aryloxycarbonyl
wherein aryl has from 6 to 10 carbon atoms, aryl-lower alkoxycarbonyl wherein
aryl has
from 6 to 12 carbon atoms, lower alkanoyl, lower alkylsulfonyl, hydroxy-lower
alkoxy-
phosphoryl and di-lower alkoxyphosphoryl, carbamoyl, carbamoyl substituted by
one or
two radicals selected from lower alkyl, carboxy-lower alkyl, lower
alkoxycarbonyl-lower
alkyl, di-lower alkylamino-lower alkyl, arninocarbox;y-lower alkyl, hydroxy-
lower alkyl
and di-lower alkoxy-lower alkyl or carbamoyl substituted by one radical
selected from
ethylene, trimethylene, tetramethylene and pentamethylene, in which a carbon
atom may
have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted by
oxygen and which may be unsaturated, and also sulfa.moyl, phosphono,
benzofuranyl, oxo
and/or by cyano and is branched or unbranched; by heterocyclyl-lower alkanoyl
selected
from thienyl-, furyl-, pyranyl-, pyrrolyl-, imidazolyl-, pyrazolyl-, oxazolyl-
, isoxazolyl-,
thiazolyl-, furazanyl, pyridyl-, pyrazinyl-, pyrimidinyl-, pyridazinyl-,
azepinyl-, indolyl-,
benzirnidazolyl-, 1H-indazolyl-, quinolyl-, isoquinolyl-, quinoxalinyl-,
quinazolinyl-
cinnolyl-, purinyl-, pteridinyl-, naphthyridinyl-, 4H-quinolizinyl-, 3,I-
benzofuranyl-, benz-
[e]indolyl-, 4,1-benzoxazinyl-, 4,1-benzothiazinyl-, carbazolyl-, a-carbolinyl-
, phen-
azinyl-, phenanthridyl-, acridyl-, phenoxazinyl-, phenothiazinyl-, 1-
azaacenaphthenyl-,
cyclohexa[b]pyrrolyl-,cyclohepta[b]pyrrolyl-, cyclohexa[d]pyrazolyl-,
cyclohexa[b]-
pyridyl-, cyclohexa[b]pyrazinyl-, cyclohexa[b]pyrimidinyl-, cyclohexa[b]-1,4-
oxazinyl-,
cyclohexa[b]-1,4-thiazinyl-, pyrolidinyl-, pyrrolinyl-, imidazolidinyl-, 2-
imidazolinyl-,
2,3-dihydropyridyl-, piperidyl-, piperazinyl-, 2,3,5,6-tetrahydropyrazinyl-,
morpholinyl-,
thiomorpholinyl-, S,S-dioxothiomorpholinyl-, indolinyl-, isoindolinyl-,
4,5,6,7-tetxahydro-
indolyl-, 1,2,3,4-tetrahydroquinolyl-, 1,2,3,4-tetrahydroisoquinolyl-, chroman-
, thio-
chroman-, 1,2,3,4-tetrahydro-3,1-benzodiazinyl-, 3,4-dihydro-3H-4,1-
benzoxazinyl-,
3,4-dihydro-3H-4,1-benzothiazinyl-, 2,3,4,5-tetrahydro-1H-5,1-benzazepinyl-
and
5,6-dihydrophenanthridinyl-lower alkanoyl, the mentioned heterocyclyl radicals
being
20~27~5
unsubstituted or substituted by lower alkyl, phenyl, 1- or 2-naphthyl, phenyl-
lower alkyl,
hydroxy-lower alkyl, lower alkoxy-lower alkyl, phenoxy- or naphthyloxy-lower
alkyl,
phenyl-lower alkoxy- or naphthyl-lower alkoxy-lower alkyl, lower alkanoyloxy-
lower
alkyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, lower
alkoxycarbonyloxy-lower
alkyl, phenyl-, naphthyl- or fluorenyl-lower allcoxycarbonyloxy-lower alkyl,
amino-lower
alkyl, carboxy-lower alkyl, hydroxy, lower alkoxy, phenyl- or naphthyl-lower
alkoxy,
amino, lower alkylamino, di-lower alkylamino, carboxy, lower alkoxycarbonyl,
phenyl- or
naphthyl-lower alkoxycarbonyl, halogen, lower alkanoyl, lower alkylsulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl, dialkoxyphosphoryl, carbamoyl, mono- or di-
lower
alkylcarbamoyl, hydroxy- or carboxy-lower alkylcarbamoyl, sulfamoyl, nitro,
oxo and/or
by cyano; by heterocyclyl-lower alkenoyl wherein heterocyclyl is selected from
pyrrolyl,
furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl,
indolyl, quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a benzo-fused,
cyclopenta-,
cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or
partially saturated; by lower alkoxycarbonyl; by aryl-lower alkoxycarbonyl
wherein aryl
has from S to 14 carbon atoms; by heterocyclyl-lower alkoxycarbonyl wherein
hetero-
cyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl, thiazolyl,
pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,
~i-carbolinyl
and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of
those
radicals, which may also be fully or partially saturated and unsubstituted or
substituted by
lower alkyl; by carboxy-lower alkanoyl; by lower alkoxycarbonyl-lower
alkanoyl; by
hydroxy-lower alkoxy-lower alkanoyl; by amino-lower alkanoyl; or by benzyloxy-
carbonylamino-lower alkanoyl wherein the amino group is not bonded in the a-
or
(3-position; by carbamoyl; by phenyl-lower alkylaminocarbonyl; by N-di-lower
alkyl-
amino-lower alkyl-N-lower alkylaminocarbonyl; by N-dihydroxy-lower alkyl-N-
lower
alkylaminocarbonyl; by 2- or 3-pyridyl-lower alkylaminocarbonyl; by N-2-
pyridyl-lower
alkyl-N-lower alkylaminocarbonyl; by sulfonyl; by lower allcylsulfonyl; by
arylsulfonyl
wherein aryl has from 6 to 10 carbon atoms and is unsubstituted or substituted
by lower
alkyl or by lower alkoxy; by heterocyclylsulfonyl wherein heterocyclyl is
selected from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl,
pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, (3-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals,
which may also
be fully or partially saturated; by sulfamoyl; or by sulfamoyl substituted by
heterocyclyl-
lower alkyl wherein heteracyclyl is as last defined, and/or by lower alkyl;
a carboxy group of the side chain is present in free form or in esterifted
form as a lower
alkyl ester group, as an aryl ester group or as an aryl-lower alkyl ester
group, wherein aryl
~~~~
is phenyl, 4-nitrophenyl, naphthyl or biphenylyl, or in amidated form as a
carbamoyl,
lower alkylcarbamoyl, di-lower alkylaminocarbamoyl, mono- or di-(hydroxy-lower
alkyl)-carbamoyl or mono- or di-(carboxy-lower alkyl)-carbamoyl group,
an amino group of the side chain is present in free form or in alkylated form
as mono- or
di-lower alkylamino or in acylated form as lower alkanoylamino, as amino-lower
alkanoylarnino, as aryl-lower alkanoylamino wherein aryl has from 6 to 14
carbon atoms
and is unsubstituted or substituted by lower alkyl, hydroxy, lower alkoxy,
carboxy,
carbamoyl or by sulfamoyl, as a lower alkoxycarbonylamino group, an
arylmethoxy-
carbonylamino group wherein aryl has from 6 to 14 carbon atoms, as piperidyl-1-
carbonyl,
morpholinocarbonyl, thiomorpholinocarbonyl or as S,S-
dioxothiomorpholinocarbonyl
and/or
a hydroxy group of the side chain is present in free form or in etherified or
esterified
form as a lower alkoxy, aryl-lower alkoxy, lower alkanoyloxy or lower
alkoxycarbonyloxy
group,
- lower alkylsulfonyl,
- 2- or 3-pyrrolyl-, 2-thienyl-, 2-furyl-, 1-pyrazolyl-, 2-, 3- or 4-pyridyl-,
2-, 3- or
5-indolyl-, (1-methyl-, 2-methyl-, 5-methoxy-, 5-benzyloxy-, 5-chloro- or 4,5-
dimethyl-
indol-2-yl)-, (1-benzylindol-2-yl or -3-yl)-, 4,5,6,7-ted-ahydroindol-2-yl-,
(2-, 3- or
4-quinolyl or 4-hydroxyquinol-2-yl)-, (1-, 3- or 4-isoquinolyl or 1-oxo-1,2-
dihydroiso-
quinol-3-yl)-, 3-pyrrolidinyl-, (3- or 4-hydroxypyrrolidin-2-yl)-, 5-
oxopyrrolidin-2-yl-, (2-
or 3-morpholinyl)-, (2- or 3-thiomorpholinyl)-, (S,S-dioxothiomorpholin-2- or -
3-yl)-, (2-
or 3-indolinyl)-, 1,2,3,4-tetrahydroquinol-2-, -3- or -4-yl)- or (1,2,3,4-
tetrahydroiso-
quinol-1-, -2- or -3-yl)-methylsulfonyl,
- phenyl- or 1- or 2-naphthyl-sulfonyl that is unsubstituted or mono- or di-
substituted by
lower alkyl,
- lower alkoxysulfonyl, or
benzyloxysulfonyl or 1- or 2-naphthyloxysulfonyl,
with the result that not more than one of the radicals Rt and R9 may be
hydrogen, and R2
and R$ are each independently of the other hydrogen or the same radicals as Rt
and Rg,
or the pairs of substituents Rl and R9, and R2 and Rs, each independently of
the other,
together with the bonding nitrogen atom and a radical selected from ethylene,
trimethyl-
ene, tetrarnethylene and pentamethylene in which a carbon atom may have been
replaced
by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by oxygen and
which may
be unsaturated, form a heterocyclic ring,
R3 is
- cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms and
is unsubsti-
20~2~~
tuted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, hydroxy,
lower alkoxy,
carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower
alkyl-
carbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy,
lowei
allcoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower
alkanoyl,
lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxy-
phosphoryl, carbamayl, mono- or di-lower alkylaminacarbamoyl, sulfamayl, mono-
or di-
lower alkylsulfamoyl, nitro and/or by cyano and is bonded to lower alkyl, or
- aryl-lower alkyl wherein aryl is selected from phenyl, indenyl, indanyl,
naphthyl,
anthryl, phenanthryl, acenaphthyl and fluorenyl, which may be unsubstituted or
mono- to
tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- ar 2-naphthyl,
hydroxy, lower
alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-
lower
alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower
alkanoyl-
amino, halogen, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-
lower
alkaxycarbonyl, lower alkanoyl, sulfo, lower alkylsuLfonyl, phosphono, hydroxy-
lower
alkoxyphosphoryl or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower
alkyl-
carbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, nitro and/or by cyano,
wherein
phenyl may be present up to three times, and wherein lower alkyl is
unsubstituted or
substituted by lower alkyl, heterocyclyl selected from pyrrolyl, furyl,
thienyl, imidazolyl,
pyrazolyl, oxazolyl, thiazalyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl, isoquin-
olyl, quinoxalinyl, ~3-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa-
or cyclo-
hepta-fused derivative of those radicals, which may also be fully or partially
saturated,
hydroxy, lower alkoxy, lower alkanoyloxy, acetoacetoxy, amino- or
benzyloxycarbonyl-
amina-Iower alkanoyloxy> aryl-lower alkanoyloxy wherein aryl has from 6 to 10
carbon
atoms, lower alkoxycarbonyloxy, mono- or di-lower alkylaminocarbonyloxy,
aryloxy-
carbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower
alkoxycarbonyloxy
wherein aryl has from 6 to 12 carbon atoms, sulfonyloxy, lower
alkylsulfonyloxy, phenyl-
sulfonyloxy, 2- or 4-toluenesulfonylaxy or 1- or 2-naphthylsulfonyloxy, amino,
mono- or
di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, mono- or di-(phenyl-
or
naphthyl-lower alkyl)-amino, lowex alkanoylamino, carboxy, esterified carboxy
selected
from lower alkoxycarbonyl, aryloxycarbanyl wherein aryl has from 6 to 10
carbon atoms,
aryl-lower alkoxycarbonyl wherein aryl has from 6 to 12 carbon atoms, lower
alkanoyl,
lower alkylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower
alkoxyphosphoryl,
carbamoyl, carbamayl substituted by one or two radicals selected from lower
alkyl, from
carboxy-lower alkyl or lower alkoxycarbonyl-lower alkyl, from di-lower
alkylamino-
lower alkyl, from aminocarboxy-lower alkyl, from hydroxy-lower alkyl and from
di-lower
alkoxy-lower alkyl, or carbamoyl substituted by one radical selected from
ethylene,
20'~~5
-79-
trimethylene, tetramethylene and pentamethylene in which a carbon atom may
have been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, and also sulfamoyl, phosphono, benzofuranyl, oxo
and/or by
cyano and is unbranched or branched,
R4 is hydrogen,
RS is hydroxy and
R6 is hydrogen,
or RS and R6 together are oxo and
R~ is
- lower alkyl,
- cycloalkyl-lower alkyl wherein cycloalkyl has from 3 to 7 carbon atoms and
is unsubsti-
tuted or mono- to tri-substituted by lower alkyl, halo-lower alkyl, hydroxy,
lower allcoxy,
carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower
alkyl-
carbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy,
lower
alkoxycarbonyl, phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower
alkanoyl,
lower alkylsulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl or di-lower
alkoxy-
phosphoryl, carbamoyl, mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono-
or
di-lower alkylsulfamoyl, vitro and/or by cyano and is 'bonded to lower alkyl,
- bicycloalkyl-lower alkyl wherein bicycloalkyl contains from 5 to 10 carbon
atoms,
- tricycloalkyl-lower alkyl wherein tricycloalkyl contains from 8 to 10 carbon
atoms,
- aryl-lower alkyl wherein aryl is selected from phenyl, indenyl, indanyl,
naphthyl,
anthryl, phenanthryl, acenaphthyl and fluorenyl, which may be unsubstituted or
mono- to
tri-substituted by lower alkyl, halo-lower alkyl, phenyl, 1- or 2-naphthyl,
hydroxy, lower
alkoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy, N,N-di-
lower
alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, lower
alkanoyl-
amino, halogen, carboxy, lower aikoxycarbonyl, benzyl-, naphthyl- or fluorenyl-
lower
alkoxycarbonyl, lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-
lower
alkoxyphosphoryl, di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower
alkyl-
carbamoyl, sulfamoyl, mono- or di-lower alkylsulfamoyl, vitro and/or by cyano,
wherein
phenyl may be present up to three times, and wherein lower alkyl is
unsubsdtuted or
substituted by lower alkyl, heterocyclyl selected from pyrrolyl, furyl,
thienyl, imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl, isoquin-
olyl, quinoxalinyl, J3-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa-
or cyclo-
hepta-fused derivative of those radicals, which may also be fully or partially
saturated,
hydroxy, lower alkoxy, lower alkanoyloxy, acetoacetoxy, amino- or
benzyloxycarbonyl-
amino-lower alkanoyloxy, aryl-lower alkanoyloxy wherein aryl has from 6 to 10
carbon
~o~~
g0 -
atoms, lower alkoxycarbonyloxy, mono- or di-lower alkylaminocarbonyloxy,
aryloxy-
carbonyloxy wherein aryl has from 6 to 10 carbon atoms, aryl-lower
alkoxycarbonyloxy
wherein aryl has from 6 to 12 carbon atoms, sulfonyloxy, lower
alkylsulfonyloxy, phenyl-
sulfonyloxy, 2- or 4-toluenesulfonyloxy, 1- or 2-naphthylsulfonyloxy, amino,
mono- or
di-lower alkylamino, N-lower alkoxy-N-lower alkylamino, mono- or di-(phenyl-
or naph-
thyl-lower alkyl)amino, lower alkanoylamino, carboxy, esterified carboxy
selected from
lower alkoxycarbonyl, aryloxycarbonyl wherein aryl has from 6 to 10 carbon
atoms, aryl-
lower allcoxycarbonyl wherein aryl has from 6 to 12 carbon atoms, lower
alkanoyl, lower
alkylsulfonyl, hydroxy-lower alkoxyphosphoryl and di-lower alkoxyphosphoryl,
carbamoyl, carbamoyl substituted by one or two radicals selected from lower
alkyl, from
carboxy-lower alkyl, from lower alkoxycarbonyl-lower alkyl, from di-lower
alkylamino-
lower alkyl, from aminocarboxy-lower alkyl, from hydroxy-lower alkyl and from
di-lower
alkoxy-lower alkyl, or carbamoyl substituted by one radical selected from
ethylene,
trimethylene, tetramethylene and pentamethylene in which a carbon atom may
have been
replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-substituted by
oxygen and
which may be unsaturated, and also sulfamoyl, phosphono, benzofuranyl, oxo
(which is
not bonded to the carbon atom that is linked to the nitrogen atom bonding the
radical R~)
and/or by cyano and is unbranched or branched,
- heterocyclyl-lower alkyl wherein heterocyclyl is preferably selected from
pyrrolyl, furyl,
thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl,
pyrimidinyl, indolyl,
quinolyl, isoquinolyl, quinoxalinyl, l3-carbolinyl and a benzo-fused,
cyclopenta-,
cyclohexa- or cyclohepta-fused derivative of those radicals, which may also be
fully or
partially saturated, for example 4-pyrrolidinylmethyl, 1-imidazolylmethyl, 2-
pyridyl-
methyl, 3-pyridylmethyl, quinolin-2-ylmethyl or indol-2-ylmethyl,
- hydroxy-lower alkyl,
- lower alkoxy-lawer alkyl,
- phenoxy-lower alkyl or nitrophenoxy-lower alkyl,
- naphthyloxy-lower alkyl,
- lower alkanoyloxy-lower alkyl,
- acetoacetoxy-lower alkyl,
- arylmercapto-lower alkyl wherein aryl has from 6 to 10 carbon atoms,
- amino-lower alkyl,
- mono- or di-lower alkylamino-lower alkyl,
- phenyl- or naphthyl-amino-lower alkyl,
- lower alkanoylamino-lower alkyl,
- piperazinylcarbonyl-lower alkyl substituted at the nitrogen atom by lower
alkyl,
2~i2~~
- 8l _
- lower allcoxycarbonylamino-lower alkyl, .
- phenyl-lower alkoxycarbonylamino-lower alkyl,
- aminocarbonylamino-lower alkyl,
- N-phenyl-lower alkyl-N-lower alkylaminocarbonylamino-lower alkyl,
- halo-lower alkyl,
- carboxy-lower alkyl,
- lower allcoxycarbonyl-lower alkyl,
- 2-halo-lower alkoxycarbonyl-lower alkyl,
- phenyl- or naphthyl-lower alkoxycarbonyl-lower alkyl,
- heterocyclyl-lower alkoxycarbonyl-lower alkyl wherein heterocyclyl is
selected from
pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridyl,
pyrazinyl,
pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl, l3-carbolinyl and a
benzo-fused,
cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those radicals, it
also being
possible for the mentioned radicals to be fully or partially saturated,
- lower alkylsulfonyl-lower alkyl,
- arylsulfonyl-lower alkyl wherein aryl has from 6 to 10 carbon atoms,
- carbamoyl-lower alkyl,
- lower alkylcarbamoyl-lower alkyl,
- di-lower alkylcarbamoyl-lower alkyl,
- hydroxy-lower alkylcarbamoyl- or di(hydroxy-lower alkyl)carbamoyl-lower
alkyl,
- N-lower alkoxy-lower alkoxy-lower alkylcarbamoyl-lower alkyl,
- carboxy-lower alkylcarbamoyl- or di(carboxy-lower alkyl)carbamoyl-lower
alkyl,
- carbamoyl-lower alkyl substituted at the nitrogen atom by one radical
selected from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, oxygen, sulfur or by sulfur mono- or di-
substituted by
oxygen, it also being possible for the radical so formed to be fully or
partially unsaturated,
- N-lower alkyl-N-heterocyclyl-lower alkylcarbamoyl-lower alkyl wherein
heterocyclyl is
selected froze pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl, oxazolyl,
thiazolyl, pyridyl,
pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl, quinoxalinyl,13-
carbolinyl and a
benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused derivative of those
radicals,
which may also be fully or partially saturated,
- sulfamoyl-lower alkyl,
- N-(phenyl- or naphthyl-lower alkyl)sulfamoyl-lower alkyl,
- sulfamoyl-lower alkyl substituted at the nitrogen atom by one radical
selected from
ethylene, trimethylene, tetramethylene and pentamethylene wherein a carbon
atom may
have been replaced by nitrogen, lower alkyl-substituted nitrogen, oxygen,
sulfur or by
~~27~5
-82-
sulfiu' mono- or di-substituted by oxygen, it also being possible for the
radical so.formed
to be fully or partially unsaturated,
- oxo-lower alkyl (wherein oxo is riot bonded to the carbon atom that is
linked to the
nitrogen atom that carries R~),
- cyano-lower alkyl,
- hydroxy-carboxy-lower alkyl,
- a-naphthyloxy-carboxy-lower alkyl,
- hydroxy-lower alkoxycarbonyl-lower alkyl,
- a-naphthyloxy-lower alkoxycarbonyl-lower alkyl,
- lower alkylcarbonyl-halo-lower alkyl,
- a-naphthyloxyethoxycarbonyl-lower alkyl,
- a-naphthyloxy-'oenzyloxycarbonyl-lower alkyl,
- esterified hydroxy-lower alkoxycarbonyl-lower alkyl wherein the hydroxy
group is
esterified by lower alkanoyl, cycloalkyl-lower alkanoyl wherein cycloalkyl has
from 3 to 7
carbon atoms, bicycloalkyl-lower alkanoyl wherein bicycloalkyl has from 5 to
10 carbon
atoms, tricycloalkyl-lower alkanoyl wherein tricycloalkyl has from 8 to 10
carbon atoms,
aryl-lower alkanoyl wherein aryl has from 6 to 14 carbon atoms and may be
unsubstituted
or mono- to tri-substituted by lower alkyl, hydroxy, lower alkoxy, carbamoyl-
lower
alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower alkylcarbamoyl-
lower
alkoxy, amino, mono- or di-lower alkylamino, halogen, carboxy, lower
alkoxycarbonyl,
phenyl-, naphthyl- or fluorenyl-lower alkoxycarbonyl, lower alkanoyl, lower
alkyl-
sulfonyl, phosphono, hydroxy-lower alkoxyphosphoryl, di-lower
aikoxyphosphoryl,
carbamoyl, sulfamoyl, nitro and/or by cyano, lower alkoxycarbonyl, 2-halo-
lower alkoxy-
carbonyl or by phenyl- or fluorenyl-lower alkoxycarbonyl,
- dihydroxy-carboxy-lower alkyl,
- dihydroxy-lower alkoxycarbonyl-lower alkyl,
dihydroxy-lower alkoxycarbonyl-lower alkyl esterified by lower alkanoyl, lower
alkoxy-
carbonyl, phenyl- or fluorenyl-lower alkoxycarbonyl, lower alkylsulfonyl or by
toluene-
sulfonyl,
- a-naphthyloxy-di-lower alkylamino-lower alkyl,
- a-naphthyloxy-carbamoyl-lower alkyl,
- a-naphthyloxy-oxo-lower alkyl (wherein oxo is not bonded to the carbon atom
that is
linked to the nitrogen atom that carries R~), or
- a-naphthyloxy-cyano-lower alkyl,
and the salts of the mentioned compounds where salt-forming groups are
present.
_83_
Special preference is given to the compounds of formula I wherein R1 and R9
are each
independently of the other hydrogen; lower alkanoyl, such as formyl, acetyl,
propionyl,
butyryl or pivaloyl, especially acetyl; aryl-lower alkanoyl wherein aryl is
phenyl, indenyl,
indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl or fluorenyl and may be
unsubstituted
or especially mono- to tri-substituted by lower alkyl, for example methyl,
ethyl or propyl,
halo-lower allcyl, for example trifluoromethyl, phenyl, 1- or 2-naphthyl,
hydroxy, lower
alkoxy, for example methoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-
lower
alkoxy, N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower
alkyl-
amino, lower alkanoylamino, for example pivaloylamino, halogen, for example
fluorine,
chlorine or bromine, carboxy, lower alkoxycarbonyl, such as tart-
butoxycarbonyl, phenyl-,
naphthyl- or fluorenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl, lower
alkanoyl,
sulfo, lower allcylsulfonyl, far example methylsulfonyl, phosphono, hydroxy-
lower alk-
oxyphosphoryl, di-lower alkoxyphosphoryl, carbarnoyl, mono- or di-lower alkyl-
carbamoyl, sulfamoyl, mono- or di-lower alkylaminosulfonyl, nitxo and/or by
cyano>
wherein phenyl may be present up to three times, for example in diphenyl-,
dibenzyl- or
triphenyl-lower alkanoyl, such as diphenyl-, dibenzyl- or triphenyl-acetyl,
and wherein
lower alkanoyl is unsubsrituted or substituted by carbamoyl or by carbamoyl
substituted at
the nitrogen atom by one or two xadicals selected from lower alkyl, carboxy-
lower alkyl,
lower alkoxycarbonyl-lower alkyl, di-lower alkylamino-lower alkyl,
aminocarboxy-lower
alkyl, hydroxy-lower alkyl and di-lower alkoxy-lower alkyl, for example by
carbamoyl,
carbamoyl substituted by one or two radicals selected from methyl, ethyl,
propyl,
isopropyl, n-butyl, isobutyl, sec-butyl, tart-butyl, n-pentyl, isopentyl,
neopentyl, tert-
pentyl, n-hexyl, isohexyl and n-heptyl, for example in N-methylcarbarnoyl, N-n-
butyl-
carbamoyl or N,N-dimethylcarbamoyl, by carboxymethylcarbamoyl
(glycinylcarbonyl),
by tart-butoxycarbonylmethylcarbamoyl, by 2-dimethylaminoethyl, by 5-amino-
5-carboxypentyl, by hydroxymethyl, by hydroxyethyl or by 2-(2,2-
dimethoxyethyl)-
carbamoyl, for example 4-chloro-, 4-methoxy- or 4-nitro-benzoyl,
naphthylcarbonyl, such
as a- or Li-naphthylcarbonyl, indenylcarbonyl, such as 1-, 2- or 3-
indenylcarbonyl,
indanylcarbonyl, such as 1- or 2-indanylcarbonyl, phenanthrenylcarbonyl, such
as 9-phen-
anthrenylcarbonyl, phenyl-lower alkanoyl, such as phenylacetyl or 3-
phenylpropionyl,
phenyl-lower alkanoyl wherein the lower alkanoyl radical is substituted by
carbamoyl,
such as 2(R,S)-carbamoyl-3-phenylpropionyl, a-naphthylacetyl, J3-
naphthylacetyl, lower
alkylphenylacetyl, such as 4-methylphenylacetyl, lower alkoxyphenylacetyl,
such as
4-methoxyphenylacetyl, 3-(p-hydroxyphenyl)-propionyl, diphenylacetyl, di-(4-
methoxy-
phenyl)-acetyl, triphenylacetyl, 2,2-dibenzylacetyl, 3-a- or 3-(3-
naphthylpropionyl,
3-phenyl- or 3-a-naphthyl-2-carbamoylpropionyl, 3-phenyl- or 3-a-naphthyl-2-
tart-butyl-
~o~~~~~
-84-
carbamoyl-propionyl, 3-phenyl- or 3-a-naphthyl-2-(2-
dimethylaminoethyl)carbamoyl-
propionyl, 3-a-naphthyl-2-(carboxy- or tert-butoxycarbonyl)methylcarbamoyl-
propionyl,
3-phenyl- or 3-a-naphthyl-2-(3-hydroxy-2-propyl)carbamoyl-propionyl, 3-phenyl-
or
3-a-naphthyl-2-(2,2-dimethoxyethyl)-carbamoylpropionyl, 3-phenyl- ar 3-a-
naphthyl-2-
(5-amino-5-carboxypentyl)-carbamoylpropionyl, especially phenyl-lower
allcanoyl, such
as phenylacetyl, or phenyl-lower alkanoyl wherein the lower alkanoyl radical
is substi-
tuted by carbamoyl, such as 2(R,S)-carbamoyl-3-phenyl-propionyl; heterocyclyl-
lower
alkanoyl wherein lower alkanoyl is unsubstituted and wherein heterocyclyl is
selected
from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl, oxazolyl,
isoxazolyl,
thiazolyl, furazanyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl,
pyridazinyl, azepinyl,
indolyl, benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl,
quinazolinyl,
cinnolyl, purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1-
benzofuranyl, 4,1-benz-
oxazinyl, 4,1-benzothiazinyl, cyclohexa[b]pyrrolyl, cyclohepta[b]pyrrolyl,
cyclohexa-
[d]pyrazolyl, cyclohexa[b]pyridyl, cyclohexa[b]pyrazinyl,
cyclohexajb],pyrimidinyl,
cyclohexa[b]-1,4-oxazinyl, cyclohexa[b]-1,4-thiaziny:l, pyrrolidinyl,
pyrrolinyl, imidazol-
idyl, 2-imidazolinyl, 2,3-dihydropyridyl, piperidyl, piperazinyl, 2,3,5,6-
tetrahydro-
pyrazinyl, morpholinyl, thiomorpholinyl, S,S-dioxo-thiomorpholinyl, indolinyl,
isoindol-
inyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-tetrahydroquinolyl, 1,2,3,4-
tetrahydroisoquinolyl,
chromanyl, thiochxomanyl, 1,2,3,4-tetrahydro-3,1-ber~zodiazinyl, 3,4-dihydro-
3H-4,1-
benzoxazinyl and 3,4-dihydro-3H-4,1-benzothiazinyl, the mentioned heterocyclyl
radicals
being unsubstituted or substituted by lower alkyl, for example methyl, phenyl,
1- or
2.-naphthyl, phenyl-lower alkyl, for example benzyl, hydroxy-lower alkyl, for
example
hydroxymethyl or 2-hydroxyethyl, lower alkoxy-lower alkyl, for example
methoxymethyl
or 2-methoxyethyl, phenoxy- or naphthyloxy-lower alkyl, for example 2-
phenoxyethyl, f-
or 2-naphthyloxymethyl, phenyl-lower alkoxy- or naphthyl-lower allcoxy-lower
alkyl, for
example benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, for example
acetoxy-
methyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, for example
benzoyloxy-,
phenylacetoxy- or 1- or 2-naphthoyloxy-methyl, -2-ethyl or -2-(2,2-
dimethylethyl), lower
alkoxycarbonyloxy-lower alkyl, for example tert-butoxy-lower alkyl, phenyl-,
naphthyl- or
fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-
benzyloxycarbonyloxy-
ethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for example
amino-
methyl, 2-aminoethyi or 2-aminopropyl, carboxy-lower alkyl, for example
carboxymethyl
or 2-carboxyethyl, hydroxy, lower allcoxy, for example methoxy or ethoxy,
phenyl- or
naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-naphthyloxy, amino,
lower
alkylamino, for example methyl-, ethyl- or tert-butyl-amino, di-lower
alkylamino, for
example dimethyl- or diethyl-amino, carboxy, lower alkoxycarbonyl, for example
20~27~.5
-8S-
methoxy-, isoprapoxy-, sec-butoxy- or tert-butoxy-carbonyl, phenyl- or
naphthyl lower
alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for example fluorine,
chlorine,
bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example
acetyl or
pivaloyl, lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl ar dialkoxyphosphoryl, for example dimethoxy-
or
diethoxy-phosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl, for example
N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, hydroxy- or
carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-methylcarbamoyl
or
hydroxy- or carboxy-ethylcarbamoyl, sulfamoyl, nitro, oxo and/or by cyano,
hetero-
cyclyl-lower alkanoyl being selected especially from unsubstituted or lower
alkyl- or
phenyl-substituted pyrrolylcarbonyl, for example 2- or 3-pyrrolylcarbonyl, 4-
or 5-methyl-
pyrrolylcarbonyl or 4- or 5-phenylpyrrolyl-2-carbonyl, thienylcarbonyl, such
as 2-thienyl-
carbonyl, furylcarbonyl, such as 2-furylcarbonyl, pyridylcarbonyl, such as 2-,
3- or
4-pyridylcarbonyl, pyrimidin-1-ylcarbonyl, indolylcarbonyl that is
unsubstituted or
substituted by lower alkyl, such as methyl, phenyl-lower alkyl, such as
benzyl, lower
alkoxy, such as methoxy, phenyl-lower alkoxy, such as benzyloxy, or by
halogen, such as
chlorine, such as 2-, 3- or 5-indolylcarbonyl, 1-methyl-, 5-methyl-, S-methoxy-
,
5-benzyloxy-, S-chloro- or 4,S-dimethyl-indolyl-2-carbonyl, 1-benzylindolyl-2-
or
-3-carbonyl, 4,5,6,7-tetrahydroindolyl-2-carbonyl, unsubstituted or hydroxy-
substituted
quinolyl-lower alkanoyl, for example quinolylcarbonyl, such as 2-, 3- or 4-
quinolyl-
carbonyl or 4-hydroxyquinolyl-2-carbonyl, unsubstituted or hydroxy-substituted
isoquinolylcarbonyl, such as 1-, 3- or 4-isoquinolylcarbonyl or 1-oxo-1,2-
dihydroiso-
quinolyl-3-carbonyl, 2-quinoxalinylcarbonyl, 2-(3,1-benzofuranyl)-carbonyl,
cyclohepta-
[b]pyrrolyl-5-carbonyl, 3-cluomanylcarbonyl, 3-thiochromanylcarbonyl,
pyrrolidinyl-
3-carbonyl, hydroxypyrrolidinylcarbonyl, such as 3- or 4-hydroxypyrrolidinyl-2-
carbonyl,
oxopyrrolidinylcarbonyl, such as 5-oxopyrrolidinyl-2-carbonyl,
piperidylcarbonyl, such as
piperidinocarbonyl or 2-, 3- or 4-piperidylcarbonyl, pyrazinylcarbonyl, such
as pyrazin-
1-ylcarbonyl, piperazinylcarbonyl, such as piperazin-1-ylcarbonyl, morpholinyl-
lower
alkanoyl, for example morpholinylcarbonyl, such as morpholinocarbonyl,
thiornorpho-
linyl-lower alkanoyl, for example thiomorpholinylcarbonyl, such as
thiomorpholino-
carbonyl, S,S-dioxothiomorpholinylcarbonyl, such as S,S-
dioxothiomorpholinocarbonyl,
indolinylcarbonyl, such as 2- or 3-indolinylcarbonyl, 1,2,3,4-
tetrahydroquinolylcarbonyl,
such as 1,2,3,4-tetrahydroquinolyl-2-, -3- or -4-carbonyl, 1,2,3,4-
tetrahydroisoquinolyl-
carbonyl, such as 1,2,3,4-tetrahydroisoquinolyl-1-, -3- or -4-carbonyl or 1-
oxo-1,2,3,4-
tetrahydroisoquinolyl-3-carbonyl, tetrazolyl-lower alkanoyl, such as 3-
(tetrazol-1-yl)-
propionyl, and pyridyl-lower alkanoyl, for example pyridylacetyl, such as 2-,
3- or
20~2~~
4-pyridylacetyl, heterocyclyl-lower alkanoyl being selected more especially
from
morpholino-lower alkanoyl, such as morpholinocarbonyl, thiomorpholino-lower
alkanoyl,
such as thiomorpholinocarbonyl, pyridyl~lower alkanoyl, such as 2-, 3- or 4-
pyridylacetyl,
quinalinyl-lower alkanoyl, such as quinoline-2-carbonyl, and tetrazolyl-lower
alkanoyl,
such as 3-tetrazol-1-ylpropionyl; amino-lower alkanoyl substiriited at the
amino nitrogen
atom by heterocyclyl-lower alkanoyl wherein heterocyclyl-Lower alkanoyl is as
defined
for heterocyclyl-lower alkanoyl R1 and R9, especially amino-lower alkanoyl
substituted at
the amino nitrogen atom by N-morpholino- or N-thiomorpholino-carbonyl,
especially
N-morpholino- or N-thiomorpholino-carbonylamino-lower alkanoyl, such as N-
morpho-
lino- or N-thiomorpholino-carbonylamino-acetyl; halo-lower alkanoyl containing
up to
three halogen atoms, especially a-haloacetyl, such as a-fluoro-, a-chloro-, a-
bromo-,
a-iodo-, a,a,a-trifluoro- or a,a,a-trichloro-acetyl, or halopropionyl, such as
13-chloro- or
13-bromo-propionyl, for example trifluoroacetyl; (N-heterocyclyl-lower
alkylcarbamoyl)-
lower alkanoyl wherein heterocyclyl is selected from pyrrolyl, furyl, thienyl,
imidazolyl,
pyrazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl,
quinolyl,
isoquinolyl, quinoxalinyl,13-carbolinyl and a benzo-fused, cyclopenta-,
cyclohexa- or
cyclohepta-fused derivative of those radicals, which rnay also be fully or
partially
saturated, from morpholine and from thiomorpholine, especially 2-(N-morpholino-
lower
alkylcarbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(?-morpholinoethyl)-
carbamoyl)-
3-methyl-butyryl, or 2-(N-(pyridyl-lower alkyl)-carbamoyl)-lower alkanoyl,
such as
2(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-3-methyl-butyryl; lower alkoxycarbonyl,
especially methoxy-, ethoxy-, isopropoxy-, isobutoxy- or tent-lower alkoxy-
carbonyl, for
example methoxycarbonyl, tent-butoxycarbonyl or isobutoxycarbonyl; aryl-lower
alkoxycarbonyl wherein aryl is phenyl, biphenylyl, 1- or 2-naphthyl,
fluorenyl, or phenyl
that is mono- or poly-substituted by lower alkyl, for example methyl or tert-
butyl,
hydroxy, lower alkoxy, for example methoxy, ethoxy or tert-butoxy, halogen,
for example
chlorine or bromine, and/or by nitro, for example phenyl-lower
allcoxycarbonyl, such as
benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl or
fluor-
enyl-lower alkoxycarbonyl, such as 9-fluorenylmethoxycarbonyl, especially
phenyl-lower
allcoxycarbonyl, such as benzyloxycarbonyl; heterocyclyl-lower alkoxycarbonyl
wherein
heterocyclyl is selected from pyrrolyl, furyl, thienyl, imidazolyl, pyrazolyl,
oxazolyl,
thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, indolyl, quinolyl, isoquinolyl,
quinoxalinyl,
J3-carbolinyl and a benzo-fused, cyclopenta-, cyclohexa- or cyclohepta-fused
derivative of
those radicals, which may also be fully or partially saturated, and from
morpholinyl and
thiomorpholinyl and is unsubstituted or substituted by lower alkyl, for
example methyl,
such as 1-methylpyrrolidin-2-yl-methoxycarbonyl, 2-furylmethoxycarbonyl, 2-
tetrahydro-
za727~
_g7_
furyl-methoxycarbonyl, 1-methyl-2-piperidyl-methoxycarbonyl or 2-morpholino-
ethoxy-
carbonyl, or 2-, 3- or 4-pyridylmethoxycarbonyl, especially tetrahydrofuranyl-
lower
alkoxycarbonyl, such as 2(1~,5)-tetrahydrofuranylmethoxycarbonyl; lower
alkylsulfonyl,'
for example methyl- or ethyl-sulfonyl, such as rnethylsulfonyl;
morpholinosulfonyl, thio-
morpholinosulfonyl, piperidinosulfonyl, 4-methylpiperazinylsulfonyl or
piperazino-
sulfonyl; N-heterocyclyl-lower alkyl-N-lower alkylcarbamoyl wherein
heterocyclyl is
selected from thienyl, furyl, pyranyl, pyrrolyl, imidazolyl, pyrazolyl,
oxazolyl, isoxazolyl,
thiazolyl, furazanyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, azepinyl,
indolyl,
benzimidazolyl, 1H-indazolyl, quinolyl, isoquinolyl, quinoxalinyl,
quinazolinyl, cinnolyl,
purinyl, pteridinyl, naphthyridinyl, 4H-quinolizinyl, 3,1-benzofuranyl,
benzje]indolyl,
4,1-benzoxazinyl, 4,1-benzothiazinyl, carbazolyl, ~-carbolinyl, phenazinyl,
phenanthridyl,
acridyl, phenoxazinyl, phenothiazinyl, 1-azaacenaphthenyl,
cyclohexa[b]gyrrolyl, cyclo-
hepta[b]pyrrolyl, cyclohexa[d]pyrazolyl, cyclohexa[b]pyridyl,
cyclohexa[b]pyrazinyl,
cyclohexa[b]pyrimidinyl, cyclohexa[b]-1,4-oxazinyl, cyclohexa[b]-1,4-
thiazinyl,
pyrrolidinyl, pyrrolinyl, imidazolidinyl, 2-irnidazolinyl, 2,3-dihydropyridyl,
piperidyl,
piperazinyl, 2,3,5,6-tetrahydropyrazinyl, morpholinyl, thiomorpholinyl, S,S-
dioxothio-
morpholinyl, indolinyl, isoindolinyl, 4,5,6,7-tetrahydroindolyl, 1,2,3,4-
tetrahydroquinolyl,
1,2,3,4-tetrahydroisoquinolyl, chxomanyl, thiochrommyl, 1,2,3,4-tetrahydro-
3,1-benzodiazinyl, 3,4-dihydro-3H-4,1-benzoxazinyl, 3,4-dihydro-3H-4,1-
benzothiazinyl,
2,3,4,5-tetrahydro-lI-I-5,1-benzazepinyl and 5,6-dihydrophenanthridinyl, the
mentioned
radicals being unsubstituted or substituted by lower alkyl, for example
methyl, phenyl, f-
or 2-naphthyl, phenyl-lower alkyl, for example benzyl, hydroxy-lower allcyl,
for example
hydroxymethyl or 2-hydroxyethyl, lower alkoxy-lower alkyl, for example
methoxymethyl
or 2-rnethoxyethyl, phenoxy- or naphthyloxy-lower alkyl, for example 2-
phenoxyethyl, f-
or 2-naphthyloxymethyl, phenyl-lower alkoxy- or naphthyl-lower alkoxy-lower
alkyl, for
example benzyloxy-lower alkyl, lower alkanoyloxy-lower alkyl, for example
acetoxy-
methyl, phenyl- or naphthyl-lower alkanoyloxy-lower alkyl, for example
benzoyloxy-,
phenylacetoxy- or 1- or 2-naphthoyloxy-methyl, -2-ethyl or -2-(2,2-
dimethylethyl), lower
alkoxycarbonyloxy-lower alkyl, for example tort-butoxy-lower alkyl, phenyl-,
naphthyl- or
fluorenyl-lower alkoxycarbonyloxy-lower alkyl, for example 2-
benzyloxycarbonyloxy-
ethyl or 9-fluorenylmethoxycarbonyloxyethyl, amino-lower alkyl, for example
amino-
methyl, 2-aminaethyl or 2-aminopropyl, carboxy-lower alkyl, for example
carboxymethyl
or 2-carboxyethyl, hydroxy, lower alkoxy, for example methoxy or ethoxy,
phenyl- or
naphthyl-lower alkoxy, for example benzyloxy or 1- or 2-naphthylmethoxy,
amino, lower
alkylamino, for example methyl-, ethyl- or tort-butyl-amino, di-lower
alkylamino, for
example dimethyl- or diethyl-amino, carboxy, lower alkoxycarbonyl, for example
20°~~~~5
-gg_
methoxy-, isopropoxy-, sec-butoxy- or tert-butoxy-carbonyl, phenyl- or
naphthyl-lower
alkoxycarbonyl, for example benzyloxycarbonyl, halogen, for example fluorine,
chlorine,
bromine or iodine, especially chlorine or bromine, lower alkanoyl, for example
acetyl or
pivaloyl, Lower alkylsulfonyl, for example methyl- or ethyl-sulfonyl,
phosphono,
hydroxy-lower alkoxyphosphoryl or dialkoxyphosphoryl, for example dimethoxy-
or
diethoxy-phosphoryl, carbamoyl, mono- or di-lower aikylcarbamoyl, for example
N-methylcarbamoyl, N-n-butylcarbamoyl or N,N-dimethylcarbamoyl, hydroxy- or
carboxy-lower alkylcarbamoyl, for example hydroxy- or carboxy-methylcarbamoyl
or
hydroxy- or carboxy-ethylcarbamoyl, sulfamoyl, nitro, oxo and/or by cyano, and
is
especially pyridyl, such as 2-, 3- or 4-pyridyl, especially N-pyridyl-lower
alkyl-N-lower
alkylcarbamoyl, such as N-(2-, 3- or 4-pyridylmethyl)-N-methylcarbamoyl; or an
acyl
radical of an amino acid the amino function of which is free or acylated by
one of the
other radicals mentioned hitherto for Rt and R9, the amino acids being
selected from
glycine (H-Gly-OH), alanine (H-Ala-OH), valine (H-Val-OH), nozvaline (a-
aminovaleric
acid), Ieucine (H-Leu-OI-I), isoleucine (H-Ile-OH), norleucine (a-
aminohexanoic acid,
H-Nle-OH), serine (H-Ser-OI-I), homoserine (a-amino-y-hydroxybutyric acid),
threonine
(H-Thr-OH), methionine (H-Met-OH), cysteine (H-C;ys-OH), proline (H-Pro-OH),
txans-3- and trans-4-hydroxyproline, phenylalanine (FI-Phe-OH), tyrosine (H-
Tyr-OH),
4-aminophenylalanine, 4-chlorophenylalanine, 4-carboxyphenylalanine,13-
phenylserine
(f3-hydroxyphenylalanine), phenylglycine, a-naphthylalanine (I-I-Nal-OH),
cyclohexyl-
alanine (H-Cha-OI-i), cyclohexylglycine, tryptophan (H-Trp-OH), indoline-2-
carboxylic
acid, 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, aspartic acid (H-Asp-
OH), aspa-
ragine (FI-Asn-OH), aminomalonic acid, aminomalonic acid monoamide, glutamic
acid
(H-Glu-OH), glutamine (H-Gln-OH), histidine (H-His-OH), arginine (H-Arg-OH),
lysine
(H-Lys-OH), 8-hydroxylysine, ornithine (a,8-diaminovaleric acid), 3-
aminopropanoic
acid, a,~y-diaminobutyric acid and a,(3-diaminopropionic acid, more especially
the radical
of an amino acid selected from valine, alanine, leucine, isoleucine, glycine,
glutamic acid
and asparagine, it being possible for each of the mentioned amino acids (with
the
exception of glycine) to be in the D-, L- or (D,L)-form, preferably (with the
exception of
Val, which may also be in the (D)- or (D,L)-form) in the L-form, and the a-
amino group
being unsubstituted or N-acylated by one of the radicals mentioned above for
R1 and R9,
especially by lower alkanoyl, phenyl-lower alkanoyl, such as phenylacetyl,
phenyl-lower
alkanoyl wherein the lower alkanoyl radical is substituted by carbamoyl, such
as
2(R,S)-carbamoyl-3-phenylpropionyl, morpholino-lower alkanoyl, such as
morpholino-
carbonyl, thiomorpholino-lower alkanoyl, such as thiomorpholinocarbonyl,
pyridyl-lower
alkanoyl, such as 2-, 3- or 4-pyridylacetyl, quinolinyl-lower alkanoyl, such
as
-89-
quinoline-2-carbonyl, tetrazolyl-lower alkanoyl, such as 3-tetrazol-1-
ylpropionyl; amino-
lower aLkanoyl substituted at the amino nitrogen atom by N-morphoiino- or
N-thiomorpholino-caxbonyl, for example'N-morpholino- or N-thiomorpholino-
carbonyl-'
amino-lower alkanoyl, such as N-rnorpholino- or N-thiomorpholino-
carbonylaminoacetyl,
halo-lower alkanoyl containing up to three halogen atoms, for example a-
haloacetyl, such
as a-fluoro-, a-chloro-, a-bromo-, a-iodo-, a,a,a-trifluoro- or a,a,a-
trichlozo-acetyl, or
halopropionyl, such as B-chloro- or 13-bromo-propionyl, especially
trifluoroacetyl,
2-(N-morpholino-lower alkyicarbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(~-
mozpho-
linoethyl)-carbamoyl)-3-methyl-butyryl, 2-(N-(pyridyl-lower alkyl)-carbamoyl)-
lower
alkanoyl, such as 2(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-lower alkanoyl, lower
alkoxy-
carbonyl, phenyl-lower alkoxycarbonyl, tetrahydrofuranyl-lower alkoxycarbonyl,
such as
2(R,S)-tetrahydrofuranylmethoxycarbonyl, lower alkylsulfonyl or N-pyridyl-
lower alkyl-
N-lower alkylcarbamoyl, such as N-(2-, 3- or 4-pyridylmethyl)-N-
methylcarbamoyl,
greatest preference being given to N-morpholinocarbonyl-glycine, N-(N-(2-, 3-
or
4-pyridyl)methyl-N-methylaminocarbonyl)-glycine, valine, N-(trifluoroacetyl)-
valine,
N-phenylacetyl-valine, N-(2- or 3-pyridyl)-acetyl-valine, N-acetyl-valine, N-
(2-carbam-
oyl-3-phenylpropionyl)-valine, N-(2(R,S)-carbamoyl-3-phenylpropionyl)-valine,
N-(2- or
3-pyridylacetyl)-valine, N-2-tetrahydrofurylmethoxycarbonyl-valine, N-(3-
(tetrazol-
1-yl)-propionyl)-valine, N-(quinoline-2-carbonyl)-val:ine, N-methoxycarbonyl-
valine,
N-isobutoxycarbonyl-valine, N-tert-butoxycarbonyl-valine, N-benzyloxycarbonyl-
valine,
N-(morpholinocarbonyl)-valine, N-(thiomorpholinocaxbonyl)valine, N-{S,S-
dioxothio-
morpholinocarbonyl)-valine, N-(N-2-pyridylmethyl-I'f-methylaminocarbonyl)-
valine,
N-morpholinocarbonylaminoacetyl-valine, N-methylsulfonyl-valine, morpholino-
sulfonyl-valine, N-acetyl-isoleucine, N-propionyl-isoleucine, N-
(benzyloxycarbonyl)-
isoleucine, N-benzyloxycarbonyl-glutamic acid, asparagine, N-benzyloxycarbonyl-
asparagine and quinoline-2-carbonyl-asparagine, wherein each of the amino acid
radicals
is preferably in the (L)- or (D,L)-form, and in the case of valine also in the
(D)-form; with
the proviso that not more than one of the radicals R1 and R9 is hydrogen,
R2, R4, R6 and Rg are hydrogen,
R3 is lower alkyl, such as isobutyl or n-butyl; cycloalkyl-lower alkyl wherein
cycloalkyl
has from 3 to 7 carbon atoms and is unsubstituted or mono- to tri-substituted
by lower
alkyl, such as isopropyl, halo-lower alkyl, such as trifluoromethyl, hydraxy,
lower alkoxy,
carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower alkoxy or N,N-di-lower
alkyl-
carbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino, halogen, such as
fluorine,
chlorine or bromine, carboxy, lower alkoxycarbonyl, phenyl-, naphthyl- or
fluorenyl-lower
alkoxycarbonyl, lower alkanoyl, lower alkylsulfonyl, for example
methylsulfonyl,
20~27~5
-90-
phosphono, hydroxy-lower alkoxyphosphoryl or di-lower alkoxyphosphoryl,
carbamoyl,
mono- or di-lower alkylaminocarbamoyl, sulfamoyl, mono- or di-lower
alkylsulfamoyl,
nitro and/or by cyano and is bonded, preferably terminally, to lower alkyl,
especially '
methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, such as
cyclobutyl-,
cyclopentyl-, cyclohexyl- or cycloheptyl-lower alkyl, such as -methyl or -
ethyl, especially
cyclohexyl-lower alkyl, more especially cyclohexylmethyl; or aryl-lower alkyl
wherein
aryl is phenyl, indenyl, indanyl, naphthyl, anthryl, phenanthryl, acenaphthyl
or fluorenyl
and is unsubstituted ar substituted by lower alkyl, for example methyl, ethyl
or isopropyl,
halo-lower alkyl, such as trifluoromethyl, phenyl, 1- or 2-naphthyl, hydroxy,
lower alkoxy,
far example methoxy, carbamoyl-lower alkoxy, N-lower alkylcarbamoyl-lower
alkoxy or
N,N-di-lower alkylcarbamoyl-lower alkoxy, amino, mono- or di-lower alkylamino,
lower
alkanoylamino, for example pivaloylamino, halogen, for example fluorine or
chlorine,
carbaxy, lower alkoxycarbonyl, benzyl-, naphthyl- or fluorenyl-lower
alkoxycarbonyl,
lower alkanoyl, sulfo, lower alkylsulfonyl, phosphono, hydroxy-lower
alkoxyphosphoryl
or di-lower alkoxyphosphoryl, carbamoyl, mono- or di-lower alkylcarbamoyl,
sulfamoyl,
mono- or di-lower alkylsulfamoyl, nitxo and/or by cyano, wherein phenyl may be
present
up to three times, such as in diphenyl-, dibenzyl- or triphenyl-lower alkyl,
for example
diphenyl-, dibenzyl- or triphenyl-2-ethyl, especially phenyl-lower alkyl that
is unsubsti-
tuted or substituted by the mentioned substituents, especially benzyl, 4-
fluoro- or
~-cyano-benzyl,
R~ is hydroxy, and
R~ is unsubstituted lower alkyl, especially isobutyl or n-butyl; or cycloalkyl-
lower alkyl,
for example as last described for cycloalkyl-lower alkyl R3, especially
cyclohexyl-lower
alkyl, more especially cyclahexylmethyl; or aryl-lower alkyl as last described
for aryl-
lower alkyl R3, especially phenyl-lower alkyl that is unsubstituted or
substituted by the
mentioned substituents, more especially benzyl, 4-fluoro- or 4-cyano-benzyl,
or a salt thereof where at least one salt-forming group is present.
Special preference is given also to the compounds of formula I wherein Rl is
lower
alkoxycarbonyl, phenyl-lower alkoxycarbonyl, the monovalent radical, bonded
via the
carboxy group, of an aliphatic amino acid selected from valine, alanine,
leucine and
isoleucine, or the radical, bonded via the carboxy group, of an aliphatic
amino acid as
defined above that is acylated at the amino nitrogen atom by one of the
radicals phenyl-
lower alkanoyl, morpholinyl-lower alkanoyl, thiomorpholinyl-lower alkanoyl,
S,S-dioxo-
thiomorpholinyl-lower alkanoyl, pyridyl-lower alkanoyl, lower alkoxycarbanyl
and
-91-
phenyl-lower alkoxycarbonyl, all the mentioned amino acids being in the D-,
D,L- or
L-form, preferably in the L-form, R~, is hydrogen, R3 is phenyl-lower alkyl,
Rq. is
hydrogen, R5 is hydroxy, R6 is hydrogen, R~ is lower alkyl, cyclohexyl-lower
alkyl or
phenyl-lower alkyl, Rg is hydrogen and R9 is one of the radicals mentioned for
R1 and the
asymmetric carbon atoms carrying the radicals R~ and RS are in the S-
configuration, and
the pharmacologically acceptable salts of such compounds.
Very special preference is given to the compounds of formula I wherein R1 is
tert-butoxy-
carbonyl, benzyloxycarbonyl, the monovalent radical, bonded via the carboxy
group, of
the amino acid valine or the radical, bonded via the carboxy group, of alanine
acylated at
the amino nitrogen atom by one of the radicals phenylacetyl, 3-pyridylacetyl,
morpholino-
carbonyl, thiomorpholinocarbonyl, tent-butoxycarbonyl and benzyloxycarbonyl,
R2 is
hydrogen, R3 is benzyl, Rq. is hydrogen, RS is hydroxy, R6 is hydrogen, R7 is
isobutyl,
cyclohexylmethyl or benzyl, Rg is hydrogen and R9 is one of the radicals
mentioned for
R1 and the asymmetric carbon atoms carrying the radicals R3 and R5 are in the
S-configuration, and the pharmacologically acceptable salts of such compounds.
Great preference is given to the compounds of formula I wherein R1 and R9 are
each
independently of the other hydrogen, lower alkanoyl, such as acetyl, phenyl-
lower
alkanoyl, such as phenylacetyl, phenyl-lower alkanoyl wherein the lower
alkanoyl radical
is substituted by carbamoyl, such as 2(R,S)-carbamoyl-3-phenyl-propionyl,
morpholino-
lower alkanoyl, such as morpholinocarbonyl, thiomotpholino-lower alkanoyl,
such as
thiomorpholino-Carbonyl, pyridyl-lower alkanoyl, such as 2-, 3- or 4-
pyridylacetyl,
quinolyl-lower alkanoyl, such as quinoline-2-carbonyl, tetrazolyl-lower
alkanoyl, such as
3-tetrazol-1-yl-propionyl, amino-lower alkanoyl substituted at the amino
nitrogen atom by
N-morpholino- or N-thiomorpholino-carbonyl, for example N-morpholino- or N-
thia-
morpholino-carbonylamino-lower alkanoyl, such as N-morpholino- or N-
thiomorpholino-
carbonylamino-acetyl, halo-lower alkanoyl containing up to three halogen
atoms, such as
trifluoroacetyl, 2-(N-morpholino-lower alkylcarbamoyl)-lower alkanoyl, such as
2(R,S)-
(N-(2-morpholinoethyl)-carbamoyl-3-methyl-butyryl, 2-(N-pyridyl-lower alkyl-
carbamoyl)-lower alkanoyl, such as 2(R,S)-(N-(2-pyridylmethyl)-carbamoyl)-3-
methyl-
butyryl, lower alkoxycarbonyl, such as methoxy-, isobutoxy- or tent-lower
alkoxy-
carbonyl, phenyl-lower alkoxycarbonyl, such as benzyloxycarbonyl,
tetrahydrofuranyl-
lower alkoxycarbonyl, such as 2(R,S)-tetrahydrofuranyl-methoxycarbonyl, Lower
alkyl-
sulfonyl, for example methyl- or ethyl-sulfonyl, morpholinosulfonyl,
thiomorpholino-
sulfonyl, N-pyridyl-lower alkyl-N-lower alkylcarbamoyl, or an acyl radical of
an amino
0~~7v5
-92-
acid selected from glycine, alanine, valine, leucine, isoleucine, glutamic
acid and.
asparagine in the (D)-, (L)- or (D,L)-form, wherein the a-amino group is
unsubstituted or
acylated by one of the other radicals Ri or R2 mentioned hitherto, greatest
preference
being given to N-morpholinocarbonyl-glycine, N-(N-(2-, 3- or 4-pyridyl)methyl-
N-methylaminocarbonyl)-glycine, valine, N-(trifluoroacetyl)-valine, N-
phenylacetyl-
valine, N-(2- or 3-pyridyl)-acetyl-valine, N-acetyl-valine, N-(2-carbamoyl-3-
phenyl-
propionyl)-valine, N-(2(R,S)-carbamoyl-3-phenyl-propionyl)-valine, N-(2- or 3-
pyridyl-
acetyl)-valine, N-2-tetxahydrofurylmethoxycarbonyl-valine, N-(3-(tetrazol-1-
yl)-
propionyl)-valine, N-(quinoline-2-carbonyl)-valine, N-methoxycarbonyl-valine,
N-iso-
butoxycarbonyl-valine, N-tent-butoxycarbonyl-valine, N-benzyloxycarbonyl-
valine,
N-(morpholinocarbonyl)-valine, N-(thiomorpholinocarbonyl)-valine, N-(S,S-
dioxothio-
morpholinocarbonyl)-valine, N-(N-2-pyridylmethyl-N-methylaminocarbonyl)-
valine,
N-morpholinocarbonylaminoacetyl-valine, N-methylsulfonyl-valine,
morpholinosulfonyl-
valine, N-acetyl-isoleucine, N-propionyl-isoleucine, N-(benzyloxycarbonyl)-
isoleucine,
N-benzyloxycarbonyl-glutamic acid, asparagine, N-benzyloxycarbonyl-asparagine
and
quinoline-2-carbonyl-asparagine, wherein the amino acid radicals are each
preferably in
the (L)- or (D,L)-form, and in the case of valine also in the (D)-Form; with
the proviso that
not more than one of the radicals Rl and R~ is hydroge:n,
R2, Rq, R6 and Rg are hydrogen,
Rg is lower alkyl, such as n-butyl or isobutyl, cycloh~exyl-lower alkyl, such
as cyclo-
hexylmethyl, or phenyl-lower alkyl that is unsubstitutf;d or substituted by
halogen, such as
fluorine, lower alkoxy, such as methoxy, or by cyano> especially benzyl, 4-
fluorobenzyl or
4-cyanobenzyl,
RS is hydroxy, and
R~ is lower alkyl; cyclohexyl-lower alkyl; or phenyl-lower alkyl that is
unsubstituted or
substituted by halogen, such as fluorine, lower alkoxy, such as methoxy, or by
cyano; as
last defined for R3,
or a salt thereof where salt-forming groups are present, still greater
preference being given
to those compounds in which Rt and/or R9 are not morpholinosulfonyl or
thiomorpholino-
sulfonyl.
Most preferred of all are the compounds mentioned in the Examples and their
salts.
20'~2~~5
-93-
The compounds of formula I and salts of such compounds having at Least one
salt-forming
group are obtained by means of processes known her se, for example as follows:
a) a hydrazine derivative of the formula
R~
I
HN ~N 'Ry (III)>
1
Rs
wherein the radicals are as defined above, is added to an epoxide of the
formula
Rz
Rs O
N (N)>
R~
R3 Ra
wherein the radicals are as defined above, free functional groups, with the
exception of
those paz~ticipating in the reaction, being optionally in protected form, and
any protecting
groups present are removed, or
b) for the preparation of compounds of formula I wherein R1 and R9 are acyl;
sulfo;
sulfonyl substituted by unsubstituted or substituted alkyl, aryl,
heterocyclyl, alkoxy, which
is unsubstituted or substituted, or by aryloxy; sulfamoyl that is
unsubstituted or substituted
at the nitrogen atom; or phosphoryl substituted by one or two identical or
different radicals
selected from substituted or unsubstituted alkyl, unsubstituted or substituted
cycloalkyl,
aryl, hydroxy, unsubstituted or substituted alkoxy, cycloalkoxy and aryloxy;
Rz and Rg
are hydrogen, unsubstituted or substituted alkyl, alkenyl or alkynyl, or
heterocyclyl, and
the remaining radicals are as defined, an amino compound of the formula
R~
R5 Rs
N
R/'i ~~>K~N~N/H (V)>
R3 R4
Ra
20'2?~5
-94-
wherein the radicals are as defined immediately above, is condensed with an
acid of the
formula
R~-OH (VI)
or with a reactive acid derivative thereof, wherein R9 is as defined
immediately above,
free functional groups, with the exception of those participating in the
reaction, being
optionally in protected form, and any protecting groups present are removed,
or
c) for the preparation of compounds of formula I wherein R1 and R~ are aryl;
sulfo;
sulfonyl substituted by unsubstituted or substituted alkyl, aryl,
heterocyclyl, alkoxy, which
is unsubstituted or substituted, or by aryloxy; sulfamoyl that is
unsubstituted or substituted
at the nitrogen atom; or phosphoryl that is substituted by one or two
identical or different
radicals selected from substituted or unsubstituted alkyl, unsubstituted or
substituted
cycloalkyl, aryl, hydroxy, unsubstituted or substituted alkoxy, cycloalkoxy
and aryloxy;
R2 and Rg are hydrogen, unsubstituted or substituted alkyl, alkenyl or
alkynyl, or hetero-
cyclyl, and the remaining radicals are as defined, an amino compound of the
formula
R7
R RB
N/N'~~~N~N/R9 (VII).
R3 R4
R8
wherein the radicals are as defined immediately above, is condensed with an
acid of the
formula
Rl-OH (VIII)
or with a reactive acid derivative thereof, wherein R1 is as defined
immediately above,
free functional groups, with the exception of those participating in the
reaction, being
optionally in protected form, and any protecting groups present are removed,
or
d) for the preparation of compounds of formula I wherein Rl and R9 are two
identical
radicals selected from aryl; sulfo; sulfonyl substituted by unsubstituted or
substituted
allcyl, aryl, heterocyclyl, alkoxy, which is unsubstituted or substituted, or
by aryloxy;
~~~z
-95-
sulfamoyl that is unsubstituted or substituted at the nitrogen atom; and
phosphoryl that is
substituted by one or two identical or different radicals selected from
substituted or
unsubstituted alkyl, unsubstituted or substituted cycloalkyl, aryl, hydroxy,
unsubstituted or
substituted alkoxy, cycloalkoxy and aryloxy; R2 and Rg are hydrogen,
unsubstituted or
substituted alkyl, alkenyl or alkynyl, or heterocyclyl, and the remaining
radicals are as
defined, a diamino compound of the formula
R~
N Rs Rs
R3 R4
Rs
wherein the radicals are as defined immediately above, is condensed with an
acid suitable
for introducing the identical radicals Rt and R9, or with reactive acid
derivatives thereof,
wherein R1 and R9 are as defined immediately above, free functional groups,
with the
exception of those participating in the reaction, being optionally in
protected form, and
any protecting groups present are removed, or
e) for the preparation of a compound of formula I wherein in place of the
radical R~ there
is a radical R7" which is unsubstituted or substituted alkyl or cycloalkyl, in
a compound
of the formula I'
R
R Rs
/N
R, i wN /.R9
R3 R4
Rs
wherein R~' is hydrogen and the remaining radicals are as defined above, the
radical R~"
is introduced by substitution with a compound of the formula XII,
R~"-X (XII)
wherein X is a leaving group and R~" is unsubstituted or substituted alkyl or
cycloalkyl,
free functional groups, with the exception of those participating in the
reaction, being
optionally in protected form, and any protecting groups present are removed,
or
2p~2
-96-
f) in a compound of formula I wherein the substituents are as defined above,
with the
proviso that in the compound of formula I in question at least one functional
group is
protected by protecting groups, the protecting groups present are removed
and, if desired, a compound of formula I obtainable in accordance with any one
of
processes a) to f) above having at least one salt-forming group is converted
into its salt or
an obtainable salt is converted into the free compound or into a different
salt and/or any
isomeric mixtures that are obtainable are separated and/or a compound of
formula I
according to the invention is converted into a different compound of formula I
according
to the invention.
The above processes are described in detail below:
I7rocess a) (Addition of an amine to an epoxide):
Depending on the meaning of R~, in the hydrazine derivative of formula III the
amino
group participating in the reaction preferably has at least one free hydrogen
atom; it may,
however, itself have been derivatised in order to increase the reactivity of
the hydrazine
derivative.
The epoxide of formula IV has especially a stn~cture l:hat allows the
preferential terminal
addition of the hydrazine derivative.
Functional groups in starting materials that are not to participate in the
reaction, especially
carboxy, amino, hydroxy, mercapto and sulfo groups, can be protected by
suitable protect-
ing groups (conventional protecting groups) which are customarily used in the
synthesis of
peptide compounds, but also in the synthesis of cephalosporins and penicillms
as well as
nucleic acid derivatives and sugars. Those protecting groups may already be
present in
the precursors and are intended to protect the relevant functional groups
against undesired
secondary reactions, such as acylation, etherification, esterification,
oxidation, solvolysis,
etc.. In certain cases the protecting groups can additionally cause the
reactions to proceed
selectively, for example stereoselectively. It is a characteristic of
protecting groups that
they can be removed easily, i.e. without undesired secondary reactions, for
example by
solvolysis, reduction, photolysis> and also enzymatically, for example also
under physio-
logical conditions. Radicals analogous to protecting groups may, however, also
be present
in the end products. Compounds of formula I having protected functional groups
may
~~72~~~
-97-
have a higher degree of metabolic stability or otherwise better
pharmacodynamic, charact-
eristics than do the corresponding compounds having free functional groups. J-
Ierein-
before and hereinafter, it is protecting groups in the narrower sense that are
referred to
unless the relevant radicals are present in the end products.
The protection of functional groups by such protecting groups, the protecting
groups them-
selves and the reactions for their removal are described, for example, in
standard works
such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum
Press,
London and New York 1973, in Th. W. Greene, "Protective Groups in Organic
Synthesis",
Wiley, New York 1981, in "The Peptides' ; Volume 3 (E. Gross and J.
Meienhofer, eds.),
Academic Press, London and New York 1981, in "Methoden der organischen
Chemie",
Houben-Weyl, 4th edition, Volume 15/1, Georg Thieme Verlag, Stuttgart 1974, in
H.-D.
Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine" ("Amino acids,
peptides,
proteins"), Verlag Chemie, Weinheim, Deerfield Beach and Basel 1982, and in
Jochen
Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate" {"The
Chemistry
of Carbohydrates: monosaccharides and derivatives"), Georg Thieme Verlag,
Stuttgart
1974.
A carboxy group is protected, for example, in the fornz of an ester group
which can be
removed selectively under mild conditions. A carboxy group protected in
esterified form
is esterifted especially by a lower alkyl group that is preferably branched in
the 1-position
of the lower alkyl group or substituted in the 1- or 2-position of the lower
alkyl group by
suitable substituents.
A protected carboxy group esterified by a lower alkyl group is, for example,
methoxy-
carbonyl or ethoxycarbonyl.
A protected carboxy group esterified by a lower alkyl group that is branched
in the
1-position of the lower alkyl group is, for example, tert-lower
alkoxycarbonyl, for example
tent-butoxycarbonyl.
A protected carboxy group esterified by a lower alkyl group that is
substituted in the 1- or
2-position of the lower alkyl group by suitable substituents is, for example,
aryimethoxy-
carbonyl having one or two aryl radicals, wherein aryl is phenyl that is
unsubstituted or
mono-, di- or tri-substituted, for example, by lower alkyl, for example tert-
lower alkyl,
such as tort-butyl, lower alkoxy, for example methoxy, hydroxy, halogen, for
example
-98-
chlorine, and/or by vitro, for example benzyloxycarbonyl, benzyloxycarbonyl
substituted
by the mentioned substituents, for example 4-nitrobenzyloxycarbonyl or 4-
methoxy-
benzyloxycarbonyl, diphenylmethoxycarbonyl or diphenylmethoxycarbonyl
substituted liy
the mentioned substituents, for example di(4-methoxyphenyl)methoxycarbonyl,
and also
carboxy esterified by a lower alkyl group, the lower alkyl group being
substituted in the f-
or 2-position by suitable substituents, such as 1-lower alkoxy-lower
alkoxycarbonyl, for
example methoxymethoxycarbonyl, 1-methoxyethoxycarbonyl or 1-ethoxyethoxy-
carbonyl, 1-lower alkylthio-lower alkoxycarbonyl, for example 1-
methylthiamethoxy-
carbonyl ar 1-ethylthioethoxycarbonyl, aroylmethoxycarbonyl wherein the aroyl
group is
benzoyl that is unsubstituted or substituted, for example, by halogen, such as
bromine, for
example phenacyloxycarbonyl, 2-halo-lower alkoxycarbonyl, for example 2,2,2-
trichlaro-
ethoxycarbonyl, 2-bromaethoxycarbonyl or 2-iodaethoxycarbonyl, as well as 2-
(tri-substi-
tuted silyl)-lower alkoxycarbonyl wherein the substituents are each
independently of the
others an aliphatic, araliphatic, cycloaliphatic or aromatic hydrocarbon
radical that is
unsubstituted or substituted, for example, by lower alkyl, lower alkoxy, aryl,
halogen
and/or by vitro, for example lower alkyl, phenyl-lawe:r alkyl, cycloalkyl or
phenyl each of
which is unsubstituted or substituted as above, for example 2-tri-lower
alkylsilyl-lower
alkaxycarbonyl, such as 2-tri-lower alkylsilylethoxycarbonyl, for example 2-
trimethyl-
silylethoxycarbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or 2-
triarylsilylethoxy-
carbonyl, such as triphenylsilylethoxycarbonyl.
A carboxy group can also be protected in the form of an organic
silyloxycarbonyl group.
An organic silyloxycarbonyl group is, for example, a tri-lower
alkylsilyloxycarbonyl
group, for example trimethylsilyloxycarbonyl. The silicon atom of the
silyloxycarbonyl-
group can also be substituted by two lower alkyl groups, for example methyl
groups, and
the amino group or the carboxy group of a second molecule of formula I.
Compounds
having such protecting groups can be prepared, for example, using
dimethylchlorosilane
as silylating agent.
A protected carboxy group is preferably tert-lower alkoxycarbonyl, for example
tert-but-
oxycarbonyl, benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 9-
fluorenylmethoxycarbanyl
or diphenylmethoxycarbonyl.
A protected amino group can be protected by an amino-protecting group, for
example in
the form of an acylamino, arylmethylamino, etherified mercaptoamino, 2-acyl-
lower
alk-1-enylamino or silylamino group or in the form of an azido group.
~t~72~~5
-99-
In a corresponding acylamino group, acyl is, for example, the acyl radical of
an organic
carboxylic acid having, for example, up to 18 carbon atoms, especially an
unsubstituted or
substituted, for example halo- or aryl-substituted, lower alkanecarboxylic
acid or an
unsubstituted or substituted, for example halo-, lower alkoxy- or nitre-
substituted, benzoic
acid, or, preferably, of a carbonic acid semi-aster. Such acyl groups are, for
example,
lower allcanoyl, such as formyl, acetyl, propionyl or pivaloyl, halo-lower
alkanoyl, for
example 2-haloacetyl, such as 2-chloro- 2-bromo-, 2-iodo-, 2,2,2-trifluoro- or
2,2,2-tri-
chloro-acetyl, unsubstituted or substituted, for example halo-, lower alkoxy-
or nitro-
substituted, benzoyl, such as benzoyl, 4-chlorobenzoyl, 4-methoxybenzoyl or 4-
nitro-
benzoyl, lower alkoxycarbonyl, preferably lower alkoxycarbonyl that is
branched in the
1-position of the lower alkyl radical or suitably substituted in the 1- or 2-
position, for
example tert-lower alkoxycarbonyl, such as tert-butoxycarbonyl,
arylmethoxycarbonyl
having one, two or three aryl radicals which are phenyl that is unsubstituted
or mono- or
poly-substituted, for example, by lower alkyl, especially tert-lower alkyl,
such as
tert-butyl, lower alkoxy, such as methoxy, hydroxy, halogen, such as chlorine,
and/or by
nitre, for example benzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,
diphenylmethoxy-
carbonyl, 9-fluorenylmethoxycarbonyl or di(4-methoxyphenyl)methoxycarbonyl,
aroyl-
methoxycarbonyl wherein the aroyl group is preferably benzoyl that is
unsubstituted or
substituted, for example, by halogen, such as bromine, for example
phenacyloxycarbonyl,
2-halo-lower alkoxycarbonyl, for example 2,2,2-trich',loroethoxycarbonyl, 2-
bromoethoxy-
carbonyl or 2-iodoethoxycarbonyl, 2-(tri-substituted silyl)-lower
alkoxycarbonyl, for
example 2-tri-lower alkylsilyl-lower alkoxycarbonyl, such as 2-
trimethylsilylethoxy-
carbonyl or 2-(di-n-butyl-methyl-silyl)-ethoxycarbonyl, or triarylsilyl-lower
alkoxy-
carbonyl, for example 2-triphenylsilylethoxycarbonyl.
In an arylmethylamino group, which is, for example, a mono-, di- or especially
tri-aryl-
methylamino group, the aryl radicals are especially unsubstituted or
substituted phenyl
radicals. Such groups are, for example, benzyl-, diphenylmethyl- or especially
trityl-
amino.
In an etherified mercaptoamino group the mercapto group is especially in the
form of
substituted arylthio or aryl-lower alkylthio, wherein aryl is, for example,
phenyl that is
unsubstituted or substituted, for example, by lower alkyl, such as methyl or
test-butyl,
lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by nitre, for
example
4-nitrophenylthio.
20'~~~5
ioo
In a 2-acyl-lower alk-1-enyl radical that can be used as an amino-protecting
group, acyl is,
for example, the corresponding radical of a lower alkanecarboxylic acid, of a
benzoic acid
that is unsubstituted or substituted, for example, by lower alkyl, such as
methyl or tert-
butyl, lower alkoxy, such as methoxy, halogen, such as chlorine, and/or by
nitro, or
especially of a carbonic acid semi-ester, such as a carbonic acid lower alkyl
semi-ester.
Corresponding protecting groups are especially 1-lower alkanoyl-lower alk-1-en-
2-yl, for
example 1-lower alkanoyiprop-1-en-2-yl, such as 1-acetylprop-1-en-2-yl, or
lower alkoxy-
carbonyl-lower alk-1-en-2-yl, for example lower alkoxycarbonyl-prop-1-en-2-yl,
such as
1-ethoxycarbonylprop-1-en-2-yl.
A silylamino group is, for example, a tri-lower alkylsilylamino group, for
example
trimethylsilylamino or tert-butyl-dimethylsilylamino. The silicon atom of the
silylamino
group can also be substituted by only two lower alkyl groups, for example
methyl groups,
and the amino group or carboxy group of a second molecule of formula I.
Compounds
having such protecting groups can be prepared, for example, using the
corresponding
chlorosilanes, such as dimethylchlorosilane, as silylating agents.
An amino group can also be protected by conversion into the protonated form;
suitable
corresponding anions are especially those of strong inorganic acids, such as
sulfuric acid,
phosphoric acid or hydrohalic acids, for example the chlorine or bromine
anion, or of
organic sulfonic acids, such as p-toluenesulfonic acid.
Preferred amino-protecting groups are lower alkoxycarbonyl, phenyl-lower
alkoxycar-
bonyl, fluorenyl-lower alkoxycarbonyl, 2-lower alkanoyl-lower alk-1-en-2-yl
and lower
alkoxycarbonyl-lower allc-1-en-2-yI.
A hydroxy group can be protected, fox example, by an acyl group, for example
lower
alkanoyl substituted by halogen, such as chlorine, such as 2,2-dichloroacetyl,
or especially
by an acyl radical of a carbonic acid semi-ester mentioned for protected amino
groups. A
preferred hydroxy-protecting group is, for example, 2,2,2-
trichloroethoxycarbonyl,
4-nitrobenzyloxycarbonyl, diphenylmethoxycarbonyl or trityl. A hydroxy group
can also
be protected by tri-lower alkylsilyl, for example trimethylsilyl,
triisopropylsilyl or tert-
butyl-dimethylsilyl, a readily removable etherifying group, for example an
alkyl group,
such as tert-lower alkyl, for example tert-butyl, an oxa- or a thia-aliphatic
or -cyclo-
aliphatic, especially 2-oxa- or 2-thia-aliphatic or -cycloaliphatic,
hydrocarbon radical, for
zo~z~~~
-101-
example 1-lower alkoxy-lower alkyl or 1-lower alkylthio-lower alkyl, such as
methoxy-
methyl, 1-methoxyethyl, 1-ethoxyethyl, methylthiomethyl, 1-methylthioethyl or
1-ethyl-
thioethyl, or ~-oxa- or 2-thia-cycloalkyl having from 5 to 7 ring atoms, such
as 2-tetra-
hydrofuryl or 2-tetrahydropyranyl, or a corresponding thia analogue, as well
as by
1-phenyl-lower allcyl, such as benzyl, diphenylmethyl or trityl, wherein the
phenyl radicals
can be substituted, for example, by halogen, for example chlorine, lower
alkoxy, for
example methoxy, and/or by nitro.
Two hydxoxy groups, especially adjacent hydroxy groups, occurring in a
molecule, or a
hydroxy group and an amino group that are adjacent to one another, can be
protected, for
example, by bivalent protecting groups, such as a methylene group that is
preferably
substituted, for example, by one or two lower alkyl radicals or by oxo, for
example
unsubstituted or substituted alkylidene, for example lower alkylidene, such as
isopropyl-
idene, cycloalkylidene, such as cyclohexylidene, a carbonyl group or
benzylidene.
A mercapto group, for example in cysteine, can be protected especially by S-
alkylation
with unsubstituted or substituted alkyl radicals, by silylation, by thioacetal
formation, by
S-acylation or by the formation of asymmetric disulfide groupings. Preferred
mercapto-
protecting groups are, for example, benzyl that is unsubstituted or
substituted in the phenyl
radical, for example by methoxy or by vitro, such as ~l-methoxybenzyl,
diphenylmethyl
that is unsubstituted or substituted in the phenyl radical, fox example by
methoxy, such as
di-(4-methoxyphenyl)-methyl, triphenylmethyl, pyxidyldiphenylmethyl,
trimethylsilyl,
benzylthiomethyl, tetrahydropyranyl, acylaminomethyl, such as acetamidomethyl,
iso-
butyrylacetamidomethyl or 2-chloroacetamidomethyl, benzoyl, benzyloxycarbonyl
or
alkyl-, especially lower alkyl-aminocarbonyl, such as ethylaminocarbonyl, as
well as
lower alkylthio, such as S-ethylthio or S-tent-butylthio, ar S-sulfo.
A sulfo group can be protected, for example, by lower allcyl, for example
methyl or ethyl,
by phenyl or in the form of a sulfonamide, for example in the form of an
imidazolide.
In the context of this Application, a protecting group, for example a carboxy-
protecting
group, is to be understood as being expressly also a polymeric carrier that is
bonded in a
readily removable manner to the functional group, for example the carboxy
gxoup, to be
protected, for example a earner suitable for the Merrifield synthesis. An
example of such
a suitable polymeric carrier is a polystyrene resin, weakly cross-linked by
copolymerisa-
tion with divinylbenzene, that carries bridge members suitable for reversible
bonding.
~o~~~~
- 102 -
The addition of the compounds of formula III to the epoxides of fornaula IV is
preferably
effected under the reaction conditions customary for the addition of
nucleophiles to
epoxides.
The addition is effected especially in aqueous solution and/or in the presence
of polar
solvents, such as alcohols, for example methanol, ethanol or ethylene glycol,
ethers, such
as dioxane, amides, such as dimethylformamide, or phenols, such as phenol, and
also
under anhydrous conditions, in apolar solvents, such as benzene and toluene,
or in
benzene/water emulsions, where appropriate in the presence of acid or basic
catalysts, for
example hydroxide solutions, such as sodium hydroxide solution, or in the
presence of
solid phase catalysts doped with the hydrazine, such as aluminium oxide, in
ethers, for
example diethyl ether, in general at temperatures of approximately from
0°C to the boiling
temperature of the reaction mixture in question, preferably from 20° to
130°C, where
appropriate under reflux, under increased pressure, for example in a bomb
tube, it being
possible also to exceed the boiling temperature, and/or under inert gas, such
as nitrogen or
argon, it being possible for each of the two compounals of formula III and N
to be present
in excess, for example in a molar ratio of from 1:1 to 1:100, preferably in a
molar ratio of
from 1:1 to 1:10, especially in a ratio of from 1:1 to 1:3.
The freeing of protected groups is effected as appropriate by the methods
described under
Process f) Removal of protecting groups).
Process b) (Formation of an amide bond)
In starting materials of formulae V and VI, functional groups, with the
exception of the
groups that are intended to participate in the reaction or that do not react
under the
reaction conditions, are protected each independently of the others by one of
the protecting
groups mentioned under Process a).
The compounds of formula VI contain a free carboxy, sulfo or phosphoryl group
or
reactive acid derivatives thereof, for example the derived activated esters or
reactive
anhydrides, and also reactive cyclic amides. The reactive acid derivatives can
also be
formed fn citu.
Activated esters of compounds of formula VI having a terminal carboxy group
are
~0~~7~5
- 103 -
especially esters unsaturated at the linking carbon atom of the esterifying
radical, for
example of the vinyl ester type, such as vinyl esters (obtainable, for
example, by traps-
esterification of a corresponding ester with vinyl acetate; activated vinyl
ester method),
carbamoyl esters (obtainable, for'example, by treatment of the corresponding
acid with an
isoxazolium reagent; 1,2-oxazolium or Woodward method), or 1-lower alkoxyvinyl
esters
(obtainable, for example, by treatment of the corresponding acid with a lower
alkoxy-
acetylene; ethoxyacetylene method), or esters of the amidino type, such as
N,N'-disub-
stituted amidino esters (obtainable, for example, by treatment of the
corresponding acid
with a suitable N,N'-disubstituted carbodiimide, for example N,N'-
dicyclohexylcarbo-
cliimide; carbodiimide method), or N,N-disubstituted amidino esters
(obtainable, for
example, by treatment of the corresponding acid with an N,N-disubstituted
cyanamide;
cyanamide method), suitable aryl esters, especially phenyl esters suitably
substituted by
electron-attracting substituents (obtainable, for example, by treatment of the
corres-
ponding acid with a suitably substituted phenol, for example 4-nitrophenol, 4-
methyl-
sulfonylphenol, 2,4,5-trichlorophenol, 2,3,4,5,6-pentachlorophenol or 4-
phenyldiazo-
phenol, in the presence of a condensation agent, such as N,N'-
dicyclohexylcarbodiimide;
activated aryl esters method), cyanomethyl esters (obtGunable, for example, by
treatment
of the corresponding acid with chloroacetonitrile in tht; presence of a base;
cyanomethyl
esters method), thioesters, especially unsubstituted or substituted, for
example nitro-
substituted, phenylthio esters (obtainable, for example, by treatment of the
corresponding
acid with unsubstituted or substituted, for example nitro-substituted,
thiophenols, inter
adia by the anhydride or carbadiimide method; activated thiol esters method),
or especially
amino or amido esters (obtainable, for example, by treatment of the
corresponding acid
with an N-hydroxyamino or N-hydroxyamido compound, for example N-hydroxysuccin-
imide, N-hydroxypiperidine, N-hydroxyphthalimide, N-hydroxy-5-norbornene-2,3-
di-
carboxylic acid imide, 1-hydroxybenzotriazole or 3-hydroxy-3,4-dihydro-1,2,3-
benzo-
triazin-4-one, for example by the anhydride or carbodiimide method; activated
N-hydroxy
esters method). Internal esters, for example y-lactones, can also be used.
Anhydrides of acids may be symmetric or preferably mixed anhydrides of those
acids, for
example anhydrides with inorganic acids, such as acid halides, especially acid
chlorides
(obtainable, for example, by treatment of the corresponding acid with thionyl
chloride,
phosphorus pentachloride, phosgene or oxalyl chloride; acid chloride method),
azides
(obtainable, for example, from a corresponding acid ester via the
corresponding hydrazide
by treatment thereof with nitrous acid; azide method), anhydrides with
carbonic acid
semi-esters, for example carbonic acid lower alkyl semi-esters (obtainable,
for example,
20~2~~~
- 104 -
by treatment of the corresponding acid with chloroformic acid lower alkyl
esters or with a
1-lower alkaxycarbonyl-2-lower alkoxy-1,2-dihydroquinoline; mixed (?-
alkylcarbonic
acid anhydrides method), or anhydrides with dihalogenated, especially
dichlarinated,
phosphoric acid (obtainable, for example, by treatment of the corresponding
acid with
phosphorus oxychloride; phosphorus oxychloride method), anhydrides with other
phosphoric acid derivatives (for example those obtainable with phenyl-N-
phenylphosphor-
amidochloridate or by reaction of alkylphosphoric acid amides in the presence
of sulfonic
acid anhydrides and/or racemisation-reducing additives, such as N-
hydroxybenzotriazole,
or in the presence of cyanophosphonic acid diethyl ester) or with phosphorous
acid deriv-
atives, or anhydrides with organic acids, such as mixed anhydrides with
organic acids,
such as mixed anhydrides with organic carboxylic acids (obtainable, for
example, by treat-
ment of the corresponding acid with an unsubstituted or substituted lower
alkane- or
phenyl-lower alkane-carboxylic acid halide, for example phenylacetic acid
chloride,
pivalic acid chloride or trifluoroacetic acid chloride; mixed carboxylic acid
anhydrides
method) or with organic sulfonic acids (obtainable, fo:r example, by treatment
of a salt,
such as an alkali metal salt, of the corresponding acid with a suitable
organic sulfonic acid
halide, such as lower alkane- or aryl-, for example methane- or p-toluene-
sulfonic acid
chloride; mixed sulfonic acid anhydrides method) and symmetric anhydrides
(obtainable,
for example, by condensation of the corresponding acid in the presence of a
carbodiimide
or 1-diethylaminopropyne; symmetric anhydrides method).
Suitable cyclic amides are especially amides having five-membered diazacycles
of
aromatic character, such as amides with imidazoles, for example imidazole
(obtainable,
for example, by treatment of the corresponding acid with N,N'-
carbonyldiimidazole;
imidazole method), or pyrazole, for example 3,5-dimethylpyrazole (obtainable,
for
example, via the acid hydrazide by treatment with acetylacetone; pyrazolide
method).
As mentioned, derivatives of carboxylic acids that are used as acylating
agents can also be
formed in situ. For example, N,N'-disubstituted amidino esters can be fozmed
in situ by
reacting a mixture of the starting material of formula V and the acid used as
acylating
agent, in the presence of a suitable N,N'-disubstituted carbodiimide, for
example
N,N'-cyclohexylcarbodiimide. In addition, amino or amido esters of the acids
used as
acylating agents can be formed in the presence of the starting material of
formula V to be
acylated, by reacting a mixture of the corresponding acid and amino starting
materials in
the presence of an N,N'-disubstituted carbodiimide, for example N,N'-
dicyclohexylcarbo-
diimide, and of an N-hydroxyamine or N-hydroxyamide, for example N-
hydroxysuccin-
~o~~~~~
- 105
imide, where appropriate in the presence of a suitable base, for example 4-
dimethyl-
amino-pyridine. Moreover, activation in situ can be achieved by reaction with
N,N,N',N'-tetraalkyluronium compounds, such as O-benzotriazol-1-yl-N,N,N',N'-
tetra-
methyluronium hexafluorophosphate, O-(1,2-dihydro-2-oxo-1-pyridyl)-N,N,N',N'-
tetra-
methyluronium tetrafluoroborate or O-(3,4-dihydro-4-oxo-1,2,3-benzotriazolin-3-
yl)-
N,N,N',N'-tetramethyluronium tetrafluoroborate. Finally, phosphoric acid
anhydrides of
the carboxylic acids of formula VI or VII can be prepared in situ by reacting
an alkyl-
phosphoric acid amide, such as hexamethylphosphoric acid triamide, in the
presence of a
sulfonic acid anhydride, such as 4-toluenesulfonic acid anhydride, with a
salt> such as a
tetrafluoroborate, for example sodium tetrafluoroborate, or with another
derivative of
hexamethylphosphoric acid triamide, such as benzotriazol-1-yloxy-
tris(dimethylamino)-
phosphonium hexafluoride, preferably in the presence of a racemisation-
reducing additive,
such as N-hydroxybenzotriazole.
In an analogous manner, many of the reaction types listed above for carboxylic
acids of
fornnula VI can also be carried out for compounds of formula III having a
terminal
sulfonyl or phosphoryl group in the condensation with compounds of formula V
to form
sulfonamides.
For example, it is possible to use activated sulfonic acid esters, for example
the corres-
ponding aryl esters, especially those substituted by nitro groups, such as
phenyl esters, it
being possible far the amine component of formula V also to be used in the
farm of an
alkali metal amide, for example an alkali metal arylamide, such as sodium
aniline amide,
or an alkali metal salt of nitrogen-containing heterocycles, for example
potassium
pyrrolide.
In addition, reactive anhydrides, such as the corresponding symmetric acid
anhydrides
(which can be prepared, for example, by reaction of the alkylsulfonic acid
silver salts with
alkylsulfonyl chlorides) or, preferably, the corresponding asymmetric acid
anhydrides, fox
example anhydrides with inorganic acids, such as sulfonyl halides, especially
sulfonyl
chlorides (obtainable, for example, by reaction of the corresponding sulfonic
acids with
inorganic acid chlorides, for example thionyl chloride, phosphon~s
pentachloride), with
organic carboxylic acids (obtainable, for example, by treatment of a sulfonic
acid halide
with the salt of a carboxylic acid, such as an alkali metal salt, analogously
to the above-
mentioned mixed sulfonic acid anhydrides method), or azides (obtainable, for
example,
from a corresponding sulfonic acid chloride and sodium azide or via the
corresponding
k t
_2~27~5
- 106 -
hydxazide and treatment thereof with nitrous acid analogously to the above-
mentioned
azide method).
The phosphoryl radicals IZ9 having the above-mentioned substituents can be
fused to
compounds of formula V by analogous processes, such as by means of activated
phosphorus derivatives, for example correspondingly substituted phosphoryl
halides
having one or more halogen atoms, such as phosphorus oxychloride, in the
absence or the
presence of bases, such as sterically hindered amines, in aqueous or non-
aqueous solvents,
any excess halogen atoms subsequently being replaced by suitable substituents
by hydrol-
ysis or by reactian with the corresponding alcohols. .
The phosphoryl radicals substituted by hydroxy, alkoxy, cycloalkoxy,
cycloalkyl-lower
alkoxy, aryloxy or by aryl-lower alkoxy can be reacted with the compounds of
formula V,
for example by reaction of the correspondingly substituted phosphates, for
example diaryl-
oxyphosphite or dialkoxyphosphite, or the correspondingly substituted mono- or
di-halo-,
such as mono- or di-chloro-phosphates, in the presence of a base, such as 2,6-
dimethyl-
pyridine, triethylamine or imidazole, in aqueous or anhydrous solvents, such
as alcohols,
far example ethanol, corresponding esters or dichloromethane or
tetrachlorometiiane,
where appropriate under a protective gas, such as argon, at temperatures of
from -50 to
100°C, preferably from -10 to 50°C, especially under the
conditions described in European
Patent .Application EP-A 0 376 040 published on 04.07.90.
The cozresponding phosphoryl radicals substituted symmetrically or,
preferably,
asymmetrically by the mentioned radicals bonded via oxy can be obtained by
reaction of
phosphorus trihalides, such as phosphorus trichloride, with the corresponding
amines of
formula V and in the presence of organic amines, such as triethylamine, the
corresponding
dichlorophosphoryl compounds being formed, reaction of those compounds with
the first
corresponding alcohol or with water which are preferably used in
stoichiometric amounts,
in the presence of a tertiary amine, and where appropriate subsequent reaction
of the
second halogen atom with a further alcohol ar water in the presence of a
tertiary amine, to
obtain the corresponding disubstituted phosphate compounds which are then
oxidised; for
example with halogens, such as iodine, peroxides, such as hydrogen peroxide,
peracids,
such as m-chloroperbenzoic acid, or with molecular oxygen.
The amino group of compounds of formula V that participates in the reaction
preferably
carnes at least one reactive hydrogen atom, especially when the carboxy,
sulfonyl or
- 107 -
phosphoryl group with which it reacts is present in reactive form; it may,
however, itself
have been derivatised, for example by reaction with a phosphite, such as
diethylchloro-
phosphite, 1,2-phenylenechlorophosphite; ethyl dichlorophosphite,
ethylenechloro- '
phosphite or tetraethylpyrophosphite. A derivative of such a compound having
an amino
group is, for example, also a carbamic acid halide or an isocyanate, the amino
group that
participates in the reaction being substituted by halocarbonyl, for example
chlorocarbonyl,
or being modified in the form of an isocyanate group; in the latter case only
compounds of
formula I that carry a hydrogen atom at the nitrogen atom of the amide group
formed by
the reaction are obtainable.
If the compound of formula V is mono-substituted at the amino group by lower
allyl or by
aryl-lower alkyl, then a corresponding urea compound also constitutes a
reactive
derivative, For example, on hating equimolar amounts of that urea compound and
the
compound of formula VI or VIII having a free carboxy group, corresponding
compounds
of formula I are obtained.
Condensation for the preparation of an amide bond can be earned out in a
manner.known
per se, for example as described in standard works such as "Houben-Weyl,
Methoden der
organischen Chemie", 4th edition, Volume 15/II (1974), Volume 1X (1955) Volume
E 11
(1985), Georg Thieme Verlag, Stuttgart, "The Peptidea" (E. Gross and J.
Meienhofer,
eds.), Volumes 1 and 2, Academic Press, London and New York, 1979/1980, or M.
Bodansky, "Principles of Peptide Synthesis", Springer-Verlag, Berlin 1984.
The condensation of a free carboxylic acid with the corresponding amine can be
carried
out preferably in the presence of one of the customary condensation agents, or
using
carboxylic acid anhydrides or carboxylic acid halides, such as chlorides, or
activated
carboxylic acid esters, such as p-nitrophenyl esters. Customary condensation
agents are,
for example, carbodiimides, for example diethyl-, dipropyl-, N-ethyl-N'-(3-
dimethyl-
aminopropyl)-carbodiimide or especially dicyclohexylcarbodiimide, also
suitable carbonyl
compounds, for example carbonylimidazole, 1,2-oxazolium compounds, for example
2-ethyl-5-phenyl-1,2-oxazolium 3'-sulfonate and 2-tert-butyl-5-
methylisoxazolium
perchlorate, or a suitable acylaznino compound, for example 2-ethoxy-1-
ethoxycarbonyl-
1,2-dihydroquinoline, N,N,N',N'-tetraalkyluronium compounds, such as O-
benzotri-
azol-1-yl-N,N,N',N'-tetramethyluroniurn hexafluorophosphate, also activated
phosphoric
acid derivatives, far example diphenylphosphoryl azide, diethylphosphoryl
cyanide,
phenyl-N-phenylphosphoroamidochloridate, bis(2-oxo-3-oxazolidinyl)phosphinic
acid
20°~2~~5
- 108
chloride or 1-benzotriazolyloxy-tris(dimethylamino)phosphonium
hexafluorophosphate.
If desired, an organic base is added, preferably a tertiary amine, for example
a tri-lower
alkylamine having bulky radicals, for example ethyl diisopropylamine or
triethylamine,
and/or a heterocyclic base, for example 4-dimethylaminopyridine or preferably
N-methyl-
morpholine or pyridine.
The condensation of activated esters, reactive anhydrides or reactive cyclic
amides with
the corresponding amines is customarily carried out in the presence of an
organic base, for
example simple tri-lower alkylamines, for example triethylamine or
tributylamine, or one
of the above-mentioned organic bases. If desired, a condensation agent is
additionally
used, for example as described for free carboxylic acids.
The condensation of acid anhydrides with amines can be effected, for example,
in the
presence of inorganic carbonates, for example ammonium or alkali metal
carbonates or
hydrogen carbonates, such as sodium or potassium carbonate or hydrogen
carbonate (if
desired together with a sulfate).
Carboxylic acid chlorides, for example the chlorocarbonic acid derivatives
derived from
the acid of formula VI, or sulfonic acid chlorides are Condensed with the
corresponding
amines preferably in the pxesence of an organic amine, for example the above-
mentioned
tri-lower alkylarnines or heterocyclic bases, where appropriate in the
presence of a
hydrogen sulfate.
The condensation is preferably carried out in an inert, aprotic, preferably
anhydrous,
solvent or solvent mixture, for example in a carboxylic acid amide, for
example
formamide or dimethylformamide, a halogenated hydrocarbon, for example
methylene
chloride, carbon tetrachloride or chlorobenzene, a ketone, for example
acetone, a cyclic
ether, for example tetrahydrofuran, an ester, for example ethyl acetate, or a
nitrite, for
example acetanitrile, or in a mixture thereof, as appropriate at reduced or
elevated
temperature, for example in a temperature range of from approximately -
40°C to approx-
imately +100°C, preferably from approximately -10°C to
approximately +50°C, and in the
case where arylsulfonyl esters are used also at approximately from
+100°C to +200°C, and
where appropriate under an inert gas atmosphere, for example a nitrogen or
argon
atmosphere.
2.0~2~~
- 109 -
Aqueous, for example alcoholic, solvents, for example ethanol, or aromatic
solvepts, for
example benzene or toluene, may also be used. When alkali metal hydroxides are
present
as bases, acetone can also be added where appropriate.
The condensation can also be carried out in accordance with the technique
known as solid
phase synthesis which originates from R. Merrifield and is described, far
example, in
Angew. Chem. 97, 801 - 812 (1985), Naturwissenschaften 71, 252 - 258 (1984) or
in R. A.
Houghten, Proc. Natl. Aced. Sci. USA 82, 5131 - 5135 (1985).
Depending on the starting compounds used, the radicals Rt and R9 in the
obtainable
compounds of formula I can be identical or different from one another.
The freeing of protected groups is effected where appropriate by the methods
described
under Process f) (Removal of protecting groups).
Process c) (Formation of an amide bond)
In starting materials of formulae VII and VIII, functional groups, with the
exception of the
groups that are intended to participate in the reaction or that do not react
under the
reaction conditions, are protected each independently of the others by one of
the protecting
groups mentioned under Process a).
The process is totally analogous to the process mentioned under Process b)
except that
instead of compounds of formula V those of formula VII are used, and instead
of
compounds of formula VI those of formula VITI are used, and, in the case of
the acylation,
Rt instead of R9 bonds to compounds of formula VII instead of the compounds of
formula V.
Depending on the starting materials used, the radicals Rl and R9 in the
obtainable
compounds of fozxnula I can be identical or different from one another.
The freeing of protected groups is effected where appropriate by the methods
described
under Process f) (Removal of protecting groups).
Process d) (Formation of an amide bond)
~U~27~5
- 110 -
In starting materials of formula IX and in the acid suitable for introducing
the identical
radicals R1 and R9, or the reactive derivatives thereof, functional groups
that are riot
intended to participate in the reaction or that do not react under the
reaction conditions are
protected each independently of the others by one of the protecting groups
mentioned
under Process a).
The acid suitable for introducing the identical radicals Rl and R9 is
preferably an acid of
formula VI or VIII.
Preferred as starting materials of formula IX that may be protected by
protecting groups
are those of formula II which are described below in the section relating to
starting
materials.
The process is totally analogous to the process mentioned under Process b),
except that
instead of compounds of formula V those of formula IX are used, and instead of
compounds of formula VI those of formula VI or VIII are used.
The freeing of protected groups is effected where appropriate by the methods
described
under Process f) (Removal of protecting groups).
Process e) (Alkylation of a secondary nitrogen atom)
In starting materials of formula I' and in the compound of formula XII
suitable for intro-
ducing the radical R~", or the reactive derivatives thereof, functional groups
that are not
intended to participate in the reaction or that do not react under the
reaction conditions are
protected each independently of the others by one of the protecting groups
mentioned
under Process a).
A leaving group X is especially a nucleofugal leaving group selected from
hydroxy esteri-
fied by a strong inorganic or organic acid, such as hydroxy esterified by a
mineral acid, for
example a hydrohalic acid, such as hydrochloric acid, hydrobromic acid or
hydriodic acid,
or by a strong organic sulfonic acid, such as a lower alkanesulfonic acid that
is unsubsti-
tuted or substituted, for example by halogen, such as fluorine, or an aromatic
sulfonic acid,
for example a benzenesulfonic acid that is unsubstituted or substituted by
lower alkyl,
such as methyl, halogen, such as bromine, and/or by nitro, for example a
methanesulfonic
acid, p-bromotoluenesulfonic acid or p-toluenesulfonic acid, or hydroxy
esterified by
207275
- 111 -
hydrazoic acid.
The substitution can take place under the conditions of a first-order or
second-order
nucleophilic substitution. '
For example, the compound of formula XII wherein X is a leaving group having a
high
polarisability of the electron shell, for example iodine, can be reacted in a
polar apzotic
solvent, for example acetone, acetonitrile, nitromethane, dimethyl sulfoxide
or dimethyl-
formamide. The reactionmay also be carried out in water to which, where
appropriate, an
organic solvent, for example ethanol, tetrahydrofuran or acetone, has been
added as
solubiliser. The substitution reaction is carried out as appropriate at
reduced or elevated
temperature, for example in a temperature range of from approximately -
40° to
approximately 100°C, preferably from approximately -10° to
approximately 50°C, and
where appropriate under an inert gas, for example under a nitrogen or argon
atmosphere.
The freeing of protected groups is effected where appropriate by the methods
described
under Process f) (Removal of protecting groups).
Process f) (Removal of protecting groups)
The xemoval of protecting groups that are not constituents of the desired end
product of
formula I, for example the carboxy-, amino-, hydroxy-, mercapto- and/or sulfo-
protecting
groups, is effected in a manner known her se, for example by means of
solvolysis,
especially hydrolysis, alcoholysis or acidolysis, or by means of reduction,
especially
hydrogenolysis or chemical reduction, as well as by photolysis, as appropriate
stepwise or
simultaneously, it being possible also to use enzymatic methods. The removal
of the
protecting groups is described, for example, in the standard works mentioned
above in the
section relating to "Protecting groups".
For example, protected carboxy, for example tert-lower alkoxycarbonyl, lower
alkoxy-
carbonyl substituted in the 2-position by a trisubstituted silyl group or in
the 1-position by
lower alkoxy or lower alkylthio, or unsubstituted or substituted
diphenylmethoxycarbonyl
can be converted into free carboxy by treatment with a suitable acid, such as
formic acid,
hydrogen chloride or trifluoroacetic acid, where appropriate with the addition
of a nucleo-
philic compound, such as phenol or anisole. Carboxy can also be freed from
lower
alkoxycarbonyl by means of bases, such as hydroxides, for example alkali metal
112 -
hydroxides, such as sodium hydroxide or potassium hydroxide. Unsubstituted or.
substituted benzyloxycarbonyl can be freed, for example, by means of
hydrogenolysis, i.e.
by treatment with hydrogen in the presence of a metal hydrogenation catalyst,
such as a '
palladium catalyst. In addition, suitably substituted benzyloxycarbonyl, such
as 4-nitro-
benzyloxycarbonyl, can also be converted into free carboxy by reduction, for
example by
treatment with an alkali metal dithionate, such as sodium dithionate, or with
a reducing
metal, for example zinc,, or a reducing metal salt, such as a chromium(II)
salt, for example
chromium(II) chloride, customarily in the presence of a hydrogen-yielding
agent that,
together with the metal, is capable of producing nascent hydrogen, such as an
acid,
especially a suitable carboxylic acid, such as an unsubstituted or
substituted, for example
hydroxy-substituted, lower alkanecarboxylic acid, for example acetic acid,
formic acid,
glycolic acid, diphenylglycolic acid, lactic acid, mandelic acid, 4-
chloromandelic acid or
tartaric acid, or in the presence of an alcohol or thiol, water preferably
being added. By
treatment with a reducing metal or metal salt, as described above, 2-halo-
lower alkoxy-
carbonyl (where appropriate after conversion of a 2-bromo-lower alkoxycarbonyl
group
into a corresponding 2-lode-lower alkoxycarbonyl group) or
aroylmethoxycarbonyl can
also be converted into free carboxy. Aroylmethoxycarbonyl can also be cleaved
by
treatment with a nucleophilic, preferably salt-forming, reagent, such as
sodium thio-
phenolate or sodium iodide. 2-(tri-substituted silyl)-It>wer alkoxycarbonyl,
such as 2-tri-
lower alkylsilyl-lower alkoxycarbonyl, can also be converted into free carboxy
by
treatment with a salt of hydrofluoric acid that yields the fluoride anion,
such as an alkali
metal fluoride, for example sodium or potassium fluoride, where appropriate in
the
presence of a macrocyclic polyether ("Crown ether"), or with a fluoride of an
organic
quaternary base, such as tetra-lower alkylammonium fluoride or tri-lower
alkylaryl-lower
alkylammonium fluoride, for example tetraethylammonium fluoride or tetrabutyl-
amtnonium fluoride, in the presence of an aprotic, polar solvent, such as
dimethyl
sulfoxide or N,N-dimethylacetamide. Carboxy protected in the form of organic
silyloxy-
carbonyl, such as tri-lower alkylsilyloxycarbonyl, for example
trimethylsilyloxycarbonyl,
can be freed in customary manner by solvolysis, for example by treatment with
water, an
alcohol or an acid, or, furthermore, a fluoride, as described above.
Esterified carboxy can
also be freed enzymatically, for example by means of esterases or suitable
peptidases, for
example esterified arginine or lysine, such as lysine methyl ester, using
trypsin.
A protected amino group is freed in a manner known Qer se and, according to
the nature of
the protecting groups, in various ways, preferably by solvolysis or reduction.
Lower
alkaxycarbonylamino, such as tent-butoxycarbonylamino, can be cleaved in the
presence
2f~~2~'~~
- 113 -
of acids, for example mineral acids, far example a hydrogen halide, such as
hydrogen
chloride or hydrogen bromide, or sulfuric or phosphoric acids, preferably
hydrogen
chloride, or strong organic acids, such as trihaloacetic acid, far example
trifluaxoacetic
acid, or formic acid, in polar solvents, such as water, or ethers, preferably
cyclic ethers,
such as dioxane, 2-halo-lower alkoxycarbonylamino (where appropriate after
conversion
of a 2-bromo-lower alkoxycarbonylamino group into a 2-iodo-lower
alkoxycarbonylamino
group), or dissolved directly in a liquid organic carboxylic acid, such as
formic acid and
aroylmethoxycarbonylamino or 4-nitrobenzyloxycarbonylamino can be cleaved, for
example, by treatment with a suitable reducing agent, such as zinc in the
presence of a
suitable carboxylic acid, such as aqueous acetic acid.
Aroylmethoxycarbonylamino can
also be cleaved by treatment with a nucleophilic, preferably salt-forming,
reagent, such as
sodium thiophenolate, and 4-nitrobenzyloxycarbonylamino also by treatment with
an
alkali metal dithionate, for example sodium dithionate. Unsubstituted or
substituted
diphenylmethoxycarbonylamino, ten-lower alkoxycarbonylamino or 2-(tri-
substituted
silyl)-lower alkoxycarbonylamino, such as 2-tri-lower alkylsilyl-lower
alkoxycarbonyl-
amino, can be freed by treatment with a suitable acid, fox example formic acid
or trifluoro-
acetic acid; unsubstituted or substituted benzyloxycar'bonylamino can be
freed, for
example, by means of hydrogenolysis, i.e. by treatment with hydrogen in the
presence of a
suitable hydrogenation catalyst, such as a platinum or palladium catalyst;
unsubstituted or
substituted triarylmethylamino or formylamino can be; freed, for example, by
treatment
with an acid, such as a mineral acid, for example hydrochloric acid, or an
organic acid, for
example formic, acetic or trifluoroacetic acid, where appropriate in the
presence of water;
and an amino group protected in the form of silylamino can be freed, for
example, by
means of hydrolysis or alcoholysis. An amino group protected by 2-haloacetyl,
for
example 2-chloroacetyl, can be freed by treatment with thiourea in the
presence of a base,
or with a thiolate salt, such as an alkali metal thiolate of thiourea, and
subsequent
solvolysis, such as alcoholysis or hydrolysis, of the resulting substitution
product; and
amino is freed from trifluoroacetylamino, for example, by hydrogenolysis with
bases, such
as alkali metal hydroxides or carbonates, such as Na2C03 or K~C03, in polar
solvents, for
example alcohols, such as methanol, at temperatures of from 0 to 100°C,
especially at
from ~0 to 80°C. An amino group protected by 2-(tri-substituted silyl)-
lower alkoxy-
carbonyl, such as 2-tri-lower alkylsilyl-lower alkoxycarbonyl, can also be
converted into
the free amino group by treatment with a salt of hydrofluoric acid that yields
fluoride
anions as indicated above in connection with the freeing of a correspondingly
protected
carboxy group. Likewise, silyl bonded directly to a hetero atom, such as
nitrogen, such as
trimethylsilyl, can be removed using fluoride ions.
CA 02072785 2003-04-17
X1489-8495
-114-
Amino protected iri the form of an azido group is converted into free amino,
for example,
'by reduction, for example by catallrtic hydrogenation with hy~Irogen in the
presence of a'
.ra.r
hydrogenation catalyst, such as platinum oxide, palladium or ltaney nickel, by
reduction
using mercapto compounds, such a.s dithiothreitoi or mercaptcaethanol, or by
treatment
with zinc in the presence of an acid, such as acetic acid. 'fhe catalytic
hydrogenation is
preferably carried out in an inert solvent, such as a halogenated hydrocarbon,
for example
methylene chloride, or in water or in a mixture of water and an organic
salvent, such as an
alcohol or dioxane, at approximately from 2U°C to 25°C, or with
cooling or heating.
A hydroxy or mercapto group protected by a suitable aryl group, a tri-lower
alkylsilyl
grroup or by unsubstituted or substituted 1-phenyl-lower alkyl is freed
analogously to a
correspondingly protected amino group, A hydroxy or mercapto group protected
by
2,2-dichloroacetyl is freed, for exarn,ple, by basic hydrolysis, and a hydroxy
or mercapto
L,~roup protected by tent-lower alkyl or by a 2-oxa- or 2-thin-aliphatic or -
cycloaliphatic
hydrocarbon radical is freed by acidolysis, for example by treatment with a
mineral acid or
a strong carboxylic acid, for example trifluoroacetic acid. Mercapto protected
by pyridyl-
diphenylmethyl can be freed, for example, using mercury(II) salts at pH 2-6 or
by zinc/-
acetic acid or by electrolytic reduction; acetamidomethyl and
isabutyrylamidomethyl can
be freed, for example, by reaction with mercury~Ii) salts at p1=1 2-6; 2-
chloroacetamido-
rnethyl can be freed, for example, using I-piperidirtothiocar~boxamide; and S-
ethylthio,
S-ten-butylthio and S-sulfa can be freed, for example, by t.ltiolysis with
thiophenol, thio-
glycolic acid, sodium thiophenolate: or l,~-dithiothreitol. "fwc~ hydroxy
groups or an
adjacent amino and hydroxy group which are protected togethc;r by means of a
bivalent
protecting group, preferably, for example, by a methylene grotap mono- or di-
substituted
by lower alkyl, such as lower alkylidene, for example isapropylidene,
cycloalkylidene, for
example cyclohexylidene, or benzylidene, can be freed by acid solvolysis,
especially in
the presence of a mineral acid or a strong organic acid, A tri-lower
alkylsilyl group is
Izkewise removed by acidolysis, for example by a mineral acid, preferably
hydrofluoric
acid, or a strong carboxylic acid. 2-halo-lower allCOxwcarbony~ is removed
using the
above-mentioned reducing agents, 1'or exancple a reducing; metal, such as
zinc, reducing
metal salts, such as chrorrciurn(II) s4~lts, or by sulfur ccampounds, for
example sodium
dithionate or preferably sodium sulfide and carbon cii:~ulfide.
A sulfa group protected in the for~rn of a sulfonic acid ester or ~.
sulfonarnicle is freed, for
example, by acid hydrolysis, for example in the presence of a mineral acid, or
preferably
~~~~7~5
l I5 -
by basic hydrolysis, for example with alkali metal hydroxide or alkali metal
carbonate, for
example sodium carbonate.
When several protected functional groups are present, if desired the
protecting groups can
be so selected that more than one such group can be removed simultaneously,
for example
by acidolysis, such as by treatment with trifluoroacetic acid, or with
hydrogen and a
hydrogenation catalyst, such as a palladium-on-carbon catalyst. Conversely,
the groups
can also be so selected that they cannot all be removed simultaneously, but
rather in a
desired sequence, the corresponding intermediates being obtained.
Additional Process Steps
In the additional process steps, which are optional, functional groups of the
starting
compounds that are not to take part in the reaction may be in unprotected or
protected
form, for example may be protected by one or mare of the protecting groups
mentioned
above under Pxocess a). The protecting groups may be retained in the end
products or
some or all of them may be removed according to one of the methods mentioned
under
Process f).
Salts of compounds of formula I having at least one salt-forming group may be
prepared in
a manner known per se. For example salts of compounds of formula I having acid
groups
may be formed, for example, by treating the compounds with metal compounds,
such as
alkali metal salts of suitable organic carboxylic acids, e.g. the sodium salt
of 2-ethyl-
hexanoic acid, with organic alkali metal or alkaline earth metal compounds,
such as the
corresponding hydroxides, carbonates or hydrogen carbonates, such as sodium or
potassium hydroxide, carbonate or hydrogen carbonate, with corresponding
calcium
compounds or with ammonia or a suitable organic amine, stoichiometric amounts
or only
a small excess of the salt-forming agent preferably being used. Acid addition
salts of
compounds of formula I are obtained in customary manner, e.g. by treating the
compounds
with an acid or a suitable anion exchange reagent. Internal salts of compounds
of formula I
comprising acid and basic salt-forming groups, e.g. a free carboxy group and a
free amino
group, may be formed, e.g. by the neutralisation of salts, such as acid
addition salts, to the
isoelectric point, e.g. with weak bases, or by treatment with ion exchangers.
Salts can be converted in customary manner into the free compounds; metal and
ammonium salts can be converted,,for example, by treatment with suitable
acids, and acid
~~~'2~~5
- 116 -
addition salts, for example, by treatment with a suitable basic agent.
Stereoisomeric mixtures, that is mixtures'of diastereoisomers and/or
enantiomers, such as,
for example, racemic mixtures, can be separated in a manner known Qer se by
suitable
separating processes into the corresponding isomers. For example mixtures of
diastereo-
isomers can be separated into the individual diastereoisomers by fractional
crystallisation,
chromatography, solvent partition etc. Racemates can be separated from one
another, after
conversion of the optical antipodes into diastereoisomers for example by
reaction with
optically active compounds, e.g. optically active acids or bases, by
chromatography on
column materials covered with optically active compounds or by enzymatic
methods, e.g.
by selective reaction of only one of the two enantiomers. This separation can
be carried
out either at the stage of one of the starting products or with the compounds
of formula I
themselves.
T'he configuration at individual chirality centres in a compound of formula I
can be select-
ively revexsed. For example the configuration of asymmetric carbon atoms that
carry
nucleophilic substituents, such as amino or hydroxy, can be reversed by second-
order
nucleophilic substitution, optionally after conversion of the bonded
nucleophilic substit-
uent into a suitable nucleofugal leaving group and reaction with a reagent
that introduces
the original substituent, or the configuration at carbon atoms having hydroxy
groups, such
as the RS-carrying carbon atom of formula I, can be reversed by oxidation and
reduction of
compounds of formula I as described below.
The radicals hydroxy RS and hydrogen R6 in a compound of formula I can be
oxidised to
an oxo group, the oxidising agents used preferably being those that
selectively convert the
hydroxy group into a keto group, for example chromic acid or a derivative
thereof, such as
pyridinium chromate or tart-butyl chromate, dichromate/sulfuric acid, sulfur
trioxide in
the presence of heterocyclic bases, such as pyridine/S03, also nitric acid,
pyrolusite or
selenium dioxide, or dimethyl sulfoxide in the presence of oxalyl chloride, in
water,
aqueous or organic solvents, such as halogenated solvents, e.g. methylene
chloride, car-
boxylic acid amides, such as dimethylformamide, or di-lower alkyl sulfoxides,
such as
dimethyl sulfoxide, in the presence or absence of basic amines, e.g. tri-lower
alkylamines,
such as triethylamine, at temperatures of from -50 to 100°C, preferably
from -10 to 50°C,
for example as described in European Patent Application EP-A-0 236 734.
Conversely, in compounds of formula I obtained in that manner in which R5 and
R6
CA 02072785 2003-04-17
21489-8495
- 117
together form an oxo group, the oxo group cart be reduced to a hydroxy group.
Suitable
reducing agents for reducing the o:xc> group in a compound of formula 1 are
those that
under the reaction conditions of the process reduce an isolated keto group
selectively or
more quickly than amide groups present irx compounds of formula 1.
There may be mentioned, especially, suitable borohydrides, such as alkali
metal boro-
hydrides, especially sodium borohydride, lithium borohydride or sodium
cyanoboro-
hydride, also zinc borahydride, or suitable aluminium hydrides, such a:~
alkali metal lower
alkoxyaluminium hydrides having voluminous radicals, e.g. lithium tri-tart-
butoxyalumin-
ium hydride.
The reduction can also be carried out with hydrogen in the presence of
suitable heavy
~r~t
metal catalysts, e.g. Raney nickel or platinum or palladium catalysts, e.g.
platinum/- or
palladium/activated carbon, or according to hrleerwein-Ponndorf-Verley with
the aid of
aluminium alkanolates, preferably aluminium-2-propanolate or ethanolate.
'The reduction can preferably be carried out with staichiometric amounts or an
expediently
measured excess of the reducing agent in an inert solvent at temperatures of
from -80°C to
the boiling point of the solvent, e.g. from -"~t~°C to tl~°C, if
necessary under a protective
gas, e.g. nitrogen or argon. An excess of the reducing agent is necessary
especially when it
reacts also with the solvent, e.g. the protons of a erotic solvent.
'JVhen sodium borohydride is used, polar erotic solvents are suitable, e.g.
methanol,
ethanol or isopropanol; when the other reducing agents are used, polar aprotic
solvents are
suitable, e.g. tetrahydrofuran.
In a compound of formula I in which R1, R2, Rg and Rc~ contain no aryl
radicals or arrrl
radicals that are not very reactive, an arrrl radical present in R~, R3 and/or
R4, especially a
phenyl radical, can be hydrogenated for exarl~ple by catalytic
lay~lrogenation, especiall!r in
the presence of heavy metal oxides, such as rltcxliumiplatinum rn~xed oxides,
e;.g. with the
1'Jishimura catalyst, preferably in a iaolar solvent, such ;as m alcohol, e.g.
methanol or
ethanol, at temperatures of from 0 to 81~°C, especially frt>m 10 to
40°C, ,and at a hydrogen
pressure of from 1 to 10 atm, preferably at approximately nc~~-mal pressure.
In an obtainable compound of formula I an amino or carboxamide group may be
substi
tuted, a carboxy group that is free or in reactive farm may be e;~t~rified or
amidated, or an
~o~~~~~
-11S-
esterified or aanidated carboxy group may be converted into a free carboxy
group.
The substitution of a carboxamide group or of another primary ar secondary
amino group,
e.g. in order to introduce radicals~such as unsubstituted or substituted
alkyl, alkenyl or
alkynyl, aryl-lower alkyl, or heterocyciyl or heterocyclyl-lower alkyl bonded
by carbon
R1, R2, Rg or R9 into compounds of formula I in which one or more of the
mentioned
radicals are hydrogen, is effected e.g. by alkylation.
Suitable agents for alkylating a carboxamide group in a compound of formula I
are e.g.
diazo compounds, e.g. diazomethane. Diazomethane can be decomposed in an inert
solvent, the free methylene formed reacting with the carboxamide group in the
compound
of formula I. The decomposition of diazomethane is carried out preferably by
catalysis,
e.g. in the presence of a noble metal in finely divided form, e.g. copper, or
of a noble
metal salt, e.g. copper(I) chloride or copper(II) sulfate.
Alkylating agents are also mentioned in German Offenlegungsschrift 2 331 133,
e.g. alkyl
halides, sulfonic acid esters, Meerwein salts or 1-substituted 3-
aryltriazenes, which can be
reacted under the conditions mentioned therein with a. compound of formula I
having a
carboxamide group.
Further alkylating agents are selected from compounds of formulae
R 1-X (X),
R2-X (XI)9
Rg-X (XIII) and
R9-X (XIV),
wherein X is a leaving group and the remaining radicals are as defined, with
the exception
of acyl, sulfo unsubstituted or substituted as above, phosphono, and
phosphoryl substituted
as above. A leaving group is especially a nucleofugal leaving group selected
from hydraxy
esterified by a strong inorganic or organic acid, such as hydroxy esterified
by a mineral
acid, e.g. a hydrohalic acid, such as hydrochloric, hydrobromic or hydriodic
acid, or by a
strong organic sulfonic acid, such as an unsubstituted or substituted, for
example halo-sub-
stituted, such as fluoro-substituted, lower alkanesulfonic acid, or an
aromatic sulfonic
acid, e.g. a benzenesulfonic acid that is unsubstituted or substituted by
lower alkyl, such as
methyl, by halogen, such as bromine, and/or by nitro, e.g. a methanesulfonic,
trimethane-
sulfonic or p-toluenesulfonic acid, and hydroxy esterified by hydrazoic acid.
20°~2'~~5
- 119 -
The reaction can be carried out under the conditions of a first-order or
second-order
nucleophilic substitution.
For example, one of the compou~lds of formulae VIII to XIII wherein X is a
leaving group
with high polarisability of the electron shell, e.g. iodine, can be reacted in
a polar aprotic
solvent, e.g. acetone, acetonitrile, nitromethane, dimethyl sulfoxide or
dimethylform-
amide. The reaction may also becarried out in water to which, where
appropriate, an
organic solvent, e.g. ethanol, tetrahydrofuran or acetone, has been added as
solubiliser.
The substitution reaction is tamed out if desired at reduced or elevated
temperature, e.g.
in a temperature range of from approximately -40° to approximately
100°C, preferably
from approximately -10° to approximately 50°C, and if desired
under an inert gas, e.g.
under a nitrogen or argon atmosphere.
For the esterification or amidation of a carboxy group in a compound of
formula I, if
desired the free acid can be used or the free acid can be converted into one
of the above-
mentioned reactive derivatives and reacted with an alcohol, with ammonia, or
with a
primary or secondary amine, or, in the case of esterification, the free acid
or a reactive
salt, e.g. the caesium salt, can be reacted with a reactive derivative of an
alcohol. For
example the caesium salt of a carboxylic acid can be reacted with a halide or
sulfonic acid
ester corresponding to the alcohol. The esterification of the carboxy group
can also be
carried out with other customary alkylating agents, e.g. with diazomethane,
alkyl halides,
sulfonic acid esters, Meerwein salts or 1-substituted 3-aryltriazenes, etc..
One of the methods described above for the removal of the carboxy-protecting
groups or,
if desired, m alkaline hydrolysis in accordance with customary reaction
conditions, such
as those specified in Organikum, 17th edition, VEB Deutscher Verlag der
Wissenschaften,
Bexlin 1988, can be used to convert an esterified or amidated carboxy group
into the free
carboxy group.
An esterified carboxy group in a compound of formula I can be canverted by
aminolysis
with ammonia or with a primary or secondary amine into an unsubstituted or
substituted
carboxamide group. The aminolysis can be carried out according to customary
reaction
conditions, such as those specified for such reactions in Organikum, 15th
edition, VEB
Deutscher Verlag der Wissenschaften, Berlin (East) 1976.
A free amino group present in a compound of formula I can be acylated, for
example to
2o~z~~~
120 -
introduce one of the radicals acyl, sulfo, substituted sulfonyl, phosphono or
substituted
phosphoryl mentioned for R1, R2, Rg or R9 . The acylation is carried out
according to one
of the methods mentioned above under Process b), c) or d) for condensation or
according
to one of the methods mentioned'for protecting groups or, for example,
according to one
of the processes mentioned in flrganikum, 17th edition, VEB Deutscher Verlag
der
Wissenschaften, Berlin (East) 1988.
In an obtainable compound of formula I wherein the substituents are as defined
and at
least one free hydroxy group is present and the remaining functional groups
are in pro-
tected form, the free hydroxy group can be acylated or etherified.
The acylation can be carried out with acylating reagents according to one of
the methods
mentioned under Processes b) to d), according to one of the methods mentioned
for
protecting groups, or according to one of the processes mentioned in
Organikum, 17th
edition, VEB Deutscher Verlag der Wissenschaften, Berlin (East) 1988.
The etherification can be carried out with the above-mentioned alkylating
agents and
under the same reaction conditions, e.g. with diazomethane, alkyl halides,
sulfonic acid
esters, Meerwein salts, 1-substituted 3-aryltriazenes, etc.,
In an obtainable compound of formula I a sulfinyl or sulfonyl group can be
produced from
a thio gxoup, and the corresponding sulfoxide or sulfone from a sulfide, by
oxidation.
The oxidation to the sulfonyl group or to the sulfone can be carried out with
most of the
customary oxidising agents. The oxidising agents used are especially
preferably those that .
oxidise the thio group or the sulfide sulfur selectively in the presence of
other functional
groups of the compound of formula I in question, e.g. amino or hydroxy groups;
examples
of SLICK oxidising agents are aromatic or aliphatic peroxycarboxylic acids,
e.g. peroxy-
benzoic acid, monoperphthalic acid, m-chloroperbenzoic acid, peracetic acid,
performic
acid or trifluoroperacetic acid. The oxidation with peroxycarboxylic acids is
carried out in
the customary solvents suitable therefor, for example chlorinated
hydrocarbons, e.g.
methylene chloride or chloroform, ethers, such as diethyl ether, esters, such
as ethyl
acetate or the like, at temperatures of from -78°C to room temperature,
e.g. from -20°C to
+10°C, preferably about 0°C. The peroxycarboxylic acid can also
be formed in situ, e.g.
with hydrogen peroxide in acetic acid or formic acid that may or may not
contain acetic
anhydride, e.g. with 30 % or 90 % hydrogen peroxide in acetic acid/acetic
anhydride. Also
- 121 -
suitable are other peroxo compounds, for example potassium peroxomonosulfate
in lower
alkanol/water mixtures, e.g. methanol/water or ethanol/water, or in aqueous
acetic acid at
temperatures of from -70°C to +30°C, e.g. from -20°C to
room temperature, and also
sodium metaperiodate in methanol or methanol/water mixtures at temperatures of
from
0°C to 50°C, e.g. approximately room temperature. If
stoichiometric amounts of the men-
tioned oxidising agents are used it is also possible for the corresponding
sulfuric acids or
sulfoxides to be obtained. There are suitable for that purpose, for example,
sodium mete-
periodate in methanol or methanol/water mixtures at temperatures of from -
15°C to room
temperature, e.g. approximately 0°C, m-chloroperbenzoic acid in
methylene chloride,
chloroform or ethyl acetate at temperatures of from -78°C to
10°C, preferably from -30°C
to 0°C, also tert-butylhypochlorite in lower alkanols, e.g. methanol,
or hydrogen peroxide
in acetone or acetic acid at temperatures of approximately 0°C, or the
above-mentioned
potassium peroxomonosulfate at low temperatures.
If desired, the corresponding thio compound or the corresponding sulfide can
be obtained
by reducing a sulfonyl group or a sulfone radical in an obtainable compound of
formula I,
for example with diisobutylaluminium hydride in ether or tetrahydrofuxan.
In an obtainable compound of formula I having a sulfinyl group, that group can
be reduced
to a thio group. Selective reducing agents that leave other functional groups
of the
compound of formula I, e.g. the amide function, unchanged are preferred.
Examples of
such selective reducing agents are dichloroborane, which is preferably used in
tetrahydro-
furan or dimethoxyethane at temperatures of from -30°C to +10°C,
triphenylphosphine in
boiling carbon tetrachloride, trichlorosilane or hexachlorodisilane, iron
pentacarbonyl,
also sodium hydrogen sulfite in aqueous/alcoholic solvents, e.g.
water/methanol, water/-
ethanol or also water/tetrahydrofuran, at temperatures of from -10°C to
+50°C, also
sodium borohydride in the presence of cobalt(II) chloride or also hydrogen in
the presence
of catalytic amounts of palladium, e.g. palladium/carbon in boiling ethanol.
Protecting groups present in a compound of formula I or suitable radicals Rl,
R2, R8 or
R9, i.e. those representing aryl, sulfo, substituted sulfo, phosphono or
substituted phos-
phoryl, can be removed according to one of the processes mentioned under
Process f),
especially by hydrolysis, for example in the presence; of bases, such as
alkali or alkaline
earth metal hydroxides, e.g. sodium hydroxide, or acids, such as organic acids
or mineral
acids, e.g. hydrogen halide, such as hydrogen chloride. The hydrolysis is
carried out under
customary conditions, for example in aqueous solution or in anhydrous
solvents,
2~'~27~5
- 122 -
especially in ethers, such as dioxane, at temperatures of from -50°C to
the reflux temp-
erature of the Corresponding reaction mixtures, e.g. from 0°C to
50°C, preferably in the
presence of a protective gas, such as argon or nitrogen.
All of the process steps specified above can be carried out under reaction
conditions that
are known her se, preferably those specifically mentioned, in the absence or
customarily in
the presence of solvents or diluents, preferably those that are inert towards
and dissolve
the reagents used, in the absence or presence of catalysts, condensation
agents or neutral-
ising agents, e.g. ion exchangers, such as ration exchangers, e.g. in the H~
form, depend-
ing on the nature of the reaction and/or the reactants at reduced, normal or
elevated temp-
erature, e.g. in a temperature range of from approximately -100°C to
approximately
190°C, preferably from approximately -80°C to approximately
150°C, e.g. at from -80 to
-50°C, at room temperature, at from -20 to 40°C or at the
boiling point of the solvent used,
under atmospheric pressure or in a closed vessel, if desired under pressure,
and/or under
an inert atmosphere, e.g. under an argon or nitrogen atmosphere.
In the case of all starting compounds and intermediates where there are
salt~forming
groups, salts may be present. Salts may also be present during the reaction of
such
compounds, provided they do not interfere in the reaction.
At all stages of the reaction, isomeric mixtures that are obtained can be
sepazated into the
individual isomers, e.g. diastereoisomers or enantiomers, or into any mixtures
of isomers,
e.g. racemates or diastereoisomeric mixtures, for example analogously to the
methods
described under "Additional I9rocess Steps".
In certain cases, for example in the case of hydrogenation, it is possible to
achieve stereo-
selective reactions, so that e.g. simplified production of individual isomers
is possible.
The solvents from which those suitable for the reaction in question can be
selected
include, for example, water, esters, such as lower alkyl lower alkanoates,
e.g. diethyl
acetate, ethers, such as aliphatic ethers, e.g. diethyl ether, or cyclic
ethers, e.g. tetrahydro-
furan, liquid aromatic hydrocarbons, such as benzene or toluene, alcohols,
such as
methanol, ethanol or 1- or 2-propanol, nitrites, such as acetonitrile,
halogenated hydro-
carbons, such as methylene chloride, acid amides, such as dimethylformamide,
bases, such
as heterocyclic nitrogen bases, e.g. pyridine, carboxylic acid anhydrides,
such as lower
alkanoic acid anhydrides, e.g. acetic anhydride, cyclic, linear or branched
hydrocarbons,
- 123 -
such as cyclohexane, hexane or isopentane, or mixtures of those solvents, e.g.
aqueous
solutions, provided nothing else is specified in the description of the
process. Such solvent
mixtures can also be used in working up, for example by chromatography or
partitioning.
The invention relates also to those embodiments of the process in which a
compound
obtainable at any stage as intermediate is used as starting material and the
remaining steps
are carried out, or the process is discontinued at any stage, or a starting
material is formed
under the reaction conditions or is used in the foam of a reactive derivative
or salt, or in
which a compound obtainable according to the process of the invention is
produced under
the process conditions and further processed in situ. The starting materials
used are pref
erably those that result in the compounds referred to above as preferred,
especially those
referred to as especially preferred, more especially preferred and/or
preferred above all.
Pharmaceutical Compositions:
The invention relates also to pharmaceutical compositions comprising compounds
of
formula I.
The pharmacologically acceptable compounds of the present invention may be
used, e.g.,
for the preparation of pharmaceutical compositions that comprise an effective
amount of
the active ingredient together or in admixture with a significant amount of
inorganic or
organic, solid or liquid, pharmaceutically acceptable carriers.
The invention relates also to a pharmaceutical composition that is suitable
for administra-
tion to warm-blooded animals, especially humans, far the treatment or
prevention of a
disease that responds to inhibition of a retroviral protease, especially a
retroviral aspartate
protease, such as HIV-I- or HIV-II-gag protease, e.g. a retroviral disease
such as AIDS,
comprising an amount of a compound of formula I effective for the inhibition
of retroviral
protease, or a pharmaceutically acceptable salt thereof, together with at
least one pharma-
ceutically acceptable carrier.
The pharmaceutical compositions according to the invention are those for
enteral, such as
nasal, rectal or oral, or parenteral, such as intramuscular or intravenous,
administration to
warm-blooded animals (humans or animals), that comprise an effective dose of
the
pharmacological active ingredient, alone or together with a significant amount
of a
pharmaceutically acceptable carrier. The dace of the active ingredient depends
on the
20~2~~5
- 124 -
species of warm-blooded animal, the body weight, the age and the individual
condition,
individual pharmacokinetic data, the disease to be treated and the mexhod of
administra-
tion.
The invention relates also to a method of treating diseases caused by viruses,
especially by
retroviruses, for example AIDS, which comprises administering a
therapeutically effective
amount of z compound of formula I according to the invention, especially to a
warm-
blooded animal, for example a human, who on account of one of the mentioned
diseases,
especially AIDS, requires such treatment. The dose to be administered to warm-
blooded
animals, for example humans of approximately 70 kg body weight, is from
approximately
3 mg to approximately 3 g, preferably from approximately 10 mg to
approximately 1.5 g,
for example from approximately 300 mg to 1000 mg per person per day, divided
prefer-
ably into 1 to 3 single doses which may, for example, be of the same size.
Usually,
children receive half of the adult dose.
The pharmaceutical compositions comprise from approximately 1 % to
approximately
95 %, preferably from approximately 20 % to approximately 90 % active
ingredient.
Pharmaceutical compositions according to the invention may be, for example, in
unit dose
form, such as in the form of ampoules, vials, suppositories, dragees, tablets
or capsules.
The pharmaceutical compositions of the present invention are prepared in a
manner known
her se, for example by means of conventional dissolving, lyophilising, mixing,
granulating
or confectioning processes.
Solutions of the active ingredient, and also suspensions, and especially
isotonic aqueous
solutions or suspensions, are preferably used, it being possible, for example
in the case of
lyophilised compositions that comprise the active ingredient alone or together
with a
carnet, e.g. mannitol, for such solutions or suspensions to be produced prior
to use. The
pharmaceutical compositions may be sterilised and/or may comprise excipients,
e.g.
preservatives, stabilisers, wetting and/or emulsifying agents, solubilisers,
salts for regulat-
ing the osmotic pressure and/or buffers, and are prepared in a manner known
her se, e.g.
by means of canventional dissolving or lyophilising processes. The said
solutions or
suspensions may camprise viscosity-increasing substances, such as sodium
carboxy-
methylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or
gelatin.
Suspensions in oil comprise as the oil component the synthetic or semi-
synthetic vegetable
2~'~2'~~~
- 125 -
oils customary for injection purposes. There may be mentioned as such
especially liquid
fatty acid esters that contain as the acid component a long-chained fatty acid
having from
8 to 22, especially from 12 to 22, carban atoms, e.g. lauric acid, tridecylic
acid, myristic
acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidic
acid, behenic
acid or corresponding unsaturated acids, e.g. oleic acid, elaidic acid, erucic
acid, brasidic
acid or linoleic acid, if desired with the addition of antioxidants, e.g.
vitamin E, ~-carotene
or 3,S-di-tert-butyl-4-hydroxytoluene. The alcohol component of those fatty
acid esters
has a maximum of 6 carbon atoms and is a mono- or poly-hydric, e.g. a mono-,
dl- or tri-
hydric, alcohol, e.g. methanol, ethanol, propanol, butanol or pentanol or the
isomers
thereof, but especially glycol and glycerol. The following examples of fatty
acid esters are
therefore to be mentioned: ethyl oleate, isopropyl myristate, isopropyl
palmitate, "Labrafil
M 2375" (polyoxyethylene glycerol trioleate, Gattefosse, Paris), "Miglyol 812"
(tri-
glyceride of saturated fatty acids with a chain length of Cg to C12, Hills AG,
Germany),
but especially vegetable oils, such as cottonseed oil, almond oil, olive oil,
castor oil,
sesame oil, soybean oil and more especially groundnut oil.
The injection compositions are prepared in customary manner under sterile
conditions; the
same applies also to introducing the compositions into ampoules or vials and
sealing the
containers.
Pharmaceutical compositions for oral administration can be obtained by
combining the
active ingredient with solid carriers, if desired granulating a resulting
mixture, and
processing the mixture, if desired or necessary, after the addition of
appropriate excipients,
into tablets, dragee cores or capsules. It is also possible for them to be
incorporated into
plastics carriers that permit the release or diffusion of the active
ingredients in measured
amounts.
Suitable carriers are especially fillers, such as sugars, e.g. lactose,
saccharose, mannitol or
sorbitol, cellulose preparations and/or calcium phosphates, e.g. tricalcium
phosphate or
calcium hydrogen phosphate, and binders, such as starch pastes using e.g.
corn, wheat,
rice or potato starch, gelatin, tragacanth, methylcellulase,
hydroxypropylmethylcellulose,
sodium carboxymethylcellulose and/or polyvinylpyrrolidone, and/or, if desired,
disinte-
grators, such as the above-mentioned starches, also carboxymethyl starch,
crosslinked
polyvinylpyrrolidone, agar, alginic acid or a salt thereof, such as sodium
alginate.
Excipients are especially flow conditioners and lubricants, e.g. silicic acid,
talc, stearic
acid or salts thereof, such as magnesium or calcium stearate, and/or
polyethylene glycol.
~o~ ~~ ~~
- las-
Dragee cores are provided with suitable, optionally enteric, coatings, there
being used,
inter alia, concentrated sugar solutions which may comprise gum arabic, talc,
polyvinyl-
pyrrolidone, polyethylene glycol and/or titanium dioxide, or coating solutions
in suitable
organic solvents, or, for the preparation of enteric coatings, solutions of
suitable cellulose
preparations, such as ethylcellulose phthalate or hydroxypropylmethylcellulose
phthalate.
Capsules are dry-filled capsules made of gelatin and soft sealed capsules made
of gelatin
and a plasticises, such as glycerol or sorbitol. The dry-filled capsules may
comprise the
active ingredient in the form of granules, e.g. with fillers, such as lactose,
binders, such as
starches, and/or glidants, such as talc or magnesium stearate, and if desired
with stabil-
isers. In soft capsules the active ingredient is preferably dissolved or
suspended in suitable
oily excipients, such as fatty oils, paraffin oil or liquid polyethylene
glycols, it being
possible also for stabilisers and/or antibacterial agents to be added. Dyes or
pigments may
be added to the tablets or dragee coatings or the capsule casings, e.g. fox
identification
purposes or to indicate different doses of active ingredient.
Starting materials:
The present invention relates also to novel st~u-ting materials and/or
intermediates and to
processes for their preparation. Preferably the starting materials and
reaction conditions
are so selected that the compounds listed above as preferred are obtained.
In the preparation of all starting materials free functional groups that are
not to participate
in the reaction in question may be in unprotected or protected form, for
example they may
be protected by the protecting groups mentioned above under Process a). Those
protecting
groups may be removed at appropriate times by the reactions described under
Process f).
The starting materials of Process a) are known or, if novel, can be prepared
according to
processes known her se, e.g. compounds of formula III can be prepared from
hydrazine or
suitable derivatives thereof and compounds of formula IV can be prepared from
suitable
amino acids or analogues thereof, for example those having one or two of the
mentioned
side chains 123 atld 124.
The compounds of formula III can be obtained, for example, from compounds of
formula
H2~-WRIl ~xV)
20~27~5
127 -
wherein Rt t is hydrogen or an amino-protecting group, as described above
under .Process
b), especially tart-lower alkoxycarbonyl, such as tart-butoxycarbonyl; aryl-
lower alkoxy-
carbonyl, such as benzyloxycarbonyl or 9-fluorenylmethoxycarbonyl, or one of
the
above-mentioned acylamino-protecting groups by, in order to prepare a compound
of
formula I wherein in place of R~ there is a xadical R~" which is unsubstituted
or sub-
stituted alkyl or cyclollkyl, alkylating with a compound of formula XII to
introduce R~",
as described above under Process e), or introducing the radical R~ by reaction
of suitable
carbonyl compounds with the free amino group of the compound of formula VIII
or an
acylated derivative thereof and subsequent reduction of the resulting
hydrazone to form
hydrazine derivatives of formula
R~-NT-I-NH-Ri i (XV I),
wherein the radicals in all of the mentioned compounds are as defined
hereinbefore and
functional groups in participating reagents that are not to take pert in the
reaction are, if
desired, protected, where appropriate removing the protecting group Rtt, if it
does not
correspond to one of the radicals Rg or R9 in compounds of formula I, and/or
removing
other protecting groups, and reacting the radicals Rg and R9 other than
hydrogen, by con-
densation under the conditions mentioned in Process b), with acids of formula
VI or of
formula
Rx-OI-I (XVII),
wherein Rg is as defined, or by alkylation with a compound of formula XIII or
XIV, as
defined above, or both, in accordance with the conditions indicated above in
the additional
process steps.
The carbonyl compounds suitable for the introduction of R~ that are used for
the prepara-
tion of compounds of formula XVI are aldehydes or ketones of which the
reactive
carbonyl group is a component of one of the mentioned radicals R~ after the
reaction with
compounds of formula XV and the subsequent reduction, preferably aldehydes
that are
suitable for the introduction of lower alkyl, cyclohexyl-lower alkyl or phenyl-
lower alkyl.
The reaction of the carbonyl compounds with the compounds of formula XVI to
form the
corresponding hydrazones is earned out under the conditions customary for the
reaction of
carbonyl compounds with amines, preferably in polar organic solvents, e.g.
ethers, such as
CA 02072785 2003-04-17
:1489-8495
- 12f3 -
tetrahydrofuran or diethyl ether, al.cohols, such as methanol or ethanol,
carboxylic acid
amides, such as ilimethylformamide, or esters, such as ethyl acetate, pr in
aqueous
solution, preferably in methanol, and also in the presence oz' absence of acid
catalysts, e.g.
carboxylic acids, such as formic acrid or acetic acid, or sulfonic acids, such
as p-toluene-
sulfonic acid, at temperatures of from 0°C' tc> the reflex
ternpcwrature of the reaction
mixture, preferably at temperatures of from 20°C to the reflex
temperate of the reaction
mixture.
The reduction of the resulting hydrazones is carried out preferably by
hydrogenation in the
presence of a suitable catalyst. Suitable catalysts used for the hydrogenation
include
metals, such as nickel, iron, cobalt or ruthenium, and noble metals and their
oxides, such
as palladium or rhodium and their oxides, where appropriate ;applied e.g. to a
suitable
support, such as barium sulfate, aluminium oxide or activated carbon, or in
the form of
~rM
skeleton catalysts, such as Raney nickel. Customary solvents far the catalytic
hydrogen-
ation are, for example, water, alcohols, such as methanol or ethanol, esters,
such as etlayl
acetate, ethers, such as dioxane, chlorinated hydrocarbons, such as
dichlotromethane, car-
boxylic acid amides, such as dimethylformamide, or carboxylic acids, such as
glacial
acetic acid, or mixtures of those solvents. The hydrogenation is carried out
at temperatures
of from 10 to 250°C, preferably from roam temperature to 101)°~,
and at hydrogen
pressures of from 1 to 200 bar, pref°erably tram 1 to 10 bar, in the
customary apparatus.
Especially preferred for the preparation of c;ompaunds of formula XV are
reaction condi-
tions analogous to those described in Je Chern. Sac. Perkin l, 1712 (1975).
The compounds of formula IV can be obtained, for example, by the reduction of
amino
acids of formula
R ~a- N %~ COOH
(XVIi:I),
R3 Rp
wherein Rl0 is hydrogen or one of the amino-protecting grr~ups mentioned under
Process
a), especially tert-lower alkoxycarbonyl, such :as tern-butoxycarbonyl, aryl-
lower alkoxy-
carbonyl, such as benzyloxycarbonyl or 9-flu~arenylmethox ycarbc~nyl, or one
of the acyl-
~o~~~~~
- 129 -
amino-protecting groups mentioned under that process, and R3 and R4 are as
defined fox
compounds of formula I, preferably of amino acids of formula ~
R~~-NH~COOH
Y (XVIII A),
R3
wherein the radicals are as defined, to aldehydes of formula
Rio NH CHO
~ (X~)>
R3/ \Ra
wherein the radicals are as defimed, preferably to the aldehydes of formula
Rya--NH~CHO
(XIX A),
R~
wherein the radicals are as defined (which are obtainable, for example, from
compounds
of foxmula XVIII A), by reaction of those aldehydes with an ylide compound,
preferably a
sulfur-glide compound, to form an epoxide of formula '
~ o
R~s N (~)>
R3 Ra
wherein the radicals are as defined, preferably to compounds of formula
2 0'~ 2'~ ~ 5
- 130 -
H
O
R,.s NH ~ (XX A),
(obtainable, for example, from compounds of formula XIX A), wherein the
radicals are as
defined, where appropriate removal of the protecting group Rrt, provided that
does not
correspond to one of the radicals R8 or R~ in compounds of formula I, and
acylation of the
amino group of the resulting compound with an acid of formula VIII or formula
R2-OH (XXI),
wherein the radicals are as defined, under the conditions described for
Process b), and/or
alkylation of the amino group of the resulting compound with reagents having
nucleofugal
leaving groups of formula X or XI, wherein the radicals are as defined, under
the condi-
tions described for additional process steps.
The reduction of amino acids of formula XVIII or XVIII A to the corresponding
aldehydes
XIX and XIX A is earned out, for example, by reduction to the corresponding
alcohols
and subsequent oxidation to the said aldehydes.
The reduction to the alcohols is carried out, for example, by hydrogenation of
the acid
halides or other activated carboxylic acid derivatives mentioned under Process
b) under
the conditions mentioned for the hydrogenation of hydxazones obtained from
compounds
of formula XVI, or with complex hydrides, such as sodium borohydride. The
subsequent
oxidation of the resulting alcohols is possible, for example, under the
conditions for the
oxidation of compounds of formula I in which RS is hydroxy and R6 is hydrogen
to
compounds of formula I in which R5 and R6 together are oxo, as described in
the addi-
tional process steps, or by oxidation of the hydroxy group with a sulfoxide,
such as
dimethyl sulfoxide, in the presence of a reagent that activates the hydroxy
group, such as a
carboxylic acid chloride; e.g. oxalyl chloride, in an inert solvent, e.g. a
halogenated hydro-
carbon, such as dichloromethane, and/or an acyclic or cyclic ether, such as
tetrahydro-
furan; at from -80 to 0°C, e.g. from -78 to -50°C.
Direct reduction of the amino acids to the aldehydes is also possible, for
example by
hydrogenation in the presence of a partially contaminated palladium catalyst
or by reduc-
- 131 -
tion of the corresponding amino acid ester, e.g. the lower alkyl ester, such
as ethyl ester,
with complex hydrides, e.g. borohydrides, such as sodium borohydride, or
preferably
aluminium hydrides, e.g. lithium aluminium hydride, lithium tri-(tert-
butoxy)aluminium
hydride or especially diisobutylall~minium hydride, in apolar solvents, e.g.
in hydro-
carbons or aromatic solvents, such as toluene, at from -100 to 0°C,
preferably from -70° to
-30°C, and subsequent reaction to form the corresponding
semicarbazones, e.g. with the
corresponding acid salts of semicarbazones, such as semicarbazide
hydrochloride, in
aqueous solvent systems, such as alcohol/water, e.g. ethanol/water, at
temperatures of
from -20 to 60°C, preferably from 10 to 30°C, and reaction of
the resulting semicarbazone
with a reactive aldehyde, e.g. formaldehyde, in an inert solvent, for example
a polar
organic solvent, e.g. a carboxylic acid amide, such as dimethylformamide, at
temperatures
of from -30 to 60°C, preferably from 0 to 30°C, and then with an
acid, for example a
strong mineral acid, SllCh as hydrogen halide, in aqueous solution, if desired
in the
presence of the previously used solvent, at temperatures of from -40 to
50°C, preferably
from -10 to 30°C. The corresponding esters are obtained by reaction of
the amino acids
with the corresponding carboxylic acids, for example ethanol, analogously to
the condi-
tions used in the condensation in Process b), for example by reaction with
inorganic acid
halides, such as thionyl chloride, in organic solvent rr~ixtures, such as
mixtures of aromatic
and alcoholic solvents, e.g. toluene and ethanol, at temperatures of from -50
to 50°C, preF
erably from -10 to 20°C.
The preparation of compounds of formulae XIX and XIX A is carried out
especially pref
erably under conditions analogous to the reaction conditions mentioned in J.
Org. Chem.
47, 3016 (1982) or 1. Org. Chem. 43, 3624 (1978).
A sulfur-ylide suitable for the reaction of compounds of formula XIX or XIX A
to form
the epoxides of formula XX or XX A is, for example, a dialkylsulfonium
methylide, e.g.
dimethylsulfonium methylide, an alkyl- or phenyl-dialkylaminosulfoxonium
methylide,
e.g. methyl- or phenyl-dimethylaminosulfoxonium methylide, or a
dialkylsulfoxonium
methylide, e.g. dimethyl- or diethyl-sulfoxonium methylide.
The relevant sulfur-ylide compound is expediently prepared in situ from the
corresponding
sulfonium or sulfoxonium salt and a base, e.g. sodium hydride, in a dipolar
aprotic solvent,
e.g. dimethyl sulfoxide, or an ether, e.g. tea~ahydrofuran or 1,2-
dimethoxyethane, and then
reacted with compounds of formula XiX or XIX A. The reaction is normally
carried out at
room temperature, with cooling e.g. to -20°C, or with gentle heating
e.g. up to 40°C. The
2~~2'~~~
- 132
simultaneously formed sulfide, sulfinamide or sulfoxide is removed during the
subsequent
aqueous working-up. ,
The reaction with a sulfur-ylide i~ carried out especially preferably
analogously to the
conditions mentioned in J. Org. Chem. 50, 4515 (1985).
The campound of formula XX (preferably XX A) can also be obtained from a
compound
of formula XIX (preferably XIX A), as defined above, by reaction thereof with
a tri-lower
alkyl-silylmethyl-Grignard compound, e.g. prepared from the corresponding halo-
methyl-
silane, such as chloromethyl-trimethylsilane, in an inert solvent, e.g. an
ether, such as
dioxane or diethyl ether, at temperatures of from 0 to 50°C, e.g. from
room temperature to
approximately 40°C, subsequent removal of the silyl radical and
formation of a double
bond, e.g. by means of treatment with a Lewis acid, such as BF3, an amino-
protecting
group Rtp present preferably also being removed, in an inert solvent, e.g. an
ether, such as
diethyl ether, or a halogenated hydrocarbon, such as dichloromethane, or a
mixture
thereof, at temperatures of from -50°C to the reflex temperature,
especially from 0 to
30°C, if necessary, acylation once more to introduce an amino-
protecting group as Rlo, as
defined above, and oxidation of the resulting double bond to the oxirane,
preferably with a
percarboxylic acid, e.g. m-chloroperbenzoic acid, in an inert solvent, e.g. a
halogenated
hydrocarbon, such as dichloromethane, at temperaturE;s of from -20°C to
the reflex temp-
erature of the mixture, e.g. at from 10 to 30°C.
The starting materials of Processes b), c) and d) are known or, if novel, can
be prepared
according to processes known ~ se, e.g. the compound of formula V can be
prepared
from suitable hydrazine derivatives of formula III wherein R9 is hydrogen and
the remain-
ing radicals are as defined for compounds of fornnula V, and suitable epoxides
of formula
IV wherein the radicals are as defined for compounds of formula V (Process b),
the
compound of formula VB can be prepared from suitable hydrazine derivatives of
formula
IIT wherein the radicals are as defined for compounds of formula VII, and
suitable
epoxides of formula IV wherein Rt is hydrogen and the remaining radicals are
as defined
for compounds of formula VII (Process c), and the compound of formula IX can
be pre-
pared from suitable hydrazine derivatives of formula III wherein R~ is
hydrogen and the
remaining radicals are as defined for compounds of formula IX (Process d) and
suitable
epoxides of formula IV wherein RI is hydrogen and the remaining radicals are
as defined
for compounds of formula IX (Process d), analogously to Process a), where
appropriate
with the use and removal of protecting groups.
- 133 -
The compounds of formula I' wherein the substituents are as defined,above can
be pre-
pared, for example, from compounds of formula III'
H
I
HN eN / R9 (III')
~R$
wherein the radicals are as defined for compounds of formula I, in the manner
described in
Process b), by reaction with a compound of formula IV, wherein any functional
groups
present that are not to take part in the reaction are in protected form as
described in that
Process and can be freed after the reaction.
There are preferred for Process d) the starting materials of formula
H
OH I ~
He/N~N~N/-H (II)~
R3
H
wherein R3 is unsubstituted or substituted alkyl or cycloalkyl; aryl;
heterocyclyl; or
unsubstituted or substituted alkenyl; and R~ is unsubstituted or substituted
alkyl or cyclo-
alkyl; aryl; heterocyclyl; or unsubstituted or substituted allcenyl, and the
salts of the said
compounds where salt-forming groups are present, which are intermediates
according to
the invention.
They may be protected especially at one or both amino groups and, in the case
where two
amino-protecting groups are present, these may be identical or different from
one another.
There may be used as amino-protecting groups, for example, the amino-
protecting groups
mentioned above in Process a). The radicals R3 and R~ mentioned for compounds
of
formula II are as defined above for compounds of formula I in the definition
of the
radicals R3 and R~.
Especially preferred are compounds of formula II wherein R3 is cyclohexyl-
lower alkyl,
~o~~~~~
- 134 -
phenyl-lower alkyl or p-fluorophenyl-lower alkyl and R~ is lower alkyl,
cyclohexyl-lower
alkyl, phenyl-lower alkyl, p-cyanophenyl-lower alkyl or p-fluorophenyl-lower
alkyl, and
the salts of the said compounds where salt-forming groups are present.
Especially preferred in particular are compounds of formula II wherein R3 is
phenyl-lower
akyl and R~ is lower alkyl, cyclohexyl-lower alkyl or phenyl-lower alkyl, and
the salts of
the said compounds where salt-forming groups are present.
More especially preferred are compounds of formula IT wherein R3 is
cyclohexylmethyl,
benzyl or p-fluorobenzyl and R~ is n-butyl, isobutyl, cyclohexylmethyl,
benzyl, p-fluoro-
benzyl or p-cyanobenzyl, and the salts of the said compounds where salt-
forming groups
are present.
More especially preferred in particular are compounds of formula II wherein R3
is benzyl
and R~ is isobutyl, cyclohexylmethyl or benzyl, and the salts of the said
compounds where
salt-forming groups are present.
Preferred above all are the compounds of formula II mentioned in the.
Examples.
The compounds of formula II wherein the substituents are as defined, or their
salts where
salt-fornZing groups are present, are prepared, for example, by adding a
hydrazine deriva-
tive of formula
R7-~-~'R11 (XVI),
wherein Rlp is an amino-protecting group, to an epoxide of formula
H
O
(~ A)
R3
wherein R11 is an amino-protecting group, and
if desired, converting a compound of formula II having at least one salt-
forming group
obtainable according to the preceding Process a) into its salt or converting
an obtainable
2072~~~
-135-
salt into the free compound or into a different salt and/or separating any
isomeric mixtures
that are obtainable and/or removing any protecting groups present in ,a
compound of
formula II and/or converting a compound of formula II according to the
invention into a
different compound of formula IT according to the invention.
The preparation and conversion of salts, the separation of isomeric mixtures,
the removal
of protecting groups and the conversion of compounds of formula II are carried
out analo-
gously to the processes described hereinbefore for compounds of formula I.
Especially preferred is the preparation of starting materials of formula II,
wherein the sub-
stituents are as defined, by the removal of protecting groups from compounds
of
formula II wherein one or both amino groups are protected by amino-protecting
groups,
especially under the conditions for the hydrolysis of compounds of formula I,
as described
in the additional process steps.
The methods for the addition of compounds of formula XVI to those of formula
XX A are
described above under Process a) in the preparation of compounds of formula I.
The preparation of the protected compounds of formula I is carried out, for
example,
according to any one of the processes mentioned so far, especially from
compounds of
formulae III and IV, wherein functional groups in those compounds are if
desired protec-
ted by protecting groups, as described in Process a).
The acids of formulae VI, VIII, XVII and XXI and the compounds having
nucleofugal
groups of formulae X, XI, XII, XIII, XIV and XV are known or, if novel, can be
prepared
according to processes known her se.
The fallowing Examples serve to illustrate the invention but do not limit the
scope thereof
m any way.
Temperatuxes are given in degrees Celsius (°C). If no temperature
details are given, the
reaction takes place at room temperature. The Itf values, which indicate the
ratio of the
seepage propagation of the substance in question to the seepage propagation of
the eluant
front, are ascertained on thin layer silica gel plates by thin layer
chromatography (TLC) in
the following solvent systems.
~?0'~2~~~
136 -
TLC eluant systems:
A chloroforrn/methanol/water/ 75:27:5:0.5
acetic acid '
B chloroform/methanol/water/ 90:10:1:0.5
acetic acid
C chloroform/methanol/water/ 85:13:1.5:0.5
acetic acid
D chlorofotm/methanol 8:1
E chloroform/methanol 95:5
F hexane%thyl acetate 2:1
G methylene chloride/diethyl 20:20:1
ether/
methanol
I-I methylene chloride/diethyl 1:1
ether
I toluene/ethyl acetate 2:1
K chlorofotm/rnethanol 5:1
J methylene chloride/diethyl 5:1
ether
L hexane/ethyl acetate 4:1
Mf hexane/ethyl acetate 5:1
N hexane/ethyl acetate 1:1
O ethyl acetate
P methylene chloride/ethanollNII3aq.90:10:1
Q methylene chlorideldiethyl 10:1
ether
R hexane/ethyl acetate 3:1
S methylene chloride/diethyl 20:1
ether
T: chloroform/methanol 30:1
U: chloroforn~/methanol 15:1
V: methylene chloride/diethyl 1:1:3
ether/
hexane
W: methylene chloride/diethyl 20:1
ether
X: methylene chloride/methanol 40:1
Y: toluene/ethyl acetate 4:1
The abbreviation "Rl(A)", for example, denotes that the Rf value was
determined in
solvent system A. The ratio of the amounts of solvent in relation to one
another is always
given in parts by volume.
20'~2'~~5
- 137 -
HPLC-gradients : ,
I: 20 % -> 100 % ~cetonitrile/0.05 % trifluoroacetic
acid in water/0.05 % trifluoroacetic acid during
35 min.
II: 0 % -> 40 % acetonitrile/0.05 % trifluoroacetic
acid in water/0.05 % trafluoroacetic acid during
30 min.
III: 20 % -> 60 % acetonitrile/0.05 % trifluoroacetic
acid in water/O.OS % trifluoroacetic acid during
60 min.
IV: 10 % -> 50 % acetonitrile/0.05 % trifluoroacetic
acid in water/O.OS % trifluoroacetic acid during
60 min.
Column (250 x 4.6 mm) filled with "reversed-phase" material Ct8-Nucleosil~ (S
~.m mean
particle size, silica gel covalently derivatised with octadecylsilanes,
Macherey & Nagel,
Diixen, Federal Republic of Germany). Detection by UV-absorption at 215 nm.
The
retention times (tRet) are given in minutes. Flow rate 1 ml/min.
The same abbreviations are used to indicate the eluant systems for the flash
chromato-
graphy and the medium pressure chromatography.
The other shortened names and abbreviations used have the following meanings:
' abs, absolute (indicates that the solvent
is anhydrous)
atm physical atmospheres
(unit of pressure) - 1 atm corresponds
to 1.013 bar
Boc tent-butoxycarbonyl
BOP benzotriazol-1-yl-oxy-tris(dimethylamino)-
phosphonium hexafluorophosphate
DIPE diisopropyl ether
DMF dimethylformamide
DMSO dimethyl sulfoxide
ether diethyl ether
~o~~~~~
- 138 -
h hours
HBTLJr O-benzotriazol-1-yl-N,N,N'
,N'-tetra-
methyl-uronium hexafluorophosphate
~
H~Bt 1-hydroxybenzotriazole
HV high vacuum
min minutes)
MS mass spectroscopy
NMM N-methylmorpholine
RT room temperature
RE rotary evaporator
brine saturated sodium chloride
solution
TFA trifluoroacetic acid
2 benzyloxycarbonyl
Mass spectroscopic measurements are obtained either by conventional MS ar
according to
the "Fast-Atom-Bombardment" (FAB-MS) method. T'he mass details refer in the
first
instance to the unprotonated molecule ian (M)+ or to the protonated molecule
ion (M+I-I)+.
The values for proton nuclear resonance spectroscopy (tH-NMR) are given in ppm
(parts
par million) based on tetramethylsilane as the internal standard, s = singlet,
d = doublet, t
= triplet, q = quartet, m = multiplet, dd = double doublet, br = broad.
The values for IR spectra are given in cm-t, and the solvent in question is in
round
brackets. If quoted, s indicates a strong, m a medium and w a weak intensity
of the band in
question.
The residue referred to as -[PheNNPhe] denotes the divalent residue of 3(S)-
amino-4-
phenyl-1-(N-benzylhydrazino)-butan-2(S)-of and has the formula
2U°~~'~~35
- 139 -
~ OH
-NH
N
~NH-
The residue referred to as -[PheNNCha] denotes the divalent residue of 3(S)-
amino-4-
phenyl-1-(N-cyclohexylmethylhydrazino)-butan-2(S)-of and has the formula
The residue referred to as -[PheNNLeu] denotes the divalent residue of 3(S)-
amino-4-
phenyl-1-(N-isobutylhydrazino)-butan-2(S)-of and has the formula
N
eNH_
~~°~2°~~5
- 140 -
The residue referred to as -[PheNNNle] denotes the residue of 3(S)-amino-4-
phenyl-1-
(N-n-butylhydrazino)-butan-2(S)-of and has the formula ,
OH
H ~N
~'NH-
The residue referred to as -[PheNN(p-F)Phe] denotes the divalent residue of
3(S)-amino-
4-phenyl-1-(N-(p-fluorophenylmethyl)-hydrazino)-butan-2(S)-of and has the
formula
/- ~ F
off w ~
-NH ~N _
~NH-
al
The residue referred to as -[(p-F)PheNN(p-F)Phe] denotes the divalent residue
of 3(S)-
amino-4-(p-fluorophenyl)-1-(N-(p-fluorophenylmethyl)-hydxazino)-butan-2(S)-of
and has
the formula
2~'~2"~~5
F
F
The residue referred to as -[PheNN(p-CN)Phe] denotes the divalent residue of
3(S)-
amino-4-phenyl-1-(N-(p-cyanophenylmethyl)-hydrazino)-butan-2(S)-of and has the
formula
c'%
OH
_NH \ . N
~~ ~NH-
The residue refeixed to as -[ChaNNLeu] denotes the divalent residue of 3(S)-
amino-4-
cyclohexyl-1-(N-isobutyl-hydrazino)-butan-2(S)-of and has the formula
OH
N
~NH-
The abbreviations customarily used in peptide chemistry are used to name
divalent
20~2'~~~
- 142 -
residues of natural a-amino acids. However, contrary to customary peptide
nomenclature
in which the amino terminus is on the left-hand side and the carboxy terminus
is on the
right-hand side, amino acids that are on the right-hand side of the zesidues -
[PheNNPhe],'
-[PheNNCha], -[PheNNLeu], -[PhaNNNle], -[PheNN(p-F)Phe], -[(p-F)PheNN(p-
F)Phe],
-[PheNN(p-CN)Phe] or -[ChaNNLeu] in the compound names, have the linking
carboxy
group on the left, which is indicated by an arrow (.-) symbolising the
reversal of the direc-
tion of linkage. The configuration at the a-cazbon atom, if it is known, is
indicated by the
prefix (L)- or (D)-. Tyrosine xesidues etherified at the phenolic hydroxy
group by the
radical R are designated by Tyr(OR). Nle denotes the residue of norleucine.
Example 1: Boc-fPheNNPheI-Boc:
A solution of 300 mg (1.14 mmol) of (2R)-[1'(S)-Boc-amino-2'-
phenylethyl]oxirane (J.
Org. Chem. S0, 4615 (1985)) and 253 mg (1.14 mmol) of tent-butyl-3-benzyl-
carbazate (J.
Chem. Sec., Perkin I, 1712 (1975)) in 4 ml of methanol is heated under reflux
for 12
hours. After cooling the reaction mixture to 0° a large portion of the
title compound
precipitates. The mother liquor is concentrated by evaporation and the residue
is dissolved
in a small amount of methylene chloride. After the dropwise addition of hexane
a further
amount of the title compound is obtained in the form of a white precipitate.
FAB-MS:
(M+H)+=486, tRet(I)=26.8 min, R f(E)=0.70.
Example 2: Z-(L)-Val-fPheNNPheI.-((L)-Val-Z):
191 mg (0.76 mmol) of Z-(L)-valine, 336 mg (0.76 mmol) of BOP and 103 mg
(0.76 mmol) of HOBt are dissolved in 5 ml of a 0.3M solution of NMM in DMF,
and after
minutes 100 mg (0.25 mmol) of H-[.PheNNPhe]-H~3HC1 are added and the mixture
is
stirred for 2 hours at RT under a nitrogen atmosphere. The reaction mixture is
concentrated by evaporation, and the residue is dissolved in methylene
chloride and
washed twice with saturated sodium hydrogen carbonate solution. The organic
phases are
filtered through cotton wadding and concentrated by evaporation and the
residue is
purified by means of chromatography on silica gel with methylene
chloride/ether (1:1).
Lyophilisation of the product-containing fractions from dioxane yields the
title compound
in the form of a white solid. FAB-MS: (M+H)+=752, tRet(I)=27.8 ruin,
Rf(E)=0.45.
The starting material is prepared as follows:
~0~2"~~~
- 143 -
a) H-~PheNNPheI-H~3HCl:
A solution of 280 mg (0.58 mmol) of Boc-[PheNNPhe]-Boc from Example 1 in 10 ml
of~
4N hydrogen chloride in dioxane is stirred for 2 hours at RT under a nitrogen
atmosphere
and then lyophilised. Lyophilisation once more from dioxane/tert-butanol
yields the title
compound in the form of a flocculent solid. FAB-MS: (M+H)+=286, tRet(m=23.1
min,
R f(C)=0.17.
Example 3: Boc-(L~Val-fPheNNPhel~f(L)-Val-Boc):
The title compound is obtained in a manner analogous to that described in
Example 2 from
50 mg (0.13 mmol) of H-[PheNNPhe]-H~3HC1, 83 mg (0.83 mmol) of Boc-(L)-valine,
168
mg (0.38 mmol) of BOP, 51 mg (0.38 mmol) of HOBt and 2.5 ml of 0.3M NMM in DMF
after chromatographic purification on silica gel with chloroform/methanol
(95:5) and
lyophilisation from dioxane. FAB-MS: (M-t-H)+=684, tRet(I)=27.4 min,
Rf(E)=0.38.
Example 4: Boc-f.PheNNChaI-Boc:
The title compound is obtained analogously to Example 1, from 231 mg (0.88
mmol) of
(2R,3S)-1-[3-Boc-amino-2-phenylethyl]oxirane and 200 mg (0.88 rnmol) of tert-
butyl-
3-cyclohexylmethyl-carbazate, in the form of a white precipitate from hexane.
FAB-.MS:
(M+H)+=492, tRet(I)=30.4 min, Rf(E)=0.78.
The starting material is prepared as follows:
a) tert-But~3-cyclohex l~yl-carbazate:
10.2 g (45.1 mmol) of cyclohexylcarbaldehyde-tent-butoxycarbonylhydrazone,
dissolved
in 400 mI of methanol, are hydrogenated in the presence of 5.1 g of 5 %
platinum on
carbon at RT and 4 atm hydrogen pressure. When the reaction is complete, the
catalyst is
removed by filtration and the filtrate is concentrated by evaporation. The
residue is
dissolved in methylene chloride and washed with water. Concentration by
evaporation of
the organic phase yields the title compound in the form of a colourless resin.
1H-NMR
(200 MHz, CDC13): 6.1 (s, br, 1H), 3.9 (s, br, 1I-I), 2.65 (d, 2H), 1.8-0.75
(m, 11H), 1.45
(s, 9H), tRet(I)=32.0 min, Rf(E)=0.75.
20~~'~~5
-144
b) Cyclohexylcarbaldehyde-tent-butoxycarbonylhydrazone:
A solution of 10.8 g (81.2 mmol) of tert-butylcarbazate and 10.1 g (90 mmol)
of cyclo-
hexylcarbaldehyde in 400 ml of ethanol is heated under reflux for 2 hours.
Half of the
solvent is then removed by distillation and the title compound is precipitated
by the
addition of water. It is directly further used in a).
Example 5: H-(L)-Val-fPheNNPheI.-((L)-Val)-H~3HCl:
A solution of 40 mg (0.06 mmol) of Boc-(L)-Val-[PheNNPhe]~((L)-Val)-Boc from
Example 3 in 4 ml of 4N hydrogen chloride in dioxane is stirred at RT for 1 h.
The
mixture is then diluted with dioxane and, after lyophilisation, the title
compound is
obtained in the form of the hydrochloride. FAB-MS: (M+H)+=484, tRet(B)=25.8
min,
R f(A)=0.45.
Example 6: N-Thiomorpholinocarbonyl-(L)-Val-fPheNNPheI.-(N-thiomorpholino-
carbonyl-(L)-Val):
35 ltl (0.25 mmol) of triethylamine and 16 mg (0.1 mmol) of (4-
thiomorpholinylcarbonyl)-
chloride are added in succession at RT to a solution of 20 mg (0.03 mmol) of H-
(L)-Val-
[PheNNPhe]~((L)-Val)-H~3HC1 from Example 5 in 0.5 ml of DMF, and the mixture
is
stirred for 1 h at RT. The reaction mixture is diluted with chloroform and
washed with
saturated sodium hydrogen carbonate solution. The organic phase is filtered
through
cotton wadding and concentrated by evaporation, and the residue is
chromatographed on
silica gel with a gradient of chlorofotm/methanol (15:1 -> 8:1). The product
fractions are
concentrated by evaporation and precipitated with methylene chloride/DIPE.
Lyophilisa-
tion from dioxane yields the title compound in the form of a flocculent solid.
FAB-MS:
(M+H)+=742, tRet(I)=21.6 min, R f(D)=0.54.
The starting material is prepared as follows:
a) (4-Thiomorpholinylcarbonyl)chloride:
A solution of 10 g (97 mmol) of thiomorpholine in 200 ml of toluene is added
dropwise at
Oo to a solution of 85 ml (165 mmol) of 20 % phosgene in toluene and the white
suspen-
sion is stirred for 1 h at RT. Excess phosgene is driven off by introducing
nitrogen, the
2~°~2~~5
- 145 -
suspension is filtered, and the filtrate is concentrated by evaporation. The
title compound
is obtained in the form of a yellow oil. IR (CH2Cl2, cm-1): 1735, 1450, 1440,
1405, 1370,
1290, 1180.
Example 7: N-Morpholinocarbonyl-(L)-Val-lPheNNPheI.-(N-morpholino-
carbonyl-(L)-Val):
210 p.1 (1.52 mmol) of triethylamine are added to a solution of 100 mg (0.25
mmol) of
H-[PheNNPhe]-H~3HCl from Example 2a), 163 mg (0.76 mmol) of N-morpholino-
carbonyl-(L)-valine and 288 mg (0.76 mmol) of HBTU in 2 ml of DMF and the
mixture is
stirred for 16 h at RT under a nitrogen atmosphere. The reaction mixture is
fully concen-
trated by evaporation, and the residue is dissolved in methylene chloride and
washed with
saturated sodium hydrogen carbonate solution. The organic phase is filtered
through
cotton wadding, concentrated by evaporation and chromatographed on silica gel
with
methylene chloride/methanol (15:1). The title compound is precipitated from
methylene
chlori.de/hexane and, after lyophilisation from dioxane/tert-butanol, is
obtained in the form
of a flocculent solid. FAB-MS: (M+H)+=710, tRet(I)'16.3 min, Rf(E)=0.16.
The starting material is prepared as follows:
a) N-Morpholinocarbonyl-(L)-valine:
2.7 g (8.4 mmol) of N-morpholinocarbonyl-(L)-valine-benzyl ester are dissolved
in 75 ml
of ethyl acetate and the solution is hydrogenated for 3 h in the presence of
500 mg of 10 %
palladium on carbon at 1 atm hydrogen pressure and RT. The catalyst is
filtered off and,
after concentrating the solvent by evaporation, the title compound is obtained
in the form
of a colourless oil. 1H-NMR (300 MHz, CD30D): 4.15 (m, 1H), 3.65 (m, 4H), 3.40
(m,
4H), 2.12 (m, 1H), 0.95 (2d, 6H).
b) N-Morpholinocarbonyl-(L)-valine-benzyl ester:
0.8 ml (8.1 mmol) of (morpholinacarbonyl)chloride (preparation: J. Mod. Chem.
31, 2277
(1988)) and 4.1 ml (24.1 mmol) of N-ethyldiisopropylamine are added to a
solution of 4 g
(10.5 mmol) of (L)-valine-benzyl ester 4-toluenesulfonate in 56 ml of
methylene chloride
and the mixture is stirred at RT for 24 h. The reaction mixture is diluted
with ethyl acetate
and washed in succession with 1N hydrochloric acid, water, saturated sodium
hydrogen
20°~2~~5
- 146 -
carbonate solution and brine, The organic phase is dried over sodium sulfate
and concen-
trated by evaporation. Chromatography on silica gel with ethyl acetate yields
N-
morpholinocarbonyl-(L)-valine-benzyl ester in the form of a colourless oil.
The ester is
directly further used in a).
Exam~h 8: Phenylace~l-(L)-Val-LheNNPheI.-(N-phenylacetyl-(L)-Val):
The title compound is obtained analogously to Example 7 from 100 mg (0.25
mmol) of
H-[PheNNPhe]-H~3HCl from Example 2a), 143 mg (0.61 mmol) of phenylacetyl-(L)-
valine (preparation: Mem. Tokyo Univ. Agric. 20, 51 (1978)), 230 mg (0.61
mmol) of
HBTU and 200 ~.1 (1.42 mmol) of triethylamine after chromatographic
purification with
methylene chloride/ether/methanol (20:20:1) and lyophilisation from
dioxane/tert-butmol.
FAB-MS: (M+H)+=720, tRet(I)=23~7 min, R f(G)=0.21.
Example 9: N-(3-P r~ld r~lacet~l)-(L)-Val-fPheNNPheI~-(N-(3-~yridylacetyl)-(L)-
Val):
The title compound is obtained analogously to Example 7 in the form of a white
solid
from 100 mg (0.25 mmol) of H-[PheNNPhe]-I-I~3HC1 from Example 2a, 576 mg
(1.52 mmol) of HBTU, 358 mg (1.52 mmol) of N-(3-pyridylacetyl)-(L)-valine and
316 y1
(2.3 rnmol) of triethylamine after chromatographic purification with
chloroform/methanol
(S:1) and lyophilisation from dioxane/tert-butanol. FAB-MS: (M+H)+=722,
tRet(II)=27.9
min, Rf(A)=0.71.
The starting material is prepared as follows:
a) N-(3-Pyrid~lacetyl)-(L)-valine:
3.4 g of N-(3-pyridylacetyl)-(L)-valine-tent-butyl ester are dissolved in 20
ml of trifluoro-
acetic acid/methylene chloride (1:l) and the solution is stirred at RT for 16
h. The reaction
solution is fully concentrated by evaporation and the residue is digested with
DIPE. The
title compound is obtained in the form of a white amozphous solid. 1H-NMR (200
MHz,
CD30D): 8.9-8.6 (m, broad, 1H), 8.5 (m, 1H), 7.95 (m, 1H), 4.33 (m, 1H), 3.93
(s, 2H),
2.2 (m, 1H), 0.98 (2d, 6H).
b) N-(3-Pyridylacet~~(L)-valine-ten-but leer:
~o~~7s~
- 147 -
4.2 ml of triethylamine are added dropwise at 0° to a solution of 3.36
g (16 mmol) of (L)-
valine-tent-butyl ester~HCI, 2 g (14.5 mmol) of 3-pyridylacetic acid and 2.17
ml
(14.3 mmol) of cyanophosphonic acid diethyl ester in 20 ml of DMF. The
reaction mixture
is stirred for 48 h at RT, and then diluted with methylene chloride and washed
with 10 %
citric acid as well as saturated sodium hydrogen carbonate solution. The
organic phase is
filtered through cotton wadding and, after removal of the solvent by
evaporation, yields
N-(3-pyridylacetyl)-(L)-valine-tert-butyl ester, which is directly further
used in a).
Example 10 : Boc-(L)-Val-fPheNNChaI~((L)-Val)-Boc:
The title compound is obtained analogously to Example 7 in the form of a
flocculent solid
starting from 500 mg (1,25 mmol) of H-[PheNNCha]-H~3HC1, 1.U8 g (4.98 mmol) of
Boc-(L)-valine, 1.89 g (4.98 mmol) of HBTU and 1.39 ml (9.96 mmol) of
triethylamine
after chromatographic purification on silica gel with methylene chloride/ether
(1:1) and
lyophilisation from dioxane. FAB-MS: (M+H)+=690, tRet(I)=29.3 ruin,
Rf(H)=0.48.
The starting material is prepared as follows:
a) H-(PheNNCha H~1 3HCl:
1.10 g (2.2 mrnol) of Boc-[PheNNCha]-Boc from Ex~unple 4 are dissolved in 20
ml of 4N
hydrogen chloride in dioxane and the solution is stirred at RT for 3 h.
Lyophilisation of
the reaction solurion yields the title compound in the form of the
hydrochloride. FAB-MS:
(M+H)+=292, tRet(B)=27.3 min.
Example 11: Z-(L)-Val-(PheNNChal~f(L)-Val)-Z:
The title compound is obtained analogously to Example 2 from 50 mg (0.12 mmol)
of
H-(PheNNCha]-H~3HC1 from Example 10a, 94 mg (0.37 mmol) of z-(L)-valine, 165
mg
(0.37 mmol) of BOP, S 1 mg (0.37 mmol) of HOBt and 2.5 ml of 0.3M NMM in DMF
after chromatographic purification on silica gel with methylene chloride/ether
(1:1) and
lyophilisation from dioxane. FAB-MS: (M+H)+=758, tRet(n=29.1 min, R f(I-
I)=O.SS.
Example 12: Boc-(PheNNLeuI-Boc:
The title compound is obtained analogously to Example 1, starting from 1.0 g
(3.8 mmol)
- 148 -
of (2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane and 715 mg (3.8 mmol) of
tertrbutyl-3-
isobutyl-carbazate (preparation: J. Chem. Soc., Perlcin I, 1712 (1975)), in
the form of a
precipitate from hexane. FAB-MS: (M+H)+=452, tRet(I)=27.2 min, Rf(I)=0.55. '
Example 13: Z-(L)-Val-fPhe~Leul.-((L)-Val)-Z:
The title compound is obtained analogously to Example 2 starting from 60 mg
(0.17 mmol) of H-[Phe~Leu]-H~3HC1, 125 mg (0.50 mmol) of Z-(L)-valine, 221 mg
(0.50 mmol) of BOP, 67 mg (0.50 mmol) of HOBt and 3.3 ml of 0.3M NMM in DMF
after chromatographic purification on silica gel with methylene chloride/ether
(3:l) and
lyophilisation from dioxane. FAB-MS: (M+H)+= 718, tRet (~=26.8 min,
Rf(H)=0.38.
The starting material is prepared as follows:
a) H-fPheNNLeuI-H~3HC1:
The title compound is obtained analogously to Example 10a), in the form of a
lyophilisate,
from 1.21 g (2.48 mmol) of Boc-[PheNNLeu]-Boc from Example 12. FAB-MS:
(M+H)+=252, tRet(n)=20.9 min, R f(K)=0.23.
Example 14: H-(L)-Val-fPheNNChaI~-((L)-Val)-H~3I°ICI:
The title compound is obtained analogously to Example 10a), from 632 mg (0.91
mmol)
of Bac-(L)-Val-[PheNNCha]~((L)-Val)-Boc from Example 10, in the form of the
hydro-
chloride after lyophilisation. FAB-MS: (M+H)+=490, tRet(B)=29.4 min,
Rf(K)=0.23.
Example 15: N-(3-PYridylacetyl)-(L)-Val-fPhe~Leul~-(N-(3-p °~idylacet~
L -_) Val):
The tide compound is obtained analogously to Example 9 from 90 mg (0.25 mmol)
of
H-[Phe~Leu]-H~3HC1 from Example 13 a), 358 mg (1.52 mmol) of N-(3-
pyridylacetyl)-
(L)-valine, 576 mg (1.52 mmol) of HBTU and 316 ~1 (2.5 mmol) of triethylamine
after
chromatographic purification with methylene chloride/methanol (15:1) and
lyophilisation
from dioxane/tert-butanol/water. FAB-MS: (M+H)+= 688, tRet(IV)= 15.5 min,
Rf(D)=
0.37.
Example 16: N-Trifluoroacetyl-fPheNN(p-F)Phe]-Boc:
~o~~~~~
- 149 -
A solution of 4.0 g (15.4 mmol) of 2(R)-[1'(S)-(trifluoroacetylamino)-2'-
phenylethyl]-
oxirane and 3.89 g (16.2 mmol) of tert-butyl-3-(p-fluorophenyl-methyl)-
carbazate in 35 ml
of methanol are heated at 80°C for approximately 20 h in a bomb tube.
The reaction
mixture is concentrated by evaporation, the residue is dissolved in a small
amount of
dichloromethane, and the title compound is precipitated therefrom using hexane
(refrig-
erator). Column chromatography (Si02, methylene chloride/ether 95:7) yields
further
product. TLC Rt(J)=0.57; tRet(I)=24.3 min; FAB-MS (M+H)~=500.
The starting materials are prepared as follows:
a) N-3(S)-Boc-amino)-2(R,S)-hydroxy-4-phenyl-1-trimethylsilyl-butane
Under a nitrogen atmosphere, 24.7 g (1.02 mol) of magnesium are placed in 100
ml of abs.
ether and over a period of 35 minutes a small amount of iodine and, at the
same time,
132.5 ml (0.95 mol) of chloromethyltrimethylsilane and 300 ml of ether am
added, the
temperature being maintained at 38°C by means of an ice bath. The
reaction mixture
obtained is then stirred for 1.5 h at RT. After the mixture has been cooled to
-60°C, a
suspension of 48.6 g (0.195 mol) of N-Boc-phenylalaninal (preparation: D.J.
Kempf, J.
Org. Chem. 51, 3921 (1986)) in 1.1 1 of ether is addedl over a period of 40
min. Over a
period of 90 min the reaction mixture is warmed to R'T and stirred for a
further 90 min at
that temperature. The mixture is then poured onto 21 of ice-water and 1.51 of
10 %
aqueous citric acid. The separated aqueous phase is extracted twice with 500
m1 of ether.
All ether extracts are washed with 500 ml of 10 % citric acid and twice with
brine. After
drying over sodium sulfate the residue is concentrated in vacuo and the
resulting title
compound is further used without additional purificatian. TLC Rf(L)=0.6; FAB-
MS
(M+H)+=338.
b) 1-Phenyl-3-buten-2(S)-amine:
35.6 ml (0.28 mol) of an approximately 48 % solution of boron trifluoride in
ether are
added at 5°C, over a period of 10 min, to a solution of 18.8 g (0.055
mol) of 3(S)-(Boc-
amino)-2(R,S)-hydroxy-4-phenyl-1-trimethylsilyl-butane in 420 ml of methylene
chloride.
The reaction mixture is then stirred at RT for 16 h, cooled to 10°C
and, over a period of 20
min, 276 ml of a 4N sodium hydroxide solution are added. The aqueous phase is
removed
and extracted twice with 400 ml of methylene chloride each time. The combined
organic
20~2~~~
- 150 -
extracts are washed with brine and dried over sodium sulfate. The title
product is. further
used without additional purification. TLC Rf (C)= 0.15; IR (methylene
chloride) (crri t):
3370, 3020, 2920, 1640, 1605. ~ '
c) N-Trifluoroacetyl-1-phenyl-3-buten-2(S)-amine:
17.0 ml (121 mmol) of trifluoroacetic acid anhydride are added dropwise, at
0°C, to 11.9 g
(81 mmol) of 1-phenyl-3-buten-2(S)-amine dissolved in 210 ml of methylene
chloride and
70 ml of pyridine. The mixture is stirred for O.S h at 0°C and then
extracted twice with
dilute HCI, water and brine. The aqueous phases are washed a further twice
with methyl-
ene chloride, dried with sodium sulfate and concentrated by evaporation: TLC
R~(M)=0.4.
d) 2(R)-f 1'(S)-(Trifluoroaceylamino)-2'=phenvlethyll-oxirane:
54.28 g (314 mmol) of m-chloroperbenzoic acid are added to a solution of 14.5
g
(60 mmol) of N-trifluoroacetyl-1-phenyl-3-buten-2(S)-amine in 600 ml of
chloroform and
the mixture is stirred for 24 h at RT to complete the reaction. The reaction
mixture is
washed twice with 10 % sodium sulfite solution, twice with saturated sodium
carbonate
solution, water and brine. The aqueous phases are extracted a further twice
with methylene
chloride and the combined organic phases are dried with sodium sulfate and
concentrated
by evaporation to yield the title compound, which is used in the next step
without being
further purified: TLC Rt{N)=0.6.
e) p-Fluoro-phenylcarbaldehyde-tart-butoxycarbonylhydrazone:
32 g (242 mmol) of tart-butylcarbazate and 30 g (242 mmol) of p-
fluorobenzaldehyde in
300 ml of ethanol are reacted analogously to Example 4 b) for 3 h at
80°C to form the title
compound, which crystallises on cooling and diluting with water: TLC
RA(N)=0.48;
tttec(n=19.4 min.
f) test-Butyl-3-(p-fluorophenyl-methyl)-carbazate:
55 g (231 mmol) of p-fluorophenylcarbaldehyde-tart-butoxycarbonylhydrazone in
500 ml
of THF are hydrogenated with 5.5 g of palladium (5 %) on carbon analogously to
Example
4 a) to yield the title compound: tH-NMR (200 MHz, CD30D): 7.35 (dd, 8 and 6
Hz, 2
H), 7.05 (t, 8 Hz, 2 H), 3.9 (s, 2 I-I), 1.45 (s, 9 H).
20'~2~~5
- 151 -
Example 17: N-Morpholinocarbonyl-(L)-Val-fPhe~(p-F)Phel-Boc:
A mixture of 185 mg (0.80 mmol) of N-morpholinocarbonyl-(L)-valine (for
preparation
see Example 7 a)), 270 mg (0.67 mmol) of H-[Phe~(p-F)Phe]-Boc, 311 mg (0.70
moral)
of BOP and 95 mg (0.70 mmol) of HOBT is dissolved at RT in 6.8 ml of 0.3M
NMM/DMF and stirred for 5 h at RT. The xeaction mixture is concentrated by
evaporation
under HV and the residue is partitioned between 4 portions of methylene
chloride and 2
portions of 1M sodium carbonate solution, water and brine. The combined
organic phases
are dried over sodium sulfate, concentrated by evaporation and purified by
column
chromatography (Si02, ethyl acetate): TLC Rr(O)=0.38; tRec(n=21.8 min; FAB-MS
(M+H)+=616.
The starting material is prepared as follows:
a) H-fPhe~(p-F)Phel-Boc:
At 70°C, 15 mi of a 1M aqueous solution of potassium carbonate are
added dropwise to a
solution of 0.3 g (0.6 mmol) of N-trifluoroacetyl-[.Phe~(p-F)Phe]-Boc (for
preparation
see Example 16) in 50 ml of methanol under a nitrogen atmosphere and the
mixture is
stirred for 25 h at that temperature. The reaction mixture is concentrated by
evaporation
under HV, methylene chloride is added to the residue and the mixture is washed
twice
with water and brine. The aqueous phases are extracted twice with methylene
chloride and
the organic phases are dried with sodium sulfate and concentrated by
evaporation. The
crude product is used in the next step without being further purified:
tRe~(I)=16.2 min.
Example 18 _ N-- Mornholinocarbonyl-(L)-Val-fF'he~(p-F)Phel~((L)-Val)-Z:
129 mg (0.34 mmol) of HBTU are added to a solution of 86 mg (0.34 mmoi) of Z-
(L)-Val
and 160 mg (0.31 mmol) of N-morpholinocarbonyl-(L)-Val-[Phe~(p-F)Phe]-H in 2.7
ml
of 0.25M NMM/CH3CN (0.25M NMM in CH3CN). After 4 h at RT the mixture is con-
centrated by evaporation and the residue is partitioned between 3 portions of
methylene
chloride and 2 portions of saturated sodium hydrogen carbonate solution and
brine. The
organic phases are dried with sodium sulfate and concentrated by evaporation
to yield the
title compound which is obtained in pure form after digestion from methylene
chloride/-
ether 1:1: TLC Rt(P)=0.4; tRe~(I)=22.4 min; FAB-MS (M+H)+=749.
~0'~27~5
- 152 -
The starting material is prepared as follows:
a) N-Morpholinocarbonyl-(L,)-Val-iPhe~(p-F)Phe]-H:
210 mg (0.34 mmol) of N-morpholinocarbonyl-(I,)-Val-[Phe~(p-F)Phe]-Boc
(Example
17) are dissolved in 105. ml of formic acid and the solution is stirred for 4
h at RT and then
concentrated by evaporation. The residue is taken up in methylene chloride and
the
solution is washed with saturated sodium hydrogen carbonate solution and
brine. Extrac-
tion of the aqueous phases with 2 portions of methylene chloride, drying the
organic
phases with sodium sulfate and concentrating by evaporation yields the title
compound,
which is used in the next step without being further purified: tRe~(I)=12.9.
Example 19: N-Morpholinocarbonvl-(L)-Val-[Phe~(p F)Phe].-((L)-Val
160 mg (0.2.1 mmol) of N-morpholinocarbonyl-(L)-Val-[Phe~(p-F)Phe].-((L)-Val)-
Z
(Example 18) in 6 ml of ethanol are hydrogenated with 40 mg of palladium (10
%) on
carbon at normal pressure. Filtration through Celite~ (siliceous earth, filter
aid from
Fluka, Buchs, Switzerland), concentration by evaporation and lyophilisation
from dioxane
yield the title compound: tRec(hYdrochloride, I)=13.4 tnin; FAB-MS (M+H)+=615.
Example 2U: N-Morpholinocarbonyl-(L)-Val-fPhew(p-F)Phel~((L)-Val).-(N-
morpholino-
carbonvl-Glv):
54 mg (0.143 mmol) of HBTU are added to a solution of 26.9 mg (0.143 mmol) of
N-
morpholinocarbonyl-glycine and 80 mg (0.130 mmol) of N-morpholinocarbonyl-(L)-
Val-
[Phe~(p-F)Phe].-((L)-Val)-H in 1.1 ml of 0.25M NMM/CH3CN and the mixture is
stirred
for 16 h at RT. The mixture is concentrated by evaporation and the residue is
partitioned
between 3 portions of ethyl acetate and water and 2 portions of saturated
sodium hydrogen
carbonate solution, water and brine. The organic phases are dried with sodium
sulfate and
concentrated by evaporation to yield the title compound which, after
dissolving in a small
amount of DMF and precipitating with RIPE is obtained in pure form:
tRet(I)=15.1 min;
FAB-MS (M+H)*=785.
The starting material is prepared as follows:
20~~7~~
- 153 -
a) N-Motpholinocarbo~l-~lycine-benzyl ester:
Analogously to Example 7 b), 7.69 g (22.8 mmol) of glycine-benzyl ester 4-
toluenesulfon-
ate and 2.8 g (19 mmol) of (morpholinocarbonyl)chloride in 118 ml of methylene
chloride
and 9 ml (53 mmol) of N-ethyldiisopropylarnine are reacted for 18 h. The title
compound
is obtained in pme form after extraction with methylene chloride and digestion
with
hexane: tRe~(I)=11.6 min.
b) N-Morpholinocarbonyl-gl cy ine:
Analogously to Example 7 a), 4.8 g (18.3 mmol) of N-morpholinocarbonyl-glycine-
benzyl
ester in 100 ml of ethyl acetate are hydrogenated with 1 g of palladium (10 %)
on carbon
to yield the title compound: tH-NMR (300 MHz, CDCI3): 3.88 (s, 2 H), 3.64 (s,
4 I-I), 3.50
(s, 2 H), 3.35 (s, 4 I-I).
Example 21: Z-(L)-Val-(Phe~(p-F)Phel-Boc:
463 mg (1.22 mmol) of HBTLJ are added to a solution of 335 mg (1.33 mmol) of Z-
(L)-
Val and 448 mg (1.11 mmol) of H-[Phe~(p-F)Phe]-l3oc (for preparation see
Example 17
a)) in 9.4 ml of 0.25M NMM/CH3CN (0.25M NMM in CI-I3CN). After stirring for 16
h at
RT, the mixture is concentrated by evaporation and the residue is partitioned
between 3
portions of methylene chloride and 2 portions of saturated sodium hydrogen
carbonate
solution and brine. The organic phases are dried with sodium sulfate and
concentrated by
evaporation to yield the title compound, which is purified by column
chromatography
(Si02, hexane/ethyl acetate 4:1 >1:l): tRec(I)=26.6 min; FAB-MS (M+H)+=637.
Example 22: Z-(L)-Val-(Phe~(p-F~hel.-((L)-Val)-Boc:
Analogously to Example 18, 165 mg (0.76 mmol) of Boc-(L)-Val and 371 mg
(0.69 mmol) of Z-(L)-Val-[Phe~(p-F)Phe]-H in 6 ml of 0.25M NMh4/CH3CN are
reacted with 289 mg (0.76 mmol) of HBTU to yield the title compound, which can
be
crystallised directly from the reaction solution and filtered off:
t~e~(I)=27.2 min; FAB-MS
(M+H)+=736.
The starting material is prepared as follows:
- 154 -
a) Z-(I,)-Val-[Phe~(p-F)Phel-H:
Analogously to Example 18 a), 440 mg (0.69 mmol) of Z-(L)-Val-[Phe~(p-F)Phe]-
Boc
are deprotected with 212 ml of formic acid to yield the title compound:
tRe~(I)=17.8 min.
Example 23: Z-(L)-Val-fPhe~(p-F)Phe].-((L)-Val)-H:
Analogously to Example 18 a), 250 mg (0.34 mmol) of Z-(L)-Val-[Phe~(p-F)Phe).-
((L)-
Val)-Boc (Example 22) are deprotected with 50 ml of formic acid to yield the
title
compound: tRe~(I)=18.0 min; FAB-MS (M+H)+=636.
Example 24: Z-(L)-Val-fPhe~(p-F)Phel~((L)-Val).-(N-mor~holinocarbo~l-Gly):
Analogously to Example 20, 32 mg (0.17 mmol) of N-morpholinocarbonyl-glycine
(Example 20 b)) and 99 mg (0.16 mmol) of Z-(L)-Val-[Phe~(p-F)Phe].-((L)-Val)-
lH in
1.3 ml of 0.25M NMM/CH3CN are reacted with 65 mg (0.17 mmol) of HBTU to yield
the
title compound, which crystallises directly from the reaction solution:
t~°~(I)=21.1 min;
FAB-MS (M+H)+=806.
Example 25: Z-(L)-Asn-fPhe~(p-F)Phel-Boc:
3.0 g (7.8 mmol) of Z-(L)-asparagine-p-nitrophenyl ester (Bachem,
Bubendorf/Switzer-
land) are added to a solution of 2.09 g (5.2 rnmol) of H-[Phe~(p-F)Phe]-Boc
(for prepar-
ation see Example 17 a)) in 68 ml of DMF and 2.7 ml (16 mmol) of N-ethyl-
diisopropyl-
amine. The mixture is stirred for 16 h at RT and concentrated by evaporation
under IIV,
and the residue is taken up in a large amount of methylene chloride (poorly
soluble) and
washed with 2 portions of 5 % potassium carbonate solution. The aqueous phases
are
extracted twice more with a large amount of methylene chloride, and the
combined
organic phases are dried with sodium sulfate and concentrated by evaporation.
The title
compound is obtained by dissalving the crude product in a small amount of
methanal and
precipitating by the addition of toluene at -20°C: tgei(I)=21.2 min.
Example 26: H-(L)-Asn-[Phe~(p-F)Phe]-Boc:
Analogously to Example 19, 0.40 g (0.61 mmol) of Z-(L)-Asn-[Phe~(p-F)Phe]-Boc
are
hydrogenated in 20 ml of methanol to yield the title compound: tRe~(I)=14.9
min.
20'~~7~5
-155 -
Examt~Ie 27: Ouinoline-2-carbonyl-(L)-Asn-fPhe~(p-F)Phe -Boc:
Analogously to Example 17, 134 mg (0.78 mmol) of quinoline-2-carboxylic acid
(Fluke,
Buchs/Switzerland) in 4 ml of 0.3M NMM/DMF are reacted with 344 mg (0.78 mmol)
of
BOP, 105 mg {0.78 mmol) of HOBT and 268 mg (0.52 mmol) of H-{L)-Asn-
[Phe~{p-F)Phe]-Boc. Since, according to HPL.C, there is still some H-(L)-Asn-
[Phe~(p-F)Phe]-Boc present after stirnng for 16 h at RT, a further 299 mg of
BOP,
70 mg of HOST, $9 mg of quinaldic acid and 113 p.1 of NMM are added. After a
further
16 h the mixture is concentrated by evaporation and the residue is partitioned
between 3
portions of methyiene chloride and 2 portions of saturated sodium hydrogen
carbonate
solution and brine. The combined organic phases are dried with sodium sulfate
and con-
centrated by evaporation. The crude product is dissolved in a small amount of
DMF,
precipitated with DIPS and cooled to -20°C to yield the title compound:
tR~~(I)=22.8 min;
FAB-MS (M+I-I)+=673.
Example 28: Z-~L~ Asn-fPhe~(p-F)Phel.-((L)-Val)-'T.,_:
88 mg (0.35 mmol) of Z-(L)-Val in 3.8 ml of 0.3N NMM/DMF are activated with
153 mg
(0.35 mmol) of BOP and 47 mg (0.35 mmol) of I-IOBT and, after 15 ruin, 144 mg
(0.23 mmol) of Z-(L)-Asn-[Phe~(p-F)Phe]-hI>2HC1 are added. The reaction
mixture is
stirred for 14 h at RT and then concentrated by evaporation, the residue is
dissolved in
2 ml of methanol and partitioned between 3 portions of methylene chloride and
2 portions
of 1M sodium carbonate solution, and the organic phases are dried with sodium
sulfate
and concentrated by evaporation. Repeated dissolution of the crude product in
a small
amount of DMF and precipitation with DIPE yield the title compound:
tRecCI)=22.2 min;
FAB-MS (M+H)*=785.
The starting material is prepared as follows:
a) Z-(L)-Asn-fPhe~~p-F)Phel-H~2HC1:
Under a nitrogen atmosphere, 2 ml of 4N HCl/dioxane (Fluke, Buchs/Switzerland)
are
added to a solution of 150 mg (0.23 mmol) of Z-(L)-Asn-[Phe~(p-F)Phe]-Boc
(Example
25) in 1 ml of dioxane. The reaction mixture is stirred for 1.5 h at RT and
then lyophilised,
and the lyophilisate is directly further reacted.
2072'~~~
- 156 -
Example 29: Trifluoroacet 1-fPhe~ p-F)Phel.-((L)-Val)-Z:
Analogously to Example 17, 239 mg (0.95 mmol) of Z-(L)-Val in 10.5 ml of 0.3M
NMM/DMF are reacted for 15 h with 421 mg (0.95 mmol) of BOP, 129 mg (0.95
mmol)
of HOBT and 0.3 g (0.63 mmol) of N-trifluoroacetyl-[Phe~(p-F)Phe]-H. Column
chrom-
atography (Si02, methylene chloride/ether 10:1) and precipitation from DMF
solution
with DIPE yield the title compound: TLC Rf(Q)=0.15; tRec(I)=25.9 min; FAB-MS
(M+H)+=633.
The starting material is prepared as follows:
a) N-Trifluoroacetyl-fPhe~(p-F)Phel-H:
At 0°C, 5 ml of trifluoroacetic acid are added to 0.20 g (0.40 mmol) of
N-trifluoroacetyl-
[Phe~(p-F)Phe]-Boc (for preparation see Example 16) in 5 ml of methylene
chloride. The
reaction mixture is stirred for 4 h at 0°C and for 2 h at RT and then
concentrated by e~rap-
oration. Lyophilisation of the residue from dioxane yields the title compound,
which is
further reacted without being purified: tRe~(I)=14.7 min.
Example 30: Z-(L)-Asn-[Phe~Phal-Boc:
Analogously to Example 25, 167 mg (0.34 mmol) of H-[Phe~Phe]-Boc in 3.6 ml of
DMF
and 0.18 ml (1 mmol) of N-ethyl-diisopropylamine are reacted with 0.20 g (0.52
mmol) of
Z-(L)-asparagine-p-nitrophenyl ester to yield the title compound, which is
obtained in pure
form by column chromatography (Si02, ethyl acetate): TLC Rt(O)=0.19;
tRe~(1)=20.9 min.
The starting material is prepared as follows:
a) N-Trifluoroacetyl-fPhe~Phe1-Boc:
Analogously to Example 16, 1.82 g (7.0 mmol) of 2(R)-[1'(S)-
(trifluoroacetylamino)-2'-
phenylethyl]-oxirane (Example 16 d)) and 1.58 g (7.1 mmol) of tert-butyl-3-
benzyl-
carbazate (J. Chem., Perlcin I, 1712 (1975)) in 15 ml of methanol are reacted
in a bomb
tube to yield the title compound, which is isolated by column chromatography
(Si02,
methylene chloride/ether 50:1): TLC Rp(J)=0.38; tRec(I)=24.5 min.
20'~2'~~~
- 157 -
b) H-fPhe~Phel-Boc:
Analogously to Example 17 a), 258 mg (0.53 mmol) of N-trifluoroacetyl-
[Phe~Phe]-Boc
in 60 ml of methanol are reacted with 10.7 ml of 1M potassium carbonate
solution to yield
the title compound.
Example 31: Z-(L)-Val-f (p-F)Phe~(~F)Phel-Boc:
Analogously to Example 21, 18 mg (0.070 mmol) of Z-(L)-Val and 27 mg (0.064
mmol)
of H-[(p-F)Phe~(p-F)Phe]-Boc in 0.6 ml of 0.25M NMM/CH3CN are reacted with
26.6 mg (0.070 mmol) of HBTU to yield the title compound, which is purified by
dissolv-
ing in a small amount of methylene chloride and precipitating with DIPE: FAB-
MS
(M+H)+=655.
The starting material is prepared as follows:
a) N-Boc-(p-fluoro~henylalanine
In 0.41 of dioxane/water 1:120 g (109 mmol) of p-fluorophenylalanine (Fluka,
Buchs,
Switzerland) are reacted with 35.5 g (163 mmol) of Boc-anhydride and 150 g
(1.09 mol)
of potassium carbonate. After 4 h, the reaction mixture is acidified with
citric acid solution
and extracted with 3 portions of ethyl acetate. The organic phases are washed
with 10
citric acid, water and brine, dried with sodium sulfate and concentrated by
evaporation.
Dissolution of the residue in a small amount of methylene chloride and
crystallisation by
the addition of hexane yields the title compound: tR~~(I)=16.9 min.
b) N-Boc-(p-fluorophenylalaninol):
At from -5°C to -10°C 9.66 ml (69 mmol) of triethylamine are
added to a solution of
17.9 g (63 mmol) of N-Boc-(p-fluorophenylalanine) in 73 ml of abs. THF, and a
solution
of 9.05 ml (69 mmol) of chloroformic acid isobutyl ester in 44 ml of abs. THF
is added
dropwise thereto. After stirring for 0.5 h at RT, the resulting precipitate is
filtered off with
suction. The filtrate is added dropwise, with cooling, to 4.77 g (126 mmol) of
sodium
borohydride in 28 ml of water. The mixture is stirred for 4 h at RT and
acidified with 10 %
citric acid, the THF is partially removed by evaporation using a RE and the
residue is
partitioned between 3 portions of ethyl acetate and 2 portions of 2N sodium
hydroxide
20'~2°~~5
- 158 -
solution, water, saturated sadaum hydrogen carbonate solution and brine. The
organic
phases axe dried with sodium sulfate, concentrated by evaporation, dissolved
in a small
amount of methylene chloride and crystallised by the addition of hexane to
yield the title'
compound: TLC Rt{N)=0.36; tRet(n=16.8 min; 1H-NMR (200 MHz, CD30D): 7.24 (dd,
8
and 5 Hz, 2 H), 6.98 (t, 8 Hz, 2 H), 3.73 (m, 1 H), 3.47 (d, 5 Hz, 2 H), 2.88
(dd, 13 and 6
Hz, 1 H), 2.62 (dd, 13 and 8 Hz, 1 H), 1.36 (s, 9 H).
c) N-Boc-(p-fluorophenylalaninal):
Under a nitrogen atmosphere, 4.44 ml (62.4 mmol) of DMSO dissolved in 76 ml of
methylene chloride are added dropwise to a solution, cooled to -60°C,
of 4.0 ml
(46.8 mmol) of oxalyl chloride in 44 ml of methylene chloride. After stirring
for 15
minutes, resulting in a clear reaction solution, 8.4 g (31.2 mmol) of N-Boc-(p-
fluoro-
phenylalaninol) in the form of a solution in 185 ml of rnethylene chloride~THF
1:1 are
added (-~ precipitation) and the mixture is then stirred for 25 min. 17.3 ml
(124.8 mmol)
of triethylamine dissolved in 38 ml of methylene chloride are then added.
After the
mixture has been stirred for 30 min, 278 ml of a 20 % potassium hydrogen
sulfate solution
are added dropwise, followed by 220 ml of hexane. The mixture is left to warm
to .RT, and
the aqueous phase is removed and extracted with 2 portions of ether. The
organic phases
are washed with saturated sodium hydrogen carbonate solution, water and brine,
dried
with sodium sulfate and concentrated by evaporation to yield the title
compound, which is
used in the next step without being further purified: tH-NMR (200 MHz, CDCl3):
9.63 (s,
1 H), 6.9-7.2 (2m, 4 H), 5.04 (m, 1 H), 4.42 (m, 1 I-I), 3.10 (m, 2 H), 1.43
(s, 9 H).
d) N-3(S)-(Boc-amino)-2(R,S)-hey-4-(p-fluorophenvl)-1-trimethvlsilvl-butane:
Analogously to Example 16 a), 1.63 g (67 mmol) of magnesium in 33 ml of abs.
ether are
reacted with 8.3 ml (60 mmol) of chloromethyltrimethylsilane to formr the
Grignard
compound which, after reaction with 13 mmol of N-Boc-(p-fluorophenylalaninal),
extrac-
tion and column chromatography (Si02, hexane/ethyl acetate 5:1 ~ 4:1), yields
the title
compound in the form of a diastereoisomeric mixture: TLC Rr(L)=0.32;
tRec(I)=24.9 min
(22 %)/25.5 min (78 %); FAB-MS (M+H)+=356.
e) 1-(L-Fluorophen~)-3-buten-2(S)-amine:
Analogously to Example 16 b), 1.1 g (3.1 mmol) of N-3(S)-(Boc-amino)-2(R,S)-
hydroxy-
.2~~~7~5
- 159
4-(p-fluorophenyl)-1-trimethylsilyl-butane in 22 ml of methylene chloride are
reacted with
1.9 ml (15.5 mmol) of an approximately 48 % solution of boron trifluoride in
ether to
yield the title compound: tH-NMR (300 MHz, CDC13): 7.2-7.10 and 7.05-6.9 (2m,
each 2
H), 5.9-5.8 (m, 1 H), 5.2-5.0 (m, 2 H), 3.57 (m, 1 H), 2.79 (dd, 12 and 6 Hz,
1 H), 2.62 (dd,
12 and 8 Hz, 1 H), 1.7 (sb, 2 H).
f) N-Trifluoroacet~(p-fluorophenyl)-3-buten-2(S)-amine:
Analogously to Example 16 c), 364 mg (2.2 mmol) of 1-(p-fluorophenyl)-3-buten-
2(S)-
amine in 1.8 ml of methylene chloride and 5.4 ml of pyridine are reacted with
460 ~tl
(3.3 mmol) of trifluoroacetic acid anhydride to yield the title compound,
which after
digestion with hexane is obtained in pure form: TLC Rt{F)=0.58; MS (M)+=261.
g} 2(R)-f 1'(S)-(Trifluoroace~lamino)-2'- p-fluorophen 1~~11-oxirane:
Analogously to Example 16 d), 359 rng (1.37 mmol) of N-trifluoroacetyl-1-(p-
fluoro-
phenyl)-3-buten-2(S)-amine in 9 ml of chloroform are: oxidised with 1.18 g
(6.87 mmol) of
m-chloroperbenzoic acid to yield the title compound: TLC Rt(R)=0.45.
h) N-Trifluoroacetyl-[(p-F)Phe~(p-F)Phel-Boc:
Analogously to Example 16, 41S mg (1.49 mmol) of 2(R)-[1'(S)-
(trifluoroacetylamino)-
2'-(p-fluorophenyl)ethyl]-oxirane and 377 mg (1.57 mmol) of tert-butyl-3-(p-
fluoro-
phenyl-methyl)-carbazate in 9 ml of methanol are reacted to yield the title
compound:
TLC Rt(S)=0.53; FAB-MS (M+H)~=518; tH-NMR (300 MHz, CD30D): 7.4-7.3 and
7.3-7.2 (2m, each 2 H), 7.05-6.9 (m, 4 H), 4.23 (m, 1 H), 3.90-3.65 (m, 3 H),
3.03-2.78 and
2.74-2.60 (2m, each 2 H}, 1.30 (s, 9 H}.
i) H-[(p-F)Phe~ p-F)Phel-Boc:
Analogously to Example 17 a), 285 mg (0.55 mmol) of N-trifluoroacetyl-
[(p-F)Phe~(p-F)Phe]-Boc in 45 ml of methanol are reacted with 14 ml of 1M
potassium
carbonate solution to yield the title compound: tR~~(I)=16.4 min.
Example 32: Z-(L)-Val-f(p-F)Phe~(p-F)Phel-H:
20'~2~~5
- 160 -
Analogously to Example 18 a), 215 mg (0.33 mmol) of Z-(L)-Val-[(p-F)Phe~(p-
F)Phe]-
Boc are deprotected with 100 ml of formic acid to yield the title compound:
FAB-MS
(M+H)~=555.
Example 33: Z-(L)-Val-((p-F)Phew(~F)Phel.-(N-(N-(2-pyridylmeth~)-N-methylamino-
carbonyl)-(L)-Val):
Analogously to Example 18, 23.6 mg (0.089 mmol) of N-(N-(2-pyridylmethyl)-N-
methyl-
aminocarbonyl)-(L)-valine (for preparation see EP 402646 A1, 19th Dec. 1990)
and 45 mg
(0.081 mmol) of Z-(L)-Val-[(p-F)Phe~(p-F)Phe]-H are reacted with 33.8 mg
(0.089 mmol) of HBTU in 0.76 ml of 0.25M NMM/CH3CN to yield the title compound
which is recrystallised with DMF/DIPE: TLC Rt(O)=0.39; FAB-MS (M+H)+=802.
Example 34: Z-(L)-Val-f(p-F)Phew(p-F)Phel~(N-(2(R,S)-carbamoyl-3-phen~=pro-
ip onyl)(L,)Val):
Analogously to Example 18, 26.0 mg (0.089 mmol) of N-(2(R,S)-carbamoyl-3-
phenyl-
propionyl)-(L)-valine (preparation: Synth., Struct., Funct., Proc. Am. Pept.
Symp., 7'}', 85,
(1981)) and 45 mg (0.081 mmol) of Z-(L)-Val-j(p-F):Phe~(p-F)Phe]-H (Example
32) are
reacted with 33.8 mg (0.089 mmol) of I-IBTU in 0.76 ml of 0.25M NMM/CH3CN to
yield
the tide compound which is recrystallised with DMF/DIPE: Rt{P)=0.64; FAB-MS
(M+H)+=829.
)xample 35: Acetyl-Val-(Phe~Phel.-(N-acetyl-Val):
Analogously to Example 7, the title compound is obtained from 100 mg (0.25
mmol) of
H-[Phe~Phe]-He3HC1 from Example 2a), 121 mg (0.76 mmol) of N-acetyl-(L)-
valine,
288 mg (0.76 mmol) of HBTU and 0.211 ml (1.52 mmol) of triethylamine in DMF
after
lyophilisation from dioxane. FAB-MS: (iVI+H)+=568, tRec(I)=15.0 min.,
Rt(B)=0.46.
Example 36: Z-(D)-Val-fPhe~Phel~-((D)-Val)-Z:
Analogously to Example 2, the title compound is obtained from 50 mg (0.123
mmol) of
H-[Phe~Phe]-Ha3HCl from Example 2a), 95 mg (0.38 mmol) of Z-(D)-valine, 168 mg
(0.38 mmol) of BOP, 5I mg (0.38 mmol) of HOBt and 2.53 ml of 0.3M NMM in DMF
after lyophilisation from dioxane. FAB-MS: (M+H)+=752, tRec(I)=26.4 min,
Rf(H)=0.21.
2~'~~'~~5
- 161 -
Example 37: Quinoline-2-carbonyl-Val- f Phe~Phel~-(N-nuinoline-2-carbon~al2
145 mg (0.53 mmol) of N-(quinoline-2-carbonyl)-(L)-valine, 235 mg (0.53 mmol)
of BOP
and 72 mg (0.53 mmol) of HOBt are dissolved in 3.5 ml of a 0.3M solution of
NMM in
DMF, after 10 min 70 mg (0.18 mmol) of H-[Phe~Phe]-H=HCl (Example 2a)) are
added,
and the mixture is stirred for 5 h at RT under a nitrogen atmosphere. The
reaction mixture
is concentrated by evaporation and the residue is dissolved in methylene
chloride and
washed twice with saturated sodium hydrogen carbonate solution, once with 10 %
citric
acid and once again with saturated sodium hydrogen carbonate solution. The
organic
phases are filtered through cotton wadding and concentrated by evaporation,
and the
residue is precipitated twice from methylene chloride/methanol by the addition
of DIPE.
Lyophilisation from dioxane yields the title compound in the form of a white
solid
(mixture of two diastereoisomers differentiable by HPLC). FAB-MS: (M+I-
I)+=794,
tR~~(A)=29.1 and 29.3 min, Rt{B)=0.81.
a) N-( uinoline-2-carbonyl)-(L)_valine:
3.28 g (15.9 mmol) of N,N-dicyclohexylcarbodiimide; and 2.0 ml (14.5 mmol) of
triethyl-
amine are added to a solution of 2.5 g (14.5 mmol) of (L)-valyl-tert-butyl
ester and 2.5 g
(14.5 mmol) of quinoline-2-carboxylic acid in 100 ml of methylene
chloride/1~IIF (10:1)
and the mixture is stirred for 18 h at RT. The reaction mixture is cooled to -
18° and
filtered off from the urea. The filtrate is concentrated by evaporation, and
the residue is
dissolved in methylene chloride and washed once with saturated sodium hydrogen
carbonate solution and once with water. The organic phases are filtered
through cotton
wadding, concentrated by evaporation and, after chromatographic purification
on silica gel
with hexane/ethyl acetate (2:1), yield N-(quinoline-2-carbonyl)-(L)-valyl-tert-
butyl ester.
2.59 g (12.2 mmol) thereof are left at RT in methylene chloride/TFA (1:1) for
4.5 h. After
concentration by evaporation the residue is purified by chromatography on
silica gel with
hexane/ethyl acetate (2:1). The product-containing fractions are concentrated
by evapora-
tion, dissolved in methylene chloride again, and converted into the
hydrochloride of the
title compound by washing with 1N sodium hydroxide solution and 1N
hydrochloric acid.
tH-NMR (200 MHz, CD30D): 1.05 and 1.07 (2d, J=6Hz, 6H), 2.40 (m, 1H), 4.65 (m,
1H),
7.70 (m, 1H), 7.85 (m, 1H), 8.00 (dxd, 1H), 8.20 (m, 2H), 8.48 (d, 1H).
Example 38: Acetyl-(L.)-Val-fPhe~Chal.-(N-acet~-(L)-Val):
~0~27~~
- 162 -
Analogously to Example 37, the title compound is obtained from 160, mg (0.40
mmol) of
H-[Phe~Cha]-H~3HC1 from Example 10a), 190 mg (1.19 mmol) of N-acetyl-(L)-
valine,
525 mg (1.19 mmol) of BOP, 160 mg (1.19 mmol) of HOBt and 7.9 ml of 0.3M NMM
in
DMF after precipitation from chloroform/methanol with DIPE and lyophilisation
from
dioxane. FAB-MS: (M+H)+=574, tRec(I)=18.1 min, RI(B)=0.30.
Example 39: N-(3-P~rfidylacetyl)-(L)-Val-(Phe~Chal.-(N-(3-pyrid~et 1y )-~)_
Val)~3HCl:
Analogously to Example 7, the title compound is obtained from 100 mg (0.25
mmol) of
H-[Phe~Cha]-H~3HC1 from Example 10a), 358 mg (1.52 mmol) of N-(3-
pyridylacetyl)-
(L)-valine from Example 9a), 576 mg (1.52 mmol) of HBTU and 0.316 ml (2.28
mmol) of
triethylamine in DMF after chromatographic purification on silica gel with
methylene
chloride/methanol (15:1) and lyophilisation of the product-containing
fractions from
dioxane. FAB-MS: (M+H)+=728, tR~i(I)=11.3 min, Rp(IJ)=0.21.
Example 40: Acetyl-Ile-(Phe~Chal~-(N-acetyl-Ile):
Analogously to Example 37, the title compound is obtained from 160 mg (0.40
mmol) of
H-[Phe~Cha]-H~3HC1 from Example 10a), 206 mg (1.19 mmol) of N-acetyl-(L)-iso-
leucine, 525 mg (1.19 mmol) of BOP, 160 mg (1.19 mmol) of HOBt and 7.9 ml of
0.3M
NMM in DMF after precipitation from methylene chloride/methanol by the
addition of
DIPS and lyophilisation from dioxane/tezt-butanol (mixture of 2
diastereoisomers
differentiable by HPLC). FAB-MS: (M+H)'''=602, iRec(~=20.4 and 20.7 min,
Rf(D)=0.33.
Example 41: Thiomort~holinocarbonyl-(L)-Val-fPhe~Chal.-(N-thiomorpholina-
carbonyl-(I,)-Val):
Analogously to Example 6, the title compound is obtained starting from 70 mg
(0.12 mmol) of H-(L-Val)-[Phe~Cha].-(N-(L)-Val)-H~3HCl from Example 14, 58 mg
(0.35 mmol) of (4-thiornorpholinylcarbonyl)chloride from Example 6a) and 0.127
ml of
triethylamine in 2 ml of DMF after chromatographic purification on silica gel
with
methylene chloride/methanol (95:5) and lyophilisation of the product-
containing fractions
from dioxane. PAB-MS: (M+H)~=748, tRe~(I)=24.0 min, Rf(B)=0.70.
2~'~27~5
- 163 -
Example 42: Z-(L)-Glu-~Phe~''t(p-F)Phel.-(CL)-Glu)-Z:
A solution of 130 mg (0.14 mmol) of Z-(L)-Glu(O-tent-but5~1)-(Phe~(p-F)Phe].-
((L)-
Glu(O-tent-butyl))-Z [(Glu(O-terf-butyl) here denotes the radical of glutamic
acid ester-
ified at they-carboxy group by a tent-butyl radical] in 8 ml of methylene
chloride/TFA
(i:1) is stirred for 3 h at RT. The solvent is evaporated off under reduced
pressure and the
residue is precipitated from methylene chloride by the addition of DIPE. The
title
compound is obtained after lyophilisation from dioxane/tert-butanol. FAB-MS:
(M+H)+=830, tRe,(I)=19.6 min, Rt(B)=0.32.
a) Z-(L)-Glu(O-tert-but r~ fPhew(p-F)Phel~-((L)-Glu(O-tert-butyl))-Z:
Analogously to Example 37, the title compound is obtained from 100 mg (0.24
mmol) of
H-[Phe~(p-F)Phe]-H~3HC1, 245 mg (0.73 mmol) of Z-(L)-glutamic acid ten-butyl
ester,
321 mg (0.73 mmol) of BOP, 98 mg (0.73 mmol) of HOBt and 4.8 ml of 0.3M NMM in
DMF after chromatographic purification on silica gel with methylene
chloride/ether (1:1).
tRec(I)=30.2 min, Rf(H)=0.17.
b) I3-fPhe~(p-F)Phe]-H~3HCl:
Analogously to Example 2a), the title compound is obtained from 1.77 g (3.51
mmol) of
Boc-[Phe~(p-F)Phe]-Boc after lyophilisation. FAB-MS: (M+H)+=304, Rt{K)=0.19.
c) Boc-FPhe~(p-F)Phel-Bac:
Analogously to Example 1, the title compound is obtained starting from 2.0 g
(7.60 mmol)
of (2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane and 2.17 g (9.04 mmol) of tent-
butyl-3-
(4-fluorophenyl-methyl)-carbazate from Example 16 f) after chromatographic
purification
on silica gel with hexane/ethyl acetate (2:1). FAB-MS: (M+H)+=504,
tRec(I)=26.2 min,
R f(F)=0.26.
Example 43: N-(2-Pyridylmethyl)-N-methylaminocarbonyl-(L)-Val-iPhe~(p-F)-
Phel~(N-(N-(2-p"~ridylmethyl)-N-methylaminocarbonyl)-(L)-V al):
Analogously to Example 37, the title compound is obtained from 70 mg (0.17
mmol) of
H-[Phe~(p-F)Phe]-H~3HCl from Example 42b), 135 mg (0.51 mmol) of N-(N-(2-
pyridyl-
2~"~27~~
-164 -
methyl)-N-methylaminocarbonyl)-(L)-valine (preparation as described in EP 0
402 646
Al of 19th Dec. 1990), 225 mg (0.51 mmol) of BOP, 69 mg (0.51 m~nol) of HOBt
and
3.4 ml of 0.3M NMM in DMF after chromatography on silica gel with methylene
chloride/methanol (15:1) and lyophilisation of the product-containing
fractions from
dioxane. FAB-MS: (M+H)*=798, tRec(IV)=35 min, Rf(U)=0.21.
Example 44: N-(3-(Tetrazol-1-yl)-pr~ionyl)-Val-[Phew(p-F)Phel~~(N-(3-(tetrazol-
1-yl)-
propionyl)-Val):
Analogously to Example 37, the title compound is obtained from 100 mg (0.24
mmol) of
H-[Phe~)p-F)Phe]-H~3HC1 (from Example 42b), 146 mg (0.61 mmol) of N-(3-
{tetrazol-
I-yl)-propionyl)-(L)-valine, 268 mg (0.61 mmol) of BOP, 82 mg (0.61 mmol) of
HOBt
and 4 ml of 0.3M NMM in DMF after precipitation from methylene chloride by the
addition of DIPE and lyophilisation from dioxane (4 diastereoisomers
differentiable by
HPLC). FAB-MS: (M+H)*=750, tR~t(IlI)=30.8; 31.4; 32.4 and 32.8 min, Rt(K)=0.5.
Example 44a: N-(3-(Tetrazol-1-~Zpropionyl)-(L)-valine:
Analogously to Example 9b, starting from 4 g (16.4 mmol) of (L)-valine-benzyl
ester~HCI,
2.1 g (14.9 mmol) of 3-(tetrazol-1-yl)-propionic acid (preparation: US 4 794
109 A of 27th
Dec. 1988), 2.4 ml of cyanophosphonic acid diethyl ester and 4.4 ml of
triethylamine in
DMF, N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine-benzyl ester is obtained after
chromato-
graphic purification on silica gel with methylene chloride/methanol (30:1).
2.66 g
(8.03 mmol) thereof are hydrogenated in methanol/water (9:1) in the presence
of 530 mg
of 10 % palladium on carbon, at 1 atm hydrogen pressure, to yield the title
compound after
precipitation from methanol/DIPE. 1H-NMR (200 MHz, CD30D): 0.9 (d, J=7I-Iz,
6H), 2.1
(m, 1H), 2.95 (m, 2H), 4.29 (d, J=6Hz, 1H), 4.78 (m, 2H), 9.15 (s> 1H).
Example 45: Z-(L)-Val-(Phe~(p-F)Phel.-((L)-VaI~Z:
Analogously to Example 37, the title compound is obtained from 100 mg (0.24
mmol) of
H-[Phe~{p-F)Phe]-H~3HCl (from Example 42b), 182 mg (0.38 mmol) of Z-(L)-
valine,
321 mg (0.73 mmol) of BOP, 98 mg (0.73 mmol) of HOBt and 4.8 ml of 0.3M NMM in
DMF after precipitation from methylene chloride by the addition of DIPE and
lyophilisa-
tion from dioxane. FAB-MS: (M+1-1)*=770, IRet(I)=26.3 min, Rf(H)=0.25.
2~72~~~
165 -
Example 46: Acetyl-Val-fPhe~(p-F)Phe].-(N-acet 1-
Analogously to Example 37, the title compound is obtained from 80 mg (0.19
mmol) of
H-[Phe~(p-F)Phe]-H~3HCi from Example 42b), 124 mg (0.78 mmol) of N-acetyl-(L)-
valine, 344 mg (0.78 mmol) of BOP, 105 mg (0.76 mmol) of HOBt and 4.5 ml of
0.3M
NMM in DMF after reprecipitation twice from methylene chloride/methanol by the
addition of DIPE and lyophilisation from dioxane/tert-butanol. FAB-MS:
(M+H)+=586,
tR~c(I)=15.8 min, Rf (F)=0.32.
Example 47: Acetyl-Val-fPheNN(p-CN)Phe].-(N-acetyl-Val):
Analogously to Example 37, the title compound is obtained in the form of a
mixture of 2
diastereoisomers differentiable by HPLC from 80 mg (0.19 mmol) of H-[Phe~(p-
CN)Phe]-H~3HC1, 124 mg (0.78 mmol) of N-acetyl-(L)-valine, 344 mg (0.78 mmol)
of
BOP, 105 mg (0.78 mmol) of I-IOBt and 4.5 ml of 0.3M NMM in DMF after
precipitation
from methylene chloride/methanol by the addition of DIPE and lyophilisation
from
dioxane. FAB-MS: (M-t-H)+=593, tRet(I)=14.4 and 14.6 min, Rt(D)=0.39.
a) H-fPhe~(L-CN)Phe]-H~3HC1:
Analogously to Example 2a), the title compound is obtained from 2.69 g (5.27
mmol) of
Boc-[Phe~(p-CN)Phe]-Boc after lyophilisation. FAB-MS: (M+H)+=311, Rt(K)=0.16.
b) Boc-[Phe~(p-CN)Phe]-Boc:
Analogously to Example 1, the title compound is obtained from 2.0 g (7.60
mmol) of
(2R)-[1'(S)-Boc-amino-2'-phenylethyl]oxirane and 1.87 g (7.6 mmol) of tent-
butyl-3-(4-
cyanophenyl-methyl)-carbazate after crystallisation from methanol/D1PE. FAB-
MS:
(M+H)+=511, tRe~(I)=25 min, RA(Y)=0.19.
c) tent-Butyl-3-(4-cyanophen 1-~yl)-carbazate:
Analagously to Example 4b), 10 g (76.3 mmol) of 4-cyartobenzaldehyde and 10 g
(76.3 mmol) of tent-butylcarbazate in ethanol are reacted to yield 4-
cyanophenylcarb-
aldehyde-tort-butoxycarbonylhydrazone. 11.1 g thereof are hydrogenated in 150
ml of
T'HF in the presence of 2 g of 10 % palladium on carbon at 2 atm hydrogen
pressure to
20°~2~~~
- 166 -
yield the title compound. 1H-NMR (200 MHz, CDCl3): 7.65 (d, J=BHz, 2H), 7.45
(d, J=8
Hz, 2H), 6.08 (s> br, 1H), 4.3 (s, br, 1H), 4.02 (s, 2H), 1.45 (s, 9H). ,
Example 48: Z-CL)-Val-fPhe~(~-CN)Phel~((L)-VaD-Z:
Analogously to Example 37, the title compound is obtained from 70 mg (0.17
mmol) of
H-[Phe~(p-CN)Phe]-H~3HCl (from Example 47a)), 125 mg (0.5 mmol) of Z-(L)-
valine,
221 mg (0.5 mmol) of BOP, 68 mg (0.5 mmol) of HOBt and 3.33 ml of 0.3M NMM in
DMF after precipitation from methylene chloride by the addition of hexane and
lyophilisa-
tion from dioxane. FAB-MS: {M+H)+=777, tR~t(I)=25.3 min, R~D)=0.69.
Example 49: Z-(L)-Ile-fPhe~Leul.-((L)-Ile)-Z:
Analogously to Example 37, the title compound is obtained from 70 mg (0.19
mmol) of
H-[Phe~Leu]-H~3HC1 (from Example 13a)), 154 mg (0.58 mmol) of Z-(L)-
isoleucine,
257 mg (0.58 mmol) of BOP, 79 mg (0.58 mmol) of HOBt and 3.88 ml of 0.3M NMM
in
DMF after chromatography on silica gel with methylene chloride/ether (3:1) and
precipita-
tion of the product-containing fractions from methylene chloride/DIPE and
lyophilisation
from dioxane. FAB-MS: (M+H)+=746, tRe~(~=28.2 min, Rf(H)=0.39.
Example 50: Isobutox c~arbonyli~',l-Val-fPhe~Leul~-(N-isobutoxycarbonyl-(L)-
Val):
Analogously to Example 37, the title compound is obtained from 70 mg (0.19
mmol) of
H-[Phe~Leu]-H~3HCl (from Example 13a)), 130 mg (0.58 rnmol) of N-(isobutoxy-
carbonyl)-(L)-valine, 256 rng (0.58 mmol) of BOP, 78 mg (0.S8 mmol) of HOBt
and
3.9 ml of 0.3M NMM in DMF after chromatography on silica gel with rnethylene
' chloride/ether (1:1) and lyophilisation of the product-containing fractions
from dioxane.
FAB-MS: (M+H)~'=650, tRei(>)=26.4 min, Rf(H)=0.38.
a) N-(Isobutox~carbonyl)-(L)-valine:
11.2 ml (85.3 mmol) of isobutyl chlorofonnate are added to a solution of 10 g
(85.3 rnrnol)
of (L)-valine in 100 ml of 2N sodium hydroxide solution and the solution is
stirred at RT
for 18 h. The reaction solution is washed with methylene chloride, acidified
with 4N
hydrochloric acid and extracted with methylene chloride. The organic extracts
are washed
with brine and filtered through cotton wadding to yield the title compound in
the form of a
20'~~7~5
167 -
colourless resin after concentration by evaporation. tH-NMR (200 MHz, CD30D):
0.95
(m, 12H), 1.9 (rn, 1H), 2.15 (m, 1H), 3.85 (d, J=7Hz, 2H), 4.05 (d broad, 1H).
Example 5i: N-(3-(Tetrazol-1-Yl)-propionyl)-(L)-Val-fPhe~Leul.-(N-3-(tetrazol-
1-
propionYl-(L)-Val):
Analogously to Example 37, the title compound is obtained from 150 mg (0.42
mmol) of
H-[Phe~Leu]-H~3HC1 (from Example 13a)), 251 mg (1.04 mmol) of N-(3-(tetrazol-1-
yl-
propionyl)-(L)-valise from Example 44a, 460 mg (1.04 mmol) of BOP, 140 mg
(1.04 mmol) of HOBt and 6.9 ml of 0.3M N-methylmorpholine in DMF after
precipitation
from methylene chloride/DIPE and lyophilisation from dioxane/tert-
butanol/water.
FAB-MS: (M+H)+=689, tRe~(I)=14.7 min, R~(K)~.36.
Example 52: Acetvl-Val-fPhe~Leul~(N-acetyl-VaD:
Analogously to Example 37, the title compound is obtained from 70 mg (0.19
mmol) of
H-[Phe~Leu]-H~3HCl (from Example 13a)), 184 mg (1.16 mmol) of N-acetyl-(L)-
valise,
512 mg (1.16 mmol) of BOP, 156 mg (1.16 mmol) of HOBt and 7.8 ml of 0.3M NMM
in
DMF after precipitation from methylene chloride/methanol by the addition of
DIPE and
lyophilisation from dioxane/tert-butanol/water (2 diastereoisomers
differentiable accord-
iIlg to HPLC). FAB-MS: (M+H)+=534, tR~~(I)=14.7 and 15.1 min, Rf(D)=0.35.
Example 53: Boc-(L)-Val-fPhe~Leul~-((L)-Val)-Boc:
Analogously to Example 7, the title compound is obtained from 300 mg (0.83
mmol) of
H-[Phe~Leu]-H~3HC1 (from Example 13a)), 722 mg (3.33 mmol) of Boc-(L)-valise,
1.262 g (3.33 mmol) of HBTU and 0.927 ml (6.66 mmol) of triethylamine in DMF
after
chromatographic purification on silica gel with methylene chloride/ether
(1:l), precipita-
tion of the product-containing fractions and lyophilisation from dioxane. FAB-
MS:
(M+H)+=650, tRe~(I)=26.3 min. Rt(II)~.64.
Example 54: H-(L)-Val-fPhe~Leul.-((L)-Val)-H~3HC1:
Analogously to Example 5, the title compound is obtained from 396 mg (0.61
mmol) of
Boc-(L)-Val-[Phe~Leu].-((L)-Val)-Boc from Example 53 and 10 ml 4N hydrogen
chloride in dioxane after lyophilisation of the reaction solution. FAB-MS:
(M+H)+=450,
~O'~~"~~
168 -
tRec(B)=24.1 min, Rf{K)=0.25.
Example 55: N-Thiomorpholinocarbonyl-(L)-Val-lPhe~Leu.-(N-thiomorpholino-
carbon~(L)-Val): . '
Analogously to Example 6, the title compound is obtained in the form of an
amorphous
solid starting from 100 mg (0.16 mmol) of H-(L)-Val-[Phe~Leu)~(L)-Val-H~3HC1,
78.5 mg (0.47 mmol) of (4-thiomorpholinylcarbonyl)chloride from Example 6a and
0.172 ml of triethylamine in DMF after chromatographic purification on silica
gel with
methylene chloride/methanol (95:5), precipitation of the product-containing
fractions from
methylene chloride/hexane and lyophilisation from dioxane. FAB-MS: (M+H)+=708,
tRet(n=21.4 min, Rf(E)=0.45.
Example 56: 2(R,S)-Tetrahydrofurlrl-methox c~ 1-(L)-Val-f Cha~Leul.-(N-2(R,S)-
tetrahvdrofurlrl-methoxycarbonyl- L( )~Val)
Analogously to Example 37, the tide compound is obtained from 80 mg (0.22
mmol) of
H-[Cha~Leu]-H~3HC1, 160 mg (0.65 mmol) of N-(2(R,S)-tetxahydrofuryl-methoxycar-
bonyl)-(L)-valine, 289 mg (0.65 mmol) of BOP, 88 m,g (0.65 mmol) of HOBt and
4.35 ml
of 0.3M NMM in DMF after chromatographic purification on silica gel with ethyl
acetate
and lyophilisation of the product-containing fractions from dioxane. FAB-MS:
(M+H)+=712, tRe~(I)=22.4 min, Rt(E)=0.21.
a) H-lCha~Leui-H~3HC1:
Analogously to Example 5, 100 mg (83 %) of the title compound are obtained
from
150 mg (0.33 mmol) of Boc-[Cha~Leu]-Boc and 10 ml of 4N hydrogen chloride in
dioxane after lyophilisation of the reaction solution. R~(K)=0.26.
b) Boc-lCha~Leui-Boc
A solution of 200 mg (0.24 mmol) of Boc-[Phe~Leu]-Boc (Example 12) in 15 ml of
methanol is hydrogenated for 4 h at 1 atm hydrogen pressure in the presence of
10 mg of
Nishimura-catalyst (Rh(III)- and Pt(1V)-oxide tnonohydrate, Degussa). The
catalyst is
removed by filtration, the solvent is fully concentrated by evaporation and
the title
compound is obtained after crystallisation from methylene chloride/hexane.
tRec(I)=26.7
~072"~~5
069 _
min, Rx(V )=0.21.
c) N-(2(R,S)-Tetrahydrofuryl-methoxycarbonyl)-(L)-valine:
Analogously to Example 50a, the title compound is obtained in the form of a
mixture of 2
diastereoisomers from 7 g (60 mmol) of (L)-valine and 9.8 g (60 mmol) of
2(R,S)-tetra-
hydrofurylmethyl-chloroformate (Hetexocycles 27, 1155 (1988)) in 100 ml of 2N
sodium
hydroxide solution and 30 ml of dioxane. tR~~(II)=23.5 and 23.8 min.
Example 57: Z-Val-iPhe~Leul.-(N-(3-(tetrazol-1-yl)-propionyl)-Val):
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 100 mg (0.21 mmol) of Z-(L)-Val-[Phe~Leu]-
H,
75 mg (0.31 mmol) of N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine from Example
44a,
137 mg (0.31 mmol) of BOP, 42 mg (0.31 mmol) of HOBt and 2 ml of 0.3M NMM in
DMF after precipitation from methylene chloride/hexane and lyophilisation from
dioxane/tert-butanol. FAB-MS: (M+H)'"=708, tRec(I)-.21.1 and 21.1 min,
Rf(D)=0.45.
a) Z-(L.)-Val-fPhe~LeuLH:
A solution of 250 mg (0.43 mmol) of Z-(L)-Val-[Phe~Leu]-Boc in 5 ml of .formic
acid is
stirred for 7.5 h at RT. After that time no more starting material can be
detected by HPLC
analysis (tRec(1)=27.5 min), and the reaction solution is concentrated by
evaporation. The
residue is dissolved in chloroform and washed with saturated sodium hydrogen
carbonate
solution. The chloroform phase is filtered through cotton wadding and yields
the crude .
title compound after removal of the solvent by evaporation. tRei(I)=16.7 min,
R f(K)=0.21. ,
zo~27~~
- 170 -
b) Z-(L,)-Val-fPhe~Leul-Boc:
Analogously to Example 37, the title compound is obtained from 230 mg (0.653
mmol) of
H-[Phe~Leu]-Boc, 247 mg (0.98 mmol) of Z-(L)-valine, 434 mg (0.98 mmol) of
BOP, ,
133 mg (0.98 mmol) of HOBt and 6.5 ml of 0.3M NMM in DMF after precipitation
from
methylene chloride/methanol by the addition of DIPE. FAB-MS: (M+H)+=585,
tRec(I)=27.5 min, Rf(C)=0.71.
c) H-fPhe~Leul-Boc:
Analogously to Example 17a), the title compound is obtained starting from 1.27
g
(2.84 mmol) of N-trifluoroacetyl-[Phe~Leu]-Boc and 24 ml of 1N aqueous sodium
carbonate solution in 90 ml of methanol by precipitation from methylene
chloride by the
addition of DIPE. tR~~(I)=14.9 min, Rf(K)=0.38.
d) N-Trifluoroacetyl-fPhe~Leul-Boc:
Analogously to Example 16, the title compound is obtained starting from 3 g
(11.57 mrnol) of 2(R)-[1'(S)-(trifluoroacetylamino)-2'-phenylethyl]-oxirane
from
Example 16d) and 2.3 g (12.15 mmol) of tart-butyl-3-isobutyl-carbazate
(preparation: J.
Chem. Soc. Perltin I, 1712 (1975)) after chromatographic purification on
silica gel with
methylene chloride/ether (20:1). tRec(I)=24.7 min, Rt(W)=0,36.
Example 58: Acetyl-Val-fPhe~Leul~(N-(2(R S)-carbamoyl-3-phenyl-prapion~V
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 140 mg (0.3 mmol) of acetyl-(L)-Val-
[Phe~Leu]-H~2HC1, 132 mg (0.45 mmol) of N-(2(R,S)-carbamoyl-3-phenyl-
propionyl)-
(L)-valine (preparation: Synth., Struct., Funct., Proc. Am. Pept. Symp., 7~,
85, (1981)),
199 mg (0.45 mmol) of BOP, 61 mg (0.45 mmol) of HOBt and 3.5 ml of 0.3M NMM in
DMF after precipitatian from methylene chloride/DIPE and lyophilisation from
dioxane.
FAB-MS: (M+H)+=667, tRe~(I)=17.9 and 18.4 min, Rf(D)=0.33.
a) Acetyl-Val-fPhe~Leul-I-I~2HCl:
Analogously to Example 2a), the title compound is obtained starting from 230
mg
~o~~~~~
- 171 -
(0.46 mmol) of acetyl-(L)-Val-[Phe~Leu]-Boc after lyophilisation, tket(I)=10.5
min,
Rt{D)=0.38. ,
b) Acetyl-Val-fPhe~Leul-Boc: '
Analogously to Example 37, the title compound is obtained from 2S0 mg (0.71
mmol) of
H-[Phe~Leu]-Boc from Example 57c), 170 mg (1.07 mmol) of N-acetyl-(L)-valine,
471 mg (1.07 mmol) of BOP, 144 mg (1.07 mmol) of I-IOBt and 7.1 ml of 0.3M NMM
in
DMF after precipitation from methylene chloride by the addition of DLPE and
lyophilisa-
tion from dioxane. FAB-MS: (M+H)+=493, tRet(I)=20.5 min, Rf(D)=0.59.
Example 59: N-Morpholinocarbonyl-(L)-Val-fPhe~Leui~(N-(3-(tetrazol-1-yl)-prop-
ionyl)-Val):
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 100 mg (0.19 mmol) of N-
rnorpholinocarbonyl-
(L)-Val-[Phe~Leu]-H~2HCl, 67 mg (0.38 mmol) of N-(3-(tetrazol-1-yl)-propionyl)-
(L)-
valine from Example 44a, 124 mg (0.28 mmol) of BOP, 38 mg (0.28 mmol) of HOBt
and
2.1 ml of 0.3M NMM in DMF after precipitation from methylene chloride by the
addition
of DIPE and lyophilisation from dioxane. FAB-MS: (M+H)~=687, tR~c(I)=15.2 and
15.4
min, Rp(D)=0.25.
a) N-Morpholinocarbonyl-(L)-VaI-[Phe~Leul-H~2HC1:
Analogously to Example 2a), the title compound is obtained starting from 279
mg
(0.49 mmol) of N-morpholinocarbonyl-(L)-Val-[Phe~Leu]-Boc after
lyaphilisation.
FAB-MS: (M+H)~"=464, tRec(B)=30.3 min, Rf(D)=0.46.
b) N-Morpholinocarbonyl-(L)-Val-fPhe~Leul-Boc:
Analogously to Example 37, the title compound is obtained from 250 mg (0.71
mmol) of
H-[Phe~Leu]-Boc (from Example 57c)), 265 mg (1.07 mmol) of N-morpholino-
carbonyl-(L)-valine from Example 7a), 471 mg (1.07 mmol) of BOP, 144 mg (1.07
mmol)
of HOBt and 7.1 ml of 0.3M NMM in DMF after precipitation from methylene
chloride/-
hexane and lyophilisation from dioxane. FAB-MS: (M+H)+=564, tRe~(I)=21.5 min,
Rt(K)=0.69.
- 172 -
Example 60: N-Trifluoroacetyl-(Phe~Leul.-(N-(2(R S)-carbam~l-3-phenyl-
propionyl)-
L -Val
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 136 mg (0.32 mmol) of N-trifluoroacetyl-
[Phe~Leu]-H~2HC1,142 mg (0.49 mmol) of N-(2(R,S)-carbamoyl-3-phenyl-propionyl)-
(L)-valine (preparation: Synth., Struct., Funct., Proc. Am. Pept. Symp., 7a',
85, (1981)),
215 mg (0.49 mmol) of BOP, 66 mg (0.49 mmol) of HOBt and 3.5 ml of 0.3M NMM in
DMF after chromatographic purification on silica gel with chloroform/methanol
(15:1),
precipitation of the product-containing fractions from methylene chloride/DIPE
and
lyophilisation from dioxane/tert-butanol. FAB-MS: (M+H)~=622, tRec{T)=21.6 and
22.0
min, Rf(K)=0.26.
a) N-Trifluoroacetyl-(Phe~Leul-H~2HC1:
Analogously to Example 2a), the title compound is obtained starting from 300
mg
(0.67 mmol) of N-trifluoroacetyl-[Phe~Leu]-Boc from Example 57d) after
lyophilisation.
Rt{W)<0.1.
Example 61: Z-~L)-Val-(Phe~Nlel.-(N-(2(R S)-(N-(:Z-morpholinoethyl)-carbamoyl)-
3-
methyl)-butyr~:
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 100 mg (0.17 mmol) of Z-(L)-Val-
[Phe~Nle]-H~2HC1, 69 mg {0.27 mmol) of 2(R,S)-(N-(2-morpholinoethyl)-
carbamoyl)-
3-methylbutyric acid (isopropylmalonic acid N-(2-morpholinoethyl)monoamide),
119 mg
(0.27 mmol) of BOP, 36 mg (0.27 mmol) of HOBt and 2.1 ml of 0.3M NMM in DMF
after precipitation from methylene chloride/DIPE and lyophilisation from
dioxane.
FAB-MS: (M+H)+=725, tRec{I)=17.2 and 17.6 rnin, R,f(D)=0.56.
a) Z-(L)-Val-(Phe~Nle1-H~2HC1:
Analogously to Example 2a), the title compound is obtained starting from 310
mg
(0.53 mmol) of Z-(L)-Val-[Phe~Nle]-Boc after lyophilisation. tRec(1)=16.4 min,
Rt(U)=0.25.
- 173 -
b) Z-(L)-~lal-fPhe~Nlel-Boc:
Analogously to Example 37, the title compound is obtained from 250 mg (0.71
mmol) of
H-(Phe~Nle]-Boc, 268 mg (1.07 mmol) of Z-(L)-valine, 472 mg (1.07 mmol) of
BOP,
144 mg (1.07 mmol) of HOBt and 7.1 ml of 0.3M NMM in DMF after chromatographic
purification on silica gel with methylene chloride/methanol (40:1) and
precipitation of the
product-containing fractions from methylene chloride/DIPE. tRec(I)=25.6 min,
Rf(X)=0.17.
c) H-fPhe~Nlel-Boc:
Analogously to Example 17a), the title compound is obtained starting from 830
mg
(1.85 mmol) of N-trifluoroacetyl-(Phe~NIe]-Boc after precipitation fzorn
methylene
chloride/DIPE. tR~c(I)=15.4 min, Rf(K)=0.54.
d) N-Trifluoroacetyl-fPhe~NIel-Boc:
Analogously to Example 16, the title compound is obtained stwting from 1 g
(3.86 mmol)
of 2(R)-(1'-(S)-(triouoroacetylamino)-2'-phenylethyl]-oxirane from Example
16d) and
720 mg (3.86 mmol) of tert-butyl-3-butyl-carbazate after chromatographic
purification on
silica gel with methylene chloride/ether (20:1). tR~~(I)=:25.3 min,
Rt(Q)=0.43.
e) tent-Butyl-3-butyl-carbazate:
Analogously to Example 4b), the corresponding tert-butoxycarbonyl-hydrazone
(25 g,
99 %) is obtained from 18.0 g (136.2 mmol) of tent-butyl-carbazate and 12.3 ml
(136.2 mmol) of n-butanal in the form of a crude product, which is
hydrogenated as
described in Example 4a) in the presence of 10 g of 5% platinum on carbon at 4
atm
hydrogen pressure. Chromatographic pzu-ification of the crude product on
silica gel with
hexane%thyl acetate (1:1) yields the title compound. Rf(N)=0.44,1H-NMR (200
MHz,
CD30D). 0.92 (t, J=7Hz, 3H), 1.43 (s, 9H), 1.30 to 1.50 (m, 4H), 2.75 (t, J=7I-
Iz, 2H).
f) 2(R,S)-(N-(2-Morpholinoeth~l)-carbarnoyl)-3-methylbutyric acid
Analogously to Example 9b) there is obtained from 7 g (43.7 mmol) of racemic
isopropyl-
malonic acid monomethyl ester CChem. Ber. 119, 1196 (1986)), 6.3 m1 (48.1
mmol) of
20'~2'~~~
- 174 -
aminoethyl-morpholine, 6.6 ml (43.7 mmol) of cyanophosphonic acid diethyl
ester and
12.8 ml (91.8 mmol) of triethylamine in DMF, 2(R,S)-(N-(2-morpholinoethyl)-
carbamoyl)-3-methyl-butyric acid methyl ester (isopropylmalonic acid N-
morpholino-
ethylamide methyl ester). This is 'stirred for 5 h in a mixture of 28 ml of 2N
sodium
hydroxide solution and 28 ml of dioxane at RT, acidified with 2N hydrochloric
acid and
fully concentrated by evaporation. The residue is digested with ethanol,
filtered off, and
concentration by evaporation of the filtrate yields the title compound. lI-I-
NMR (200
MHz, CD30D): 0.95 and 1.00 (2d, J=7H, 6H), 2.25 (m, 4H), 2.70 (m, 6H), 2.75
(d, J=8Hz,
1H), 3.45 (m, 2H), 3.75 (m, 4H).
Exam 1p a 62: Z-(L)-Val-fPhe~Nlel~(N-(3-(tetrazol-1-~_propionyl)-Val):
Analogously to Example 37, the title compound is obtained (in the form of 2
diastereo-
isomers differentiable by HPLC) from 1(?0 mg (0.18 mmol) of Z-(L)-Val-
[Phe~Nle]-
H~2HCl (from Example 61a)), 65 mg (0.27 mmol) of N-(3-(tetrazol-1-yl)-
propionyl)-(L)-
valine from Example 44a, 119 mg (0.27 mmol) of BOP, 36 mg (0.27 mmol) of HOBt
and
2.1 ml of 0.3M N-methylmorpholine in DMF after precipitation from methylene
chloride/-
DIPE and lyophilisation from dioxane/tert-butanol. F,AB-MS: (M+H)+=708,
tR~~(I)=20.3
and 20.6 min, Rf(D)=0.43.
ExamQe 63: Z-CL)-Val-fPhe~Nlel~(N-(2(R,S)-(N-(2-pvridylmethyl)-carbamoyl)-3-
methyl)-butyryp (dibenzenesulfonate):
Analogously to Example 37, the title compound is obtained in the form of the
free amine
from 95 mg (0.17 mmol) of Z-(L)-Val-[Phe~Nle]-H~2HC1 from Example 61a), 60 mg
(0.26 mmol) of (R,S)-isopropylmalonic acid N-(2-picolyl)-monoamide, 113 mg
(0.26 mmol) of BOP, 35 mg (0.26 mmol) of HOBt and 2.0 ml of 0.3M NMM in DMF
after chromatographic purification on silica gel with methylene
chloride/methanol (15:1).
The free amine is dissolved in methylene chloride, 2 eduivalents of
benzenesulfonic acid
are added, and precipitation is effected by the addition of DIPE.
Lyophilisation from tert-
butanol yields the dibenzenesulfonate salt (in the form of 2 diastereoisomers
differentiable
by HPLC). FAB-MS: (M+H)+=703, tRec(I)=17.7 and 18.0 min, Rf(D)=0.54.
a) Isopropylmalonic acid N-(2-picolyl)monoamide:
10.6 ml (103 mmol) of N-methylmorpholine are added to a solution of 15 g (93.6
mmol)
20°~2'~~~
175
of isopropylmalonic acid monomethyl ester (preparation: Chem. Ber. 119, 1196
(1986)) in
150 ml of THF and subsequently 13.5 ml (103 mmol) of isobutyl chlproformate
are added
dropwise thereto. After 30 min 15.3 ml (150 mmol) of 2-picolylamine are added
and the
resulting suspension is.stirred for 2 h. The reaction mixture is diluted with
1N sodium
hydroxide solution and water and washed with methylene chloride, and the
organic phase
is filtered through cotton wadding and concentrated by evaporation.
Crystallisation of the
residue yields isopropylmalonic acid N-(2-picolylamide) methyl ester, which is
hydro-
lysed in 2N sodium hydroxide solution and dioxane as described in Example 61f)
to yield
the title compound. tRec(B)=16.0 min.
Example 64: Z-(L)-Val-(Phew(p-F)Phel.-(N-(3-(tetrazol-1- 1~)-propionyl)-(L)-
Val)
(benzenesulfonate):
Analogously to Example 37, the title compound is obtained in the form of the
free amine
from 100 mg (0.16 mmol) of 2-(L)-Val-[Phe~(p-F)Phe]-H from Example 22a), 59 mg
(0.25 mmol) of N-(3-(tetrazol-1-yl)-propionyl)-(L)-valine from Example 44a,
109 mg
(0.25 mmol) of BOP, 33 mg (0.25 mmol) of HOBt and 1.19 ml of 0.3M N-methyl-
morpholine in DMF after precipitation from methylene chloride/DIPE. The free
amine is
dissolved in methylene chloride/methanol, 1 equivalent of benzenesulfonic acid
is added,
and precipitation is effected by adding hexane. Lyophilisation from tert-
butmol yields the
title compound in the form of the benzenesulfonate salt. FAB-MS: (M+H)'"'=760,
tRe~(1)=21.6 min, R~B)=0.49.
Examyle 65: Methylsulfonyl-fPhe~Phel.-(N,=phenylacetyl-(L)-ValO
132 mg (0.28 mmol) of methylsulfonyl-[Phe~Phe]-H-2HC1 is reacted analogously
to
Example 7 with 197 mg (0.84 mmol) of N-phenylacetyl-(L)-valine (preparation:
Mem.
Tokyo Univ. Agric. 20, Sl (1978)), 317 mg (0.S4 mmol) of HBTU and 0.23 ml
(1.67 mmol) of triethylamine in DMF to yield the title compound after
precipitaton from
methanol by the addition of ether. FAB-MS: (M+H)+=581, tRec(I)=20.2 min,
Rr(B)=0.64.
a) Methvlsulfonvl-fPhe~Phei-H~2HCl:
Analogously to Example 2a), the title compound is obtained starting from 130
mg
(0.28 mmol) of methylsulfonyl-[Phe~Phe]-Boc after lyophilisation. FAB-MS:
(M+H)~=364, tRe~(II)=28.5 min, Rf (K)=0.56.
2072~~~
- 176 -
b) MethvlsulfonYl-fPhe~Phel-Boc:
Analogously to Example 16a), tht; title compound is obtained as a
diastereoisomeric
mixture in a ratio of 4:1 starting from 1.1 g (4.56 mmol) of 2(R)-[1'(S)-
(methylsulfonyl-
amino)-2'-phenylethyl]oxirane and 1,11 g (5.02 mmol) of tert-butyl-3-benzyl-
carbazate
(preparation: J. Chem. Soc. Perlcin I, 1712 (1975)). By crystallisation from
methylene
chloride/hexane the ratio in favour of the 2S-diastereoisomer is improved to
10:1.
FAB-MS: (M+H)+=464, tRet(~=21.3 min, RA(N)=0.26.
c) 2(R)-(1'(S)-(Methylsulfonylamino)-2'-phen 1y ethylloxirane~
2.36 g (13.6 mmol) of methansulfonic acid anhydride and 1.88 ml (13.6 mmol) of
triethyl-
amine are added at O~C to a solution of 1 g (6.8 mmol) of 1-phenyl-3-buten-
2(S)-amine
from Example 16b) in 10 ml methylene chloride and the mixture is stirred for 1
h. The
xeaction mixture is washed with water and saturated sodium hydrogen carbonate
solution
and the organic phase is filtered through cotton wadding and concentrated by
evaporation
to yield 2(S)-methylsulfonylamino-1-phenyl-3-butene. 1 g (4.4 mmol) of that
crude
product is dissolved in 30 ml of methylene chloride, 3.05 g (17.7 mmol) of 4-
chloroper-
benzoic acid are added at RT and stirring is earned oust for 18 h. The
reaction solution is
washed 5 times with 10 % aqueous sodium sulfite solution, filtered through
cotton
wadding and fully concentrated by evaporation. According to iH-NMR the crude
product
contains both the (2R)- and the (2S)-epimer in a ratio of 4:1. tH-NMR (200
MHz,
CD30D); 2.30 and 2.52 (2 s, together 3H), 2.6 to 3.2 (m, 5H), 3.55 (m, 1H),
7.32 (m, 5H).
Example 66: Methox c~yi-(L)-Val-[Phe~Leul~(N-methox cy arbonyl-(L,)-VaIO
Analogously to Example 37, the title compound is obtained from 200 mg (0.55
mmol) of
H-[Phe~Leu]-H~3HC1 (from Example 13a)), 291 mg (1.66 mmol) of N-methoxycar-
bonyl-(L)-valine (preparation: Chem. Lett. 705, (1980)), 735 mg (1.66 mmol) of
BOP,
225 mg (1.66 mmol) of HOBt and 11 ml of 0.3M NMM in DMF after precipitatian
from
rnethylene chloridelDlPE and lyophilisation from dioxane. FAB-MS: (M+H)~=566,
tttet(I)=18.6 min, Rt(U)=0.33.
20'?'27~~
- 177 -
Example 67: Methox~carbon~-(L)-Val-fPhe~(p-F)Phel--(N-methoxycarbonyl-(L)-
Val):
Analogously to Example 37, the title compound is obtained from 200 mg (0.48
mmol) of
H-jPhe~(p-F)Phe]-H~3HCl (from Example 42b)), 255 mg (1.45 mmol) of N-methoxy-
carbonyl-(L)-valine (preparation: Chem. Lett. 705, (1980)), 643 mg (1.45 mmol)
of BOP,
196 mg (1.45 mmol) of HOBt and 9.7 ml of 0.3M NMM in DMF after precipitation
from
methylene chloride/DIPE and lyophilisation from dioxane. FAB-MS: (M+H)+=618,
tR~,(1)=19.5 min, R~U)=0.22.
Example 68: Methoxycarbonyl-(L)-Val-fPhe~(p-CN)Phel~(N-methoxycarbonyl-(L)-
V
Analogously to Example 37, the title compound is obtained from 200 mg (0.48
mmol) of
H-[Phe~(p-CN)Phe]-H~3HC1 (from Example 47a)), 250 mg (1.43 mmol) of N-methoxy-
carbonyl-(L)-valine (preparation: Chem. Lett. 705, (1980)), 631 mg (1.43 mmol)
of BOP,
193 mg (1.43 mmol) of HOBt and 9.5 ml of 0.3M NMM in DMF after chromatographic
purification on silica gel with methylene chloride/methanol (15:1) and
lyophilisation of
the product-containing fractions from dioxane. FAB-MS: (M+H)+=625, tRe~(I)=18
min,
Rt(U)=0.31.
Exam 1-p a 69: Z-(L)-Val-f (p-F)Phew(p-F)Phel.-(N-(2(R,S)-(N-(2-morpholinoeth
1 -carb-
amoyl)-3-methyl)-butyr~):
Analogously to Example 18, 23.0 mg (0.089 mmol) of 2(R,S)-(N-(2-
morpholinoethyl)-
carbamoyl)-3-methylbutyric acid (Example 61 f)) and 45 mg (0.081 mmol) of Z-
(L)-Val-
j(p-F)Phe~(p-F)Phe]-H (Example 32) are reacted with 33.8 mg (0.089 mmol) of
HBTU
in 0.76 ml of 0.25M NMM/CH3CN to yield the title compound which is
reprecipitated
with DMF/DIPE: TLC Rt{P)=0.42; FAB-MS (M+H)~'=795.
Example 70: Z-(L)-Va1-f (p-F)Phe~(~ F)Phel~(N-(2(R,S)-(N-(2-pyridylmethyD-carb-
amo~l)-3-methyl)-butyr
Analogously to Example 18, 21.0 mg (0.089 mmol) of rac. isopropylmalonic acid
N-(2-
picolyl)amide (Example 63 a)) and 45 mg (0.081 mmol) of Z-(L)-Val-[(p-F)Phe~(p-
F)Phe]-H (Example 32) are reacted with 33.8 mg (0.089 mmol) of HBTU in 0.76 ml
of
0.25M NMM/CI-33CN to yield the title compound which is reprecipitated with
20"~~'~~5
- 178 -
DMF/DIPE: TLC R;f(P)=0.52; FAB-MS (M+H)+=773.
Example 71:
The following compounds can be prepared analogously to one of the afore-
mentioned
processes:
a) Z-(L)-Val-[(p-F)Phew(p-F)Phe].-((L)-Val).-(N-morpholinocarbonyl-Gly);
b) N-Morpholinocarbonyl-(L)-Val-[(p-F)Phew(p-F)Phe].-((L)-Val).-(N-morpholino-
carbonyl-Gly);
c) N-(Quinoline-2-carbonyl)-(L)-Asn-[Phe~(p-F)Phe]~((L)-Val)-Z
d) N-(Mozpholinosulphonyl)-(L)-Val-[Phe~Leu].-(N(morpholinosulphonyl)-(L)-Val)
Example 72: Gelatine solution:
A sterile-Filtered aqueous solution, with 20 % cyclodextrins as solubilisers,
of one of the
compounds of formula I mentioned in the preceding Examples as active
ingredient, is so
mixed under aseptic conditions, with hearing, with a sterile gelatine solution
containing
phenol as preservative, that 1.0 ml of solution has the following composition:
active ingredient 3 mg
gelatine 150.0 mg
phenol 4.7 mg
dirt. water with 20 % cyclodextrins
as solubilisers 1.0 ml
Example 73: Sterile dry substance for infection:
mg of one of the compounds of formula I mentioned in the preceding Examples as
active
ingredient are dissolved in 1 ml of an aqueous solution with 20 mg of mannitol
and 20 %
cyclodextrins as solubilisers. The solution is sterile-filtered and introduced
under aseptic
conditions into a 2 ml ampoule, deep-frozen and lyophilised. Before use, the
lyophilisate
is dissolved in 1 ml of distilled water or 1 ml of a physiological saline
solution. The
20'~2"~~~5
- 179 -
solution is administered intramuscularly or intravenously. This formulation
can also be
introduced into a twin-chambered injection ampoule.
Examgle 74: Nasal spray;
S00 mg of finely ground (<S.0 N.m) powder of one of the compounds of formula I
men-
tioned in the preceding Examples is suspended as active ingredient in a
mixture of 3.S ml
of Myglyol 812 and 0.08 g of benzyl alcohol. The suspension is introduced into
a
container with a metering valve. S.0 g of Freon 12~ are introduced under
pressure through '
the valve into a container. The "Freon" is dissolved in the Myglyol/benzyl
alcohol mixture "
by shaking. The spray container contains approximately 100 single doses which
can be
administered individually.
Example 7S: Film-coated tablets
The following ingredients are used for the preparation of 10 000 tablets each
containing
100 mg of active ingredient:
active ingredient 1000 g
corn starch 680 g
colloidal silica 200 g
magnesium stearate 20 g
stearic acid 50 g
sodium carboxymethyl starch 2S0 g
water quantum satis
A mixture of one of the compounds of formula I mentioned in the preceding
Examples as
active ingredient, SO g of corn starch and the colloidal silica is processed
with a starch
paste, made from 2S0 g of corn starch and 2.2 kg of demineralised water, to
form a moist
mass. This is forced through a sieve having a mesh size of 3 rnm and dried at
4S° for
30 min in a fluidised bed drier. The dry granules are pressed through a sieve
having a
mesh size of 1 mm, mixed with a pre-sieved mixture (1 mm sieve) of 330 g of
corn starch,
the magnesium stearate, the stearic acid and the sodium carboxymethyl starch,
and
compressed to form slightly biconvex tablets.
