Note: Descriptions are shown in the official language in which they were submitted.
Merck Patent Gesellschaft 2 ~3
mit beschrankter Haftung
6100 D a r m s t a d t
Amino acid derivatives
The invention relates to novel amino acid deriva-
tives of the formula I
X-W-CR1R2-Co-Y-NH-CHR3-CR4-CooRs
in which
X LS H, R6-O--CmH2m-CO--I R~-CmH2m-O-CO--, R6-CmH2m-CO-,
R6-SO2-, R7R3N-C~H2m-Co-, R9-NH-C(=NH)-NH-
CmH2m--CO--~ R700C-CmH2m-Co--~ R703S-CmEI2m-CO--~
R7-o-(CH2CH2o)~-CmH2m-co- or A3N -CmH2m-CO- An
W i8 O or NH,
Y is ~Ala or Isoser,
R , R
and R8 are each H or A,
R , R
and R6 are each H, A, Ar, Ar-alkyl, Het, Het-alkyl,
cycloal.kyl having 3-7 C atoms, which is unsub-
~ti.tuted or monosubstituted or polysub~tituted
by A, AO and/or Hal, cycloalkylalkyl having 4-
11 C atoms, bicycloalkyl or tricycloalkyl each
ha~ing 7 14 C atoms, or bicycloalkylalkyl or
tri.cycloalkylalkyl each having 8-18 C atoms,
R4 is (H, OH), (H, NH2) or =O,
Rs is H, A or cycloalkyl having 3-7 C atoms,
R7R8N is also an unsubstituted pyrrolidino, piperid-
ino, morpholino or piperazino group or one
which is suhstituted by A, OH, NH2~ NHAr NA2
NH~c, NH-CO-CIH2~-O-R9, NH-co-o-c~H2x-R ~
hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl,
HAN-alkyl, A2N-alkyl, A3N~alkyl Ane, NH-CO-NH2,
NH-CO-NHA, guanidinyl or guanidinylalkyl,
R is M, A, Ar-alkyl or CN,
m and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10,
n is 0, 1, 2 or 3,
- 2 ~ 2~ 2
Ax is unsubsti~uted phenyl or phenyl which is
monosubstituted or polysubstituted by A, OA,
Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NAz,
NHAc, NH-S02-A, SA, SO-A, SO2-A, SO2NH2~ S02NHA,
COOH, COOAI CONH2r CN, ~ninoalkyl, HAN-alkyl,
A2N-alkyl,A3N~-alkyl Aneand/orguanidinylalkyl,
or is unsubstituted naphthyl,
Het is a saturated or unsaturated 5- or 6-membered
heterocyclic radical having 1-4 N, O andJor S
atoms, which can ~e fused to a benzene ring
and/or monosubstituted or polysubstituted by A,
OA, Hal, CF3, OH, NOz, carbonyl oxygen, MH2,
NHA, NA2, NHAc, NH-COOA, NHCOO~r, NHCOOCH~Ar,
NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH,
COOA, CONH2, CN, Ar, Ar-al~yl, Ar-alkenyl,
hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl
and/or A3N~-alkyl Ane and/or whose N and/or S
heteroatoms can also be oxidised,
Hal is F, Cl, Br or I,
Ac is A-CO-, Ar-CO , Ar-alkyl-CO- or A-NH-CO-,
Ane is an anion, which can also be absent, if
instead of this a carboxyl group contained in
the compound of the formula I i5 present in the
fo~n of a carboxylate anion,
-alkyl is an alkylene group having 1-8 C atoms and
A is alkyl having 1~8 C atoms,
in which in addition instead of one or more ~NH-CO groups
there can also be one or more -NA-CO groups,
and their ~alts.
Similar compounds are disclosed in EP-A-249,096.
The invention was based on the object of finding
novel compounds having useful properties, in particular
those which can be used for the preparation of medica-
ments.
3S It ha~ been found that the compounds of the
formula I and their salts have very useful properties. In
particular~ they inhibit the activity of human plasma
renin. This action can be detected, for example, by the
method of F. Fyhrqui~t et al., Clin. Chem. 22/ 250-256
- 3 - 2050~92
(1976). It is noteworthy that these compounds are very
specific inhibitors of renin; as a rule about 100 to
1000 times as high concentrations of these compounds are
necessary for the inhibition of other aspartylproteinases
(for example pepsin and cathepsin D) as for renin inhi-
bition. The actions of the compounds on the blood pres-
sure and/or on the heart rate and the inhibition of the
renin activity in the blood plasma can additionally be
determined in conscious monkey~, for example female
monkeys (Macaca fascicularis); in this connection blood
pressure and heart rate can be measured following the
method of M.J. Wood et al., J. Hypertension 4, 251-254
(1985). To stimulate renin activity, the animals are in
thi~ case expediently pretreated with a saluretic. Blood
~amples for determining the plasma renin activity can be
obtained by puncture of the femoral vein.
The compounds can be employed as medicament
- active compounds in human and veterinary medicine, in
particular for the prophylaxis and for the treatment of
cardiac, circulatory and vascular diseases, in particular
hypertension, cardiac insufficiency and hyperaldo-
steronism. In addition, the compounds can be used for
diagnostic purposes in patients with hypertension or
hyperaldosteronism in order to determine the possible
contribution of the renin activity to the maintenance of
the pathological condition. Such diagnostic tests can be
carried out in a similar manner to that given in
EP-A-77,028.
The abbreviations of amino acid radicals
mentioned above and below are for the radical~ -NR'-Rn-
CO-, as a rule -NH-CHR-CO- (in which R, R' and R" have
the specific meaning known for each amino acid), of the
following amino acids:
Ada 3-(1-adamantyl)alanine
Ala alanine
~Ala ~-alanine
Bia 3-(2-benzimidazolyl)alanine
Cal 3-cyclohexylalanine
Gly glycine
His histidine
Hph homophenylalanine (2-amino 4-phenylbutyric
acid)
Ile isoleucine
Leu leucine
~al 3-(p-methoxyphenyl)alanine
Nle norleucine
Phe phenylalanine
Tia 3-~thienyl)alanine [for example 2-Tia =
3-(2-thienyl)alanine]
Tiz 3-(thiazolyl)alanine [for example 2-Tiz =
3-~2-thiazolyl)alanine]
Trp tryptophan
Tyr tyrosine.
In addition, the following hav0 the meaning
below:
BOC tert.-butoxycarbonyl
BOM benzyloxymethyl
imi-BOM benzylo~ymethyl in the l-position of the
imidazole ring
CBZ benzyloxycarbonyl
DCCI clicyclohexylcarbodiLmide
DME climethylformamide
DNP 2,4-dinitrophenyl
imi-DNP 2,4-dinitrophenyl in the l-position of the
imidazole ring
ETOC ethoxycarbonyl
FMOC 'i-fluorenylmethoxycarbonyl
HOBt 1-hydroxybenzotriazole
IPOC isopropoxycarbonyl
Pla the radical of phenyllactic acid
-O-CH(CH2C6Hs)~CO- (S-form)
PO~ phenoxy~cetyl
THF tetrahydrofuran.
If the abovementioned amino acids can occur in
several enantiomexic forms, all these forms and also
their mixtures (for example the DL-forms) are included
above and below, for example as constituents of the
compounds of ~he formula 1. The L-forms are preferred. If
_ 5 _ 2~3~9~
individual compounds are mentioned below, the abbrevia-
tions of these amino acids in each case relate to the
L-form, if not expressly stated otherwise.
The invention further relates to a process for
the preparation of an amino acid derivative of the
formula I and of its salts, characterised in that it is
set free from one of its functional derivatives by
treating with a solvolysing or hydrogenolysing agent
or in that a carboxylic acid of the formula II
X-Gl-OH II
in which
Gl (a) is absent,
(b) i~ -W-CRlR2_co-
~(c) is -W-CRlR2_co_y_,
or one of its reactive derivatives
is reacted with a compound of the formula III
H - G 2 -NH - CHR3-CR4-CooR5 III
in which
G2 (a) i8 -W-CRlR2-CO-Y-,
(b) is _y_,
( C ) i8 absent,
and in that a functionally modified amino and/or hydroxy
group i8 optionally set free in a compound of the formula
I by treating with solvolysing or hydrogenolysing agents
and/or a free amino group is acylated by treating with an
acylating agent and/or an aminoketo acid derivative of
the formula I, R4 = O, is reduced or reductively aminated
to prepare a compound of the formula I, R~ = (H, OH) or
(H, NH2) and/or an ester of the formula I, R5 = A is
hydrolysed and/or an acid of the formula I, R5 = H is
esterified and/or a compound of the formula I is conver-
ted into one of its salts by treating with an acid.
Above and below, the radi-cals or parameters Rl to
R~, W, X, Y, m, n, x, Ar, Het, Hal, Ac, An, A, Gl and G2
have the meanings indicated in the formulae I, II or III
- 6 - 20~0~2
unless expressly stated otherwise.
In the above formulae, A has 1-8, preferably 1,
2, 3 or 4 C atoms. A is preferably methyl, furthermore
ethyl, propyl, isopropyl, butyl, isobutyl, sec.-butyl, or
tert.-butyl, additionally also pentyl, 1-, 2- or
3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl,
l-ethylpropyl, hexyl, 1-, 2-, 3- or 4-methylpentyl, 1,1-,
1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or
2-ethylbutyl, l-ethyl-l-methylpropyl, 1-ethyl-2-methyl-
propyl, 1,1,2- or 1,2,2-trLmethylpropyl, heptyl, octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cycloheptyl, but also, for
example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or
4-methylcyclohexyl.
Accordingly, cycloalkylalkyl is preferably
cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl,
2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl,
cyclohexylmethyl, 2-cyclohexylethyl, but also, for
example, 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-,
3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-decalyl,
2-bicyclo[2.2.1~heptyl or 6,6-dimethyl-2-bicyclot3.1.11-
heptyl.
Tricycloalkyl is preferably l-adamantyl.
Hal is preferably F, Cl or Br, but also I.
Ac is preferably A-C0-, such as acetyl, propionyl
or butyryl, Ar-C0- such as benzoyl, o-, m- or p-methoxy-
benzoyl or 3,4-dimethoxybenzoyl, or A-NH-C0- such as
N-methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl, in addition preferably
o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m- or
p-methoxyphenyl, o-, m- or p-fluorophenyl, o-, m- or
p-chlorophenyl, o-, m- or p-bromophenyl, o-, m- or
p-iodophenyl, o-, m- or p-trifluoromethylphenyl, o-, m-
or p-hydroxyphenyl, o-, m- or p-sulfamoylphen~l, 2,3-,
2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl,
3,4,5-trimethoxyphenyl, o-, m-, or p-aminophenyl, o-, m-
or p-aminomethylphenyl, o-, m- or p-dimethylaminomethyl-
phenyl, o-, m- or p-guanidinomethylphenyl, 1- or
_ 7 _ 20~92
2-naphthyl.
Accordingly, Ar-alkyl is preferably benzyl, 1- or
2-phenylethyl, o-, m- or p-methylbenzyl, 1- or 2-o-, -m-
or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or 2-o-,
-m- or -p-ethylphenylethyl, o-, m- or p-methoxybenzyl, 1-
or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or
p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl,
o-, m- or p-chlorobenzyl, 1- or 2-o-, -m- or -p-chloro-
phenylethyl, o-, m- or p-bromobenzyl, 1- or 2-o-, -m- or
-p-bromophenylethyl, o-, m- or p-iodobenzyl, 1- or 2-o-,
-m- or -p-iodophenylethyl, o-, m- or p-trifluoromethyl-
benzyl, o-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-,
2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxy-
benzyl, o-, m- or p-aminobenzyl o-, m- or p-aminomethyl-
benzyl, o-, m- or p-dimethylaminomethylbenzyl, o-, m- or
p-guanidinomethylbenzyl, 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl,
1-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, 1-, 3-,
4- or 5-pyrazolyl, 2-, 4- or 5-oxazolyl, 3-, 4- or
5-isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothi-
azolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyr~midinyl,
furthermore preferably 1,2,3-triazol-1-, -4- or -5-yl,
1,2,4-triazol-1-, -3- or -5-yl, 1- or 5-tetrazolyl,
1,2,3-oxadiazol-4- or -5-yl, 1,2,4-oxadiazol-3- or -5-yl,
1,3,4-thiadiazol-2- or -5-yl, 1,2,4-thiadiazol-3- or
-5-yl, 2,1,5-thiadiazol-3- or -4-yl, 2-, 3-, 4-, 5- or
6-2H-thiopyranyl, 2-, 3- or 4-4H-thiopyranyl, 3- or
4-pyridazinyl, pyrazinyl, 2-, 3-, 4-, 5-, 6- or 7-benzo-
furyl, 2-, 3-, 4-, 5-, 6- or 7-benzothienyl, 1-, 2-, 3-,
4-, 5-, 6- or 7-indolyl, 1-, 2-, 3-, 4-, 5-, 6- or 7-iso-
indolyl, 1-, 2-, 4- or 5-benzimidazolyl, 1-, 3-, 4-, 5-,
6- or 7-benzopyrazolyl, 2-, 4-, 5-, 6- or 7-benzoxazolyl,
3-, 4-, 5-, 6- or 7-benzisoxazolyl, 2-, 4-, 5-, 6- or
7-benzothiazolyl, 2-, 4-, 5-, 6- or 7-benzisothiazolyl,
4-, 5-, 6- or 7-benæ-2,1,3-oxadiazolyl, 2-, 3-, 4-, 5-,
6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-, 6-, 7- or 8-iso-
quinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl, 1-, 2-, 3-, 4-,
5-, 6-, 7-, 8- or 9-acridinyl, 3-, 4-, 5-, 6-, 7- or
8-cinnolyl, 2-, 4-, 5-, 6-, 7- or 8-quinazolyl. The
8 2050~2
heterocyclic radicals can also be partially or completely
hydrogenated. Het can thus also be, for example, 2,3-di-
hydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4-
or -5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2- or
-3-thienyl, 2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl,
2,5-dihydro-1-, -2-, -3-, -4- or -S-pyrrolyl, 1-, 2- or
3-pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl,
2,3-dihydro-1-, -2-, -3-, -4- or -S-pyrazolyl, tetra-
hydro-l-, -3- or -4-pyrazolyl, 1,4-dihydro-1-, -2-, -3-
or -4-pyridyl, 1,2,3,4-tetrahydro-1-, -2-, -3-, -4-, -5-
or -6-pyridyl, 1,2,3,6-tetrahydro-1-, -2-, -3-, -4-, -5-
or -6-pyridyl, 1-, 2-, 3- or 4-piperidinyl, 2-, 3- or
4-morpholinyl, tetrahydro-2-, -3- or -4-pyranyl, 1,4-di-
oxanyl, 1,3-dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or
-4-pyridazinyl, hexahydro-l-, -2-, -4- or -5-pyrimidinyl,
1-, 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-1-, -2-, -3-,
-4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-1-,
-2-, -3-, -4-, -5-, -6-, -7- or -8-isoquinolyl.
The heterocyclic radicals can also be substituted
as indicated. Het can also preferably be, for example:
2-amino-4-thiazolyl, 4-carboxy-2-thiazolyl, 4-carbamoyl-
2-thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2-
methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl,
4-carbamoylpiperidino, in addition, for example, 3-, 4-
or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-di-
methyl-3-furyl, S-nitro-2-furyl, 5-styryl-2-furyl, 3-, 4-
or S-methyl-2-thienyl, 2-, 4- or S-methyl-3-thienyl,
3-methyl-S-tert.-butyl-2-thienyl, S-chloro-2-thienyl,
S-phenyl-2- or -3-thienyl, 1-, 3-, 4- or S-methyl-2-
pyrrolyl, 1-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimeth-
yl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl,
5-methyl-3-isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or
5-methyl-2-thiazolyl, 2- or 5-methyl-4-thiazolyl, 2- or
4-methyl-5-thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-,
5- or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3-
pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6-
chloro-2-pyridyl, 2-, 4-, 5- or 6-chloro-3-pyridyl, 2- or
3-chloro-4-pyridyl, 2,6-dichloropyridyl, 2-hydroxy-3-,
-4-, -5- or -6-pyridyl (= lH-2-pyridon-3-, -4-, -5- or
2~0~92
-6-yl),5-phenyl-lH-2-pyridon-3-yl,5-p-methoxyphenyl-lH-
2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5-
pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-
methylureido-lH-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl,
4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimid-
inyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrLm-
idinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-
benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzo-
thienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl,
1-methyl-5- or -6-benzimidazolyl, l-ethyl-S- or -6-benz-
imidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl,
2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino
or 3-benzyl-2,5-dioxopyrrolidino.
~ is generally preferably H; R6-C~H2m-O-CO- such
as BOC; R6-CmH2m-CO- such as formyl or acetyl; R6-S02-, in
particular A-S02- such as methylsulfonyl; R7R3N-CmH2~-Co-,
in particular 4-BOC-aminopiperidinocarbonyl, 4-amino-
piperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-
dimethylaminopiperidinocarbonyl, 4-ethoxycarbonylamino-
piperidinocarbonyl, morpholinocarbonyl, piperazino-
carbonyl or 4-BOC-piperazinocarbonyl.
The group Y is preferably ~Ala.
W i8 preferably NH.
R1, R5, R7, and R8 are each preferably H, in addi-
tion preferably methyl; R5 i8 preferably al~o ethyl,
propyl, i~opropyl, n-butyl, isobutyl, cyclopentyl or
cyclohexyl. R7R~ is preferably also pyrrolidino, piperi-
dino, morpholino, aminopiperidino such as 4-aminopiperi-
dino, hydroxypiperidino such as 4-hydroxypiperidino,
alkylaminopiperidino such as 4-methylaminopiperidino,
dialkylaminopiperidino such a~ 4-dimethylaminopiperidino,
ethoxycarbonylaminopiperidino such as 4-ethoxycarbonyl-
aminopiperidino or BOC-aminopiperidino such a~ 4-BOC-
aminopiperidino, morpholino or 4-BOC-piperazino.
R2 is preferably Ar-alkyl, in particular benzyl
or p-methoxybenzyl; in addition preferably A, in parti-
cular n-butyl or isobutyl; cycloalkylalkyl, in particular
cyclohexylmethyl; or Het-alkyl, in particular 2-thienyl-
methyl. The group -W-CRlR2-CO- is preferably one of the
20S0~9~
-- 10 --
radicals Phe or Pla, in addition Ada, Bia, Cal, His, Hph,
Ile, Leu, Mal, Nle, Tia, Tiz, Trp or Tyr.
R3 is preferably cycloalkylalkyl, in particular
cyclohexylmethyl, in addition preferably alkyl, in
particular n-butyl or isobutyl; Ar-alkyl, in particular
benzyl or p-methoxybenzyl; Het-alkyl, for example 2-
thienylmethyl; or cycloalkyl, in particular cyclohexyl.
R4 is preferably (H, OH).
R9 is preferably H, methyl or CN.
The parameter m is preferably 1, 2, 3, 4 or 5; n
is preferably 1; x is preferably 1 or 2.
CmH~ and CrH~ are preferably straight-chain, that
is to say preferably -(CH2) m~ or -(CH2)~-.
Accordin~ly, the group X i8 in particular prefer-
ably H; R7R8N-(CH2)m-Co-, in particular H2N-CmH~-CO- such
as aminocarbonyl, aminoacetyl (H-Gly~), 3-aminopropionyl
(H-~Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-amino-
hexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-amino-
nonanoyl, 10-aminodecanoyl, ll-aminoundecanoyl, but also,
for example, 2-aminopropionyl (Ala), 2-amino-2-methyl-
propionyl, 3-amino-3-methylbutyryl; ANH-CmH~-CO- such as
methylaminocarbonyl, ethylaminocarbonyl, methylamino-
acetyl (sarcosyl), 3-methylaminopropionyl, 4-methylamino-
butyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl,
6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methyl-
aminooctanoyl, 9-methylaminononanoyl, 10-methylamino-
decanoyl, ll-methylaminoundecanoyl; AkN-C~H~-CO- such as
dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethyl-
aminopropionyl, 4-dimethylaminobutyryl, 5-dimethylamino-
pentanoyl, 6-dimethylaminohexanoyl, 6-diethylaminohexan-
oyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl,
9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11-
dimethylaminoundecanoyl; pyrrolidino-CmH~-CO- such as
pyrrolidinocarbonyl,pyrrolidinoacetyl,3-pyrrolidinopro-
pionyl, 4-pyrrolidinobutyryl, S-pyrrolidinopentanoyl, 6-
pyrrolidinohexanoyl, 4-pyrrolidinoheptanoyl, 8-pyrroli-
dinooctanoyl,9-pyrrolidinononanoyl,10-pyrrolidinodecan-
oyl; piperidino-CmH~-CO- such as piperidinocarbonyl,
piperidinoacetyl, 3-piperidinopropionyl, 4-piperidino-
20~0~2
butyryl, 5-piperidinopentanoyl, 6-piperidinohexanoyl, 7-
piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidino-
nonanoyl, 10-piperidinodecanoyl; morpholino-CmH2m-CO- such
as morpholinocarbonyl, morpholinoacetyl, 3-morpholino-
propionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl,
6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morphol-
inooctanoyl,9-morpholinononanoyl,10-morpholinodecanoyl;
4-hydroxypiperidino-CmH2m-CO- such as 4-hydroxypiperidino-
carbonyl, 4-hydroxypiperidinoacetyl; 4-aminopiperidino-
CmH2m-CO- such as 4-aminopiperidinocarbonyl, 4-amino-
piperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4-
aminopiperidinojbutyryl, 5-(4-aminopiperidino)pentanoyl,
6-(4-aminopiperidino)hexanoyl, 7-(4-aminopiperidino)hept-
anoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperi-
dino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOC-
aminopiperidino-CmH2m-CO- such as 4-BOC-aminopiperidino-
carbonyl, 4-BOC-aminopiperidinoacetyl; 4-dialkylamino-
piperidino-CmH2~-CO- such as 4-dimethylaminopiperidino-
carbonyl, 4-dimethylaminopiperidinoacetyl; 4-alkoxycarb-
onylaminopiperidino-CmH2m-CO- such as 4-ethoxycarbonyl-
aminopiperidinocarbonyl, 4-methoxycarbonylaminopiperi-
dinoacetyl; 4-guanidinopiperidino-C H2m-CO- such as 4-
guanidinopiperidinocarbonyl, 4-guanidinopiperidinoacetyl;
4-carboxypiperidino-C H2m-CO- such as 4-carboxypiperidino-
carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonyl-
piperidino-C~H2~-CO- such as 4-methoxycarbonylpiperidino-
carbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxy-
carbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidino-
acetyl; 4-AcNH-piperidino-C.H2.-CO- such as
4-acetamidopiperidinocarbonyl, 4-acetamidopiperidino-
acetyl; morpholino-C H2m-CO- such as morpholinocarbonyl
or morpholino w etyl; 4-BOC-piperazino-C H2m-CO- such as 4-
BOC-piperazinocarbonyl or 4-Boc-piperazinoacetyl;
H2N-C(=NH)-NH-C H2m-CO- such as guanidinoacetyl, 3-guani-
dinopropionyl, 4-guanidinobutyryl, 5-guanidinopentanoyl,
6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidino-
octanoyl; NC-NH-C(=NH)-NH-CmH2m-CO- such as N'-cyano-
guanidinoacetyl, 3-(N'-cyanoguanidino)propionyl, 4-(N'-
cyanoguanidino)butyryl, 5-(N'-cyanoguanidino)pentanoyl,
2 ~ 2
- 12 -
6-(N'-cyanoguanidino)hexanoyl, 7-(N~-cyanoguanidino)-
heptanoyl, 8-(N'-cyanoguanidino)octanoyl; HOOC-CmH~-CO-
such as malonyl, succinyl, glutaryl, adipyl, 6-carboxy-
hexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carb-
S oxynonanoyl, l~-carboxydecanoyl, ll-carboxyundecanoyl;
AOOC-C~H~-CO- such as methoxycarbonylacetyl, 3-methoxy-
carbonylpropionyl, 4-methoxycarbonylbutyryl, S-methoxy-
carbonylpentanoyl, 6-methoxycarbonylhexanoyl, 7-methoxy-
carbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxy-
carbonylnonanoyl, 10-methoxycarbonyldecanoyl, ethoxy-
carbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarb-
onylbutyryl,5-ethoxycarbonylpentanoyl,6-ethoxycarbonyl-
hexanoyl, 7-ethoxycarbonylheptanoyl, 8-ethoxycarbonyl-
octanoyl, 9-ethoxycarbonylnonanoyl, 10-ethoxycarbonyl-
decanoyl; H-S03-CmHam-CO- such as sulfoacetyl, 3-sulfo-
propionyl, 4-sulfobutyryl, 5-sulfopentanoyl, 6-sulfohexa-
noyl, 7-sulfoheptanoyl, 8-sulfooctanoyl, 9-sulfononanoyl,
10-sulfodecanoyl; A-SO3-CmHam-CO- such as methoxysulfonyl-
acetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonyl-
butyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonyl-
hexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyl-
octanoyl, 9-methoxysulfonylnonanoyl, 10-methoxysulfonyl-
decanoyl, ethoxysulfonylacetyl, 3-ethoxysulfonyl-
propionyl, 4-ethoxysulfonylbutyryl, 5-ethoxysulfonyl-
pentanoyl, 6-ethoxysulfonylhexanoyl, 7-ethoxysulfonyl-
heptanoyl, 8-ethoxysulfonyloctanoyl, 9-ethoxy~ulfonyl-
nonanoyl, 10-ethoxysulfonyldecanoyl; Rff-CmH~-O-CO-, in
particular A-O-CO- ~uch as ETOC, IPOC, BOC and also
Ar-C~Ham-O-CO- such as CBZ; R5-CmHam-Co-, in particular
A-CO- such as acetyl, trimethylacetyl or 3,3-dimethyl-
butyryl, but also formyl; or R6-SOz- such as A-SO2-,
preferably methylsulfonyl.
The compounds of the formula I can have one or
more chiral centres and therefore occur in different
- optically active or optically inactive - forms. The
formula I includes all these forms. If R3 differs from H
and/or R4 is (H, OH) or (H, NHa), the 2R-hydroxy, 2R-
amino, 3S-aminoj 2R-hydroxy-3S-amino and 2R,3S-diamino
enantiomers are preferred (the C atom which carries the
- 13 - 203~92
radical R4 being allocated the 2-position and the C atom
which carries the radicals X-W-CRlR2-C0-Y-NH and R3 being
allocated the 3-position.
The abovementioned cycloalkyl and phenyl groups
are preferably unsubstituted or preferably carry 1 to 3,
in particular 1 or 2 substituents.
The invention accordingly relates in particular
to those compounds of the formula I in which at least one
of the said radicals has one of the abovementioned
preferred meanings. Some preferred groups of compounds
can be expressed by the following sub-formulae Ia to Ik:
Ia H-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ib R6--O--CmH2o~--Co-W-CRlR2-Co-Y-NH-CHR3--CR4-CooR5;
IC R6-CmH2~-O-CO-W--CRlR2-CO--Y-NH-ClIR3-CR4-CoOR5;
Id R6-CmH2~-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ie R7R8N--CmH2m--CO--W-CRlR2-Co-Y-NH-CHR3--CR4-CooRs;
I f R9-NH-C ( =NH ) -NH-CmH2o,-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-
CooR5;
Ig R700C-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ih R703S-CmH2.-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
I i R7-o- ( CH2CH20 ) n-CmH2",-CO--W--CRlR2-CO--Y--NH--CHR3-CR4--CooR5;
I ~ R7RaN-Co-W-CRlR2-Co-Y-NH-CHR3-CR4-CooR5;
Ik 4-Aminopiperidinocarbonyl-W-CRlR2-CO-Y-NH-CHR3-CR4-
cooR5 .
~articularly preferred compounds are those of the
sub-formulae:
(a) Iaa to Ika which correspond to the formulae Ia to
Ik, but in which additionally
-W-CRlR2-C0- is Phe, Pla, Nal or
3 0 -CH2-CH ( CH2C~Hs ) ~CO~;
(b) Iab to Ikb and also Iaab to Ikab, which correspond
to the formulae Ia to Ik and also Iaa to Ika, but in
which additionally
Y is ~Ala.5 (c) Iac to Ikc, Iaac to Ikac and also Iabc to Ikbc,
which correspond to the formulae Ia to Ik, Iaa to
Ika and also Iab to Ikb, but in which additionally
- 14 - 2~992
R3 is cyclohexylmethyl.
Particularly preferred compounds are those of the
sub-formulae:
I and Ia to Ik , which correspond to the formulae I and
also Ia to Ik and those compounds which correspond to the
other abovementioned sub-formulae, but in which
additionally
R4 is (H, OH);
I~ and Ia~ to Ik~, which correspond to the formulae I and
also Ia to Ik and those compounds which correspond to the
other abovementioned sub-formulae, but in which
additionally
R5 is alkyl having 1-3 C atoms.
A particularly preferred group of compounds
corresponds to the formula I
in which
X is H, AO-CO-, H-CO-, 4-BOC-aminopiperidinocarbonyl,
4-hydroxypiperidinocarbonyl, 4-aminopiperidinocarb-
onyl, 4-A2N-piperidinocarbonyl, 4-AOOC-NH-piperi-
dinocarbonyl, piperazinocarbonyl, 4-BOC-piperazino-
carbonyl, morpholinocarbonyl or A-SO2-,
-W-CRlRZ-cO- i8 Phe or Pla,
Y i~ ~Ala or Isoser,
R3 is cyclohexylmethyl,
R~ is (H, OH) and
R5 is alkyl having 1-3 C atoms.
The compounds of the formula I and also the
starting substances for their preparation are otherwise
prepared by methods known per se, such as are described
in the literature (for example in the standard works such
as Houben-Weyl, Methoden der organischen Chemie (Methods
of Organic Chemistry), Georg-Thieme-Verlag, Stuttgart;
and in addition EP-A-45,665, EP-A-77,028, EP-A-77,029,
EP-A-81,783 and EP-A-249,096), to be precise under
reaction conditions which are known and suitable for the
i said reactions. Use can also be made here of variants
which are known per se but are not mentioned here in
greater detail.
The starting substances, if desired, can also be
2 a ~ 2
- 15 -
formed in 8itU, such that they are not isolated from the
reaction mixture, but Lmmediately reacted further to give
the compounds of the formula I.
The compounds of the formula I can be obtained by
setting them free from their functional derivatives by
solvolysis, in particular hydrolysis, or by hydrogen-
olysis.
Preferred starting substances for the solvolysis
or hydrogenolysis are those which otherwise correspond to
the formula I, but instead of one or more free amino
and/or hydroxy groups contain correspondingly protected
amino and/or hydroxy groups, preferably those which
in~tead of an H atom which is bonded to an N atom, carry
an amino protective group, for example those of the
formula I, but instead of an His group contain an
N(im)-R~-His group (in which R~ is an amino protective
group, for example BOM or DNP), or those of the formula
X-W-CR1RZ-Co-Y-NH-CHR3-CH(NHR~)-CooR5.
In addition, starting substances are preferred
which instead of the H atom of a hydroxy group carry a
hydroxy protective group, for example those of the
formula
X-~-CRlRZ-Co-Y-NH-CHR3-CHoR~-CooR5~ in which R~ is a
hydroxy protective group.
Several - identical or different - protected
amino and/or hydroxy groups can also be present in the
molecule of the starting substance. If the protective
groups present are different from one another, they can
in many cases be removed selectively.
The expression ~amino protective group~ is
generally known and relates to groups which are suitable
for protecting an amino group from chemical reactions
(for blocking), but which are easily removable after the
desired chemical reaction has been carried out at another
site in the molecule. Typical of such groups are in
particular unsubstituted or substituted acyl, aryl (for
example DNP), aralkoxymethyl (for example BOM) or aralkyl
groups (for example benzyl, 4-nitrobenzyl, triphenyl-
methyl). Since the amino protec~ive groups are removed
2 ~ 9 2
- 16 -
after the desired reaction (or reaction sequence), their
nature and size is otherwise not critical; but those with
1-20 C atoms, in particular 1-8 C atoms, are preferred.
The expression ~acyl group" is to be interpreted in the
widest sense in connection with the present process. It
includes acyl groups derived from aliphatic, araliphatic,
aromatic or heterocyclic carboxylic acids or sulfonic
acids and also in particular alkoxycarbonyl, aryloxy-
carbonyl and aralkoxycarbonyl groups. Examples of acyl
groups of this type are alkanoyl such as acetyl, propion-
yl or butyryl; aralkanoyl such as phenylacetyl; aroyl
such as benzoyl or toluyl; aryloxyalkanoyl such as POA;
alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-tri-
chloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxy-
carbonyl and FMOC. Preferred amino protective groups are
BOC, DNP and BOM, and in addition CBZ, FMOC, benzyl and
acetyl.
The expression ~hydroxy protective group~ is
likewise generally known and relates to groups which are
suitable for protecting a hydroxy group from chemical
reactions, but which are easily removable after the
desired chemical reaction has been carried out at another
site in the molecule. Typical of such groups are the
abovementioned unsubstituted or substituted aryl, aralkyl
or acyl groups, and in addition also alkyl groups. The
nature and size of the hydroxy protective groups is not
critical, since they are removed again after the desired
chemical reaction or reaction sequence; groups with 1-20 C
atoms, in particular 1-10 C atoms, are preferred.
Examples of hydroxy protective groups are, among others,
tert.-butyl, benzyl, p-nitrobenzoyl, p-toluenesulfonyl
and acetyl, benzyl and acetyl being particularly
preferred.
The functional derivatives of the compounds of
the formula I to be used as starting substances can be
prepared by customary methods of amino acid and peptide
synthesis, such as, for example, are described in the
said standard works and patent applications, for example
2050~92
- 17 -
also by the solid phase method according to Merrifield.
The compounds of the formula I are set free from
their functional derivatives - depending on the protec-
tive group used - for example with strong acids, expedi-
ently with trifluoroacetic acid or perchloric acidl butalso with other strong inorganic acids such as hydro-
chloric acid or sulfuric acid, strong organic carboxylic
acids such as trichloroacetic acid or sulfonic acids such
as benzene- or p-toluenesulfonic acid. The presence of an
additional inert solvent is possible, but not always
necessary.
Suitable inert solvents are preferably organic,
for example carboxylic acids such as acetic acid, ethers
such as tetrahydrofuran or dioxane, amides such a~ DMF,
halogenated hydrocarbons such as dichloromethane, and in
addition also alcohols such as methanol, ethanol or
isopropanol and also water. In addition, mixtures of the
abovementioned solvents are suitable. Trifluoroacetic
acid i~ preferably used in excess without addition of a
further solvent, perchloric acid in the form of a mixture
of acetic acid and 70 % perchloric acid in the ratio 9;1.
The reaction temperatures for the cleavage are expedi-
ently between about O and about 50; the reaction is
preferably carried out between 15 and 30 (room tempera-
ture).
The BOC group can, for example, preferably beremoved with 40 % trifluoroacetic acid in dichloromethane
or with about 3 to 5 N HCl in dioxane at 15-30C, the
FMOC group with an about 5-20 % solution of dimethyl-
amine, diethylamine or piperidine in DMF at 15-30. The
DNP group is also removed, for example, with an about
3-10 % solution of 2-mercaptoethanol in DMF/water at
15-30.
Protective groups which can be removed by hydro-
genolysis (for example BOM, CBZ or benzyl) can be
removed, for example, by treating with hydrogen in the
presence of a catalyst (for example a noble metal cata-
lyst such as palladium, expediently on a support such as
carbon). Suitable solvents in thiY case are the
2 ~ 2
- 18 -
abovementioned, in particular, for example, alcohols such
as methanol or ethanol or amides such as DNF. The hydro-
~enolysis is as a rule carried out at temperatures
between about 0 and 100 and at pressures between about
1 and 200 bar, preferably at 20-30 and at 1-10 bar. The
CBZ group is easily hydrogenolysed, for example, on 5-
10 ~ Pd-C in methanol at 20-30.
Compounds of the formula I can also be obtained
by direct condensation (peptide synthesis) from a car-
boxylic acid component (formula II) and a hydroxyl or
amino component (formula III). Suitable carboxylic acid
components are, for example, those of the sub-formulae
(a) X-OH, (b) X-W-CRlR2-COOH or (c) X-W-CR1R2-CO-Y-OH,
suitable hydroxyl or amino components are thoqe of the
sub-formulae
(a) HW-CRlR2-Co-Y-NH-CHR3-CR4-CooR5,
(b) H-Y-NH-CHR3-CR4-CooR5 or
( c ) H2N-CHR3-CR4-CooR5 .
The reaction is expediently carried out in this
case by customary methods of peptide synthesis, such as
are described, for example, in Houben-Weyl, loc.cit.,
Volume 15/II, pages 1-806 (1974); these methods can also
be transferred, if W = O, to the conden~ation according
to (a)~ an ester bond being formed.
The reaction is preferably carried out in the
presence of a dehydrating agent, for example of a carbo-
diimide such as DCCI or dimethylaminopropylethyl-
carbodiimide, and in addition propanephosphonic anhydride
(cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl
azide or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline,
in an inert solvent, for example a halogenated hydro-
carbon such as dichloromethane, an ether such as THF or
dioxane, an amide such as DMF or dimethylacetamide, or a
nitrile such as acetonitrile, at temperatures between
about -10 and 40, preferably between 0 and 30.
Instead of II or III, suitable reactive deriva-
tives of these substances can also be employed in the
reaction, for example those in which reactive groups are
intermediately blocked by protective groups. The acid
19 20~0~92
derivatives II can be used, for example, in the form of
their activated ester~, which are expediently formed in
situ, for example by addition of HOBt or N-hydroxy-
succinimide.
The starting sub~tances of the formulae II and
III are for the greatest part known. If they are not
known, they can be prepared by known methods, for example
the abovementioned methods of condensation and removal of
protective groups.
If desired, a functionally modified amino and/or
hydroxy group in a compound of the formula I can be set
free by solvolysi5 or hydrogenolysis according to one of
the methods described above.
Thus, for example, a compound of the formula I
lS which contains an R9-C~H2~-O-CO-NH-, an AcNH- or an AOOC-
group can be converted into the corresponding compound of
the formula I which instead of this contains an H2N- or
an HOOC-group, expediently by selective solvolysis
according to one of the abovementioned methods. AOOC-
groups can be hydrolysed, for example, with NaOH or KOH
in water-dioxane at temperatures between O and 40,
preferably 10 and 30.
It is also possible to acylate a compound of the
formula I which contains a free primary or secondary
amino group. Thus, in particular, compounds of the
formula I, in which X is H, can be reacted with acylating
agents of the formula X-Cl or X-Br (in which X is differ-
ent from H), expediently in the presence of an inert
solvent such as THF and/or of a base such as pyridine or
triethylamine at temperatures between -10 and +30.
Furthermore, keto compounds of the formula I
(R~ = O) can be reduced to compounds of the formula I
~R4 = (H, OH)], for example with a complex metal hydride
such as NaBH4, which does not simultaneously reduce the
peptide carbonyl groups, in an inert solvent such as
methanol at temperature~ between about -10 and +30.
Reto compounds of the formula I (R4 = O) can also
be converted into compounds of the formula I (R4 = H, NH2)
by reductive amination. Reductive amination can be
- 20 - 2~ 92
carried out in one or more steps. Thus, for example, the
keto compound can be treated with ammonium salts, for
example ammonium acetate, and NaCNBH3, preferably in an
inert solvent, for example an alcohol such as methanol,
at temperatures between about 0 and 50, in particular
between 15 and 30. It is furthermore possible to convert
the keto compound into the oxime first with hydroxylamine
in a customary manner and to reduce this, for example by
catalytic hydrogenation on Raney nickel, to the amine.
If desired, an ester of the formula I in which
R5 = A can be hydrolysed to the corresponding acid of the
formula I in which R5 = H, for example with sodium
hydroxide or potassium hydroxide, in a lower alcohol such
as methanol or ethanol at temperatures between about 0
and +30-. Conversely, an acid of the formula I (R5 = H)
can be esterified to give the corresponding ester of the
formula I (R5 = A), for example with diazoalkanes such as
diazomethane in dioxane or with an alkyl halide such as
methyl iodide or isopropyl bromide in an inert solvent
such as DMF in the presence of a base such as potassium
carbonate at temperatures between about 0 and +30.
A base of the formula I can be converted into the
respective acid addition salt using an acid. Suitable
acids for this reaction are in particular those which
give physiologically acceptable salts, thus inorganic
acids can be used, for example sulfuric acid, nitric
acid, hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric acids such as orthophos-
phoric acid, sulfamic acid, and in addition organic
acids, in particular aliphatic, alicyclic, araliphatic,
aromatic or heterocyclic mono- or polybasic carboxylic,
sulfonic or sulfuric acids, for example formic acid,
acetic acid, trifluoroacetic acid, propionic acid,
pivalic acid, diethylacetic acid, malonic acid, succinic
acid, pimelic acid, fumaric acid, maleic acid, lactic
acid, tartaric acid, malic acid, citric acid, gluconic
acid, ascorbic acid, nicotinic acid, isonicotinic acid,
methane- or ethanesulfonic acid, ethanedisulfonic acid,
2-hydroxyethanesulfonic acid, benzenesulfonic acid,
2 ~ ~ O ~ 9 2
-
p-toluenesulfonic acid, naphthalenemonc- and -disulfonic
acids, and laurylsulfuric acid. Salts with physiologic~
ally unacceptable acids, for example picrates, can ~e
used for the isolation and/or purification of the
compounds of the formula I.
The novel compounds of the formula I and their
physiologically acceptable salts can be used for the
production of the pharmaceutical prepaxations by bringing
them into a suitable dosage form together with at least
one e~cipient or auxiliary and, if desired, together with
one or more other active compound(s). The preparations
thus obtained can be employed as medicaments in human or
veterinary medicine. Suitable excipients are organic or
inorganic substances which are suitable for enteral (for
example oral or rectal) or parenteral administration or
for administration in the form of an inhalation spray and
do not react with the novel compounds, for example water,
vegetable oils t benzyl alcohols, polyethylene glycols,
glycerol triacetate and other fatty acid glycerides,
gelatin, soya lecithin, carbohydrates such as lactose or
starch, magnesium stearate, talc or cellulose. For oral
administration, tablets, coated tablets, capsules,
syrups, juices or drops are used in particular; especi-
ally of interest are coated tablets and capsules having
enteric coaltings or capsule shells. Suppositories are
used for rectal administration, and solutions, preferably
oily or aqueous solutions, and in addition suspensions,
emulsions or implants are used for parenteral admini-
stration. For administration as inhalation sprays, sprays
can be used which contain the active compound either
dissolved or suspended in a propellant gas mixture (for
example fluorochlorohydrocarbons). The active compound in
this case is expediently used in micronised form, it
being po~sible for one or more additional physiologically
tolerable solvents to be present, for example ethanol.
Inhalation solutions can be administered with the aid of
customary inhalers. The novel compounds can also be
lyophilised and the lyophilisates obtained used, for
ex~mple, for the production of in~ection preparations.
- 22 ~
The preparations mentioned can be sterilised and/or can
contain auxiliaries such as preservatives, stabilisers
and/or wetting agents, emulsifiers, s~lts for aff~cting
the osmotic pressureJ buffer substances, colourants
and~or flavourings. If desired, they can also contain one
or more other active compounds, for example one or more
vitamins.
The substances according to the invention are as
a rule administered in analogy to other known commer-
cially available peptides, but in particular in analogy
to the compounds described in EP-A-249,096, preferably in
dosages be~ween about 10 mg and 1 g, in particular
between 50 and 500 mg per dosage unit. The daily dosage
is preferably between about 0.2 and 20 mg/kg, in parti-
cular bet~een 1 and 10 mg/kg of body weight. The specific
dose for each specific patient, howe~er, depends on a
wide variety of factors, for example on the activity of
the ~pecific compound employed, on the age, body weight,
general state of health, sex, on the diet, on the time
and route of administration, and on the excretion rate,
medicament combination and severity of the particular
disease to which the treatment applies. Parenteral
administration is preferred. Renin-dependent hypertension
and hyperaldosteronism can be effectively treated by
~5 administration of dosages between, in particular, about
0.2 and 20, preferably between 1 and l0 mg/kg of body
weight. For diagnostic purposes the novel compounds can
expediently be administered in individual doses between
about 0.1 and 10 mg/kg of body weight.
Above and below, all temperatures are indicated
in C. In the following examples "customary working up"
means: water is added if necessary, the pH is adjusted to
between 2 and 8, depending on the constitution of the
final product, the mixture is extracted with ethyl
acetate or dichloromethane, the organic phase is separ~
ated off, dried over sodium sulfate and evaporated, and
the residue is purified by chromatography on silica gel
and/or crystallisation. TFA = trifluoroacetate. FAB =
mass spectrum by the "fast atom bombardment" methodO
- 23 - 2~ 92
Example 1
1 g of isopropyl 3S-[tert.-butoxycarbonyl-L-(N-
imi-benzyloxymethylhistidyl)-~-alanylamino]-4-cyclohexyl-
2R-hydroxybutyrate [= I~isopropyl 3S-(BOC-(imi-BOM-His)-
S ~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate~; obtainable
by condensation of BOC-(imi-BOM-His)-~-Ala-OH with
isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate] is
dissolved in 30 ml of ethanol, and hydrogenated on 0.3 g
of 10% Pd-C at 20 and 1 bar until Hz absorption has
stopped, the mixture is filtered and evaporated and iso-
propyl 3S-(BOC-His-~Ala-amino)-4-cyclohexyl-2R-hydroxy-
butyrate is obtained after chromatographic purification
on silica gel.
Isopropyl 3S-(4-carboxypiperidinocarbonyl-Phe-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate is obtained
analogously by hydrogenolysis of isopropyl 3S-(4-benzyl-
oxycarbonylpiperidinocarbonyl-Phe-~Ala-amino)-4-cyclo-
hexyl-2R-hydroxybutyrate.
Example 2
A mixture of 1 mmol of ethyl 3s-[Boc-(imi-DNp-
His)-~Ala-amino]-4-cyclohexyl-2R-hydroxybutyrate (obtain-
able by condensation of ethyl BOC-(imi-DNP-His)-~-Ala-OH
with 3S-amino-4-cyclohexyl-2R-hydroxybutyrate], 2 g of 2-
mercaptoethanol, 20 ml of DMF and 20 ml of water i8
ad~usted to pH 8 with stirring at 20 using aqueous Na2CO3
solution and the mixture is stirred at 20 for a further
2 hours. Customary working-up gives ethyl 3S-(BOC-His-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 3
A solution of 2.15 g of methyl 3S-amino-4-cyclo-
hexyl-2R-hydroxybutyrate in 60 ml of dichloromethane is
treated with 1.01 g of N-methylmorpholine. 4.5 g of 4-
BOC-aminopiperidinocarbonyl-Phe-~Ala-OH, 1.35 g of HOBt
and a solution of 2.06 g of DCCI in 50 ml of dichloro-
methane are added with stirring, the mixture is ~tirred
at 0-5 for 12 hours, the precipitated dicyclohexylurea
is filtered off and the filtrate is evaporated. Customary
working-up gives methyl 3S-(4-BOC-aminopiperidino-
carbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate~
20~0~92
- 24 -
m.p. 113-114.
Example 4
Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 104-
105, is obtained analogously to Example 3 using iso-
propyl 3S-amino-4-cyclohexy1-2R-hydroxybutyrate.
Example 5
Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-
Isoser-amino)-4-cyclohexyl-2R-hydroxybutyrate~2isomers~
m.p. 115-116 and m.p. 102-103 respectively, are
obtained analogously to Example 3 using 4-BOC-amino-
piperidinocarbonyl-Phe-Isoser-OH and isopropyl 3S-amino-
4-cyclohexyl-2R-hydroxybutyrate.
Example 6
The following are obtained from isopropyl 3S-
amino-4-cyclohexyl-2R-hydroxybutyrate analogously to
Example 3
(a) isopropyl 3S-(BOC-Phe-~Ala-amino)-4-cyclohexyl-2R-
hydroxybutyrate, m.p. 120-122, using BOC-Phe-~Ala-
OH;
(b) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-
piperidinocarbonyl-Phe-~Ala-amino)-butyrate, m.p.
120-121-, using 4-hydroxypiperidinocarbonyl-Phe-
~Ala-OH;
(c) i8opropyl 3S-(4-BOC-piperazinocarbonyl-Phe-~Ala-
amino)-4-cyclohexyl-2R-hydroxybutyrate,m.p.86-87-,
using 4-BOC-piperazinocarbonyl-Phe-~Ala-OH;
(d) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-
carbonyl-Phe-~Ala-amino)-butyrate, m.p. 112-113,
using morpholinocarbonyl-Phe-~Ala-OH;
(e) isopropyl 4-cyclohexyl-3-(4-dimethylaminopiperidino-
carbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate, hydro-
chloride, m.p. 219-220, using 4-dimethylamino-
piperidinocarbonyl-Phe-~Ala-OH;
(f) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylamino-
piperidinocarbonyl-Phe-~Ala-amino)-2R-hydroxy-
butyrate using 4-ethoxycarbonylaminopiperidino-
carbonyl-Phe-~Ala-OH;
2~0~92
- 25 -
(g) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylpiperi-
dinocarbonyl-Phe-~Ala-amino)-2R-hydroxybutyrate,
m.p. 117-118, using 4-ethoxycarbonylpiperidino-
carbonyl-Phe-~Ala-OH; (h) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-
piperidinocarbonyl-Phe-Isoser-amino)-butyrate using
4-hydroxypiperidinocarbonyl-Phe-Isoser-OH.
Example 7
The following are obtained from 4-hydroxypiperi-
dinocarbonyl-Phe-~Ala-OH analogou~ly to Example 3
(a) methyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-
dinocarbonyl-Phe-~Ala-amino)-butyrate using methyl
3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(b) ethyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-
15dinocarbonyl-Phe-~Ala-amino)-butyrate using ethyl
3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(c) n-butyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperi-
dinocarbonyl-Phe-~Ala-amino)-butyrate using n_butyl
3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
20(d) cyclohexyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxy-
piperidinocarbonyl-Phe-~Ala-amino)-butyrate using
cyclohexyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate;
(e) i80propyl 2R-hydroxy-3S-(4-hydroxypiperidino-
carbonyl-Phe-~Ala-amino)-5-methylhexanoate using
25isopropyl 3S-amino-2R-hydroxy-5-methylhexanoate;
(f) isopropyl 2R-hydroxy-3S-(4-hydroxypiperidino-
carbonyl~Phe-~Ala-amino)-4-phenylbutyrate using
isopropyl 3S-amino-2R-hydroxy-4-phenylbutyrate;
Example 8
30The following are obtained from isopropyl 4-
cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)butyrate
analogously to Example 3
(a) isopropyl 3S-(3-BOC-amino-3-methylbutyryl-Phe-~Ala-
amino)-4-cyclohexyl-2R-hydroxybutyrate using 3-BOC-
35amino-3-methylbutyric acid;
(b) isopropyl 3S-(6-BOC-aminohexanoyl-Phe-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate using 6-BOC-amino-
hexanoic acid;
.
- 25 -
(c~ isopropyl 4-cyclohexyl-2R-hydroxy 3S-(3,6 t 8-trioxa-
nonanoyl-Phe-~Ala-amino)-butyrate using 3,6,8-
trioxanonanoic acid.
Example 9
The following are obtained from isopropyl 3S- (H-
~Ala-amino)-4~cyclohexy1-2R-hydroxybutyrate [FAB: M -~ 1
= 315; obtainable by condensation of CBZ-~Ala-OH with
isopropyl 3S-amino~4-cyclohexyl-2R~hydroxybutyrate to
~ive isopropyl 3S-(CBZ-~Ala-amino)-4-cyclohexyl-2R-
hydroxybutyrate ~FAB: M + 1 = 449) and hydrogenolysis]
analogously to Example 3
(a) isopropyl 4-cyclohexyl-2R-hydroxy-3S~(H Pla-~la-
amino)-butyrate, m.p. 54-55l using H-Pla-OH;
(b) isopropyl 3S-(H-CO-Phe-~Ala-amino)-4-cyclohexyl-2R-
hydroxybutyxate, m.p. 108 tdec.), using H-CO Phe~
OH;
(c) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholino-
carbonyl-Pla-~Ala-amino)-butyrate using moxpholino-
carbonyl-Pla-OH;
(d) to (m) using acids of the formula 4-~OC-aminopiperi-
dinocarbonyl-Z-OH
(Z = Ada, Calf Leu, Mal, Nle, Pla, 2-Tia, 2-Tiz, Trp
and Tyr respectively);
(d) isopropyl 3S (4-BOC-aminopiperidinocarbonyl-Ada-
~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(e) isopropy~l 3S-(4-BOC-aminopiperidinocarbonyl-Cal-
~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(f) isopropyl 3S-~4-BOC-aminopiperidinocarbonyl-Leu-
~Ala-ami.no)-4-cyclohexyl-2R-hydroxybutyrate;
(g) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Mal-
~Ala~amino)-4-cyclohexyl-2R-hydroxybutyrate;
(h) isopropyl 3S-(4-BOC-aminopiparidinocarbonyl-Nle-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(i.) isopropyl 3S-(4-BOC-aminopiperidinocar~onyl-Pla-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(~) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2-Tia-
~Ala amino)-4-cyclohexyl-2R-hydroxybutyrate;
(k) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2~Tiz-
~Ala-amino)-4 cyclohexyl-2R-hydroxybutyxate;
- 27 - 2 05 ~9 2
(1) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Trp-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate;
(m) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Tyr-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 10
A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-
hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 115 mg of tri-
methylsilyl isocyanate and 25 ml of THF is stirred at 20
for 2 hours. 2.5 ml of 1 N aqueous hydrochloric acid are
added to remove the protective group, the mixture is
stirred at 20 for a further 15 min, and worked up in the
customary manner to give isopropyl 3S-(N-carbamoyl-Phe-
~Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.
Example 11
A mixture of 461 mg of isopropyl 4-cyclohexyl-2R-
hydroxy-3S-(H-Phe-~Ala-amino)-butyrate, 71 mg of ethyl
isocyanate and 25 ml of THF is stirred at 20 for 3
hours. The mixture i8 worked up in the customary manner
to give isopropyl 4-cyclohexyl-3S-tN-(N-ethylcarbamoyl)-
Phe-~Ala-amino~-2R-hydroxybutyrate.
Example 12
A solution of 1 g of methyl 3S-(4-~OC-amino-
piperidinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-
hydroxybutyrate in 20 ml of dichloromethane and 20 ml of
trifluoroacetic acid i8 3tirred at 20 for 1 hour and
then evaporated. Methyl 3S-(4-aminopiperidinocarbonyl-
Phe-~Ala-amino)-4-cyclohexy1-2R-hydroxybutyrate, TFA,
m.p. 163-164, are obtained.
The following are obtained analogously by cleav-
ing the appropriate BOC derivatives with trifluoroacetic
acid:
isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate, TFA, m.p. 185-186, 1/3
citrate, m.p. 119-120
isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-Isoser-
amino)-4-cyclohexyl-2R-hydroxybutyrate~ TFA, 2-isomers,
m.p. 118-119 and 155-156 re~pectively
isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-amino)-
butyrate, TFA, m.p. 77-78
2 ~ ~ O ~ 9 2
- 28 -
isopropyl 4-cyclohexy1-2R-hydroxy-3S-(piperazinocarbonyl-
Phe-~Ala-amino)-butyrate, TFA, m.p. 113-114
isopropyl 3S-~3-amino-3-methylbutyryl-Phe-~Ala-amino)-4-
cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(6-aminohexanoyl-Phe-~Ala-amino)-4-cyclo-
hexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Ada-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Cal-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Leu-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Nal-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-~4-aminopiperidinocarbonyl-Nle-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Pla-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tia-~Ala-
amino)-4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tiz-~Ala-
amino)-4-cyclohexyl-2R-hydroxybutyrate
i~opropyl 3S-(4-aminopiperidinocarbonyl-Trp-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
isopropyl 3S-(4-aminopiperidinocarbonyl-Tyr-~Ala-amino)-
4-cyclohexyl-2R-hydroxybutyrate
Example 13
(a) A mixture of 1 g of methyl 3S-(4-~OC-aminopiperi-
dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-
hydroxybutyrate, 50 ml of dioxane and 20 ml of 2 N
aqueous NaOH ~olution is stirred at 20 for 3 hours.
The mixture i8 worked up in the customary manner and
gives 3S-(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-
amino)-4-cyclohexyl-2R-hydroxybutyric acid.
(b) The crude acid obtained according to (a) is stirred
with 25 ml of DMF, 1 ml of i80propyl iodide and
200 mg of R2C03 for 24 hours. The mixture i8 worked
up in the customary manner and gives isopropyl 3S-
(4-BOC-aminopiperidinocarbonyl-Phe-~Ala-amino)-4-
2~0092
- 29 -
cyclohexyl-2R-hydroxybutyrate, m.p. 104-105.
Example 14
Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-~Ala-
amino)-butyrate, TFA, m.p. 77-78, is obtained by hydro-
genolysis of isopropyl 3S-(CBZ-Phe-~Ala-amino)-4-cyclo-
hexyl-2R-hydroxybutyrate analogously to Example 1.
Example 15
(a) 449 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-
Phe-~Ala-amino)butyrate are dissolved in 25 ml of
THF. A solution of 117 mg of methanesulfonyl chlor-
ide in 3 ml of THF is added dropwise with stirring.
The mixture is stirred at 20 for a further 3 hours,
and worked up in the customary manner to give
isopropyl 4-cyclohexyl-2R-hydroxy-3S-(methane-
sulfonyl-Phe-~Ala-amino)butyrate, m.p. 115-116.
(b) Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(isopropyl-
sulfonyl-Phe-~Ala-amino)butyrate is obtained analo-
gously using isopropylsulfonyl chloride.
(c) Isopropyl 3S-(acetyl-Phe-~Ala-amino)-4-cyclohexyl-
2R-hydroxybutyrate i8 obtained analogously u~ing
acetyl chloride.
Example 16
(a) Isopropyl 4-cyclohexyl-3S-~4-hydroxypiperidino-
carbonyl-Phe-~Ala-amino)-2-oxobutyrate is obtained
from 4-hydroxypiperidinocarbonyl-Phe-~Ala-OH and
isopropyl 3S-amino-4-cyclohexyl-2-oxobutyrate
analogously to Example 3.
(b) A solution of 1 g of the above ketoester in 25 ml of
methanol is hydrogenated on 0.1 g of 10% Pd-C at 20
and 1 bar until absorption of Hz is complete. After
filtering and evaporating, a mixture of isopropyl 4-
cyclohexyl-2R- and -2S-hydroxy-3S-(4-hydroxypiperi-
dinocarbonyl-Phe-~Ala-amino)butyrate is obtained,
which can be separated on ~ilica gel.
Example 17
A solution of 586 mg of the ketoester obtainable
according to Example 16 (a) and 1.43 g of Na2CO3 10 H20
in 5 ml of methanol and 5 ml of water is treated with
70 mg of hydroxylamine hydrochloride and stirred at 20
2~0~92
- 30 -
for 14 hours. The precipitated oxLme is filtered off,
dried, dissolved in 10 ml of methanol and hydrogenated at
20 and 5 bar on 0.4 g of Raney Ni. The catalyst is
filtered off, the filtrate is evaporated and the mixture
S of isopropyl 2R- and 2S-amino-4-cyclohexyl-3S-(4-hydroxy-
piperidinocarbonyl-Phe-~Ala-amino)butyrate obtained is
separated.
The examples below relate to pharmaceutical
preparations.
Example A: Tablets
A mixture of 1 kq of i~opropyl 4-cyclohexyl-2R-
hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-~Ala-amino)-
butyrate, 4 kg of lactose, 1.2 kg of maize starch, 200 g
of talc and 100 g of magnesium stearate i8 compressed to
give tablets in a customary manner in such a way that
each tablet contains 100 mg of active compound.
Bxample B: Coated tablets
Tablets are pressed analogously to Example A, and
are then coated in a customary manner with a coating of
sucrose, maize starch, talc, tragacanth and colourant.
Example C: Capsules
500 g of isopropyl 3S-(BOC-Phe-~Ala-amino)-4-
cycIohexyl-2R-hydroxybutyrate are filled into hard
gelatine capsules in a customary manner in such a way
that each capsule contains 500 mg of active compound.
Bxample D: In~ection vials
A solution of 100 g of methyl 3S-(4-aminopiperi-
dinocarbonyl-Phe-~Ala-amino)-4-cyclohexyl-2R-hydroxy-
butyrate trifluoroacetate in 4 1 of doubly distilled
water is ad~usted to pH 6.5 with 2N hydrochloric acid,
sterile filtered and poured into in~ection vials. The
solution i8 lyophilised under sterile conditions and the
vials are sterile sealed. Each in~ection vial contains
100 mg of active compound.
Example E: Suppositories
A mixture of 50 g of isopropyl 4-cyclohexyl-2R-
hydroxy-3S-(methanesulfonyl-phe-~Ala-amino)butyrate is
fused with 10 g of soya lecithin and 140 g of cocoa
- 31 - 2~
butter, poured into moulds and allowed to cool. Each
Ruppository contain~ 250 mg of active compound.
