Note: Descriptions are shown in the official language in which they were submitted.
2062~
-- 2 --
Merck Patent Gesellschaft March 3, 1991
mit beschrankter Haftung
D a r m s t a d t
Peptide analogues
The invention relates to new peptide analogues
of the formula I
Rl-z-NR2-cHR3-cR4-cH2-cRsR6-y
in which
Rl is H, R7-o-CmH2m-Co-, R7-CmH2m-o-Co-,
R7-CmH2m-Co- ~ R7-So2-, RaR9N-CmH2m-Co-,
R10-NH-C(=NH)-NH-CmHzm-CO-,
R8OOC-CmH2m-CO-, RBO3S-CmH2m-CO- or
Rll--CmH2~--(T)~--(V)y~CnH2n~L(R7~Cp}12p)--
CrH2r--CO~ ~
z is 0 to 4 amino acid residues which are
linked together in the manner of a peptide
and are selected from the group comprising
Abu, Ada, Ala, ~Ala, Arg, Asn, Asp, Bia,
Cal, Dab, Gln, Glu, Gly, His, N(Lm)-A-His,
Hph, Ile, Isoser, Leu, tert.-Leu, Lys,
Mal, Met, ~Nal, ~Nal, Nbg, Nle, Nva, Orn,
Phe, Pia, Pro, Pya, Ser, Thr, Tia, Tic,
Trp, Tyr and Val,
Y i 8 -CN, -NO2, -CH2-NRl2Rl3, -CH2-NR12-So2Rl4,
-cH2-NRl2-CoRl4, -CH2-NRl2-Co-NH-Rl4,
-CH2-NRl2-CS-NH-Rl4 or -CORls,
R2, R8, R9 and Rl3 are each H or A,
R4 is (H, Rl7) or =O,
R5 i OH oR7 oCoR7, osiRlSRl9R2o~ NRaR9 or
-0-(2-tetrahydropyranyl),
Rs is H, A, Ar or aralkyl,
R5 and Rs together are also (=0),
Rl8 is H~ OH, oR7, NR8R9, oSiR13R19R20 or
-0-(2-tetrahydropyranyl),
R17 i8 OH or NH2,
2062~6~
-- 3 --
R5 and R17 together are also -Tl-(CR3R7)-T2-,
R3, R7, Rll, Rl2 and Rl4 are each H, A, Ar, Ar-alkyl, Het or
Het-alkyl, unsubstituted or singly or
multiply, by A, AO and/or Hal, substituted
cycloalkyl having 3-7 C atoms, cycloalkyl-
alkyl having 4-11 C atoms, bicycloalkyl or
tricycloalkyl each having 7-14 C atoms, or
bicycloalkylalkyl or tricycloalkylalkyl
each having 8-18 C atoms,
R11 is also R8O-, R3R9N-, R3OoC- or A3N+ An9,
R13, Rl9 and R20 are each A, Ar or aralkyl,
R1~ is H, A or CN,
L is CH or N,
T, T1 and T2 are each O or NR6,
V is CHOR2, CO, S, SO or SO2,
R~R9N and NR12R13 are also each a pyrrolidino, piperidino,
morpholino or piperazino group which is
unsubstituted or is substituted by A, OH,
NH2, N~A, NA2, NHAc, NH-Co-C~H2~-o-R15, NH-
Co-o-C~H2r-R15, hydroxyalkyl, COOH, COOA,
CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl,
A3N~ alkyl Ane, NH-CO-NH2, NH-CO-NHA,
guanidinyl or guanidinylalkyl,
R15 is A or Ar-alkyl,
s and y are each 0 or 1,
m, n, p, r and x are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or
10,
Ar is phenyl which i8 unsubstituted or is
substituted one or more times by A, OA,
Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA,
NA2, NHAc, SA, SO-A, SO2-A, SO2NH2, SO2NHA,
COOH, COOA, CONH2, CN, aminoalkyl, HAN-
alkyl, A2N-alkyl, A3N+ alkyl Ane and/or
guanidinyl-alkyl, or is unsubstituted
naphthyl,
Het is a saturated or unsaturated 5- or 6-
membered heterocyclic radical which has 1-
4 N, O and/or S atoms and can be fused
2062~6~
- 4
~ with a benzene ring and/or be substituted
one or more times by A, OA, Hal, CF3, OH,
NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc,
SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA,
CONH2, CN, NH-SO2-A, Ar, Ar-alkyl, Ar-
alkenyl, hydroxyalkyl, aminoalkyl, HAN-
alkyl and/or A2N-alkyl, and/or whose N
and/or S hetero atoms can also be oxid-
ized,
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,
in its place, a carboxyl group contained
in the compound of the formula I is in the
form 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, furthermore, it is also possible for one or
more -NH-CO- groups to be replaced by one or more -NA-CO-
groups,
with the provisos that
a) in the case R1 = R11-CmH~-(T)~-V-CnH~-L(R7-CpH2p)-
CrH2r-CO- with V = S, SO or SO2,
and
y = _CH2NR12R13 with R12 = Rl3 = H, R5 then is oCoR7,
oSiR1aRl9R20, NRaR9 or -o-(2-tetrahydropyranyl)~
b) in the case R1 = R11-CmH~-(T)8-V-C~H~-L(R7-CH~H2p)-
CrH2r-CO- with V = S, SO or SOz, and Y = CORl6, Rl6
then is H, OH, oR7, OSiR1aR19R20 or -0-(2-tetrahydro-
pyranyl),
as well as the salts thereof.
Similar compound4 are disclosed in EP-A 249,096.
The invention had the object of finding new
compounds with valuable properties, in particular those
which can be used for the preparation of medicaments.
It has been found that the compounds of the
formula I and the saltc thereof have very valuable
properties. In particular, they inhibit the activity of
2~206~
-- 5
human plasma renin. This action can be detected, for
example, by the method of F. Fyhrquist et al., Clin.Chem.
22, 250-256 (1976). The noteworthy point is that these
compounds are very specific inhibitors of renin; as a
rule, the concentrations of these compounds necessary for
the inhibition of other aspartyl proteinases (for example
pepsin and cathepsin D) are about 100 to 1000 tLmes as
high as for renin inhibition. The actions of the com-
pounds on the blood pressure and/or on the heart rate, as
well as the inhibition of renin activity in blood plasma
can furthermore be determined in conscious monkeys, for
example female monkeys (Macaca fascicularis); it is
possible in this for the blood pressure and heart rate to
be measured by a modification of the method of ~.J. Wood
et al., J. Hypertension 4, ~51-254 (1985). In order to
stimulate renin activity in this, the animals are prefer-
ably pretreated with a saluretic. Blood samples for the
determination of the plasma renin activity can be
obtained by puncture of the femoral vein.
The compounds can be used as pharmaceutically
active substance~ in human and veterinary mPdicine, in
particular for the prophylaxis and for the treatment of
diseases of the heart, circulation and vessel~, especi-
ally of hypertension, cardiac insufficiency and hyper-
aldosteronism. In addition, the compounds can be used for
diagnostic purposes in order to determine, in patients
with hypertension or hyperaldosteronism, the possible
contribution of the renin activity to maintaining the
pathological state. The procedure for such diagnostic
tests can be similar to that indicated in EP-A 77,028.
The abbreviations quoted hereinbefore and herein-
after for amino acid residues represent the radicals
-NR'-R"-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:
Abu 2-aminobutyric acid
Ada 3-(1-adamantyl)-alanine
Ala alanine
~Ala ~-alanine
2062~6~
-- 6 --
Arg arginine
Asn a~paragine
Asp aspartic acid
Bia 3-(2-benzimidazolyl)-alanine
S Cal 3-cyclohexylalanine
Dab 2,4-diaminobutyric acid
Gln glutamine
Glu glutamic acid
Gly glycine
His histidine
N(im)-A-His histidine substituted in the 1 or 3 position
of the imidazole ring by A
Hph homophenylalanine (2-amino-4-phenylbutyric
acid)
Ile isoleucine
Isoser isoserine
Leu leucine
tert.-Leu tert.-leucine
Lys lysine
Mal 3-(p-methoxyphenyl)-alanine
Met methionine
~Nal 3-(~-naphthyl)-alanine
~Nal 3-(~-naphthyl)-alanine
Nbg 2-norbornyl-glycine
?s Nle norleucine
Nva norvaline
N-Me-His N-methyl-histidine
N-Me-Phe N-methyl-phenylalanine
Orn ornithine
Phe phenylalanine
Pia 3-(piperidyl)-alanine ~e.g. 2-Pia = 3-(2-
piperidyl)-alanine]
Pro proline
Pya 3-(pyridyl)-alanine te.g. 3-Pya = 3-(3-
pyridyl)-alanine]
Ser serine
Thr threonine
Tia 3-(thienyl)-alanine te.g. 2-Tia = 3-(2-
thienyl)-alanine]
20~206~
- 7 -
Tic 1,2,3,4-tetrahydroisoquinoline-1-carboxylic
acid
Trp tryptophan
Tyr tyrosine
S Val valine.
Further meanings hereinafter are:
BOC tert.-butoxycarbonyl
BOM benzyloxymethyl
imi-BOM benzyloxymethyl in the 1 position of the
imidazole ring
CBZ benzyloxycarbonyl
DAPECI dimethylaminopropylcarbodiimide
DCCI dicyclohexylcarbodiimide
DMF dimethylformamide
~5 DNP 2,4-dinitrophenyl
imi-DNP 2,4-dinitrophenyl in the 1 position of the
imidazole ring
ETOC ethoxycarbonyl
FMOC 9-fluorenylmethoxycarbonyl
HOBt 1-hydroxybenzotriazole
IPOC isopropoxycarbonyl
NMM N-methylmorpholine
POA phenoxyacetyl
THF tetrahydrofuran.
If the abovementioned amino acids can occur in
several enantiomeric forms, then all these forms, as well
as mixture~ thereof (for example the DL forms), are
included hereinbefore and hereinafter, for example as
constituent of the compounds of the formula I. The L-
forms are preferred. Where individual compounds are
mentioned hereinafter, then the abbreviations of these
amino acids each relate to the L-form unless expressly
indicated otherwise.
The invention furthermore relates to a process
for the preparation of a peptide analogue of the formula
I, and of the salts thereof, characterized in that it is
liberated from one of its functional derivatives by
treatment with a solvolyzing or hydrogenolyzing agent, or
in that a carboxylic acid of the formula II
2~fi~0b'~
-- 8
R1-G1 OH II
in which G1 is (a) absent,
(b) z,
(c) Z,
or one of the reactive derivatives thereof,
is reacted with an amino compound of th~ formula III
H-G2-NR2-CHR3-CR4-CE~2-CRSR6-y III
in which G2 is (a) Z,
(b) absent,
( C ) Z2 and
zl + z2 are together Z,
and in that a functionally modified amino and/or hydroxyl
group in a compound of the ormula I is liberated where
appropriate by treatment with solvolyzing or hydrogeno-
lyzing agents, and/or a free amino group is acylated by
treatment with an acylating agent and/or for the
preparation of a compound of the formula Il R4 = ~H, OH)
or (H, NH2), an amino keto acid derivative of the formula
I, R4 = O, is reduced or reductively aminated, and/or a
radical R1 is converted to another radical R1, and/or a
compound of the formula I is converted by treatment with
an acid into one of the salts thereof.
~ereinbefore and hereinafter the radicals and
parameters R~ to R20, Z, Y, L, T, T1, T2, V, m, n, p, r, s,
x, y, Ar, Het, Hal, Ac, An, A, Gl, GZ, 31 and Z2 have the
meanings indicated for the formulae I, II or III unless
expressly indicated otherwise.
Aintheabovementionedormulaehas 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, as well as pentyl, 1-, 2- or 3-methylbutyl,
1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,
1-l 2-, 3- or 4-methylpentyl, 1,1-l 1,2-, 1,3-, 2,2-,
2~3- or 3,3-dLmethylbutyl, 1- or 2-ethylbutyl, l-ethyl-
l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- ~r 1,2,2-
2~620~3
g
trLmethylpropyl, heptyl or octyl.
Cycloalkyl is preferably cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl or cyoloheptyl, but is also, for
example, 1-, 2- or 3-methylcyclopentyl, or 1-, 2-, 3- or
4-methylcyclohexyl.
-alkyl- is an alkylene group having 1-8 C atoms,
preferably 1, 2, 3 or 4 C atoms. -alkyl- is preferably
methylene, ethylene, propylene, butylene, and furthenmore
pentylene, hexylene, heptylene, octylene, isopropylene,
l-ethylpropylene ox 1-, 2- or 3-methylbutylene.
Correspondingly, cycloalkylalkyl is preferably
cyclopropylmethyl, 2-cyclopropylethyl, cyclobutylmethyl,
2-cyclobutylethyl,cyclopentylmethyl,2-cyclopentylethyl,
cyclohexylmethyl, 2-cyclohexylethyl, but is also, for
example 1-, 2- or 3-methylcyclopentylmethyl, or 1-, 2-,
3- or 4-methylcyclohexylmethyl.
Bicycloalkyl is preferably 1- or 2-d~calyl, 2-bi-
cyclo[2.2.1]heptyl or 6,6-dimethyl-2-bicyclo~3,1,1]hept~
yl .
Tricycloalkyl is preferably 1-adamantyl.
Hal is preferably F, Cl or Br, but is also I.
Ac is preferably A-CO-, such as acetyl, propionyl
or butyryl, Ar-CO- such as benzoyl, o-, m- or p-methoxy-
benzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as N-
methyl- or N-ethylcarbamoyl.
Ar is preferably phenyl and is furthermore
preferably G-, 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-sulfamoylphenyl, 2,3-,
2,4-, 2,5-, 2,6-, 3,4- or 3,5-d~ne~hoxyphenyl, 3,4,5-
trimethoxyphenyl, o-, m- or p~aminophenyl, o-, m- or p-
aminomethylphenyl, o-, m- or p-dimethylaminomethylphenyl~
o-, m- or p-~uanidinomethylphenyl, or 1- or 2-naphthyl.
Correspondingly, Ar-alkyl is preferably benzyl,
1- or 2-phenylethyl, o-, m- or p-me~hylbenzyl, 1- or 2-
o-, -m- or -p-tolylethyl, o-, m- or p-ethylbenzyl, 1- or
2-o-,-m-or-p-ethylphenylethyl,o-,m-orp-me~hoxybenzyl,
206206S
-- 10 --
l- or 2-o-, -m- or -p-methoxyphenylethyl, o-, m- or p-
fluorobenzyl, l- 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, l- 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-trimethoxybenzyl, o-,
m- or p-aminobenzyl, o-, m- or p-aminomethylbenzyl, o-,
m- or p-dimethylaminomethylbenzyl, o-, m- or p-guanidino-
methylbenzyl, or 1- or 2-naphthylmethyl.
Het is preferably 2- or 3-furyl, 2- or 3-thienyl,
l-, 2- or 3-pyrrolyl, 1-, 2-, 4- or 5-imidazolyl, l-,
3-, 4- or 5-pyrazolyl, 2-, 4- or S-oxazolyl, 3-, 4- or 5-
isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazo-
lyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl,
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-pyrid-
azinyl, pyrazinyl 2-, 3-, 4-, 5-, 6- or 7-benzofuryl,
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-
isoindolyl, l-, 2-, 4- or 5-benzimidazolyl, l-, 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-benz-2,1,3-oxadiazolyl,
2-, 3-, 4-, 5-, 6-, 7- or 8-quinolyl, 1-, 3-, 4-, 5-,
6-, 7- or 8-isoquinolyl, 1-, 2-, 3-, 4- or 9-carbazolyl,
l-, 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 heterocyclic radicals can also be
partially or completely hydrogenated. Thus, Het can also
be, for example, 2,3-dihydro-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-,
206206~
11
-2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-1-, -2-, -3-,
-4- or -5-pyrrolyl, 1-, 2- or 3-pyrrolidinyl, tetrahydro-
1-, -2- or -4-imidazolyl, 2,3-dihydro-1-, -2-, -3-, -4-
or -5-pyrazolyl, tetrahydro-l-, -3- or -4-pyrazolyl, 1,4-
dihydro-l-, -2-, -3- or -4-pyridyl, 1,2,3,4-tetrahydro-
1-, -2-, -3-, -4-, -5- or -6-pyridyl, 1,2,3,6-
tetrahydro-l-, -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-dioxanyl, 1,3-
dioxan-2-, -4- or -5-yl, hexahydro-1-, -3- or -4-pyridaz-
inyl, 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 ~ubstituted
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, furthermore, for example, 3-, 4-
or 5-methyl-2-furyl, 2-, 4- or 5-methyl-3-furyl, 2,4-
dimethyl-3-furyl, 5-nitro-2-furyl, 5-styryl-2-furyl, 3-,
4- or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl,
3-methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, 5-
phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-2-pyr-
rolyl, 1-methyl-4- or -S-nitro-2-pyrrolyl, 3,5-dimethyl-
4-ethyl-2-pyrrolyl, 4-methyl-S-pyrazolyl, 5-methyl-3-
isoxazolyl, 3,4-dimethyl-5-isoxazolyl, 4- or 5-methyl-2-
thiazolyl, 2- or S-methyl-4-thiazolyl, 2- or 4-methyl-S-
thiazolyl, 2,4-dimethyl-5-thiazolyl, 3-, 4-, S- 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 -6-yl), S-
phenyl-lH-2-pyridon-3-yl, S-p-methoxyphenyl-lH-2-pyridon-
3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-S-pyridyl, 2-
hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'-methylureido-lH-
4-pyridon-S-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-~-
206~06~
- 12 -
pyrimidinyl, 2-, 5- or 6-methyl-4-pyrLmidinyl, 2,6-
dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl, 5-
chloro-2-methyl-4-pyrimidinyl, 3-methyl-2-benzofuryl, 2-
ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-,
5-, 6- or 7-methyl-3-indolyl, 1-methyl-5- or -6-ben-
zimidazolyl, l-ethyl-5- or -6-benzimidazolyl, 3-, 4-,
5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxo-pyrrolidino, 2-
oxo-piperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-
dioxopyrrolidino.
Rl is, in general, preferably R8R9N-CmH2~-Co- or
R7-CmH~-o-Co-, furthermore preferably R7-C~H2~-Co-, R~OOC-
CmH2~-CO- or Rll-CmH2m--(T)~--(V)~~CnH2n~L(R -CpH2p)~CrH2r~C~-
The group Z preferably consists of one or two of
the stated amino acid residues; however, it can also
contain three or four amino acid residues or be absent.
Z is preferably His, Phe or Phe-His, furthermore pre-
ferably Cal-His, Mal-His, ~Nal-His, ~Nal-His, Phe-Abu,
Phe-Ala, Phe-~Ala, Phe-Ser, Phe-Asn, Phe-Gln, Phe-Glu,
Phe-Gly, Phe-Nle, Phe-Pya (especially Phe-3-Pya), Phe-Tia
(especially Phe-3-Tia), Tia-His (especially 3-Tia-His),
Trp-His, Tyr-His or Pro-Phe-His.
Y is, in general, preferably -CN or -CH2-NR12-
So2Rl4, furthermore preferably -cH2-NRl2-Co-NHRl4 or
--CH2--NRl2-CS -NHRl~ .
R2, R8, R9 and Rl3 are each preferably H and
furthermore preferably methyl. R8R9N is also preferably
pyrrolidino, piperidino, morpholino, amino-piperidino
such as 4-aminopiperidino, alkylaminopiperidino such as
4-methylaminopiperidino, or dialkylaminopiperidino such
as 4-dimethylaminopiperidino.
R3 is preferably cycloalkylalkyl, especially
cyclohexylmethyl, furthermore preferably alkyl, especi-
ally isobutyl; Ar-alkyl, especially benzyl; cycloalkyl,
especially cyclohexyl.
R4 is preferably (H, R17), in which R17 is OH or
NH2 .
R4 is especially preferably (H, OH).
R5 is preferably OH, oR7, oCOR7 or OSiRl8R19R20.
Preferably, R5 together with R17 also is
20~20~5
- 13 _
-Tl-(CR3R7)-TZ
R6 is pre~erably H or A, particularly methyl.
R5 and R6 together are also preferably (=O).
R7 is preferably A, especially methyl, ethyl,
isopropyl or tert.-butyl; or Ar, especially phenyl, 1- or
2-naphthyl.
R10 is preferably H, methyl or CN.
Rl1 is preferably H; A, especially methyl or
tert.-butyl; R8R9N, especially A2N such as (CH3~2N, piperi-
dino or 4-aminopiperidino.
Rl2 and Rl3 are preferably H or A, especially
methyl.
Rl4 is preferably A, especially methyl, ethyl,
propyl, isopropyl, butyl, isobutyl, sec.-butyl, tert.-
butyl, pentyl or isopentyl; cycloalkylalkyl, especially
cyclohexylmethyl; Ar-alkyl, especially benzyl; Ar,
especially phenyl or aminophenyl such as p-aminophenyl.
R15 is preferably A having 1-4 C atoms, especially
isopropyl or tert.-butyl; or Ar-alkyl, especially benzyl.
R16 is preferably H, OH or oR7.
Rl7 is preferably OH.
RlB, Rl9 and R2~ independently of one another are
each preferably A, particularly methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec.-butyl, tert.-butyl,
pentyl or isopentyl; Ar, particularly phenyl or Ar-alkyl,
particularly benzyl.
L is preferably CH, furthermore preferably N.
T is preferably O or NR6, in which R6 is H or A.
Tl and T2 are preferably O.
V is preferably CO or SO2.
The parameter s i8 preferably 0 but also 1; y is
preferably 1 but also 0. The sum s + y is preferably 1
but also 0 or 2. The parameter m is preferably 1, 2, 3,
4 or 5; n is preferably 1; pH is preferably l; r is
preferably 1 or 0. The groups CmH2~, CnH2n, CpH2p and C~2r
are preferably straight-chain and thus are preferably
-(CH2)m-, -(CH2)n-, -(CH2)p- or -~CH2~
Accordingly, the group Rl i~ specifically and
preferably R8R~N-(CH2)m-CO-, especially H2N-CmH2m-CO- such
2 ~ 6 ~
- 14 -
as aminocarbonyl, aminoacetyl (H-Gly)-, 3-aminopropionyl
(H-~Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohex-
anoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminonona-
noyl, 10-aminodecanoyl, ll-aminoundecanoyl, but also,
S for example, 2-amino-propionyl (Ala), 2-amino-2-methyl-
propionyl; ANH-C~H~-CO- such as methylaminocarbonyl,
methylaminoacetyl (sarcosyl~, 3-methylaminopropionyl, 4-
methylaminobutyryl,5-methylaminopentanoyl,6-methylamin-
ohexanoyl, 6~ethylaminohexanoyl, 7-methylaminoheptanoyl,
8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methyl-
aminodecanoyl, ll-methylaminoundecanoyl; ~2N-CmH~-CO-
such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-di
methylaminopropionyl,4-dimethylaminobutyryl,5-dimethyl-
aminopentanoyl, 6-dimethylaminohexanoyl, 6-diethylamino-
hexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylamino-
octanoyl,9-dimethylaminononanoyl,10-dimethylaminodecan-
oyl, 11-dimethylaminoundecanoyl; A O-CO-NH-C~H~-CO- such
as BOC-Gly, ETOC-Gly-, IPOC-Gly, BOC-~Ala, ETOC-~Ala,
IPOC-~Ala, 4-BOC-amino-butyryl, 5-BOC-amino-pentanoyl, 6-
BOC-amino-hexanoyl, 7-BOC-amino-heptanoyl, 8-BOC-amino-
octanoyl, 9-BOC-amino-nonanoyl, 10-BOC-amino-decanoyl,
ll-BOC-amino-undecanoyl; ArCH2-O-CO-NH-CmH2m-CO~ ~uch as
CBZ-Gly-, CBZ-~Ala, 4-CB~-amino-butyryl, 5-CBZ-amino-
hexanoyl, 7-CBZ-amino-heptanoyl, 8-CBZ-amino-octanoyl, 9-
CBZ-amino-nonanoyl, 10-CBZ-amino-decanoyl, ll-CBZ amino-
undecanoyl; pyrrolidino-C~H~-CO- such as pyrrolidinocar-
bonyl, pyrrolidino-acetyl, 3-pyrrolidino-propionyl, 4-
pyrrolidino-butyryl, 5-pyrrolidino-pentanoyl, 6-
pyrrolidino-hexanoyl, 4-pyrrolidino-heptanoyl/ 8-
pyrrolidino-octanoyl, 9-pyrrolidino-nonanoyl, 10-
pyrrolidino-decanoyl; piperidino-C~H~-CO- such as piperi-
dinocarbonyl, piperidinoacetyl, 3-piperidino-propionyl,
4-piperidino-butyryl, 5-piperidino-pentanoyl, 6-piperi
dino-hexanoyl, 7-piperidino-heptanoyl, 8-piperidino-
octanoyl, 9-piperidino-nonanoyl, 10-piperidino-decanoyl;
morpholino-C~H~-CO- such as morpholinocarbonyl, mor-
pholinoacetyl, 3-morpholino-propionyl, 4~morpholino-
~utyryl, 5-morpholino-pentanoyl, 6-morpholino-hexanoyl,
7-morpholino-heptanoyl, 8-morpholino-octanoyl, 9-mor-
2~6206~
- 15 -
pholino-nonanoyl,10-morpholino-decanoyl;4-amino-piperi-
dino-CmH~-CO- such as 4-amino-piparidino-carbonyl, 4-
amino-piperidino-acetyl, 3-(4-amino-piperidino)-propion-
yl, 4 (4-amino-piperidino)-butyryl, 5-(4-amino-piperi-
5 dino)-pentanoyl, 6-(4-amino-piperidino)-hexanoyll
7-(4-amino-piperidino)-heptanoyl, 8-(4 amino-piperidino)-
octanoyl, 9-(4-amino-piperidino)-nonanoyl, 10-(4-amino-
piperidino)-decanoyl; 4-dialkylamino-piperidino-C~H~-CO-
such as 4-dim~thylamino-piperidinocarbonyl~ 4-dLmethyl-
amino-piperidino-acetyl; 4-guanidino-piperidino-C~H~-CO-
such as 4-guanidino-piperidino-carbonyl, 4-guanidino-
piperidino-acetyl; 4-carboxy-piperidino-CmH~-CO- such as
4-carboxy-piperidino-carbonyl, 4-carboxy-piperidino-
acetyl; 4-alkoxycarbonyl-piperidino-CmH~-CO- such as 4-
lS methoxycarbonyl-piperidino-carbonyl, 4-ethoxycarbonyl-
piperidino-carbonyl, 4-methoxycarbonyl-piperidino-acatyl,
4-ethoxycarbonyl~piperidino-acetyl; 4-AcNH-piperidino-
C~H~-CO- such as 4-acetamido-piperidino-carbonyl, 4-
acetamido-piperidino-acetyl; H2N-C(=NH~-NH-CmH~-CO- such
as guanidinoacetyl, 3-guanidino-propionyl, 4-guanidino-
butyryl, 5-guanidino-pentanoyl, 6-guanidino-hexanoyl, 7-
guanidino-heptanoyl, B-guanidino-octanoyl; NC-NH-C(=NH)-
Nff-C~H~-CO- such as N'-cyanoguanidino-acetyl, 3-(N'-
cyanoguanidino)-propionyl, 4-(N'-cyanoguanidino)-butyryl,
5-(N'-cyano~lanidino)-pentanoyl, 6-(N'-cyanoguanidino)-
hexanoyl, 7-(N~-cyanoguanidino)-heptanoyl, 8-(N' -cyano-
guanidino)-oc:tanoyl; HOOC-C~H~-CO- such as malonyl,
succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxy-
heptanoyl, 8-carboxyoctanoyl, 9-carboxynonanoyl, 10-
carboxy-decanoyl, ll-carboxyundecanoyl; AOOC-C~H~-CO-
such as methoxycarbonyl-acetyl, 3-methoxycarbonyl-prop-
ionyl, 4-methoxycarbonyl-butyryl, 5 -me thoxycarbonyl-
pentanoyl~6-methoxycarbonyl-hexanoyl,7-methoxycarbonyl-
heptanoyl,8-methoxycarbonyl-octanoyl,9-methoxycarbonyl-
nonanoyl, 10-methoxycarbonyl-decanoyl, ethoxycarbonyl-
acetyl, 3-ethoxycarbonyl-propionyl, 4-ethoxycarbonyl-
butyryl, 5-ethoxycarbonyl-pentanoyl, 6-ethoxycarbonyl-
hexanoyl, 7-ethoxycarbonyl-heptanoyl, 8-ethoxycarbonyl-
octanoyl, 9-ethoxycarbonyl-nonanoyl, 10-ethoxycarbonyl-
- 16 - 206206~
decanoyl; H-S03-CmH2m-CO- such as sulfo-acetyl, 3-sulfo-
propionyl, 4-sulfo-butyryl, 5-sulfo-pentanoyl, 6-sulfo-
hexanoyl, 7-sulfo-heptanoyl, 8-sulfo-octanoyl, 9-sulfo-
nonanoyl, 10-sulfo-decanoyl; A-SO3-C~Hzm-CO- such as
methoxysulfonyl-acetyl, 3-methoxysulfonyl-propionyl,
4-methoxysulfonyl-butyryl, 5-methoxysulfonyl-pentanoyl,
6-methoxysulfonyl-hexanoyl, 7-methoxysulfonyl-heptanoyl,
8-methoxysulfonyl-octanoyl, 9-methoxysulfonyl-nonanoyl,
10-methoxysulfonyl-decanoyl, ethoxysulfonyl-acetyl, 3-
ethoxysulfonyl-propionyl, 4-ethoxysulfonyl-butyryl, 5-
ethoxysulfonyl-pentanoyl, 6-ethoxysulfonyl-hexanoyl, 7-
ethoxysulfonyl-heptanoyl, 8-ethoxysulfonyl-octanoyl, 9-
ethoxysulfonyl-nonanoyl, 10-ethoxysulfonyl-decanoyl;
R11-CmH2m-Co-CnH2n-CH(R7-CpH2p)-CrHzr-CO-, especially
A-CO-CH2-CH(Ar-CH2)-CO- quch as 2-benzyl-4-oxo-5,5-di-
methylhexanoyl, 2-(l-naphthylmethyl)-4-oxo-5,5-dimethyl-
hexanoyl; furthermore R8RgN-CO-CH2-CH(Ar-CH2)-CO- such as
2-benzyl-3-(4-aminopiperidinocarbonyl)-propionyl, 2-(1-
naphthylmethyl)-3-(4-aminopiperidinocarbonyl)-propionyl;
R11~CmH2m~S02~CnH2n~CH(R7~CpH2p)~CrH2r~CO~~ especially
A-SO2-CH2-CH(Ar-CH2)-CO such as 2-benzyl-3-tert.-butylsul-
fonylpropionyl, 2-(l-naphthylmethyl)-3-tert.-butylsul-
fonylpropionyl; R1l-CmH2m-NH-CO-CnH2n-CH(R -CpH2p)-CrH2r-C0-,
especially R9R9N-(CH2)~-NH-CO-CH2-CH(Ar-CH2)-C0- such as 2-
benzyl-3-(N-3-dimethylaminopropyl-carbamoyl)-propionyl,
2-(1-naphthylmethyl)-3-(N-3-dimethylaminopropyl-car-
bamoyl)-propionyl, 2-benzyl-3-(N-5-dimethylaminopentyl-
carbamoyl)-propionyl; A-CH(R7-CpH2p)-CrH2r-Co-, especially
A-CH(Ar-CH2)-CO- such as 2-benzylhexanoyl, 2-benzyl-
heptanoyl; R11-CmH2m-NH-CO-, especially R~R9N-(CH2)m-NH-Co-
such as N-3-dimethylaminopropyl-carbamoyl, N-5-dimethyl-
aminopentyl-carbamoyl; R11-CmH2m- N(R7-CpH2p)-CrH2r-Co-,
especially A-N(Ar-CH2)-CO- such as N-benzyl-N-butyl-
carbamoyl, N-benzyl-N-isopentyl-carbamoyl; R7-CmH2m-o-Co-
especially A-O-CO- such as ETOC, IPOC, BOC as well as
Ar-CmH2m-O-CO- such as CBZ; R7-CmH2m-Co- ~uch as 3,3-di-
methylbutyryl.
Accordingly, the group Y is specifically and
preferably -CN; -CH2NH-SO2R1~, e~pecially -CH2-NH-SO2-A such
- 17 _ 2 ~ ~2 ~ ~
as methane-, ethane-, propane-, 2-methylpropane- and
butane-sulfonamidomethyl, furthermore, for e~ample,
phenylmethane- and cyclohexylmethane-sulfonamidomethyl;
-CH2-NH-Co-NH-R14-, especially -CH2-NH-CO-NH-A such as N'-
methylureidomethyl, Nr-propylureidomethyl, N'-butyl-
ureidomethyl, N'-isopentylureidomethyl, furthermore
-CH2-NH-CO-NH-Ar such as N'-phenylureidomethyl and N'-p-
aminophenylureidomethyl; -CH2-NH-CS-NH-R 14~ especially
-CH2-NH-CS-NH-A such as N'-methylthioureidomethyl;
-CH2-NH-CoR14, especially -CH2-NH-CO-A such as acetamido-
methyl, propionamidomethyl and butyramidomethyl.
I f Rl = Rll-CmH2m- ( T ) a-V-CnH2n-L ( R7-CpH2p ) -CrH2r-CO-
with V = S, SO or SO2 and at the same time Y = -CH2-NH2,
R5 is oCoR7, OsiRlaRlsR2~ NRaRg or O (~ t t h d
Furthermore, Rl5 is H, OH, OR7, OSiRl8R13R20 or
-O-(2-tetrahydropyranyl), if R1 = Rll-C~H~-(T),-V-C H~-
L(R7-CpH2p)-CrH2r-Co- with V = S, SO or SO2 and Y is COR16.
The compounds of the formula I may have one or
more chiral centres and therefore exist in Yarious,
optically active or optically inactive, forms. The
formula I embraces all these forms, the S enantiomers
genexally being preferred.
The abovementioned cycloalkyl and phenyl groups
are preferably unsubstituted or carry preferably 1 to 3,
especially 1 or 2, substituents~
Accordingly, the invention particularly relates
to those compounds of the formula I in which at least one
of the said radicals has one of the preferred meanings
indicated hereinbefore. Some preferred groups of com-
pounds can be represented by the following part-formulae
Ia to Ik:
Ia R7-CmH2m-o-Co-Z-NH-CHR3-CHoH-CH2-CHoH-Y;
Ib R7-CmH2m-Co-Z-~H-CHR3-CHoH-CH2-CHoH-Y;
Ic R~R9N-CmH2~-Co-z-NH CHR3-CHoH-CH2-CHoH-Y;
Id R -NH-C(=NH)-NH-CmH2m-Co-Z-NH-CHR3-C~oH-CH2-CHoH-Y;
Ie R800C-C ~ 2m-CO-Z-MH CHR3-CHoH-CH2-CHoH-Y;
- 18 - 2062~6~
If R3R9N-C H2 -Co-z-NH-cHR3-cH-cH -CH-Y
Tl-CR3R7 T2
Ig 3CmH2m (T)s (V)y-cnH2n-L(R -cpH2p)-crH
CHR -CHOH-CH2-CHR -Y;
Ih 4-Aminopiperidinocarbonyl-Z-NH-CHR3-CHOH-CH2-CHOH-Y;
Ii A-CO-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-CH2~CHOH-Y;
Ij A-SO2-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-CH2-CHR5-Y;
Ik R3R9N-CgH2m-NH-CO-CH2-CH(ArCH2)-CO-Z-NH-CHR3-CHOH-
CH2-CHR -Y.
Particularly preferred are compounds of the part-
formulae:
(a) Iaa to Ika, which corre~pond to the formulae Ia to
Ik but in which additionally
Z is His, Phe, Phe-~Ala, Phe-Ser or Phe-His;
(b) Iab to Ikb and Iaab to Ikab, which correspond to the
formulae Ia to Ik and Iaa to Ika but in which
additionally
R3 is isobutyl or cyclohexylmethyl.
Especially preferred are compounds of the part-
formulae:
I* and Ia* to Ik*, which correspond to the formulae I and
Ia to Ik, as well as those compounds which correspond to
the other abovementioned part-formulae but in which
additionally
Y is -CN, -CH2-NH-CO-NH-R1~, -CH2-NH-Co-R14 or -CH2-NH-
So2-R14 and
R1~ is A, Ar-alkyl or cycloalkylalkyl
I~ and Ia~ to Ik~, which correspond to the formulae I and
Ia to Ik, as well as those compounds which correspond to
the other abovementioned part-formulae but in which
additionally
Y is -CH2-NH-SO2-A.
The compounds of the formula I, as well as the
19 206206~
starting materials for the preparation thereof, are
furthermore prepared by methods which are known per se
and as are described in the literature (for example in
the standard works such as Houben-Weyl, Methoden der
organischen Chemie (Methods of Organic Chemistry),
published by Georg Thieme, Stuttgart; as well aq EP-A
45665, 2P-~ 77028, EP-A 77029, EP-A 81783, EP-A 249096),
specifically under reaction conditions which are known
and suitable for the said reactions. In this connection
it is also possible to make use of variants which are
known per se and which are not mentioned in detail
herein.
It is also possible, if desired, to form the
starting materials in situ so that they are not isolated
from the reaction mixture but are immediately reacted
further to give the compounds of the formula I.
The compounds of the formula I can be obtained by
liberating them from their functional derivatives by
solvolysis, in particular hydrolysis, or by hydrogenoly-
sis.
Preferred starting materials for the solvoly~isor hydrogenolysis are ~hose which correYpond to the
formula I apart from containing, in place of one or more
free amino and/or hydroxyl groups, corresponding protec-
ted amino and/or hydroxyl groups, preferably those whichcarry an amino protective group in place of an H atom
bonded to an N atom, for example those which correspond
to the formula I but contain in place of an His group an
N(im)-R'-His group (in which R~ is an amino protective
group, for example BO~ or DNP), or those of the formula
Rl-Z-NR2-CHR3-CH(NHR')-CHz-CR6(NHR~)-Y.
Further preferred starting materials are those
which carry, in place of the H atom of a hydroxyl group,
a hydroxyl protective group, for example those of the
formula Rl-Z-NR2-CHR3-CHoR~-CH~-CR6oRn-Y in which R~ is a
hydroxyl protective group.
It is also possible for more than one - identical
or different - protected amino and/or hydroxyl groups to
be present in the molecule of the ~tarting material. If
6 ~
- 20 -
the protective groups which are present differ from one
another it is possible in many cases to eliminats them
selectively.
The term 'amino protective ~roup" is generally
known and relates to groups which are suitable for
protecting ~blocking) an amino group from chemical
reactions but which can easily be removed after the
desired chemical reaction has been carried out elsewhere
in the molecule. Typical of such groups are, in par-
ticular, unsubstituted or substituted acyl, aryl (forexample DNP), aralkoxymethyl (for example BOM) or aralkyl
groups (for example benzyl, 4-nitrobenzyl, triphenyl-
methyl~. Since the amino protective groups are removed
after the desired reaction (or reaction sequence), their
nature and size are not otherwise critical; however,
those which are preferred have 1-20, in particular 1-8,
C atoms. The term ~acyl group~' in connection with the
present process is to be interpreted in ~he widest sense. -
It embraces acyl groups derived from aliphatic, aralipha-
tic, aromatic or heterocyclic carboxylic acids or sul-
fonic acids, as well as, in particular, alkoxycarbonyl,
aryloxycarbonyl and, especially, aralko~ycarbonyl groups.
Examples of such acyl groups are alkanoyl such as acetyl,
propionyl, butyryl; aralkanoyl such as phenylacetyl;
aroyl such as benzoyl or toluyl; aryloxyalkanoyl such as
POA; alkoxycarbonyl such as methoxycarbonyl, ETOC, 2,2,2-
trichloroethoxycarbonyl, IPOC, BOC, 2-iodoethoxycarbonyl;
aralkyloxycarbonyl such as CBZ, 4~methoxybenzyloxycar-
bonyl, FMOC. Preferred amino protective groups are BOC,
DNP and BOM, as well as C~Z, FMOC, benzyl and acetyl.
The term 'hydroxyl protective group' is likewise
generally known and relates to groups which are suitable
for protecting a hydroxyl group from chemical reaction~
but which can easily be removed after tha desired chemi-
cal reaction has been carried out elsewhere in themolecule. Typical of such groups are the abovementioned
unsubstituted or substituted aryl~ aralkyl or acyl
groups, as well as alkyl groups. The nature and size of
the hydroxyl protecti~e groups are not critical because
- 21 - 2062~65
they are removed again after the desired chemical
reaction or reaction sequence; preferred groups have 1-
20, especially 1-10, C atoms. Examples of hydroxyl
protective groups are, inter alia, tert.-butyl, benzyl,
p-nitrobenzoyl, p-toluenesulfonyl and acetyl, with benzyl
and acetyl being particularly preferred.
The functional derivatives of the compounds of
the formula I which are to be used as starting materials
can be prepared by customary methods of amino acid and
peptide synthesis as are described, for example, in the
said standard works and patent applications, for example
also by the solid-phase method of Merrifield.
The liberation of the compounds of the formula I
from their functional derivatives is effected - depending
on the protective group used - for example with strong
acids, preferably with trifluoroacetic acid or perchloric
acid, but also with other strong inorganic acids such as
hydrochloric 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 and preferred inert
solvents are organic, for example carboxylic acids such
as acetic acid, ethers such as tetrahydrofuran or diox-
ane, amides such as dimethylformamide (DMF), halogenatedhydrocarbons such a~ dichloromethane, as well as alcohols
such as methanoI, ethanol or isopropanol, and water.
Furthermore suitable are mixtures of the abovementioned
solvents. Trifluoroacetic acid is preferably used in
excess without the addition of another solvent, and
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 preferably between
about 0 and about 50, preferably between 15 and 30 (room
temperature).
The BOC group can be eliminated, for example,
preferably with 40% trifluoroacetic acid in
dichloromethane or with about 3 to 5 N HCl in dioxane at
15-30, and the FMOC group with an approximately 5-20%
- 22 - 2062065
solution of dimethylamine, diethylamine or piperidine in
DMF at 15-30. Elimination of the DNP group i8 effected,
for example, also with an approximately 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 elimin-
ated, for example by treatment with hydrogen in the
presence of a catalyst (for example a noble metal cata-
lyst such as palladium, preferably on a support such as
carbon). Solvents suitable for this are those mentioned
above, especially, for example, alcohols such as methanol
or ethanol or amides such as DMF. Hydrogenolysis is, as
a rule, carried out at temperatures between about 0 and
100 under pressures between about 1 and 200 bar, prefer-
ably at 20-30 and under 1-10 bar. Hydrogenolysis of the
CBZ group is effected satisfactorily, for example, on 5-
109~ Pd-C in methanol at 20-30.
Compounds of the formula I can also be obtained
by direct peptide synthesis from a carboxylic acid
component (formula II) and an amine component (formula
III). Examples of suitable carboxylic acid components are
those of the part-formulae (a) Rl-OH, (b) Rl-Z-OH, and of
amine components are those of the part-formulae (a) H-Z-
NR2-CHR3-CR~-CH2-CR5R6-Y, (b) H-NR2-CHR3-CR4-CH2-CR5R6-Y. The
peptide linkage can, however, also be formed within the
group Z; this entails a carboxylic acid of the formula
Rl-Z1-OH being reacted with an amino compound of the
formula H-Z2-NRZ-CHR3-CR~-CH2-CR5R5-Y, where z~ + Z2 = Z. The
methods preferably used for this are those customary in
peptide synthesis, as are described, for example, in
Houben-Weyl, l.c., Volume 15/II, paqes 1-806 (1974).
The reaction i~ preferably effected in the
presence of a dehydrating agent, for example a carbodi-
imide such as DCCI or dimethylaminopropylethylcarbodi-
imide, or else propanephosphonic anhydride (compare
Angew. Chem. 92, 129 (1980)), diphenyl phosphoryl azide
or 2-ethoxy-N-ethoxycarbonyl-1,2-dihydroquinoline, in an
inert solvent, for example a halogenated hydrocarbon such
as dichloromethane, an ether such as THF or dioxane, an
- 23 - 2~ 6~
amide such as DMF or dimethylacetamide, or a nitrile such
as acetonitrile, at temperatures between about -10 and
40, preferably between 0 and 30.
It is also possible, in place o II or III, to
use suitable reactive derivatives of these substances in
the reaction, for example those in which reactive groups
have undergone intermediate blocking with protective
groups. The acid derivatives II can be used, for example,
in the form of their activated esters which are
preferably formed in situ, for example by addition of
HOBt or N-hydroxysuccinimide.
Urea derivatives of the formula I [R1 = R3-NH-Co-
or Rl1-C~H~-(T)a-(V)y--CnH~-NH~CO~] can be obtained, for
example, by reacting an appropriate isocyanate (for
example of the formula RB-NCO; can be prepared from an
amine of the formula R8-NH2 and phosgene) with an amine of
the formula H-Z-NR2-CHR3-CR4-CH2-CR5R6-Y (IIa), preferably
in an inert solvent such as THF at temperatures between
about -10 and 40, preferably between 10 and 30.
The starting materials of the formulae II and III
are mostly known. Those which are unknown can be
prepared by known methods, for example the abovementioned
methods of peptide synthesis and of elimination of
protective g:roups.
The amino component of the formula IIIb can be
obtained, for example, in accordance with the following
general scheme.
~C~2~
R3~ -C1~2-C~0 C113N02 R3-CX-C~}I-C82-CH N2
> l l l
BOC-N O ~a~ BOC-N O OH
~C~ C
(b)
2 ~ ~ ~
-- 24 --
R3-CII~ CH2-C~-CN 2 2
I I I I I i
BOC-N ~O OH BOC-N O OSiR R19R
~C~ \C/
~CH
R3-CH-CH-CH2-CH-CN R3-CH-CH-CH2-CH 2
BOC-N O OSiR R 9R 3~ BOC-N O OSiRR 9R2
,C ~C~
(c)
The compound (c) can be varied as required on the
substituent CH2NH2 (corresponds to Y) by known methods.
ElLmination of the silyl group, of the BOC protective
group and cLeavage of the oxa~olidinyl ring result in,
for example, the amine component H2N-CHR~-CHOH-CH2-CHOH-
CH2NH2. Pept:ide coupling with, for example, Rl-Z-OH is
then subsequently carried out by customary methods.
If cle~ired, it is possible for a functionally
modified amino and./or hydroxyl group in a compound of th~
formula I to be liberated by solvolysis or hydrogenolysis
by one of the methods described above.
Thus, for example, a compound of the formula I
which contains an R15-CrH2l-o-Co-NH-, an AcNH-, an ArCH2-
S03- or an AOOC- group can be converted into the
corresponding compound of the formula I which contains in
its stead an H2N-, an HS03- or an HOOC- group, preferably
by selective solvolysi~ by one of the method~ indicated
above. AOOC- groups can be hydrolyzed, for example, with
NaO~ or KOH in water/dioxane at temperatures between O
and 40, preferably 10 and 30.
20620~
- 25 -
It is al~o 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 Y is a CH2-NH-Rl2 group can be reacted
S with acylating agents of the formulae Rl4-SO2Cl, ~l4-COCl
or Rl4-NCo, preferably in the presence of an inert solvent
such as THF and/or of a base such as pyridine or tri-
ethylamine at temperatures between -10 and +30.
Furthermore, for example, keto compounds of the
formula I (R4 = O and/or R5R8 = O) can be reduced to
compounds of the formula I (R4 = (H, OH) and/or R5R6 = 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
temperatures between about -10 and +30.
Keto compounds of the formula I (R4 = O and/or
R5R6 = o) can also be converted into compounds of the
formula I (R4 = H, NH2 and/or R5R6 = H, NH2) by reductive
amination. The reductive amination can be carried out in
one or more stages. 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 O and 50, in particular between 15 and 30.
It is furthermore possible initially to convert the keto
compound into the oxime, using hydroxylamine in a cus-
tomary manner, and to reduce the oxime to the amine, for
example by catalytic hydrogenation on Raney nickel.
A base of the formula I can be converted into the
relevant acid addition salt u ing an acid. Particularly
suitable acids for this reaction are those which provide
physiologically acceptable salts, thus it is po~sible to
use inorganic acids, for example sulfuric acid, nitric
acid, hydrohalic acids such as hydrochloric acid or
hydrobromic acid, phosphoric acid~ such as orthophos-
phoric acid, sulfamic acid, as well as organic acids, in
particular aliphatic, alicyclic, araliphatic, aromatic or
heterocyclic mono- or polybasic carboxylic, sulfonic or
sulfuric acids, for example formic acid, acetic acid,
20~206~
- 26 -
- 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, p-toluenesulfonic acid, naphtha-
lene-mono- and -disulfonic acids and lauryl sulfuric
acid. Salts with physiologically unacceptable acids, for
example picrates, can be used to isolate and/or purify
the compounds of the formula I.
The new compounds of the formula I and the
physiologically acceptable salts thereof can be used to
prepare pharmaceutical products by converting them,
together with at least one vehicle or auxiliary and, if
desired, together with one or more other active
compound(s), into a suitable dosage form. The composi-
tions obtained in this way can be used as medicaments in
human or veterinary medicine. Suitable vehicles 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 a
spray for inhalation and which do not react with the new
compounds, for example water, vegetable oils, benzyl
alcohols, polyethylene glycols, glycerol triacetate and
other fatty acid glycerides, gelatine, soya lecithin,
carbohydrate~ such as lactose or starch, magnesium
stearate, talc and cellulose. Used orally are, in
particular, tablets, coated tablets, capsules, syrups,
elixirs or drops; specifically of interest are lac~uered
tablets and capsules with enteric coatings or capsule
shells. Used rectally are suppositories, and for
parenteral administration are solutions, preferably oily
or aqueous solutions as well a~ suspensions, emulsions or
implants. For administration by spray for inhalation, it
is possible to use sprays which contain the active
substance either dissolved or suspended in a propellant
gas mixture (for example chlorofluorohydrocarbons). The
active substance is preferably used for this in
- 27 - 206206~
micronized form, with one or more additional physiologi-
cally tolerated solvents po~sibly being present, for
example ethanol. Solutions for inhalation can be
administered with the aid of customary inhalers. The new
compounds can also be freeze-dried and the resulting
lyophilisates used, for example, to prepare products for
injection. The stated compositions can be sterilized
and/or contain auxiliaries such as preservatives,
stabilizers and/or wetting agents, emulsifiers, salts to
influence the osmotic pressure, buffer substances,
colorants and/or flavourings. They can, if desired, also
contain one or more other active substances, 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 especially in analogy to
the compounds described in EP-A 249,096, preferably in
dosages between 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 par-
ticular between 1 and 10 mg/kg, of body weight. The
specific dose for each particular pa~ient depends,
however, on a wide variety of factors, for example on the
activity of the specific compound used, on the age, body
weight, general state of health and sex, on the diet, on
the time and route of administration and on the rate of
excretion, medicinal substance combination and severity
of the particular disease for which the therapy is
applied. Parenteral administration i8 preferred.
Renin-dependent hypertension and hyperaldo-
steronism can be effectively treated by administration of
dosages between, in particular, about 1 and 300, prefer-
ably between 5 and 50, mg/kg of body weight. For diagnos-
tic purposes, it is possible and preferable for the new
compounds to be administered in single doses, particu-
larly in about 0.1 and 10 mg/kg of body weight.
All temperature~ stated hereinbefore and herein-
after are in C. In the examples which follow, ~usual
working up" means: if necessary, water is added, the pH
- 28 - 2062065
is ad~usted to between 2 and 8, depending on the con-
stitution of the final product, extraction i8 carried out
with ethyl acetate or dichloromethane, the organic phase
is separated off, dried over sodium sulfate, filtered and
concentrated, and purification is carried out by chrom-
atography on silica gel and/or crystallization.
Exam~le 1
a) A mixture of 380 mg (0.45 mmol) of N-t5S-(BOC-Phe-
(imi-BOM-His)-amino)-6-cyclohexyl-2S,4S-dihydroxy-
hexyl]-propanesulfonamide (m.p. 159-161)
[obtainable by reaction of (4S,5S)-3-BOC-4-cyclo-
hexylmethyl-2,2-dimethyl-5-oxazolidinyl-acetaldehyde
with NaCN in the presence of glacial acetic acid in
THF at 4 to give 2-~(4S,5S)-3-BOC-4-cyclohexyl-
methyl-2,2-dimethyl-5-oxazolidinyl]-(lR,S)-
1-hydroxy-propionitrile; reaction with tert. butyl-
dimethylchlorosilane in the presence of imidazole at
room temperature to give 2-[~4S,5S)-3-BOC-4-cyclo-
hexylmethyl-2,2-dimethyl-5-oxazolidinyl]-(lR,S)-
l-(trimethylsilyloxy)-propionitrile; hydrogenation
in methanol on Raney Ni at room temperature to give
3-~(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl-
5-oxazolidinyl~-(2R,S)-2-(trimethylsilyloxy)-propyl-
amine; reaction with l-propanesulfonyl chloride in
THF in the presence of triethylamine at 10 to give
N-[3-{(4S,5S)-3-BOC-4-cyclohexylmethyl-2,2-di~thyl-
5-oxazolidinyl}-(2R,S)-2-trimethylsilyloxy-propyl]-
propanesulfonamide, separation of the diastereomers
by chromatography; elimination of the trimethylsilyl
group from the 2S epimer by reaction with tetra-
butylammonium fluoride in ether, cleavage with HCl-
saturated ethyl acetate to give N-(5S-amino-6-cyclo-
hexyl-2S,4S-dihydroxy-l-hexyl)-propanesulfonamide
(m.p. 102-104-); condensation with BOC-(imi-BOM-
His)-QH in the presence of HOBt, NMM and DAPECI in
DNF to give N-t5S-BOC-(imi-His)amino-6-cyclohexyl-
2S,4S-dihydroxy-l-hexyl)-propanesulfonamide (m.p.
131-133); elimination of the BOC group with
HCl/ethyl acetate and condensation with BOC-Phe-OH
20~2n6~
- 29 ~
in the presence of HOBt, NMM and DAPECI hydro-
chloride in DMF], 590 mg (9.3 mmol) of ammonium
formate and 480 mg of Pd-carbon in 38 ml of methanol
is stirred at room temperature for 20 hours. The
mixture is filtered, the solution is concentrated,
27 ml of a 5~ NaHCO3 solution are added~ and the
mixture is stirred and filtered with suction.
Purifica~ion of the crystals results in N-[5S-(BOC-
Phe-His-amino)-6-cyclohexyl-2S,4S-dihydroxyhexyl]-
propanesulfonamide, m.p. 125-127.
b) This and the followin~ compounds can likewi~e be
obtained from the corresponding Lmi-DNP-His deriva-
tive~ by elimination of the DNP group in the fol-
lowing way: a mixture of the corresponding DNP
deriva~ive with 2-mercaptoethanol in DMF and water
is adjusted to pH 8 with aqueous Na2CO3 solution
while ~tirring at 20 and is stirred for 2 hours.
The usual working up results in the required final
product.
The following are obtained analogously from the
corresponding imi-BOM or imi-DNP derivatives:
N-[5S-(BOC Phe-His~amino)-2R,4S-dihydroxy-6-cyclo-
hexylhexyl]-propanesulfonamide/ m.p0 165-168
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl~-propanesulfon~mide
N-[2S,4S-dihydroxy-5S-~4-BOC-amino~piperidinocarbonyl-
Pho-His-amirlo)-6-cyclohexylhexyl]-3-methylbutanoamide,
m.p. 120 130~ (decomposition)
N-~2R,4S-dihydroxy-5S-(4-BOC-amino~piperidinocarbonyl-
3~ Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutanoamide,
m.p. 120-130 (decomposition)
N-[2S,4S-dihydroxy-5S-(4-BOC-amino piperidinocarbonyl-
Phe-Hi~-amino)-6-cyclohexylhexyl]-N'-isopropylurea, m.p.
137-140
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-Hi~-amino)-6-cyclohexylhexyl]-3-methylbutanoamide,
m.p. 137-140
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-Hi~-amino)-6-cyclohexylhexylJ-N~-ethylurea/m.p.129
206206S
- 30 -
(decomposition)
N-~2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-N~-ethylurea,m.p.143
(decomposition)
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butyl-sulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-methane~ulfon-
amide
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butyl-sulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butyl-sulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-butanesulfonamide
N-t2S,4S-dihydroxy-SS-(2-benzyl-heptanoyl-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-SS-(2-benzyl-4-oxo-5,5-dimethyl-
hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butyl-sulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-morpholinocarbonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-[2S,4S-dihydroxy-SS-(2-~1-naphthylmethyl)-3-morpholino-
carbonyl-propionyl-His-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-(N-benzyl-N-isopentyl-carbamoyl-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-SS-(2-(1-naphthylmethyl)-3-(N-
(3-dimethylaminopropyl)-carbamoyl-propionyl-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-SS-(2-benzyl-3-(4-BOC-aminopiperidino-
carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-
propanesulfonamide
N-[2S,4S-dihydroxy-SS-(2-(1-naphthylmethyl)-3-(4-BOC-
amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(CBZ-Phe-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
~2~
- 31 -
N-[2S,4S-dihydroxy-5S-(3,3-dimethylbutyryl-Phe-His-
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-propionyl-
Phe-His~amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(6-BOC-amino-hexanoyl-Phe-His-
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(6-methoxycarbonyl-hexanoyl-Phe-
His-amino)-6 cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl)-
carbamoyl-Phe-His-amino)-6 cyclohexylhexyl]-propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-
carbamoyl-Phe-His-amino)-6-cyclohexylhexyl]- propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-(BOC-Mal-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(CBZ-Mal-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(3,3-dimethylbutyryl-Mal-His-
amino) 6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(2-BOC-amino-2-methyl-propionyl-
Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(6 BOC-amino-hexanoyl-Mal-His-
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(6-methoxycarbonyl-he~anoyl-Mal-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(N-(3-dimethylaminopropyl)-
carbamoyl-Mal-Hi3-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-
carbamoyl-Mal-Hi~-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-~4-BOC-aminopiperidinocarbonyl-Nal-
His-amino)-6-cyclohexylhexyl]-methanesulfonamide
N-~2S,45-dihydroxy-5S-(BOC Phe-His-amino)-6-cyclo-
2062~6~
- 32 -
hexylhexyl]-2-methylpropanesulfonamide
N-~2S,4S-dihydroxy-5S-tBOC-Cal-His-amino)-6-cyclo-
hexylhexyl]-2-methylpropanesulfonamide
N-[2S,4S-dihydroxy-5S-(BOC-~Nal-His-amino)-6-cyclo-
hexylhexyl]-2-methylpropanesulfonamide
N-[2S,4S-dihydroxy-5S-~BOC-2-~ia-His-amino)-6-cyclo-
hexylhexyl]-2-methylpropanesulfonamide
N-t2S,4S-dihydroxy-SS-(BOC-Trp-His-amino)-6-cyclo-
hexylhexyl]-2-methylpropanesulfonamide
N-[2S,4S-dihydroxy-SS-(BOC-Pro-Phe-His-amino)-6-cyclo-
hexylhexyl]-2-methylpropanesulfonamide
N-t2S,4S-dihydroxy-SS-(3,3-dimethylbutyryl-Pro-Phe-N-Me-
His-amino)-6-cyclohexylhexyl]-2-methylpropanesulfonamide
N-t2S,4S-dihydroxy-SS-(4-CBZ-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-propanesulfonamide.
N-t2S,4S-dihydroxy-5S-(2-benzyl-2-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-methanesulfon-
amide
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-butanesulfonamide
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-2-methylpropane-
sulfonamide
N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-Hi~-amino)-6-cyclohexylhexyl]-phenylmethane-
sulfonamide
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-cyclohexyl-
methanesulfonamide
N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-N'-propylurea
N-t2S,4S-dihydroxy-SS-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-N'-butylurea
N-t2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-N~-propylthiourea
N-[2S,4S-dihydroxy-5S-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-N~-(p-amin
2062065
- 33 -
phenyl)-urea
N-[2S,4S-dihydroxy-5s-(2-benzyl-3-tert.-butylsulfonyl-
propionyl-His-amino)-6-cyclohexylhexyl]-4-methyl-pentano-
amide
ExamPle ?
0.01 mol of N-methylmorpholine is added to a
solution of 0.01 mol of N-[2S,4S-dihydroxy-5S-(H-~Ala-
-amino)-6-cyclohexylhexyl]-propanesulfonamide [obtainable
by condensation of BOC-~Ala-OH with N-(2S,4S-dihydroxy-
SS-amino-6-cyclohexylhexyl)-propanesulfonamide to give
N-[2S,4S-dihydroxy-SS-(BOC-~Ala-amino)-6-cyclohexyl-
hexyl]-propanesulfonamide and elimination of the BOC
group with 4 N HCl in dioxane] in 60 ml of dichloro-
methane. While stirring, 0.01 mol of 4-dimethylamino-
piperidinocarbonyl-Phe-OH, 1.35 g of HOBt and a solution
of 2.06 g of DCCI in 50 ml of dichloromethane is added,
the mixture is stirred at 2-6 for 14 h, the precipitated
dicyclohexylurea is filtered off, and the filtrate is
evaporated. The usual working up results in
N-~2S,4S-dihydroxy-SS-(4-dimethylamino-piperidino-
carbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-
sulfonamide.
N-t2S,4S-dihydroxy-5S-(4-BOC-amino-piperidino-
carbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-
sulfonamide i8 analogou~ly obtained as a colorless foam
with 4-BOC-amino-piperidinocarbonyl-Phe-OH.
The following are obtained analogously:
N-[2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-~Ala-amino)-6-cyclohexylhexyl~-2-propanesulfonamide,
colourless foam
N-t2S,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-2-Tia-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-t2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-
carbamoyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2S,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-car-
bamoyl-Phe-2-Tia-amino)-6-cyclohexylhexyl]-propane-
~ulfonamide
_ 34 _ 20620fi~
Example 3
In analogy to Example 2, N-(2S,4S-dihydroxy-
5S-(BOC-Phe-Gly-amino)-6-cyclohexylhexyl)-propane-
sulfonamide is obtained from BOC-Phe-Gly-OH and
N-(2S,4S-dihydroxy-SS-amino-6-cyclohexylhexyl)-propane-
sulfonamide.
The following are obtained analogously
N-(2S,4S-dihydroxy-SS-(BOC-Phe-Abu-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-5S-(BOC-Phe-Ala-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-SS-(BOC-Phe-~Ala-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-5S-(BOC-Phe-Asn-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-5S-(BOC-Phe-Gln-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-SS-(BOC-Phe-Nle-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-2R,4S-dihydroxy-SS-(BOC-Phe-Ser-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-2R,4S-dihydroxy-5S-(BOC-Phe)-6-cyclohexylhexyl)-
propanesulfonamide
N-(2S,4S-dihydroxy-SS-(BOC-Phe-3-Pya-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
N-(2S,4S-dihydroxy-SS-(BOC-Phe-2-Tia-amino)-6-cyclo-
hexylhexyl)-propanesulfonamide
Example 4
~n analogy to Example 2, N-[2S,4S-dihydroxy-
5S-(4-BOC-aminopiperidinocarbonyl-Phe-Gly-amino)-
7-methyl-octyl]-ethanesulfonamide is obtained from 4-BOC-
aminopiperidinocarbonyl-Phe-OH and N-[2S,4S-dihydroxy-
5S-(H-Gly-amino)-7-methyl-octyl]-ethanesulfonamide.
ExamE~le S
A solution of 1 g of N-[2S,4S-dihydroxy-
5S-(4-BOC-aminopiperidinocarbonyl-Phe-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide in 20 ml of 4 N HCl
2 ~
- 35 -
in dioxane is stirred at 20 for 30 min and then evapora-
ted. N-[2S,4S-dihydroxy-5S-(4-amino-piperidinOCarbonyl-
Phe-His-amino)-6-cyclohexylhexyl~-propanesulfonamide,
dihydrochloride is obtained.
The following are obtained analogously by
cleavage of the corresponding BOC derivatives:
N-[2S,4S-dihydroxy-55-(2-benzyl-3-(4-aminopiperidino-
carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-
propanesulfonamide
N-[2S,4S-dihydroxy-5S-(2-(1-naphthylmethyl)-3-(4-amino-
piperidinocarbonyl)-propionyl-His-amino)~6-cyclo-
hexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-
~Ala-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-
2-Tia-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-~2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Mal-His-
amino)-6-ryclohexylhexyl]-propanesulfonamide
N-t2S,4S-dihydroxy-5S-(2-amino-2-methyl-propionyl-Phe-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-~2S,4S-dihydroxy-5S-(2-amino-2-methyl-[propionyl-Mal-
His-amino)-6-cyclohexylhexyl~-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(6-aminohexanoyl-Phe-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide
N-t2S,4S-dihydroxy-5S-(6-aminohexanoyl-Mal-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe
~Ala-amino)-6 cyclohexylhexyl]-2-propanesulfonamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-
amino)-6-cyclohexylhexyl]-3-methylbutanoamide
N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-His-
amino)-6-cyclohexylhexyl]-N'-isopropylurea
N-t2S,4S-dihydroxy-5S-~4-aminopiperidinocarbonyl-Phe-His-
amino)-6-cyclohexylhexyl]-me~hanesulfonamide
N- r 2S,4S-dihydroxy-5S-(4-c~inopiperidinocarbonyl-Mal-His-
amino)-6-cyclohexylhe~yl]-methanesulfonamide.
2~2~
36
Example 6
Hydrogenolysis (on 10% Pd-C in ethanol at 20) of
N-~2S,4S-dihydroxy-5S-(4-CBZ-~ninopiperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide results
in N-[2S,4S-dihydroxy-5S-(4-aminopiperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide.
Example 7
The following are obtained in analogy to Example
1 from the corresponding imi-BOM-His derivatives:
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-
His-amino)-6-cyclohexylhexyl~-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Mal-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(3~BOC-amino-3-methylbutyryl-Phe-
N-Me-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-
His-amino)-6-cyclohexylhexyl]-1-methylethanesulfonamide
N-~2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Mal-
His-amino)-6-cyclohexylhexyl~-1-methylethanesulfonamide
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-
N-Me-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfon-
amide
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-
His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe~
Hi~-amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-[2R,4S-dihydroxy-5S-(3-BOC-amino-3-methylbutyryl-Phe-
N-Me-His-amino)-6-cyclohexylhexyl]-N'isopropyl-urea
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-1-methylethanesulfon-
amide
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Mal-His- mino)-6-cyclohexylhexyl]-1-methylethanesulfon-
amide
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-cyclohexane-sulfonamide
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl~-cyclohexane-sulfonamide
- 37 - 2062~
N-t2R~4s-dihydroxy-ss-(4-Boc-amino-piperidinocarbon
Phe-His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea
N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea
N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea
N-[2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea
N-t2R,4S-dihydroxy-5S-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea
N-t2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-
Phe-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide
N-[2R,4S-dihydroxy-SS-(4-BOC-amino-piperidinocarbonyl-
Mal-His-amino)-6-cyclohexylhexyl]-3-methylbutyramide
N-t2R,4S-dihydroxy-5S-(2R-benzyl-4-(4-BOC-amino-piperi-
dinocarbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-
propane~ulfonamide
N-t2R,4S-dihydroxy-SS-(2S-benzyl-4-(4-BOC-amino-piperi-
dinocarbonyl)-propionyl-His-amino)-6-cyclohexylhexyl~-
propanesulfonamide
N-t2R,4S-dihydroxy-5S-(2R-(l-naphthylmethyl)-3-(4-BOC-
amino-piperidinocarbonyl)-propionyl-Hi~-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-5S-(2S-(l-naphthylmethyl)-3-(4-BOC-
amino-piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-BOC-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-t2R,4S-dihydroxy-5S-(2S-benzyl-5-N-BOC-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-BOC-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl~-1-methylethane-
sulfonamide
N-t2R,4S-dihydroxy-SS-(2S-benzyl-5-N-BOC-N-methyl-amino-
2062065
-- 38 --
pentanoyl-His-amino ) -6-cyclohexylhexyl ] -l-methylethane-
sul f onamide
N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-5-N-BOC-N-methyl-amino-
pentanoyl-His-amino ) -6 -cyclohexylhexyl ] -N ~ -ethyl-urea
N- [ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-5-N-BOC-N-methyl-amino-
pentanoyl-His-amino ) -6-cyclohexylhexyl ~ -N ~ -ethyl-urea
N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino ) -6-cyclohexylhexyl ] -l-methylethane-
sul f onamide
N- [ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino) -6-cyclohexylhexyl ] -1-methyl-ethane-
sulfonamide
N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino ) -6-cyclohexylhexyl ] -cyclohexane-
sulfonamide
N- t 2R, 4S-dihydroxy-SS- ( 2S-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino ) -6-cyclohexylhexyl ] -cyclohexane-
sulfonamide
N- t 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino) -6-cyclohexylhexyl ] -N~ -ethyl-urea
N- ~ 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-
propionyl-His -amino ) - 6 -cyc lohexylhexyl ] -N ~ -ethyl -urea
N- [ 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino) -6-cyclohexylhexyl ] -N ' -isopropyl-urea
N- t 2R, 4S-dihydroxy-5S- ( 2S-benzyl-3-tert . -butylsulfonyl-
propionyl-His-amino) -6-cyclohexylhexyl ] -N~ -isopropyl-urea
N- t 2R, 4S-dihydroxy-5S- t 2R-benzyl-heptanoyl-His-amino ) -
6-cyclohexylhexyl ] -propanesulfonamide
N- t 2R, 4S-dihydroxy-5S- ( 2S-benzyl-heptanoyl-His -amino ) -
6-cyclohexylhexyl ] -propanesulfonamide
N- t 2R, 4S-dihydroxy-5S- ( 2R- ( l-naphthylmethyl ) -
3 -morpholinocarbonyl-propionyl-His-amino ) -
6 -cyclohexylhexyl ] -propanesulfonamide
N- t 2R, 4S-dihydroxy-5S- ( 2S- ( l-naphthylmethyl ~ -
3 -morpholinocarbonyl-propionyl-His-amino ) -
6 -cyc lohexylhexyl ] -propanesul f onamide
N- 1 2R, 4S-dihydroxy-5S- ( 2R-benzyl-3-tert . -butylthio-
propionyl -Hi~ -amino ) - 6 -cyclohexylhexyl ] -propanesul f on-
2062065
- 39 -
amide
N-[2R,4S-dihydroxy-5S-(2S-benzyl-3-tert.-butylthiopro-
pionyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-sS-(2R-benzyl-3-tert.-butylsulfinyl-
propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-[2R,4S-dihydroxy-SS-(2S-benzyl-3-tert.-butylsulfinyl-
propionyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-[2R,4S-dihydroxy-5S-(2R-benzyl-4-oxo-5,5-dimethyl-
hexanoyl-~is-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(2S-benzyl-4-oxo-5,5-dimethyl-
hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(2R-benzyl-4-hydroxy-5,5-dimethyl-
hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(2S-benzyl-4-hydroxy-5,5-dimethyl-
hexanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidino-
carbonyl-Phe-His-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2R,4S-dihydroxy-5S-(4-dimethylamino-piperidino-
carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-
sulfonamide
N-[2R,4S-dihydroxy-5S-(N-(5-dimethylaminopentyl)-car-
bonyl-Phe-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-[2R,4S-dihydroxy-5S-(N-~5-dimethylaminopentyl)-car-
bonyl-Mal-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide.
Example 8
The following are obtained in analogy to Example
5 from the corresponding BOC derivatives:
N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl~-propanesulfonamide, hydro-
chloride
N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-[2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Phe-His-
~6206~
- 40 -
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Mal-His-
amino)-6-cyclohexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me-
His-amino)-6-cyclohexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-
amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Mal-His-
amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me-
His-amino)-6-cyclohexylhexyl]-1-methyl-ethanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-
amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-Mal-
amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide
N-t2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-His-
amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-~2R,4S-dihydroxy-5S-(3-amino-3-methylbutyryl-Phe-Mal-
amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-[2R,4S-dihydroxy-SS-(3-amino-3-methylbutyryl-Phe-N-Me~
His-amino)-6-cyclohexylhexyl]-N~-isopropylurea
N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl3-1-methylethanesulfonamide
N- E 2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-1-methylethanesulfonamide
N-~2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide
N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-cyclohexanesulfonamide
N-~2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-N'-ethyl-urea
N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-N~-isopropyl-urea
N-t2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-N'-isopropyl-urea
N-12R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea
206~6~
- 41 -
N-[2R,4S-dihydroxy-5S-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-N'-phenyl-urea
N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Phe-
His-amino)-6-cyclohexylhexyl]-3-methylbutyramide
N-[2R,4S-dihydroxy-SS-(4-amino-piperidinocarbonyl-Mal-
His-amino)-6-cyclohexylhexyl]-3-methylbutyramide
N-[2R,4S-dihydroxy-5S-(2R-benzyl-3-(4-amino-[piperidino-
carbonyl)-propionyl-.His-amino)-6-cyclohexylhexyl]-
propanesulfonamide
N-[2R,4S-dihydroxy-SS-(4-aminopiperidinocarbonyl-Phe-
~Ala-amino)-6-cyclohexylhexyl]-2-propanesulfonamide
N-[2R,4S-dihydroxy-SS-(2S-benzyl-3-(4-aminG-piperidino-
carbonyl)-propionyl-His-amino)-6-cyclohexylhexyl]-
propanesulfonamide
N-[2R,4S-dihydroxy-SS-(2R-(l-naphthylmethyl)-3-(4-amino-
piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-SS-(2S-(l-naphthylmethyl)-3-(4-amino-
piperidinocarbonyl)-propionyl-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide
N-t2R,4S-dihydroxy-5S-(2R-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-t2R,4S-dihydroxy-5S-(2S-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-propanesulfon-
amide
N-~2R,4S-dihydroxy-SS-(2R-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-1-methylethane-
sulfonamide
N-t2R,4S-dihydroxy-SS-(2S-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-l-methylethane
sulfonamide
N-t2R,4S-dihydroxy-SS-(2R-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea
N-[2R,4S-dihydroxy-SS-(2S-benzyl-5-N-methyl-amino-
pentanoyl-His-amino)-6-cyclohexylhexyl]-N~-ethyl-urea.
Example 9
A mixture of 730 mg of N-t2R,4S-dihydroxy-5S-
2~3~2~
- 42 -
(4-aminopiperidino-carbonyl-Phe-His-amino)-6-cyclohexyl-
hexyl]-propanesulfonamide, 90 mg of S-methylisothiourea,
5 ml of ethanol and 5 ml of watex is stirred at 50 for
2 h. The usual working up results in N-~2R,4S-dihydroxy-
5S-(4-guanidino-piperidinocarbonyl-Phe-His-amino)-
6-cyclohexylhexyl]-propanesulfonamide.
N-[2R,4S-dihydroxy-5S-~4-guanidino-piperidino-
carbonyl-Mal-His-amino~-6-cyclohe~ylhexyl]-propane-
sulfonamide is obtained analogously.
Example 10
A mixture of 730 mg of N-[2R,4S-dihydroxy-
5S-(4-aminopiperidino-carbonyl-Phe-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide, 115 mg of trLme~hylsilyl
isocyanate and 10 ml of THF is tirred at 20 for 16 h.
It is then stirred into water, and worked up in the usual
way to result in N-[2R,4S-dihydroxy-5S-(4 ureido-piperi-
dinocarbonyl-Phe-His amino)-6-cyclohexylhexyl]-propane-
sulfonamide.
N-[2R,4S-dihydroxy-5S-(4-ureido-piperidino-
carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-
sulfonamide is obtained analogously, and, using ethyl
isocyanate:
N-[2R,4S-dihydroxy-5S-~4-N'-ethylureido-piperidi.no-
carbonyl-Phe-His amino)-6-cyclohexylhe~yl]-propane-
sulfonamide
N-[2R,4S-dihydroxy-5S-(4-N'-ethylureido-piperidino-
carbonyl-Mal-His-amino)-6-cyclohexylhexyl]-propane-
sulfonamide.
xample 11
a) 0.48 g (0~53 mmol) of2,2-dimethyl-4S-[2-cyclohexyl~
lS-(BOC-Phe-His(DNP)-amino)-ethyl]-6R-~3-isopropyl-
ureido)-methyl-1,3-dioxane [obtainable by reaction
of 3-[(45,5S)-3-BOC-4-cyclohexylmethyl-2,2-dimethyl
5-oxazolidinyl]-(2R,S)-2-trimethylsilyloxy)-propyl-
amine (see Ex~mple 1) wi~h isopropyl isocyanate in
THF in the presence of triethylamine at 0 to give
N-[3-{(4S,5S~ 3-BOC-4-cyclohexyLmethyl-2,2 dimethyl-
43 20~206~
5-oxazolidinyl~-(2R,S)-trimethylsilyloxypropyl]-N'-
isopropylurea, separation of the diastereomers by
chromatography; elimination of the trimethylsilyl
groups from the 2R epimer by reaction with tetra-
butylammonium fluoride at 0, this product i8
stirred in ethyl acetate with HCl-saturated ethyl
acetate at 0 for 48 hours, water is added and
extraction is carried out with 3296 NaOH, the organic
phase is worked up and, after purification by
chromatography on silica gel, 2,2-dimethyl-
4S-[2-cyclohexyl-lS-aminoethyl]-6R-(3-isopropyl-
ureido)-methyl-1,3-dioxane is obtained; condensation
with BOC-Phe-His(DNP)-OH in DMF in the presence of
HOBt, NMM and DAPECI] in 5 ml of DMF is mixed with
0.2 ml of 5% NaHCO3 solution, and then 0.14 ml
(2 mmol) of 2-mercaptoethanol is added. After 12
hours, 50 ml of H20 are added, and the precipitate
which forms is taken up in CH2C12. The crystalline
residue is purified on silica gel to result in
2,2-dimethyl-4S-t2-cyc lohexyl-lS-(BOC-Phe-His-
amino) -ethyl] -6 R- ( 3 - isopropylureido)methyl-
1,3-dioxane, m.p. 134-140 (decomposition).
The following is obtained analogously:
4S-[2-cyclohexyl-lS-{(4-BOC-amino-piperidino-
carbonyl ) -Phe-His-amino~-ethyl ]-2-methyl-
6R-(3-methylbutyryl-aminomethyl)-1,3-dioxane.
b) The following are obtained by elimination of the BOC
group in a known manner
2,2-dimethyl-4S-t2-cyclohexyl-lS-(Phe-His-amino)-
ethyl]-6R-(3-isopropylureido)-methyl-1,3-dioxane and
4S-t2-cyclohexyl-lS-{(4-aminopiperidinocarbonyl)-
Phe-His-amino}-ethyl]-2-methyl-6R-(3-methylbutyryl-
aminomethyl)-1,3-dioxane.
The examples which follow relate to pharmaceu-
tical compositions.
Example As Tablets
A mixture of 1 kg of N-~2R,4S-dihydroxy-5S-
(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclo-
20~206S
hexylhexyl]-3-methyl-butyramide~ 4 kg of lactose, 1.2 kg
of maize starch, 200 g of talc and 100 g of magnesium
stearate is compressed in a customary manner to give
tablets in such a way that each tablet contains 100 mg of
active compound.
Example B: Coated tablets
Tablets are compressed in analogy to Example A
and are then coated in a customary manner with a coating
composed of sucrose, maize starch, talc, tragacanth and
colorant.
Example C: Capsules
500 g of N-t2S-,4S-dihydroxy-SS-(4-a~inopiperi-
dinocarbonyl-Phe-~Ala-amino)-6-cyclohexylhexyl]-propane-
sulfonamide hydrochloride are dispensed in a customary
manner into hard gelatine capsules so that each capsule
contains 500 mg of active compound.
Example D: Injection ampoules
A solution of 100 g of N-[2S,4S-dihydroxy-
5S-(4-aminopiperidinocarbonyl-Phe-His-amino)-6-cyclo-
hexylhexyl]-propanesulfonamide dihydrochloride in 4 1 of
double distilled water i~ ad~usted to pH 6.5 with 2 N
hydrochloric acid, filtered sterile and dispensed into
in~ection ampoules. These are lyophilized under sterile
conditions and sealed sterile. Each in~ection ampoule
contains 50 mg of active compound.
Example E: Suppositorie~
A mixture of 50 g of N-t2S,4S-dihydroxy-
5S-(2-benzyl-3-tert.-butylsulfonylpropionyl-His-amino)-
6-cyclohexylhexyl]-methanesulfonamide hydrochloride with
10 g of soya lecithin and 140 g of cocoa butter is
melted, poured into moulds and left to cool. Each sup-
pository contains 250 mg of active compound.
