IE913050A1 - Amino acid derivatives - Google Patents

Abstract

Amino acid derivatives of the formula I X-W-CR<1>R<2>-CO-Y-NH-CHR<3>-CR<4>-COOR<5> I in which R<1> to R<5>, W, X and Y have the meanings indicated in Claim 1, and the salts thereof inhibit the activity of human plasma renin.

Description

Amino acid derivatives Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt The invention relates to novel amino acid derivatives of the formula I X-W-CR1R2-CO-Y-NH-CHR3-CR*-COOR5 I in which X W Y R1, R7 and Ra R2, R3 and R6 R* R5 R7R®N R9 m and n is H, R6-O-CmH2m-CO-, R6-CmH2m-O-CO-, R^C^-CO-, R6-SO2-, R7RsN-CmH2ffi-CO-, R9-NH-C ( =NH) -NHC^-CO-, R'OOC-CJi^-CO-, R7O3S-CmHZn]-CO-, R7-O-(CH2CH2O) „-0^-00- or Ag^-CJI^-CO- Απ’, is O or NH, is flAla or Isoser, are each H or A, are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsubstituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 411 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, is (H, OH), (H, NH2) or =0, is H, A or cycloalkyl having 3-7 C atoms, is also an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one which is substituted by A, OH, NH2, NHA, NAa, NHAc, NH-CO-CxH2x-O-R9, NH-CO-O-CxH2i-R9, hydroxyalkyl, COOH, COOA, CONH2, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®alkyl An®, NH-CO-NH2, NH-CO-NHA, guanidinyl or guanidinylalkyl, is H, A, Ar-alkyl or CN, are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, is 0, 1, 2 or 3, x Ar Het is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, hydroxyalkyl, NH2, NHA, NA2, NHAc, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, aminoalkyl, HAN-alkyl, A2N-alkyl, A3N®-alkyl An® and/or guanidinylalkyl, or is unsubstituted naphthyl, is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, 0 and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF3, OH, NO2, carbonyl oxygen, NH2, NHA, NA2, NHAc, NH-COOA, NHCOOAr, NHCOOCHjAr, NH-SO2-A, SA, SO-A, SO2-A, SO2NH2, SO2NHA, COOH, COOA, CONH2, CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A2N-alkyl and/or A3N®-alkyl An® and/or whose N and/or S heteroatoms can also be oxidised, Hal is 20 Ac is An® is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -NH-CO groups there can also be one or more -ΝΑ-CO groups, and their salts.

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 medicaments .

It has 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. Fyhrquist et al., Clin. Chem. 22, 250-256 (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 inhibition. The actions of the compounds on the blood pressure and/or on the heart rate and the inhibition of the renin activity in the blood plasma can additionally be determined in conscious monkeys, 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 this case expediently pretreated with a saluretic. Blood samples 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 hyperaldosteronism. 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 radicals -NR'-RC0-, 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 homophenylalanine (2-amino-4-phenylbutyric Hph acid) He isoleucine 5 Leu leucine Mai 3-(p-methoxyphenyl) alanine Nle norleucine Phe phenylalanine Tia 3-(thienyl)alanine [for example 2-Tia = 10 3-(2-thienyl) alanine] Tiz 3-(thiazolyl)alanine [for example 2-Tiz = 3-(2-thiazolyl) alanine] Trp tryptophan Tyr tyrosine. 15 In addition, the following have the meaning below: BOC tert.-butoxycarbonyl BOM benzyloxymethyl imi-BOM benzyloxymethyl in the 1-position of the 20 imidazole ring CBZ benzyloxycarbonyl DCC I dicyclohexylcarbodiimide DMF dimethylformamide DNP 2,4-dinitrophenyl 25 imi-DNP 2,4-dinitrophenyl in the 1-position of the Imidazole ring ETOC ethoxycarbonyl FMOC 9-fluorenylmethoxycarbonyl HOBt 1-hydroxybenzotriazole 30 IPOC isopropoxycarbonyl Pla the radical of phenyllactic acid -O-CH(CH2C6H5)-CO- (S-form) POA phenoxyacetyl THF tetrahydrofuran.

If the abovementioned amino acids can occur in several enantiomeric 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 the formula I. The L-forms are preferred. If individual compounds are mentioned below, the abbreviations 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 5 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-G1-OH II in which G1 (a) is absent, (b) is -W-CR^-CO-, (c) is -W-CR1R2-C0-Y-, or one of its reactive derivatives is reacted with a compound of the formula III H-G2-NH-CHR3-CR*-COOR5 III in which G2 (a) is -W-CR1R2-CO-Y-, (b) is -Y-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is 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, R* = 0, is reduced or reduct ively 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 converted into one of its salts by treating with an acid.

Above and below, the radicals or parameters R1 to R9, W, X, Y, m, n, x, Ar, Het, Hal, Ac, An, A, G1 and G2 have the meanings indicated in the formulae I, II or III 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, 1- 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, 1-ethyl-l-methylpropyl, l-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropy1, 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-methylcyclopentylmethy1, 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-bicyclo[3.1.1]heptyl.

Tricycloalkyl is preferably 1-adamantyl.

Hal is preferably F, Cl or Br, but also I.

Ac is preferably A-C0-, such as acetyl, propionyl or butyryl, Ar-CO- such as benzoyl, ο-, m- or p-methoxybenzoyl or 3,4-dimethoxybenzoyl, or A-NH-CO- such as N-methyl- or N-ethylcarbamoyl.

Ar is preferably phenyl, in addition preferably o—, m- or p-tolyl, ο-, m- or p-ethylphenyl, ο-, m- or p-methoxyphenyl, ο-, m- or p-fluorophenyl, ο-, m- or p-chlorophenyl, ο-, m- or p-bromophenyl, ο-, m- or p-iodophenyl, ο-, m- or p-trifluoromethylphenyl, ο-, mor p-hydroxyphenyl, ο-, m- or p-sulfamoylphenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, ο-, m-, or p-aminophenyl, ο-, mor p-aminomethylphenyl, ο-, m- or p-dimethylaminomethylphenyl, ο-, m- or p-guanidinomethylphenyl, 1- or 2-naphthyl.

Accordingly, Ar-alkyl is preferably benzyl, 1- or 2- phenylethyl, ο-, m- or p-methylbenzyl, 1- or 2-o-, -mor -p-tolylethyl, ο-, m- or p-ethylbenzyl, 1- or 2-ο-, -m- or -p-ethylphenylethyl, ο-, m- or p-methoxybenzyl, 1or 2-0-, -m- or -p-methoxyphenylethyl, ο-, m- or p-fluorobenzyl, 1- or 2-o-, -m- or -p-fluorophenylethyl, ο-, m- or p-chlorobenzyl, 1- or 2-ο-, -m- or -p-chlorophenylethyl, ο-, m- or p-bromobenzyl, 1- or 2-o-, -m- or -p-bromophenylethyl, ο-, m- or p-iodobenzyl, 1- or 2-o-, -m- or -p-iodophenylethyl, ο-, m- or p-trifluoromethylbenzyl, ο-, m- or p-hydroxybenzyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dimethoxybenzyl, 3,4,5-trimethoxybenzyl, ο-, m- or p-aminobenzyl ο-, m- or p-aminomethyl15 benzyl, ο-, m- or p-dimethylaminomethylbenzyl, ο-, 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 -isoxazolyl, 2-, 4- or 5-thiazolyl, 3-, 4- or 5-isothiazolyl, 2-, 3- or 4-pyridyl, 2-, 4-, 5- or 6-pyrimidinyl, furthermore preferably 1,2,3-triazol-l-, -4- or -5-yl, 1,2,4-triazol-l-, -3- or -5-yl, 1- or 5-tetrazolyl, l,2,3-oxadiazol-4- or -5-yl, l,2,4-oxadiazol-3- or -5-yl, 1,3,4-thiadiazol-2- or -5-yl, l,2,4-thiadiazol-3- or -5-yl, 2,l,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-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, 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-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, 1-, 2-, 3-, 4-, - , 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. Het can thus also be, for example, 2,3-dihydro-2-, -3-, -4- or -5-furyl, 2,5-dihydro-2-, -3-, -4or -5-furyl, tetrahydro-2- or -3-furyl, tetrahydro-2- or -3-thienyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 2,5-dihydro-l-, -2-, -3-, -4- or -5-pyrrolyl, 1-, 2- or 3- pyrrolidinyl, tetrahydro-1-, -2- or -4-imidazolyl, 2,3-dihydro-l-, -2-, -3-, -4- or -5-pyrazolyl, tetrahydro-1-, -3- or -4-pyrazolyl, 1,4-dihydro-l-, -2-, -310 or -4-pyridyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5or -6-pyridyl, 1,2,3,6-tetrahydro-l-, -2-, -3-, -4-, -5or -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-Ι-, -3- or -4-pyridazinyl, hexahydro-Ι-, -2-, -4- or -5-pyrimidinyl, 1- , 2- or 3-piperazinyl, 1,2,3,4-tetrahydro-l-, -2-, -3-, -4-, -5-, -6-, -7- or -8-quinolyl, 1,2,3,4-tetrahydro-l-, -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-carbamoyl2- thiazolyl, 4-(2-aminoethyl)-2-thiazolyl, 4-amino-2methyl-5-pyrimidinyl, 2-amino-5,6-dimethyl-3-pyrazinyl, 4- carbamoylpiperidino, in addition, for example, 3-, 425 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-, 4or 5-methyl-2-thienyl, 2-, 4- or 5-methyl-3-thienyl, 3- methyl-5-tert.-butyl-2-thienyl, 5-chloro-2-thienyl, - phenyl-2- or -3-thienyl, 1-, 3-, 4- or 5-methyl-230 pyrrolyl, l-methyl-4- or -5-nitro-2-pyrrolyl, 3,5-dimethyl-4-ethyl-2-pyrrolyl, 4-methyl-5-pyrazolyl, -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-, - or 6-methyl-2-pyridyl, 2-, 4-, 5- or 6-methyl-3pyridyl, 2- or 3-methyl-4-pyridyl, 3-, 4-, 5- or 6chloro-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), 5-phenyl-lH-2-pyridon-3-yl, 5-p-methoxyphenyl-lH2-pyridon-3-yl, 2-methyl-3-hydroxy-4-hydroxymethyl-5pyridyl, 2-hydroxy-4-amino-6-methyl-3-pyridyl, 3-N'methylureido-1H-4-pyridon-5-yl, 4-methyl-2-pyrimidinyl, 4,6-dimethyl-2-pyrimidinyl, 2-, 5- or 6-methyl-4-pyrimidinyl, 2,6-dimethyl-4-pyrimidinyl, 2,6-dihydroxy-4-pyrimidinyl, 5-chloro-2-methyl-4-pyrimidinyl, 3-methyl-2benzofuryl, 2-ethyl-3-benzofuryl, 7-methyl-2-benzothienyl, 1-, 2-, 4-, 5-, 6- or 7-methyl-3-indolyl, l-methyl-5- or -6-benzimidazolyl, l-ethyl-5- or -6-benzimidazolyl, 3-, 4-, 5-, 6-, 7- or 8-hydroxy-2-quinolyl, 2-oxopyrrolidino, 2-oxopiperidino, 2,5-dioxopyrrolidino or 3-benzyl-2,5-dioxopyrrolidino.

X is generally preferably H; R6-CmH2m-O-CO- such as BOC; R6-CmH2m-CO- such as formyl or acetyl; R6-SO2-, in particular A-SO2- such as methyl sulf onyl; R7R8N-CmH2m-CO-, in particular 4-BOC-aminopiperidinocarbonyl, 4-aminopiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4dimethylaminopiperidinocarbonyl, 4-ethoxycarbonylamino20 piperidinocarbonyl, morpholinocarbonyl, piperazinocarbonyl or 4-BOC-piperazinocarbonyl.

The group Y is preferably 0Ala.

W is preferably NH.

R1, R5, R7, and R® are each preferably H, in addi25 tion preferably methyl; R5 is preferably also ethyl, propyl, isopropyl, n-butyl, isobutyl, cyclopentyl or cyclohexyl. R7R8N is preferably also pyrrolidino, piperidino, morpholino, aminopiperidino such as 4-aminopiperidino, hydroxypiperidino such as 4-hydroxypiperidino, alkylaminopiperidino such as 4-methylaminopiperidino, dialkylaminopiperidino such as 4-dimethylaminopiperidino, ethoxycarbonylaminopiperidino such as 4-ethoxycarbonylaminopiperidino or BOC-aminopiperidino such as 4-BOCaminopiperidino, morpholino or 4-BOC-piperazino.

R2 is preferably Ar-alkyl, in particular benzyl or p-methoxybenzyl; in addition preferably A, in particular n-butyl or isobutyl; cycloalkylalkyl, in particular cyclohexylmethyl; or Het-alkyl, in particular 2-thienylmethyl. The group -W-CR1R2-CO- is preferably one of the radicals Phe or Pla, in addition Ada, Bia, Cal, His, Hph, lie, Leu, Mai, 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 2thienylmethyl; 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.

CJi^ and CjHa, are preferably straight-chain, that is to say preferably -(CH2)m- or -(CH2)X-.

Accordingly, the group X is in particular prefer15 ably H; R7R8N-(CH2)m-CO-, in particular H^-C^H^-CO- such as aminocarbonyl, aminoacetyl (H-Gly-), 3-aminopropionyl (H-^Ala-), 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 9-aminononanoyl, 10-aminodecanoyl, 11-aminoundecanoyl, but also, for example, 2-aminopropionyl (Ala), 2-amino-2-methylpropionyl, 3-amino-3-methylbutyryl; ANH-C^H^-CO- such as methylaminocarbonyl, ethylaminocarbonyl, methylaminoacetyl (sarcosyl), 3-methylaminopropionyl, 4-methylaminobutyryl, 5-methylaminopentanoyl, 6-methylaminohexanoyl, 6-ethylaminohexanoyl, 7-methylaminoheptanoyl, 8-methylaminooctanoyl, 9-methylaminononanoyl, 10-methylaminodecanoyl, 11-methylaminoundecanoyl; A^-C^Han-CO- such as dimethylaminocarbonyl, dimethylaminoacetyl, 3-dimethylaminopropionyl, 4-dimethylaminobutyryl, 5-dimethylamino30 pentanoyl, 6-dimethylaminohexanoyl, 6-diethylaminohexanoyl, 7-dimethylaminoheptanoyl, 8-dimethylaminooctanoyl, 9-dimethylaminononanoyl, 10-dimethylaminodecanoyl, 11dimethylaminoundecanoyl; pyrrol idino-CnHan-CO- such as pyrrolidinocarbonyl, pyrrolidinoacetyl, 3-pyrrolidinopro35 pionyl, 4-pyrrolidinobutyryl, 5-pyrrolidinopentanoyl, 6pyrrolidinohexanoyl, 4-pyrrolidinoheptanoyl, 8-pyrrolidinooctanoyl,9-pyrrolidinononanoyl,10-pyrrolidinodecanoyl; piperidino-CnHan-CO- such as piperidinocarbonyl, piperidinoacetyl, 3-piperidinopropionyl, 4-piperidinoIE 913050 butyryl, 5-piperidinopentanoyl, 6-piperidinohexanoyl, 7piperidinoheptanoyl, 8-piperidinooctanoyl, 9-piperidinononanoyl, 10-piperidinodecanoyl; morpholino-C^H^-CO- such as morpholinocarbonyl, morpholinoacetyl, 3-morpholino5 propionyl, 4-morpholinobutyryl, 5-morpholinopentanoyl, 6-morpholinohexanoyl, 7-morpholinoheptanoyl, 8-morpholinooctanoyl, 9-morpholinononanoyl, 10-morpholinodecanoyl; 4-hydroxypiperidino-CmH2m-CO- such as 4-hydroxypiperidinocarbonyl, 4-hydroxypiperidinoacetyl; 4-aminopiperidino10 C^H^-CO- such as 4-aminopiperidinocarbonyl, 4-aminopiperidinoacetyl, 3-(4-aminopiperidino)propionyl, 4-(4aminopiperidino)butyryl, 5-(4-aminopiperidino)pentanoyl, 6-(4-aminopiperidino)hexanoyl, 7-(4-aminopiperidino)heptanoyl, 8-(4-aminopiperidino)octanoyl, 9-(4-aminopiperi15 dino)nonanoyl, 10-(4-aminopiperidino)decanoyl; 4-BOCaminopiperidino-CnHzn-CO- such as 4-BOC-aminopiperidinocarbonyl, 4-BOC-aminopiperidinoacetyl; 4-dialkylaminopiperidino-QnHaj-CO- such as 4-dimethylaminopiperidinocarbonyl, 4-dimethylaminopiperidinoacetyl; 4-alkoxycarb20 onylaminopiperidino-C^H^-CO- such as 4-ethoxycarbonylaminopiperidinocarbonyl, 4-methoxycarbonylaminopiperidinoacetyl; 4-guanidinopiperidino-CmHan-CO- such as 4guanidinopiperidinocarbonyl, 4-guanidinopiperidinoacetyl; 4-carboxypiperidino-C^H^-CO- such as 4-carboxypiperidino25 carbonyl, 4-carboxypiperidinoacetyl; 4-alkoxycarbonylpiperidino-CJH^-CO- such as 4-methoxycarbonylpiperidinocarbonyl, 4-ethoxycarbonylpiperidinocarbonyl, 4-methoxycarbonylpiperidinoacetyl, 4-ethoxycarbonylpiperidinoacetyl; 4-AcNH-piperidino-CnH2m-CO- such as 4-acetamidopiperidinocarbonyl, 4-acetamidopiperidinoacetyl; morpholino-CJHjjj-CO- such as morpholinocarbonyl or morpholinoacetyl; 4-BOC-piperazino-CmH2m-CO- such as 4BOC-piperazinocarbonyl or 4-BOC-piperazinoacetyl; h2N-C (=NH) -NH-CjnH2m-C0- such as guanidinoacetyl, 3-guani35 dinopropionyl, 4-guanidinobutyryl, 5-guanidinopentanoyl, 6-guanidinohexanoyl, 7-guanidinoheptanoyl, 8-guanidinooctanoyl; NC-NH-C(=NH)-NH-C^^-CO- such as N'-cyanoguanidinoacetyl, 3-(Ν'-cyanoguanidino)propionyl, 4-(N'cyanoguanidino) butyryl, 5-(N'-cyanoguanidino)pentanoyl, 6-(Ν'-cyanoguanidino)hexanoy1, 7-(N'-cyanoguanidino)heptanoyl, 8-(Ν'-cyanoguanidino)octanoyl; HOOC-CmH2m-COsuch as malonyl, succinyl, glutaryl, adipyl, 6-carboxyhexanoyl, 7-carboxyheptanoyl, 8-carboxyoctanoyl, 9-carb5 oxynonanoyl, 10-carboxydecanoyl, 11-carboxyundecanoyl; AOOC-C.Ji^-CO- such as methoxycarbonylacetyl, 3-methoxycarbonylpropionyl, 4-methoxycarbonylbutyryl, 5-methoxycarbonylpentanoyl, 6-methoxycarbonylhexanoyl, 7-methoxycarbonylheptanoyl, 8-methoxycarbonyloctanoyl, 9-methoxy10 carbonylnonanoyl, 10-methoxycarbonyldecanoyl, ethoxycarbonylacetyl, 3-ethoxycarbonylpropionyl, 4-ethoxycarbonylbutyryl, 5-ethoxycarbonylpentanoyl, 6-ethoxycarbonylhexanoyl, 7-ethoxycarbonylheptanoyl, 8-ethoxycarbonyloctanoyl, 9-ethoxycarbonylnonanoyl, 10-ethoxycarbony115 decanoyl; H-SOa-C^H^-CO- such as sulfoacetyl, 3-sulfopropionyl, 4-sulfobutyryl, 5-sulfopentanoyl, 6-sulfohexanoyl, 7-sulfoheptanoyl, 8-sulfooctanoyl, 9-sulfononanoyl, -sulfodecanoyl; A-SOa-C^^-CO- such as methoxysulfonylacetyl, 3-methoxysulfonylpropionyl, 4-methoxysulfonyl20 butyryl, 5-methoxysulfonylpentanoyl, 6-methoxysulfonylhexanoyl, 7-methoxysulfonylheptanoyl, 8-methoxysulfonyloctanoyl, 9-methoxysulfonylnonanoyl, 10-methoxysulfonyldecanoyl, ethoxysulfonylacetyl, 3-ethoxysulfonylpropionyl, 4-ethoxysulfonylbutyryl, 5-ethoxysulfonyl25 pentanoyl, 6-ethoxysulfonylhexanoyl, heptanoyl, 8-ethoxysulfonyloctanoyl, nonanoyl, 10-ethoxysulfonyldecanoyl; particular A-O-CO- such as ETOC, IPOC, BOC and also Ar-CnHan-O-CO- such as CBZ; R^C^H^-CO-, in particular 30 A-CO- such as acetyl, trimethylacetyl or 3,3-dimethylbutyryl, but also formyl; or R6-SO2- such as A-SO2-, preferably methylsulfonyl.

The compounds of the formula I can have one or more chiral centres and therefore occur in different 35 - optically active or optically inactive - forms. The formula I includes all these forms. If R3 differs from H and/or R* is (H, OH) or (H, NH2), the 2R-hydroxy, 2Ramino, 3S-amino, 2R-hydroxy-3S-amino and 2R,3S-diamino enantiomers are preferred (the C atom which carries the 7-ethoxysulfonyl9-ethoxysulfonylR6-CmH2m-O-CO-, in radical R4 being allocated the 2-position and the C atom which carries the radicals X-W-CR1R2-CO-Y-NH and R3 being allocated the 3-position.

The abovementioned cycloalkyl and phenyl groups 5 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: la H-W-CR1RZ-CO-Y-NH-CHR3-CR4-COOR5; Ib R6-O-CmH2ni-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; IC R6-CmH2ai-O-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; Id R6-CBH2m-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; Ie R7R8N-CmH2m-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5 ? If Ra-NH-C ( =NH) -NH-CmH2m-CO-W-CR1R2-CO-Y-NH-CHR3-CR4COOR5; Ig R7OOC-CmH2in-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; lh R7O3S-CIBH2lII-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; Ii R7-O- (CH2CH2O)n-CmH2ni-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; I j R7R8N-CO-W-CR1R2-CO-Y-NH-CHR3-CR4-COOR5; Ik 4-Aminopiperidinocarbonyl-W-CR1Rz-CO-Y-NH-CHR3-CR4COOR5.

Particularly 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-CR1R2-C0- is Phe, Pla, Mai or -CH2-CH (CH2C6H5) -CO-; (b) lab 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 0Ala. (c) lac to Ike, Iaac to Ikac and also Iabc to Ikbc, which correspond to the formulae Ia to Ik, Iaa to Ika and also lab to Ikb, but in which additionally R3 is cyclohexylmethyl.

Particularly preferred compounds are those of the sub-formulae: I* and Ia* to Ik*, which correspond to the formulae I and 5 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-, Η-CO-, 4-BOC-aminopiperidinocarbonyl, 4-hydroxypiperidinocarbonyl, 4-aminopiperidinocarbonyl, 4-A2N-piperidinocarbonyl, 4-AOOC-NH-piperi20 dinocarbonyl, piperazinocarbonyl, 4-BOC-piperazinocarbonyl, morpholinocarbonyl or A-SO2-, -W-CR1R2-CO- is Phe or Pla, Y is £Ala or Isoser, R3 is cyclohexylmethyl, R4 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 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 formed in situ, such that they are not isolated from the reaction mixture, but immediately reacted further to give the compounds of the formula I.

The compounds of the formula I can be obtained by 5 setting them free from their functional derivatives by solvolysis, in particular hydrolysis, or by hydrogenolysis .

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 instead 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-CR1R2-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-W-CR1R2-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, triphenylmethyl). Since the amino protective groups are removed 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, aryloxycarbonyl and aralkoxycarbonyl groups. Examples of acyl groups of this type are alkanoyl such as acetyl, propionyl or 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-iodoethoxycarbony1; aralkyloxycarbonyl such as CBZ, 4-methoxybenzyloxycarbonyl 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 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 protective group used - for example with strong acids, expedi5 ently 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 inert solvents are preferably organic, for example carboxylic acids such as acetic acid, ethers such as tetrahydrofuran or dioxane, amides such as 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 is 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 expediently between about 0 and about 50°; the reaction is preferably carried out between 15 and 30° (room tempera25 ture).

The BOC group can, for example, preferably be removed with 40 % trifluoroacetic acid in dichloromethane or with about 3 to 5 N HCI in dioxane at 15-30C, the FMOC group with an about 5-20 % solution of dimethyl30 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 hydro35 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 catalyst such as palladium, expediently on a support such as carbon). Suitable solvents in this case are the abovementioned, in particular, for example, alcohols such as methanol or ethanol or amides such as DMF. The hydrogenolysis 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 510 % Pd-C in methanol at 20-30°.

Compounds of the formula I can also be obtained by direct condensation (peptide synthesis) from a car10 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-CR^-COOH or (c) X-W-CR1R2-CO-Y-OH, suitable hydroxyl or amino components are those of the sub-formulae (a) HW-CR1R2-CO-Y-NH-CHR3-CRi‘-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 15/11, pages 1-806 (1974); these methods can also be transferred, if W = 0, to the condensation 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 carbodiimide such as DCCI or dimethylaminopropylethylcarbodiimide, and in addition propanephosphonic anhydride (cf. Angew. Chem. 92, 129 (1980)), diphenylphosphoryl azide or 2-ethoxy-N-ethoxycarbonyl-l,2-dihydroquinoline, in an inert solvent, for example a halogenated hydrocarbon 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 derivatives 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 derivatives II can be used, for example, in the form of their activated esters, which are expediently formed in situ, for example by addition of HOBt or N-hydroxysuccinimide .

The starting substances 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 solvolysis or hydrogenolysis according to one of the methods described above.

Thus, for example, a compound of the formula I which contains an R9-CxH2x-O-CO-NH-, an AcNH- or an AOOCgroup 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. AOOC20 groups can be hydrolysed, for example, with NaOH or KOH in water-dioxane at temperatures between 0 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 cimino 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 different from Η), 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 (R4 = 0) 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 temperatures between about -10 and +30°.

Keto compounds of the formula I (R4 = 0) can also be converted into compounds of the formula I (R4 = H, NH2) by reductive amination. Reductive amination can be 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 orthophosphoric 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, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, and laurylsulfuric acid. Salts with physiologically unacceptable acids, for example picrates, can be 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 preparations by bringing them into a suitable dosage form together with at least one excipient 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, 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; especially of interest are coated tablets and capsules having enteric coatings 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 administration. 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 possible 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 example, for the production of injection preparations.

The preparations mentioned can be sterilised and/or can contain auxiliaries such as preservatives, stabilisers and/or wetting agents, emulsifiers, salts for affecting the osmotic pressure, 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 commer10 cially available peptides, but in particular 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 parti15 cular between 1 and 10 mg/kg of body weight. The specific dose for each specific patient, however, depends on a wide variety of factors, for example on the activity of the specific 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 administration of dosages between, in particular, about 0.2 and 20, preferably between 1 and 10 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 separated 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 method.

Example 1 g of isopropyl 3S-[tert.-butoxycarbonyl-L-(Nimi-benzyloxymethylhistidyl) -y3-alanylamino ] -4-cyclohexyl2R-hydroxybutyrate [= isopropyl 3S-(BOC-(imi-BOM-His)5 ySAla-amino)-4-cyclohexyl-2R-hydroxybutyrate; obtainable by condensation of BOC-(imi-BOM-His)-£-Ala-0H 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 H2 absorption has stopped, the mixture is filtered and evaporated and isopropyl 3S-(BOC-His-0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate is obtained after chromatographic purification on silica gel.

Isopropyl 3S-(4-carboxypiperidinocarbonyl-Phe15 j9Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate is obtained analogously by hydrogenolysis of isopropyl 3S-(4-benzyloxycarbonylpiperidinocarbonyl-Phe-0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.

Example 2 A mixture of 1 mmol of ethyl 3S-[BOC-(imi-DNPHis)-^Ala-amino]-4-cyclohexyl-2R-hydroxybutyrate (obtainable by condensation of ethyl BOC-(imi-DNP-His)-jS-Ala-OH with 3S-amino-4-cyclohexyl-2R-hydroxybutyrate], 2 g of 2mercaptoethanol, 20 ml of DMF and 20 ml of water is adjusted to pH 8 with stirring at 20° using agueous Na2C03 solution and the mixture is stirred at 20° for a further 2 hours. Customary working-up gives ethyl 3S-(BOC-Hisβ Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate.

Example 3 A solution of 2.15 g of methyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate in 60 ml of dichloromethane is treated with 1.01 g of N-methylmorpholine. 4.5 g of 4B0C-aminopiperidinocarbonyl-Phe-j3Ala-0H, 1.35 g of HOBt and a solution of 2.06 g of DCCI in 50 ml of dichloro35 methane are added with stirring, the mixture is stirred 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-aminopiperidinoc ar bony 1 -Phe - β Al a-amino) -4 -eye lohexy 1 - 2 R-hydroxybutyr a te, m.p. 113-114°.

Example 4 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 104105°, is obtained analogously to Example 3 using isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate.

Example 5 Isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-PheIsoser-amino)-4-cyclohexyl-2R-hydroxybutyrate, 2 isomers, m.p. 115-116° and m.p. 102-103° respectively, are obtained analogously to Example 3 using 4-BOC-aminopiperidinocarbonyl-Phe-Isoser-OH and isopropyl 3S-amino4-cyclohexyl-2R-hydroxybutyrate.

Example 6 The following are obtained from isopropyl 3Samino-4-cyclohexyl-2R-hydroxybutyrate analogously to Example 3 (a) isopropyl 3S-(BOC-Phe-0Ala-amino)-4-cyclohexyl-2Rhydroxybutyrate, m.p. 120-122°, using BOC-Phe-£AlaOH; (b) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiper idinocarbonyl-Phe-^Ala-amino ) -butyrate , m.p. 120-121°, using 4-hydroxypiperidinocarbonyl-Phe0Ala-OH; (c) isopropyl 3S-(4-BOC-piperazinocarbonyl-Phe-^Alaamino)-4-cyclohexyl-2R-hydroxybutyrate, m.p. 86-87°, using 4-BOC-piperazinocarbonyl-Phe-^Ala-OH; (d) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholinocarbonyl-Phe-0Ala-amino)-butyrate, m.p. 112-113°, using morpholinocarbonyl-Phe-£Ala-OH? (e) isopropyl 4-cyclohexyl-3-(4-dimethylaminopiperidinocarbonyl-Phe-^Ala-amino)-2R-hydroxybutyrate, hydrochloride, m.p. 219-220°, using 4-dimethylaminopiperidinocarbonyl-Phe-^Ala-OH; (f) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylaminopiperidinocarbonyl-Phe-^Ala-amino)-2R-hydroxybutyrate using 4-ethoxycarbonylaminopiperidinocarbonyl-Phe-0Ala-OH; (g) isopropyl 4-cyclohexyl-3-(4-ethoxycarbonylpiperidinocarbonyl-Phe-/3Ala-amino)-2R-hydroxybutyrate, m.p. 117-118°, using 4-ethoxycarbonylpiperidinocarbonyl-Phe-£Ala-OH; (h) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-Isoser-amino)-butyrate using 4-hydroxypiperidinocarbonyl-Phe-Isoser-OH.

Example 7 The following are obtained from 4-hydroxypiperidinocarbonyl-Phe-^Ala-OH analogously to Example 3 (a) methyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-butyrate using methyl 3 S-amino-4-eyelohexyl-2 R-hydroxybutyrate; (b) ethyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-butyrate using ethyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate; (c) n-butyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-butyrate using n-butyl 3 S-amino-4-eyelohexyl-2 R-hydroxybutyrate; (d) cyclohexyl 4-cyclohexyl-2R-hydroxy-3S-(4-hydroxypiper idinocarbonyl -Phe-^Ala-amino) -butyrate using cyclohexyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate; (e) isopropyl 2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-5-methylhexanoate using isopropyl 3S-amino-2R-hydroxy-5-methylhexanoate; (f) isopropyl 2R-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)-4-phenylbutyrate using isopropyl 3S-amino-2R-hydroxy-4-phenylbutyrate; Example 8 The following are obtained from isopropyl 4cyclohexyl-2R-hydroxy-3S-(H-Phe-0Ala-amino) butyrate analogously to Example 3 (a) isopropyl 3S-(3-BOC-amino-3-methylbutyryl-Phe-0Alaamino)-4-cyclohexyl-2R-hydroxybutyrate using 3-BOCamino-3-methylbutyric acid; (b) isopropyl 3S-(6-BOC-aminohexanoyl-Phe-£Ala-amino)4-cyclohexyl-2R-hydroxybutyrate using 6-BOC-aminohexanoic acid; (c) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(3,6,8-trioxanonanoyl-Phe-^Ala-amino)-butyrate using 3,6,8trioxanonanoic acid.

Example 9 The following are obtained from isopropyl 3S-(H^Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate [FAB: M + 1 = 315; obtainable by condensation of CBZ-y3Ala-OH with isopropyl 3S-amino-4-cyclohexyl-2R-hydroxybutyrate to give isopropyl 3S- (CBZ-^SAla-amino)-4-cyclohexyl-2Rhydroxybutyrate (FAB: M + 1 = 449) and hydrogenolysis] analogously to Example 3 (a) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Pla-£Alaamino)-butyrate, m.p. 54-55°, using H-Pla-OH; (b) isopropyl 3S-(H-CO-Phe-j3Ala-amino)-4-cyclohexyl-2Rhydroxybutyrate, m.p. 108° (dec.), using H-CO-PheOH; (c) isopropyl 4-cyclohexyl-2R-hydroxy-3S-(morpholinocarbonyl-Pla-^Ala-amino)-butyrate using morpholinocarbonyl-Pla-OH; (d) to (m) using acids of the formula 4-BOC-aminopiperidinocarbonyl-Z-OH (Z = Ada, Cal, Leu, Mai, Nle, Pla, 2-Tia, 2-Tiz, Trp and Tyr respectively); (d) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-AdajflAla-amino)-4-cyclohexyl-2R-hydroxybutyrate; (e) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Caly3Ala-amino) -4-cyclohexyl-2R-hydroxybutyrate; (f) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-LeuβAla-amino)-4-cyclohexyl-2R-hydroxybutyrate; (g) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Maly9Ala-amino) -4-cyclohexyl-2R-hydroxybutyrate; (h) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Nle0 Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate; (i) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-Pla0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate; (j) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2-Tia0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate; (k) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-2-Tiz£Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate; •Ε 913050 (l) isopropyl 3S-(4-BOC-aminopiperidinocarbonyl-TrpAla-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-2Rhydroxy-3S-(H-Phe-^Ala-amino)-butyrate, 115 mg of trimethylsilyl 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-2Rhydroxy-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 is worked up in the customary manner to give isopropyl 4-cyclohexyl-3S-[N-(N-ethylcarbamoyl) 2 0 Phe-£Ala-amino]-2R-hydroxybutyrate.

Example 12 A solution of 1 g of methyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-^Ala-amino)-4-cyclohexy1-2Rhydroxybutyrate in 20 ml of dichloromethane and 20 ml of trifluoroacetic acid is stirred at 20’ for 1 hour and then evaporated. Methyl 3S-(4-aminopiperidinocarbonylPhe-0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate, TFA, m.p. 163-164”, are obtained.

The following are obtained analogously by cleav30 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-Isoseramino)-4-cyclohexyl-2R-hydroxybutyrate, TFA, 2-isomers, m.p. 118-119* and 155-156” respectively isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-0Ala-amino)butyrate, TFA, m.p. 77-78“ isopropyl 4-cyclohexyl-2R-hydroxy-3S-(piperazinocarbonylPhe-^Ala-amino)-butyrate, TFA, m.p. 113-114° isopropyl 3S-(3-amino-3-methylbutyryl-Phe-£Ala-amino)-4cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(6-aminohexanoyl-Phe-^Ala-amino)-4-cyclohexyl-2 R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Ada-^Ala-amino)4-eyelohexy1-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Cal-^Ala-amino)10 4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Leu-£Ala-amino)4-cyclohexyl-2 R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Mai-0Ala-amino)4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Nle-£Ala-amino)4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Pla-0Ala-amino)4-eyelohexy1-2 R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tia-£Ala20 amino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-2-Tiz-0Alaamino)-4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Trp-0Ala-amino)4-cyclohexyl-2R-hydroxybutyrate isopropyl 3S-(4-aminopiperidinocarbonyl-Tyr-0Ala-amino)4-cyclohexyl-2R-hydroxybutyrate Example 13 (a) A mixture of 1 g of methyl 3S-(4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-4-cyclohexyl-2R30 hydroxybutyrate, 50 ml of dioxane and 20 ml of 2 N aqueous NaOH solution is stirred at 20° for 3 hours. The mixture is worked up in the customary manner and gives 3S-(4-BOC-aminopiperidinocarbonyl-Phe-0Alaamino)-4-cyclohexyl-2R-hydroxybutyric acid. (b) The crude acid obtained according to (a) is stirred with 25 ml of DMF, 1 ml of isopropyl iodide and 200 mg of K2CO3 for 24 hours. The mixture is worked up in the customary manner and gives isopropyl 3S(4-BOC-aminopiperidinocarbonyl-Phe-0Ala-amino)-4IE 913050 cyclohexyl-2R-hydroxybutyrate, m.p. 104-105’. Example 14 Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(H-Phe-/3Alaamino)-butyrate, TFA, m.p. 77-78’, is obtained by hydro5 genolysis of isopropyl 3S-(CBZ-Phe-0Ala-amino)-4-cyclohexyl-2R-hydroxybutyrate analogously to Example 1. Example 15 (a) 449 mg of isopropyl 4-cyclohexyl-2R-hydroxy-3S-(HPhe-^Ala-amino)butyrate are dissolved in 25 ml of THF. A solution of 117 mg of methanesulfonyl chloride 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-(methane15 sulfonyl-Phe-0Ala-amino)butyrate, m.p. 115-116°. (b) Isopropyl 4-cyclohexyl-2R-hydroxy-3S-(isopropylsulfonyl-Phe-0Ala-amino)butyrate is obtained analogously using isopropylsulfonyl chloride. (c) Isopropyl 3S-(acetyl-Phe-0Ala-amino)-4-cyclohexyl20 2R-hydroxybutyrate is obtained analogously using acetyl chloride.

Example 16 (a) Isopropyl 4-cyclohexyl-3S-(4-hydroxypiperidinocarbonyl-Phe-£Ala-amino)-2-oxobutyrate is obtained from 4-hydroxypiperidinocarbonyl-Phe-/9Ala-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 H2 is complete. After filtering and evaporating, a mixture of isopropyl 4cyclohexyl-2R- and -2S-hydroxy-3S-(4-hydroxypiperidinocarbonyl-Phe-^Ala-amino)butyrate is obtained, which can be separated on silica 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 mg of hydroxylamine hydrochloride and stirred at 20’ for 14 hours. The precipitated oxime 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 of isopropyl 2R- and 2S-amino-4-cyclohexyl-3S-(4-hydroxypiper idinocarbonyl -Phe-^Ala-amino ) butyrate obtained is separated.

The examples below relate to pharmaceutical preparations.

Example A: Tablets A mixture of 1 kg of isopropyl 4-cyclohexyl-2Rhydroxy-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 is compressed to give tablets in a customary manner in such a way that each tablet contains 100 mg of active compound.

Example 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)-4cyclohexyl-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.

Example D: Injection vials A solution of 100 g of methyl 3S-(4-aminopiperidinocarbony 1 -Phe-^Ala-amino) -4 -eye lohexy 1 - 2 R-hydroxybutyrate trifluoroacetate in 41 of doubly distilled water is adjusted to pH 6.5 with 2N hydrochloric acid, sterile filtered and poured into injection vials. The solution is lyophilised under sterile conditions and the vials are sterile sealed. Each injection vial contains 100 mg of active compound.

Example E: Suppositories A mixture of 50 g of isopropyl 4-cyclohexyl-2Rhydroxy-3S-(methanesulfonyl-Phe-^Ala-amino) butyrate is fused with 10 g of soya lecithin and 140 g of cocoa butter, poured into moulds and allowed to cool. Each suppository contains 250 mg of active compound.

Merck Patent Gesellschaft mit beschrankter Haftung 6100 Darmstadt

Claims (13)

1. 5 1. Amino acid derivatives of the formula I X-W-CR 1 R 2 -CO-Y-NH-CHR 3 -CR A -COOR 5 I in which X w Y R 1 , R 7 and R 8 R 2 , R 3 and R 6 R* R 5 R 7 R a N R 9 m and x n Ar is H, R 6 -0-CnH2a)-C0-, R 5 -CmH 2m -O-CO-, R 6 -CDH2m-C0-, R 6 -SO2-, R 7 R 8 N-CniH2m-CO- , R 9 -NH-C ( =NH) -NHCJi^-CO-, R 7 OOC-CmH 2m -CO-, R^S-CJi^-CO-, R 7 -O-(CH2CH2O)n-CmH2m-CO- or A3N + -CmH 2m -CO- An‘, is 0 or NH, is fiAla or Isoser, are each H or A, are each H, A, Ar, Ar-alkyl, Het, Het-alkyl, cycloalkyl having 3-7 C atoms, which is unsubstituted or monosubstituted or polysubstituted by A, AO and/or Hal, cycloalkylalkyl having 411 C atoms, bicycloalkyl or tricycloalkyl each having 7-14 C atoms, or bicycloalkylalkyl or tricycloalkylalkyl each having 8-18 C atoms, is (H, OH), (H, NH 2 ) or =0, is H, A or cycloalkyl having 3-7 C atoms, is also an unsubstituted pyrrolidino, piperidino, morpholino or piperazino group or one which is substituted by A, OH, NH 2 , NHA, NAs, NHAc, NH-CO-C x H 2i -O-R®, NH-C0-0-C x H 2x -R 9 , hydroxyalkyl, COOH, COOA, C0NH 2 , aminoalkyl, HAN-alkyl, A^-alkyl, A 3 N®alkyl An®, NH-CO-NH 2 , NH-CO-NHA, guanidinyl or guanidinylalkyl, is H, A, Ar-alkyl or CN, are each 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, is 0, 1, 2 or 3, is unsubstituted phenyl or phenyl which is monosubstituted or polysubstituted by A, OA, - 33 Hal, CF 3 , OH, NO 2 , hydroxyalkyl, NH 2 , NHA, NA 2 , NHAc, NH-SO 2 -A, SA, SO-A, S0 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, aminoalkyl, HAN-alkyl, A^-alkyl, A 3 N®-alkyl Αηθ and/or guanidinylalkyl, or is unsubstituted naphthyl, Het is a saturated or unsaturated 5- or 6-membered heterocyclic radical having 1-4 N, 0 and/or S atoms, which can be fused to a benzene ring and/or monosubstituted or polysubstituted by A, OA, Hal, CF 3 , OH, N0 2 , carbonyl oxygen, NH 2 , NHA, NA 2 , NHAc, NH-COOA, NHCOOAr, NHCOOCH^Ar, NH-SO 2 -A, SA, SO-A, SO 2 -A, SO 2 NH 2 , SO 2 NHA, COOH, COOA, CONH 2 , CN, Ar, Ar-alkyl, Ar-alkenyl, hydroxyalkyl, aminoalkyl, HAN-alkyl, A 2 N-alkyl and/or A 3 N®-alkyl Αηθ and/or whose N and/or S heteroatoms can also be oxidised, Hal is F, Cl, Br or I, Ac is Α-CO-, Ar-CO-, Ar-alkyl-CO- or A-NH-CO-, Αηθ is an anion, which can also be absent, if instead of this a carboxyl group contained in the compound of the formula I is present 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 in addition instead of one or more -NH-CO groups there can also be one or more -ΝΑ-CO groups, and their salts.

2. a) Methyl 3S-(4-aminopiperidinocarbonyl-Phe-0Alaamino)-4-cyclohexyl-2R-hydroxybutyrate; b) isopropyl 3S-(4-aminopiperidinocarbonyl-Phe-0Alaamino)-4-eyelohexyl-2R-hydroxybutyrate; c) isopropyl 3S-(4-aminopiperidinocarbonyl-PheIsoser-amino)-4-cyclohexyl-2R-hydroxybutyrate.

3. 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 - 34 II X-G 1 -OH in which G 1 (a) is absent, (b) is -W-CR 1 R 2 -CO-, 5 (c) is -W-CR 1 R 2 -CO-Y-, or one of its reactive derivatives is reacted with a compound of the formula III h-g 2 -nh -CHR 3 -CR 4 -COOR 5 III in which G 2 (a) is -W-CR 1 R 2 -CO-Y-, (b) is -Y-, (c) is absent, and in that a functionally modified amino and/or hydroxy group is 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, R* = 0, is reduced or reductively aminated to prepare a compound of the formula I, R* = (H, OH) or (H, NH 2 ) and/or an ester of the formula I, R 5 = A is hydrolysed and/or an acid of the formula I, R 5 = H is esterified and/or a compound of the formula I is converted into one of its salts by treating with an acid.

4. Process for the production of pharmaceutical preparations, characterised in that a compound of the formula I and/or one of its physiologically acceptable salts is brought into a suitable dosage form together with at least one solid, liquid or semi-liquid excipient or auxiliary.

5. Pharmaceutical preparation, characterised in that it contains at least one compound of the formula I and/or one of its physiologically acceptable salts.

6. Use of compounds of the formula I or of their physiologically acceptable salts for the production of a medicament. - 33

7. Use of compounds of the formula I or of their physiologically acceptable salts in the control of renindependent hypertension or hyperaldosteronism.

8. An amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.

9. A process for the preparation of an amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, substantially as hereinbefore described and exemplified.

10. An amino acid derivative of the formula I given and defined in Claim 1 or a salt thereof, whenever prepared by a process claimed in Claim 3 or 9.

11. A pharmaceutical preparation according to Claim 5, substantially as hereinbefore described and exemplified.

12. Use according to Claim 6, substantially as hereinbefore described and exemplified.

13. Use according to Claim 7, substantially as hereinbefore described.