AU616072B2 - Renin-inhibiting dipeptides, a process for the preparation thereof, agents containing these, and the use thereof - Google Patents

Description

-MEOW-,

COMMONWEALTH OF AUSTRALIA 1 For PATENTS ACT 1952-69 1 6 0 7~i~ COMPLETE

SPECIFICATION

(ORIGINAL)

Class I t. Class Application Number: Lodged: *Complete Specification Lodged:

S.

S

5e Accepted: Published: *Priority: Related Art see Name of Applicant: Address of Applicant Artual Inventor: Address for Service HOECHST AKTIENGESELLSCHAFT 50 Bruningstrasse, D-6230 Frankfurt/Main of Germany 80, Federal Republic WOLFGANG RUGER, HANSJORG URBACH, DIETER RUPPERT, BERNWARD SCHOLKENS AHM M A faemr Patent Trademark Attorneys 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: RENIN-INHIBITING DIPEPTIDES, A PROCESS FOR THE PREPARATION THEREOF, AGENTS CONTAINING THESE, AND THE USE THEREOF The following statement is a full description of this invention, including the best method of performing it known to -r 14 in which A, B, D, E, X, Y and Rz have the same

J

HOECHST AKTIENGESELLSCHAFT HOE 88/F 324 Dr.WI/PP Description Renin-inhibiting dipeptides, a process for the preparation thereof, agents containing these, and the use thereof EP-A 172,346, EP-A 172,347, EP-A 189,203, EP-A 229,667, EP-A 230,266, EP-A 255,082, EP-A 273,893 and EP-A 274,259 disclose dipeptide derivatives and the use thereof as renin inhibitors.

New dipeptide derivatives which, surprisingly, despite the absence of a structural element which has hitherto been regarded as essential, highly effectively inhibit the enzyme renin in vitro and in vivo have been found.

The invention relates to compounds of the formula I RIS R 2 1 i 1 -N R -N-C-A-B-NH-CH-D-E-X-Y 15 0 f: 20 in which

R

1 denotes, indepedently of one another, hydrogen, (C 1

C

10 )-alkyl which is optionally singly or doubly unsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C)-alkoxy, (Ci-C 7 alkanoyloxy, carboxyl, (Cl-C) -alkoxycarbonyl, Cl, Br, amino, (C 1 -alkylamino, di-(C 1

-C

7 )-alkylamino,

(C

1 -Cs)-alkoxycarbonylamino, (C,-C 1 5 )-aralkoxycarbonylamino and 9-fluorenylmethyloxycarbonylamino, or (C 3 -cycloalkyl, (C 3

-C

8 )-cycloalkyl-(Ci-C 6 alkyl, (C 6

-C

14 )-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C 1

C

7 )-alkoxy, (C 1

-C

7 -alkyl, (C 1

-C

7 )-alkoxycarbonyl, amino, anilino which is optionally substituted by up

I

4t %cI

I

Ur .d ,1~ i, 3 lil(- I) 11~ii 15 ~1 1.

2 to 2 halogens, and trifluoromethyl; (C 6

-C

14 )-aryl- (Cl-C,)-alkyl in which the aryl moiety is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C 1

-C

7 )-alkoxy, (Cl-C 7 )-alkyl, (Cl-C 7 alkoxycarbonyl, amino, (C1-C 7 )-alkylamino, di-(Cl-

C

7 )-alkylamino, carboxyl, carboxymethoxy, amino-

(C

1

-C

7 -alkyl, (C 1

-C

7 -alkylamino- (C 1

-C

7 -alkyl, di-(Cl-C 7 -alkylamino-(C 1

-C

7 -alkyl, (Cl-C 7 -alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cl-C 7 alkoxysulfonyl, sulfo- and guanidinomethyl, or represents the radical of a 3- to 8-membered mono- .:cyclic or 7- to 13-membered bicyclic heterocycle which has at least one carbon atom, 1-4 nitrogen 15 atoms and/or 1 sulfur or oxygen atom as ring members and is optionally substituted by one, two or three identical or different radicals from the series *00* comprising F, Cl, Br, hydroxyl, (Cl-C 7 )-alkoxy, (Cl-

C

7 )-alkyl, (Cl-C 7 )-alkoxycarbonyl, amino or trifluoromethyl., or forms, together with the adjacent nitrogen atom and R1, a 3- to 8-membered monocycle ~or a 7- to 13-membered bicycle which has at least 1 carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can option- .25 ally be substituted by one, two or three identical .00.0.

or different radicals from the series comprising (Cl-C)-alkyl, hydroxyl, hydroxy-(Cl-C 6 -alkyl, (Cl- C,)-alkoxy, (Cl-C 6 -alkoxy-(Cl-C) -alkyl, carboxyl, carboxy- C-C) -alkyl, Ci-C) -alkoxycarbonyl, (C 1 -alkoxycarbonyl- -alkyl, halogen, amino, amino- (Cl-C) (C-C 6 )-alkylamino-alkyl, (C 1 -C)-alkyl, di- -alkylamino or di- (C 1

-C

6 -alkylamino- (C 1

C

6 -alkyl; A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of a natural or unnatural amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspartic acid, p-2-thienylalanine, p-3-thienylalanine, p- 16 -16- Synthesis, Biology (Academic Press, New York 1979). The -3- 2-furylalanine, 6-3-furylalanirie, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chiorophenylalanine, methionine sulfone, methionine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexyiglycine, im-methylhistidine, 0-methyltyrosine, O.-benzyltyrosine, 0tert butyltyrosine, phenyiglycine, 1-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, f-2-benzo[b]thienylalanile, p3 benzo[b]thienylalanine, 2-f luorophenylalanine, 3fluorophenylalanine, 4-f luorophenylalanine, norleucine, cysteine, S-methyl-cysteine, 1,2,3,4- :otetrahydroisoquinoline-3-carboxylic acid, homophenylalanine, DOPA, 0-dimethyldopa, 2-amino-3- (2i 5 thienyl)-butyric acid, benzodioxol-5-ylalanine, Nmethyl-histidine, 2-amino--4- (3-thienyl) butyric acid, 3- (2-thienyl) -serine, (Z )-dehydrophenylalanine, dehydrophenylalanine, 3-dioxolan-2-yl) alanine, Npyrrolylalanine, 3- or 4-pyrazolyl)alanine, (4thiazolyl)alanine, 4- or cyclopentyiglycine, tert.-butyiglycine or phenylserine, it being possible for each amino group optionally to be substituted by (Cl-C,)alkyl, formyl, -alkoxycarbonyl or benzyloxycarbonyl; 9:69:25 B denotes a radical, which is linked N-terminal with A and C-terminal with -NH-CH-R 2 1 of a natural or unnatural amino acid as defined for A, it being ***possible for the amino group optionally to be substituted as described under A; R denotes hydrogen, (CI-Cl 0 )-alkyl, (C.-C 7 )-cycloalkyl,

(C

4

-C

7 -cycloalkyl- (C 1

-C

4 -alkyl, (C,-C 1 4 -aryl, (C6-

C

14 -aryl- (C 1

-C

4 -alkyl or heterocyclyl- C 1

-C

4 -alkyl, the heterocycle containing 4 7 ring members, of which 1 or 2 are sulfur and/or oxygen atoms;T D denotes a group from the series comprising -CH- C_ -CHSO or

OR

3 hH-R 4 62

C

2

-NW-

-17 Compounds of the general formula IV can be prepared in a -4in which

R

3 denotes hydrogen; (CI-Cl.) -alkyl; (C 1

-C

6 -alkancyl; (CrCq) -cyc loalkanoyl; phenyl, phenyl -(Cl-CA) -alkyl or benzoyl, each of which is optionally substituted in the aromatic moiety by one, two or three radicals from the group comprising (C 1

-C

4 )-alkyl, (C1-C4) alkoxy, Cl, F, Br, nitro, trifluoromethyl or one inethylenedioxy; (C 1 -Cl 0 -alkylaminothiocarbonyl, (Cl- Cl 0 )-alkylaininocarbonyl, it being possible for each

(C,-C

1 0 )-alkyl radical to be substituted as described under R 1 (Cl-C 6 -alkanoyloxy- (Cl-C 2 -alkyl, alkoxycarbonyloxy- (Cl-C 2 -alkyl or

CH

2

CH

3 3 0 R 4 denotes hydrogen, (Cl-Cr,) -alkanoyl, (C 5

-C

8 )-_cycloalkanoyl, phenylcarbonyl, phenyl-(Cl-C,)-alkanoyl, N-

(C

1

-C

4 -alkyl-l, 4-dihydronicotinoyl, a radical -CH C- *H 0 in which R is the side-chain of a natural amino acid, or (Cl-C 5 ,)-alkoxycarbonyl, (C 5 -C,)-cycloalkyloxycarbonyl, phenoxycarbonyl, (C 1 -alkanoyloxy- (Cl-C 2 -alkoxycarbonyl, phenylcarbonyloxy-c- 2 alkoxycarbonyl, (Cl-Cr,) -alkanoyloxy- -alkyl, phenylcarbonyloxy- (Cl-C 2 -alkyl, (C 1

-C

6 -alkanoylaininomethyl, phenylcarbonylaminomethyl or an optionally substituted acrylic acid derivative which is linked via the 3 position, it being possible in all the radicals R 4 which contain phenyl for this phenyl radical optionally to be substituted by one, two or three radicals from the group comprising (C 1

-C

4 alkyl, (Cl-C 4 )-alkoxy, Cl, Br, F, nitro, trifluoromethyl or one methylenedioxy, x denotes 0, 1 or 2, -181- The compounds of the formula I according to the invention

I

and E is absent or denotes a group from the series comprising -(CH2)1- -CHF-, -CF 2 CE- -CE -CH-,

-(CE)

1 3

-,OR

3

OR

3

~CE

2 S~ y' .C CH 2 CH_ -CH Cin which

*R

3 is as defined above,

*R

5 denotes the side-chain of a natural amino acid, hydroxy- (C,-C 6 -alkyl, (C 1

-C

6 -alkoxy or (C 2 alkenyloxy, R5 is hydrogen or -alkyl, y denotes 0, 1 or 2, is absent or denotes a group from the series comprising S S S. S S S OS 0

S

S..

*SSS

SS

S

and x

*SS*

S

S. S 5* S S 5* -ct, (C 2 1 4

-NH-C-

0 V 0 and 15 Y denotes hydrogen, fluorine, (C 1 -C,)-alkyl, (C 5 cycloalkyl, -alkoxy, (C 5 -cycloalkoxyr, amnino, (C 1

-C

6 -alkylamino, di- (Cl-C 6 -alkylamino,

C

14 -aryl, 4 -aryl- (C 1

-C

6 -alkyl, it being possible for each aryl radical to be unsubstituted or mono-, di- or trisubstituted as def ined above under R 3 hydroxyl, azido, azido-(Cl-Cr,) -alkyl, (C 1 -alkylthio, (Cl-C 6 -alkylsul fonyl, -cyc loalkyithic, (C 5 -C8) -cycloalkylsulfonyl, heterocyclyl or heterocyclyl- (C 1

-C

6 -alkyl, each heterocycle being a 3- to 8-membered monocycle or a 7- to 13-membered bicycle having at least one carbon atom and one to -vi -4 19

S,

as well as the physiologically tolerated salts thereof.

The centers of chirality in the compounds of the formula I may have the R or S or R,S configuration.

AlKyl can be straight-chain or branched. A corresponding statement applies to radicals derived therefrom such as, for example, alkoxy, alkylthio, alkylamino, dialkylamino, alkanoyl and aralkyl.

Cycloalkyl also means alkyl-substituted radicals such as, for example, 4-methylcyclohexyl or 2,3-dimethylcyclopentyl.

(C

6

-C

14 )-aryl is, for example, phenyl, naphthyl, biphenylyl or fluorenyl; phenyl is preferred. A corresponding 15 statement applies to radicals derived therefrom such as, for example, aryloxy, aroyl, aralkyl and aralkyloxy.

Aralkyl means an unsubstituted or substituted (C 6

-C

14 aryl radical which is linked to (Cl-C)-alkyl, such as, for example, benzyl, a- and p-naphthylmethyl, halobenzyl 20 and alkoxybenzyl, but with aralkyl not being restricted to the said radicals.

A radical of a 3- to 8-membered monocyclic or 7- to 13membered bicyclic heterocycle having at least one carbon atom, 1-4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members means radicals of heteroaromatics as defined, for example, in Katritzky, Lagowski, Chemistry of Heterocycles, Berlin, Heidelberg 1968, pages 3 5, as well as the partially or completely hydrogenated derivatives thereof. The heteroaromatic radical can be substituted by one, two or three, preferably one or two, identical or different radicals from the series comprising F, Cl, Br, hydoxyl, (Ci-C 7 )-alkoxy, (Ci-C)-alkyl, (Ci-

C

7 )-alkoxycarbonyl, amino or trifluoromethyl. Examples of monocyclic heteroaromatics are thiophene, furan, pyrrole, 20 n A Ot

I

-7 imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, 1,2,4-triazole, thiazole, tetrazole, isothiazole, oxazole and isoazole. Examples of bicyclic heteroaromatics are benzothiophene, benzofuran, indole, isoindole, indazole, benzimidazole, quinoline, isoquinoline, phthalazine, quinoxaline, quinazoline and cinnoline. A corresponding statement applies to the radicals derived from heteroaryl, such as, for example, completely or partially hydrogenated heteroaryl, heteroaryloxy, heteroaryl and heteroaryl-alkyl.

The amino acids A and B in formula I are linked together by an amide linkage and they are natural or unnatural aamino acids of the L or D or D,L configuration, preferably of the L configuration.

15 Salts of compounds of the formula I mean, in particular, pharmaceutically utilizable or non-toxic salts.

S**

Salts of these types are formed, for example, from compounds of the formula I which contain acidic groups, for example carboxyl, with alkali metals or alkaline earth metals such as Na, K, Mg and Ca, as well as with physiologically tolerated organic amines such as, for example, triethylamine and tri-(2-hydroxyethyl)-amine.

Compounds of the formula I which contain basic groups, for example an amino group or a guanidino group, form 25 salts with inorganic acids such as, for example, hydrochloric acid, sulfuric acid or phosphoric acid and with organic carboxylic or sulfonic acids such as, for example, acetic acid, citric acid, benzoic acid, maleic acid, fumaric acid, tartaric acid and p-toluenesulfonic acid.

Preferred compounds of the formula I are those in which

R

i denotes, independently of one another, hydrogen, (Ci-C 10 )-alkyl which is optionally substituted by up to three identical or different radicals from the

FI

i i:: i e i: ?i i 21 I/ml x hour. PRA values in the presence of the test -8series comprising hydroxyl, (Cl-C 4 )-alkoxy, (Cl-C 4 alkanoyloxy, carboxyl, (Cl-C 4 -alkoxycarbonyl, Cl, Br, amino, (Cl-CO)-alkylamino, di-(Cl-C 4 -alkylamino or (Cl-C 4 -al1koxyc arbonyl amino, or (C 5

-C

7 -cycloalkyl,

(C

6

-C

14 )-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (C 1

-C

4 alkoxy, (Cl-C 4 -alkyl, (Cl-C 4 -alkoxycarbonyl, amino and trif luoromethyl, or (C 6

-C

1 4 -aryl- (C 1

-C

6 -alkyl in which the aryl moiety is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl-C 4 alkoxy, (Cl-C 4 )-alkyl, (Cl-C 4 )-alkoxycarbonyl, amino, (C -C 4 -alkyl amino, di-(Cl-C 4 )-alkylamino, carboxyl, carboxymethoxy, amino- (C 1

-C

4 -alkyl, (Cl-C 4 -alkylamino- (C 1

-C

4 -alkyl, di- (C 1

-C

4 -alkyl amino- (C 1

-C

4 alkyl, (C 1

-C

4 -alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cl-C 4 )-alkoxysulfonyl, sulfo- and guanidinomethyl, or represents the radical of a 3- to 8membered monocyclic or 7- to 13-membered bicyclic heterocycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as o a ring members and which is optionally substituted by a ea one, two or three identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl- CO C-alkoxy, (C 1 -CJ) -alkyl, (C 1

-C

4 -alkoxycarbonyl, amino or trifluoromethyl, or forms, together with the adjacent nitrogen atom and R1, a 3- to 8-membered a monocycle or a 7- to 13-membered bicycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can optionally be substituted by one, two or three identical or different radicals from the series comprising (Cl-C 6 ,)-alkyl, hydroxyl, hydroxy- (Cl-C 5 -alkyl, (Cl-C 6 -alkoxy, (C 1 -alkoxy- (C 1 alkyl, carboxyl, carboxy- (Cl-C) -alkyl, (C 1

-C

6 alkoxycarbonyl, (C 1

-C

6 -alkoxycarbonyl- (Cl-C 6 -alkyl, halogen, amino, amino- (C 1

-C

6 -alkyl, (Cl-C) -alkylamino- (C 1 -alkyl, di- -alkylamino or -22 denal use is possible. The dosage of the active substance -9di- (C 1

-C

6 -alkylamino- (C,-C 6 -alkyl; A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of a natural. or unnatural amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, fi- 2-thienylalanine, p-3-thienylalanine, p-2-furylalanine, p-3-furylalanine, 4-chlorophenylalanine, 2pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methyihistidine, 0-methyltyrosine, O-benzyltyrosine, 0- tert. -butyl tyro sine, phenylglycine, l-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, 2-f luorophenylalanine, 3fluorophenylalanine, 4-f luorophenylalanine, homoa :6 phenylalanine, DOPA, 0-diinethyldopa, 2-axnino-4- (2acd, benzodioxol-5-ylalanine, Nmethyl-histidine, 2-amino-/4- 3-thienyl)butyric acid, 3- (2-thienyl)-serine, (Z )-dehydrophenylalanine or 0 Vil(E) -dehydrophenylalanine; B denotes a radical, which is linked N-terminal with 2 A and C-terminal with -NH-CH-R of a natural or unnatural amino acid from the series comprising o 06 phenylalanine, histidine, tyrosine, tryptophan, *o:o methionine, leucine, isoleucine, asparagine, aspartic acid, p-2-thienylalanine, p-3-thienylalanine, piase~:252-furylalanine, ,-3-furylalanine, lysine, ornithine, 0 valine, alanine, 2,4-diaminobutyric acid, arginine, 0 4-chlorophenylalanine, inethionine sulfone, methio- 00 nine sulf oxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methyl- 30 histidine, 0-methyltyrosine, 0-benzyltyrosine, 0tert. -butyltyrosine, phenylglycine, l-naphthylalanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, ,-2-benzo[b]thienylalanine, benzo[b]thienylalanine, 2-f luorophenylalanine, 3fluorophenylalanine, 4-f luorophenylalanine, norleucine, cysteine, S-methyl-cysteine, 1,2,3,4tetrahydroisoquinoline-3-carboxylic acid, homov phenylalanine, DOPA, 0-dimethyldopa, -23 DNP DP 2, 4-dinitrophenyl 2 -amino- 4 -thienyl) -butyric acid, ylalanine, N-methyl-histidine, 2-amino-4- (3-thienyl) -butyric acid, 2-thienyl) -serine, dehydrophenylalanine, -dehydrophenylalanine, (1,3-dioxolan-2-yl )alanine, N-pyrrolylalanine, 3- or 4-pyrazolyl)alanine, (4-thiazolyl)alanine, 4- or 5-pyrimidyl)alanine, cyclopentyiglycine, tert. -butyiglycine or phenylserine, R2 denotes hydrogen, (Cl-C 1 0 )-alkyl, (C 4

-C

7 )-cycloalkyl,

(C

4

-C

7 -cycloalkyl- (Cl-C 4 -alkyl, (C 6

-C

14 -aryl, (C6- C1 4 -aryl- (C 1

-C

4 -alkyl or heterocyclyl- (C 1

C

4 -alkyl, the heterocycle having 4 7 ring members, of which 1 or 2 are sulfur and/or oxygen atoms, and D denotes a group from the series comprising -CH- C- /-CH 2 ~O~o .2OR 3 NH- R 4 0 2 6 0 0in which goe R 3 denotes hydrogen, R 4 denotes hydrogen, x denotes 0, 1 or 2, 0 and 00 0 E is absent or denotes a group from the series *0 0 *0comprising 0-(CH 2 1 -CHF-, C-, 2)13- 2, CH -CH 2

-CH-,

:%OR

3

OR

3

~CH

2 SO~ I C- ,-C 2 -CH- ,-CH=C-

R

5 in which

R

3 is hydrogen, R denotes the side-chain of a natural amino acid, hydroxy- (Cl-C 6 -alkyl, (Cl-C 5 -alkoxy or 24 11

(C

2

-C

6 -alkenyloxy,

R

6 is hydrogen or (C 1

-C

6 )-alkyl, Y denotes 0, 1 or 2, and X is absent or denotes a group from the series comprising

-NH--

0 0 and Y denotes hydrogen, fluorine, (C 1

-C

6 )-alkyl, (C 5 -Cs)cycloalkyl, C-C) -alkoxy, (C 5

-C

8 -cycloalkoxy, amino, C-C 5 -alkylamino, di- C-C 6 -alkylamino, (C 6

C

14 )-aryl, (C 1

-C

6 )-alkyl, it being possible for each aryl radical to be unsubstituted or mono-, di- or S. trisubstituted as defined above under R 3 or hydrox- S• yl, azido, azido-(Ci-C) -alkyl, (Ci-C 6 )-alkylthio, 15 (Ci-C 6 )-alkylsulfonyl, (C 5 -Cs)-cycloalkylthio, (Cs-C)cycloalkylsulfonyl, heterocyclyl or heterocyclyl- (Ci-C) -alkyl, each heterocycle being a 3- to 8membered monocycle or a 7- to 13-membered bicycle having e.t least one carbon atom and one to six heteroatoms from the series comprising O, N or S, as well as the physiologically tolerated salts thereof.

Particularly preferred compounds of the formula I are those in which R denotes, independently of one another, hydrogen, (Ci-C 10 )-alkyl which is optionally substituted by up to three identical or different radicals from the series comprising hydroxyl, carboxyl, amino, (CI-C)alkylamino, di-(Ci-C 4 )-alkylamino or (Ci-C 4 )-alkoxy- i carbonylamino, or phenyl which is optionally substituted by one or two radicals from the series comprising F, Cl, hydroxyl, amino or trifluoromethyl, or phenyl-(Ci-C 4 )-alkyl, in which the phenyl moiety is optionally substituted by one or two identical or different radicals from the series 25 the ice bath for 1 hour and at room temnerni-nm= fin -7 -12comprising F, Cl, hydroxyl, amino, (Cl-C 4 -alkyl- Fmaino, di- (C 1

-C

4 -alkylamino, carboxyl, amino- (Cl-

C

4 -alkyl, (C 1

-C

4 -alkylamino- (C 1

-C

4 -alkyl, di- (Cl-

C

4 -alkylamino- (Cl-C 4 -alkyl, or f orms, together with the adjacent nitrogen atom and R 1 a 3- to 8-membered monocycle or a 7- to 13-membered bicycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can optionally be substituted by one, two or three identical or different radicals from the series comprising (C 1

-C

6 )-alkyl, hydroxyl, hydroxy- -alkyl, (C 1 -alkoxy- (C 1

-C

6 -alkyl, carboxyl, carboxy-(C-C 6 -alkyl, (Cl-C 6 -alkoxycarbonyl, (Cl-

C

6 -alkoxycarbonyl- -alkyl, halogen, amino, amino- (Cl-C 6 -alkyl, (C 1

-C

6 -alkylamino- C 1

-C

6 -alkyl, di- (Cl-Cr 6 -alkyl amino or di- (C 1

-C

6 -alkyl amino (C-

C

6 -alkyl, A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of an amino acid from the series comprising phenylalanine, tyrosine, fi-2thienylalanine, p-3-thienylalanine, 4-chlorophenylalanine, 0-methyltyrosine, l-naphthylalanine, 2fluorophenylalanine, 3-f luorophenylalanine or 4fluorophenylalanine, B denotes a radical, which is linked N-terminal with A and C-terminal with -NH-CHR of an amino acid from the series comprising phenylalanine, histidine, leucine, P-2-thienylalanine, p-3-thienylalanine, $:too:lysine, norvaline, 2-f luorophenylalanine, 3-f luorophenylalanine, 4-f luorophenylalanine, norleucine, Smethylcysteine, (l,3-dioxolan-2-yl)alanine, 3- 4-pyrazolyl)alanine, 4-thiazolylalanine or 4- or 2 R denotes isobutyl, cyclohexylmethyl, benzyl or (1,3dithiolan-2-yl )methyl,L D denotes a group -CH- ,and R 3 is hydrogen,

OR'

E is absent or denotes a group from the series -26-K amount of 4-thw-r -13comprising

-CH

2

-CH-

OR

3

OR

3

R

in which R 3 is hydrogen, and R 5 denotes the side-chain of a natural amino acid, X is absent or denotes the group from the series comprising

-NH-C-

0 0 and denotes hydrogen (Cl-C,)-alkyl, (C, 5 -C,)-cycloalkyl, amn, -alkyl amino, di- (C 1 -alkyl amino, (C 6 14 -aryl, C.-C 14 )-aryl- (C,-C 6 -alkyl, it being possible for each aryl radical to be unsubstituted or mono-, di- or trisubstituted as defined above under R 3 or hydroxyl, azido, (Cl-C 6 )-alkylthio, (Cl-C 6 alkylsulfonyl, (C.

5

-C

6 -cycloalkylthio, C 5 -cyclo- .015 alkylsulfonyl, heterocyclyl or heterocyclyl-(C-C,)cc alkyl, each heterocycle being a 3- to 8-membered monocycle or a 7- to 13-meinbered bicycle having at least one carbon atom and one to six heteroatoms C from the series comprising 0, N or S, as well as the physiologically tolerated salts thereof.

The invention also relates to a process for the preparation of compounds of the general formula I, which comprises a) reacting a compound of the general formula II H-A-BNHrH-DEX-Y -27 coolinq in ice, first 38.6 ml (0.28 moll of absolntp 14 in which A, B, D, E, X, Y and R 2 have the same meaning as in the general formula I (page with an isothiocyanate of the general formula III

RI-N=C=S

in which R 1 has the same meaning as in the general formula I, in a suitable organic solvent such as, for example, benzene, toluene, chlorobenzene, an aliphatic hydrocarbon, an aliphatic chlorinated hydrocarbon, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide or else dispensing with a solvent, in each case as derived with or without the addition of a Lewis acid or of a Lewis base as catalyst, such as, for exam- S. ple, of a tertiary amine, preferably triethylamine, 1,4-diazabicyclo[2.2.2]octane, cyclohexyldimethyl Samine, benzyldimethylamine, 4-methylmorpholine, tetramethylguanidine or 4-dimethylaminopyridine, at a temperature between -80°C and the boiling point of the solvent, preferably between -30 0 C and where appropriate providing sensitive functional groups such as hydroxyl or amino groups with a protective group beforehand, and removing this protective group again at the end, or b) coupling a compound of the general formula IV with 25 a free carboxyl group

R

1

S

ooo 1 I\ R1-N-C-A-OH in which R 1 and A have the same meaning as in formula I, or a reactive derivative thereof, with the corresponding fragment with a free amino group of the general formula V i 28- 3S-hexanol 15 j 15

R

I

H-B-NH-CH-D-E-X-Y

in which B, D, E, X, Y and R 2 have the same meaning as in formula I, and, where appropriate, eliminating protective group(s) temporarily introduced to protect other functional groups, or c) coupling a compound of the general formula VI with a free carboxyl group R1S

RI-N-C-A-B-OH

*O 0 in which R 1 A and B have the same meaning as in formula I, or a reactive derivative thereof, with So othe corresponding fragment with a free amino group 10 of the general formula VII R2 2

N-CH-D-E-X-Y

in which R 2 D, E, X and Y have the same meaning as in formula I, and, where appropriate, eliminating protective group(s) temporarily introduced to protect other functional groups, and converting the compound obtained in this way into its physiologi- 10 cally tolerated salt.

Methods suitable in process variants b) and c) for the production of an amide linkage are described, for example, in Houben-Weyl, Methoden der organischen Chemie (Methods of Organic Chemistry) Volume 1/2; Bodanszky et al., Peptide Synthesis, 2nd ed. (Wiley Sons, New York 1976) or Gross, Meienhofer, The Peptides: Analysis, 1 y_ 1

:A

29

I:

*I .1 16 Synthesis, Biology (Academic Press, New York 1979). The following methods are preferably employed: the active ester method with N-hydroxy-succinimide as ester component, coupling with a carbodiimide such as dicyclohexylcarbodiimide or with propanephosphonic anhydride and the mixed anhydride method with pivaloyl chloride.

The preceding and following operations necessary for the preparation of compounds of the formula I, such as the introduction and elimination of protective groups, are known from the literature and are described, for example, in T.W. Greene, "Protective Groups in Organic Synthesis".

Salts of compounds of the formula I with salt-forming groups are prepared in a manner known per se, by, for example, reacting a compound of the formula I with a basic group with a stoichiometric amount of a suitable acid. Mixtures of stereoisomers, in particular mixtures of diastereomers, which result when racemic acids A or B are used can be separated in a manner known per se by fractional crystallization or by chromatography.

20 Compounds of the general formula II are obtained from compounds of the general formula VIII

R

2 PG-A-B-NH-CH-D-E-X-Y (VIII) in which A, B, D, E, X, Y and R 2 have the same meaning as in formula I, and PG denotes an amino-protective group such as, for example, a tert.-butyloxycarbonyl or a benzyloxycarbonyl protective group, by elimination of this protective group under the customary conditions, for example by acid hydrolysis or by hydrogenolysis.

The isothiocyanates of the general formula III are known from the literature or can be obtained from precursors, which can be bought, in a manner analogous to that for the compounds known from the literature.

i

A!

1 17 Compounds of the general formula IV can be prepared in a manner known from the literature from the isothiocyanates of the general formula III and the amino acids H-A-OH in free or OH-protected form.

Compounds of the general formula V are obtained by coupling of compounds of the formula VII with protected amino acid derivatives PG-B-OH, in which PG has the same meaning as in formula VIII, and B has the same meaning as in formula I, under conditions as are described under process variant followed by elimination of the protective group PG.

Compounds of the general formula VI can be obtained by reaction of dipeptides H-A-B-OH in free or OH-protected form with isothiocyanates of the general formula III or by coupling of compounds of the general formula IV with amino acids H-B-OH, where appropriate in OH-protected I form, followed by elimination of the protective group which is used where appropriate.

Compounds of the general formula VII are the so-called central building blocks of previously disclosed renin inhibitors whose preparation varies widely depending on the definition of the radicals R 2 D, E, X and Y and is described in numerous patent applications and publications. The following may be mentioned here by way of example and as representatives of other citations: EP 255,082, EP 230,266, EP 229,667, EP 258,183, German Offenlegungsschrift 3,729,729; J. Chem. Soc. Perkin Trans. I 1987, 1177, J. Med. Chem. 30 1617 (1987); J.

Org. Chem. 53 869 (1988); etc.

Compounds of the general formula VIII can be obtained by coupling of protected amino acid derivatives PG-A-OH onto compounds of the general formula V or by coupling of protected dipeptides PG-A-B-OH onto compounds of the general formula VII.

m/ ;r rr e~abi,,~ liN' 30 -1 18 The compounds of the formula I according to the invention exhibit enzyme-inhibiting properties; in particular, they inhibit the action of the natural enzyme renin. This is surprising and unexpected inasmuch as all known renin inhibitors (for a recent review, see, for example, W.

Greenelee, Pharmac. Res. 4, 364 (1987)) carry a carbonyl group or a sulfone group at the P 4 position that position of the renin inhibitor which is equivalent to the -CS- functionality in the compounds of the formula Hence, they have in this position an oxygen atom which can function as a hydrogen-bonding acceptor and is potentially of great importance for the interaction with the enzyme. It is therefore surprising that replacement of the oxygen by a sulfur atom, with its larger volume and its lower tendency to form hydrogen bonds, likewise results in highly effective renin inhibitors which even S exceed the action of the oxygen-analogous compounds.

go 0 Renin is a proteolytic enzyme from the class of aspartyl proteases which is secreted as a consequence of various stimuli (volume depletion, sodium deficiency, p-receptor stimulation) from the juxtaglomerular cells of the kidney into the blood circulation. There it eliminates the decapeptide angiotensin I from the angiotensinogen which is secreted by the liver. This decapeptide is converted 25 by angiotensin converting enzyme (ACE) into angiotensin II. Angiotensin II plays an essential part in the regulation of blood pressure, because it raises the blood pressure directly by vasoconstriction. In addition, it stimulates the secretion of aldosterone from the adrenal 30 and, in this way, via inhibition of sodium excretion, ooo increases the extracellular fluid volume, which in turn contributes to raising the blood pressure. Inhibitors of the enzymatic activity of renin bring about a reduced formation of angiotensin I, the consequence of which is a reduced formation of angiotensin II. The lowering of the concentration of this active peptide hormone is the direct cause of the action of renin inhibitors to lower blood pressure.

,31 S31I A- -J -1 19 The activity of renin inhibitors can be examined by in vitro tests. These entail measurement of the reduction in the formation of angiotensin I in various systems (human plasma, purified human renin).

1. Principle of the test For example human plasma which contains both renin and angiotensinogen is incubated at 37°C with the compound to be tested. During this, angiotensini I is liberated from angiotensinogen under the action of renin and can subsequently be measured with a commercially available radioimmunoassay. This angiotensin liberation is inhibited by renin inhibitors.

2. Obtaining the plasma The blood is obtained from volunteer subjects (about 0.5 1 per person; Bluko sampler supplied by ASID Bonz und Sohn, Unterschleissheim) and collected in partially evacuated bottles while cooling in ice. Coagulation is prevented by addition of EDTA (final concentration mM). After centrifugation (HS 4 (Sorvall) rotor, 3500 rpm, 0-4°C, 15 min; repeat if necessary) the plasma is o. cautiously removed by a pipette and frozen in suitable portions at -30 0 C. Only plasmas with sufficiently high renin activity are used for the test. Plasmas with a low renin activity are activated by a cold treatment (-4 0 C, 3 25 days) (prorenin renin).

3. Test procedure Angiotensin I is determined using the Renin-Maia) kit (Serono Diagnostics Coinsins, Switzerland). The plasma is incubated in accordance with the instructions given therein: Incubation mixture: 1000 pl of plasma (thawed at 4i 32 1.

20 0-4 0

C)

100 pl of phosphate buffer (pH 7.4) (Addition of 10 4 M ramiprilate) pl of PMSF solution pl of 0.1 Genapol PFIC 12 pl of DMSO or test product The test products are generally made into a 10- 2 M solution in 100 dimethyl sulfoxide (DMSO) and diluted appropriately with DMSO; the incubation mixture contains a maximum of 1 DMSO.

The mixtures are mixed in ice and, for the incubation, S placed in a water bath (37 0 C) for 1 hour. A total of 6 5 samles (100 pl each) are taken from an additional mixture without inhibitor and without further incubation for determination of the initial angiotensin I content of the plasma used.

The concentrations of the test products are chosen such that the range of 10-90 enzyme inhibition is approximately covered (at least five concentrations). At the end of the incubation time, three 100 pl samples from each mixture are frozen in precooled Eppendorf tubes on dry ice and stored at about -25°C for the angiotensin I determination (mean from three separate samples).

Angiotensin I radioimmunoassay (RIA) i The instructions for use of the RIA kit (Renin-MaiaR kit, Serono Diagnostics Coinsins, Switzerland) are followed exactly.

The calibration plot covers the range from 0.2 to 25.0 nm of angiotensin I per ml. The basal angiotensin I content of the plasma is subtracted from all the measurements.

The plasma renin activity (PRA) is reported as ng of ang ii 33 -CH2 CH3 I~_il _ii_ Ii~ II 21 I/mi x hour. PRA values in the presence of the test substances are related to a mixture without inhibitor 100 and reported as activity remaining. The IC 50 value is read off from the plot of activity remaining against the concentration of the test product (logarithmic scale).

The compounds of the general formula I described in the present invention show inhibitory actions at concentrations of about 10 5 to 10-10 mol/l in the in vitro test.

Renin inhibitors bring about a lowering of blood pressure in salt-depleted animals. Because human renin differs from the renin of other species, primates such as, for example, Rhesus monkeys are employed in the in vivo test of renin inhibitors. Primate renin and human renin have 15 substantially homologous sequences. Endogenous renin release is stimulated by injection of furosemide.

The test compounds are subsequently administered by continuous infusion, and their action on the blood pressure and heart rate is measured. The compounds of the 20 present invention are active in this test in a dose range of about 0.1-5 mg/kg and on intraduodenal administration by gastroscope in the dose range of about 1-50 mg/kg. The compounds of the general formula I described in the present invention can be used as antihypertensives 25 and for the treatment of cardiac insufficiency.

0 The invention therefore also relates to the use of compounds of the formula I as medicines and pharmaceutical products which contain these compounds. Use in primates, especially in humans, is preferred.

Pharmaceutical products contain an affective amount of the active substance of the formula I together with an inorganic or organic excipient which can be used in pharmacy.

Intranasal, intravenous, subcutaneous, oral or intraduo- 34 34 1 I1 22 denal use is possible. The dosage of the active substance depends on the warm-blooded species, the body weight, age and the mode of administration.

The pharmaceutical products of the present invention are prepared in dissolving, mixing, granulating or coating processes known per se.

For the form for oral use, the active compounds are mixed with the additives customary for this purpose, such as excipients, stabilizers or inert diluents, and converted by customary methods into suitable dosage forms such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspension or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, 15 potassium phosphate, lactose, glucose, magnesium stearyl fumarate or starch, especially corn starch. This prepar- *ation can be carried out both as dry and wet granules.

Examples of suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil and fish liver oil.

25 Sr

S

55.5

S

0e..~ For subcutaneous or intravenous administration, the active compounds, or the physiologically tolerated salts thereof, are converted into solutions, suspension or emulsions, if desired with the substances customary for this purpose, such as solubilizers, emulsifiers or other auxiliaries. Examples of suitable solvents are: water, physiological sodium chloride solutions or alcohols, for example ethanol, propanediol or glycerol, as well as sugar solutions such as glucose or mannitol solutions, or as a mixture of the various solvents mentioned.

List of abbreviations used: i' i: ir 6.

2.

i i

E-I

AcOH Boc

DCI

acetic acid tert.-butoxycarbonyl desorption chemical ionization

V

i- 35 I 23

DNP

DMF

El

FAB

M

MeOH

MPLC

MS

R.T.

m.p.

2,4-dinitrophenyl dimethylformamide electron impact fast atom bombardment molecular peak methanol medium-pressure colum chromatography mass spectrum room temperature melting point The other abbreviations used for amino acids correspond to the three-letter code customary in peptide chemistry, as is described, for example, in Eur. J. Biochem. 138, 9- 37 (1984). Unless expressly indicated otherwise, the 15 amino acids are always in the L configuration.

S.

The examples which follow serve to illustrate the present invention without restricting it thereto.

06•e Example 1: l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.butylamino-thiocarbonyl-Phe-His)-amino]-3S-hexanol

SB«

la) H-His(DNP)-OH 4 ml of HC1-saturated dimethoxyethane are added dropwise at 0-5 0 C to a solution of 0.42 g (1 mmol) of Boc-His(DNP)- OH in 5 ml of dimethoxyethane, and the mixture is stirred 25 at 0-5 0 C for 1 hour and at room temperature for 3 hours.

*1* The reaction solution is concentrated in vacuo and evaporated twice more with toluene. Yield: g of the title compound as hydrochloride.

RF (Methylene chloride/MeOH/AcOH/water 70:30:1:1) 0.16.

Ib) Boc-Phe-His(DNP)-OH li 'c: i- 1 1: /r r

I

36 24 0.362 g (1 mmol) of Boc-Phe hydroxysuccinimide ester dissolved in 5 ml of ethanol and 5 ml of THF is added at room temperature to 0.5 g (1 mmol) of H-His(DNP)-OH hydrochloride in 12.5 ml of 0.25 N sodium bicarbonate solution. The reaction mixture is stirred at room temperature for three days. Then 0.83 g of citric acid is added, as a result of which the title compound separates out as an oil. The product is extracted with methylene chloride, the organic phase is dried over sodium sulfate and concentrated, a little ethyl acetate is added to the residue, and the title compound is precipitated by addition of diisopropyl ether and filtered off with suction. Yield: 0.47 g (83 Rf (methylene chloride/MeOH 7:3) 0.43; MS (FAB) 569 5 Ic) 2S-Amino-l-cyclohexyl-6-(2-pyridyl)-3S-hexanol 5 ml of HCl-saturated dimethoxyethane are added dropwise to 214 mg (0.513 mmol) of 3-Boc-4S-cyclohexylmethyl-2,2dimethyl-5-(3-(2-pyridyl)-propyl)-oxazolidine in 10 ml of dimethoxyethane in an ice bath, and the mixture is stirred at OOC for one hour and at room temperature for hours. The reaction solution is concentrated in vacuo and evaporated twice more with toluene. Yield: 179 mg of the S" title compound as dihydochloride.

Id) l-Cyclohexyl-6-(2-pyridyl)-2S-N-(Boc-Phe-His(DNP))- 5 amino)-3S-hexanol 1.5 g (3.18 mmol) of 2S-amino-l-cyclohexyl-6-(2-pyridyl)- 3S-hexanol dihydrochloride (Example ic) and 1.8 g (3.18 mmol) of Boc-Phe-His(DNP)-OH (Example Ib) are dissolved in 15 ml of absolute dimethylformamide. To this is added 0.59 g (6.36 mmol) of 1-hydroxybenzotriazole hydrate, and the mixture is cooled to about 4°C in an ice bath. Successively added at this temperature are 2.44 ml (19.1 mmol) of N-ethylmorpholine and 0.65 g (3.18 mmol) of dicyclohexylcarbodiimide, and the mixture is stirred in i i 37 37 A IA R 25 the ice bath for 1 hour and at room temperature for 7 hours. After it has stood overnight, a further 0.9 g (1.59 mmol) of Boc-Phe-His(DNP)-OH, 0.28 g (3.18 mmol) of 1-hydroxybenzotriazole hydrate and 0.32 g (1.58 mmol) of dicyclohexylcarbodiimide are added, and the mixture is stirred at room temperature for a further 10 hours. The precipitate is filtered off with suction, the filtrate is concentrated in vacuo, the residue is dissolved in ethyl acetate, and the solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated, and the crude product (3.8 g) is purified by medium-pressure column chromatography on silica gel (methylene chloride/ MeOH 98:2, 95:5, 1.8 g (68 of the title compound 15 are obtained.

SRf (methylene chloride/MeOH 9:1) 0.46; MS (FAB) 827 S* le) 1-Cyclohexyl-6-(2-pyridyl)-2S-(N-(Phe-His(DNP))amino)-3S-hexanol 2 ml of ice-cold trifluoroacetic acid are poured onto 72 mg of l-cyclohexyl-6-(2-pyridyl)-2S-(N-(Boc-Phe- His(DNP))-amino)-3S-hexanol at 0-5°C, and the mixture is stirred at this temperature for two hours. The reaction solution is concentrated in vacuo and evaporated twice 5 with toluene. Yield: 83 mg of the title compound as the bis(trifluoroacetate).

If) l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert. butylaminothiocarbonyl-Phe-His(DNP)-amino]-3S-hexanol 0.06 ml (0.42 mmol) of triethylamine and 0.061 ml (0.46 mmol) of tert.-butyl isothiocyanate are added to a solution of 88 mg (0.092 mmol) of l-cyclohexyl-6-(2-pyridyl)- 2S-[N-(Phe-His(DNP))-amino]-3S-hexanol (from Example le) in 2 ml of absolute DMF, and the mixture is stirred at room temperature for 5 hours and left to stand over the weekend. It is then stirred at 40 0 C for 1 hour, the same -38- 44 26 amount of tert.-butyl isothiocyanate is again added, and the mixture is stirred at 40 0 C for a further 2 hours and at 60°C for 9 hours. The reaction solution is poured onto ice-water and extracted with ethyl acetate, and the combined extracts are washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated, and the crude product (86 mg) is purified by MPLC on silica gel (methylene chloride/MeOH 95:5, 9:1).

Yield: 39.3 mg (51 of the title compound.

Rf (methylene chloride/MeOH 9:1) 0.39; MS (FAB) 842 Ig) l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.-butylaminothiocarbonyl-Phe-His)-amino]-3S-hexanol "1 5 0.1 ml (1 mmol) of thiophenol is added to 39 mg (0.046 mmol) of l-cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.-butylaminothiocarbonyl-Phe-His(DNP))-amino]-3S-hexanol (from Example If) in 5 ml of acetonitrile, and the mixture is stirred at room temperature for 4 hours. The reaction solution is concentrated in vacuo, and the crude product is purified by MPLC on silica gel (methylene chloride/ MeOH 95:5, 24.3 mg (78 of the title compound are obtained.

Yield: 24.3 mg (78 of the title compound.

25 Rf (methylene chloride/MeOH 9:1) 0.14; MS (FAB) 676 Example 2 l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.-butylaminothiocarbonyl-Phe-Nva)-amino]-3S-hexanol 2a) Boc-Phe-Nva-OMe 15.0 g (0.056 mol) of Boc-Phe-OH and 9.4 g (0.056 mol) of Nva-OMe hydrochloride are dissolved in 250 ml of absolute methylene chloride. To this are added dropwise, while 1.r m 27 cooling in ice, first 38.6 ml (0.28 mol) of absolute triethylamine and then 36.4 ml of propanephosphonic anhydride (50 in methylene chloride). The reaction solution is stirred at room temperature for 3 hours and left to stand overnight. To hydrolyze, it is poured onto ice-water and stirred vigorously for 2 hours, and the organic phase is separated off and washed with 10 strength citric acid solution, saturated sodium bicarbonate solution and water, dried over sodium sulfate and concentrated.

Yield 20.8 g (98 of the title compound.

Rf (methylene chloride/MeOH 9:1) 0.69; MS (DCI) 378 (M+1) 2b) Boc-Phe-Nva-OH .5 20.1 g (0.053 mol) of Boc-Phe-Nva-OMe (Example 2a) are suspended in 30 ml of water and 30 ml of dioxane. 2.5 g (0.106 mol) of lithium hydroxide are introduced at room temperature, and the mixture is stirred at room temperature for 3 hours. The reaction solution is acidified with 10 strength sodium bisulfate solution, and the product is filtered off with suction and stirred with diisopropyl ether.

SYield: 19.1 g (98 MS (DCI) 364 (M+l) 2c) l-Cyclohexyl-6-(2-pyridyl)-2S-(N-(Boc-Phe-Nva)amino)-3S-hexanol 0.8 g of the title compound is obtained from 1.7 g (3.36 mmol) of 2S-amino-l-cyclohexyl-6-(2-pyridyl)-3S-hexanol dihydrochloride (Example Ic) and 1.22 g (3.36 mmol) of Boc-Phe-Nva-OH (Example 2b) in analogy to the process indicated in Example Id).

Rf (methylene chloride/MeOH 9:1) 0.53; MS (FAB) 623 (M+1) 2d) l-Cyclohexyl-6-(2-pyridyl)-2S-(N-(Phe-Nva)-amino)- 40 i -99 I~ 28 3S-hexanol 92 mg of the title compound are obtained as the dihydrochloride from 97 mg of l-cyclohexyl-6-(2-pyridyl)-2S-(N- (Boc-Phe-Nva)-amino)-3S-hexnaol (Example 2c) in analogy to the process indicated in Example Ic).

2e) l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.-butylaminothiocarbonyl-Phe-Nva)-amino]-3S-hexanol 101 mg (0.17 mmol) of l-cyclohexyl-6-(2-pyridyl)-2S-[N- (Phe-Nva)-amino]-3S-hexanol (from Example 2d) are dissolved in 4 ml of absolute dimethylformamide and, at room temperature, 104 pl (0.73 mmol) of freshly distilled triethylamine and 22.5 pl (0.17 mmol) of tert.-butyl isothiocyanate are successively added. After the mixture S has been stirred overnight, a further 10 pl (0.076 mmol) 15 of tert.-butyl isothiocyanate are added, the mixture is stirred at room temperature for a further 8 hours, the solvent is removed by distillation under high vacuum, the residue is taken up in ethyl acetate, the solution is washed with saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried over sodium sulfate and concentrated, and the crude product (129 mg) is purified by MPLC on silica gel (methylene chloride/ methanol 98:2; 95:5).

53.5 mg (49 of the title compound are obtained.

Rf (methylene chloride/MeOH 9:1) 0.43; MS (FAB) 638 0 0 000 000 0 .0 0000 0** 0 0000 0

I

00 *0 Example 3 l-Cyclohexyl-6-(2-pyridyl)-2S-[N-(tert.-butylaminothiocarbonyl-Phe-Nva)-amino]-3S-(tert.-butylaminothiocarbonyloxy)-hexane mg (0.16 mmol) of l-cyclohexyl-6-(2-pyridyl)-2S-[N- (Phe-Nva)-amino]-3S-hexanol are reacted as described in Example 2e) with 0.104 ml (0.73 mmol) of triethylamine ;i 41 29 and 0.106 ml (0.8 mmol) of tert.-butyl isothiocyanate at room temperature for 10 hours and worked up analogously.

16 mg (13 of the title compound are obtained.

Rf (methylene chloride/MeOH 9:1) 0.81; MS (FAB) 753 The following compound is also obtained using suitable starting materials and using the processes described in Examples 1-3: Example 4 1-ylhxl6(-yiy)2S[-et-uyaioho carbonyl-Phe-Nva) -amino] -3R-hexanol 0 0* S. S

S**

S

OOS*

*0*S Rf (methylene chloride/MeOH 9:1) 0.46; MS (FAB) =638 Example 1-Cyclohexyl-6-(2-7oyridyl) (morpholinothiocarbonyl- Phe-Nva) -amino] -3S-hexanol MS(FAB) 652 (M+1) Example 6 1 -Cyclohexyl.-O- (2-pyridyl) -2S- (morpholinothiocarbonvl- Phe-His) -amino]-3S-hexanol MS(FAB) 690 (M+1) S S

S

S.

S.

S

S

S.

I.

S..

S

S

w 42

Claims (7)

1. A compound of the formula I 1 1 1 R -N-C-A-B-NE1-CH-D-X-y in which Ri denotes, indepedently of one another, hydrogen, (C 1 Cl 1 0 )-alkyl which is optionally singly or doubly unsaturated and which is optionally substituted by up to 3 identical or different radicals from the series comprising hydroxyl, (Cl-C 7 )-alkoxy, (Cl-C 7 alkanoyloxy, carboxyl, C-C)-alkoxycarbonyl, Cl, Br, amino, (C 1 -alkyl amino, di- (Cl-C 7 -alkyl amino, (Cl-C 5 -alkoxyc arbonyl amino, (C 7 -C 1 5 -aralkoxy- carbonylamino and 9 -f luorenylmethyloxycarbonyl amino, or -cycloalkyl, (C 3 -cycloalkyl- (Cl-C, 6 alkyl, (C.-C 1 )-aryl which is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (Cl- a.C 7 -alkoxy, -alkYl, (C 1 ,-C 7 -alkoxycarbonyl, amino, anilino which is optionally substituted by up 'a to 2 halogens, and trifluoromethyl; (C,-Cl 4 )-aryl- d (C,-C,,)-alkyl in which the aryl moiety is optionally *.aaa.*substituted by one or two identical or different radicals from the series comprising F, Cl, Br, I, hydroxyl, (C 1 -C 7 -alkoxy, (Cl-C 7 -alkyl, (Cl-C 7 alkoxycarbonyl, amino, (C,-C 7 -alkylamino, di- (Cl- C7)-alkylamino, carboxyl, carboxymethoxy, amino- (C 1 -C 7 -alkyl, (Cl-C 7 -alkylamino- (Cl-C 7 -alkyl, di- (Cl-C 7 -alkylamino- (C 1 -C 7 -alkyl, (Cl-C 7 -alkoxy- carbonylmethoxy, carbamoyl, sulfamoyl, (Cl-CA) alkoxysulfonyl, sulfo- and guanidinomethyl, or represents the radical of a 3- to 8-menibered mono- cyclic or 7- to 13-membered bicyclic heterocycle which has at least one carbon atom, 1-4 nitrogen 31 atoms and/or 1 sulfur or oxygen atom as ring members and is optionally substituted by one, two or three identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl-C 7 )-alkoxy, (C 1 C 7 -alkyl, (C,-C 7 -alkoxycarbonyl, amino or tri- fluoromethyl, or forms, together with the adjacent nitrogen atom and R 1 a 3- to 8-membered monocycle or a 7- to 13-membered bicycle which has at least 1 carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can option- ally be substituted by one, two or three identical or different radicals from the series comprising (Cl-C 6 -alkyl, hydroxyl, hydroxy- -alkyl, (C 1 C 5 ,)-alkoxy, (C,-C 6 -alkoxy- -alkyl, carboxyl, carboxy- (Cl-C 6 -alkyl, (Cl-C 6 -alkoxycarbonyl, (C 1 CO)-alkoxycarbonyl- -alkyl, haoe, mi, amino- (Cl-C 6 (C 1 -C 6 -alkylamino-alkyl, -alkyl, di- -alkylamino or di- (C 1 -C 6 -alkylamino- (C 1 -alkyl; Mac* A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of a natural or un- natural amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspar- ~tic acid, p-2-thienylalanine, 6-3-thienylalanine,

2-furylalanine, p-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, a 4-chlorophenylalanine, methionine sulfone, methio- nine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, *cyclohexylalanine, cyclohexylglycine, un-methyl- histidine, 0-methyltyrosine, O-benzyltyrosine, 0- tert.-butyltyrosine, phenylglycine, 1-naphthyl- alanine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, p-2-benzo[b]thienylalanine, A3 benzo [b Ithienylalanine, 2-f luorophenylalanine, 3- fluorophenylalanine, 4-f luorophenylalanine, nor- leucine, cysteine, S-methyl-cysteine, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, homo-4 phenylalanine, DOPA, 0-dimethyldopa, 2-amino-3- (2- -32 thienyl)-butyric acid, benzodioxol-5-ylalanine, N- methyl-histidine, 2-amino-4-(3-thienyl)butyric acid,

3-(2-thienyl)-serine, (Z)-dehydrophenylalanine, dehydrophenylalanine, 3-dioxolan-2-yl) alanine, N- pyrrolylalanine, 3- or 4-pyrazolyl)alanine, (4- thiazolyl)alanine, 4- or cyclopentylglycine, tert.-butylglycine or phenyl- serine, it being possible for each amino group optionally to be substituted by (Cl-C,)alkyl, formyl, (Cl-C 6 )-alkoxycarbonyl or benzyloxycarbonyl; B denotes a radical, which is linked N-terminal with A and C-terminal with -NH-CH-R 2 of a natural or unnatural amino acid as defined for A, it being possible for the amino group optionally to be substituted as described under A; R 2 denotes hydrogen, (C 1 -C 10 )-alkyl, (C 4 -C 7 )-cycloalkyl, (C 4 -C 7 -cycloalkyl-(Cl-C 4 )-alkyl, (C 6 -C 1 4 )-aryl, (C 6 C 1 4 )-aryl- (Cl-C 4 -alkyl or heterocyclyl- (C 1 -C 4 -alkyl, the heterocycle containing 4 7 ring members, of which 1 or 2 are sulfur and/or oxygen atoms; D denotes a group from the series comprising -CH- -CH- -CH 2 -SO- or -CH 2 -NH- OR 3 1H-R 4 O OR in which *R denotes hydrogen; (Cl-C 10 )-alkyl; (C 1 -C 6 -alkanoyl; (C.-C,)-cycloalkanoyl; phenyl, phenyl-(C-C 4 -alkyl or ***benzoyl, each of which is optionally substituted in the aromatic moiety by one, two or three radicals from the group comprising (C 1 -C 4 )-alkyl, (Cl-C 4 *n alkoxy, Cl, F, Br, nitro, trifluoromethyl or one methylenedioxy; (Cl-C 10 )-alkylaminothiocarbonyl, (C 1 Cla)-alkylaminocarbonyl, it being possible for each (C 1 -C 10 )-alkyl radical to be substituted as described under R 1 (C 1 -alkanoyloxy-(C 1 -alkyl, (C 1 -C 6 alkoxycarbonyloxy-(C-C 2 -alkyl or A' 0 0 33 CH 2 _7 CH 3 denotes hydrogen, (Cl-C 6 )-alkanoyl, (C 5 -C 8 -cyclo- alkanoyl, phenylcarbonyl, phenyl- (Cl-C 4 -alkanoyl, N- (Cl-C 4 -alkyl-1,4-dihydronicotinoyl, a radical CH C-, in which R is the side-chain of a natural amino acid, or (Cl-C 6 )-alkoxycarbonyl, (C 5 -C 8 -cycloalkyl- oxycarbonyl, phenoxycarbonyl, (Cl-C 6 -alkanoyloxy- (C 1 -C 2 -alkoxycarbonyl, phenylcarbonyloxy- (Cl-C 2 alkoxycarbonyl, 6 -alkanoyloxy- (C 1 -C 2 -alkyl, phenylcarbonyloxy- (Cl-C 2 -alkyl, (C,-C 6 -alkanoyl- aminomethyl, phenylcarbonylaminoinethyl or an option- ally substituted acrylic acid derivative which is linked via the 3 position, it being possible in all the radicals R 4 which contain phenyl for this phenyl radical optionally to be substituted by one, two or three radicals from the group comprising (Cl-C 4 alkyl, (Cl-C 4 )-alkoxy, Cl, Br, F, nitro, trifluoro- methyl or one methylenedioxy, denotes 0, 1 or 2, is absent or denotes a group from the series comprising -(CH 2 1 3 -CEF-, -CF 2 -C C 2 H- 1 33 OR 3 OR -CH 2 -SO _CH-C-CH- in which R 3 is as defined above, R 5 denotes the side-chain of a natural amino acid, hydroxy- (Cl-C 6 -alkyl, -alkoxy or (C 2 -C 6 x and E *e S. S* S S.. S 344 alkenyloxy, R 6is hydrogen or -alkyl, y denotes 0, 1 or 2, and X is absent or denotes a group from the series comprising 2 1 4 00 and Y denotes hydrogen, f luorine, (C,-C 6 -alkyl, (C 5 -C 8 cycloalkyl, (Cl-C, 6 -alkoxy, (C 5 -cycloalkoxy, amino, -alkylanino, di- -alkylanino, C 14 -arylI (C,-C 1 4 -aryl- (C 1 -C 6 -alkyl, it being possible for each aryl radical to be unsubstituted or mono-, di- or trisubstituted as defined above under R hydroxyl, azido, azido-(Cl-C 6 )-alkyl, C 6 -alkylthio, (Cl-C 6 -alkylsulfonyl, (C 5 -C 8 -cyclo- alkylthio, (C 5 -cycloalkylsulfonyl, heterocyclyl or heterocyclyl- (C 1 -C 6 -alkyl, each heterocycle being a 3- to 8-membered monocycle or a 7- to 13-membered bicycle having at least one carbon atom and one to six heteroatoms from the series comprising 0, N or as well as the physiologically tolerated salts thereof. 2. A compound of the forzmula I as claimed in claim 1, wherein R1 denotes, independently of one another, hydrogen, 0:0*0:(Ci-Cio)-alkyl which is optionally substituted by up to three identical or different radicals from the series comprising hydroxyl, (Cl-C 4 )-alkoxy, (C 1 -C 4 alkanoyloxy, carboxyl, (Cl-C 4 -alkoxycarbonyl, Cl, Br, amino, (C,-C 4 -alkyl amino, di- (C -C 4 -alkyl amino or (Cl-C 4 -alkoxycarbonylarnino, or (C 5 -C 7 -cycloalkyl, (C 6 -C 14 -aryl which is optionally substituted by one 35 or two identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl-C 4 alkoxy, (Cl-C 4 )-alkyl, -(C 1 -C 4 )-alkoxycarbonyl, amino and trifluoromethyl, or (C 6 -C 1 4 )-aryl-(Cl-C,)-alkyl in which the aryl moiety is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl-C 4 alkoxy, (Cl-C 4 )-alkyl, (Cl-C 4 )-alkoxycarbonyl, amino, (C 1 -C 4 )-alkylamino, di-(C 1 -C 4 -alkylamino, carboxyl, carboxymethoxy, amino- (Ci-C 4 -alkyl, (C,-C 4 -alkyl- amino- (C 1 -C 4 )-alkyl, di-(Cl-C 4 -alkylamino-(Cl-C 4 alkyl, (C,-C 4 )-alkoxycarbonylmethoxy, carbamoyl, sulfamoyl, (Cl-C 4 )-aikoxysulfonyl, sulfo- and guani- dinomethyl, or represents the radical of a 3- to 8- membered monocyclic or 7- to 13-membered bicyclic heterocycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atoms as *ring members and which is optionally substituted by one, two or three identical or different radicals from the series comprising F, Cl, Br, hydroxyl, (Cl- C4) -alkoxy, (Cl-C 4 -alkyl, C-C 4 -alkoxycarbonyl, amino or trifluoromethyl, or forms, together with the adjacent nitrogen atom and R 1 a 3- to 8-membered monocycle or a 7- to 13-membered bicycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can optionally be substituted by one, two or three identical or different radicals from the series comprising (C-CO)-alkyl, hydroxyl, hydroxy- (Cl-C 6 -alkyl, (Cl-C 6 -alkoxy, -alkoxy- (Cl-C 6 alkyl, carboxyl, carboxy- -alkyl, (C-C 6 alkoxycarbonyl, (C-C 6 )-alkoxycarbonyl-(Cl-C) -alkyl, halogen, amino, amino- (Cl-C 6 -alkyl, (C 1 -alkyl- amino- (C,-C 6 -alkyl, di-(C 1 -C,)-alkylamino or di- (Cl-C 6 -alkylamino- (C 1 -alkyl; A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of a natural or un- natural amino acid from the series comprising phenylalanine, histidine, tyrosine, tryptophan, p- -36 2-thienylalanine, ,-3-thienylalanine, p-2-furyl- alanine, pi-3-furylalanine, 4-chlorophenylalanine, 2- pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexyiglycine, im-methyihistidine, 0-methyl- tyrosine, O-benzyltyrosine, 0- tert. -butyl tyro sine, phenyiglycine, 1-naphthylalanine, 2-naphthylalanine,

4-nitrophenylalanine, 2-f luorophenylalanine, 3- fluorophenylalanine, 4-f luorophenylalanine, homo- phenylalanine, DOPA, 0-dixnethyldopa, 2-amino-4-(2- thienyl) -buty-ric acid, benzodioxol-5-ylalanine, N- methyl-histidine, 2--imino-4- (3-thienyl) butyric acid, 2-thienyl) -serine, (Z )-dehydrophenylalanine or -dehydrophenylalanine; B denotes a radical, which is linked N-terminal with A and C-terminal with -NH-CH-R of a natural or unnatural amino acid from the series comprising *phenylalanine, histidine, tyrosine, tryptophan, methionine, leucine, isoleucine, asparagine, aspart- ic acid, p-2-thienylalanine, p-3-thienylalanine, p- 2-furylalanine, e-3-furylalanine, lysine, ornithine, valine, alanine, 2,4-diaminobutyric acid, arginine, 4-chlorophenylalanine, methionine sulf one, methio- nine sulfoxide, 2-pyridylalanine, 3-pyridylalanine, cyclohexylalanine, cyclohexylglycine, im-methyl- histidine, 0-methyltyrosine, 0-benzyltyrosine, 0- tert butyltyrosine, phenyiglycine, 1-naphthylala- nine, 2-naphthylalanine, 4-nitrophenylalanine, norvaline, f-2-benzo[b]thienylalanine, p-3- benzo[b]thienylalanine, 2-f luorophenylalanine, 3- fluoropheriylalanine, 4-f luorophenylalanine, nor- cysteine, S-methyl-cysteine, 1,2,3,4- tetrahydroisoquinoline-3-carboxylic acid, homo- phenylalanine, DOPA, 0-dimethyldopa, 2 -amino -4 (2 2-thienyl -butyric acid, ylalanine, N-methyl-histidine, 2-amino-4- (3-thi- enyl)-butyric acid, 3-(2-thienyl)-serine, dehydrophenylalanine, -dehydrophenylalanine, (1,3-dioxolan-2-yl)alanine, N-pyrrolylalanine, 371 3- or 4-pyrazolyl)alanine, (4--thiazolyl)alanine, 4- or 5-pyrimidyl)alanine, cyclopentyiglycine, tert. -butyiglycine or phenylserine, R 2 denotes hydrogen, (Cl-C 1 0 )-alkyl, (C 4 -C 7 )-cycloalkyl, (C 4 -C 7 -cycloalkyl- (Cl-C 4 -alkyl, (C 6 -C 1 J)-aryl, (C 6 Cjj) -aryl- (C,-C 4 -alkyl or heterocyclyl- (C 1 -C 4 -alkyl, the heterocycle having 4 7 ring members, of which 1 or 2 are sulfur and/or oxygen atoms, and D denotes a group from the series comprising CH- -CH- C_ -CH 2 or -CH -N- R 3 4 in which R R 3 denotes hydrogen, R~ an 4 denotes hydrogen, x denotes 0, 1 or 2, E is absent or denotes a group from the series comprising -(CR 2 1 3 -CEF-, -CE' 2 -CH- ,-CH 2 -CH-, 3 13 OR 3 OR -CH 2 -CH- ,-CH 2 -CH- ,-CH=C- *0*g 15 in which R 3 is hydrogen, see: W1 denotes the side-chain of a natural amino acid, hydroxy- (C 1 -C 6 -alkyl, -alkoxy or (C 2 -'C 6 -alkenyloxy, 6 R is hydrogen or (Cl-C) -alkyl, Y denotes 0, 1 or 2, and X is absent or denotes a group from the series 38 comprising -(CF 2 )1- 4 -NH-C- O O and Y denotes hydrogen, fluorine, (Ci-C 6 )-alkyl, (Cs-Cs)- cycloalkyl, (CI-C 6 -alkoxy, (C 5 -cycloalkoxy, amino, (C 1 -C 6 -alkylamino, di-(Ci-C 6 -alkylamino, (C 6 C 14 )-aryl, (C 1 -C 6 )-alkyl, it being possible for each aryl radical to be unsubstituted or mono-, di- or trisubstituted as defined above under R 3 or hydrox- yl, azido, azido-(CI-C 6 )-alkyl, (CI-C,)-alkylthio, (Ci-C 6 )-alkylsulfonyl, (C 5 -cycloalkylthio, cycloalkylsulfonyl, heterocyclyl or heterocyclyl- (Ci-C 6 )-alkyl, each heterocycle being a 3- to 8- membered monocycle or a 7- to 13-membered bicycle having at least one carbon atom and one to six •heteroatoms from the series comprising O, N or S, S. as well as the physiologically tolerated salts thereof. 3. A compound of the formula I as claimed in one or more of claims 1 to 2, wherein R 1 denotes, independently of one another, hydrogen, (C 1 -C 10 )-alkyl which is optionally substituted by up to three identical or different radicals from the series comprising hydroxyl, carboxyl, amino, (C 1 -C 4 alkylamino, di-(Ci-C 4 -alkylamino or (Ci-C 4 )-alkoxy- carbonylamino, or phenyl which is optionally sub- stituted by one or two radicals from the series comprising F, Cl, hydroxyl, amino or trifluoro- methyl, or phenyl-(Ci-C 4 )-alkyl, in which the phenyl moiety is optionally substituted by one or two identical or different radicals from the series comprising F, Cl, hydroxyl, amino, (Cl-C 4 )-alkyl- amino, di-(C 1 -C 4 -alkylamino, carboxyl, amino-(Ci- C 4 -alkyl, (Ci-C 4 -alkylamino-(Ci-C 4 -alkyl, di- (C- C 4 -alkylamino-(CI-C 4 -alkyl, or forms, together with the adjacent nitrogen atom and R 1 a 3- to 8-membered l- 1 monocycle or a 7- to 13-membered bicycle which has at least one carbon atom, 1 4 nitrogen atoms and/or 1 sulfur or oxygen atom as ring members and which can optionally be substituted by one, two or three identical or different radicals from the series comprising (C.-C 6 )-alkyl, hydroxyl, hydroxy- (Cl-CO)-alkyl, (Cj-Cr) -alkoxy- (Cj-C 6 -alkyl, carboxyl, carboxy-(C,-C,) -alkyl, -alkoxycarbonyl, (C 1 C 6 -alkoxycarbonyl- -alkyl, halogen, amino, amino- (Cl-Cr 6 -alkyl, (Cl-Cr)-lyaio C- 6 -alkyl, di (Cl-C 6 alkyl amino or di- (C 1 -C 6 -alkylamino- (Cj- C 6 -alkyl, A denotes a radical, which is linked N-terminal with -CS- and C-terminal with B, of an amino acid from the series comprising phenylalanine, tyrosine, fi-2- thienylalanine, f-3-thienylalanine, 4-chlorophenyl- alanine, 0-methyltyrosine, l-naphthylalanine, 2- fluorophenylalanine, 3-f luorophenylalanine or 4- fluorophenylalanine, B denotes a radical, which is linked N-terminal with A and C-terminal with -Nli-CHR of an amino acid from the series comprising phenylalanine, histidine, leucine, p-2-thienylalanine, p-3-thienylalanine, lysine, norvaline, 2-f luorophenylalanine, 3-f luoro- phenylalanine, 4-f luorophenylalanine, norleucine, S- methylcysteine, (1,3-dioxolan-2-yl)alanine, 3- or 4-pyrazolyl)alanine, 4-thiazolylalanine or 4- or R2 denotes isobutyl, cyclohexylmethyl, benzy'L or (1,3- dithiolan-2-yl )methyl, D denotes a group H- and R 3 is hydrogen, OR 3 *E is absent or denotes a group from the series comprising -CH- CH 2 -7i- -CH- tR 3 OR 3 404 40 in which R 3 is hydrogen, and R 5 denotes the side-chain of a natural amino acid, X is absent or denotes the group from the series comprising -NH-C- I o1 0 o and Y denotes hydrogen (Ci-C,)-alkyl, (C 5 -Cs)-cycloalkyl, amino, (Cl-C) -alkylamino, di-(CI-C 6 -alkylamino, (C 6 C 14 )-aryl, C 6 -C 14 )-aryl-(Ci-Cs)-alkyl, it being pos- sible for each aryl radical to be unsubstituted or oo S mono-, di- or trisubstituted as defined above under S. 3 R 3 or hydroxyl, azido, (Ci-C 6 )-alkylthio, (Ci-C 6 alkylsulfonyl, (C 5 -CB)-cycloalkylthio, C 5 -C 8 )-cyclo- alkylsulfonyl, heterocyclyl or heterocyclyl-(CI-C 6 alkyl, each heterocycle being a 3- to 8-membered monocycle or a 7- to 13-membered bicycle having at least one carbon atom and one to six heteroatoms from the series comprising 0, N or S, as well as the physiologically tolerated salts thereof. 4. A process for the preparation of a compound of the general formula I as claimed in one or more of claims 1 to 3, which comprises a) reacting a compound of the general formula II R 2 i H-A-B-NH-CH-D-E-X-Y in which A, B, D, E, X, Y and R 2 have the same meaning as in the general formula I, with an iso- thiocyanate of the general formula III R I -N=C=S I 41 in which R 1 has the same meaning as in the general formula I, in a suitable organic solvent such as, for example, benzene, toluene, chlorobenzene, an aliphatic hydrocarbon, an aliphatic chlorinated hydrocarbon, diethyl ether, tetrahydrofuran, dioxane, acetone, acetonitrile, dimethylformamide, dimethyl sulfoxide or else dispensing with a solvent, in each case as desired with or without the addition of a Lewis acid or of a Lewis base as catalyst, such as, for ex- ample, of a tertiary amine, preferably triethyl- amine, 1,4-diazabicyclo[2.2.2]octane, cyclohexyl- dimethylamine, benzyldimethylamine, 4-methyl- morpholine, tetramethylguanidine or 4-dimethylamino- pyridine, at a temperature between -80 0 C and the boiling point of the solvent, preferably between -30 0 C and +80°C, where appropriate providing sensi- tive functional groups such as hydroxyl or amino groups with a protective group beforehand, and removing this protective group again at the end, or *see b) coupling a compound of the general formula IV with a free carboxyl group a R S R1-N-C-A-OH o in which R 1 and A have the same meaning as in formula I, or a reactive derivative thereof, with the corresponding fragment with a free amino group of S" the general formula V R 2 I D H-B-NH-CH-D-E-X-Y f I 42 42 in which B, D, E, X, Y and R 2 have the same meaning as in formula I, and, where appropriate, eliminating protective group(s) temporarily introduced to protect other functional groups, or c) coupling a compound of the general formula VI with a free carboxyl group R 1 S R-I N- -A-B-OH in which R 1 A and B have the same meaning as in formula I, or a reactive derivative thereof, with the corresponding fragment with a free amino group of the general formula VII •R 2 H 2 N-CH-D-E-X-Y in which R 2 D, E, X and Y have the same meaning as in formula I, and, where appropriate, eliminating protective group(s) temporarily introduced to protect other functional groups, and converting the Scompound obtained in this way into its physiologi- cally tolerated salt.

5. The use of a compound of the formula I as claimed in one or more of claims 1 to 3 as a medicine. a

6. The use of a compound of the formula I as claimed in o. one or more of claims 1 to 3 for the treatment of high blood pressure.

7. A pharmaceutical agent containing a compound of the formula I as claimed in one or more of claims 1 to 3. DATED this 16th day of November 1989. HOECHST AKTIENGESELLSCHAFT WATERMARK PATENT TRADEMARK ATTORNEYS QUEEN STREET MELBOURNE. VIC. 3000.