AU594711B2 - A method for the treatment of atherosclerosis, thrombosis and peripheral vesseldisease - Google Patents

Abstract

The preferred angiotensin converting enzyme inhibitors have the formula I <IMAGE> in which n is 1 or 2, R, R<1>, R<2> and R<3> are identical or different and each is hydrogen or an organic radical, and R<4> and R<5> form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system. Agents containing these compounds for treating the specified diseases are also described.

Description

A

4 t C 59 47 Irm 1l COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION (ORIGIN AL)1 Class I t. Class Application Number: Lodged: .~43 Complete Specification Lodged: Accepted: Published: Priority: 7TLIk document cgnta ins the ali1ci dmeiits mtide underi Soctjon 49 and Is correct for rinting.

ReIa~tpq Art: 0 0 N\ame ?if Applicant: Address of Applicant 0 0 HOECHST AKTIENGESELLSCHAFT 45 Bruningstrasse, D-6230 Frankfurt/Main Fecaral Republic of Germany BERNWARD SCHOLKENS E DWD. WATERS SONS, QUEEN STREE~T, MELBOURNE, AUSTRALIA, 3000.

tl Complqte Specification for the invention entitled: A METHOD FOR THE TREATMENT OF ATHEROSCLEROSIS, AND PERIPHERAL VESSELDISEASE

THROMBOSIS

The following statement Is a full description of this invention, Including the best method of perfoyming It known to 1, uS 2* 1 -la- HOECHST AKTIENGESELLSCHAFT HOE 85/F 229 Dr.WS/gm A method for the treatment of atherosclerosis, thrombosis and peripheral vessel disease The invention relates to a method for the treatment of .atherosclerosis, of thrombosis and/or of peripheral vessel disease by oral or parenteral administration of compounds which inhibit angiotensin converting enzyme.

Particularly suitable for this purpose are compounds of the formula I R OOC CH N C CH NH CH (CH -R R4 5 1 1

OOR

2 R R R COOR

(I)

I i ii 3 i i i j I i ,n1 in which n is 1 or 2, 10 R hydrogen, an optionally substituted aliphatic radical having 1-8 carbon atoms, an optionally sub- S' stituted alicyclic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted arali- 15 phatic radical having 7-14 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 7-14 carbon atoms, or a radical OR a or SR a in which R a represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an opt- 20 ionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted heteroaromatic radical having 5-12 ring atoms, R denotes hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted alicyclic radical having 3-9 carbon atoms, an optionally substituted alicyclicaliphatic radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-16 carbon atoms, an optionally substituted heteroaromatic radical having 5-12 ring "i 3 "i i c I~-~CI 2 atoms, or the side chain, protected where necessary, of a naturally occurring a-amino acid,

R

2 and R 3 are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted alicyclic radical having 3-9 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted araliphatic radical having 7-16 carbon atoms, and

R

4 and R form, together with the atoms carrying them, a heterocyclic, mono-, bi- or tricyclic ring system having 4 to 15 carbon atoms.

Particularly suitable ring systems of this type are those of the following group: i

B

jt1t fil I I I I

II

II I' I i 1 15 Tetrahydroisoquinoline decahydroisoquinoline octahydroindole octahydrocyclopentaEb3pyrrole 2-azaspiroE4.53decane 2-azaspiro[4.43nonane spiroC(bicycloC2.2.13heptane)-2,3'-pyrrolidine](G); spiroC(bicyclo[2.2.23octane)-2,3'-pyrrolidine] 20 2-azatricycloE4.3.0.1 6 9 decane decahydrocycloheptaEb3pyrrole octahydroisoindole octahydrocyclopentaCc3pyrrole 2, 3 ,3a,4,5,7a-hexahydroindole 2-azabicycloE3.1.03hexane all of which can optionally be substituted. However, the unsubstituted systems are preferred.

In the case of compounds which have several chiral atoms, all possible diastereomers are suitable, as racemates or enantiomers or mixtures of various diastereomers.

The cyclic amino acid esters which are suitable have the following structural formulae.

if r 1- -3-

~T/

1

COOR

3 K27 COOR 3 A

B

COOR

3 .3

COOR

COOR

3 0000 0 0 on00 0000 0 00 00 0 0 0 008 0 0 0 0 0 0s 00 0 *004 0001 COOR3

I

83- CoOR 3 I3 COORJ

COOR

COOn 3 rrrr (trr:

I

-I

A preferred embodiment comprises use of compounds of the formula I in which n is 1 or 2, R denotes hydrogen, alkyl Iaving 1-8 carbon atoms, aLkenyL havirg 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C 1

-C

4 alkyl, (C 1 -CO-aLkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C 1

-C

4 )-akytamino, di-(C 1

-C

4 j o A -4 aLkylamino, (C 1-C 4 )-aL kanoyLamino, methyLenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or bicyclic heteroaryLoxy which has 5-7 or 8ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen, and which can be substituted as described above for aryL, amino-( Cl-C 4 )-aLkyl, (Cl-C 4 )-aLkanoyLamino-( C 1

C

4 )-aL kyl, C C 7 -Cl3)-aroyL amino-(C 1

-C

4 )-aLkyL, (C 1

C

4 )-aLkoxycarbonyLamino-(C 1

-C

4 )-aLkyL, CC 6

-C

12 aryL-(Cl-C4)-aLkoxycarbonyLamino-(C-C 4 )-aLkyL, (C 6-C I a r yI-(~Cl1- C 4) -aIk y Ia m ino C1- C 4 a 1k y (C 1

-C

4 )-aLkyL amino-(C -C 4 )-alkyL, di-( C 1

-C

4 )-aLkyLamino-(Cl-C 4 )-atkyL, guanidino-(C 1

-C

4 )-aLkyL, imidazoLyL, indloLyL, (Cl-C 4 )-aLkyLthio, (CC-C 4 atkyLthio-(Cl-C 4 )-aLkyL, (C 6

-C

1 2 )--aryLth io-(CC-C 4 alkyL which can be substituted in the aryL moiety as described above for aryL, (C 6 -Cl 2 )-aryL-(C-

C

4 )-aLkyLthio which can be substituted in the aryL moiety as described above for aryL, carboxy- (Cl-C 4 )-aLkyL, carboxyL, carbamoyL, carbamoyL- "lC-C 4 )-aLkyL, (C 1

-C

4 )-aLkoxycarbonyL-(Cl-C 4 aLkyL, (C 6 -Cl2)-aryLoxy-(Cl-C 4 )-aLky( which can be substituted in the aryl moiety as described above for aryt, or (C 6 -Cl 2 )-aryL-(Cl-C 4 )-aLkoxy which can be substituted in the aryL moiety as described above for aryl, Rdenotes hydrogen, aLkyL having 1-6 carbon atoms, aLkenyL having 2-6 carbon atoms, aLkynyL having 2-6 carbon atoms, cyctoaLkyL having 3-9 carbon atoms, cycLoalkenyL having 5-9 carbon atoms, (C 3

-C

9 cycLoaLkyL-(C-C 4 )-aLkyl, (C 5

-C

9 )-cycLoaLkenyL- (Cl-C 4 )-atkyt, optionally partiaLLy hydrogenated aryL which has 6-12 carbon atoms and can be substituted as described above for R, (C6-Cl 2 )-aryL-(C1-

C

4 )-at~kyL or (C 7

-C

13 )-aroyL-(Cl or C 2 )-aLkyl, both '13

I

t -5 of which can be substituted as the abovementioned aryl, mono- or bicyclic, optionally partially hydrogenated heteroaryL which has 5-7 or 8-10 ring atoms respectively, 1 or 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as the abovementioned aryL, or the optionally protected side chain of a naturally occurring ca-amino acid R l-CHCNH 2

)-COOH,

R 2and R 3are identical or different and denote hydrogen, aLkyL having 1-6 rarbon atoms, aLkenyL having 2-6 carbon atoms, di-(Cl-C 4 )-aLkyLamino-(C-C 4 aLkyL, (Cl-C 5 )-aLkanoyLoxy-(Cl-C 4 )-aL kyL, (Cl-C 6 aLkoxycarbonyLoxy-(Cl-C 4 )-aLkyL, (C 7 -C 13 )-aroyLoxy- (C -C 4 -aLkyL, (C 6 -C I2)-aryLoxycarbonyLoxy-(Cl-C 4 aLkyL, aryL having 6-12 carbon atoms, (C 6

-C

12 aryL-(Cl-C 4 )-aLkyL, (C3-C 9 )-cycLoaLkyL or 0 a 4(C 3

-C

9 )-cycLoaLkyL-(Cl-C 4 )-aLkyL, and

R

4 and R 5 have the abovementioned meaning.

A particularly preferred embodiment comprises use of compounds of the formula I in which n is 1 or 2, R denotes (Cl-C 6 )-alkyL, (C2-C 6 )-aLkenyL, CC 3

-C

9 cycLoaLkyL, amino-(Cl-C 4 )-alkyL, (C 2

-C

5 )-acyLamino- (Cl-C 4 )-aLkyL, CC7-Cl3)-aroyLamino-( Cl-C 4 )-aLkyL,

(CC

1 4 )-aLkoxycarbonyLamino-(Cl-C 4 )-aLkyl, (C 6 -Cl 2 aryL-(Cl-C4)-aLkoxycarbonyLalino-(Cl-C 4 )-aLkyL,

CC

6

-C

1 2 )-aryL which can be mono-, dli- or trisubstituted by (C 1

-C

4 )-aLkYL, (C 1 -C4)-aLkoxy, hydroxyL, halogen, nitro, amino, (Cl-C 4 )-aLkyLamino, di-(Cl-

C

4 )-aLkyLaniino and/or methyLenedioxy, or 3-indoLyL, in particular methyl, ethyl, cycl.ohexyL, tert.butoxycarbonyL amino-(Cl-C 4 )-aLkyL, benzoytoxycarbonyLamino-(C 1

-C

4 )-aLkyL, or phenyL which can be monoor dlisubstituted, or in the case of methoxy trisubstituted, by phenyL, (Cl-C 2 )-aLkyL, (C 1 or CZ)aLkoxy, hydroxyL, fluorine, chlorine, bromine, amino, (Cl-C 4 )-aLkyLamino, di-(Cl-C 4 )-aLkyLamino, r

I

-6 nitro and/or iethylenedlioxy, Rdenotes hydrogen or (Cl-C 6 )-aLkyi which can optionaLly be substituted by amino, (Cl-C 6 )-acyLamino or benzoylamino, (C 2

-C

6 )-aLkenyt, (C 3

-C

9 )-cyc LoaL kyL,

(C

5

-C

9 )-cyc LoaLkenyL, CC 3

-C

7 )-cyc LoaLkyL-(Cl-C4)alkyl, (C 6 -Cl 2 )-aryL or partia~Ly hydrogenated aryl, each o' which can be substituted by (Cl-CO)-aLkyL,

(C

1 or C 2 )-aLkoxy or halogen, (C 6 -Cl 2 )-aryL-(Cl to C4)-aLkyL or (C 7 -Cl3)-aroyL-(Cl-C 2 )-aLkyL, both of which can be substituted in the aryL radical as defined above, a mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectiveLy, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoims representing nitrogen atoms, or a side chain of a naturally occurring, optionally protected ai-amino acid, but in particular hydrogen, (Cl-C 3 aLkyL, (C 2 or C 3 )-aLkenyL, the optionally protected side chain or Lysine, benzyL, 4-methoxybenzyt, 4ethoxybenzyt, phenethyL, 4-aminobutyL or benzoyLme ethy L, R2 and R3denote identical or different radicals hydrogen, (Cl-C 6 )-aLkyL, (C2-C 6 )--aLkenyL or (C 6 -Cl 2 aryL-(Cl-C 4 )-aLkyL, but in particular hydrogen, (Cl--C 4 )-aLkyl or benzyL, and R 4 and R5have the abovementioned meaning.

0 0 0 It is particularly preferred to use compounds of the formula I in which n is 2, IQ R denotes phenyL, Rdenotes methyl, R 2 and R3denote identical or different (Cl-C 6 )-aLkyL radicals or (C 7 -Cl 0 )-araLkyL radicals such as benzyL or nitrobenzyL, and R4and R 5 to~ether represent a radlical of the formula ~1 20 r i 71 7 I tt t tt ,I t *1 It *I It 4 I I I( I II 11p CH2 lp

X

LCH

2 in which m denotes 0 or 1, p denotes 0, 1 or 2, and X denotes -CH 2

-CH

2

-CH

2 or -CH=CH-, it also being possible for a 6-ring formed with X to be a benzene ring.

In this context and in the following, aryl is to be understood preferably to be substituted phenyl, biphenylyl or naphthyl. A corresponding statement applies to radicals derived from aryl, such as aryloxy and arylthio. Aroyl is particularly understood to be benzoyl. ALiphatic radicals can be straight-chain or branched.

A mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, is to be understood to be, for example, thienyl, benzo- [b3thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyt, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated.

'I

Naturally occurring c-amino acids are described in, for example, Houben-Weyl, Methoden der Organischen Chemie (Methods of Organic Chemistry), Vols. XV/1 and XV/2.

Where R1 represents a side chain of a protected naturally occurring a-amino acid such as, for example, Sj -L I 1

C

r~ .5 *i i 1 8 protected Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, HyL, Cys, Orn, Cit, Tyr, Trp, His or Hyp, the preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, Vols. XV/1 and XV/2). In the case where R1 denotes the protected side chain of Lysine, the known amino protective groups, but in particular Z, Boc or (Ci-C6)-alkanoyl, are preferred.

Suitable and preferred as 0-protective groups for tyrosine are (C 1

-C

6 )-alkyl, in particular methyl or ethyl.

ACE inhibitors of the formula I can be prepared by reacting together their fragments in a suitable solvent, where appropriate in the presence of a base and/ or of a coupling auxiliary, where appropriate reduction of unsaturated compounds which have resulted as inter- 15 mediates, such as Schiff's bases, and elimination of protective groups which have been introduced temporarily to protect reactive groups and, where appropriate, conversion of the resulting compounds into their physiologically tolerated salts.

20 It is possible in the said manner to react compounds of the formula V with compounds of the formula VI 0 0 0060 0 0 0 000 0 0o 00 0 0 00 0 0 0 O 9 a 0 0 00 0 0 .6 0 60 0 R OOC-CH-N-H 14 5 R R HOOC-CH-NH-CH- (H 2 )n-R 11 2 R COOR j t t 0000 0 0P

(V)

(VI)

t The reaction of these compounds can, for example, be carried out in analogy to known peptide coupling processes in the presence of coupling auxiliaries such as carbodiimides (for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl carbonates in CH3CN. Amino groups in compounds of the formula V can be activated with tetraethyl diphosphite.

The compounds of the formula VI can be converted into i r 9 -9active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbodiimide derivatives, and thus be activated (cf. Schroder, Lubke, The Peptides, VoL.

1, New York, 1965, pages 76-136).

It is likewise possible to react compounds of the formula VII with compounds of the formula VIII, with the formation of compounds of the formula I

R

3

-CH-Y

1 2 -CH- (CH 2

)-R

R

4 5 II 1 2 OR lOOR (VII) (VIII) V 10 in which either Y represents amino and Y represents S* a leaving group, or Y represents a leaving group and Y represents amino. Examples of suitable leaving groups are Cl, Br, I, alkylsulfonyloxy or arylsulfonylox y.

Alkylations of this type are advantageously carried out in water or an organic solvent, in the presence of a base.

Furthermore, compounds of the formula IX can be condensed with compounds of the formula X

R

3

OOC-CH-N---C-CQ

1

QC-(CH

2

-R

TV R4 5 I1 2 e 20 R R R 2 R COOR (Ix) (x) in which either 0 represents amino hydrogen and Q represents oxo, or 1 represents oxo and Q2 represents amino hydrogen.

The condensation is advantageously carried out in water

I

S- 10 or an organic solvent such as a lower alcohol, and in the presence of a reducing agent such as NaBH 3

CN,

whereupon compounds of the formula I are obtained directly. However, it is also possible to reduce the Schiff's bases or enamines which result as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula I, for example by hydrogenation in :he presence of a transition metal catalyst.

Finally, reaction of compounds of the formula IX (Q H NH 2 with compounds of the formula XI, or their reaction with compounds of the formulae XII and XIII, oe also results in compounds of the formula I o 0 o>00 R OOC-CH-CH-CO-R

(XI)

So 0

OCH-COOR

2

R-CO-CH

3 (XII)

(XIII)

o 15 there being reduction of Schiff's bases produced as intermediates, and conversion of a carbonyl group into trc methylene by reduction.

In the abovementioned formulae V-XIII, R-R 5 and n are as defined in formula I. Protective groups introduced temporarily to protect reactive groups not involved in the reaction are eliminated after reaction is complete in a manner known per se (cf. Schroder, L'bke, loc.

cit., pages 1-75 and 246-270).

It is possible and particularly advantageous to use the following compounds in the method according to the invention: N-(1-S-carboethoxy-3-phenylpropyl)-SalanyL-S-1,2,3,4tetrahydroisoquinoline-3-carbo'yl ic acid r

I

11 N-C l-S-carboethoxy-3-cycLohexyLpropyL)-S-atanyL-Sl, 2 3 ,4-tetrahydroisoquin.,L ine-3-carboxyt ic acid N-C 1-S-carboethoxy-3-phenyLpropyL)-S-LysyL-S-1,2,3,4tetrahydroisoquinoL ine-3-carboxyt ic acid N-C l-S-carboethoxy--3-phenyLpropyt )-0-ethyL-S-tyrosyL- S-l, 2 3 ,4-tetrahydroisoquinot ine-3-carboxyL ic acid N-C l-S-carboethoxy-3--phenyLpropyL anyL-3S-decahydro-isoquinoLine-.3-carboxyL ic acid N-(l-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-

C

2

S,

3 aS,7aS)-octahydroindoLe-2-carboxyLic acid N-C l-S-carboethoxy-3-cycLohexyLpropyL)-S-aLanyL-

C

2

S,

3 aS,7aS)-octahydroindoLe-2-carboxyL ic acid N-C 1-S-car-boethoxy-3-phenyLpropyL )-S-LysyL-(2S,3aS,7aS octahydroindote-2-carboxyL ic acid N-C l-S-carboethoxy-3-cycLohexyLpropyL )-S-LysyL- 2

S,

3 aS,7aS)-octahydroindoLe-2-carboxy-jc acid N-C l-S-carboethoxy-3-cycLohexyLpropyL )-S-LysyL-

C

2 S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid N-C l-S-carboethoxy-3-pheny~propyL)-methyL-Styrosy1..

(2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid N-C 1-S-carboethoxy-3-phenyLpropyL)--ethy-S-tyrosy..

2

S,

3 aS,7aS)-octahydroindoLe-2-carboyL ic acid N-C l-S-carboethoxy-3-(3,4-dimethyLphenyLpropyL)-saLanyt-(2S,3aS,7aS )-octahydroindoLe-2-carboxyL ic acid N-C l-S-carboethoxy-3-(4-ftuoropheny)-propyL-S-aLanyL-.

2 S,3aS,7aS)-octahydroindoLe-2-carboxyL.ic acid N-C 1-S-carboethoxy-3-(4-methoxyphenyL )-propyL]-S-aLanyL (2S,3aS.7aS)-octahydroindoLe-2-carboxyL ic acid N-C 1-S-carboethoxy-3-(3,4-dimethoxyphenyL)-propyL]-SaLanyL-(2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid N-(l-S-carboethoxy-3-cycLopentyLpropyL)-S-aLanYL- (2S,3aS,76S)-octahydroindoLe-2-carboxy1 ic acid N-C 1-S-carboethoxy-3-phenyLpropyL)-S-aLanyL- (2S,3aR,?aS)-octahydroit'idoLe-2-carboxyL ic acid N-C 1-S-carboethoxy-3-cyctohexytpropyL )-S-aLa~,yL- (2S,3aR,7aS)-octahydroindoLe-carboxyt ic acid N-(1-S-carboethoxy-3-phenytropyL)-S-LysyL-(2s,3aR,7aS)octahydroindoLe-2-carboxyL ic acid I 1

I

12 F S S S 55 55 St S S 5 S t~

S

I

IS

555 S S N-(l-S-carboethoxy-3-cycLohexyLpropyt)-S-LysyL- (2S,3aR,7aS)-octahydroindoLe-2-carboxyL ic acid (2S,3aS,7aR)-octahydroindoLe-2-carboxyL ic acid 1-S-carboethoxy--3-phenyLpropyL )-S-aLanyL- (2S,3aR,7aR)-octahydroindoLe-2-carboxyL ic acid 1-S-c arboethoxy-3-phenyLp ropy L)-S-LysyL-(2S,3aR,7aSoctahydroindote-2-carboxyL ic acid 1-S-c arboethoxy-3-cyciLohexyLpropyL )-S-aL any L- (2S,3aR,7aR)-octahydroindoLe-2-carboxyL ic acid syL-(2S,3aR,7 aR )-oct ahydroindoLe-2-c arbox)L ic a cid N-(1-S-carboethoxy-3-phenytpropyL)-S-aLanyL- (2S,3aS,7-aR)-octahydroindoLe-2-carboxyL acid 15 1-s-c arboethoxy-3-phenyLpropyL )-0-ethyL-S-tyrosyL- (2S,3aS,7aS)-octahy'droindoLe-2-carboxyL ic acid N-(l-S-carboethoxy-3,4-dimethyLphenyLprQpyL)-S-aLanyL- (2S,3aS,7aS)-octahydroindoL,e-2-carboxyL ic acid N-E1-S-carboethoxy-3-(4-fLuorophenyL)-propyLj-S-aLanyL- (2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid N 1-S-c arboethoxy-3-(4-,,nethoxyphenyL )-propyLJI-S- aL aniyt- (2S,3aS,7aS)-octahydroirdoie-'?-carboxyL ic acid N-E1-S-carboethoxy-3-(3,4-dimethoxyphenyL)-propy1)-$aLanyL-(2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid 25 1-S-c arboethoxy-3-cyctLope ntyLpropy )-S-aL any L- (2S,3aS,7aS)-octahydroincloLe-2-carboxyl ic acid N-(1-S-carboethoxy-3-phenyLpropyL)-S-aLaiyL-cis-endo-2azabicycLoE3.3.0)octane-3-S-carboxyL ic acid N-(l-S-c arboethox>'-3-phenyLp ropy L)-S-LysyL-c is-endo-2azabic>cLoE3.3.03octane-"3-S-carboxyL ic acid I-S-c arboethoxy-3-cycLohexy~p ropy a Lany L-c ISendo-2-azabicycLoE3.3.03octane-3-S-carboxy,1ic acid N-(l-S-carboxy-3'-cycLohexytpropyL)-S-aLanyL-cis-endo-2azabicycLoC3.3.0oactane-3-S-carbox'L ic acid 1-S-c arboethoxybutyL )-S-aL a rjL-cis-endlo-2-azabicy~tLo-' C3.3.03octane-3-S-cerboxyL ic acid N-(l-S-carboethoxy-3-(3,4-dimethoxyphenytpropYL)-S-aLanyLcis-endo-2-azabicycLot3.3.03octane-3-S-carboxyL ic acid

J

rIF 7': 13 N-(l-S-carboethoxy-3-cycLopentyt~propyL)-S-aLanyL-c isendo-azabicycto-[3.3.Ojoctane-3-S-carboxyL ic acid N-(1-S-carboethoxy-3-phei'yLpropyL)-0-niethyL-S-tyrosyLcis-endo-2-azabicycLoE3.3.0)octane-3-S-carboxyLic acid N-(1-S-carboethoxy-3-phenyLpropyL)-0-ethyL-S-tyrosyLcis-endo-2-azabicycLo[3.3.0]octane-3-S-carboxyLic acid N-(1-S-carboethoxy-3--(4-fLuorophenyLpropyL)-S-aLanyLcis-endo-azabicycLo[3.3.Oloctane-3-S-carboxyL ic acid N-(1-S-carboethoxy-3-(4-methoxyphenyLpropyL )-S-aLanyLcis-endo-2-azabicycLoE3.3.Q]octane-3-S-car, oxyL ic ac id N-(1-S-carboethoxy-3-phenyLpropyL)-S-LysyL-(2S,3aR,6aS)octahydrocycLopenta~b~pyrroLe-2-carboxyL ic acid 1-S-carboethoxy-3-cycLohexyLpropyL )-LysyL-(2S,3a,6aS)octahydrocyctopenta~blpyrroLe-2-carboxyL ic acid 1-S-ca-",'oethoxy-3-phenyLpropy1 )-O-ethyL-S-tyrosyL- (2S,3aR,6aS)-octahydrocycLopentalbjpyrroLe-2-carboxyL ic 1-S-carboethoxy-3-phenyLpropyL )-S-atanyL-2- C2S,3aR,6aS)-octahydrocycLopenta~blpyrroLe-2-carboxyL ic N -S -c ar bo et ho x y-3-ph e n y p rop yI)- S -a Ia riyL-2 i z isp i ro- E4.53cdecane-3-S-carboxyL ic acid N -car bo e tho xy -3-phen yip rop yI) ethyl -2-tyr o s yIazaspiro-[4.5)decane-3-S-carboxyL ic acid N-(l-s-carboethoxy-3-phenyLpropyL)-S-Lysyt-2-azaspiro- [4.5]decane-3-S-carboxyL ic acid N-(l-S-carboethoxy-3-cy'cLohexyLpropyL)-S-StanyL-2-azaspiro[4.53clecane-3-$-carboxyL ic acid 1-S-carboethoxy-3-cy-cLohexyLpropyL )-s-lysyL-2-azaspiro[4.5]decane-3-S-carboxyL ic acid N-(1-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-2-azaspiro- E4.4]nonane-3-S-carboxyLic acid N -carbo e tho xy -3-phen yip rop y I) -0-e thyLI- S -tyr o sy1-2azaspiroE4.4]nonane-3-S-carboxyL ic acid N-(l-S-carboethoxy-3-phevwyLpropyL)-S-1ysyL-2-azaspiro- C4.4jnonane-3-S-carboxyLic acid N-(l-S-carboethoxy-3-cycLohexyLpropyL)-S-aLanyL-2-azaspirot4.4Jnonane-3-S-carboxyL ic acid /4]

I

h 14 N-(1-S-carboethoxy-3-cycLopentyLpropyL)-S-aLanyL-2azaspiroC4.4]nonane-3-S-carboxyt ic acid N-(l-S-carboethoxy-3-cycLopentyLpropyL)-S-LysyL-2-azaspiroC4.4Jnonane-3-S-carboxytic acid N-C-S-carboethoxy-3-phenytpropyL )-S-aLanyL.-spiro- [bicycLo[2.2.l)heptane-2,3--pyr-oLidine)-5'--S-carboxyLic a c id N-C 1-S-carboethoxy-3-phenyLpropyL)-0-ethyL-S-tyrosyLspirolbicycto[2.2.llheptane-2,3'-pyrroLidine-5--Scar-boxyLic acid N-(1-S-carboethoxy-3-phenypropyL)-S-LysyL-spiro-CbicycLo E2.2.ljheptane-2,3'-pyrroL idine)-5'-S-carboxyL ic acid N-(1-S-carboethoxy-3-cycLohexytpropyL)-S-aLanyL-spiro- [bicycLoE2.2.l)heptane 2,31-pyrroL idinej-51-S-carboxyt ic ac idc N-(1-S-carboethoxy-3-cyctohexytpropyL)-S-LysyL-spirolb icycL o[2. 2 .1J hept ane-2 3 1-py r roL i li neJ-5 I-S-c arboxyi c ac id N-C 1-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-spiro-CbicycLoE2.2.2)octane-2,3'-pyrroLidineJ-51-S-carboxyL ic a c, i d N-C( 1-S-carboethoxy-3-phenyLpropyL )-0-ethyt -tyrosyLsp iro~bicyc LoE2.2 .2Joc tane-2,3 '-pyrrot id isje)-5 I-ScarboxyLic acid N-C 1-S-carboethoxy-3-phenyLpropyL)-S--LysyL-spirolbicyctoC2.2.2)octane-2,3!-pyrroLidineJ-5--S-carboxyLic a c id 1-s-carboethoxy-3-cyc LohexyLpropyL )-S-at anyL-spi ro- Eb icycto[2 .2.2]octane-2,3 I-pyrroL idine)-5 I-S-ca rboxyL ic a c id N-(1-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-2-azatricyctot4.3.0.1 1 6 9 decane-3-S-carboxyL ic acid N-C 1-S-carboethoxy-3-phenyLprapyt )-0-ethyL--S-tyrosyL- 2-azatricycto[4.

3 .0.1 1 6 9 Jdecane-3-S-carboxyL ic acid N-C 1-S-carboethoxy-3-phenytpropyL )-S-LysyL-2-azatricyc to[4.3.0.1 1 6 9 decane-3-S-carboxyt ic acid N-(1-S-carboethoxy-3-cycLohexytpropyL)-S-atanyL-2azatricycto[4.3.O. 1 6 9 decane-3-S-carboxyL ic acid r -j 15 N-(l-S-arboethoxy-3-cyctohexyLpropyL)-S-Ly~syL-2-azatricycLoE4.3.D. 1ef, 9 Joecane-3-S-carboxyL ic a,,:id N-C 1-S-carboethc~xy-3-phenyLpropyI,)-S-atanyL-dec,3hydrocycLoheptalbjpyrroLe-2-S-carboxyL ic acid N-C 1-S-carboethoxy-3-phenyLpropyt )-0-ethyL-S-tyrosyLdecahydrocycLohepta~b~pyrroLe-2-S-carboxyL ic acid N-(1-S-carboethoxy-3-phenyLpropyL)-S-LysyL-decahydrocycLohepta~blpyrroLe-2-S-carboxyL ic acid N-(l-S-carboethoxy-3-cycLohexytpropyL)-S-aLanyL-decahydrocycLohepta~blpyrroLe-2-S-carboxyL ic acid N-C 1-S-carboethoxy-3-cycLohexytropyL)-S-LysyL-decahydrocycLoheptalblpyrroLe-2-S-carboxy.ic acid N-C l-S-carboethoxy-3-phenyLpropyt)--aLanyL-trans-octa- 0000 hydroisoindoLe-1-S-carboxyL ic acid N-C 1-S-carboethoxy-3-phenytpropyt )-S-aLanYL-c is-ccta- 4 *t 00o1ahydroisoindoLe--S-carboxyLc acid N-(l-S-carboethoxy-3-cycLohexyLpropyL)-S-atanyLtc is- 20octahydroisoincloLe-1-S-carboxyL ic acid N-C1-S-carboethoxy-3-phenhyLpropyL)-S-aLanyL-cisroc-ycropeonao~prro--S-carboxy ic acid N-C1-S-carboethoxy-3-py~heyLpropyL)-S-aLanyL-c sohydrocycLopenta~clpyrroLe--S-carboxy ic acid benzyL ester N-C 1-S-carboethoxy-3-cyctohexytpropyL)-S-LysyL-cis-octahydrocycLopenta~clpyrroLe-1-S-carboxyL ic acid N-(l-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-2,3,3a,4,5, la-hexahydroindoLe-cis-endo-2-S-carboxytic acid N-C 1-S-carboethoxy-3-phenyLpropyL )-s-LysyL-2,3,3a,4,5, 7a-hexihydroindo~e-cis-endo-2-S-carboxy~ic acid N-C 1-S-carboethoxy-3-cycLohexytpropyL)-S-Lysyt.-2-azabicycLoE3.1.0]hexane-3-S-carboxyL ic acid N-(1-S-carboxy-3-phienyLpropyL)-S-LysyL-2-azabicyc~fo- [3.1.O3hexane-cis-enoK-3S-ca oxylic acid N-(1-S-carboethoxy-3-cyctopentyLpropyl)-S-aLanyL-2-azabicycLot3. 1.0]hexane-3-carboxyL ic acid N-C1-S-carboethoxy-3-phenyLpropyL)-S-aLanyL-cis-endo-2t-r~i "1 ii

I

i i: ii i i 1 Ri 2? 16 azabicycloC3.1.0]hexane-3-S-carboxylic acid N-(1-S-carboethoxy-3-cyclohexylpropyl)-S-alanyl-cisendo-2-azabicyclo[3.1.03hexane-3-S-carboxylic acid.

These compounds can be prepared by, for example, the process described in German Patent Application P 3,333,455.2, in which process the tert.-butyl or benzyl esters described in the application are converted into the monocarboxylic acid derivatives in known manner by acid or alkaline hydrolysis or by hydrogenolysis catalyzed by noble metals. The Ne-benzyloxycarbonyl protective group of the lysine derivatives is removed by hydrogenolysis catalyzed by noble metals. The compounds Listed above can be readily converted with physiologically tolerated acids or bases (in the case of mono- or dicarboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.) ard be used as salts according to the invention.

The compounds of the formula I are inhibitors of angiotensin converting enzyme (ACE) or intermediates in the preparation of such inhibitors, and they can also be used to control high blood pressure of various etiologies. The compounds of the formula I are disclosed in, for example, US Patent 4,129,571, US Patent 4,374,829, European Patent A-79,522, European Patent A-79,022, European Patent A-49,658, European Patent A-51,301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72,352, US Patent 4,350,704, European Patent A-50,800, European Patent A-46,953, US Patent 4,344,949. European Patent A-84,164, US Patent 4,470,972, European Patent A-65,301 and European Patent A-52,991.

Also advantageous are orally effective ACE inhibitors such as, for example, ramipril, enalapril, captopril, lisinopril, perindopril, cilazapril, RHC 3659, CGS 13945, CGS 13928C, CGS 14824A, CI-906, SCH 31846, zofenopril, fosenopril, alacepril and others. Orally j w v Isirt 1 u ll l 17 effective ACE inhibitors are described in, for example, Brunner et at., J. Cardiovasc. Pharmacol. 7 (Suppl. I) (1985) S2-S11.

Preferred ACE inhibitors are those disclosed in European Patent A-79022, of the formula III

COOH

(S)

H NH CH CH 2

CH

2

CH

3

OOR

(III)

in which R denotes hydrogen, methyl, ethyl or benzyl, in particular the compound of the formula III in which R denotes ethyl (ramipril).

Other preferred ACE inhibitors are those disclosed in European Patent A-84,164, of the formula IV t 10 ~i I t

COOH

(S)

SCH NH CH CH CH 2 CH R (Iv) 1* in which R denotes hydrogen, (C 1

-C

4 )-alkyl or benzyl, in particular the compound of the formula IV, in which R denotes ethyL, In carrying out the method according to the invention, the angiotensin converting enzyme inhibitors described above can be administered to mammals such as monkeys, dogs, cats, rats, humans etc. The compounds which are suitable for the use according to the invention are advantageously incorporated in pharmaceutical products in customary manner. They can be converted into the customary administration forms, such as capsules, tablets, coated tablets, solutions, ointments and emulsions, as well as into a depot form. The active compound can, L 1 I fLw" 18 i whe;e appropriate, PLso be in microencapsulated form.

The products can contain additional, tolerated organic or inorganic substances, for example granulating auxiliaries, adhesives and binders, lubricants, suspending agents, solvents, antibacterial agents, wetting agents and preservatives. Forms for oral and parenteral administration are preferred. The compounds of the formula I can be administered in dosages of 0.1-50 mg per dose once to three times a day.

It is also possible according to the invention to use the ACE inhibitors in combination with substances which influence prostaglandin metabolism. Examples of such substances are stable prostacyclin analogs, inhibitors *ao of thromboxane synthetase, and thromboxane antagonists.

4 4 15 Hence the invention also relates to pharmaceutical compositions containing a) an ACE inhibitor or its physio- S logically tolerated salt and b) a substance which 4*4* influences prostaglandin metabolism or its physiologically tolerated salt, and to their use for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease.

The invention furthermore relates quite generally to products containing the substances mentioned above under a) and as combination products for concurrent, separate or sequential administration for the treatment of atnerosclerosis, of thrombosis and/or of peripheral vessel disease.

An increased aggregability of the blood platelets plays a particularly important part in the development of atherosclerosis. Examples of sequelae are thromboses and peripheral vessel disease; these diseases are the main cause of the increased morbidity and mortality associated with high blood pressure. Blood platelets contain an angiotensin-I-processing system, and their -19membrane has binding sites with high affinity for angiotensin II. The fact that angiotensin converting enzyme (ACE) is preponderantLy located on the luminal cytopLasmic membrane of the endothelial cells points to pLatelet/endothelium interactions being associated with local angiotensin II production; ACE inhibitors can interfere with this. Furthermore, inhibition of ACE potentiates the action of bradykinin by preventing its breakdown. It is known that bradykinin is a potent stimulator of the release of prostacyclin from endotheLial ceLLs; bradykinin is in turn a potent inhibitor of platelet aggregation.

The activity of the compounds of the formula I on 0 0 platelet aggregation and thus on atherosclerosis, oo o 15 thrombosis and peripheral vessel disease, as well as 00 0 0 other disease states associated with increased aggreg- 0 ability of the blood platelets, can be deduced from a 0o o 0 variety of test models.

0 o 0o o In each of the examples which follow use is made of the results with N-(1-S-carboethoxy-3-phenyLpropyl)-Salanyl-cis-endo-2-azabicyclo[3.3.0]octane-3-S-carboxylic B0 O acid (Formula II).

0 0 CH-NH- CH-CH2-CH I Hi CO22 Platelet-rich rabbit plasma is obtained as stated by Born (Arzneimittel-Forsch. 31, 2012 (1981)). Platelet aggregation is measured by the increase in light pass- I I ing through a cell which contains this plasma. The platelet count is adjusted to 450,000/mm 3 by dilution with autologous, platelet-poor plasma. The compound of the formula II has, in concentrations of 0.1-10 pg/ml of plasma, no effect on the aggregation induced by 0.24 mmol/L arachidonic acid, 5 mmol/L ADP or 4 pg/ml collagen. In contrast, the inhibition, brought about by 4 pg/ml PGI 2 of aggregation caused by arachidonic acid is increased to 100% by th compound of the formula II in the said dose range.

B In vivo results 1. Acute study r 1 g G Conscious rabbits received a single oral dose af 1.0-10.0 mg/kg of the compound of the formula II.

S 15 After 1 hour, the animals are sacrificed, and I t f platelet-rich plasma is obtained. Platelet aggreg- I t ation is determined as described under A).

There is found to be a reduction in aggregation in respon;e to the three stimulators described there, in particular in response to arachidonic acid. A potentiation of the PGI 2 effect is also observed.

S2. Chronic study j Conscious rabbits received 1 mg/kg/d of the compound I of the formula II for 14 days, and then the procedure was continued as described under Pronounced inhibition of the platelet aggregation induced by arachidonic acid and ADP is found in all animals.

The examples which follow indicate the forms for administration to treat atherosclerosis, thrombosis and peripheral vessel disease by the method according to .r~I ;n* 21 the invention. The compounds of the formula I can be converted into the corresponding forms for administration in analogy to the examples.

Example 1 Preparation of the agent used according to the invention for oral administration in the treatment of atherosclerosis, of thrombosis and of peripheral vessel disease.

1000 tablets each containing 10 mg of 1-N-(1-S-carboethoxy-3-phenylpropyL)-S-alany-1S,3S,5S-2-azabicycLo- C3.3.03octane-3-carboxyic acid are prepared with the following auxiliaries: i i i i j: I I, $1 1-S-carboethoxy-3-phenypropyl)-S-alanyL- 1S,3S,5S-2-azabicycloE3.3.01octane-3carboxylic acid Corn starch Gelatine Microcrystalline cellulose Magnesium stearate 10 g 140 g 7.5 g 2.5 g 2.5 g 20 1-S-carboethoxy-3-phenypropy)-S-alanyL-1S,3S,5S- 2-azabicycloC3.3.3octane-3-carboxy ic acid and corn starch are mixed with an aqueous gelatine solution.

The mixture is dried and milled to granules. Microtrystaline cellulose and magnesium stearate are mixed with the granules. The resilting granules are compressed to form 1000 tablets, each tablet containing mg of the ACE inhibitor.

These tablets can be used for the treatment of athirosclerosis, of thrombosis and/or of peripheral vessel disease.

-22 j ExampLe 2 1000 tabLets each containing 10 mg of N-C 1-S-carboethoxy-3-phenyLpropyl )-S--aLanyL-C2S,3aR,7aS )-octahydroindoLe-2-carboxyLic acid hydrochLoride are prepared in analogy to Example 1.

Example 3 Gelatine capsules each containing 10 mg of N-(1-Scarboethoxy-3-phenyLpropyL)-S-aLanyLlS,3S,5S-2-azabicycLoL3.3.0)octane-3-carboxyLic acid are filled with the following mixture: N-(l-S-carboethoxy-3-phenyLpropyL)-S-aLanyL- 1S,3S,5S-2-azabicycLo[3.3.0]octane-3carboxyLic acid 10 mg Magnesium stearate 1 mg Lactose V1~4 mg These capsules can be used for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel di s ea se.

Example 4 The preparation of an injection solution for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease is described below: N-(1-S-carboxy-3-phenyLpropYL)-S-aLanyL- IS,3S,5S-2-azabicycLot3.3.0)octane-3carboxyLic acid 250 mg MethyLparab?n 5 9 PropyLparaben 1 g Sodium chloride 25 g Water for injections 5 L -23- N -Cl-S-carboxy-3-phenyLpropyL )-S-aLanyLlS,3S,5S-2azabicycLo[3.3.O]octane-3-carboxyLic acid, the preservat ives and sodium chloridle are dlissolved in 3 L of water for injections, and the solution is riade up to L with water for injections. The solution is filtered sterile, and dispensed aseptically into presterilized bottles, which are closed with sterilized rubber caps.

Each bottLe contains 5 mL of solution.

Example t S I I S Ii S 5 45 S I I 4 ~S IS 55 44 4 S S S S j Tablets which can be used for the treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease are prepared as described in Example 1, with the exception that in place of N-(l-S-carboethoxy-3phenyLpropyL)-S-aLanyLlS,3S,5S-2-azabicycLo[3.3.0J- 15 octane-3S-carboxyLic acid N-(.-S-carboxy-3-phenytpropyL)-S-aLanyLlS,3S,5S-2azabicycLof3.3.Ojoctane-3-carboxyL ic acid or N-(1-S-carboxy-3-phenyLpropyL)-S-aLanyL-2S,3aR,laSoctahydroindoLe-2-carboxyl ic acid or N-C 1-S-carboethoxy-3-phenyLpropyL )-S-aLanyL-c is- 2,3,3 a 4,5,7a-hex ahydro['I HI indoLe-2-S-endo-c arboxyL i c ac id or N-C 1-S-carboxy-3--phenyLpropyL)-S-aLanyL-cis-2,3, 3 a,4, 5,7a-hexahydroE1lI~indote-2S-endo-carboxyLic acid or N-C 1-S-carboxy-3-phenyLpropyL )-S-LysyL-IS,3S,5S-2azabicycLoE3.3.03octane-3-carboxyL ic acid or N-(l-S-carboethoxy-3-cycLohexyLpropyL)-S-aLanyL- 1S,3S,5S-2-azabicycLot3.3.03octane-3-carboxyL ic acid or N-C 1-S-carboxy-3-cycLohexyLpropyl)-S-LysyL-1S,3S,5S-2azabicycLot3.3.03octane-3-carboxyLic acid are used.

Example-6 An injection soLution is prepared in anaLogy to the procedure described in ExampLe 4, with the exception that in ptace of N-C1-S-carboethoxy-3-phenyLpropyL)-S- -24aLanyL-lS,3S,5S-2-azabicycLoC3.3.Ojoctane-3-carboxyLic a c id 1-S-carboxy-3-phenyLpropyL )-S-aLanyL-1S,3S,5S-2azabicycLo[3.3.0)octane-3-carboxyL ic acid or 1-S-carboethoxy-3--phenyLpropyL )-S-atanyL-2S,3aR,7aSoctahydroindoLe-2-carboxyLic acid hydrochloride or N-(l-S-carboxy-3-phenyLpropyL)-S-aLanyt-2S,3aR,7aSoctahydroindote-2-carboxyt ic acid or N-(1-S-carboethoxy-3-cycLohexyLpropyL)-S-aLany--cis- 2,3,3a,4,5,7a-hexahydroE 1H] indoLe-2-S--endo-carboxyL ic ac id or 1-S-c arboxy-3-pheny L propy L)-S-a LanyL-c is-2,3,3a.4,5, 7a-hexahydro~lH~indoLe-2-S-endo-carboxyL ic acid or N-(1-carboxy-3-phenyLpropyL)-S-LysyLl-S,36,5S-2-azabicycLoE3.3.O]octane-3-carboxyLic acid oi, N-(1-S-carboethoxy-3-cycLohexyL)-S-aLanyL-lS,3S,5S-2azabicycLoC3.3.0]octarie-3-carboxyL ic acid or N-(l-S-carboxy-3-cycLohexyLpropyt )-S-LysyL-lS,3S,5S-2azabicycLoE3.3.O]octane-3-carboxyLic acid are used.

Claims (2)

1. 6-12 carbon atoms, an optionally substituted arali- phatic radical having 7-14 carbon atoms, an option- ally substituted alicyctic-aiphatic radical having
2. 7-14 carbon atoms, or a radical ORa or S, in -"wh hich R represents an optionally substituted .7 aliphatic radical having 1-4 carbon atoms, an opt- ionally sv stituted aromatic radical, having 6-12 carbon atoms, or an optionally substituted hetero- aromatic radical having 5-12 ring atoms, R 1 denotes hydrogen, an optionally substituted ali- phatic radical having 1-6 carbon atoms, an option- ally substituted alicyctic radical having 3-9 carbon atoms, an optionally substituted alicyclic- aliphatic radical having 4-13 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atums, an optionally substituted araliphatic radical having 7-16 carbon atoms, an optioriatLy U ri 14- 26 substituted heteroaromatic radical having 5-12 ring atoms, or the side chain, protected where necessary, of a naturaLLy occurring a-amino acid, 2 3 R and R are identical or different and denote hydro- gen, an optionally substituted aliphatic radical having 1-6 carbon atoms, an optionally substituted aLicyclic radical having 3-9 carbon atoms, an opt- ionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted aralipha- tic radical having 7-16 carbon atoms, and 4 5 R and R form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 4 to 15 carbon atoms, or its physiologically tolerated salt. 00 0""0 Q The method as clai.ed in claim 1 wherein &no so there is administration of comsounds of the formula I a o I Saa in which R and R together with the atoms carrying them represent an optionally substituted system from the series comprising tetrahydroisoquinoLine, decahydro- isoquinoline, octahydroindoe, octahydrocyclopentadb) pyrrole, 2-azaspiroC4.53decane, 2-azaspiroC4.43nonane, spiroE(bicyclo[2.2.l3heptane)-2,3'-pyrroLidine3, spiro- E(bicyclo[2.2.23octane)-2,3-pyrroL idine3, 2-azatri- cyco[4.3.0.1 6 9 3decane, decahydrocycLoheptalb3pyrrole, octahydroisoindl.e, octahydrocyclopentaCc3pyrroe, 2,3,3a,4,5,7a-hexahydroindoLe and 2-azabicyclo[3.1.03- hexane. I The method as claimed in one of claims 1 to 2, wherein there is zdministration of compunds of the formula I in which n is 1 or 2, R denotes hydrogen, alkyl having 1-8 carbon atoms, alkenyL having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C 1 -C 4 aLkyt, (Cl-C 4 )-alkoxy, hydroxyl, halogen, nitro, t-j -27 000Q o 0000 4040 0 00 I' 00 00 09 00 0 0 0 00 0 6 0000 amino, aminomethyl, (Cl-C 4 )-aLkyL amino, di-(C -C 4 al kylarnino, (CC-C 4 )-aLkanoyLamino, methylenedioxy, carboxyl, cyano and/or suLfamoyl, aLkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryL, mono- or bicyctic heteroaryloxy which has 5-7 or 8- ring atoms respectiveLy, 1 to 2 of these ring atoms representing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen, and which can be substituted as described above for aryl, amino-(ClC-C 4 )-aLkyL, (C 1 -C 4 )-aLkanoyLamino-(C 1- C 4 )-aL kyl, (C 7 -Cl 3 )-aroyLamino-(C -C 4 )-aLkyL, (C 1 C4)-atkoxycarbonytamino-(Cl-C 4 )-aLkyL, (C 6 -C 12 aryL-(Cl-C 4 )-aLkoxycarbonyLamino-(Cl-C 4 )-aLkyL, (C6-Cl2)-aryt-(Cl-C 4 )-aLkyLamino-(Cl-C 4 )-atkyL, (Cl-C 4 )-atkyt amino-(Cl-C 4 )-alkyL, di-(Cl-C 4 )-aLkyL- amino-(Cl-C 4 )-alkyL, guanidino-(C -C 4 )-alkyL, imid-zoLyt, indlolyl, (Cl-C 4 )-aLkytthio, (C 1 -C 4 aLkyL th io-( C-C 4 )-aLkYL, (C 6 -C 12 )-aryLthjo-(C -C 4 alkyl which can be substituted in the aryl moiety as described above for aryl, (C6-Cl2)-aryL-(C- C 4 )-aLkyLthio which can be substituted in the aryL moiety as described above for aryl, carboxy-(Cl- C 4 )-aLkyL, carboxyl, carbamoyL, carbamoyL-(Cl-C 4 aLkyL, (C l-C 4 )-aLkoxycarbonyL-(Cl-C 4 )-aLkyL, (C 6 C 12 )-aryLoxy-(Cl-C 4 )-aLkyL which can be substitu- ted in the aryl moiety as described above for aryl, or (C 6 -Cl 2 )-aryL-(Cl-C 4 )-atkoxy which can be substituted in the aryl moiety as described above for aryL, Rdenotes hydrogen, aLkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, alkynyl having 2-6 carbon atoms, cycLoalkyL having 3-9 carbon atoms, cycLoaLkenyL having 5-9 carbon atoms, (C 3 -C 9 cycLoaLkyL-(Cl-C4)-aLkyL, (C5-C9)-cyctoaLkenyL- (Cl-C 4 )-aLkyL, optionalLy partially hydrogenated aryL which has 6-12 carbon atoms and can be substi- tutod as described above for R, (C-I)arL(l 0 tO 0S 00 0 I al- -28- C 4 )-aLkyL. or (C7-C13)-aroyL-(Cl or C 2 )-aLkyL, both of which can be substituted as the abovementioned aryl, mono- or bicyclic, optionally partially hydro- genated heteroaryL which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms represent- ing sulfur or oxygen atoms and/or 1 to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as the abovementioned aryL, or the optionally protected side chain of a naturally occurring a-amnino acid R 1 -CH(NH 2 )-COOH, R 2 and R 3are identical or different and denote hydro- gen, aLkyl having 1-6 carbon atoms, aLkenyL having 2-6 carbon atoms, di-(Cl-C 4 )-aLkyLamino-(C--C 4 al kyL, (Cl-C 5 )-aLkanoyLoxy-(C-C 4 )-aLkyl, (CC-C 6 aLkoxycarbonyLoxy-( Cl-C 4 )-aLkyL, CC 7 -C l3)-aroyLoxy- (C 1 -C 4 -aLkyL, (C 6 -C 12 )-aryLoxycarbonyLoxy-(C -C 4 aLkyL, aryt having 6-12 carbon atoms, (C 6 -Cl 2 aryL-( Cl-C 4 )-aLkyL, (C 3 -C 9 )-cycLoaLkyL or (C3-C9)-cyct oaLkyL-(C 1 -C 4 )-aLkyL, and Rand R 5have the abovementioned meaning. yj,. The method as claimed in one of claims 1 to,3, wherein there is administration of ES,S,S,S,S)-N-(1- carboethoxy-3-phenyLpropyL)-aLanyL-octahydroindoLe-2- carboxyL ic acid, N-C 1-CS)-carboethoxy-3-phenyLpropyL (S)-atanyLj-2S,.3aR,7aS-octahydroindoLe-2-carboxyLic acid, CS,S,S,S,SJ-N- 1-carboethoxy-3-phenyLpropyL aLanyL)-decahydroisoquinoLine-3-carboxyL ic acid, ES,S,S)-N-C(1-carboethoxy-3-phenyLpropyL)-aLanyL]- tetrahydroisoquinoLine-3-carboxyLic acid, N-01-S- carboethoxy-3-phenyLpropyL)-S-aLanyL-cis-endo-2-aza- bicycLoE3.1.O]hexane-3-S-carboxyLic acid or N-C 1-S- carbpethoxy-3 ,phenyLpropy1)-S-aLanyL-cis-endo- 2,,7,3a,4,5,7a-h ,xahydroindoLe-2-S-carboxyL ic acid. S.The method as claimed in one of cLaims 1 to wherein there is administration of (S,S,S,S,S)-N-C1- carboethoxy-3-phenyLpropyL)-atanyL-2-azabicycLoE3.3.OJ- r *11i I- I 1 W 29 octane-3-carboxylic acid. 6. The method as claimed in claim 4 or 5, wherein in place of the ethyl esters there is administration of the corresponding dicarboxylic acids. 7. A method of treatment of atherosclerosis, of thrombosis and/or of peripheral vessel disease by administering to a patient suffering therefrom a pharmacologically effective amount of a compound of formula as claimed in any one of claims 1 to 6. DATED this 30th day of June, 1989 HOECHST AKTIENGESELLSCHAFT o o 00o0 0400 0 00 o eo 0 6 0 0 e0 0 4 0 I tO t WATERMARK PATENT TRADEMARK ATTORNEYS Queen Street MELBOURNE. VIC. 3000 AUSTRALIA 4 C t 0 COl~ 0 0 4 C C CC L KJS:SC(1.43) 0