AU621278B2 - Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfunctions - Google Patents

Abstract

The invention relates to novel compounds having a nootropic activity, the use of ACE inhibitors as medicaments having nootropic activity, agents containing them, and their use in the treatment and prophylaxis of cognitive malfunctions.

Description

i' II~ CL-~ S6-21 278o COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION

(ORIGINAL)

Class Int. Class Application Number: 7064/Y7 Lodged: Complete Specification Lodged: Accepted: Published: Priority: 4 I S Related Art: .*4 Name of Applicant: *e tC I Address of Applicant: I I It Actual Inventor: S'Address for Service: 4 oQ HOECHST AKTIENGESELLSCHAFT 45, Bruningstrasse, D-6230 Frankfurt/Main Federal Republic of Germany FRANZ HOCK, JOSEF SCHOLTHOLT, HANSJORG URBACH, RAINER HENNING, ULRICH LERCH, WOLF-ULRICH NICKEL and WOLFGANG RUGER.

EDWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.

Complete Specification for the invention entitled: "COMPOUNDS HAVING A COGNITION ADJUVANT ACTION, AGENTS CONTAINING THEM, AND THE USE THEREOF FOR THE TREATMENT AND PROPHYLAXIS OF COGNITIVE

DYSFUNCTIONS"

The following statement is a full description of this invention, including tt f best method of performing it known to la COMPOUNDS HAVING A COGNITION ADJUVANT ACTION, AGENTS CONTAINING THEM, AND THE USE THEREOF FOR THE TREATMENT AND PROPHYLAXIS OF COGNITIVE DYSFUNCTIONS The invention relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically tolerated salts as medicaments having a cognition adjuvant action (improving cognitive function) and to the use thereof in the preparation of corresponding pharmaceutical formulations.

Examples of suitable compounds for this novel use are those of the formula I X X 2

(I)

in which X 1 denotes R 3 00C CH N C -(CHR

I

S14 15 II R R 0 Nj 0 m 2 o r 3

CH

2 or R00C 0 j00R 3

COOR

X

2 denotes O 6 7 -CH SH, -CH -S-C-R -CH -P-R or 1 2 2 2( o 0 OR -Y )p-CH-(CH )n-R 2

COOR

Y1 represents or -CH 2 Y2 represents -NR 9 or -CH 2 m is 0 or 1 n is 0, 1 or 2, p is 0 or 1 R denotes hydrogen, an optionally substituted aliphatic radical having -rr 15 Sr 4r 5 20 .r t1~ S C t 2- 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4-20 carbon at'ms, an optionally substi.ed heteroaromatic or heteroaromatic-(C 1

-C

8 )-al~jhatic radical having 5-12 ring atoms, or a radical ORa or SRa, in which Ra represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted heteroaromatic radical having Ii 5-12 ar0n atoms, R denotes hydrogen, an optionally substituted 1-21 carbon atoms, an optionally substituted 3-20 carbon atoms, an optionally substituted having 4-20 carbon atoms, an optionally substituted 6-12 carbon atoms, an optionally substituted 7-32 carbon atoms, an optionally substituted aliphatic radical having alicyclic radical having alicyclic-aliphatic radical aromatic radical having araliphatic radical having heteroaromatic or heterL I 5 C

I

t c I ii', 30 aromatic-(C 1

-C

8 )-aliphatic radical having 5-12 ring atoms, or, if not already covered by the above definitions, 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 1-21 carbon atoms, San optionally substituted alicyclic radical having i--I 3-20 carbon atoms, an optionally substituted aromatic radicaL having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, R represents hydrogen or (C 1

-C

6 )-aky and represents (C 1

-C

6 )-aky, (C 3

-C

6 )-cycoalkyL or or 4 5 R and R form, together with the -atoms carrying them, a mono-, bi- or tricyclic, heterocyclic ring system having 3 to 15 ring carbon atoms, R6 denotes hydrogen, amino, (C 1

-C

6 )-alky, (C 6

-C

12 aryl or (C 7

-C

13 )-arakyL, 7 ,i R denotes (C1-C 6 )-aky or (C7-C13)-araky, preferably

-(CH

2 4

-C

6

H

R8 denotes (C 1

-C

6 )-aLkyl, which is optionally monottCt r substituted by (C 1

-C

6 )-akanoyLoxy, preferably 2-methyl-1-propionyloxypropyl, and 9 t R denotes hydrogen or (C 1

-C

6 )-alky; such as compounds of the formula II, It. R00C CH- N -C CH- NH JH (CH)-R (II) 4 5 1 1 2 0 R COOR in which n is 1 or 2, R denotes hydrogen, an optionally substituted aliphatic radical having 4 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted alicyclic-aLiphatic radical 4 having 4-20 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic-(C 1 -Cg)-aliphatic radical having 5-12 ring atoms, or a radical ORa or SR a in which Ra represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted heteroaromatic radical having 5-12 ring atoms,

R

1 denotes hydrogen, an optionally substituted aliphatic radical having 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, c c an optionally substituted alicyclic-aliphatic radical having 4-20 carbon atoms, an optionally substituted aromatic radical having .t 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic-(C 1

-C

8 )-aliphatic radical having 5-12 K ring atoms, or, if not already covered by the above definitions, the side-chain, protected where necessary, of a naturally occurring a-amino acid,

R

2 and R are identical or different and denote hydrogen, an optionally substituted aliphatic radical having 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, and 4 5 R and R form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms.

An optionally substituted aliphatic radical is understood to be an aliphatic acyclic radical, i.e. a radical with an open, straight or branched carbon chain such as, for example, alkyl, alkenyL, alkynyl and corresponding multiply unsaturated radicals. It is preferably unsubstituted or, as described below, for example, for carboxy, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, aryLalkyaminoalkyl, alkylaminoalkyl, dialkylaminoaLkyl, alkylthioalkyl, a-ylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl,

T

alkanoyLoxyaLkyL, alkoxycarbonyloxyalkyL, aroyloxyalkyl or aryloxycarbonyLoxyalkyl, monosubstituted.

An optionally substituted alicyclic radical, and the corresponding optionally substituted alicyclic-aliphatic radical 15 which is linked via an open carbon chain, is a preferably monoto pentacyclic, isocyclic, nonaromatic radical which has \1single bonds or asymmetrically distributed double bonds I and can also be branched carry open-chain aliphatic side-chains) and is Linked via a ring carbon atom or a side-chain carbon atom. It is preferably unsubstituted.

When several rings are components of a radical of this type, C they are fused, spiro-linked or isolated. Examples of radicals of this type are cycloalkyl, cycloalkernyl, cycloalkylalkyl, bicycloalkyl, tricycloalky and radicals derived from mono-, bi- or oligocyclic terpenes such as menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, menthanyl, neomenthyl, neoisomenthyl, pinanyl and thujanyl; they are preferably unsubstituted (according to the present definition, aliphatic side-chains are not substituents).

An optionally substituted aromatic radical is preferably aryl such as phenyl, biphenylyl or naphthyl, which is optionally mono-, di- or trisubstituted as indicated below for aryl. Radicals derived from aryl, such as aralkyl, aryloxy, aryLthio or aroyl, preferably benzoyl, can be substituted as for aryl.

r 6 An optionally substituted heteroaromatic radical is preferably an aromatic mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 12, preferably up to 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 is understood to be, for example, thienyl, benzoCb3thieny, furyl, pyranyl, benzofuryL, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindoLyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazoyL or isothiazolyl. These radicals can also be partially or completely hydrogenated. A heteroaromatic radical and the corresponding heteroaromaticaliphatic radical can be substituted as defined below.

0000 An optionally substituted araliphatic radical is under- 0000 stood to be, in particular, aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is 0 0 20 as defined above and which can be substituted in the manner *0 indicated there.

g R and R can form, with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 25 15 ring carbon atoms and preferably has up to 2 sulfur 0 atoms and up to 2 nitrogen atoms in the ring, in particu- S* lar up to 1 sulfur atom.

Particularly suitable ring systems of these types are 30 those of the following group: Pyrrolidine thiazolidine tetrahydroisoquinoline decahydroisoquinoline octahydroindole indoline octahydrocyclopentaEblpyrroe 2-azaspiroE4.5decane 2-azaspiroE4.4]nonane spiroE(bicycoE2.2.ljheptane)- 2,3'-pyrroLidinel spiroE(bicycloE2.2.2octane)-2,3'pyrrolidinel 2-azatricycLoE4.3.0.1 6 9 Jdecane decahydrocycloheptaEb3pyrroe octahydroisoindole -7 octahydrocycLopenta~clpyrrole CL); 2,3,3a,4,5,7a-hexahydroindlole CM); 2-azabicycLoE3.1.0]hexane 1,2,3,3a,4,6ahexahydrocycLopentalbjpyrroLe CP), all of which can optionally be substituted. PyrroLidline and thiazoLidine CR); can be monosubstituted by, for example, CC 6 -Cl 2 )-aryL, (phenyL, 2-hydroxyphenyL etc.), CC 6

-C

1 2)-aryLmercapto (such as phenylmercapto) or CC 3 -Cj')-cycLoalkyL (such as cyclohexyl). Tetrahydroisoquinoline can carry, for example, in the aryl moiety, up to 2 (Cl-C 6 )-aLkoxy radicals, preferably methoxy radicals. A corresponding statement applies to the other ring systems. However,-the unsubstituted systems are preferred.

With compounds of the formula I or II which have several chiraL atoms all possible diastereomers, as racemates or enantiomers, or mixtures of various diastereomers are suitable.

The suitable heterocycLic ring systems have the following structural formulae.

g *r C r C C tI t

CC

C t1 t t t

-A-

r' Ccr...cXR op 3

CO*

COOR 3 00 0 0 *qoR 0~ a a a Q00W 00*0 0 0 *000 *0 o 0 *00 0* 00* a.

a o 4 00 00 (4 4$ 44 4' 4 $4 4$ (4 4 4 44 1 (4

G

C R3

COCOOR

CI

R

COOR3

L

COOX3 (-COO

R

3 CrN

COOR

3 ii N dC>'N

COOR

3 I R -9- A preferred embodiment comprises use of compounds of the formula I, preferably those of the formula II, in which a) n is 1 or 2; b) R 1. denotes hydrogen; 2. denotes alkyl having 1-18 carbon atoms; 3. denotes an aliphatic acyclic radical of the formula CaH(2a-b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and b represents an integer 2 to a; 4. denotes a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula CcH(2c-d-1), which is optionally branched, in which c represents an integer 3 to 20, and d represents an even number 0 to j 5. denotes aryl which has 6-12 carbon atoms and can

S

t be mono-, di- or trisubstituted by (C 1

-C

8 )-alkyl,

S(C

1

-C

4 )-alkoxy, hydroxyl, halogen, nitro, amino, ottt aminomethyl, (C 1

-C

4 )-alkylamino, di-(C 1

-C

4 CL t t alkylamino, (C 1

-C

4 )-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl; 6. if n is 2, denotes (C 6

-C

12 )-aryl-(C 1

-C

8 )-alkyl or di-(C 6

-C

12 )-aryl-(C 1

-C

8 )-alkyL, each of t Ct ct which can be substituted in the ary' moiety as described under I.b)5; or 7. alkoxy having 1-4 carbon atoms; 8. aryloxy which has 6-12 carbon atoms and can be substituted as described under 9. mono- or bicyclic heteroaryloxy or heteroaryl-

(C

1

-C

8 )-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 to 2 rin.g atoms representing sulfur or oxygen and/or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as described under amino-(C 1

-C

8 )-alkyl; 11. (C 1

-C

4 )-alkanoylamino-(C 1

-C

8 )-alky 12. (C7-C13)-aroylamino-(Ci-Cg)-alkyl; 1 ,I I 4

A

ii

V

66 20 6 161 306 13. (C 1

-C

4 )-aLkoxycarbonyLamino-(Cl-C 8 )-aLkyL; 14. CC 6 -Cl 2 )-aryL-(Cl-C 4 )-aLkoxycarbonyLamino-

(CC-C

8 )-atkyL;

(C

6

-C

12 )-aryL-(Cl-C 4 )-aLkyLamino--(Cl-C8)a Lk y L; 16. (Cl-C 4 )-aLkyLamino-(Cl-C 8 )-aLkyL; 17. di-(Cl-C 4 )-aLkyLamino-(Cl-C 8 )-aLkyL; 19. imidazolyl; 20. indoLyL; 21. (Cl-C 4 )-aLkyLthio; 22. if n is 2, (CC-C 4 )--aLkyLthio-(C 1

-C

8 )-aLkyL; 23. (C 6

-C

12 )-aryLthio-(Cl-C 8 )-atkyL which can be substituted in the aryl moiety as described under 24. (C 6 -Cl 2 )-aryL-(C 1

-C

8 )-aLkyLthio which can be substituted in the aryL moiety as described under if n is 2, carboxy-(Cl-C 8 )-aLkyL; 26. carboxyl; 27. carbamoyL,; 28. if n is 2, carbamoyL-(Cl-C 8 )-aLkyL; 29. (Cl-C 4 )-aLkoxy-carbonyL-(C-C 8 )-aLkyL; if n is 2, (C6-C12)-aryLoxy-(Cj-C8)-aLkyL which can be substituted in the aryl moiety as described under I.b)5; or 31. denotes (C 6 -Cl 2 )-aryL-(Cl-C 8 )-aLkoxy which can be substituted in the aryL moiety as described under 1. denotes hydrogen; 2. denotes alkyl having 1-18 carbon atoms; 3. denotes an aliphatic radlical of the formula CaH(2a-.b+l), in which dloubLe bonds, if their number exceeds 1, are not cumuLative, a represents an integer 2 to 18, and b represents an even number 2 to a; 4. denotes a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radlical of the formula ~1 A 2 d) R 2 C t s 25 t I30 E 14 It 11 CcH(2c-d-1), which is optionally branched and in which c represents an integer 3 to 20 and d represents an even number 0 to aryl which has 6-12 carbon atoms and can be substituted as described under 6. (C6-C12)-aryl-(C1-C 8 )-alkyl or (C7-C 13 aroyl-(Cl-C 8 )-alkyl, both of which can be substituted as described for aryl under 7. mono- or bicyclic, optionally partially hydrogenated, heteroaryl or heteroaryl-(Ci-C 8 )-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 or 2 ring atoms representing sulfur or oxygen and/ or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as described for aryl under I.b)5; or 8. if not already covered by c) 1. the optionally protected side-chain of a naturally occurring a-amino acid of the formula R 1

-CH(NH

2

)-COOH;

3 and R are identical or different and 1. denote hydrogen; 2. alkyl having 1-18 carbon atoms; 3. denote an aliphatic acyclic radical of the formula CaH(2a-b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and b represents an even number 2 to o; 4. a mono-, di-, tri-, tetra- or pentacyclic, nonaromatic hydrocarbon radical of the formula CcH(2c-d-1), which is optionally branched and in which c represents an integer 3 to 20 and d represents an even number 0 to di-(Ci-C 4 )-alkylamino-(Ci-C 8 )-alkyl; 6. (Cl-C5)-alkanoyloxy-(Ci-C 8 )-alkyl; 7. (Cl-C6)-atkoxy-carbonyoxy-(Cl-C8)-alkyl; 8. (C7-Ci3)-aroyloxy-(i-C8)-alkyL; 9. (C6-C12)-aryLoxycarbonyLoxy-(Ci-C8)-alkyL; 0. aryl having 6-12 carbon atoms; or

I

_r ar_-_~L a# 12 11. denote (C 7

-C

20 )-araLkyL; it being possible for the radicaLs mentioned under dl) and 11. to be substituted in the aryt moiety as described under and e) R 4 and R 5 form, togeth~er with the atoms carrying them, a mono-, bi- or tricycLic heterocycLic ring system having 3 to 15 ring carbon atoms.

A particuLarLy preferred ambodiment tomprises use of compounds of the formula I, preferably those of the formula 11, in which n is 1 or 2, R denotes hydrogen, alkyt having 1-8 carbon atoms, aLkenyt having 2-6 carbon atoms, cycLoaLkyl having 3-9 carbon atoms, aryL which has 6-12 carbon atoms and can be mono-, dli- or trisubstituted by (Cj-C 4 )-aLkyL, (Cl-C 4 aLkoxy, hydroxyl,, halogen, nitro, amino, aminomethyL, C (C I-C 4 )-atkytamino, di-(Cl-C 4 )-aLkyLamino, (Cl-C4)-aLkanoyLamino, methyLenedlioxy, 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 o~f these ring atoms represent ing nitrogen, and which can be substituted as described above for aryl, amino- (Cl-C 4 )-atkyL, (Cl-C 4 )-aLkanoyta~iino-(C 1

-C

4 )aLkyt, (C7-Cj3)-aroylamino-(CI-C 4 )-aLkyt,

(C

1

-C

4 )-aLkoxycarbonyLamino-(C 1

-C

4 )-aLkvl, (C6-CI2)-aryL-(Cl-C4)-aLkoxycarbonylamino-

(C

1

-C

4 )-atkyt, -13- (Cl-C 4 )-aLkyLamino-(C 1

-C

4 )-atkyL, di-(C 1

-C

4 )-atkyLamino-(Cl-C 4 )-atkyt, guanidino-(Cl-C 4 )-aLkyL, imidlazotyt, indlotyt,

(C

1

-C

4 )-atkytthio, (Cl-C 4 )-aLkyLthio-(Cl-C 4 )-aLkyt,

(C

6 -Cl 2 )-aryLthio-(Cl-C 4 )-atkyL which can be substituted in the aryL moiety as described above for aryt,

(C

6

-C

1 2)-aryL-(Cl-C 4 )-aLkyLthio which can be substituted in the aryL moiety as described above for aryt, carboxy-(CI-C 4 )-aLkyL, carboxyl, carbamoyt, carbamoyt-(Cl-C 4 )-atkyt, (Cl-C4)-atkoxycarbonyt-(Cl-C 4 )-aLkyt, (C6-C 1 2)-arytoxy-(Cl-C 4 )-aLkyt which can be substituted in the aryt 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 aryt, 4 L t R denotes 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, t t V t 4 cycloaLkenyL having 5-9 carbon atoms, A 331 (C5-C9)-cycLoaLkenyL-(C l-C 4 )-aLkyL, optionally partiaLLy hydrogenated aryL which has 6- 12 carbon atoms and can be substituted as described above for R, (C 6

-C

12 )-aryL-(C 1

-C

4 )-aLkyL or (C 7 -Cl 3 aroyl-(Cl or C2)-aLkyL, both of which can be substituted as for the preceding aryl, mono- or bicycLic, optionaLy partially hydrogenated heteroaryL which has or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms, The following statement is a full description of this invention, including tt,.N best method of performing it known to :.us 17 ~-ii-1 4 o 4 4 4* 4 0*e* 44 4 9 9 44~O 4* 444 4 4 0t (4 4* 4t 4 t -C C -14 and/or I to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as for the preceding aryl, or the optionally protected side-chain of a naturally occurring ot-amino acid, R 1-CH(NH 2

)-COOH,

Rand R 3 are identical or different and denote hydrogen, aLkyL having 1-6 carbon atoms, aLkenyL having 2-6 carbon atoms, di-(Cl-C 4 )-aLkyLamino-(Cl-C4)-aLkyL, (Cl-C 5 )-aLkanoyLoxy-(Cl-C4 )-aLkyL, (Cl-C 6 )-aLkoxycarbonyLoxy-(Cl-C4)-aLkyL,

(C

7 -Cl 3 )-aroyLoxy-(Cl-C4 )-aLkyL,

(C

6 -Cl 2 )-aryLoxycarbonyLoxy-(Cl-C4)-aLkyL, aryL having 6-12 carbon atoms,

(C

3

-C

9 )-cycLoaLkyL or

(C

3

-C

9 )-cycLoaLkyL-(Cl-C4)-aLkyL, and 20 R4and R 5 have the abovementioned meaning, particularly such compounds in which n is 1 or 2, R denotes (Cl-C 6 )-alkyl, (C 2

-C

6 )-aLkenyL, CC 3

-C

9 cyc LoaLkyL, amino-(Cl-C4)-aL kyL, (C 2

-C

5 )-acyLamino- 25 (C 1

-C

4 )-aLkyL, (C 1 -Cl 3 )-aroyLamino-(Cl-C 4 )-aLkyL, (Cl-C 4 )-alkoxycarbonyLamino-(Cl-C4)-aLkyL,

(C

6 -Cl 2 aryL-(C 1

-C

4 )-aLkoxycarbonyLamino-(Cl-C4 )-aLkyL,

(C

6

-C

12 )-aryL which can be mono-, di- or tr 4 substituted by (Cl-C 4 )-alkyl, (Cl-C 4 )-aLkoxy, hydroxyL, haLogen,~ nitro, amino, (Cl-C 4 )-alkyLamino, di-(Cj-C 4 )-aLkyLamino and/or methyLenedioxy, or 3indoLyL, in particular methyl, ethyl, cycLohexyL, tert.-butoxycarbonyLamino-(C j-C 4 )-atkyL, benzoyLoxycarbonyLamino-(Cl-C4)-alkyL, or phenyL which can 35 be mono- or disubstituted, or in the case of methoxy trisubstituted, by phenyL, (Cl-C2)-aLkyL, (C 1 or

C

2 )-atkoxy, hydroxyL, fluorine, chlorine, bromine, amino, (C 1

-C

4 )-aLkyLamino, di-(C 1

-C

4 )-aLkyLamino, 15 nitro and/or methylenedioxy, R1 denotes hydrogen or (C 1

-C

6 )-akyL which can optionally be substituted by amino, (C1-C 6 )-acyamino or benzoylamino, or (C 2

-C

6 )-alkenyl, (C 3

-C

9 )-cycloalkyL, (C5-C9)-cycloalkenyL, (C 3

-C

7 )-cycloalkyl-

(C

1

-C

4 )-alky, (C 6

-C

12 )-ary or partially hydrogenated aryl, each of which can be substituted by

(C

1

-C

4 )-akyl, (C 1 or C 2 )-alkoxy or halogen, or (C6-C12)-aryL-(C1 to C 4 )-akyL or (C 7

-C

13 )-aroyl-

(C

1

-C

2 )-alky, both of which can be substituted in the aryl radical as defined previously, a mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 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, or a side-chain of a naturally occurring, optionally protected a-amino acid, but in particular hydrogen, (C 1

-C

3 )-alkyl, (C 2 or C 3 )-alkenyl, 20 the optionally protected side-chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzy, phenethyl, see 4-aminobuty or benzoylmethyl, *2 3 R and R denote identical or different radicals hy- 25 drogen, (C 1

-C

6 )-aky, (C 2

-C

6 )-alkenyl or (C6-C12) aryl-(C 1

-C

4 )-alky, but in particular hydrogen,

(C

1

-C

4 )-alky or benzyl, and .9 4 5 R and R have the abovementioned meaning.

If R represents a side-chain of a protected naturally occurring a-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, GLu, GLn, Arg, Lys, HyL, Cys, Orn, *6 Cit, Tyr, Trp or His, preferred protective groups are the 35 groups customary in peptide chemistry (cf. Houben-Weyl, vol. XV/1 and XV/2). In the case where R1 denotes the protected side-chain of Lysine, the known amino protective groups are preferred, but in particular Z, Boc or (Cl-C6) -16 alkanoyl. Suitable and preferred 0-protective groups for tyrosine are (Cl-C 6 )-aLkyL, in particular methyl or e th y L.

It is possible and particularly advantageous to use the following compounds according to the invention: 2-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-S-1,2,3,4tetrahydroisoquinoL ine-3-carboxyL ic acid 2-EN-C1-S-carbethoxy-3-cycLohexyLpropyL )-S--alanyL]-S-1,2, 3,4-tetrahydroisoquinoL ine-3-carboxyL-ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-LysyLJ-S-1,2,3,4tetrahydroisoquinoL ine-3-carboxyL ic acid 2-EN-C 1-S-carajethoxy-3-phenyLpropyL)-0-ethyL-S-tyrosyL]-S- 1,2,3,4-tetrahydroisoquinoL ine-3-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyLJ-C3S)-decahydroisoquinoL ine-3-carboxyL ic acid 1-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyLJ-C2S,3aS, 7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-( 1-S-carbethoxy-3-cyc LohexyLpropyL )-S-aLanyL J-(2S, 3aS,7aS)-octahydroindoLe-2-carboxyLic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL )-S-lysyL]-C2S,3aS, tttc 7aS)-octahydroindoLe-2-carboxyLic acid CVC C 1-EN-C 1-S-carbethoxy-3-cyc LohexyLpropyL )-S-lysyL )-(2S,3aS, tt 25 7aS)-octahydroindoLe-2-carboxylic acid 1-EN-Cl-S -car beth ox y-3-rc c10hex y Iprop yI) S Iys y I)-(2s, 3aS,7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-phenylpropyL )-0-methyL-S-tyrosyl J- C l"S(2S,3aS,7aS)-octahydroindoLe-2-carboxyl ic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL )-0-ethyL-S-tyrosyL J- (2S,3a5,7aS)-octahydroindoLe-2-carboxylic acid 1-EN-C 1-S-carbethoxy-3-C3,4-dimethyLphenyLpropyL)-S-aLanyL]-C2S,3aS,7aS)-octahydroindoLe-2-.carboxyL ic acid 1 -EN-E1-S-carbethoxy-3-(4-fLuorophenyL)-propyL]-S-aLanyL]- (2S,3aS,7aS)-octahydroindoLe-2-carboxyLic acid 1-EN-E1-S-carbethoxy-3-(4-methoxyphenyL)-propylJ-S-aLanyL]- (2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-E1-S-carbethoxy-3-(3,4-dimethoxyphenyL)-propyL]-S- -17aLanyL]-(2S,3aS,,7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-C 1-S-carbethoxy-'3-cycLopentytpropyL)-S-aLanyL]-(2S, 3aS,7aS)-octahydroindoLe-2-carboxyt ic acid 1-EN-(1-S-carbethoxy-3-phenyLpropyt)-S-aLanyL]-(2S,3aR, 7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-(1-S-carbethoxy-3-cycLohe-xyLpropyL)-S-aLanyL]-(2S, 3aR,7aS)-octahydroindoLe-carboxyL ic acid 1-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-Lysyt]-(2S,3aR, 7aS)-octahydroindote-2-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-cyc Lohexyipropyt )-S--LysyL 3aR,7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-(l-S-carbethoxy-3-phenyLpropyL)-0-ethyL-S-tyrosyL]- (2S,3aS,7aR)-octahydroindoLe-2-carboxyL ic acid 1-EN-( 1-S-carbpthoxy-3-pheny~propy1)-S-a~anyLJ-C2S,3aR, 7aR)-octahydroindoLe-2-carboxyt ic acid 1-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-LysyL]-(2S,3aR, 7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-(1-S-carbethoxy-3-cycLohexytpropyL)-S-aLanyL]-C2S, 3aR,7aR)-octahydroindoLe-2-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-cyc LohexyipropyL )-O-ethyL-S-tyrosyL (2S,3aR,7aR)-octahydroindoLe-2-carboxyLic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-(2S,3aS, 7aR)-octahydroindoLe-2-carboxyLic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL )-0-ethyL-S-tyrosyt (2S,3aS,7aiS)-octahydroindo~e-2-carboxyLic acid 1-EN-C 1-S-carbethoxy-3,4-dimethiyLphenyLpropyt )-S-aLanyLJ- (2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid (2S,3aS,7aS)-octahydroindoLe-2-carboxytic acid 301-EN-E1-S-carbethoxy-3-(4-methoxyphenyL )-propyL]-S-aLanyL]- (2S,3aS,7aS)-octahydroindoLe-2-carboxyLic acid 1-EN-E1-S-carbethoxy-3-(3,4-dimethoxyphenyL)-propyL]-SaLanyL])-(2S,3aS,7aS)-octahydroindoLe-2-carboxyL ic acid 1-EN-( 1-S-carbethoxy-3-cycLopentyLpropyL )-S-aLanytJ-(2S, 3aS,7aS)-octahydroindoLe-2-carboxyLic acid 2-CN-C1-S-carbethoxy-3-phenyLpropyL)-S-atanytJ-cis-endo- 2-azabicyctoE3.3.0]octane-3-S-carboxyL ic acid 2-EN-(1-S-carbethoxy-3-phenytpropyL)-S-LysyL]-cis-endo- -18 2-azabicycLoE3.3.0]octane-3-S-carboxyL ic acid 2-EN-(1-S-carbethoxy-3-cycLohexytpropyL)-S-atanyL]-cisendo-2-azabicycLoE3.3.0octane-3-S-carboxyL ic acid 2-EN-(1-S-carboxy-3-cyctohexytpropyL)-S-atanyLJ-cis-endo- ?-azabicycLoE3.3.O]octane-3-S-carboxyLic acid 2-EN-C 1-S-carbethoxy-butyt)-S-atanyL]-c is-endo-2-azabicycLoE3.3.Ojoctane-3-S-carboxyL ic acid I 2-EN-C 1-S-carbethoxy-3-(3,4-dimethoxyphenyLpropyL)-S-aLanyL]-cis-endo-2-azabicycLoE3.3.0]octane-3-S-carboxyt ic acid 2-EN-C 1-S-carbethoxy-3-cycLopentyLpropyL)-S-aLanyLJ-c isendo-azabicycto-E3.3.O]octane-3-S-carboxyL.ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-O-methyL-,'-tyrosy1Jcis-endo-2-azabicycLoE3.3.0]octane-3-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL )-0-ethyL-S-tyrosyL Jc is-endo-2-azabicycLot3.3.0]octane-3-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-(4-fLuorophenyLpropyL)-S-aLanyLJc is-endo-2-azabicycLoE3.3.O]octane-3-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-(4-methoxyphenyLpropyL )-S-aLanyL]- 4c is-endo-2-azabicyctoE3.3.0]octane-3-S-carboxyL ic acid a.:u20 1-EN-C 1-S-carbethoxy-3-phenytpropyt )-S-LysyLJ-(2S,3aR, I t 6aS)-octahydrocycLopentalblpyrroLe-2-carboxyt ic acid 1-EN-C 1-S-carbethoxy-3--cyctohexytpropyL )-LysyL]-(2S,3aR, 1-EN-C1-S-carbethoxy-3-phenyLpropyL)-O-ethyt-S-tyrosyL]- (2S,3aR,6aS)-octahydrocycLopentabpyrroLe-2-carboxyLic a c id 1-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-2-(2S,3aR, t 6aS)-octahydrocycLopenta~blpyrroLe-2-carboxyLic acid a a a 2-EN-C 1-S-carbethoxy-3-phenyLpropyL )-S-aLanyL]-2-azaspiro-E4.5]decane-3-S-carboxyL ic acid ~a~a 2-EN-C 1-S-carbethoxy-3-phenyLpropyt )-O-ethyL-2-tyrosyLJ- 2-azaspi ro-E4.5]decane-3-S-carboxyL ic acid 2-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-LysyLJ-2-azaspiro- E4.51clecane-3-S-carboxyL ic acid 7 .35 2-EN-C 1-S-carbethoxy-3-cycLohexyLpropyL )-S-atanyL]-2-azaspiroE4.5]decane-3-S-carboxyt ic acid 2-EN-(1-S-carbethoxy-3-cyctohexytpropyL)-S-tysyLJ-2-azaspiroE4.5]decane-3-S-carboxyt ic acid 2-EN-(1-S-carbethoxy-3-phenytpropyL)-S-aLanyt)-2-azaspiro- [4.4Jnonane-3-S-carboxyt ic acid mIu1uatea 06L0W for aryL. RadicaLs derived from aryt, such as araLkyL, arytoxy, arytthio or aroyL, preferabLy benzoyL, can be substituted as for aryL.

I -19- 2-EN-C 1-S-carbethoxy-3-phenyLpropyl )-O-ethyL-S-tyrosyL J- 2-azaspiroE4.4Jnonane-3-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-LysytL-2-azaspiro- E4.43nonane-3-S-carboxyLic acid 2-EN-C 1-S-carbethoxy-3-cycLohexyLpropyL )-S-aLanyLJ-2-azaspiroE4.4]nonane-3-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-cycLopentyLpropyL)-S-aLaflyL]-2-azaspiroE4.4]nonane-3-S-carboxyL ic acid 2-EN-C1-S-carbethoxy-3-cycLopentyLpropyL)-S-LysyL2-2-azaspi roE4.4]nonane-3-S-carboxyL ic acid 1'-EN-C1-S-carbethoxy-3-phenyLpropyL)-S-aLany~if-spiro~bicycLoE2.2.1]heptane-2,3'-pyrrotidineJ-5'-S-carboxyl ic acid 1'-EN-(1-S-carbethoxy-3-phenyLpropyL)-O-ethyL-S-tyrosyL]spiro~bicycLoE2.2.1]heptane-2,3'-pyrroL boxyLic acid 1'-EN-C1-S-carbethoxy-3-phenyLpropyL)-S-LysyL]-spirolbicycLoE2.2.1',:ptane-2,3'-pyrroLidine]-5'-S-carboxyL ic acid 1 '-EN-C 1-S-cdrbethoxy-3-cycLohexyLpropyl)-S-aLanyL]-spiro- EbicycLoE2.2.1]heptane-2,31-pyrroLidineJ5'-S-carboxyLic a c id Er t l'-EN-C1-S-carbethoxy-3-cycLohexyLpropyL)-S-LysyL]-spiro- EbicycLoE2.2.1]heptane-2,3'-pyrrol idine]-5'-S-carboxyL ic cc:~ 1'-EN-C 1-S-carbethoxy3-phenyLpropyL)-S-aLanyL]-spiro- EbicycLoE2.2.2.loctane-2,-3'-pyrroL idine]-5'-S-carboxyL ic Cr a c id 1 '-EN-C 1-S-carbethoxy-3-phenyLpropyl )-O-ethyLtyrosyL s p iro-[bicycLoE2.2.2]octane-2,3'-pyrroL a tt boxylic acid 1 '-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-LysyLJ-spiro~bicycLoE2.2.2]octane-2,3'-pyrroL idinej-5'-S-carboxyL ic acid 1'-EN-C1-S-carbethoxy-3-cycLohexyLpropy-L)-S-aLanyL]-spiro- EbicycLo[2.2.2]octane-2,3'-pyrroLidineJ-5'-S-carboxyLic a c id CC 35 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-atanyL3-2-azatricycLo[4.3.a. 1 6 9 Jdecane-3-S-carboxyt ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL )-O-ethyL-S-tyrosyL J- 2-azatricycto[4.3.0.1 1 6 9 decane-3-S-carboxyt ic acida pyrrotidine) 2-azatricycLoE4.3.0.1 9 decale decahydrocycLoheptaEb)pyrroLe octahydroisoindote A .1 20 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-LysyL]-2-azatricycLoE4.3.0.1 1 6 9 decane-3-S-carboxyL ic acid 2-EN-(1-S-carbethoxy-3-cycLohexyLpropyL)-S-aLanyL]-2-azatricycLoE4.3.0.1 6 9 decane-3-S-carboxyLic acid 2-EN-C 1-S-carbethoxy-3-cycLohexyLpropyt )-S-tysyL]-2-azatricyctoE4.3.0.1 6 9 decane-3-S-carboxyL ic acid 1-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-decahydrocycLohepta~blpyrroLe-2-S-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL)-O-ethyL-S-tyrosyL]decahydrocycLohepta~blpyrroLe-2-S-carboxyt ic acid 1-EN-(l-S-carbethoxy-3-phenyLpropyL)-S-LysyL]-decahydrocycLoheptalblpyrroLe-2-S-carboxyt ic acid 1-EN-C 1-S-carbethoxy-3-cycLohexyLpropyL)-S-aLanyLJ-decahydrocycLoheptalblpyrroLe-2-S-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-cycLohexyLpropyL )-S-LysyL]-decahydrocycLoheptalblpyrroLe-2-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-transoctahydroisoindoLe-l-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-atanyL]-cis-octahydroisoindoLe-1-S-carboxyL ic acid 2-EN-C -S-carbethoxy-3-cycLohexyLpropyL)-S-aLanyL]-transoctahydroisoindoLe-1-S-carboxyL ic acid 2-EN-C1-S-carbethoxy-3-cycLohexytpropyL)-S-aLanyL]-cisoctahydroisoindoLe-1-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy,-3-phenyLpropyL)-S-aLanyL]-cis-octahydrocyctopenta~clpyrroLe-1-S-carboxyL ic acid 2-EN-C1-S-carbethoxy-3-cycLohexyLpropyt)-S-aLanyL]-cisoctahydrocycLopenta~clpyrroLe-l-S-carboxyt ic acid benzyL ester 2-EN-C 1-S-carbethoxy-3-cyctohexytpropyt )-S-LysyL isoctahydrocycLopenta~clpyrroLe-1-S-carboxyL ic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-2,3,3a,4, 5,7a-hexahydroindoLe-cis-endo-2-S-carboxyLic acid 1-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-LysyL]-2,3,3a,4, 5,la-hexahydroindoLe-cis-endo-2-S-carboxyL ic acid 2-EN-C 1-S-carbethoxy-3-cyctohexytpropyt)-S-LysyL]-2-azabicyctoE3.1.0]hexane-3-S-carboxyL ic acid 2-EN-C 1-S-carboxy-3-phenyLpropyL)-S-LysyL]-2-azabicycLo- 4 t tcc C I 41 C cc 21 E1. .0)Ohexane-cis-endo-3-S-carbo xyLic acid 2-EN-(l-S-carbethoxy-3-cycLopentyLpropyL)-S-aLany)--2azabicycto[3. 1.0)hexane-3-carboxyLic acid 2-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyLJ-cis-endo- 2-azabicycLoE3.1.0]hexane-3-S-carboxyLic acid 2-EN-C 1-S-carbethoxy-3-cyctohexyLpropyL )-S-aLanyL]-c isendo-2-azabicycLoE3. 1.0)hexane-3-S-carboxytic acid I '-EN-C 1-S-carbethoxy-3-phenyLpropyL )-S-aLanyL]-C3' S,5 spiro-bicycLoE2.2.2]octane-2,3'-pyrroLidine-5'-carboxyL ic V 1 '-EN-C 1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-3'R,5 spiro-bicycLoE2.2.2]octane-2,3'-pyrroLidine-5'-carboxyL ic 1 '-EN-C1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-C3'S,5'R)spiro-bicycLoE2.2.2]octane-2,3'-pyrroL idine-5'-carboxyL ic fa ac id U 1 -EN-C1-S-carbethoxy-3-phenyLpropyt)-S-aLanyL]-3'R,5'R)f~ spi r o-bicycLoE2.2.2]octane-2,3'-pyrroL idine-5'-carboxyL ic a c id 1 '-EN-C 1-R-carbethoxy-3-phenyLpropyL)-S-aLanyL]-C3'S,5'R)spiro-bicycLoE2.2.2]octane-2,3'-pyrroL ,t~ctt( 1 -EN-(1-R-carbethoxy-3-phenyLpropyL)-S-aLanyL]-C3'S,5'S)spiro-bicyctoE2.2.2]octane,2,3'-pyrroLidine-5'-carboxyt ic a c id 11'-EN-(1-R-carbethoxy-3-phenyLpropyL)-S-aLanyL]-C3'R,5'S)spiro-bicycLoE2.2.2]octane-2,3'-pyrroL idine-5 '-carboxyL ic c 30 acd '-EN-C 1-R-carbethoxy-3-phenyLpropyt)-S-aLanyL]-C3'R,5'R)s p iro-bicycLo[2.2.2]octane-2,3'-pyrroLidine-5'-carboxyLic 1'-EN-CI-S-carbethoxy-3-phenyLpropyL)-R-aLanyL]-(3'S,5'S)- ~s sp iro-bicycLoE2.2.2]octane-2,3'-pyrroL cid l'-[N-(1-S-carbethoxy-3-phenyLpropyL)-R-atanyL]-C3'R,5'S)spiro-bicycLoE2.2.2]octane-2,3'-pyrroLidine-5'-carboxytic a c id -22 1V-EN-(l-S-carbethoxy-3-phenytpropyL)-R-aLanyL]-(3'S,5'R)spiro-bicycLoE2.2.2loctane-2,3'-pyrroLidine-5'-carboxyt ic acid 11-EN-C1-S-carbethoxy-3-phenyLpropyL)-R-aLanyL]-(3'R,5'R)spiro-bicycto[2.2.2]octane-2,31-pyrroi idine-5 '-carboxyt ic ac id l'-[N-(l-R-carbethoxy-3-phenyLpropyL)-R-aLanyL]-C3'S,5'S)spiro-bicycLoE2.2.2]octane-2,3'-pyrroLidine-5'-carboxyt ic ac id 1 '-[N-(1-R-carbethoxy-3-phenyLpropyt)-R-aLanyL]-(3'R,5'S)spiro-bicycLoE2.2.2]octane-2,3'-pyrro~idine-5'-carboxyt ic ac id 1'-EN-(1-R-carbethoxy-3-phenyLpropyL)-R-aLanyL]-(3'S,5'R)spiro-bicycLo[2.2.2]octane-2,3'-pyrroL idine-5 '-carboxyt ic ac id 1 '-EN-C 1-R-carbethoxy-3-phenyLpropyL)-R-aLanyL]-(3'R,5'R)spiro-bicycLo[2.2.2Joctane-2,3'-pyrroLidine-5'-carboxyt ic ac id canybe prepared by, for example, the process described in #vrm P A-l;eL:i., P 33 33 44r-, in which the tert.-butyl or benzyl derivatives described in the application are converted in a known manner, *Ottt by acid or alkaline hydrolysis or by hydrogenoLysis cata- Lyzed with noble metals, into the monocarboxyLic acid derivatives. The N--benzyLoxycarbonyL protective group of the Lysine derivatives is removed by hydrogenotysis catalyzed with noble metals. The compounds Listed above 4 can readily be converted with physiologically tolerated acids or bases (in the case of mono- or dicarboxyLic acids) into the corresponding salts (for example hydrochLor ides, maLeates, fumarates etc.), and be used as salts according to the invention.

The compounds of the formula I are inhibitors of angiotensin converting enzyme (ACE) or are intermediates in the preparation of such inhibitors.. amdz they eam aks bt

'T

1 -23 Od6it iolfges Some of the compounds of the formula I and processes for their preparation are disclosed in, for example, US Patent 4,129,571, US Patent 4,374,829, European Patent A-79522, European Patent A-79022, European Patent A-49658, European Patent A-51301, US Patent 4,454,292, US Patent 4,374,847, European Patent A-72352, US Patent 4,350,704, European Patent A-50800, European Patent A-46953, US Patent 4,344,949, European Patent A-84164, US Patent 4,470,972, European Patent A-65301 and European Patent A-52991. New compounds of the formula I are prepared in an analogous manner.

Orally effective ACE inhibitors (some of the active compounds already mentioned above) are also advantageous, such as, for example, ramipril, enalapril(f), captopril(a), lisinopril(g), cilazapril(o), RHC 3659, CGS 13945, CGS 13928C(1), CGS 14824A(h), CI-906(j), zofenopril(e), fosenopril(p), alacepril, CI-925(k), pentopril(q), CV 3317(m), indolapril(h), YS 980(b), fentiapril(c), pivopril(d), S 20 perindopril(i), and others. Orally effective ACE inhibitors are described in, for example, Brunner et al., a. J. Cardiovasc. Pharmacol. 7 (Suppl. I) C19853 2-11.

t*4 4 1 t I

IA'

h 4r .24 HS-CH 2 -1

HS-CH

2 -c-O-N) 2 H (b CD 2

H

4

SI

Ii .3 (d) t t C fs

CHL

H

CH3 C 2 C2H C-CH-NH -c2 (CH 2*-H2-C2 2 C It

C

C

I

11.

NH D C C.C H 2 2 23 £iNHO 6 t 3 I 22~ Ii C-OH-NH-CH1-- 2 2k 0013 WC

H

X's 3,4 OCH 3 (k) N-c ~CH-NH cH'0 22j *A

A'

013 c 2

C

2

H

C1 2 H CD 2

C

2 H. .44, 4 4, 41 4 4 1144 41

I

A101 2 Q Moo N 2C?5' 2 0 2-p .0 ~t3C\ .oco

HC'

26 The ACE inhibitors which are disclosed in European Patent A-79022 and are of the formula III

COOH

(III)

H Cj- HmNH mC)IinCHam 0 CH idOlt in which R denotes hydrogen, methyl, ethyl or benzyl, are preferred, in particular the compound of the formula III in which R denotes ethyl (ramipril).

Also preferred are the ACE inhibitors which are disclosed in European Patent A-84164 and are of the formula IV COOH (IV) CH-NHa CH CH- CH 0 3 4 9* a in which aR4 denotes hydrogen, (C 1

-C

4 )-aky or benzyl, in particular the compound of the formula IV in which R4 denotes ethyl.

Furthermore, preference is given to 1'-CN-(1-S-carboethoxy-3-phenypropy)-S-aLanyLJ-exo- or a *j e endo-spirobicycloE2.2.2Joctane-2,3'-pyrroLidin-5'-yLcargot-, 30 boxylic acid and isomers, and (S,S,S)-1-methyl-2-(1-carbethoxy-3-phenyipropyl)-2H-undecahydrocycLopentae4.53pyrroloCl,2-apyrazine-3,8-dione.

The invention also relates to new compounds of the formula FFII II R OOC FH N C CH NH CH (CH 4 R' 5 2doo2 SR R:R 80O 27- A. in which I.a) n is 1 or 2; b) R 1. denotes hydrogen; 2. denotes atkyL having 1-18 carbon atoms; 3. denotes an aliphatic acycLic radical of the formula CaH(2a-b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and h~ represents an integer 2 to a; 4. denotes a mono-, di-, tri-, tetra- or pentacycLic, non-aromatic hydrocarbon radical of the formula CcH(2c-d-1), which is optionally branched, in which c represents an integelr 3 to 20, and d representsi ?n even number 0 to denotes aryL which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (Cl-C 8 )-aLkyL,

(C

1

-C

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

-C

4 -aLkanoyLamino, methyLenedioxy, carboxyL, cyano and/or suLfamoyL; 6. if n is 2, denotes (C 6 -Cl 2 )-aryL-(Cj-C 8 )-aLkyL or di-(C 6 -Cl 2 )-aryL-(Cj-C 8 )-aLkyL, each of which can be substituted in the aryL moiety as described under I.b)5; or 7. aLkoxy having 1-4 carbon atoms; 8. a.*4'which has 6-12 carbon atoms and can be substituted as described under 9. mono- or bicycLic heteroaryLoxy or heteroaryL- (Cl-C 8 )-atkyL which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms represeniting carbon and 1 to 2 ring atorws representing sulfur or oxygen and/or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryL as described under amino-(Cl-C 8 )-aLkyL; 11. (CI-C4)-atkanoyLamino-(Cl-C 8 )-aLkyL; 12. (C7-Cl3)-aroyLamino-(C 1 l-C 8 )-aLkyL; 13. (Cl-C4)-atkoxycarbonyLamino-C 1

-C

8 )-aLkyL; *1 9* 9**e U I

I

PP# S t

I

U.

p 468 *4

U

6I4 66 p *4 46 PP

P

S

It t %T 0,~ Hr 28 14. (C 6

-C

12 )-aryL-(Cl-C 4 )-aLkoxycarbonyLamino- (Cl-C 8 )-aLkyL;

(C

6 -Cl 2 )-aryL-(Cl-C 4 )-aLkyLamino-(Cl-C 8 a Lk y L; 16. (Cl-C 4 )-aLkyLamino-(Cl-C 8 )-aLkyL; 17. di-(CI-C4)-aLkyLamino-(C--C 8 )-aLkyL; 18. guanidino-(Cj-C 8 )-aLkyL, 19. imidazoLyL; indoLyL; 21. (C 1

-C

4 -aLkyLth io; 22. if n is 2, (C 1

-C

4 )-aLkylthio-(Cl-C 8 )-aLkyL; 23. (C6-Cl2)-aryLthio-(Cl-C 8 )-aLkyL which can be substituted in the aryl moiety as described under 24. (C 6

-C

12 )-aryL-(Cl-C 8 )-aLkyLthio which can be substituted in the aryl moiety as described under if n is 2, carboxy-(Cl-C 8 )-aLkyL; 26. carboxyL; 27. carbamoyL; 28. if n is 2, carbamoyL-(Cl-C 8 )-aLkyL; 29. (Cl-C4)-aLkoxycarbonyL-(Cl-C 8 )-aLkyL; *4 t tir

I

U

c)

R

1

I

C L, which can be substituted in the aryl moiety as described under I.b)5; or 31. denotes (C6-Cl2)-aryL-(Cj-C 8 )-aLkoxy which can be substituted in the aryl moiety as described under 1. denotes hydrogen; 2. denotes aLkyL having 1-18 carbon atoms; 3. denotes an acyclic aLiphatic radlical of the formula CaH(2a-.b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and b represents an even number 2 to a; 4. denotes a mono-, dli-, tri-, tetra- or pentacycLic, non-aromatic hydrocarbon radlicaL of the formula CcH(2c-d-.1), which is optionaLLy branched, in fl 29 which c represents an integer 3 to 20, and d represents an even number 0 to aryl which has 6-12 carbon atoms and can be substituted as described under 6. (C 6

-C

12 )-aryl-(C 1

-C

8 )-alkyL or (C 7

-C

13 )-aroyl-

(C

1

-C

8 )-alkyl, both of which can be substituted as for aryl under 7. mono- or bicyclic, optionally partially hydrogenated, heteroaryl or heteroaryl-(C 1

-C

8 )-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these-ring atoms representing carbon and 1 or 2 ring atoms representing sulfur or oxygen and/ or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as described for aryl under I.b)5; or 8. if not already covered by c) 1. the optionally protected side-chain of a naturally occurring a-amino acid of the formula R 1

-CH(NH

2

)-COOH;

d) R and R 3 are identical or different and 1. denote hydrogen; 2. alkyl having 1-18 carbon atoms; 3. denote an aliphatic acyclic radical of the formula CaH(2a-b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and b represents an even number 2 to a; 4. a mono-, di-, tri-, tetra- or pentacyclic, nonaromatic hydrocarbon radical of the formula CcH(2c-d-1), which is optionally branched and in which c represents an integer 3 to 20, and d represents an even number 0 to di-(C1-C4)-a.Lkylamino-(C1-C8)-alkyl; 6. (C 1

-C

5 )-alkanoyloxy-(C 1

-C

8 )-alkyl; 7. (C 1

-C

6 )-alkoxycarbonyloxy-(C 1

-C

8 )-alkyl; 8. (C 7

-C

13 )-aroyloxy-(C 1

-C

8 )-alkyl; 9. (C 6 -C12)-aryloxycarbonyloxy-(Cl-C 8 )-alkyl; aryl having 6-12 carbon atoms; or 11. denote (C 7 -C20)-aralkyl; it being possible r I Ir ~t 4 L 4 ~r '4 4 *1 44 *t It i

A

:s It 30 for the radicals mentioned under d) and 11. to be substituted in the aryl moiety as described under I.b)5; and e) R and R 5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms, and physiologically acceptable salts thereof.

II. excepting compounds of the formula II and their salts in which a b i If.'

I

t t I Ltrt C C i I.

n is 1 or 2, R denotes 1. hydrogen, 2. alkyl having 1-8 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 4. 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

-C

4 )-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C -C 4 )-alkylamino, di-(C 1

-C

4 alkylamino, (C 1

-C

4 )-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, 6. alkoxy having 1-4 carbon atoms, 7. aryloxy which has 6-12 carbon atoms and can be substituted as described under II. b) 8. mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 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, and which can be substituted as described under 9. amino-(Cl-C4)-alkyl, 10. (Cl-C 4 )-alkanoylamino-(C 1

-C

4 )alkyl, 11. (C 7 -C13)-aroylamino-(C 1

-C

4 )-alkyl, 12. (Ci-C 4 )-alkoxycarbonylamino-(Cl-C 4 )-alkyl, 13. (C6-Ci2)-aryl-(C1-C4)-alkoxycarbonylamino- (Cl-C 4 )-alkyl, 14. (C6-C12)-aryl-(C1-C4)-alkylamino-(C1-C4)-alkyl, 30

I

C C 35 tit -31- (Cl-C 4 )-aLkyLamino-(Cl-C 4 )-atkyt, 16. di-(Cl-C 4 )-aLkytamino-(Cl-C 4 )-atkyL, 17. guanidino-(Cl-C 4 )-aLkyL, 18. imidazoLyL, 19. indoLyL; 4 20. (Cl-C 4 )-aLkyLthio, 21. (Cl-C 4 )-aLkyLthio-(Cl-C 4 )-aLkyL, 22. (C 6 -Cl 2 )-aryLthio-(C-C 4 )-aLkyL which can be substituted in the aryl moiety as described under 11I. b) 23. (C 6 -Cl 2 )-aryL-(Cl-C 4 )-aLkyLthio which can be substituted in the aryL moiety as described under II b) *24. carboxy-(Cl-C 4 )-aLkyL, 25. carboxyL, 26. carbamoyL, 27. carbamoyL-(Cl-C 4 )-aLkyL, 28. (Cl-C4)-aLkoxycarbonyt-(C 1

C

4 )-aLkyL, 29. (C 6 -Cl 2 )-aryLoxy-(C-C 4 )-aLkyL which can be sub- 00 stituted in the aryl moiety as described under or

(C

6 -Cl2)-aryL-(Cl-C 4 )-a~koxy which can be substituted in the aryl moiety as described under 6 t c) R denotes 1. hydrogen, aLkyl having 1-6 carbon atoms, 3..knLhaig26cabnaos 3. aLkenyL having 2-6 carbon atoms, cycLoatkyt having 3-9 carbon atoms, cycloatkenyL having 5-9 carbon atoms, 7. CC 3

-C

9 )-cycLoaLkyt-(C-C 4 )-atkyL, 8. C5-C9)-cycLoaLkenyL-(C 1

-C

4 )-aLkyL, 9. optionaLly partialLy hydrogenated aryt which has 6-12 carbon atoms and can be substituted as dlescribed under (C6-Cl2)-aryL-(C-C 4 )-aLkyL or (C7-Cl3)-aroy1- 32

(C

1 or C 2 )-aLkyL, both of which can be substituted in the aryL moiety as described under I I .b 11. mono- or bicycLic, optionaLLy partially hydrogenated heteroaryl which has 5-7 or 8-10 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, and which can be substituted as described under II.b)5; or 12. if not embraced by the above definitions, the optionally protected side-chain of a naturally occurring si-amino acid of the formula

R

1

-CH(NH

2

)-COOH;

V

4 4 IC C C C(

'C

dl) R2and 1.

2.

3.

4.

5.

6.

7.

8.

9.

11 12.

Rare identical or different and denote hydrogen, aLkyL having 1-6 carbon atoms, aLkenyL having 2-6 carbon atoms, di-(Cl-C 4 )-aLkyLamino-(C 1

-C

4 )-alkyL, (Cl-C 5 )-aLkanoytoxy-(C-C 4 )-aLkyL, (Cl-C 6 )-aLkoxycarbonyLoxy-(C 1

-C

4 )-aLkyL,

(C

7 -Cl 3 )-aroyLoxy-(C-C 4 )-aLkyL, (CC-Cl2)-aryLoxycarbonyLoxy-(Cl-C 4 )-aLkyL, aryL having 6-12 carbon atoms,

CC

6 -Cl 2 )-aryL-(Cl-C 4 )-aLkyL,

(C

3

-C

9 )-cycLoaLkyL or (C3-C9)-cycLoatkyL-(Cl-C 4 )-aLkyL, and ll 30 e) R 4and R5have the meaning defined under I.e), and a) n b) R compounds of the formula 1I in which is 1 or 2; denotes 1. hydrogen; 2. aLkyt having 1-8 carbon atoms; 3. aLkenyL having 2-6 carbon atoms; 4. cyctoaLkyL having 3-9 carbon atoms; aryL which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (CC-C 4 )-aLkyL, (C 1

-C

4 alkoxy, hydroxyt, haLogen, nitro, amino, aminomethyl, (CC-C 4 )-aLkyLamino, di-(CC-C 4 )-aLkyLamino, (Cl-C 4 )-aLkanoytamino, methyLenedioxy, carboxyL, cyano and/or sutfamoyL; 6. aLkoxy having 1-4 carbon atoms; 7. aryLoxy which has 6-12 carbon atoms and can be substituted as described under *110 8. mono- or bicyclic heteroaryLoxy which has 5-7 or 8-10 ring ato-ms respectively, UP to 9 of these CCk r ring atoms representing hhdM and 1 or 2 of these ring atoms representing sulfur or oxygen and/or 1 to 4 of these ring atoms representing nitrogen, and which can be substituted as described under 9. amino-(C 1

-C

4 )-aLkyL; (Cl-C 4 )-atkanoyLamino-(Cl-C4)-aLkyL; 11. (C 7 -Cl 3 )-aroyLamino-(C-C 4 )-atkyL; 12. (Cl-C 4 )-aLkoxycarbonyLamino-(Cl-C 4 )-aLkyt; 13. (C 6

-C

12 )-aryL-(CC-C 4 )-aLkoxycarbonytamino- (C -C 4 )-aLkyLt; 14 if n is2, ryL(C-C4)-aLkyLino-(Cl-C 4 a~kyl; 1. i(C-C)-ayLhino-C 1 -)alkt hic caLb subsiu ted inthe C4)arkyt oeyasdsrbe ne ~frr~ I12. i which can b 19 as escibd ude ~24. if n is 2, (caro-( 1

-C

4 )~hi-tkl;C)akL cabox -34- 26. carbamoyL; 27. if n is 2, carbamoyt-(Cl-C 4 )-aLkyL; 28. (Cl-C 4 )-aLkoxycarbonyL-(C-C 4 )-aLkyL; 29. if n is 2, CC 6 -Cl2)-aryLoxy-(Cl-C 4 )-aLkyL which can be substituted in the aryl moiety as described under B.b)5; or

(C

6 -Cl 2 )-aryL-(Cl-C 4 )-aLkoxy which can be substituted in the aryL moiety as described under c) R represents the side-chain of valine, Leucine, norvatine, norLeucine, methionine, ornithine, cycLohexyLalanine, 2-thienyLaLanine, 3-thienyLaLanine, 0O-CC3-C 5 )-aLkyLtyrosine, isoLeucine, isovaline or C -phenyLgLycime; d) Rand Rare identical or different and denote 1. hydrogen; 2. aLkyL having 1-6 carbon atoms; 3. aLkenyL having 2-6 carbon atoms; 4. d C 1 C 4 -aLkytamino-(Cl-C 4 )-aLkyL; (Cl-C 5 )-aLkanoyLoxy-(Cl-C 4 )-aLkyL 6. (Cl-C6)-aLkoxycarbonytoxy-(Cl-C 4 )-aLkyL; t 7. (CIl a o xy l C a k V*t 8. (C6-Cl2)-ary~oxycarbonyLoxy-(Cl-C 4 )-aLkyL; 9. aryL having 6-12 carbon atoms; 11. CC 3

-C

9 )-cycLoaLkyL; or 12. (C3-C 9 )-cycLoaLkyL-(C-C 4 )-aLkyL, and e) Rand R 5 have the meaning defined under and their physiologically tolerated salts, or C. in which a n, R, Rand Rare as defined above under B. and Rrepresents the side-chain of alanine, Lysine or c-acyLLysine, and IIIc) Rand R are identical or different and denote propyL, isopropyL, n-butyL, isobutyL, sec.-butyL, n-pentyL, sec.-pentyL, iso-pentyL, neopentyL, n-hexyL, isohexyL, cyctobutyL, cycLopentyL, cycLohexyL, cycLoheptyL, cycLooctyL, cycLohexenyL, cycLoheptenyL, 35 phenyl, ct- or 0-naphthyl, 3- or 4-biphenylyL, phenethyl, 3-phenyLpropyl, benzhydryl, c-methylbenzyL, ct-methylenebenzyl, 3- or 4-phenyLbenzyl, bibenzyl-a-yL, styryl, 1-indanyl or 9-fLuorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, being substituted as defined, where appropriate, under 2 3 or one of the radicals R and R denotes hydrogen, and the other is as defined above, 2 3 or R represents benzyl, and R represents benzyl, hydrogen or one of the abovementioned definitions, and their physiologicalLy tolerated salts.

4 5 R and R form, together with the atoms carrying them, preferably a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 15 ring carbon atoms and up to 2, preferably up to 1, ring sulfur atom(s) and up to 1, preferably no, additional ring nitrogen atom, preferably from the series comprising pyrrolidine, thiazolidine, tetrahydroisoquinoline, deca- 20 hydroisoquinoline, octahydroindole, indoline, octa- Ll I hydrocyclopentaEblpyrroLe, 2-azaspiroE4.51decane, c r2-azaspiroE4.4]nonane, spiroC(bicycoE2.2.13heptane)- 2,3'-pyrrolidine3, spiro[(bicycloC2.2.22octane-2,3'- C F 6,9 pyrrolidinel, 2-azatricycloE4.3.0.1 I' 9 decane, decahydrocycLoheptaEbl;,yrroLe, octahydroisoindole, octahydrocyclopentaEc3pyrroe, 2,3,3a,4,5,7a-hexahydroindole, 1,2,3,3a,4,5a-hexahydrocyclopentaEb]pyrroLe and 2-azabicyclo[3.1.0hexane.

30 Suitable salts of the compounds of the formulae I and II u c are, depending on the acidic or basic nature of these compounds, alkali metal or alkaline earth metal salts or salts with physiologically tolerated amines, or salts with inor- S ganic or organic acids such as, for example, HCI, HBr, H 2 S0 4 t L maleic acid, fumaric acid, tartaric acid and citric acid.

The capillary structure of the blood vessels in the brain differs from that in other regions of the body. The brain I

Q

-36capillaries are surrounded by a layer of endothelial cells which are particularly closely linked together (by tight junctions). In addition, brain capillaries have very many fewer of the pores through which, in other blood capillaries, low molecular weight substances can penetrate into or emerge from the surrounding tissue. In this way, in the brain capillaries the property of lipid solubility has a very much greater importance for partition between blood and surrounding tissue than is the case for the remainder of the body.

Hence the preferred compounds of the formula II are those 1 2 3 in which at least one of the radicals R, R R and R represents a lipophilic radical, such as a long-chain aliphatic, alicyclic-aliphatic, araliphatic or heteroaraliphatic radical, a sufficiently large alicyclic radical, or an appropriately substituted alicyclic, aromatic or heteroaromatic radical, or contains a radical of this type as a part-structure.

In this respect, particularly suitable compounds of the I formula II are those in which V R denotes 1. (C 9

-C

18 )-alkyl; S 2. (C 7

-C

1 8 )-alkenyl; I: 3. a radical which has 4-18 carbon atoms and is defined as above under A.I.b)3 and in which b 4; 4. a radical which has 4-20 carbon atoms and is defined as above under A.1.b)4 and in which d 2; 30 5. is as defined above under 6. heteroarylalkyl which is defined as above under A.I.b)9; 7. amino-(C 5

-C

8 )-alkyL; 8. amino-(C5-C 8 )-alkyl; 9. (C 1

-C

4 )-alkanoylamino-(C 5

-C

8 )-alkyl; (C7-C13)-aroylamino-(C 5

-C

8 )-alkyl; 11. (C1-C 4 )-alkoxycarbonylamino-(C 5

-C

8 )-alkyl; 12. (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino- S(C 5

-C

8 )-alkyl;

A

p., 37 13. (CG-C 1 2 )-aryl-(C 1 -C 4 )-alkylamino-(C 5

-C

8 alkyl; 14. (C 1 -C 4 )-alkylamino-(C 5

C

8 )-alkyl; di-(-C 4 )-alkylamino-(C 5

C

8 )-alkyi; 16. guanidino-(C 5 -C 8 )-alkyl; 17. if n is 2, (C 1 -C 4 )-alkylthio-(C 5 -Ca )-alkyl; 18. (C 6- C 1 2 )-arylthio-(C~ 5-C 8 )-alkyl which can be substituted in the aryl moiety as described above under 19. (C 6- C 1 2 )-aryl-(C 5 C)-alkylthio which can be substituted in the aryl moiety as described above under if n is 2, carboxy-(C 5 -C,)-alkyl; 21. if n is 2 carbamoyl-(C 5 -C 8 )-alkyl; 22. (C 1 -C 4 )-alkoxycarbonyl-(C 5

-C

4 )-alkyl; 23. if n is 2, (C 6- c 1 2 )-aryloxy-(C 5

-C

8 )-alkyl which can be substituted in the aryl moiety as described above under A.I.b)5; or 24. (C6- C 1 2 )-aryl-(C 5

C

8 )-alkoxy which can be substituted in the aryl moiety as described above under A.I.b)S.

too:Q 37a The physical data of suitable preferred examples of the compounds of the formula II is as follows: n R Ri R2 R3 HOOC-CH -N R4 1 (0H 2 1 o0H 3

OH

3

C

2

H-

5

H

less polar diastereomer D20 0,50 CH 3 OH); MS more polar diastereomer [aC] 2 0 =-22.5 CH 3 OH); MS

D

1 (CH 2 1 oCH 3 H H 52.90 CH 3 OH), MS (DCI) 529 1) 1 CH(CH 3 2

OH

3

C

2 1- 5

CH

2

C

6

H

5 [a]I D _29.80 CH 3 OH), MS (DCI) 459 1) [a]I 20 _0.60 CH 3 OH), MS (DCI) 459 1) 2 OH 3

OH

3

C

2 1- 5

CH

2 0 6

H

5 MS (DCI) :499 for both diastereomers 2 OH 3

OH

3

C

2 1- 5

H

less polar diastereomer D 40.80 OH more polar diastereomer [aJ] D _4.50 CH~ 2 C 6 1- 5 0H 2

-C

6

H

4 -O-nO 3

H

7

C

2

H-

5

H

D

DCI) 481 )CI) 481

D

D (diastereomers)

H

H

30 H) 30 H) H mp: 5300 3 (DCI) 605

H

2 C 6

H-

5

D=

2 C 6

H-

5 [a]I D=

OH

2

-O

6

:H

4 -O-nO 3

H

7

H

+32.00 OH 2

OI

2 mp: 120-1270C

OH

2

-C

6

H

5

H

+32.60 OH 2

OI

2 MP: C~ (deco

H

mp.) -37b Compounds of the formula II n R R 2R 3 HOOC-CH-N- R R 2 C 6HS CH 2 CH(CH 3 2 H H H mp: 156*C (decomp.) other diastereomer mp: 1370 (decomp.),ta]20=+39 D CH 3

OH)

2 C 6 HS CH(CH 3

-C

2

H

5 H H H mp: 127*C (decomp.); MS (DCI): 485 2 n-C 4 H 9 CH 3 C 2 HS CH 2

C

6 HS D less polar diastereomer [aJ20 -51.60 (cml, CH 3

OH)

D

more polar diastereomer (a]J20= -26.80 (cml. CH 3

OH)

D

2 n-C 4 ;H C3 C 2 H H 1 less polar diastereomer (a]20= +6,00 CH 0 H D more polar diastereomer (ca]210= +4.40 (c=l,CH 3 H);MS 4DCI):597 D (M +l= 2 n-C 4 H CH 3 H H D 1st diastereomer [a)20 -+10.40 CH 3

OH)

D3 2nd diastereomer mp: 104-108'C Ahsddi t iwonal compounds of the formula TI which are suitable are 1. (C -C 18 )-alkyl; 3. (C -C,,)-alkynyl; 4. aradical which has 4-18 carbon atoms and is defined as above under A.I~c)3. and in which b 2 and only double bonds are present; S. a radical which is as defined above under A.I.c)4t excepting cycloalkyl and cycloalkenyl having up to 9 carbon atoms; til 6. optionally substituted (C )-aryl-(C 5 )-alkyl;- 7. optionally substituted (C7-C 13 )-aroyl-(C 3 )-alkyl.

or -38 8. optionally substituted heteroaryL-(Cj-C 8 )-aLkyL, and those compounds of the formula II in which R 1 represents the side-chain of vaLine, Leucine, norvaLine,. norteucine, meth ionine, orni thime, cycLohexyLaLanine, 2-th ienyLaLanine, 3-thienyLaLanine, O-(C 3

-C

5 )-atkyLtyrosine, isoLeucine, isovatine or C-phenytgLycine.

R

2 and R3are then identical or different and preferably denote 1. (C 7 -Cl 8 )-aLkyL; 2. (C 7 -Cl 8 )-aLkenyL; 3. a radlical which has 4-18 carbon atoms and is defined as above under A.I.d)3. and in which b 4; 4. a radlical which is as defined above under A.I.0)4, excepting (C 3

-C

9 )-cycLoaLkyL and (C 3

-C

9 )-cycLoaLkyL-(C 1

-C

4 )-atkyL di-(C 1

-C

4 )-aLkyLamino-(C 5

-C

8 )-aLkyL; 6. (CC-C5)-aLkanoyLoxy-(C 5

-C

8 )-aLkyL; 7. (Cl-C 6 )-aLkoxycarbonyLoxy-(C 5

-C

8 )-aLkyL 20 8. (C 7 -Cl3)-aroyloxy-CC 5

-C

8 )-aLkyL; 9. t (Cl 6 -C2 0 )-araLkyL; tV it being possible for the radicaLs mentioned under 9.

and 10. to be substituted in the aryL moiety as described above under or one of the radicals R2and R denotes hydrogen and the other is as defined above.

in addition, preferred compounds of the formula II are those in which R2and R3are identical or different and denote propyl, isopropyt, n-butyL, isobutyL, sec.-butyt, n-pentyL, sec.-pentyL, isopentyL, neopentyL, n-hexyL, isohexyL, cycLobutyL, cycLopentyL, cyctohexyL, cyctoheptyL, cyctooctyl, cycLohexenyL, cycloheptenyL, menthyt, phenyL, or 0-naphthyt, 3- or 4-biphenyLyL, phenethyL, 3phenyLpropyL, benzhydryL, ci-methyLbenzyLp a-methyLenebenzyL, 3- or 4-phenyLbenzyL, bibenzyL-ct-yL, styryL, 1-indlanyL or 9-fLuorenyL, with phenyL, and phenyL as a part-structure of one of the said radicaLs, optionally being substituted -39 as defined above under or one of the radicals

R

2 and R 3 denotes hydrogen and the other is as defined above, or R 2 represents benzyl, and R 3 represents benzyl, hydrogen or one of the abovementioned definitions.

The invention also relates to a process for the preparation of a compound of the formula II, which comprises reacting together its fragments in a suitable solvent, where appropriate in the presence of a base and/or of a coupling aid, reducing, where appropriate, unsaturated compounds which have formed as intermediates, such as Schiff's bases, eliminating protective groups which have been introduced temporarily to protect reactive groups, esterifying, where appropriate, compounds of the formula II having one or more free carboxyl groups, and converting, where appropriate, the resulting compounds into their physiologically tolerated salts.

It is possible, for example, in the said manner to react compounds of the formula V with compounds of the formula

VI.

S R 00C-CH-N-H HOOC-CH-NH-CH-(CH -R R R R

(VI)

tt The reaction of these compounds can be carried out, for example, in analogy to known peptide coupling methods in an organic solvent such as DMF, CH 2 CL2 or DMA in the presence of coupling aids such as carbodiimides (for example I' dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl ca;bonate, in a solvent such as CH 3

CN.

Amino groups in compounds of the formula V can be.actie 30 vated with tetraethyl diphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbodiimide derivatives and thus activated (cf. Schrdder, LIbke, The Peptides, volume 1, New York 1965, pages 76 136). The reaction is preferably carried out between 0 C and the boiling point of the reaction mixture.

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 II

R

3

OOC-CH-N-C-CH-Y

1 2

-CH-(CH

2

)-R

R R 5 0 R COOR 2 (VII) (VIII) in which either Y 1 represents amino and Y 2 represents a leaving group, or y1 represents a leaving group and Y2 represents amino. Examples of suitable leaving groups are CL, Br, I, alkylsulfonyloxy or arylsulfonyloxy.

Alkylations of this type are expediently carried out in water or an organic solvent such as a lower aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glycol ethers, at a temperature between -20 0 C and the boiling point of the reaction mixture, in the presence of a base such as an alkali metal hydroxide 20 or an organic amine.

t. Furthermore, it is possible to condense compounds of the formula IX with compounds of the formula X

R

3

OOC-CH-N-C-C-Q

1 Q2=q-(C C 2

)-R

4 15 0'1 2 n o R R COOR (Ix) (x) in which either Q 1 represents amino hydrogen and Q2 represents oxo, or Q represents oxo and Q represents amino hydrogen. The condensation is expediently carried out in water or an organic solvent such as a lower aliphatic alcohol, at a temperature between -20 0 C and the boiling point of the reaction mixture, in the presence of a reducing

A

41 agent, such as NaBH 3 CN, compounds of the formula I being obtained directly. However, it is also possible to reduce Schiff's bases or enamines which are produced as intermediates, where appropriate after previous isolation, with the formation of compounds of the formula II, for example by hydrogenation in the 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 formula XII and XIII, expediently in the presence of a base such as sodium alcoholate, in an organic solvent such as a lower alcohol, at a temperature between -10°C and the boiling point of the reaction mixture, also results in compounds of the formula II (n 2),

R

2 0OC-CH=CH-COR (XI)

OCH-COOR

2

(XII)

,Do. R-CO-CH (XIII) *44 with Schiff's bases which have been produced as intermediates being reduced as described above, and a carbonyl group being converted by reduction (for example with a S 20 complex hydride) into methylene.

In the abovementioned formulae V XIII, R R 5 and n are r as defined in formula II. Protective groups temporarily introduced to protect reactive groups not involved in the reaction are eliminated in a manner known per se after the OF 9 reaction is complete (cf. Schrbder, LUbke, loc. cit., pages 1 75 and.246 270; Greene, "Protective Groups in Organic Synthesis", New York 1981).

The new compounds of the general formula I or II can also be prepared, for example, using methods of esterification familiar to the expert (see, for example, Buchler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, pages i -i i i i 42 802 825; Houben-Weyl, Methoden der Organischen Chemie, (Methods of Organic Chemistry), volume E5, 1985, pages 656 773).

a) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals

R

2 and R 3 denotes hydrogen with an appropriate alcohol with acid catalysis (mineral acid or acid ion exchanger).

b) Alkylation of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R 2 and R 3 denotes hydrogen with a compound R 2 Z or

R

3 Z, in which Z denotes a leaving group which can be displaced nucleophilically (such as halogen, tosylate), in a polar protic or dipolar aprotic solvent, in the presence of a base such as an alkali metal hydroxide or alcoholate.

o 0 9 9 *9 9 4 *9* *414cr c) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R and R denotes hydrogen with a diazoalkene in an inert organic solvent such as CH 2

CL

2 4~i j The cognition adjuvant action of the compounds according 25 to the invention has been tested in the inhibitory (passive) avoidance test (step-through model) in mice having a body weight of 20-25 g. A modified form of the test c method described by J. KOPP, Z. BODANECKY and M.E. JARVIK has been described by J. BURES, 0. BURESOVA and J. HUSTON 30 in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983).

I It I t I According to the statements in this literature, a substance is said to have cognition adjuvant activity when it is able to abolish the amnesia induced in the experimental animals by an electroconvulsive shock or the amnesia induced by scopolamine.

1 43 The experiments were carried out by modified test methods.

The comparison compound used was the known cognition adjuvant 2-oxo-l-pyrrolidinylacetamide (piracetam). The marked superiority of the compounds according to the invention over the comparison substance was evident from the fact that the scopolamine-induced amnesia in the inhibitory avoidance test can be abolished with an oral MED (minimal effective dose) of 1.0-30 mg/kg. The comparison substance has an oral MED of about 500-1,000 mg/kg.

Most of the compounds according to the invention have only Low toxicity.

By reason of their pharmacological properties, the compounds according to the invention are suitable nt 4 .y for the treatment -f high bled pressure but La fo the- treetmrt of cognitive dysfunctions of various etiologies, as occur with, for example, ALzheimer's disease or senile dementia.

Hence the invention also relates to the use of the com- I r. pounds according to the invention for the treatment and t prophylaxis of cognitive dysfunctions in patients with high blood pressure.

The invention furthermore embraces medicaments containing the said compounds, processes for their preparation and the use of the compounds according to the invention for the preparation of medicaments which can be used for the treatment and prophylaxis of the abovementioned diseases.

It is possible, in practicing the method according to the invention, to use the angiotensin converting enzyme inhibitors which are described above in mammals such as monkeys, dogs, cats, rats, humans etc.

The medicaments are prepared by processes which are known per se and familiar to those skilled in the art. The -44pharmacologically active compounds active compound) according to the invention are used as medicaments either as such or, preferably, combined with suitable pharmaceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95%, preferably between 10 and The auxiliaries suitable for the desired medicament formulation are familiar to those skilled in the art by reason-of their expert knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxiliaries and other active compound vehicles, it is possible to use, for example, antioxidants, dispersing agents, emulsifiers, antifoam agents, masking flavors, preservatives, solubilizers or colorants.

The active compounds can, for example, be administered 2 orally, rectally or parenterally (for example intravenously 20 or subcutaneously), oral administration being preferred.

For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable presentations such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or ,t oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, in particular corn starch. This formulation can take the form of dry and of moist granules. Examples of suitable oily excipients or solvents t, are vegetable or animal oils such as sunflower oil or fishliver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if appropriate with the substances customary for this purpose such as solubilizers, emulsifiers or other auxiliaries.

Examples of suitable solvents are water, physiological saline solution or alcohols such as ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, as well as a mixture of the various solvents mentioned.

The following examples 1-6 indicate the forms used for the prophylaxis and treatment of cognitive dysfunctions by the method according to the invention. The compounds according to the invention can be converted into the appropriate use forms in analogy to the examples.

Example 1 Preparation of the agent used according to the invention for oral use in the treatment and prophylaxis of cognitive dysfunctions.

20 1000 tablets each containing 10 mg of 2-EN-(1-S-carbethoxytttt3-phenylpropyl)-S-alanyL]-1S,3S,5S-2-azabicycLoE3.3.0]octane-3-carboxylic acid are prepared using the following auxiliaries: 2-EN-(1-S-carbethoxy-3-phenypropy)- 10 g S-alanyl]-(1S,3S,5S)-2-azabicycoE3.3.0]octane- 3-carboxylic acid corn starch 140 g gelatin 7.5 g microcrystalline cellulose 2.5 g magnesium stearate 2.5 g t 2-EN-(1-S-Carbethoxy-3-phenylpropy)-S-aLanyL]-(1S,3S,5S)- 2-azabicycloE3.3.0octane-3-carboxyic acid and corn starch are mixed with an aqueous gelatin solution. The mixture is dried and milled to form granules. Microcrystalline cellulose and magnesium stearate are mixed with the granules.

Ii

A

46 The resulting granules are compressed to form 1000 tab- Lets, each tablet containing 10 mg of the ACE inhibitor.

These tablets can be used for the treatment and prophy- Laxis of cognitive dysfunctions.

Example 2 Gee.

e P PG P Peep

POPS

P P

POOP

*0CC

P

*QPS

PG

fl P POP

PP

PPP

PP

0 P PG OP

P

o P 0 P

P-PP

PP P 0 0

PG

In analogy to Example 1, 1000 tablets each containing mg of 1'-EN-(l-S-carbethioxy-3-phenyLpropyL)-S-aLanyL]- (3'S,5'S)-spirobicycLoC2.2.2)octane-2,3'-pyrroL carboxyLic acid are prepared.

Example 3 Gelatin capsules each containing 10 mg of 1'-[N-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-(3'R,5'S)-spirobicyc Lo- C2.2.2]octane-2,3'-pyrroLidine--5-carboxyt ic acid are filled with the following mixture: 1'-EN-(1-S-Carbethoxy-3-phenyLpropyL)-S-aLanyL]-(3'R,5'S)spirobicycLo[2.2.2]octane-2,3'-pyrroLidine-5'--carboxyLic a c id 10 mg Magnesium stearate 1 mg Lactose 214 mg These capsules can be used for the treatment and prophy- Laxis of cognitive dysfunctions.

30 Example 4 The preparation of an injection solution is described below: 2-CN-(1-S-Carboxy-3-phenyLpropyL)-S-aLanyL]- C1S,3S,5S)-2-azabicycLoC3.3.Ojoctane-2-carboxyLic acid MethyLparaben 250 mg 5 g 47 PropyLparaben i g Sodium chloridle 25 g Water for injections 51L 2-CN-( 1-S-Ca rboxy-3-ph enY IpropyL) -S-aLanyL S, 3S, 2-azabicycLo[3.3.O]octane-3-carboxyLic acid, the preservatives and sodium chloridle are dissolved in 3 L of water for injections, and the soLution is made up to 5 L with water for injections. The solution is filtered sterile and dispensed aseptically into presteriLized vials, which are closed with sterilized rubber caps. Each viaL contains 5 ml of solution.

Example Tablets which can be used for the treatment or prophyLaxis of cognitive dysfunctions are prepared as described in Example 1 with the exception that in place of 2-EN-(1-Scarbethoxy-3-phenyLpropyL )-S-aLanyL]-( 1S,3S,5S)-2-azabi- 20cycto[3.3.0loctane-3S-carboxyLic acid use is made of 2-[N- 20(1-S-carboxy-3-phenyLpropyL)-S-aLanyL]-C 1S,3S,5S)-2-azabi- Ott cycLoE3.3.0]octane-3-carboxyLic acid or 1-EN-(1-S-carboxy- 3-phenyLpropyL )-S-aLanyL]-C2S,3aR,7aS)-octahydroindoLe-2carboxyLic acid or 1-[N-(1-S-carbethoxy-3-phenyLpropyL)- S-aLanyL]-c is-2,3,3a,4,5,7a-hexahydrolHJ indoLe-2-S-endocarboxyLic acid or 1-EN-(1-S-carboxy-3-phenyLpropyL)-SaLanyLJ-cis-2,3,3a,4,5,7a-hexahydro~lH~indoLe-2S-endocarboxyLic acid or 2-EN-(1-S-carboxy-3-phenyLpropyL)-S- LysyL]-C1S,3S,5S)-2-azabicycLoE3.3.0]octane-3-carboxyLic acid or 2-EN-( 1-S-carbethoxy-3-cycLohexyLpropyL )-S-aLanyL 1S,3S,5S)-2-azabicycLoE3.3.0)octane-3-carboxyLic acid or N-(1-S-carboxy-3-cycLohexyLpropyL)-S-LysyL-(1S,3S,5S)-2azabicycLo[3.3.0]octane-3-carboxyL ic acid or 1 carbethoxy-3-phenyLpropyL )-S-aLanyL]-exo-spirobicycLo- C2.2.2]octane-2,31-pyrroLidin-5'-S-yLcarboxyLic acid or (S,S,S)-1-methyL-2-( 1-carbethoxy-3-phenyLpropyL )-2H-undecahydrocycLopentaC4.5]pyrroLoll,2-alpyrazine-3,8-dione or 1'-EN-(1-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]-endospirobicycLo[2.2.2Joctane-2,3'-pyrroLidin-5'-S-yLcarboxyLic acid.

-48- Example 6 An injection solution is prepared in analogy to the procedure described in Example 4 with the exception that in pLace of 2-EN-(l-S-carbethoxy-3-phenyLpropyL)-S-aLanyL]- C1S,3S,5S)-2-azabicycLo[3.3.0)octane-3-carboxyL ic acid use is made of 2-EN-C1-S-carboxy-3-phenyLpropyL)-S-aLanyL]- C 1S,3S,5S)-2-azabicycLoE3.3.0]octane-3-carboxyL ic acid or 1-EN-( 1-S-carbethoxy-3-phenyLpropyL )-S-aLanyL]-C2S,3aR, 7aS)-octahydroindoLe-2-carboxyLic acid hydrochloridle or 1-[N-C1-S-carboxy-3-phenyLpropyL )-S-aLanyL]-(2S,3aR,7aS)octahydroindoLe-2-carboxyLic acid or 1-EN-C1-S-carbethoxy- 3-cycLohexyLpropyL )-S-aLanyL]-cis-2,3,3a,4,5,7a-hexahydro- E1HlindoLe-2-S-endo-carboxy Lic acid or 1-EN-C 1-S-carboxy- 3-phenyLpropyL )-S-aLanyL]-cis--2,3,3a,4,5,7a-hexahydroE1H]indoLe-2-S-endo-carboxyLic acid or 2-EN-C1-carboxy-3phenyLpropyL )-S-LysyL]-C1S,3S,5S)-2-azabicycLo[3.3.O]octane-3-carboxyL ic acid or 2-EN-C 1-S-carbethoxy-3-cycLo- 20hexyLpropyL)-S-aLanyLJ-1S,3S,5S)-2-azabicycLo3.3.0octane.

203-carboxyLic acid or 2 -[N-C1-S-carboxy-3-cycLohexyLpropYL)- S-LysyLJ-ClS, 3 S,5S)-2-azabicycLoE3.3.0.]octane-3-carboxyL ic acid or l'-EN-(l-S-carboxy-3-phenyLpropyL)-S-aLanyL]-endospirobicycLoE 2 .2.2]octane-2,3'-pyrroLidine-5'-S-carboxyL ic Ccacid or 1 '-EN-C l-S-carboxy-3-phenyLpropyL)--S-aLanyL]-exospirobicycLo[ 2 .2.2)octane-2,3'-pyrroLidine-5'-S-carboxyL ic cc. The Eape -95 which now follow are intended to iLLustrate the process according to the invention for the preparation of the new compounds of the formula I and II, without confining the invention to them.

Example 7: COctadecyL 2 -EN-ClS)-ethoxycarbonyL-3-phenyLpropyLS-aLanyL c is,endo-2-azabicycLo[3.3.0]octane-3-S-carboxyLate 23 g of octadecyL cis,endo-2-azabicycLo[3.3.O]octane-3carboxyLate prepared in analogy to European Patent A-79022 49 are reacted with 6.7 g of HOBt, 13.8 g of N-(1S)-carbethoxy- 3-phenylpropyl-S-alanine and 10.2 g of dicyclohexylcarbodiimide in 200 ml of dimethylformamide. After stirring at room temperature for 3 hours, the precipitated dicyclohexylurea is filtered off with suction, the filtrate is concentrated, the residue is taken up in 1 1 of ethyl acetate, and the solution is extracted by shaking with 3 x 500 ml of strength NaHCO 3 solution. The organic phase is concentrated and chromatographed on a column of 1 kg of silica gel with ethyl acetate/petroleum ether in the ratio 2:1, and in this way is separated into the title compound and the diastereomeric compound.

Example 8: 1-EN-(1S)-Dodecyloxycarbonyl-3-phenylpropyl-S-alanyl]-2S, 3aR,7aR-octahydroindole-2-carboxylic acid a) Benzyl 1-EN-(1S)-dodecyloxycarbonyl-3-phenylpropyl-Salanyl]-2S,3aR,7aR-octahydroindole-2-carboxylate 10 mmol of benzyl S-alanyl-2S,3aR,7aR-octahydroindole-2carboxylate (prepared as in European Patent A-84164) are 20 dissolved in 30 ml of anhydrous ethanol. Ethanolic potassium hydroxide is used to adjust the pH of the solution to 7.0, and 1 g of powdered molecular sieve and then 10 mmol of dodecyl 2-keto-4-phenylbutyrate, are added. A solution of 1 g of sodium cyanoborohydride in 25 10 ml of anhydrous ethanol is slowly added dropwise.

After a reaction time of 20 hours at 20 to 250C, the Sreaction solution is filtered, and the solvent is removed by distillation. The residue is taken up in ethyl acetate/water. After the ethyl acetate phase has been 30 evaporated, the residue is chromatographed on silica gel with ethyl acetate/cyclohexane b) The compound obtained as in a) is hydrogenated in ethanol in the presence of palladium/animal charcoal at 20-25 0 C under atmospheric pressure. After the catalyst has been removed, 0.5 N ethanolic hydrogen chloride is added to the solution until it gives an acid reaction.

The solution is concentrated in vacuo, and the residue is crystallized by trituration with diisopropyl ether.

Example 9: Isobutyl 2-EN- (2S)-ethoxycarbonyl-3-phenyL propyl aLanyL]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3-carboxyLate 2.00 g (4.80 mmol) of 2-EN-CE(1S)-ethoxycarbonyL-3-phenyLpropyl]-L-aLany]-(1S,3S,5S)-2-azabicycloE3.3.0]octane- 3-carboxylic acid were dissolved in 100 ml of isobutanol, 0.1 mL of concentrated sulfuric acid was added, and the mixture was boiled under reflux for 15 hours. After cooling, the solvent was removed in a rotary evaporator, and the residue was taken up in methylene chloride. This soLution was washed once with water, once with saturated aqueous NaHCO 3 solution and again with water, dried over ~MgS0 4 and concentrated, and impurities were removed by chromatography on 200 g of silica gel (mobile phase methylene chloride/ethyl acetate 8:2).

*0 20 Yield: 51% of theory of oily product.

[a]o Ea20 -28.20 (c 1, methanol) D0 This product was dissolved in ether, the pH was adjusted to 2 with saturated ethereal hydrochloric acid, the solvent was evaporated off, and the residue was crystallized from diiso- 25 propyl ether.

0 Data on the hydrochloride: Melting point 123- 124 C +17.70 (c 1, methanol) Example S 30 Benzhydry 2-EN-C(1S)-ethoxycarbonyL-3-phenyLpropyL]-Lalany]-(1S,3S,5S)-2-azabicycLoE3.3.0]octane-3-carboxyLate 2.07 g (4.97 mmol) of 2-EN-E(1S)-ethoxycarbonyL-3-phenyLpropyl]-L-aany]-(1S,3S,5S)-2-azabicyclo[3.3.0]octane-3- 51 carboxyLic acid were dissoLved in 50 ml of acetone and, while cooling in ice, a solution of 1.16 g (5.98 mmoL) of diphenyLdiazomethane in 50 ml of acetone was added dropwise.

The solution was then stirred at room temperature for 26 hours, the solvent was evaporated off in a rotary evaporator, and the residue was purified by f'lash chromatography on 150 g of silica gel (mobile phase toLuene/ethanoL 98:2).

Yield: 2.55 g (88 of oily product *1 D2 _33.80 (c 1, methanol).

Example 11: Oc tadecyL -EN-t (is)-ethoxycarbonyL-3-phenyLpropyL J-LaLanyL)-( 1S,3S,5S)-2-azabicycLoE3.3.0)octane-3-carboxy late 2.08 g (5.00 mmoL) of 2-CN,-E(1S)-ethoxycarbonyL-3-phenyLpropyL)-L-aLanyL3-(1S,3s,5.S)-2-azabicycto[3.3.03octane-3c.FrboxyLic acid were dissolved in 25 ml of absolute dimethyLformamidle, 1.00 g (10.0 mmoL) of potassium bicarbonate was added, and the mixture was stirred at 40 0 C for 90 minutes.

After cooling to room temperature, a solution of 4.00 g (12.0 mmoL) of 1-bromooctaelicane in 20 ml of absolute di- 20 methyLformamide was adder, i.,,wise, and the mixture was stirred at 40 0 C for 4 hoWr The solvent wbs removed in #44* a rotary evaporator at about 1 torr, and the residue was partitioned between water and methyLene chloride. The organic phase was separated off, dried over MgSO 4 and concentrated. 3.05 g (92 of the product were isolated from the crude product (5.40 g) after column chromatography on 200 g 'IV 1 9, of silica gel (mobile phase toLuenie/ethanoL 99:1).

I~(I 2 19.60 (c 1, methanol) Example 12:.

aenzyL 2.-N-E(1S)-benzyhydroLoxycarbonyL-3-phenyLpropyL aLanyL 3-(iS,3Se,5S)-2-azabicyc LoC3.3 .03o tane-3-carboxyL ate a) SenzhydryL (2R)-hydroxy-4-phenyLbutyrate A soLution of 10.1 g (52.1 mmoL) of diphenyLdiazomethane in 4030 mL of absolute acetone was added dropwise over 52 minutes to a solution of 7.40 g (41.1 mmol) of (2R)hydroxy-4-phenylbutyric acid in 200 mL of absolute acetone while cooling in ice, and the reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated off, and the residue was triturated with 100 mL of petroleum ether. 6.4 g of crystalline product were obtained. The mother liquor was concentrated, and a further 6.0 g of the product were isolated by column chromatography on 700 g of silica gel (mobile phase toluene/ethanol 99:1).

Total yield: 12.4 g (87 Melting point 88 89 0 c.

ICA2 -1.8o (c 5, methanol).

D

b) Benzyl 2-EN-CE(1S)-benzhydryLoxycarbony-3-pheny!.propyL]- L-alany)-(1S,3S,5S)-2-azabicycoE3.3.0octane-3-carboxylate bl) 1.80 g (4.33 mmol) of benzyl 2-(N-tert.butoxycarbonyl- L-aany)-(1S,3S,5S)-2-azabicycloE3.3.0octane-3-car- *00 boxylate were dissoLved in 4.5 ml of trifluoroacetic :.20 acid, and the reaction solution was stirred at room 8 8temperature for 90 minutes. It was then concentrated and, to remove trifluoroacetic esters, toluene was evaporated off three times in a rotary evaporator.

The residue, which comprised 1.90 g of benzyl 2-(L- 't 25 alanyl)-(lS,3S,5S)-2-azabicycloE3.3.03octane-3-carboxylate trifluoroacetate, was dissolved in 10 mL of absolute methylene chloride (solution A).

b 2 1.63 g (4.71 mmol) of benzhydry (2R)-hydroxy-4-phenyLbutyrate from Example 12 a) Were dissolved together with 0.4 mL of absolute pyridine in 25 mL of absolute methylene chloride and, at -10 0 C, 1.41 g (5.00 mmol) of trifluoromethanesultonic anhydride were added dropwise within 20 minutes. The cooling bati was then removed and, after room temperature had been reached, the solvent was evaporated off. The residue was r 53 filtered through 50 g of silica gel using methylene chloride, and the filtrate was concentrated. 1.70 g of benzhydryl 4-phenyl-(2R)-trifluoromethylsulfonyloxybutyrate were obtained and were dissolved in 10 ml of absolute methylene chloride (solution B).

b 3 1.0 ml (7.40 mmol) of triethylamine was added to solution A and then, at OC, solution B was slowly added dropwise. The cooling bath was removed and the reaction solution was stirred at room temperature for 19 hours, then washed three times with water, dried over MgSO 4 and concentrated. The residue was purified by chromatography on 80 g of silica gel (mobile phase cyclohexane/ethyl acetate 8:2 and 7:3), and 0.95 g of the desired product was obtained.

Melting point 81-85 0

C.

Ca] 2 0 -55.2o (c 1, methanol) By suitable combinations of the methods described in the foregoing examples, the following additional compounds are prepared (the designation of the ring systems corresponds 20 to that for the compounds of the general formulae I and II): ta p 1: R 00C CH

,N

14 h5 -54- -TH NE CH CH CH 3 OOR 2

R

3 00C-CH-N- 14 ExampL e

I

S

'S

S

S..

S S C S S S 5 13 Ring system A -C 2H 5-CH11( cH 3 2 14 Ring system B -C H -CH 2 -CH(CH 3 2 R in g system C -CE 3 -C 2 16 Ring system -C 2 E -CH(C 6

E

5 2 17 R in g system D -C 2 H 18 Ring system D -C 0 19 Ring system D -C 2

HE

20 R in g system D -C 2

HE

21 R in g system D -C 2 22 Ring system D -C 2

E

5

-(CH

2 2 23 Ring system E -C 2

H

5 -(cEH 2 5 -cH 3 24 Ring system P -CH -CH(C 6

HE

5 2 Ring system G -C 2

E

5 -CH(CH 3) 2 26 Ring system G -C 2

E

5 -CE(C 6

E

5 2 i I

N

3 R 00C C~t N 4 15S NH CH CE CH 0 CH COOR 2

R

3 0C-E-N- E4 e Exampte R R L~1~

J)

S

S

4.55

S.

S S 0. 27 28 29 31 32 33 34 36 37 38 39 41 Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring system system system system system system system system system system system system system system system

H

H

H

Hl

H

H

H

H

H

Hl

I

J

IC

-c 2H5

-C

2

E

C

2

H

C

2

E

C2H

CE

2s

C

2

H

C

2

E

5 g

H.

CEH

C

2

H

5

CE

3 C 2

H

C

2

H

C 2

H

5 H -g C 2 H a

-(CE

2 )2-

-CH(CE

3 2

-CH

2 -CHC c 3 a)2 -(cH 2 5 -cH 3

-Q

3

-CH

2

-(D

-CE(C

6 H 5 2 -(CH 2) 8- D -CE(C 6 E 5 2

-(CE

2 4

-CH

3 -c(H

E

3 )3 i i RIOOC 4 A 5 56 -CH-NH-CH- CH CRH CR

COOR

R

3 00C-CH-N- (4 R R Example t y *444 *i I CC 51* 42 Ring system M C 2

E

5

-(CH

2 2

-CE(CR

3 3 43 Ring system. N C 2 H 5 -C(4-F-C 6H 44 Ring system., N C 2

H

5

-CH(C

3 2 Ring system 0 C 2 5 (CB2)Z" 46 Ring system P C 2

R

5 47 Ring system 7 C 2 R 48 Ring system A CH 2 CR(C 3 2 -CE 2 49 Ring system B CH(CH 3 2

-C(CH

3 3 Ring system C CR(C 6

E

5 2

-H

51 Ring system D CE 2 -CH2_ D 52 Ring system' D CE -CE(CE 3 2 _CE D 2 3EC=- CHjOH]i 53 Ring system D CR 2

-CR(CE

3 2 -H CH. "11 54 Ring system D CE 2

-CE(C!!

3 2 -CE(C0E 5 2 Ring system. D CE(C 6

E

5 2

-C(CH

3 3 56 Ring system D CH(C 6

E

5 2

_H

rl-P 57

R

3 00C CH H C 14 R5 1 NH- CH -C -C CH H 2 2\, CH3 COOR R 00-CH-N- 14 R R ExampLe 9r,.

C

O ft Of ft 4* ft 3f 9 ft *4 ft. f ft. f *ftt f 57 58 59 61 62 63 64 65 66 67 68 69 71

I

I

I

Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring Ring system system system syster syster system system system syster system system system system system system

E

G

G

H

H

H

H

H

H

H

H

H

I

-CH -CH(CH 3)2

-CH(C

6

H

5 )2

-CH(C

6

H

5 2

-CH

2 CH(CH 3 )2

-CH

2 CH

(OH

3 2

-CH

2 CH(H

O

3 2

-CH

2 -D

-OH(C

6 5 2

-CH(C

6

H

5 2

-CH(C

6

H

5 2 -CH( C 6 H0) 2 -o -(cH 2 5 -CH 3

II

I

I

I

I

I

-(OH

2 5

-CH

3 -CH(4-F-C 6

H

4 )2

-C(CH

3 3 -CH2~i

-H

-CH(C

6 H 5 2 -c(C

H

3 3 -CH2

-H

-CH(C 6

H

5 2 -cE2c6H 5)2 2

R

3 00C -H N- R4 R5 C -CE NH CH CH 2

OH

2 0 CE COOR

R

3

OOC-CH-N-

14 '5 [O~j D Examo Le 4 I Itt

LI

72 R in g 73 R in g 74 R in g R in g 76 R in g 77 R in g 78 R in g 78a R in g 78b R in g s ys temi system system syst em s,y s t e m system system syst em system 1

M

N

0

P

-Q

-(CH 2 -CE(CH 3 2 -CH(C 6

H

5 2 -CH(CH 3 )2 -CE (CH 3 -C(cH 3 3 c 2 H 5 Menthyl

-CHC

6

H

-c(C 3

)H

2 CE3

-C(C

6

H

5 2 -C (CE 3 )3 Menthyl Cv

CH

2

C

6

E

I

Q

D

G

42Z7.0' tL H O-i rIAp±Lz3

PR

3 00C-_ CH- -N -C

CH

3 Mn Example cH tq 3 x m.

79 Ring system 0 -cE(C 6

H

5 2

-CH

2

SH

Ring system 0 (H2C-H -CH 2 SH 2 81 p 3 oCC-CH 2 -CH(C 6

H

5 2 -CH 2 -3-CO-C(CH 3 6 82 R 3 00OC-CH 2 -CH(CH 3 2 -CH 2

S-.CO-~C-(CH

3 3 83 CH 0 cH(r 5

B

5 -N2.-C I I

I

R 00C 4

R

5 11

C

R

3 00C-CH-N- ExamoL e

V

V

I cs t c t I 84 R3o-C2N -cH(4-F-c 6 H 4 2

-NH-CH-(CH)-

1

COOC

2 HSi

R

3 0OC-CH 2

-CE

2

'ZH-H(H

2 2 COO-CH (C 2 Hr) 2 u 86 Ring system H H -CH 2 4 -(CH 6 c0 3 2 CH-CH-0-C-C 2 1 NE- -H CH 2 0 COOR 2

CH%

2

-C.OOR

3 ExampLe Y 1 R2R 87 CH 2 -c 2 H 5

-CH(C

6

H

5 2 88 S -CH(C 6

H

5 2

(E)-H

89 CH 2 -CH To~ t .t 1. 10

A

3 j~NH CH 2CH-CH-{U R OC COOR Example

-CH(C

6

H

5 2

-C(CH

3 3 91 -CH(C 6

H

5 2

-CH(C

6

H

5 2 Example 92 4-[N-(1S)-Carboethoxy-3-phenyLpropyL)-S-benzyL]-exospiro- (bicycLo[2.2.2]octane-2,3-pyrroL idine)-5-carboxylic acid a) Benzyl ester of N-(1S-carbethoxy-3-phenylpropyl)-S- L e uc m ne 3.4 g (10 mmoL) of ethyl 2-(D)-trifLuoromethyLsuLfonyLoxy-4-phenyLbutyrate and 5.9 g (15 mmol) of the benzyL ester of L-Leucine tosyLate were mixed in 50 ml of abs.

CH

2

CI

2 and, after addition of 4.2 ml of triethylamine, the mixture was stirred at room temperature for hours. After concentration of the solution, the product was isolated by column chromatography (silica gel, cycLohexane/ethyL acetate 3.2 g of colorless oil were obtained.

1 M -0-9 d H3) 1.2 (to CH 3 1.8 (mn, cH 2 2.6 (in, CH 2 3.3 (in, CH) 4.1 CH 2 5.1Cm, CH 2 7.3 (at CH) ppm.

b) N-C 1-S-Carboethoxy-3-phenyLpropyL )-S-Leucime 3.1 g of the benzyL ester obtained in a) were cleaved by 61 hydrogenolysis with 500 mg of Pt/C in 200 mL of ethanol. After removal of the catalyst by filtration and concentration of the solution, 2.3 g of colorless crystals of the carboxylic acid of melting point 120- 1210C were obtained.

'NIMR 6- 0.9 CH 1.25 CH 3 1.8-2,1 (m,CH 2 2.7 CH2), 3.3 CH), 4.25 CH2), 7.2 CH) ppm.

c) 4-EN-(1S)-Carbothoxy-3-phnypropy)-S-LeucyL-exospirobicycloC2.2.2]octane-2,3-pyrroidine-5-carboxyLic acid 2 g (6.2 mmoL) of N-(l-S-carboethoxy-3-phenylpropyL)- 8-eucine and 1.9 g (3.9 mmol)-of benzyl exo-spiro- (bicycloE2.2.2-octane-2,3-pyrroidine)-5-carboxyLate were stirred in 100 ml of dimethylformamide with 4.3 mL of triethylamine and 6.5 ml of n-propyphosphonic anhydride at room temperature overnight. Th, reaction solution was taken up in ethyl acetate and shaken twice tipwith aqueous NaHCO 3 solution and once each with 10 aqueous citric acid, saturated aqueous NaHCO 3 solution and saturated aqueous NaCL solution. The organic phase was then separated off, dried and concentrated. The crude product, with a yield of 2.8 g, was separated into the two diastereomers by column chromatography (silica gel, toluene/ethyl acetate 95:5). 1 g of pure product waa obtained for each benzyl ester. 1 g of the first diastereomer was hydrogenated with Pd/C in 40 mL of ethanol. 780 mg of crystalline carboxylic acid of melting point 131-132 0 C were obtained.

Rotation EaJ 0 -2.8o (c 1, methanol) 860 mg of the second diastereomer were hydrogenated with Pd/C in 35 ml of ethanol and, after removal of the catalyst by filtration and concentration of the solution, the yield was 720 mg.

Melting point: the substance sinters above 65 0

C

Rotation ECJ3 -22.2o (c 1, methanol) -~c K7 62 ExamoLe 93 4-CN-(lS)-CarboxyL-3-phenyLpropyL)-s-LeucyLJ-exo-spiro- (bicycLoC2.2.2Joctane-2,3-pyrroL idine)-5-carboxyL ic acid 102 mg (0.2 mmoL) of the carboxytic acid from Example 92c) we-re stirred in aqueous 4N K(OH solution until aLL t-he s ub stance had dissolved. The solution was applied to an i on exchanger C (R)AmberLite R 120) and eLuted with a 2% strength solution of pyridline in water. The yield was 70 mg.

Rotation Ca] 20 +3.90(c=1 ehnL The following compounds of the formula II are prepared in analogous manner (the designations of the ring systems correspond to those for the compounds of the general formulae I and IN): HOC -CH -N -C CH -C CE 2

C?

2

J

J4 h 5 il 6000~H

N

I..

*S1' C- S

*SS&

S tt~ t HOO CH NH Li 2 CH (CH 3 2 CU (H c 3

CU

2 CH 3

CH

2

C

6 U 5 CE9- C01 1

(CH

2 -Cyclohexyl)

CH

2

C

6 4 OCH 3

CH

2

-C

6

H

4

OC

2 H5

CU

2

C

6

H

4 -0C 3

H

7

CH

2

-COH

4 -0 9

(CH

2 4

-NH

2

(CH

2 )3 NH 2

CU

2 -Hr Ll CH 3 'CH- CH

CH

2 -C CH

A

A

A

C

G

C

C

A

D52 i ti

A

A

A

RA4,,o~ 63 HOOC -CH -N-C -CH -CH -CH 2

CH

2 .c A' 4 R51 11 OOC 2

H

HOOC -CH-1H 4 4 1 CH (CH 3 2

B

CH(CH 3

)CH

2 CH, 3

CH

2

C

6 H 5

B

CH

2

-C

6

H

11 I D

CH

2

-C

6

H

4 7 OCH3 H

C

2

-C

6

H

4 70C 2

H

5

G

CH

2

-C

6

H

4 -On-C 4

H

9

C

2 4

-NH

2

C

2 3 -'lH 2

G

CH

2 -CHg-S-CH 3

D

CH CH a It

CH

2 -C CHI B

S

64 HOOC CH

A

5 CH CH CH 2

CH

2 i 1 600C 2 H 5 2 H0CC CH 14

R

NH [d\l2o CH(CH 3 2 CH(C CE)CH CH~

CH

2

C

6 H 5

CE

2

C

6

E

1

CE

2

-C

6

H

4 -OCH 3

CH

2

-C

6

H

4 0C 2

E

5

C

C

C

-s polar chias-e&e-o/-i rylov!- Vda( cla-erwma-$ a a." a C A At

C

tC, C C C C C

C"

CH

2

-C

6

E

4 -On-C 3

E

7

CH

2

-C

6 4-On-C 4

E

9

(CH

2 4

-NH

2

(CH

2 3

-NH

2

CH

2

-CH

2 -S CHH3 CE- CE aH ci C E 2

CE

p53-57 0

(C

G

H

H

65 HOOC CH N A4 R' CH CH CH 2 H4 R

CONC

2 H HOOC CH NH

R

4

R

CH(CH 3 2 CE (CE 3

)CH

2 CH 3

CH

2 C 6 H 5 I d secpey"me- '16404 e=1 H3H I td~aie~ne (th 013 NH; *555

S

S.,

I

4 S let, I S 4 It 4 Ii

V

Cit I

I

CE

2

C

6

E

11 i

CH

2

C

6

E

4

OCE

3

CH

2

-C

6

E

4 0C 2

H

CE

2 -c 6

H

4 -On-C 3

H

7

CH

2

-C

6

H

4 On-C4 H 9

(CH

2 )3 -NH 2

CE

2 -CHt-

S-CH

3

CH

2 C CH S o 66 HOOC CH j 5 CH CH CH 2

CH

2 P' 6 00C 2 H 5 2 HOOC CH NH CH (CH 3 2

CH(CH

3

)CH

2 CH 3

CH

2 c 6 H

CH

2

-C

6

H

1 1

CH

2

-C

6

H

4 OCH 3

CH

2

-C

6

H

4 -0C 2 H

CH

2

-C

6

H

4 On-C 3

H

7

CH

2

-C

6

H

4 On-C 4 H 9

(CH

2 4

"H~

2

(CH

2 3

-NH

2

CH

2 -CH- 8-CH 3 CH CM

CH

2

CH

2 s e 00 01146 67 HOOC CH N C CH il CE CH 2

CHE

2 COOC 2 H HOOC CH NH 4 k CH (CH 3 )2 CH (CE 3

)CH

2 CH 3

CA

2 C 6

H

CH

2

-C

6

E

1 1

CE

2

C

6

H

4 OCH 3

CH

2

-C

6

H

4 -0C 2

H

CH

2

-C

6

H

4 On-C 3

H

7

CH

2

-C

6

H

4 On-C 4 H 9

(CE

2 4

"H

2

(CE

2 3

-NH

2

CH

2

-CH

2 -S CH, CH- CH

CH

2 c CH ft 4. a 4 ft ff44 t; a t it'~ ft f 4 II %t *4

I

ftt a.

a a I.t 14 4; a 4l *4 '9 4 '4 4, 68 HOOC CH N C j4 5 6 CH CH CH 2

CH

2 P' C00 2 H 5 2 2 HOOC CH NH

R

4

R

i 0 CH(CH 3 2 CH( CH 3

)CH

2 CH 3

CH

2

C

6 H

CH

2

C

6

H

1 1

CH

2

-C

6 Hi 4 OCH 3

CH

2

-C

6 H 4 -0OC 2 H

CH

2

-C

6 H 4 -On-C 3 H 7

CH

2

-C

6 H 4 -On-C 4 H 9

(CH

2 4 I2

CH

2 -CHg- S-CH 3 CH- CH

CH

2 C CH 111 o k t~g ci 69 RLON CH N C CH k1 CH CH 2 CH 2 cooc 2

H

HOOC CH j4

NH

CH(CH 3 2 CH(H C 3

C

2 CH 3 0 H- C =(H 3

OHJ

I

ii

C

C

"S.

CH

2

C

6

H

5

CH

2

-COH

1

CH

2

C

6

H

4 0C 2

E

CH

2

-C

6

H

4 On-C 3

H

7

CH

2

-C

6 On-C 4

H

9

CE

2

CE

2 S -CH 3 CE- CE 11 1 CH C CE 2 0

L

Q

G

I

I It I 70 HOOC CH -N- '5

R

CH CH CH 2 CH 2 S

COOC

2

H

HOOC CH WH 1I 4 f CH(CH 3 2

CH

2 7 C 6 H

CH

2

-C

6 H, 1

CH

2

-C

6

H

4 OCH 3

CH

2

-C

6 H 4 0C 2 H

CH

2

-C

6 H 4 -On-C 3 H 7

CH

2

-C

6

H

4 On-C 4 H 9 CH- CH

CH

2 c CH S o 0 0 00 0 .o 0 a 00 is 000 000 0 00 0 00 -71- HOOC-CH-N-C -CH CH CH 2

-CH

2 i4 k 600C2H

H

1 HOOC -CH -NH

CH(CH

3

N

CH(CCH

3 )CH CH 3

P

vCH 2

-C

6 H 5

Q

CH -C H 1

N

CH

2 -C H 4 On-C H 9

D

IICH- CH

ICH

2 -C CHI P CH(CH )CH CH~ Q CH(CH )CH CH 3

I

CH2-C6H1; Example 94: 1-CN-(1S)-Carboethoxybutyl )-S-aLanyL]-octahydrocycLopenta- EblpyrroLe)-2-carboxyLic acid a) Ethyl DL-2-tr ifluoromethylsulfonyloxypentanoate g (34 mmol) of ethyL 2-hydroxyvalerate and 2.85 g 1 (35.9 mmol) of absolute pyridine were dissolved in 100 ml of absolute CH 2

CI

2 under protective gas, the solution was cooled to 0 0 C and 9.66 g (34 mmoL) of trifLuoromethanesuLfonic anhydride were added. The mixture was warmed to room temperature and stirred for 6 hours. T~ie solution was concentrated and the resulting crude product was purified by column chromatography (silica gel, petro- Leum ether/CH 2

CL

2 The yield was 9.3 g of a 72 colorless, slightly viscous liquid.

IR: 2880 3000 1770, 1420, 1200 1220 1150, 620 cm-1 b) Benzyl ester of N-(1-S-carboethoxybutyl)-S-atanine 4.9 g (17.6 mmol) of the trifluoromethanesuLfonic ester thus obtained were dissolved, under nitrogen, in 70 mL of absolute CH 2

CL

2 with 4.08 g of the benzyl ester of L-aanine hydrochloride (19 mmol) with the addition of 5.4 ml of triethylamine, and the solution was stirred at room temperature for 3 hours. It was then concentrated, the crude product was taken up in ethyl acetate, and the solution was washed three times with water, dried and concentrated. The diastereomers were separated by column chromatography (silica gel, cyclohexane/ethyl acetate The yield of each isomer was 500 mg. The diastereomer isolated in the first filtration had the S,S configuration.

H NMR 6 0.9 (tCH 3 1.3 (t,C 3 1.35 (dCB 3 1.4 (m,CH 2 o 1.6 (m,CH 2 1.9 3.3 3.4 (q,CH), 4.2 (m,CH 2 5.15 (q,CH 2 Ph), 7.4 CH aromat.) ppm.

c) N-(l-S-Carboethoxybutyt)-S-alanine 600 mg (1.95 mmol) of benzyl ester (diastereomer A) were hydrogenated with Pd on charcoal in 34 ml of ethanot. The catalyst was then filterel off, and the solution was concentrated in vacuo. The product was then obtained as a white solid with a melting point of 1370 and a yield of 430 mg.

d) 430 mg (1.98 mmoL) of N-(1-S-carboethoxybutyL)-S-aLanine S 3 and 486 mg (1.98 mmol) of benzyL L(-)-octahydrocycLopentalblpyrrote-2-carboxyLate were dissolved, under nitrogen, in 20 ml of dimethylformamide, the solution was cooLed to -100C, and 1.5 mL of triethylamine and 2 ml of n-propylphosphonic anhydride were added. The solution r

I

i 73 was stirred at -10 0 C for 1 hour and then at room temperature overnight. It was then taken up in 200 ml of ethyl acetate and washed with saturated aqueous NaHCO 3 solution, 10% aqueous citric acid and saturated aqueous NaCI solution. After the solution had been dried and concentrated, the diastereomeric compounds were separated by column chromatography (silica gel, cyclohexane/ ethyl acetate The yield was 360 mg. Both diastereomers were hydrogenated with Pd/C in ethanol as described in Example 94 c) and, after concentration of the solution, they were obtained as white solids.

Example 1-[N-(1S)-Carboxybutyl)-S-alanyl]-(octahydrocyclopenta- Eblpyrrole)-2-carboxylic acid 60 mg (0.17 mmol) of carboxylic acid (Example 94 d) were stirred into 2 ml of 4 N aqueous KOH solution until the S substance had completely dissolved. The solution was then applied to a strongly acid ion exchanger and eluted with a i 2% strength solution of pyridine in water. The yield after concentration of the solution was 39 mg.

In analogy to the compounds prepared in Examples 94 and it is possible to synthesize the following additional compounds of the formula II

H

R

3 00C CH N C CH N CH (CH2)n-R R R5 R COO 2 in which, with n 2, R 1 is CH 3

R

2 is C 2

H

5

R

3

H

is H, and R and the part of the molecule R 3 0OC-CH-N a4 1 3s are substituted as indicated in the table detailed below.

-74- R HOOC-CH-NH j4

CH

3

A

-CH CH CH 3

A

4 (CH 2 9 -CH~ 3C 2-Naphthyl D I4-Biphenylyl A

-(CH

2 13 -CH 3

A

.1R

HOOC-CH-NH

14

CH

3

B

-CH CH CH 3

B

-(CH

2 9 -CH 3

D

2-Naphthyl F 4-Biphenylyl C f (CH 2 13

-CH

3

B

4 r- 75 R HOOC-1CH-NH CH 3

C

-CH

2

CH

2 CH 3

C

-(CH2)-CH 3G 2-Naphthyl G 4-Biphenylyl D R HOOC-CH-NH CH 3

D

-CH.

2 CHCH% D 2-Naphthyl H 4-Biphenylyl H R HOOC-OH-NH CH 3

G

-CH

2

CH

2 CH 3

G

-(CH

2 9 -CH 3 K 2-Naphthyl I 4-Biphenylyl L, -(CH)13-H t a t 76 B EOOC-CH-NH CH 3

H

CH

2

CH

2 CH 3

H

-(CH

2 9

-CH

3

N

2-Naphthyl m 4-Bipheznylyl N -(CH 2 )i 3 -cH 3

N

R HOOC-CH-NH 14 CR, N -CH 2

CH

2 CH3 N -(CH )-CH 3 2-Naphthyl N tot4-Biphenylyl P

-(CH

2 )iH 2 CH3 0 -(0H 2 9 -CH, P 4-Biphenylyl Q

-(CH

2 13

-CH

3

P

R HOOC-.CH-NH CH 3 p -CH 2 CH 2 CH 3

P

-(CH 2 1 -CH 3

Q

4-Biphenylyl H :xamote 96: n-0c:yL 2-CN-(iS-ethoxycarbonyL-3-QnenyLoropyi )--a-LanyLt- (1S,ZS ,5 S azab icycLoa 3 3 0oc tan e-3-c arbo xy Late 2.07 g (5 rnmoL) of 2-EN-(1S-etnoxycaroonyL-3--phenyLpropyL)- S-atanyt>I( 1S,3_S,5SS)-2-azaoicy/ctoC3.3.0]octane-3-carboxytic acid (ramipriL) and 0.50 a(5 mmot) of potassium bicaroonace are stirred in 25 mL of dimethyLformamice a: 1- 0 0' -or 1 .5 hours a nd after cooLing to room temperature, asoLution of 1.16 g (6 mmoL) of 1-bromooctane in 20 ML of dimechytformamide is added dropwise, and the mixture is stirred at room temperature overnight. The pH is aojusted to 6 by addition of 0. iN HCL, the mixture is ditec w ith water and extrac-ted three times with methytene chLoride, and the combined organic phases are dried, concencrated and purified by roLumn chromatograohy on 120 g of siLica geL (mobiLe phase totuene/ethanoL 95:5).

YieLd: 2.35 g of oiLy product; C a 1. 2 5 23-90 (c methanoL).

S 35 ExampLe 97: n-Octyt 2-EN-( 1S-el--hoxycarbonyL-3-phenyLorooyL )-S-aLanyL:- (1S,3,S,.S)-2-aza'oicycLoC3.3.Q]octane-3-carboxytate r C hydrogen maleare 528 mg (1 nimoL of the ester obtained in ExamoLe 96 are dissolved in 20 nil of ether, and a soLur ion of 116 mg (1,mmoL) of maLeic acid in 4 mL of acetone is added. T he 3 soLvents are removed by evaporation, and the residue is crystaLL ized with di isoPropyL ether.

Y ie l: 0 .5 1 g (7 9 of co Lo r Le ss cr ys t a Ls melting point 89-90 C.

ExampLe 98: 2 ct en yL 2- CN 1 S- et hoaxy c ar b an y L ph eny Lp rap y L )S -a La n yL I- (1S,_3S, 5S) 2 -a za b ic ycLo C3 3 0 oc t an e -c a r bo xy Lat e hydrogen maLeate 2.08 a (5 mmoL) of 2 -EN-(1S-ethoxycarbonyL-3-phenyLpropyL)-.

S-aLanyLJ-(lS, 3

S,S)-

2 -azabicycLoC3.3.Joctane3carboxy- Lic acid (ramipriL) and 1.00 g (10 nimoL) of potassium bicarbonate are stirred in 25 mL of dimethyLf ormamidle at 40 0

C

for 1.5 hours, the mixture is cooled to 0 0 C, and a soLutaon o f 2 .3 g 12 m m aL) o f E 1-b r omo -2 -oc t en e i n 2 0 m L o f dimethyLformamide is added dropuise. The reaction soLution is stirred at 0 0 C for 4 hours, poured in 500 ml of water and extracte.dl three times with ethyl acetate, the .~.combined extracts are washed twice with saturated sodium bicarbonate solution and three times with water, dried and concentrated, and the crude product (3.4 g) is punified by flash chromatography on 125 g of silica gel (mobile phase cycLohexane/ethyL acetate 8:2 and 1:1).

1.93 g of an oily product are obtained and converted into the hydrogen mateate in analogy to Example 97.

Yield: 2.0 g of colorLess crystaLs, mel ting point 81-84 0 C Example 99: 3-OctynyL. a-EN-( lS-ethox.yc arbonyL-3-phenyL p ropy L )-S-aLanyL3-(lJS, 3 S,5S) 2 ?-azabicycLoC3.3.03octane-3-carboxyLate 4~J' -~hydrogen maLeate

I

9 g (11.8 mmoL) of 2-CN-(1S-ethoxycaroonyL-3-pnenyLpropyL)-S-aLanyL]-(1S,3S,5S)-2-azaoicycLoC3.3.00ocrane-3carboxyLic acid (ramipriL) and 2.4 g (23.6 mmoL) of potassium bicarbonate are stirred in 90 mL of dimethyLformamide at 400C for 2 hours, and then a soLution of 2.41 g (11-8 mmoL) of mesyLate from Reference ExampLe 3 in 30 mi of dimethyLformamide is added, and the mixture is stirrea at 40 0 C for a furthe, 9 hours. The reaction soLution is diLuted with 250 mL of water and extracted three times with etnyL acetate, the combined organic phases are wasned with saturated sodium bicarbonate solution ano with water, .ried ano concentrated, and the crude product (5.6 g) is purified by chromatograohy on 200 g of siLica geL (mobiLe phase toLuene/ethanoL 99:1). 3.45 g of oiLy product are obtained, and 1.3 g of this are converted into the hydrogen maLeate in anaLogy to ExampLe 97.

Yield: 0.8 g of coLorLess crystaLs, meLting point 68-70 0

C.

ExampLe 100: EthyL 2-CN-(1S-n-octyLoxycarbonyL-3-phenyLpropyL)--aanyL]-(1S,3S,5S)-2-azabicycLoC3.3.0octane-3-carboxyLate hydrogen maleate 1.43 g (2.8 mmoL) of carboxyLic acid from Example 106 are stirred in 25 mL of ethanolic hydrochLoric acid at coom temperature. After 5 days, a further 25 mL of ethanolic hydrochLoric acid are added., the mixture is stirred overnight and concentrated, the residue is taken up in ethyl acetate, the solution is washed three times with saturated sodium bicarbonate solution and once with water, dried e and concentrated, and the crude product (1.16 g) is purified by flash chromatography on 80 g of silica gel (mobiLe phase toluene/ethanoL 99:1). 0.62 g of oiLy product is obtained and converted into the hydrogen maLeate in analogy to Example 97.

Yield: 0.50 g of colorless crystals, melting point-- 7z3 5 84-86 0

C.

ExanpLe 101: L 2-C 1iS-e thoxyc a r'ony L-3-P hnenyiLoaroc yL )S -a Lany L I- C iS,3TS,5S)-2-azabicycLoE3.3.0]octane-3--carboxyLace hyoro- D gen maLeate A soaLu t ion o f 1 .3 19 g7 .5 mmcl o af d ie chy L a zodic a rbox yL a te in 10 mL of absoLute tetrahydrofuran is added dropwise at 0 0 C to a soLution of 1.97 g (7.5 mmoL) of! triphenyLphosphine and 0.72 g (5 mmol) of 5-nonanoL in 100 mL of abso- Luce tetrahydrofuran, the mixture is stirred for minutes and then, at 0 0 C, a soLution of 2.08 g (5 mmoL) of 2-CN-( 1S-ethoxycarbonyL-3-phenyLpropyL )-S-aLanyL]- C 1S,3S,5S)- 2-azabicycLoC3.3.0]octane-3-carboxyLic acid (ramiariL) in 25 mL of absolute tetrahydrofuran is added, and the mixture is stirred at O 0 C for one hour and at room temperature overnight. The reaction solution is concentrated, the residue is taken up in ethyl acetate, the soLution is washed twice with ZN sodium hydroxide soLution and once with water, dried and concentrated, and the crude product (5.09g) is purified by fLash chromatography twice on 200 g of siLica gel (mfobiLe phase a) toLuene/ethanoL 99:1, b) methyLene chloride/ethyl acetate The product obtained in this way (1.74 g, 64%) is converted into the hydrogen maLeate in anaLogy to ExampLe 97.

Yield: 1.6 g meLting point 103-105 0

C.

Example 102: SenzhydryL 2-CN-(lS-menthyLoxycarbonyL-3-phenyLpropyL)-S- A soLution of 0.59 g (3 mmoL) of benzophenone hydrazone in 12 mL of ether is added dropwise at room temperature to a suspension of 2.95 g of nickel peroxide hydrate in 12 ml of ether and, after stirring for one hour, the- vio- Let soLution is fiLtered with suction throu9gh CeLite and concentrated. The 35 mmoL of diphenyldiazomethane obtained i in this way are dissolved in 32 ml of absolute acetone and aodea dropwise, whiLe coo~ing in ice, to a soLution of 1.31 g (2.5 mmoL of 2-CN-( 1S-men.ThyLoxycarbonyL-3-phenyLpropyL )-S-aLanyL -(lS,3S,SS)-2-azabicycLoC3.3.0Joctane-3carboxyLic acid (see Example 132) in 32 mL of absolute acetone. The mixture is subseauentLy stirred at room temperature for 38 hours and concentrated, and the crude product is purified by column chromatography on silica geL (mobiLe phase toLuene/ethanoL 99.5:0.5 or cycLonexane! ethyl acetate 8:2).

YieLd: 1.63 g of oiLy product; Cal 2 5 -:57.9 (c 1, methanol).

Example 103: n-OctyL 2-CN-(3-cycLohexyL-1S-ethoxycarbonyLpropyL a Lany L 1 S, 3S 5S zab ic yc LoaC3 .3 0 o ct a ne-3-c arboax y La te 1.8 g (6.7 mmoL) of octyL ester from Reference ExampLe 2d), 1.92 g (6.7 mmoL) of N-(3-cycLohexyLlS-ethoxycarbon- S 20 yLpropyL )-S-aLan ine and 4.6 mL of absolute triethyL amine are dissolved in 30 ml of absolute dimethyLformamide, the solution is cooled to -50C, and 6.7 ml of, a 50% strength solution of propanephosphonic anhydride in methyLene chloride is slowly added dropwise. The reaction solution is stirred at room temperature overnight, poured into 200 ml of water and extracted three times with ethyl acetate, the combined organic phases are washed with water, strength citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride soLution, dried and concentrated, and the crude product (3.1 g) is purified by flash chromatography on 120 g of silica gel (mobile phase toLuene/ethanol.7199:1).

YieLd: 2.48 9 of colorless oil, -26.40 c 1, methanol).

I I MOMMW :.<amoLe 104: 32enzy L Z-CN-( 1 S-e thoxyc arbonyi tr idecy L)-S-ph enyL a La nyL]-( IS,S7S,5S )-2-azab icycLoC3.3 O]octane-3-carboxyL ace -m L (25 mmol of absolute tr iethyLamine and 5 .0 ml -of a 50% strength solution of propaneohosphonic anhydride in .ethyLene chlor ide are success ively added dropw ise to a solution of 2.19g (5 mmcL) of N-(1S-ethoxycarbonyl-n-cridecyL )-S-phenyLaLanine and 1 .49g (5 mmoL of benzyL lS,3S 1S)-2-azab icycLoC3 .3.Cloc cane-3-ca rboxy Late in mL of absolute dimethyLf ormamide, and the react ion soLution is stirred at room temoerature overnight. I t i s then poured into water and extracted severaL t im es w itrh ethyL acetate, the combined extracts are washed with water, 10% citric acid soLution, saturated sodium bicarbonate solut ion and saturated sodium chLo. e solut ion, dried and concentrated, and the crude product (3.15 g) is purified by flash chromatography on silica gel (mobile phase cycLohexane/ethyL acetate 7:3).

Yield: 2.76 g of oily product Da, -8.00 (c 0.97, ethanol).

:25 Example 105: SenzyL 2-EN-C iS-n-octyLoxycarbonyL-3-phenyLpropyL aLanyL]-C 1S,3S,5S)-2-azabicycLoE3.3.Ojoctane-3-carboxyLate 30 6.0 ml (43.4 mmcl) of absolute triethyLamine and 9.2 g of n-octyL 4-phenyL-2R-tr ifLuoromethanesuL fonyLoxybu tyrate, dissolved in 20 mL of absolute methyLene chloride, are success ively added dropuise at 0 0 OC to a so lut ion of 9.39g (21.7 mmol) of trifLuoroacetate from Reference Examp~e 1b) in 100 mL of absolute methyLene chloride. The mixture is aL Lowed to reach room temperature, s tirred f or hours, extracted three times with water, dried and concentrated, and the crude product (11.4 g) is purified J _R b y f La sh c hro ma toag r achy o n 4 50 g o f s i Lic a ge L mob i Le ;n ase cycilohexane/ethyL acetace 9:1, 3:2, 7:3).

YieLd: 6.95 g of oiLy product, CalD 5 -35.10 (c methanoL).

ExarncLe 106: Tert.butyLammonium 2-EN-( 1S-n-octyLoxycar'oonyL-3-phenyLpropyL)-S-aLanyL]-( 1S,3S,5S)-2-azabicycLoC3.3.O]octane- 3-c arooxy Late 5.45 a (9.2 mmoL) of benzyL ester from ExampLe 105 are hydrogenated on 1 g of paLLadium/charcoaL 10%) in 300 mL of ethanoL at room temperature for 20 minutes. Removal of the cataLyst by f iltration with suction, and concentration result in 4.1 g of 2-CN-(1S-n-octyLoxycarbonyL-3-phenyLpropyL)--S-aLanyL]-(1S,3S,5S)-2-azabicycLo- C3.3.O1octane-3-carboxylic acid.

j 190 mg of tert.butyLamine are added to 1.3 g of this acid in ethanoL, the soLvent is evaporated off, and the residue is crystalLized with diisopropyL ether.

'~~'YieLd: 1.27 g of colorLess crystaLs, i 25 a meLting point 141-143 0

C.

ExampLe 107: n-OctyL 2-EN-C 1S-carboxy-3-phenyLpropyL)-S-aLanyLJ- 2, 30 (lS,3S,SS)-2-azabicycloC3.3.O]octane-3-carboxyLate 2.65 g (5 mmol) of ethyl ester from ExampLe 96 are dissolved in 18 ml of tetrahydrofuran, 7.5 ml of 1N sodium hydroxide solution are added, and the- mixture is stirred at room temperature for 48 hours. it is neutraLized by addition of 7.5 ml of 1N hydrochloric acid. The reaction mixture is concentrated, the residue -is suspended. in.

water, the mixture is extracted twice with ethyl acetate, 1- the combined organic phases are~ washed w ith s.atur a ted sodium cnLor ide soLution, dr ieo and concen tra tea, ano :he truce product (2.05 g) is purified by chromatography on a of S iL ic a g eL toLuene/e thanoaL 9 The product obtained in this way 15 g; 46%) is triturated in 50 mL of petro Leum ether, Lef t to-stand i n the coLd, fIiLtered of f 'with suct ion and dr ied.

YieLd: 0.83 g of coLorLess crystaLs; meLting point 6-6 1 C The foL Low ina compounds according to the i nven tion a re addi tionaL Ly obta ined by use of su itabLe s tart ing ma teriaLs and aopL ication of the process es des c ribed i n Ex ampL es 9 6 -10 7 ExampLe 108: n-Oc tyL 2-NC1S-ethoxycarbonyL-n-heptyL)-S-aL anyL I- 1S,3-S, 53 )-Z-azabi cyc LoC3 .3.0loc tane-3-carboxyL ate ExampLe 109: j n-DecyL 2-EN-C 1S-ethoxycarbonyL-3-phenyLpropyL )-S-aLanyL C 1S,3S,5S )-2-azabicycLoE3.O.0octane-3-carboxyLate; Cal 0 =25.8 (c methanoL).

ExampLe 110: n-TetradecyL 2-EN-C 1S-ethoxycarbonyL-3-phenyLpropyL aLanyLl-( 1S,3S,5S)-2-azabicycLoC3.3.0)octane-3-carboxyLate; CaZ 19.8O C c 1, methanoL).

0 ExamQLe 111: 2-OctynyL a-EN-C 1S-ethoxycarbonyL-3-phenyLpropyL )-S-atanyL)-(lS,3S,5S)-Z-azabicycLoC3.3.03octane-3-carboxyLate me9nR7-7~C N ~hydrogen maLeate mLtig7-23 n-OctyL 1S-isobutyLoxycaroonyL-3-phenyLpropyL aLanyL -1S,3S,55)-2-azabicyc LoC3.3.01ocrane-3-carboxyL are; C CL '-377 (c methanaL).

ExampLe 113: n-Qc tyL 2-CN-( 1 S-n-oc tyLoxycarbcnyL -3-pheny L propy L aLanyL]-(iS,3S,5S)-2-azabicycLoE3.3.0]octane-3-carboxyLace; Ca 25 1 8.6o (c mnethanoL).

ExampLe 114: n-OctyL 2-C,4-(i1S-n-oc radecy Loxyc arbony L-3-pheny L propy L S-aL anyL] 15 ,3S,55 )-2-azabicyc LoE3.3 .0]octane-3-c arboxy- Late; Ca--1 25 1 5 2 0 1, methanoL).

:ExamLe 115: n-OctyL 1 1S-ethoxycarbonyL-3-phenyLpropyL )-S-aLanyL~spiro~bicycLoE3.3.0]octane-2,3'S-pyrr-oLidinej-5 carboxyL ate.

ExampLe 116: n-NonyL 1'-CN-(1S-ethoxycarbonyL-3-phenyLpropyL)-S-aLanyLlspi ro~bicyc LoCZ.2..ZJoctane-2,3 IS-pyrroL idine 1-5 'ScarboxyLate hydrogen raLeate; meLting point 110 0

C.

ExampLe 117: n-DecyL 1 1S-ethoxycarbonyL-3-phenyLpropyL )-S-aLanyL~spiro~tbicycLoCZ.Z.aloctane-2,3'S-pyrroLidine]-5'S- RA4/ carboxyLate hydrogen maLeate; meLting point 96 0

C.'

T-

:xampLe 118: *0 0O S 0 0

S

SO

6

S

n-OctyL 2-EN-C 1S-ethoxycar'oonyL-3-ohenyLpropyL )-S-3LanyL 1- (1R,3R,;R )-Z-azabicycLoC3 .3 Oloctane-3-c arboxy L are; Ca 7 (c 1.16, methanoL).

ExampLe 119: n-OctyL 2-CN-( 1S-ethoxycarbonyL-3-phenyLpropyL )-R-aLanyi (lS,3S,5S)-2-azabicycLoC3.3.0]octane-3-carboxyLa cc; Cal Z +18.0 0(c 1, methanoL).

ExamcLe 120: n-OctyL 2-EN-C 1R-ethoxycarbonyL-3-phenyLpropyL )-R-aLanyL (lS,3S,5S)-2-azabicycLoC3.3.Oloctane-3-carboxyLate; Cal D +9.4o (c mechanoL).

ExamaLe 121: n-OctyL 2-EN-(1S-ethoxycarbonyL-3-phenyLpropyL )-S-aLanyL]- C 1S,3S,5S)-2-azabicycLoE3.3.0J-7-octane-3-carooxyLate; +21.20 (c 1, methanoL).

EL2

D

ExampLe 122: n-Oc tyL 2-EN-C 1 S-e thoxyc arbanyL -3-pheny L propy L -S-a Lany L I- (1R,3R,SR)-2-azabicycLoE3.3.02-7-octane-3-carboxyLate; Cal 2 -51.4o Cc methanoL).

D

ExampLe 123: n-Oc tyL es te r of N-EN- 1 S-e thoxyc arbony L-3-pheny-Lprocyt)L S-aLanyt2-S-proLine hydrogen maLeate; melting point '105-107 C.

:xampLe 124: 2-CN-( 1S-E thoxycarbonyL -n-tr idecy L )-S-PnenyL a Lany L I 1S,S,5S)-2-azabicyc~o[3.3.0Joctane-3-caoxyL ic acid; CaJ D +27.20 (c methanoL).

ExampLe 125: 3enzyL 2-CN-( iS-ethoxyc arbonyL-n-tr idecy L -S-a L any L IJ- 1S,3S,55S)-2-azabicycLoE3.3.0]octale-3-carboxyL ate.

ExampLe 126: aenzyL 1R-ethoxycarbonyL-n-tr idecyL -S-a Lany L I- C 1S,3S,SS)-2-azabicycLoC3.3.Ojoctane-3-carboxyLate.

ExampLe 127: SenzyL Z-CN-( 1 S-n-octadecyLoxycarbonyL-3-phenyLp ropy L aLanyL 1S,3S,5S)-2-azab icycLoC3.3.0]octane-3-carboxyL ate Ca 5= -28.60 (c methanoL).

D

ExampLe 128: BenzyL 2-EN-(1S-menthyLoxycarbonyL-3-phenyLpropyL)-SaLanyL]-( 1S,3S,5S)-2-azabicycLoE3.3.0]octane-3-carboxyLate; Ca -63.2o Cc methanoL).

Example 129: 3,3-D ipheny L--propyL 2-EN-C IS-e tho xyc arbony L-3-p heny L pro pyL)-S-aLanyLJ-(lS,3S,SS)-2azabicycLoE3.3.0oJctale-3carboxytate hydrogen maLeate; meLting point 122-124 0

C.

-xanoL~e 130: 1'-EN-(1S-ethoxycarbon>'L-3-phenyLpropyL)-S-aLanyL'AsoiroCbicyctoC2..2.2)octane-2,3'S-pyrroLidineJ-5'S.- :carooxyLate hydrogen maLeace; meLting point 121 0

C.

ExampLe 131: Tert.butyLammonium 2-EC9-( 1S-n-octadecyLoxycaroonyL-3phenyI.propyL)-S-aLanyL)-(1S,3S,5S)-2-azabicycLoC3.3.0Joctane-3-carboxyLate; meLting point 133-135 0 c.

ExampLe 132: rert.butyLamrnonium 2-EN-( 1s-menthyLoxyc~rbonyL-3-phenyLprooyL)-S-aLanyLJ-(lS,3S,5S)-2-azabicycLoE3.3.O]octane-3carnoxyLate; meLting point'164-167 0

C.

Reference Example 1: 1) Benzyl 2-(S-aLanyt)-(1S,3S,5S)-2-azabicycLoC3.3.0J- ~1 octane-3-carboxyLate trifLuoroacecare 1a)-eenzyL 1-(N-tert.butyioxycarbonyL-S--3LanyL )-(1S,3SSS)- 2-azabicycLoC3.3.0]occane--carboxyLact 61.5 g (0.251 moL) of benzyL (1S,3S,5S)-2-azabicycLa- C3.3.O1octane-3-carboxylate, 47.5 g (0.251 moI) of BOC-Lalanine and 173 mL (1.26 mol) of aosoLuce triethyamine are dissoLved in 1,025 mL of absolute dimethyLformamide, 252 ml of a 50% strength soLution of propanepnosphonic anhydride in dichLoramethane are added dropwise at and the mixture is stirred at -5OC for 30 minutes and at room temperature for four hours. rhe reaction soLution is partitioned between water and ethyl acetate, the aqueous phase is extracted once more with ethyl acetate, and the combined organic phases are washed with saturated sodium bicarbonate solution, 10% strength citric acid solution water and saturated sodium chloride soLution, dried and concentrated.

YieLd: 93.2 g of oily product.

25 ib) Benzvl 2-(S-aLanyL 1S,3S,SS)-2-azabicycLoC3.3.0J-

SI

S

.5 octane-3-carboxyLate trifluoroacetate 215 mL of absolute trifluoroacetic acid are poured over 93.2 g (0.224 mot) of BOC derivative from Reference Exampie la) at 00C, and the mixture is stirred at OOC for hours. Excess acid is removed by evaporation in vacuo at 0 c and the residue is crystallized from 1',00 mL of absolute dii!opropy ether.

Yield: 82.6 g melting point 148-150 0

C.

Reference Example 2.: 2) n-OctyL C 1S,3S,SS)-2-azabicycLoC3.3.0]octane-3-carooxy- 2a) BenzyL 2-tert.butyLoxycarbonyL-( 1S,-3S,'SS)-2-azaoicycLoC3.3.0)octane-3-carboxyL ace A soLution of 39.29g (0.180 moI) of di-tert.butyL dlicarbonate in 60 mL of absolute methyLene chloridle i slowLy added droowise at 00 C to a solution of 40.0 g (0.163 moL) of benzyL C 1S,3.,5S)-2-azabicycloC3.3.O]octane-3-carboxylate and 23.4 ml (0.169 moL) of absoLute triethyLamine in 300 niL of absoLute methyLene chLoricde, and the mixture is stirred at 00 C for 15 minutes and at room temperature for one hour. The reaction solution is washed with strength citric acid solution, saturated sodium bicarbonate solution and water, dried and concentrated.

yieLd: 55.6 g of oily prot_'ct, £0125 _1.20 (c methanoL).

D

2b) n-Tetl2tbutyLoxycarbonyL-(SS,3S,5S)-2-azabi-.01 cco30octane-3-carbox vL ic acid 32 5.3 g (0.167 moL) of acid ee from Reference Examp) n S 25.3 are 253droen)e o poa fiu bicarbonate area in2LtrVfehnLa "N Th/aayti itrdofwt utoadtefL i n 1500 m L o f d ime thy L formam ide a t 4.0 0 C focr 1 .3 5nou r s.

After cooLing, 48.9 g (0.2.53 moL) of 1-bromooctane are added dropwise, and the mixture is stirred at room temnperature overnight. The reaction mixture is poured into water, extracted three times with ethyL acetate, and the combined organic phases are washed with. saturateo sooium bicarbona te soLution and water, dr ied ano concentrated, and the c rude product (44.3 g) is purified by fLash chromatography on siLica gel (900 g, mobiLe phase toLuene! ethanoL 95:5 or 99.5:0.5) in two portions.

YieLd: 35.4 g of oiLy product, +5.70 (c 1, methanoL).

EaJ The fIoLLowing are obtained in an anaLogous way: n-octy L 2- ter t .buty Loxyc arbony 1 RS,3RS ,5RS azab icy cL o- C3 .3 -7-octene-3)-carboxyL ate; n-oc tyL ester of N-tert.butyLoxycarbonyL-S-proLine.

2d) n-Oc tyL( 1S,3S,5S )-2-azab icycLoC3 .3 .0 1octane-3-c arboxyLate 2.6 g (7.0 mmoL) of BOC compound from Reference ExampLe 2c -are stirred wi'h 9 rnL of trif Luoroacetic acid at 0CIO f or 1.5 hours. 'he excess acid is removed by evaporation in vacuo, the residue is taken up in water, the soLution is basified with sodium bicarbonate and extracted with ethyL acetate, and the organic phase is washed once more 25 with water, dried and concentrated, and the product is rapidLy reacted further.

YieLd: 1.8 g of oiLy product.

The foLLowing are obtained in an anaLogous way: n -o ct yL (1IR S,3 RS 5RS-2 a zab ic yc L o C 3.3 .0 7- oc te n e- 3-car boxytate; 4 n-octyL ester of S-proLine.

hydrogen mateate -fe rfc e Ex aMOLe 3: 71) c:ynyL mehanesuLzlonate 7.47 g (65 mmoL) of methanesuLfonyL cnLoride are addea dra aw is e rto a so Lu tion of 7.356 g 60 mmo L) of 3 -oc tyn- 1-o L a-nd 12.45 mL (90 mmoL) of triethyLamine in 225 ML of ietnyLene chLoridle at 10 0 C within 30 minutes, ano the Ti x tu re is ati r red for one hour. The reaction soLu:tIon s .asnec with water, saturatea sodium bicarbonate soLu- ,ion and again with water, dried ano concencraze.

Y iaLo: 11.9 g of oiLy product.

6ttt a a a St St **tt t Si' a a tSS Sr S It 'I C S 'a

CC

5551 S a a S C I St a S S t

Claims (2)

1. The use of angiotensin-converting enzyme inhibitors of the formula II as medicaments having a cognition adjuvant action wherein formula II is defined as: R 3 OOC CH N C CH NH CH (CH 2 )n-R (II) R RO R COOR 2 in which n is 1 or 2; R denotes hydrogen, an optionally substituted aliphatic radical having 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 .carbon atoms, an optionally substituted alicyclic-aliphatic radical having S4-20 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic- (C-C )-aliphatic radical having 5-12 ring atoms, or a radical ORa or SRa, in which R a represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted heteroaromatic radical having 5-12 S ring atoms, R denotes hydrogen, an optionally substituted aliphatic radical having 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, 95 an optionally substituted alicyclic-aliphatic radical having

4-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic- (Cl-C.)-aliphatic radical having 5-12 ring atoms, or, if not already covered by the above definitions, 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 1-21 carbon atoms, an optionally substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, and R 4 and R 5 form, together with the atoms carrying them, a mono-, bi- or tricyclic ring system which has 3 to 15 ring carbon atoms and up to 2 ring sulfur atoms and up to 2 ring nitrogen atoms, preferably from the series comprising pyrrolidine, tetrahydroisoquinoline, decahydroisoquinoline, octa- hydroindole, indoline, octahydrocyclopenta[b]pyrrole, 2-azaspiro[4,5]decane, 2-azaspiro[4,4]nonane, spiro[(bicyclo- [2.2.1]heptane)-2,3'-pyrrolidine], spiro[(bicyclo[2.2.2]- octane)-2,3'-pyrrolidine], 2-azatricyclo[4.3.0.1 6 9 ]decane, decahydrocyclohepta[b]pyrrole, octahydroisoindole, octahydro- cyclopenta[c]pyrrole, 2,3,3a,4,5,7a-hexahydroindole, 1,2,3,3a,4,5a-hexahydrocyclo-penta[b]pyrrole and 2-azabicyclo- [3.1.0]hexane. ii St C( S by fLash chromatograohy an 450 g of siLica geL mob i Le -96- 2. The use as claimed in one of claim 1, wherein upe is made of (S,S,S,S,S)-1-[N-(1-carbethoxy-3-phenylpropyl)-alanyl]- octahydroindole-2--carboxylic acid, l-[N-(l-S-carbethoxy-3-phenyl- propyl)-S-alanyl]-(2S,3aR,7aS)--octahydroindole-2-carboxylic acid, (S,S,S,S,S)-2-[N-(l-carbethoxy-3-phenylpropyl)-alanyl]- decahydroisoquinoline-3-carboxylic acid, h carbethoxy-3-phenylpropyl)-alanyl]-tetrahydroisoquinoline-3- carboxylic acid, (S,S,S,S,S)-2-[N-(l-carbethoxy-3-phenylpropyl)V alaynll-2-azabicyclol3.3.O.I-octane-3-carboxylic acid, 2-N-(l-S- carbethoxy-3-phenylpropyl)-S-alanyl]-cis,endo-2-azabicyclo- 4 (3.l.O]-hexane-3--S-carboxylic acid or l-[N-(l-S-carbethoxy- 3-phenylpropyl alanyl J-cis, endo-1H-2 3a, 4,5, 7a-hexahydro- indole-2-S- or -2-R-carboxylic acid. 3. The use as claimed in one of claims 1-3, wherein use is made of l'-(N-(l-S-carbethoxy-3-phenylpropyl)-S-alaynl]-exo/endo- spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, 1 l-S-carbethoxy-3-phenylpropyl alanyl spirobicyclo(2.2.2]-octane-2,3'-pyrrolidine-5'-carboxylic acid, l'-[N-(l-S--carbethoxy-3-phenylpropyl)-S-alanyll-(3'S,5'R)-spiro- bicyclo[2.2.2]-octane-2,3'-pyr-rolidine-5--carboxylic acid, 1'-(N-(l-S-carbethoxy--3-phenylpropyl)-S-alanylj-(3'R,5's)- spirobicyclo[2.2.2.loctane-2,3'-pyrrolidine-5'-carboxylic acid, l'-(N-(l-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'R,5'R)- spirobicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, l'-[N-(l-R--carbethoxy-3-phenylpropyl)-.S-alanylJ-(3'S,5'S)- spirobicyclo-[2.2.2]octane-2,3'--pyrrolidine-5'-carboxylic acid, l'-tN-(-R-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'S,5'R)-spiro- bicyclo[2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, (l-R-carbethoxy-3-phenylpropyl alanyl1- R, I bicyclo[2.2.2loctane-2,3'-pyrrolidine-5'-carboxylic acid, 1-R-carbethoxy-3-phenylpropyl)-S-alanyl]-(3'R,5'R)-spirobicyclo- [2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid, l'-IIN-(l-S- carbethoxy-3-phenylpropyl )-R-alanyl -spi robicyclo- [2.2.2 ]octane-2, 3 -pyrrolidine-5'-carboxylic acid, 1 carbethoxy-3-phenylpropyl)-R-alanyl]-(3'R,5'S)-spirobicyclo-- [2.2.2]octane-2,3'pyrrolidine-5'-carboxylic acid, 1 the combined organic phases are, wasneu -97 carbethuxy-3--phenylpropyl)-R-alanyl-(3'S,5'R)-spirobicyclo- f2.2.2]octane-2,3-pyrrolidine--5'-carboxylic acid, carbethoxy-3-phenylpropyl)-R-alanyll-(3'R,5'R)-spirobicyclo- [2.2.2loctane-2,3'-pyrrolidine-5'-carboxylic acid, carbethoxy-3-phenylpropyl)-R-alanyl]I-( 3'S,5 S)-spirobicyclo- t2.2.2]octane-2, 3'-pyrrolidine-5'-carboxylic acid, l-R- carbethoxy-3-phenylpropyl>-R-alanyl]-(3'R,5S)-spirobicyclo- [2.2.2)octane-2,3'pyrrolidine-5'-carboxylic acid, carbethoxy-3-phenylpropyl )-R-alanylI-( 3'S, [2.2.2]octane-2,3'-pyrrolidine-5'--carboxylic acid or carbethoxy-3--phenylpropyl )-R-alanyl 3'R, f2.2.2loctane-2,3'-pyrrolidine-5'carboxylic acid. 4. The use as claimed in claim 1, wherein use is made of (S,S,S)-1-methyl-2-(1-carbethoxy--3-phenylpropyl)-2H- undecahydrocyclopentall4,5]pyrrolo[l,2-alpyrazine- 3,8-dione. DATED this 20th day of August, 1991 I1 t WATERMARK PATENT TRADEMARK ATTORNEYS 2nd Floor "The Atrium" t 290 Burwood Road .Hawthorn Victoria 3122 AUSTRALIA DBM/KJS:EK(15:36) JL ZIC