NZ219764A

NZ219764A - Heterocyclic compounds and pharmaceutical compositions

Info

Publication number: NZ219764A
Application number: NZ219764A
Authority: NZ
Inventors: Josef Scholtholt; Hansjorg Urbach; Rainer Henning; Franz Hock; Ulrich Lerch; Wolf-Ulrich Nichel; Wolfgang Ruger
Original assignee: Hoechst Ag
Priority date: 1986-03-27
Filing date: 1987-03-25
Publication date: 1990-11-27
Also published as: CS276179B6; NO871282L; OA08506A; FI871304A0; DE3610391A1; JPS62240698A; PH27210A; EP0243645A3; IE870784L; CN1031267C; ATE102954T1; NO871282D0; NO178546B; CS212687A3; DK153587D0; EP0243645A2; PT84564A; MA20919A1; CN87102304A; ZA872230B

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

<div class="application article clearfix" id="description"> New Zealand Paient Spedficaiion for Paient Number £19764 J 1% 2 NO DRAWINGS <§ # Priority Date{s): , 3 • ^ ^ * Complete Specification Fi!ed:^}.3*tJ?-Class: Urtf.k/. S&JZZnl j, i£; Publication Date: •. .2.7. NUtf. ;19aQ P.O. Journal, No: - Class Com: iTvp77?j.. | J.QU-.. N- .■Ss.Tl .tr-teO./ .ip;. ■ 'j. vtt?TYT m?7\T 7\*K*npk Patents Act 1953 Class Cont: . ft kJj. Wa,. Sy ?ri,(v>.1Hy.CdMPLETE specification # COMPOUNDS HAVING A COGNITION ADJUVANT ACTION, AGENTS CONTAINING THEM, AND THE USE THEREOF FOR THE TREATMENT AND PROPHYLAXIS OF COGNITIVE DYSFUNCTIONS We, HOECHST AKTIENGESELLSCHAFT, a corporation organized under the laws of the Federal Republic of Germany of D-6230 Frankfurt am Main 80, Federal Republic of Germany, do hereby declare the invention, for which we pray that a Patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the ^following statement : - // \ ,0/ - 1 - (Followed by 1A) - IA - HOCCI1GT AKTICNGCGCLLSC11ArT-r HOC 06/T 069 .MS/frP 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 X1 - X2 (I) in which j} denotes 0$ 2 X denotes F, COOR' or R3OOC - CH - N - 0 - (CHR1L - A* « R OOC 0 -CH0SH , -CH0-S-C-R6 , -CH0-:'-R7 °r 2 2 ii 2 0 OR 8 Y' m n P R -r- ( CHj ) -CH-(CH2 ) n-R COOR represents -S- or -CH2-, g represents -NR- or -CH2"/ is 0 or 1, is 0, 1 or 2, is 0 or 1, denotes hydrogen, an optionally substituted aliphatic radical having 2.10764 - 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 aral iphatic radical having 7-32 carbon atoms, an optionally substituted all cyclic-aliphatic radical having 4-20 carbon atoms, an optionally substituted heteroaromatic or hetero-aromatic-(C<j-Cg)-al iphatic radical having 5-12 ring atoms, or a radical 0Ra or SRa, in which 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, 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 alicyclic-aliphatic radical having 4-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, t an optionally substituted heteroaromatic or hetero-aromatic-(C-|-Cg)-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, nd 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, represents hydrogen or (C i-C$)-alkyl and represents (C<j-C6)-alkyl, (Cj-C^J-cycloalkyl or or and form, together with the atoms carrying them, a mono-, bi- or tricyclic, heterocyclic ring system having 3 to 15 ring carbon atoms, denotes hydrogen, amino, (C<|-C6)-alkyl, (C^-C12^"~ aryl or (Cy-C^J-aralkyl, denotes (Ci-C$)-alkyl or (C7-C^J-aralkyl, preferably -(CHg^-C^Hs, denotes (C-|—C^) —alkyl, which is optionally mono-substituted by (C-j-C^-alkanoyloxy, preferably 2-methyl-1-propionyloxypropyl, and denotes hydrogen or CC-| —C^> —alkyl; such as compounds of the formula II, « « * OOC - CH - N - C - CH - NH - CH - (CH5)_-R (II) A4 ii E1 COOR2 ^ which is 1 or 2, 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 - 4 - having 4-20 carbon atoms, an optionally substituted heteroaromatic or hetero-aromatic-(Ci-C8)-aliphatic radical having 5-12 ring atoms, or a radical 0Ra or SRa, in which 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, 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 alicyclic-aliphatic radical having 4-20 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 heteroaromatic or hetero-aromatic-(C<|-Cg)-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, 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 and R^ form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms. n - 5 - 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 unsatu-5 rated radicals. It is preferably unsubstituted or, as described below, for example, for carboxyl, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, a Iky I -aminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthio-10 aLkyl, carboxyalkyl, carbamoylalkyI, alkoxycarbonylalkyl, r?s w aLkanoyloxya Ikyl, alkoxycarbonyloxyalkyl, aroyLoxyaLkyI 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 mono-to pentacyclic, isocyclic, nonaromatic radical which has single bonds or asymmetrically distributed double bonds and can also be branched (i.e. carry open-chain aliphatic side-chains) and is Linked via a ring carbon atom or a 20 side-chain carbon atom. It is preferably unsubstituted. When several rings are components of a radical of this type, they are fused, spiro-linked or isolated. Examples of radicals of this type are cycloalkyl, cycloaIkenyL, cyclo-alkylalkyl, bicycloalkyl, tricycloalkyl and radicals de-25 rived from mono-, bi- or oligocyclic terpenes such as menthyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, menthanyl, neomenthyl, neoiso-menthyl, pinanyl and thujanyl; they are preferably unsub-stituted (according to the present definition, aliphatic 30 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, 35 aryloxy, arylthio or aroyl, preferably benzoyl, can be substituted as for aryl. O PiV'jJ - 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 sul-5 fur or oxygen atoms and/or 1 to 4 of these ring atoms repre-O senting nitrogen atoms, and is understood to be, for example, thienyl, benzoCblthienyl, furyl, pyranyl, benzofuryl, pyr-rolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrid-azinyl, indazolyl, isoindolyl, indolyl, purinyl, quinol-10 izinyl, isoquino Iiny I , phthalazinyl, naphthyridinyl, quin-f**) oxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated. A heteroaromatic radical and the corresponding heteroaromatic-15 aliphatic radical can be substituted as defined below. An optionally substituted araliphatic radical is undei— stood to be, in particular, aralkyl radicals such as aryl-alkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is 20 as defined above and which can be substituted in the manner indicated there. 4 5 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 atoms and up to 2 nitrogen atoms in the ring, in particular up to 1 sulfur atom. Particularly suitable ring systems of these types are 30 those of the following group: Pyrrolidine (0); thiazolidine (J?); tetrahydroisoquinoline (A); decahydroisoquinoline (B); octahydroindole (£); indoline (£); octahydrocyclopentaCbJpyrrole (l>) ; 2-azaspiroC4.5]decane (E,); 35 2-azaspiroC4.4]nonane (F); spiroC(bicycloC2.2.1^heptane)-2,3'-pyrrolidineD (J3); spiroC(bicycloC2.2.23octane)-2,3'-pyrrolidine] (jO; 2-azatricycloC4.3.0.1^'^Jdecane H); decahydrocycloheptaCbDpyrrole (J); octahydroisoindole (K); - 7 - octahydrocyclopentaEcDpyrrole (1.) ; 2,3,3a,4,5,7a-hexahydro-indole (^1); 2-azabicycloC3.1.ODhexane (rO ; 1, 2, 3, 3a, 4,6a-hexahydrocyclopentaCb]pyrrole (£), all of which can optionalLy be substituted. Pyrrolidine (j)) and thiazolidine (Jp; 5 can be monosubstituted by, for example, (C^-C^^aryl-, (phenyl, 2-hydroxyphenyl etc.), (C^-C^J-arylmercapto (such as pheny Imercapto) or (Cj-C^-cyc loalkyl (such as cyclo-hexyl). Tetrahydroi soqui nol i ne (_A) can carry, for example, in the aryl moiety, up to 2 (C-j-C^ )-alkoxy radicals, prefer-10 ably 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 15 chiral atoms all possible diastereomers, as racemates or enantiomers, or mixtures of various diastereomers are suitable. The suitable heterocyclic ring systems have the following 20 structural formulae. o CCt""cK COOR* •COOR O . fi ' % _ ^x^-coor3 C^^)- "OR3 ^^^WOR3 QQcooJ k' a i 1 Q> ~/Ow 8- COOR" r I o COOR3 ^ >-COOR- I M N c "• G>< 0-coor3 CO" O CO"coor3 Q- COOR: \ COOR2 2 1976/ 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 rep resents 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 (c-2); 5. denotes aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C-j-CgJ-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C-j-C^J-alkylamino, di — (C-j—C4) — alkylamino, (Ci~C4)-alkanoylamino, methylene-dioxy, carboxyl, cyano and/or sulfamoyl; 6. if n is 2, denotes (C$-Ci2)~ary'--(c1~c8*~a'-lcy'-or di-(C£-Ci2)~aryl-~(c1"c8^~a'-'cy'-' 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. aryloxy which has 6-12 carbon atoms and can be substituted as described under I.b)5; 9. mono- or bicyclic heteroaryloxy or heteroaryl-(C-|-Cg)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 to 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 under I.b)5; 10. amino-(C-j-C8)-alkyl; 11. (C<|-C4)-alkanoylamino-(C<|-Cg)-alkyl; 12. (C7-Ci3)-aroylamino-(C<|-C8)-alkyl; r?, •S»£n,-.°-. " " ""."VSv^-T'^Vt.-Vi • f! - 10 - 13. (Ci-C4)-alkoxycarbonylamino-(C<|-Cg)-alkyl; 14. (C6-C<|2>~aryl-(Ci-C4)-alkoxycarbonylamino-( C -|-Cg) -a I ky I ; 15. (C6-C'|2^~ary'-~^i-C4)-aLkyLamino-(Ci-C8)-5 alkyl; 16. (C'|-C4)-alkylamino-(C']-Cg)-alkyl; 17. di-(C<|-C4)-alkylamino-(C<|-Cg)-alkyl; 18. guanidino-(Ci-Cg)-alkyl, 19. imidazolyl; 10 20. indolyl; 21. (C-j-C4)-aLkyLthio; 22. if n is 2, (Ci-C4>-alkyLthio-CC1-Cg)-aLkyL ; 23. (C^-C^i-arylthio-CCi-CgJ-alkyl which can be substituted in the aryL moiety as described 15 under I.b)5; 24. <C^ — c12^ — aryL — <Ci~Cs> — aLkyLthio which can be substituted in the aryL moiety as described under I.b)5; 25. if n is 2, car bo xy-(C<|-Cg)-alkyl; 20 26. carboxyL; 27. carbamoyl; 28. if n is 2, carbamoyl-(Ci-Cg)-alkyl; 29. (C<|-C4)-aLkoxy-carbonyl-(Ci-Cg)-alkyl; 30. if n is 2, (C6-Ci2^~ary'-ox>""^c1"c8^"a'-'cy'- O 25 which can be substituted in the aryl moiety as described under I.b)5; or 31. denotes (C6-C'j2^~ary'-~^c1"'c8^~a'-'coxy which can be substituted in the aryl moiety as described under I.b)5; 30 c) R 1. denotes hydrogen; 2. denotes alkyl having 1-18 carbon atoms; 3. denotes an aliphatic radical of the formula CaH(2a-b+1)' ""n which double bonds, if their number exceeds 1, are not cumulative, a represents 35 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 radical of the formula o 'y ^ I v / o -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 (c-2); 5. aryL which has 6-12 carbon atoms and can be substituted as described under I.b)5; 6. (C$-Ci2)-aryL-(C1-Cg)-alkyL or (C7-C13)-aroyl-(Ci~Cg)-alkyl, both of which can be substituted as described for aryl under I.b)5; 7. mono- or bicyclic, optionally partially hydrogen-10 a t e d , heteroaryl or heteroaryl-(Ci~Cg)-alkyl which (^0 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 15 which can be substituted in the heteroaryl as des cribed for aryl under I.b)5; or 8. if not already covered by c) 1. - 8., the optionally protected side-chain of a naturally occurring 1 a-amino acid of the formula R -CH(NH2)~COOH; 2 3 20 d) R 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)/ which double bonds, if 25 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, non-aromatic hydrocarbon radical of the formula 30 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 (c-2); 5- di-(C-|-C4)-alkylamino-(C-j-C3)-alkyl; 6. (C-|-C5)-alkanoyloxy-(Ci-Cg)-alkyl; 35 7. (C<j-C6)-alkoxy-carbonyloxy-(Cf-Cg)-alkyl; 8. (C7-Ci3)-aroyloxy-(Ci-Cg)-alkyl; 9. (C6-C-]2)~aryl-oxycarbonyloxy-(C<]-Cg)-alkyl; 10. aryl having 6-12 carbon atoms; or n 11. denote (C7-C2())-aralky L; it being possible for the radicals mentioned under d) 8., 9., 10. and 11. to be substituted in the aryl moiety as described under I -b)5; and e) and R5 form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms. A particularly preferred embodiment comprises use of compounds of the formula I, preferably those of the formula II, in which n is 1 or 2, R denotes hydrogen, alkyl having 1-8 carbon atoms, alkenyl having 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C -| — C4)—alkyl, ( C-j—C4) — alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C-j-C^J-alkylamino, di-CC^-C^-alkylamino, (Ci-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyL, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be substituted as described above for aryl, mono- or 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 above for aryl, amino-(C«|-C4>-alkyl, (C<|-C4)-alkanoy lam ino-CC^-C^) alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (Ci-C4)-alkoxycarbonylamino-(Ci-C4)-alkyl, (C6-Ci2>-aryl-(Ci-C4)-alkoxycarbonylamino- (C<|-C4)-alkyl, (C6-C-|2^~ary'-~^c1~c4)"a'-'cylamino-CCi-C4)-alkyl, 2 19 764 - 13 - ~— (Ci-C4)-alkylamino-(C<|-C4)-alkyl, di-(Ci-C4)-alkylamino-(Ci-C4)-alkyl/. guanidino-(Ci-C4)-alkyl/. imidazolyl, indolyI, (C<|-C4)-alkylthio, (Ci-C4)-alkylthio-(C')-C4)-alkyL/ (Cg-C 12)-aryI1hio-(C1-C4)-aIkyL which can be substituted in the aryl moiety as described above for aryl, <C6-Ci2>-aryl-<Ci-C4)-alkylthi° which can be substituted in the aryl moiety as described above for aryl, carboxy-(C-j-C4)-alkyl, carboxyl, carbamoyl, carbamoyl-(Ci-C4)-alkyl, (Ci-C4)-alkoxycarbonyl-(Ci-C4)-alkyl, <C6-Ci2)-aryloxy-(Ci-C4)-alkyl which can be substituted in the aryl moiety as described above for aryl, or (C^-Ci2)~aryI"<C1-C4)-alkoxy which can be substituted in the aryl moiety as described above for aryl, 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, cycloalkenyl having 5-9 carbon atoms, (C3-C9)-cycloalkyl-(C<|-C4)-alkyl, (C5-C9)-cycloalkenyl-(Ci-C4>-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described above for R, (C^-C125~aryC1-C4)-alkyI or <C7—C13), aroyl-(Ci or C2)-alkyl, both of which can be substituted as for the preceding aryl, 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, 2 19764 - 14 - and/or 1 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 i occurring a-amino acid, R -CH(NH2)-COOH, 2 3 R and R are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(Ci-C4)-alkylamino-(Ci-C4)-alkyl, (C<|-C5)-alkanoyloxy-(C<|-C4)-alkyl, (C<|-C6)-alkoxycarbonyloxy-(Ci-C4)-alkyl, <C7-Ci3)-aroyloxy-CCi-C4)-alkyl, (C6-Ci2)~ary'-0xycarbonyloxy-(Ci-C4)-alkyl, aryl having 6-12 carbon atoms, <c6-ci2>-aryl-<c1-c4>-atkyl, (C3-C9>-cycloaIky I or (C3-C9)-cycloalkyl-(Ci-C4)-alkyl, and R^ and R"* have the abovementioned meaning, particularly such compounds in which n is 1 or 2, R denotes CC-j—3 — alkyL, (Cg-C^J-alkenyl, (C3-C9)- cycloalkyl, amino-(C<|-C4)-alkyl, (C2-C5)-acylamino-(C-|-C4)-alkyl, (C7-C<|3)-aroylamino-(C<|-C4)-alkyl, (Ci-C4)-alkoxycarbonylamino-(C'j-C4)-alkyl, aryl-(Ci-C4)-alkoxycarbonylamino-(Ci-C4)-alkyl, (C^-C12)-aryl which can be mono-, di- or tri-substituted by ( C-j — C4>—alkyL, ( C <|-C4)-al koxy, hy-droxyl, halogen, nitro, amino, (Ci-C4)-alkylamino, di-(C«{-C4)-alkylamino and/or methylenedioxy, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert.-butoxycarbonylamino-(Ci~C4)-aLkyl, benzoyloxy-carbonylamino-(C-|-C4)-aLkyl, or phenyl which can be mono- or disubstituted, or in the case of methoxy trisubstituted, by phenyl, (C<j-C2)-alkyl, (C-j or C2)-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C<|-C4)-alkylamino, di-(Ci-C4)-alkylamino, nitro and/or methylenedioxy, 1 R denotes hydrogen or CC-) — C^) — al kyl which can optionally be substituted by amino, (Ci-C^J-acylamino or benzoylamino, or (C2-C6)-alkenyl, (Cj-C^-cyclo-alkyl, (C5~C9)-cycloalkenyI, (C3-C7>-cycloalkyl-< C-j—C^) —alkyl^ (C6-C12>-aryl or partially hydrogenated aryl, each of which can be substituted by (C-j-C^-alky I, (C-| or C2>-alkoxy or halogen, or ( C6-C12 ^-3ry I-C C1 to C4)-alkyl or <C7-Ci3)-aroyl-(Ci~C2)-alkyl, 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 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, or a side-chain of a naturally occurring, optionally protected a-amino acid, but in particular hydrogen, (C<j-C3)-alkyl, (C2 or C3>-alkenyl, the optionalLy protected side-chain of lysine, benzyl, 4-methoxybenzyI, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, 2 3 R and R denote identical or different radicals hydrogen, (C -j-C^J-alkyl, (C2-C$)-alkenyl or (C^-C^*-aryl-(Ci-C4)-alkyl, but in particular hydrogen, (C<|-C4)-alkyl or benzyl, and R^ and have the abovementioned meaning. •1 If R represents a side-chain of a protected naturally occurring a-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or His, preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, 1 vol. XV/1 and XV/2). In the case where R denotes the protected side-chain of lysine, the known amino protective groups are preferred, but in particular Z, Boc or (C^-C^)- '.v " - 16 - d, I y alkanoyL. Suitable and preferred O-protective groups for tyrosine are (C-j-C^J-alkyl, in particular methyl or ethyl. 5 It is possible and particularly advantageous to use the following compounds according to the invention: 2-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 10 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-S-1,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysyl3-5-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2 — [N —(1-S-ca rbethoxy-3-phenyI propyl)-0-ethyl-S-tyrosyI]-S-15 1,2,3,4-tetrahydroisoquinoline-3-carboxyIic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(3S)-deca-hydroisoquinoline-3-carboxylic acid 1-C N—(1-S-carbethoxy-3-phenylpropyI)-S-alany13-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 20 1-[N-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl3-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyI)-S-lysyl]-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 1—C N—(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-(2S,3aS, 25 7aS)-octahydroindole-2-carboxylic acid 1 — UN— <1-S-carbethoxy-3-eyelohexylpropyl)-S-lysyl]-(2s, 3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-ca rbethoxy-3-phenylpropyl)-0-methyl-S-tyrosyI3-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 30 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl3-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1 — C N — (1-S-carbethoxy-3-(3,4-dimethylphenyIpropyl)-S-ala-nyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-[N-C1-S-carbethoxy-3-(4-fluorophenyl)-propyl3-S-alanyl3-35 (2S,3aS,7aS)-octahydroindole-2-carboxyIic acid 1-[N-[1-S-carbethoxy-3-(4-methoxyphenyl)-propyl3-S-alanyl3-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-[N-C1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl3-S- - 17 - alanyl]-(2S/3aS/7aS)-octahydroindole-2-carboxyLic acid 1-CN-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl]-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylU-(2S,3aR, 5 7aS)-octahydroindole-2-carboxylic acid w' 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-(2S, 3aR,7aS)-octahydroindole-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyL)-S-Lysyl3-(2S/.3aR/ 7aS)-octahydroindoLe-2-carboxylic acid 10 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl]-(2S, 3aR ,7aS)-oc tahydro i ndo I e-2-ca rboxyl i c* acid 1-C N-(1-S-carbethoxy-3-phenyl propyl)-0-e thyL-S-tyrosyI]-(25,385,7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl3-(2S/3aR, 15 7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysyl3-(2S,3aR, 7aS)-octahydroindole-2-carboxylic acid 1 — C N—(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-(2S, 3aR,7aR)-octahydroindole-2-carboxylic acid 20 1-CN-(1-S-carbethoxy-3-cyclohexyIpropyI)-0-ethyl-S-tyrosy 13-(2S,3aR,7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(2S,3aS, 7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenyIpropyI)-O-ethyl-S-tyrosylD-25 (2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3,4-dimethylphenylpropyl)-S-alanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-C1-S-carbethoxy-3-(4-fIuorophenyI)-propyl]-S-aI any I]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 20 1-CN-C1-S-carbethoxy-3-(4-methoxyphenyl)-propyl3-S-alanylJ-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-C1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl]-S-alanyl]-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1 — C N-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl]-(2S, 35 3aS,7aS)-octahydroindole-2-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenyIpropyI)-S-aIanylD-cis-endo-2-azabicycloC3.3.03octane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysyl]-cis-endo- o - 18 - 2-azabicycIoC3.3.OJoc tane-3-S-c arboxy Ii c acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-cis-endo-2-azabicycloC3.3.Q]octane-3-S-carboxylic acid 2-tN-C1-S-carboxy-3-cyclohexylpropyl)-S-alanyl3-cis-endo-5 2-azabicycloC3.3.0]octane-3-S-carboxylic acid - 2-CN-(1-S-carbethoxy-butyl)-S-alanyl]-cis-endo-2-aza- bicycloC3.3.03octane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-C3,4-dimethoxyphenylpropyl)-S-aLa-ny13-c i s-endo-2-azab icycloC3.3.03octane-3-S-carboxylic acid 10 2-CN-C1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl]-cis- ( ' ; endo-azabicyclo-C3.3.0]octane-3-S-carboxyl ic acid 2-CN-(1-S-carbethoxy-3-phenyLpropyL)-0-methyl-S-tyrosyL]-cis-endo-2-azabicycloC3.3.03octane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenyLpropyl)-0-ethyL-S-tyrosyl ]-15 cis-endo-2-azabicycLoC3.3.0]octane-3-S-carboxyIic acid 2-CN-C1-S-carbethoxy-3-(4-fluorophenyLpropyL)-S-alanyl]-cis-endo-2-azabicycloC3.3.0]octane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-(4-methoxyphenyLpropyI)-S-alanylD-cis-endo-2-azabicycloC3.3.03octane-3-S-carboxylic acid 20 1-CN-C1-S-carbethoxy-3-phenylpropyl)-S-lysyl]-C2S,3aR, 6aS)-octahydrocyclopentaCb3pyrrole-2-carboxylic acid 1 — C N — <1-S-carbethoxy-3-cyc LohexyLpropyl)-lysyL U-(2S,3aR, 6aS)-octahydrocyclopentaCb]pyrrole-2-carboxylic acid 1-CN-<1-S-carbethoxy-3-phenyLpropyL)-0-ethyL-S-tyrosyLD-w' 25 C2S,3aR,6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid 1 — C N — <1-S-carbethoxy-3-phenyl propyl)-S-alanyl3-2-(2S,3aR, 6aS)-octahydrocyclopentaCb!lpyrrole-2-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-2-aza-30 spiro-C4.5]decane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenylpropyl)-0-ethyl-2-tyrosyl3-2-azaspiro-C4.5]decane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenyI propyl)-S-lysyI]-2-azaspiro-C4.5]decane-3-S-carboxylic acid 35 2-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl3-2-aza-spiroC4.5]decane-3-S-carboxylic acid 2-C N-(1-S-carbethoxy-3-cyclohexyIpropyI)-S-lysy13-2-aza-spiroC4.53decane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenyLpropyl)-S-alanyl]-2-azaspi ro-C4.43nonane-3-S-carboxylic acid 2 19764 n - 19 - 2-CN-C1-S-carbethoxy-3-phenylpropyL)-0-ethyl-S-tyrosylJ-2-azaspiroC4.4]nonane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenylpropyl)-S-lysyl3-2-azaspiro-E4.4]nonane-3-S-carboxylic acid 5 2-CN-C1-S-carbethoxy-3-cycLohexyLpropyl)-S-aLanyL]-2-aza-sp i roC4.43nonane-3-S-carboxy Lie acid 2-C N-C1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyL 3-2-aza-spiroC4.4]nonane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-cycLopentylpropyl)-S-lysyl3-2-aza-10 spiroC4.4]nonane-3-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-phenylpropyl)-S-alany I]-spiroCbi-cycloC2.2.1]heptane-2,3'-pyrrolidine]-5'-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-phenyI propyl)-0-ethyl-S-tyrosylH-spiroCbicycloC2„2.1]heptane-2,3'-pyrrolidine3-5,-S-car-15 boxyli c acid 1'-CN-C1-S-carbethoxy-3-phenylpropyl)-S-lysyl]-spiroCbi-cycloC2.2.1]heptane-2,3*-pyrrolidine}-5'-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylIl-spiro-CbicycloC2.2.1]heptane-2,3'-pyrrolidine's'-S-carboxylic 20 acid 1'-CN-C1-S-carbethoxy-3-eyelohexylpropyl)-S-lysyl]-spiro- CbicycloC2.2.1]heptane-2,3,-pyrrolidineD-5,-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-phenylpropyI)-S-alany13-spiro-O 25 CbicycloC2.2.2.3octane-2,3'-pyr rolidine]-5'-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-phenylpropyl)-0-ethyltyrosyl]-spiro-CbicycloC2.2.2]octane-2,3'-pyrrolidine]-5'-S-car-boxy I i c acid 30 1'-CN-C1-S-ca rbethoxy-3-phenylpropyI)-S-lysylJ-spiro Cbi-cycloC2.2.2]octane-2,3'-pyrrolidine3-5'-S-carboxylic acid 1'-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-aIanyl3-spi ro-CbicycLoC2.2.23octane-2,3'-pyrrolidine]-5,-S-carboxylic acid 35 2-CN-C1-S-carbethoxy-3-phenylpropyI)-S-alanylH-2-azatri- 6 9 cycloC4.3.0.1'3decane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenylpropyI)-0-ethyl-S-tyrosyI]- 6 9 2-azatricycloC4.3.0.1/Ddecane-3-S-carboxylic acid O .... o 2 - 20 - 2-CN-C1-S-carbethoxy-3-phenyl propyl)-S-lysyl3-2-azatr i- cycloC4.3.0.1^'']decane-3-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl]-2-aza- 6 9 tricycloC4.3.0.1 ' ]decane-3-S-carboxylic acid 5 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyI3-2-aza- ' ^ 6 9 tricycloC4.3.0.1 ' ]decane-3-S-carboxylic acid 1-CN-C1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-decahydro- cycloheptaCb]pyrrole-2-S-carboxylic acid 1 — C N — (1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyI3- 10 decahydrocycloheptaCb3pyrrole-2-S-carboxylic acid ^ 1-CN-C1-S-carbethoxy-3-phenylpropyl)-S-lysyl3-decahydro- cycloheptaCb3pyrrole-2-S-carboxylic acid 1-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyL3-deca-hydrocycloheptaCb]pyrrole-2-S-carboxylic acid 15 1-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl3-deca-hydrocycloheptaCbJpyrrole-2-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenylpropyI)-S-alanyl3-trans-octahydroisoindole-1-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-phenylpropyl)-S-alanyl3-cis-octa-20 hydroisoindole-1-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl3-trans-octahydroisoindole-1-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-cycIohexyIpropyl)-S-alanyl3-cis-octahydroisoindole-1-S-carboxylic acid 25 2-CN-C1-S-carbethoxy-3-phenylpropyl)-S-alanyl3-cis-octa-hydrocyclopentaCc3pyrrole-1-S-carboxylic acid 2-CN-C1-S-carbethoxy-3-cycIohexylpropyI)-S-alanyl3-cis-octahydrocyclopentaCc3pyrrole-1-S-carboxylic acid benzyl ester V—^ 30 2-CN-C1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl3-cis-octahydrocyclopentaCc3pyrrole-1-S-carboxylic acid 1-CN-C1-S-carbethoxy-3-phenyI propyl)-S-alanyl3-2,3,3a,4, 5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid 1-CN-C1-S-carbethoxy-3-phenylpropyl)-S-lysyl3-2,3,38,4, 35 5,7a-hexahydroindole-cis-endo-2-S-carboxyIic acid 2-CN-C1-S-carbethoxy-3-cycIohexylpropyI)-S-lysy13-2-aza-bicycloC3.1.03hexane-3-S-carboxylic acid 2-CN-C1-S-carboxy-3-phenylpropyl)-S-lysyl3-2-azabicyclo- O o - 21 - C3.1.0]hexane-cis-endo-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanyl]-2- azabicyclo[3.1.0]hexane-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl2-cis-endo- 2-azabicycloC3.1.0]hexane-3-S-ca rboxyIic acid 2-CN-(1-S-carbethoxy-3-eyelohexyLpropyL)-S-aLanyL]-cis- endo-2-azabicyclo[3.1.0]hexane-3-S-carboxylic acid I'-CN-d-S-carbethoxy-S-phenyLpropyn-S-alanylU-n'S,5 • S) ■ 10 spiro-bicycloC2.2.23octane-2,3'-pyrrolidine-5*-carboxylic acid 1'— C N —(1-S-c arbethoxy-3-phenyLpropyL)-S-alanyLD—S'R^S'S)-spiro-bicyclo[2„2.23octane-2,3*-pyrrolidine-5'-carboxylic acid 15 1,-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl3-(3'S/.5,R)-spiro-bicycloC2.2.23octane-2,3'-pyrrolidine-5'-carboxylic acid 1,-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyLj-(3;R,5sR)-spiro-bicycloC2.2.2Doctane-2,3,-pyrroli d ine-5'-carboxylic 20 acid 1,-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanyL3-(3,S,5,R)-spiro-bicycloC2.2.23octane-2,3*-pyr rolidine-5'-carboxylic acid 1,-CN-(1-R-carbethoxy-3-phenyLpropyL)-S-alanyl]-(3,S/5'S)-25 spiro-bicycloC2.2.23octane,2,3'-pyrrolidine-5,-carboxylic acid 1,-CN-(1-R-carbethoxy-3-phenyLpropyL)-S-alanyl]-(3'R,5'S)-spiro-bicycloC2.2.23octane-2,3*-pyrrolidine-5'-carboxylic acid (3 30 11 — C N—(1-R-carbethoxy-3-phenylpropyI)-S-alany I]-(31R,5'R)-spiro-bicycloC2.2.23octane-2,3,-pyrrolidine-5'-carboxylic acid 11-CN-(1-S-carbethoxy-3-phenylpropyI)-R-aLanyl]-(3'S,5'S)-spiro-bicycloC2.2.23octane-2,3'-pyrrolidine-51-carboxyIi c 35 acid 1 * — C N—(1-S-carbethoxy-3-phenylpropyI)-R-alanyl3-(3'R,5,S)- spiro-bicycloC2.2.2]octane-2,3,-pyrrolidine-5,-carboxylic acid 2197 - 22 - 11 - CN- (1-S-ca rbe thoxy-3-pheny I p ropy D-R-alanylU-^'S^'R)-sp iro-bicycloC2.2.23octane-2,3*-pyrrol id ine-5'-carboxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyIJ-R-alanylH-CS'R^S'R)-spiro-bicycloC2.2.2]octane-2/3'-pyrrolidine-51-carboxylic acid I'-CN-O-R-carbethoxy-S-phenylpropyD-R-alanylD-^'S^'S)-spiro-bicycloC2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-( 1-R-carbethoxy-3-phenyl propyl )-R-a I any III -(3^,5* S )-spiro-bicycloC2.2.2]octane-2/3*-pyrrolidine-5'-carboxylic acid I'-CN-n-R-carbethoxy-S-phenylpropyD-R-alanyll-^'S^'R)-spiro-bicycloC2.2.23octane-2,3,-pyrrolidine-5,-carboxy-lic ac id 1'-CN-(1-R-carbethoxy-3-phenylpropyI)-R-aI any 13-(3•R,51R)-spiro-bicycloC2.2.2]octane-2,3'-pyrrolidine-5,-carboxy-lic acid These compounds can be prepared by, for example, the process described in "New Zealand Patent Specification No. 209544, in which the tert.-butyl or benzyl derivatives described in the application are converted in a known manner, by acid or alkaline hydrolysis or by hydrogenolysis catalyzed with noble metals, into the monocarboxyLic acid derivatives. The Ne-benzyLoxycarbonyl protective group of the lysine derivatives is removed by hydrogenolysis catalyzed with noble metals. The compounds listed above can readily be converted with physiologically tolerated acids or bases (in the case of mono- or dicarboxylic acids) into the corresponding salts (for example hydrochlorides, maleates, fumarates etc.), 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, and they can also be used for controlling high blood pressure of a variety^Y^T>^ !■ J ' ~9f£B!990 - 23 - etiologies. 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, New Zealand Patent No. 202378, New Zealand Patent No. 198195, -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, New Zealand Patent No. 202903, 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, enalapriI(f), captopriI(a), lisinopril(g), cilazapril(o), RHC 3659, CGS 13945, CGS 13928CC1), CGS 14824A(h), CI-906(j), zofenopril(e), foseno-pril(p), alacepril, CI-925(k), pentopriI(q), CV 3317(m), indolapriI(h), YS 980(b), fentiapriI(c), pivopril(d), perindopri I (i), and others. Orally effective ACE inhibitors are described in, for example, Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. 1) C1985 3 2-11. 2 1 - .24 - f"3 H5-CH2-CH-C0-N I (a) . C02« r* HS-CH2-CH-C0-N. (b) P C02H ; (OiJ)3-CO-S-m.-Sco? ^ <*> I (c) (ai ch2-co2h ^^CO-S-CHj-C^CO-NTJ JD-CH-NH-CH ^ ,,, K atVi "> t.„2__W'oyv© cjbu„ (CH2)4-NH2 C02H (a) "^CH-NH-CH a2^H5 (i) - 25 - H = y 2 CH.CH-CH-" C-CH-NH-CH^ 2 2 * ^3 ^5 ,i, •HSQ^ C02H ^2*0 C-CH-NH-CH z 2 \=/ «! i i 0 <*3 % X«H (j) X*« 3,4 OCHj(k) I 2" ^"2^2-0 r_rH_NH_rM * w ^C-CH-NH-CH 0 1 1 CHj COjC^Hg (1) N-CO O^-CO^H (m) <o« co„a WV CHg-CO^ (n) CD2H 4 % ~ (o) I2 P O 0 - ~ I • * " CH, VwH" : ' • \ 0,1 -■» <g) a j££>Z\ u fc$J: ' '■ Z': - v "' ■ ^ » 219784 O - 26 - ^ The ACE inhibitors which are disclosed in New Zealand Patent Specification 'No. 202378 and are of the formula III H. ^\^C00H ^ (III) >D - pH - MH - CH - CH2 - CH2~Y__ ) o CH3 iooR in which R denotes hydrogen, methyl, ethyl or benzyl, are pre-10 ferred, in particular the compound of the formula III in which R denotes ethyl (ramipriL). Also preferred are the ACE inhibitors which are disclosed in New Zealand Patent Specification No. 202903 and are of the formula IV 15 o> COOH (iv) (5) (S) s ls>l r\ H ZC - CH - NH - CH - CH5 - CH, -< \> cT i„ ln(w» 2 . 2 \=/ 20 w ch3 iooR* in which R^ denotes hydrogen, (Ci—C4>—alkyL or benzyL, in particular the compound of the formula IV in which R^ denotes 25 ethyl. Furthermore, preference is given to I'-CN-d-S-carboethoxv-S-phenylpropyU-S-alanylJ-exo- or endo-spirob i eye Io[2.2.23octane-2,3'-pyrrolidin-5'-ylcai— 30 boxylic acid and isomers, and (S,S,S)-1-methyl-2-(1-car-bethoxy-3-phenyl propyl)-2H-undecahydrocyclopentat4.5D-pyrroloC1,2-a3pyraz ine-3,8-dione. The invention also relates to new compounds of the formula II ROOC -CH-N-C-CH-NH-CH- (CH9) -R l a ic U I i I o 2d. R R 0 R1 COOR Vv 'V r» . . _ f-, .V - 27 - 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)' which double bonds, if their number exceeds 1, are not cumulative, a rep resents 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 (c-2); 5. denotes aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C -j — Cg>—alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C<|-C4)-alkylamino, di — C C-j — C4)-alkylamino, (Ci-C4)-alkanoylamino, methylene-dioxy, carboxyl, cyano and/or sulfamoyl; 6. if n is 2, denotes (C6-C'|2^-ary'--(Ci-Cg)-alkyl or di-(C$-C<|2)~aryl-(Ci-C8)-alkyl, each of which can be substituted in the aryl moiety as described under I.b)5; or 7. alkoxy having 1-4 carbon atoms; 8. aryloxy which has 6-12 carbon atoms and can be substituted as described under I.b)5; 9. mono- or bicyclic heteroaryIoxy or heteroaryl-(C-]-Cg)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 to 2 ring atoms representing sulfur or oxygen and/or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as described under I.b)5; 10. amino-(Ci-Cg)-alkyl; 11. (Ci-C4)-alkanoylamino-(Ci-Cg)-alkyl; 12. (C7-Ci3)-aroylamino-(C<|-Cg)-alkyl; 13. (C1-C4)-alkoxycarbonylamino-(Ci-Cg)-al-kyT; 14. (C6-C12)-aryl-(C1-C4>-alkoxycarbonylamino-(C-|-Cg)-alkyl; 15. (C6-C<|2)~ary'--(Ci-C4)-alkytamino-(Ci-Cg)-alkyL; 16. (Ci-C4)-alkylamino-(Ci-Cg)-alkyl; 17. di-(Ci-C4)-alkylamino-(C<]-C8)-alkyl; 18. guanidino-(C<|-Cg)-alkyl, 19. imidazolyL; 20. indolyl; 21. (C-j—C4)—aLkyLthio; 22. if n is 2, (C1-C4 )-a I ky L t h io-< C 1-Cg)-a I ky I; 23. (C6~Ci2^~ary'-thio-(Ci-C8)-aLkyL which can be substituted in the aryl moiety as described under I.b)5; 24. (C6-Ci2^-aryL-(Ci-Cg)-alkylthio which can be substituted in the aryL moiety as described under I.b)5; 25. if n is 2, carboxy-(C-)-Cg)-alkyl; 26. carboxyl; 27. carbamoyl; 28. if n is 2, carbamoyl-(C<j-Cg)-alkyl; 29. (C<|-C4)-alkoxycarbonyl-(Ci-Cg>-alkyl; 30. if n is 2, (C$-C -jg ^ ~ary loxy-( C <j-Cg)-aL ky I which can be substituted in the aryl moiety as described under I.b)5; or 31. denotes (C^-C-j2^~ary*- — ^c1—C8^""a*-'c0xy which can be substituted in the aryL moiety as described under I.b)5; 1. denotes hydrogen; 2. denotes alkyl having 1-18 carbon atoms; 3. denotes an acyclic aliphatic 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. denotes a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula CcH(2c-d-1)/ which is optionally branched, in £mx1?> . -.... 2 - 29 - which c represents an integer 3 to 20, and d represents an even number 0 to (c-2); 5. aryL which has 6-12 carbon atoms and can be substituted as described under I.b)5; 5 6. (C6-C12)-aryl-(Ci-C8)-alkyl or (C7~Ci3)-aroyl- (C-|-C8)-alkyl, both of which can be substituted as for aryl under I.b)5; 7. mono- or bicyclic, optionally partially hydrogenated, heteroaryl or heteroaryl-(C<|-Cg)-alkyl which 10 has 5-7 or 8-10 ring atoms respectively, up to '.JJ 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 des- 15 cribed for aryl under I.b)5; or 8. if not already covered by c) 1. - 8., the optionally protected side-chain of a naturally occurring a-amino acid of the formula R -CH(NH2)-C00H; 2 3 d) R and R are identical or different and 20 1. denote hydrogen; 2. alkyl having 1-18 carbon atoms; 3. denote an aliphatic acyclic radical of the for-mula CaH(2a-b+1)' 10 lch double bonds, if their number exceeds 1, are not cumulative, a 25 represents an integer 2 to 18, and b represents an even number 2 to a; 4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula CcH(2c-d-1 )/• which is optionally branched and 30 in which c represents an integer 3 to 20, and d represents an even number 0 to (c-2); 5. di-(Ci-C4)-alkylamino-(Ci-Cg)-alkyl; 6. ( C -j — C 5 )-a lkanoyloxy-(Ci-Cg)-al ky I; 7. (Ci-C6)-alkoxycarbonyloxy-(Ci-Cg)-alkyl; 35 8. (C7-C<j3)-aroyloxy-(C<|-Cg)-alkyl; 9. (C6-C12)-aryloxycarbonyloxy-(Ci-C8)-alkyl; 10. aryl having 6-12 carbon atoms; or 11. denote (C7-C20^"ara'-'cyl; it being possible for the radicals mentioned under d) 8., 9., 10. and 11. to be substituted in the aryl moiety as described under I.b)5; and e) and R5 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) n is 1 or 2, b) 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, 5. aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (Ci-C4)-alkyl, (C<)-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C-]-C4)-alkylamino, di — (C-j —C4) — alkylamino, (Ci-C4)-alkanoylamino, methylene-dioxy, 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) 5; 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 II.b)5.; 9. amino-(Ci-C4)-alky I, 10. (C<|-C4)-alkanoylamino-(Ci-C4)alkyl, 11. (C7-Ci3)-aroylamino-(Ci-C4)-alkyL, 12. (C<|-C4)-alkoxycarbonylamino-(C"|-C4)-alkyl, 13. (C6-Ci2^~ary'-~^c1~c4^~a'-koxycarbonylamino-(Ci-C4)-alkyl, 14. (C6"Ci2)~aryl-~(c1~c4)~a'-ky,-an'ino~(c1~c45~aLkyl, 2197 - 31 - 15. (Ci-C^-alkylamino-CCi-C^-alkyl, 16. di-(Ci-C4)-aLkylaniino-CCi-C4)-alkyL/ 17. guanidino-(Ci-C4)-aLkyl, 18. imidazolyl, 19. indolyl; 20. (Ci—C 4) — a Ikylthio, 21. C C-j—C4>~aL kyL th io—(C -j — C4) —al kyl, 22. <C^—C-|2^~ary'- io—(C-| —C4)—al kyL which can be substituted in the aryl moiety as described under II.b)5; 23. (C^-Ci2^~aryl-(Ci-C4)-alkylthio which can be substituted in the aryL moiety as described under II.b)5; 24. carboxy-( C<j-C4)-alkyl, 25. carboxyl, 26. carbamoyl, 27. carbamoyl-(C<|-C4)-alkyL, 28. (C i-C4)-alkoxycarbonyl-(C'j-C4)-alkyl, 29. (C$-Ci2)~aryloxy-(Ci-C4)-aLkyl which can be substituted in the aryl moiety as described under II.b)5; or 30. ^c6"~^12^~i~C4) — atkoxy which can be substituted in the aryl moiety as described under 11.b)5; denotes 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 4. alkynyl having 2-6 carbon atoms, 5. cycloalkyl having 3-9 carbon atoms, 6. cycloalkenyl having 5-9 carbon atoms, 7. (C3-C9>-cycloalkyl-(Ci-C4)-alkyl, 8. (C5-C9>-cycLoalkenyL-(Ci-C4)-alkyl, 9. optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described under II.b)5; 10. (C$-Ci2)~aryl-(Ci-C4)-alkyl or (C7-C<|3<),-aroyl- /O, 2 (C-j or CgJ-alkyl, both of which can be substituted in the aryL moiety as described under II.b)5; 11. mono- or bicyclic, optionaLLy partially hydro-5 genated 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 10 under II.b)5; or 12. if not embraced by the above definitions, the optionalLy protected side-chain of a naturally occurring a-amino acid of the formula 15 R1-CH(NH2)-C00H; d) and R"* are identical or different and denote 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 20 4. di-(Ci-C4)-alkylamino-(Ci-C4)-alkyl, 5. (C<i-C5)-alkanoyloxy-(Ci-C4)-alkyl, 6. (Ci-C6)-alkoxycarbonyloxy-(Ci-C4)-alkyl, 7. (C7-Ci3)-aroyloxy-(Ci-C4)-alkyl, 8. (C6-Ci2^~aryLoxycarbonyLoxy-(Ci-C4)-alkyl, 25 9. aryl having 6-12 carbon atoms, 10. <C6-Ci2>-aryl-(Ci-C4>-alkyl, 11. (Cj-C^-cycloalkyl or 12. (C3-C9)-cycloalkyl-(Ci-C4)-alkyl, and 30 e) R^ and have the meaning defined under I.e), B. and compounds of the formula II in which a) n is 1 or 2; b) R denotes 35 1. hydrogen; 2. alkyl having 1-8 carbon atoms; 3. alkenyl having 2-6 carbon atoms; 4. cycloalkyl having 3-9 carbon atoms; \ n N ' 5 V_ ' 10 © 15 20 O 25 L4^1V O 30 5. aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C-j-C4)-aLkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, amino-methyl, (C-j-C4)-alkylamino, di-(C-|-C4)-alkyl-amino, (C-j-C4)-alkanoyl amino, 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 B.b)5; 8. mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon 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 B.b)5; 9. amino-(C-j-C4)-alkyl; 10. (Ci-C4)-alkanoylamino-(Ci-C4)-alkyl; 11. (Cy-CijJ-aroy I ami no-( C-j-C4>-alky 1; 12. (Ci-C4)-alkoxycarbonylamino-(Ci-C4)-alkyl; 13. CC£-C<|2>~aryt--(C"|-C4)-alkoxycarbonylamino-CC <|-C4)-alkyl; 14. (C6-C'|2>'~a''yl-CC<i-C4)-alkylannno-(Ci-C4)-alkyl; 15. (Ci-C4)-alkylamino-(Ci-C4)-alkyl; 16. di-(C<|-C4)-alkylamino-(C<|-C4)-alkyl; 17. guanidino-(C<|-C4)-alkyl; 18. imidazolyl; 19. indolyl; 20. (C<j-C4)-alkylth io; 21. if n is 2, (Ci-C4)-alkylthio-(C-j-C4)-alkyl; 22. (C6-Ci2)-arylthio-(C<|-C4>-alkyl which can be substituted in the aryl moiety as described under B.b) 5; 23. <C$-Ci2)-aryl-( C q-C4>-alky I th io which ^c.aa„be substituted in the aryl moiety as descr B.b)5; 24. if n is 2, carboxy-(C-|-C4)-alkyl; 25. carboxyl; vty. ity n o V J J 2 26. carbamoyl; 27. if n is 2, carbamoyl-(C-|-C4)-alkyL; 28. (C-|-C4)-aLkoxycarbonyL-(Ci-C4)-alkyl; 29. if n is 2, (C6"Ci2^~ary'-oxy~^c1~c4^"a'-kyl which 5 can be substituted in the aryl moiety as described under B.b)5; or 30. (C^-Ci2^"aryl-(Ci-C4)-alkoxy which can be substituted in the aryl moiety as described under B.b)5; •1 c) R represents the side-chain of valine, leucine, 10 norvaline, norleucine, methionine, ornithine, cyclo-hexylalanine, 2-thienylalanine, 3-thienylalanine, • 0-(C3-C5)-alkyltyrosine, isoleucine, isovaline or C-phenylglycine; d) and R^ are identical or different and denote 15 1. hydrogen; 2. alkyl having 1-6 carbon atoms; 3. alkenyl having 2-6 carbon atoms; 4. di-(C-|-C4)-alkylamino-(Ci-C4)-alkyl; 5. (Ci-C5)-alkanoyloxy-(C<|-C4)-alkyl; 20 6. (Ci-C6)-alkoxycarbonyloxy-(Ci-C4)-alkyl; 7. (C7-C<i3)-aroyloxy-(Ci-C4)-alkyl; 8. (C6-Ci2^~aryl-Oxycarbonyloxy-(Ci-C4)-alkyl; 9. aryl having 6-12 carbon atoms; 10. (C6-C12)"aryl-(Ci-C4)-alkyl; (^) 25 11. (C3-C9>-cycloalkyI; or 12. (C3-C9)-cycloalkyl-(Ci-C4)-alkyl, and e) and R^ have the meaning defined under A.I.e), and their physiologically tolerated salts, or (^j 30 C. in which a) n, R, R^ and are as defined above under B. and * b) R represents the side-chain of alanine, lysine or e-acyllysine, and 2 3 c) R and R are identical or different and denote 35 propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl, iso-pentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, cyclooctyl, eye lohexenyI, eyeloheptenyI, .v. , V D 2 - 35 - phenyl, a- or 0-naphthyl, 2-, 3- or 4-biphenylyI, ~~— phenethyl, 3-phenylpropyl, benzhydryl, a-methyl- benzyl, a-methylenebenzyl, 2-, 3- or 4-phenyIbenzyI, bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl, 5 with phenyl, and phenyl as a part-structure of one of the said radicals, being substituted as defined, where appropriate, under A.II.b)5, 2 3 or one of the radicals R and R denotes hydrogen, and the other is as defined above, 2 3 10 or R represents benzyl, and R represents benzyl, (Tj. hydrogen or one of the abovement ioned definitions, and their physiologically tolerated salts. R^ and R^ form, together with the atoms carrying them, preferably a mono-, bi- or tricyclic hetero-15 cyclic 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 hydroisoquinoIine, octahydroindole, indoline, octa- hydrocyclopentaCb]pyrrole, 2-azaspiroC4.5]decane, 2-azaspiroC4.4Unonane, spiroC(bicycloC2.2.1]heptane)-2,3*-pyrrolidine], spiroKbicycloCZ^^Doctane^^'-pyrrolidine}, 2-azatrieyeloC4.3.0.1 ' ]decane, deca-25 hydrocycloheptaCbDpyrrole, octahydroisoindole, octa- hydrocyclopentaCcDpyrrole, 2,3,3a,4,5,7a-hexahydro-indole, 1,2,3,3a,4,5a-hexahydrocyclopentaCb]pyrrole and 2-azabicycloC3.1.0]hexane. 30 Suitable salts of the compounds of the formulae I and II 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 inorganic or organic acids such as, for example, HCl, HBr, H2SO4, 35 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 219764 - 36 - capillaries 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 12 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 formula II are those in which R denotes 1. (C9—Cis^~al-kyl; 2. (C7-Cig)-alkenyl; 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; 5. is as defined above under A.I.b)5; 6. heteroarylalkyl which is defined as above under A.I.b)9; 7. amino-(C5-Cg)-alkyl; 8. (Cf-C4)-alkanoylamino-(C5-Cg)-alkyl; A 9. (C7-Ci3)-aroylamino-(C5-Cg)-alkyl; 10. (Ci-C4)-alkoxycarbonylamino-CC5-Cg)-alkyl; 11- (C6-C-|2)~af,yl-(Ci-C4)-alkoxycarbonylamfno-^' (C5-C8)-alkyl; [(* V1. - % k X" * * * c 219764 - 37 - 12. (C6-C<|2)~aryL-(Ci-C4)-alkylamino-(C5-C3)-alkyl; 13. <C-)-C4)-alkyl.annno-(C5-Cg)-alkyl; 14. d i-(Ci-C4)-alkylami no-(C5-Cg)-alky I ; 5 15. guanidino-(C5-Cg)-alkyl; 16. if n is 2, (Ci-C4>-alkyIthio-(C5~Cg)-alkyLj 17. (C6-Ci2)"3rylthio-(C5-Cg)-alkyl which can be substituted in the aryl moiety as described above under A.I.b)5; 10 18. (C^-Ci2^~ary'-~(c5~c8^~a'-'cyl-t',io which can be substituted in the aryl moiety as described above under A.I.b)5; 19. if n is 2, carboxy-(C5-Cg)-alkyl; 20. if n is 2, carbamoyI-(C5-C8)-aIkyI; 15 21. (C-|-C4)-alkoxycarbony l-(C5~C4)-alkyl; 22. if n is 2, (C^-C12>-aryIoxy-(C5-C8)-aIkyI which can be substituted in the aryl moiety as described above under A.I.b)5; or 23. (C^-C<|2^~aryL~(C5-Cg)-alkoxy which can be 20 substituted in the aryl moiety as described above under A.I.b)5. Additional compounds of the formula II which are suitable are those in which A 25 8 denotes 1. (C7~Cig)-alkyl; 2. (C7-C-jg)-alkenyl; 3. (C7-C-jg)-alkynyl; 4. a radical which has 4-18 carbon atoms and is 30 defined as above under A.I.c)3. and in which r b >, 2 and only double bonds are present; 5. a radical which is as defined above under A.I.c)4, excepting cycloalkyl and cyclo-alkenyl having up to 9 carbon atoms; 35 6. optionally substituted (C£-C<j2>-aryL~ (C5~Cg)-alkyl; 7. optionalLy substituted (C7-C<j3)-aroyl- <C3~Cg)-alkyl or ^ 8. optionaLLy substituted heteroaryl-(C<|-Cg)-alkyl, and those compounds of the formula II in which R represents the side-chain of valine, Leucine, norvaline, norleucine, methionine, ornithine, cyclohexylalanine, 2-thienylalanine, 3-thienylalanine, 0-(C3-C5>-aLkyLtyrosine, isoleucine, isovaline or C-phenyIglycine. R^ and R^ are then identical or different and preferably denote 1. (C7-C18)-alkyl; 2. ( C7-C -jgJ-al kenyl; 3. a radical which has 4-18 carbon atoms and is defined as above under A.I.d)3. and in which b > 4; 4. a radical which is as defined above under A.I.d)4, excepting CC3-C9)-cycloalkyL and (C3-C9>-cyclo-alkyl-(Ci-C4)-alkyl; 5. di-(C<|-C4)-alkylamino-(C5-Cg)-alkyl; 6. (Ci-C5>-aLkanoyLoxy-(C5-C8)-alkyL; 7. (Ci-C6)-aLkoxycarbonyloxy-(C5-Cg)-alkyl; 8. (C7-Ci3)-aroyloxy-(C5-C8>-alkyl; 9. (C6-Ci2)-aryloxycarbonyLoxy-(C5-Cg)-alkyl; 10. (C16-C2o)-aralkyl; it being possible for the radicals mentioned under d)8., 9. and 10. to be substituted in the aryl moiety as described 2 3 above under A.I.b)5.; or one of the radicals R and R denotes hydrogen and the other is as defined above. In addition, preferred compounds of the formula II are 2 3 those in which R and R are identical or different and denote propyl, isopropyl, n-butyL, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl, isopentyl, neopentyl, n-hexyl, iso-hexyl, cyclobutyl, cyclopentyl, cyclohexyL, cycLoheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, menthyl, phenyl, a- or 8-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenyLpropyI, benzhydryl, a-methylbenzyl, a-methylenebenzyL, 2-, 3- or 4-phenyLbenzyl, bibenzyl-a-yI, styryl, 1-indanyl or 9-fluorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, optionalLy being substituted 2 1976 as defined above under A.I.b)5., or one of the radicals 2 3 R and R denotes h/drogen and the other is as defined 2 3 above, or R represents benzyl, and R 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. R500C-CH-N-H HOOC-CH-NH-CH-(CH,) -R i5 ioo*2 2 ' (V) (VI) 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, CH2CI2 or DMA in the presence of coupling aids such as carbodiimides (for example dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydrides, dialkylphosphinic anhydrides or N,N-succinimidyl carbonate, in a solvent such as CH3CN. Amino groups in compounds of the formula V can be.activated with tetraethyl diphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbo-di imide derivatives and thus activated (cf. Schro'der, /' ••". , - .S' r?i O Lilbke, The Peptides, volume 1, New York 1965, pages 76 -136). The reaction is preferably carried out between -20°C and the boiling point of the reaction mixture. ^ 5 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 R300C-CH-N—C-CH-Y1 Y2-CH-(CH,) -R i a «5 " '1 I o 2 n R R 0 R1 COOR (VII) (VIII) 1 2 in which either Y represents amino and Y represents a 1 2 10 leaving group, or Y represents a leaving group and Y represents amino. Examples of suitable leaving groups are CI, Br, I, alkylsulfonyloxy or arylsulfonyloxy. Alkylations of this type are expediently carried out in 15 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°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. Furthermore, it is possible to condense compounds of the formula IX with compounds of the formula X R300C-CH-N—C-C-*Q1 Q2«C-(CH0) -R Q ^ <5 « COOR " (IX) (X) 1 2 in which either Q represents amino + hydrogen and Q 1 2 25 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°C and the boiling point of the reaction mixture, in the presence of a reducing © - 41 - ' 8 * 2 agent, such as NaBHjCN, compounds of the formula I £eing 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 5 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 = 10 H + NH2) with compounds of the formula XI, or their reac-CD tion 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, 15 also results in compounds of the formula II (n = 2), R200C-CH=CH-C0R (XI) OCH-COOR2 (XII) R-CO-CHj (XIII) 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 20 complex hydride) into methylene. In the abovementioned formulae V - XIII, R - and n are as defined in formula II. Protective groups temporarily introduced to protect reactive groups not involved in the O 25 reaction are eliminated in a manner known per se after the reaction is complete Ccf. Schroder, 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 30 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 - 42 - 802 - 825; Houben-Weyl, Methoden der Organischen Chemie, (Methods of Organic Chemistry), volume E5, 1985, pages 656 - 773). rr\. 5 a) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals 2 3 R and R denotes hydrogen with an appropriate alcohol with acid catalysis (mineral acid or acid ion exchanger) 10 b) Alkylation of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radi- 2 3 2 cals R and R denotes hydrogen with a compound R Z or R^Z, in which Z denotes a leaving group which can be displaced nucleophiIically (such as halogen, tosylate), 15 in a polar protic or dipolar aprotic solvent, in the presence of a base such as an alkali metal hydroxide or alcoholate. c) Reaction of a mono- or dicarboxylic acid of the general 20 formula I or II in which at least one of the radicals 2 3 R and R denotes hydrogen with a diazoalkene in an inert organic solvent such as CH2CI2- 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 method described by J. KOPP, Z. BODANECKY and M.E. JARVIK has been described by J. BURES, 0. BURES0VA and J. HUSTON 30 in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983). According to the statements in this literature, a sub-35 stance 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. v.s. n (?) 10 20 tyj 25 2 The experiments were carried out by modified test methods. The comparison compound used was the known cognition adjuvant 2-oxo-1-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 com-15 pounds according to the invention are suitable not only for the treatment of high blood pressure but also for the treatment of cognitive dysfunctions of various etiologies, as occur with, for example, Alzheimer's disease or senile dementi a. Hence the invention also relates to the use of the compounds according to the invention for the treatment and 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 30 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 35 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 .-iSSti.. *'* r ; f 2 - 44 - pharmacoLogically 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 5 tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95%, preferably between 10 and 75%. The auxiliaries suitable for the desired medicament for-10 mulation are familiar to those skilled in the art by reasonof their expert knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxiliaries and other active compound vehides, it is possible to use, for example, antioxidants, dispersing 15 agents, emulsifiers, antifoam agents, masking flavors, preservatives, solubilizers or colorants. The active compounds can, for example, be administered 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 25 by the customary methods into suitable presentations such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, lac-V—' 30 tose, 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 are vegetable or animal oils such as sunflower oil or fish-liver oil. 35 For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspens ions or emulsions, if appropriate with the substances customary for this purpose O ' r\< - '1 "•> . - 45 - 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 5 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 10 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 15 Preparation of the agent used according to the invention for oral use in the treatment and prophylaxis of cognitive dysfunct ions. 20 1000 tablets each containing 10 mg of 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-1S,3S,5S-2-azabicycloC3.3.0]-octane-3-carboxylic acid are prepared using the following auxiliaries: (^) 25 2—CN — (1-S-carbethoxy-3-phenylpropyI)- 10 g S-alanylD-(1S,3S,5S)-2-azabicycloC3.3.OHoctane-3-carboxylic acid corn starch 140 g O 30 gelatin 7.5 g microcrystalline cellulose 2.5 g magnesium stearate 2.5 g 2-CN-C1-S-Carbethoxy-3-phenylpropyI)-S-alany I]-(1S,3S,5S)-35 2-azabicycloC3.3.03octane-3-carboxyIic acid and corn starch are mixed with an aqueous gelatin solution. The mixture is dried and milled to form granules. Mi crocrystalIine cellulose and magnesium stearate are mixed with the granules. The resulting granules are compressed to form 1000 tablets, each tablet containing 10 mg of the ACE inhibitor. These tablets can be used for the treatment and prophylaxis of cognitive dysfunctions. 5 Example 2 In analogy to Example 1, 1000 tablets each containing 10 mg of 11 — CN— <1-S-carbethoxy-3-phenylpropyI)-S-alanyl]-10 (3,S,5,S)-spirobicycloE2.2.2]octane-2,3,-pyrrolidine-5 • -carboxylic acid are prepared. Example 3 15 Gelatin capsules each containing 10 mg of 1• — CN — C1-S-carb-ethoxy-3-phenyI propyl)-S-alanyl]-(3'R,5'S)-spirobicyclo-C2.2.2]octane-2,3,-pyrrolidine-5•-carboxylic acid are filled with the following mixture: 20 1'-CN-(1-S-Carbethoxy-3-phenylpropylJ-S-alanyll-CS'R^'S) spirobicycloC2.2.2]octane-2,3'-pyrrolidine-5'-carboxylic acid 10 mg Magnesium stearate 1 mg 25 Lactose 214 mg These capsules can be used for the treatment and prophylaxis of cognitive dysfunctions. (3) 30 Example 4 The preparation of an injection solution is described below: 35 2-CN-(1-S-Carboxy-3-phenyIpropyl)-S-alanyl]-( 15,35,55)-2-azabieye IoC3.3.0]octane-2-carb-oxylic acid 250 mg Methylparaben 5 g - 47 - Propylparaben Sodium chloride Water for injections 2-CN-(1-S-Carboxy-3-phenylpropyI)-S-alany ID-(1S,3S,5S)- ^ 5 2-azabicycloC3.3.0Hoctane-3-carboxylic acid, the preserva- f tives and sodium chloride are dissolved in 3 I of water for injections, and the solution is made up to 5 I with water for injections. The solution is filtered sterile and dispensed aseptically into presterilized vials, which 10 are closed with sterilized rubber caps. Each vial con-tains 5 ml of solution. Example 5 15 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-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl!]-(1S,3S,5S)-2-azabi-cycloC3.3.0Hoctane-3S-carboxyIic acid use is made of 2-CN-20 (1-S-carboxy-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabi-cycloC3.3.0]octane-3-carboxylic acid or 1-CN-C1-S-carboxy- 3-phenylpropyI)-S-alanyl]-(2S,3aR,7aS)-octahydro indole-2-carboxylic acid or 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylD-cis-2,3,3a,4,5,7a-hexahydroC1H3indole-2-S-endo- 25 carboxylic acid or 1-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl]-cis~2,3,3a,4,5,7a-hexahydroC1H3indole-2S-endo-carboxylic acid or 2-CN-(1-S-carboxy-3-phenyIpropyl)-S-lysyl]-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylic ^ acid or 2-CN-(1-S-carbethoxy-3-cyclohexylpropyI)-S-a1 any I 3- 30 lS,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxyl ic acid or N-(1-S-carboxy-3-cycIohexylpropyI)-S-lysyI-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylic acid or 1'-CN-(1-S-carbethoxy-3-phenyI propyl)-S-alanyl]-exo-spirobicyclo-C2.2,2]octane-2,3'-pyrrolidin-5'-S-ylcarboxylic acid or 35 (S,S,S)-1-methyl-2-(1-carbethoxy-3-phenylpropyI)-2H-un-decahydrocyclopentaC4.5DpyrroloC1,2-a]pyrazine-3,8-dione or 1 • —C N—(1-S-carbethoxy-3-phenyIpropyl)-S-alanyl]-endo-spirobieyeloC2.2.2Doctane-2,3'-pyrrol idin-5'-S-ylcarb-oxylic acid. n O O 21076' - 48 - Example 6 An injection solution is prepared in analogy to the procedure described in Example 4 with the exception that in 5 place of 2-CN-(1-S-carbethoxy-3-phenyIpropyL)-S-aI any I3-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylic acid use is made of 2-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl3-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylic acid or 1 — C N—(1-S-carbethoxy-3-phenylpropy L)-S-alanyL]-(2S,3aR, 10 7aS)-octahydroindole-2-carboxylic acid hydrochloride or 1-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl3-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid or 1 — CN —(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl3-cis-2,3,3a,4,5,7a-hexahydro-C1H3indole-2-S-endo-carboxylic acid or 1 — CN— <1-S-carboxy-15 3-phenylpropyI)-S-alany 13-c is-2,3,3a,4,5,7a-hexahydroC1H 3-indole-2-S-endo-carboxylic acid or 2-CN-(1-carboxy-3-phenyIpropyl)-S-lysyl3-(1S,3S,5S)-2-azabicycloC3.3.03-octane-3-carboxylic acid or 2-CN-(1-S-carbethoxy-3-cyclo-hexylpropyI)-S-alanyl3-(1S,3S,5S)-2-azabicycloC3.3.03octane-20 3-carboxylic acid or 2-CN-(1-S-carboxy-3-cycLohexylpropyI)-S-lysyl3-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylic acid or 11-CN-(1-S-carboxy-3-phenylpropyI)-S-alany I3-endo-spirobicycloC2.2.23octane-2,3'-pyrrolidine-5'-S-carboxylic acid or 11-CN-(1-S-carboxy-3-phenyIpropyI)-S-alany I3-exo-25 spirobicycloC2.2.23octane-2,3'-pyrroIidine-5'-S-carboxylic acid. u The Examples 7-95 which now follow are intended to illustrate the process according to the invention for the prepa-30 ration of the new compounds of the formula I and II, - without confining the invention to them. Example 7; Octadecyl 2-CN-(1S)-ethoxycarbonyl-3-phenylpropyI-S-alany I 3-35 c is,endo-2-azabi cycloC3.3.03octane-3-S-carboxylate 23 g of octadecyl cis,endo-2-azabicycloC3.3.03octane-3=r-.-. carboxylate prepared in analogy to European PatenJt^A^'7'9022 =! pr ^ - V» * * " uT' v\ . V O , r- O S.y ' V. - 49 - are reacted with 6.7 g of HOBt, 13.8 g of N-(lS)-carbethoxy-3-phenylpropyl-S-alanine and 10.2 g of dicyclohexylcarbodi-imide in 200 ml of dimethylformamide. After stirring at room temperature for 3 hours, the precipitated dicyclohexylurea 5 is filtered off with suction, the filtrate is concentrated. r 1 the residue is taken up in 1 I of ethyl acetate, and the solution is extracted by shaking with 3 x 500 ml of 5% strength NaHC03 solution. The organic phase is concentrated and chromatographed on a column of 1 kg of silica 10 gel with ethyl acetate/petroleum ether in the ratio 2:1, and (T) • in this way is separated into the title compound and the diastereomeric (S,S,R) compound. Example 8: 1-CN-(lS)-Dodecyloxycarbonyl-3-phenylpropyl-S-alanyl]-2S, 15 3aR,7aR-octahydroindole-2-carboxylic acid a) Benzyl 1-CN-(1S)-dodecyloxycarbonyl-3-phenylpropyl-S-alanyl]-2Sr3aR,7aR-octahydroindole-2-carboxylate 10 mmol of benzyl S-alanyl-2S,3aR,7aR-octahydroindole-2-carboxylate (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 (4A), and then 10 mmol of dodecyl 2-keto-4-phenyIbutyrate, 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 25°C, the /—\ reaction 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 (1:4). b) The compound obtained as in a) is hydrogenated in ethanol in the presence of palladium/animal charcoal (10%) at 20-25°C under atmospheric pressure. After the catalyst vsKS^gSj-'-'D-f sr1- -v. a®fe.,v'\,:'' '•■ t '•' ■■ V - 50 - 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. 5 Example 9: Isobutyl 2-CN-C(2S)-ethoxycarbony I-3-phenylpropyI3-L-alanyl]-(1S,3S,5S)-2-azabicycloC3.3.ODoctane-3-carboxylate 2.00 g (4.80 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl3-(1S,3S,5S)-2-azabicycloC3.3.0]octane-10 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 sol-15 ution was washed once with water, once with saturated aqueous NaHC03 solution and again with water, dried over MgSO^, and concentrated, and impurities were removed by chromatography on 200 g of silica gel (mobile phase methylene chloride/ethyl acetate 8:2). 20 Yield: 51% of theory of oily product. CaU2® = -28.2° (c = 1, methanol) 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. Data on the hydrochloride: v—■' Melting point 123- 124°C Co3^ = +17.7° (c = 1, methanol) Example 10: 30 Benzhydryl 2-CN-C(1S)-ethoxycarbonyl-3-phenylpropyl]-L- alanyl]-(1S,3S,5S)-2-azab i eyeloC3.3.03octane-3-carboxylate 2.07 g (4.97 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl3-(lS,3S,5S)-2-azabicycloC3.3.03octane-3- n - 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 diphenyIdiazomethane in 50 ml of acetone was added dropwise, The solution was then stirred at room temperature for 26 5 hours, the solvent was evaporated off in a rotary evaporator, and the residue was purified by flash chromatography on 150 g of silica gel (mobile phase toluene/ethanol 98:2). Yield: 2.55 g (88 %) of oily product Ca]20 = -33.8° (c = 1, methanol). 10 Example 11: Octadecyl 2-CN-C (1S)-ethoxycarbonyl-3-phenylpropylIl-L-alanyl3-(lS,5S,5S)-2-azabicycloC3.3.03octane-3-carboxylate 2.08 g (5.00 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-propyl]-L-alanyl]-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-15 carboxylic acid were dissolved in 25 ml of absolute dimethyl-formamide, 1.00 g (10.0 mmoI) of potassium bicarbonate was added, and the mixture was stirred at 40°C for 90 minutes. After cooling to room temperature, a solution of 4.00 g (12-0 mmol) of 1-bromooctadecane in 20 ml of absolute di-20 methyIformamide was added dropwise, and the mixture was stirred at 40°C for 4 hours. The solvent was removed in 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^ and concen-25 trated. 3.05 g (92 %) of the product were isolated from the crude product (5.40 g) after column chromatography on 200 g of silica gel (mobile phase toluene/ethanol 99:1). Ca]2^ = -19.6° (c = 1, methanol) Example 12; 30 Benzyl 2-CN-C(iS)-benzyhydroloxycarbonyl-3-phenylpropyl3-L-alanyL3-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate a) Benzhydryl (2R)-hydroxy-4-phenylbutyrate A solution of 10.1 g (52.1 mmol) of diphenyldiazomethane 35 in 400 ml of absolute acetone was added dropwise over t -* O - 52 - 20 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 5 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 10 toluene/ethanol 99:1). Total yield: 12.4 g (87 %). Melting point 88 - 89°C. Ca3jj° = -1.8° (c = 5, methanol). b) Benzyl 2-CN-C(1S)-benzhydryIoxycarbonyI-3-phenylpropy13-15 L-alanyl3-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy- late O b-j) 1.80 g (4.33 mmol) of benzyl 2-(N-tert.butoxycarbonyl-L-alanyl)-(1S,3S,5S)-2-azabicyc LoC3.3.03octane-3-car-boxylate were dissolved in 4.5 ml of trifluoroacetic 20 acid, and the reaction solution was stirred at room temperature 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-25 alanyl)-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy late trifluoroacetate, was dissolved in 10 ml of absolute methylene chloride (solution A). bg) 1.63 g (4.71 mmol) of benzhydryl (2R)-hydroxy-4-phenyI butyrate from Example 12 a) were dissolved together 30 with 0.4 ml of absolute pyridine in 25 ml of absolute methylene chloride and, at -10°C, 1.41 g (5.00 mmol) of trifluoromethanesulfonic anhydride were added drop-wise within 20 minutes. The cooling bath was then removed and, after room temperature had been reached, 35 the solvent was evaporated off. The residue was 2 1976 filtered through 50 g of silica gel using methylene chloride, and the filtrate was concentrated. 1.70 g of benzhydryl 4-phenyl-<2R)-trifluoromethylsulfonyloxy-butyrate were obtained and were dissolved in 10 ml of 5 absolute methylene chloride (solution B). b3) 1.0 ml (7.40 mmol) of triethylamine was added to solution A and then, at 0°C, solution B was slowly added dropwise. The cooling bath was removed and the reaction solution was stirred at room temperature 10 for 19 hours, then washed three times with water, • dried over MgS04 and concentrated. The residue was purified by chromatography on 80 g of silica gel (mobile phase eyelohexane/ethyl acetate 8:2 and 7:3), and 0.95 g (30%) of the desired product was obtained. 15 Kelting point 81-85°C. Ca]2" = -55.2° (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) - 54 - •X * * R OOC - - VI - C -CH - NH R4 R5 0 CH3 " ?H "<*2 " CH2~Q COOR r'I Example 30c-ch-n ia 1 ra r 5 r2 r5 13 R ixig system' a -c2h5 -ch(ch3)2 14 R i ng system b -c2h5 -ch2-ch(ch3)2 15 Ring system c -ch5 -CH2-© 16 Ring system c -c2h5 -ch(c6h5)2 17 Ring system d -c2h5 o 18 Ri ng system d ~c2?5 -o 19 Ring system d -c2h5 -<o> 20 Ring system d -c2h5 ^oKo> 21 Ring system d -c2h5 "W 22 Ring system d -c2h5 —(ch2)3-^2)^ 23 Ring system e -c2h5 -(ch2)5-ch3 24 Ring system p -CHj -ch(c6h5)2 25 Ring system 0 -c2h5 -ch(ch3)2 26 Ring system 6 -c2h5 -ch(c6h5)2 o 219764 r5ooc - 55 - CH - N - C -CH - NH 14 I5/1T R R 0 CH, -<JH-COOR CH0 - CH, o O r5ooc-ch-n- 'A I "5 2 1 Example R4 R R R 27 Ring system 8 "C2H5 -(CH2)2-© 28 Ri ng system H c2h5 -0H(CHj)2 29 Ring system H c2h5 -CH2-CH(CHj)2 30 Ri ng system H c2h5 -(ch2)5-ch3 31 Ri ng system H c2h5 -0 32 Ring system H C2H5 -#-CH3 33 Ri ng system E c2h5 -<§>-© 34 Ri ng system H °2H5 35 Ri ng system H H -0H2^) 36 Ri ng system E c2h5 -ch(c6h5)2 37 Ring system H c2h5 -«>H2)8-® 38 Ring syst em I CH, -<§> 39 Ring system J c2h5 -ch(C6H5)2 . 40 Ring system K c2h5 -(ch2)4-ch3 | 41 Ring system L 02h5 -c(ch?)3 $ i ■ -'/j // Xt/VE V* o * - 56 - r500c - ch - h - c -ch - nh - ch - ch0 - ch0-/"^ ia u i \ o 2 2 \^/ r r 0 ch? coor r5ooc-ch-n-Example r4 r5 r2 r3 42 Ring system M c2h5 -(ch2)2-ch(ch3)3 43 Ri ng system .. N c2h5- -ch(4-p-c6h4)2 44 Ring system. - N c2h5 -ch(ch3)2 45 Ring system 0 c2h5 -'ch2>2-# 46 Ring system P c2h5 ■o 47 Ring system 3 c2h5 ~©~T 48 Ring system a ch2ch(ch3)2 CM n o 1 49 Ring system b ch(ch3)2 -c(ch3)3 50 Ring system c ch(cfih5)2 -h 51 Ring system : d ch2- -ch2-© 52 Ring system • d ch2-ch(ch3)2 -ch2-® 53 Ring system d ch2-ch(ch3)2 -h 54 Ring system d ch2-ch(ch3)2 -ch(06h5)2 r*- ^ 55 Ri ng system . d ch(c6h5)2 -c(ch3)3 56 Ri ng system ■ d ch(c6h5)2 - -h t ■*-' f- /o n r Example ;300c-ch- fc* -n-1 5 r? r2 r5 57 Ri ng system ■ e -@>-ch3 -(ch2)5-ch3 58 Ri ng system e -ch2-ch(ch3)2 -ch(4-p-c6h4)2 59 Ri ng system g -ch(c6h5)2 -ch2-©> 60 Ri ng system 0 -ch(c6h5)2 -0(CHj)3 61 Ri ng system h -ch2ch(ch3)2 62 Ring system h -ch2ch(ch3)2 -h 63 Ring system h -ch2ch(ch3)2 -ch(c6h5)2 64 Ring system h -ch2-@ -CHjig) 65 Ring system h -c(ch3)j 66 Ring system h -ch(c6h5)2 cm w 0 1 67 Ring system h -ch(c6h5)2 -h 68 Ring system h -ch(c6h5)2 -c(ch3)3 69 Ri ng system h -ch(c6h5)2 -ch(c6h5)2 70 Ring system i ■o 71 Ring system j -(ch2)5-ch3 -ch(c6h5)2 , v. ••• • •■ -v-V.■ •■-•'> . '\ 2197R4 n5s; r\ - 58 - , # « * r^ooc - ch - n - c -ch - nh - ch - ch- - ch, u i c h i '2 4 r4 r* 0 chj coor* -o Examp Le -ch-n- i4 R- ROOC-CH-N-,5 o o 72 Ri ng system K -O -°r® 73 Ring system 1 -ch2)2h@> -(ch2)5-ch3 74 Ring system K -(CH2)2-CH(CHj)2 -ch(c6h5)2 75 Ring system - n -ch(c6h5)2 -c(ch3)2-ch2ch3 76 Ring system 0 -0h(CHj)2 -ch(c6h5)2 77 Ring system p -ch(ch3)2 -c(ch3)3 78 Ring system Q -0(CHj)j -ch2-@ 78a Ring system d c2h5 Menthyl 781) Ring system 6 Menthyl ch2°6h5 ^ •r3OOC-CH-N-C-/CH \-X2 ui ' Example R OOC-CH-N- ' 4 JL5 r r a\ °s V i ; / v £ 9..;;^ ~nr- 79 Ring system 0 -CH(C6H5)2 80 Ring system 0 - (CH2) 5-CH3 -ch2sh -ch2sh 81 R3OCC-CH9-N- 6 -CH(C6H5)2 -CH2-S-00-C(CH3)3 1 p 7 q *-• p a L ^ / b 4 59 - 82 R OOC-CH2-N- 6 -CH(CH3)2 -CH2-S-€0-C-(CH3)3 1 83 CH3°>V~vv^v£00R -CH(C6H5)2 -NH-CH-(CH2) 2-^^ CH r300c 4 4 4 r - n - c -ch - nh — ch - ch,, A i c ii ' '2 34 k? 0 ch, coor 2 £ - ch, -© Example r-^ooc-ch-n- b5 A« m 64 R^00C-CH2-K- -ch(4-f-c6h4)2 -nh-ch-(ch2)2-(q) 1 cooc2h5 85 r500c-ch2-n- -CH2-@> -HH-CH-(CH2)2^g> i coo-ch(c2h5) 2 66 Ring system H H —ch2-f-(ch2)4-c>> . 9 (ch3)2ch-ch-o-c-c2h5 0 oc> Example Y 1 nh - $h - ch2 - ch; y ~^0 coor2 ch,-coor3 R- 87 ch2 .c2H5 -ch(c6h5)2 88 S -ch(c6h5)2 -(ch2)5-ch, 89 CH, -ch2-ch(ch3)2 -ch2 /"v 2 ^ Example R R (T) w 90 -CH(C6H5)2 -C(CH3)5 91 -CH(C6H5)2 -CH(C6H5)2 Example 92 4-CN-(1S)-Carboethoxy—3-phen/lpropyl)-S-benzyl3-exospiro-(bicycloC2.2.2]octane-2,3-pyrrolidine)-5-carboxylic acid 5 a) Benzyl ester of N-(1S-carbethoxy-3-phenylpropyl)-S-leuc ine 3.4 g (10 mmol) of ethyl 2-(D)-trifluoromethyIsulfonyl-Q oxy-4-phenyIbutyrate and 5.9 g (15 mmol) of the benzyl 10 ester of L-leucine tosylate were mixed in 50 ml of abs. CH2CI2 and, after addition of 4.2 ml of triethylamine, the mixture was stirred at room temperature for 6.5 hours. After concentration of the solution, the pro-duct was isolated by column chromatography (silica gel, 15 eyelohexane/ethyl acetate 9:1). 3.2 g of colorless oil were obtained. 1H NMR 6= 0.95 (d, CH^), 1.2 (t, CHj) 1.B (mf CH2) 2.6 (m, CH2) 3.3 (m, CH) 4.1 (q, CH2) 5«1 (b» CHg) 7.3 (b| CH) ppa. b) N-(1-S-Carboethoxy-3-phenylpropyl)-S-leucine 3.1 g of the benzyl ester obtained in a) were cleaved by hydrogenolysis with 500 mg of Pt/C (10%) 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 120-121°C were obtained. KMR 6= 0.9 (d, CHj), 1,25 (t, CHj), 1.8-2,1 (m,CH2), 2.7 (mf CH2), 3.3 (*, CH), 4.25 (g, CH2), 7.2 (8, CH) ppm. 4-CN-(1S)-Carbethoxy-3-phenylpropyl)-S-leucyl3-exo-spirobicycloC2.2.23octane-2,3-pyrrolidine-5-carboxylic acid 2 g (6.2 mmol) of N-(1-S-carboethoxy-3-phenylpropyl)- 5-leucine and 1.9 g (3.9 mmol) of benzyl exo-spiro-(bicycloC2.2.23-octane-2,3-pyrrolidine)-5-carboxylate were stirred in 100 ml of dimethylformamide with 4.3 ml of triethylamine and 6.5 ml of n-propyIphosphonic anhydride at room temperature overnight. The reaction solution was taken up in ethyl acetate and shaken twice with aqueous NaHC03 solution and once each with 10 % aqueous citric acid, saturated aqueous NaHC03 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 was 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°C were obtained. Rotation Ca3jj = -2.8° (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°C Rotation Ca3[> = -22.2° (c = 1, methanol) 62 2 Example 93 4-CN-(1S)-Carboxyl-3-phenylpropyI)-S-leucyl]-exo-spiro-(bicycloC2.2.2]octane-2,3-pyrrolidine)-5-carboxylic acid 102 mg (0.2 mmol) of the carboxylic acid from Example 92c) were stirred in aqueous 4N KOH solution until all the substance had dissolved. The solution was applied to an ion ( o \ exchanger ( Amberlite R 120) and eluted with a 2% strength solution of pyridine in water. The yield was 70 mg. Rotation Cot□ ^^ = +3.9° (c = 1, methanol) 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 II): ♦ hooc - ch - N - C r 1 HOOC - CH - NH ch(ch5)2 ch(ch3)ch2ch5 ch2c6h5 a a a CH2- CgHj1 (CH2-Cyclohexyl) C ch2-c6h4 ochj ch2—cgh^ 0c2h5 ch2-c6h4-0c5h7 ch2-c6h4-oc4h9 (ch2)4-nh2 g c 0 a D a a (CH2) 3 -NH2 CH2-OH^S CH5 CH— CH h ii CH~ - C CH a I) R1 HOOC - CH - NH r4 r5 ch(ch3)2 b ch(ch3)ch2ch3 b CH2C6H5 B ch2-c6h11 d ch2-c6h4-och3 h ch2-c6h4-oc2h5 g chg-cgh^on-cjhy 6 cho-crh.-on-c.hq c (cI2)®-£h2 49 c (ch2)3-nh2 g ch2-ch2- s-ch3 d ch— ch ch? - c ch b G R1 HOOC - CH - NH CH(CH3)2 C CH(CH5)CH2CHj C ch2-cghj^ £ ch2-c6h4-och5 I ch2-c6h4- oc2h5 h CH2"CgH4—On-C^Hy H CH2-C6H4-0n-C4Hg G (ch2)4-nh2 G (ch2)5~nh2 H ch2-ch2-s-ch5 H CH— CH ^ CHP - C CH o 2 2 19764 - 65 - (T\ hooc - ch - k - c - ch - ch - ch« - chp 14 i5 a 4,1 „ x&/ ^ r4 r5 0 r' cooc2h5 r1 hooc - ch - nh R4 R5 ^ ch* - c ch o 2 ch(ch5)2 d ch(ch5)ch2ch5 d ch2c6h5 d chrc6h11 f chg-cgh^ochj n ch2-c6h4-oc2h5 i ch2-c6h4-0n-c5h? I ch2-c6h4-0n-c4h9 h (ch2)4-hh2 h (ch2)3-kh2 0 chg-chg-s-chj i ch ch t ■ o 2 - 66 - HOOC - CH - N - C - CH - CH - CH9 - CH, i4 r5 s *1 linnn » 2 w o cooc2h5 R1 HOOC - CH - NH r* i5 CH(CH5)2 CH(CH3)CH2CH3 chpcrhc CVC6H11 ch2-c6h4- 0ch5 ch2-c6h4-oc2h5 CH2-C6H4-On-CjHy CH2-C6H4-0n-C4Hg (ch2)4-nh2 (ch2)3-nh2 CH2-CHg- S-CHj CH—CH CH9 - C CH ^b' g £ h g 0 N N 1 N p p o - 67 - * HOOC - CH - N - C - CH - CH - CH9 - CH, 'a 1*5 11 '1 1 \m/ R4 R? 0 R C00C2H5 HOOC - CH -R* m k* H P I H P 0 0 N Q q q o 0 CH(CHJ)2 CH(CHj)CH2CH5 c^2cghjj ch2~c6h11 ch2-c6h4- och3 ch2-cgh4~0c2hj CH2-CgH4- On-C3H? ch2-c6h4-0n-.c4h9 (ch2)4-hh2 (ch2)3-kh2 ch2-ch2-s ch3 ch2 - 0 CH—CH l< h CH S' q **•7; © - 68 - hooc - ch - n - c - ch - ch - ch, - ch, lA i5 X a™ „ r\ r4 r5 0 r' c00coh 2 5 r1 hooc - ch - nh r4 r5 CH(CH3)2 i CH(CH5)CH2CH3 6 ch2c6h5 n CH2-C6Hh i ch2-c6h4-och5 q ch2-c6h4-oc2h5 p CH2-C6H4-0n-C5H7 p CH2-C6H4-0n-C4Hg 0 (ch2)4-nh2 p ch2-ch2- s-ch5 n ch— ch ch, - c ch h 2 w o s i HO 0 - ?HO i ii HO —HO 0 ^ho-s-^ho-^ho 1 6H*0-"0 JrH90-2H0 o ^o-«o -*H9O-zHO 0 sh300-*h90-2h3 1 . * lh90-2h0 0 SH902H0 H £H02HO(£HO)HO 0 2(CH0)H0 S? t? HK - HO - OOOH 5H20000 .H 0 CH ■m 7 I M I a I F| ^ HO ~ HO - HO "" HO 0 - H - HD - OOOH - 69 - o o (J O " /:'■ f" ' . "' n o /■ \ 2 - 70 - HOOC - CH - N - C - CH - CH - CH0 — CH, - • A • K « I 1 ® VBs/ o*r bP n e' nr\r\n u O H4 R5 0 R1 C00C2H5 R1 HOOC - CH - NH r4 r5 p p k d d d q CH— CH ' * CH, - C CH N ch(ch5)2 ch2-c6h5 CH2-c6Hh ch2-c6h4- OCHj ch2-c6h4- oc2h5 ch2-c6h4- On-CjH, CH2~"C6H4~ 0n-C4H( ^ J-. - 71 - hooc - ch - n - c - ch - ch - cho - ch r4 r5 0 r1 aooc^r 2 " cb2 "o 2 5 r1 hooc - ch - nh r4 r5 ch(ch5)2 n ch(ch5)ch2ch3 p ch2-c6h5 q ch2~c6h11 n ch2"~cgh4* on-c^h^ d ch— ch h k ch, - c ch p ^s" ch(ch5)ch2ch3 q ch(ch3)ch3ch3 i ch2-c6hn 0 ch2~cgh^^ q Example 94; 1-CN-(lS)-Carboethoxybutyl)-S-alanylU-octahydrocyclopenta-[b]pyrrole)-2-carboxylic acid 5 a) Ethyl DL-2-trifluoromethylsulfonyloxypentanoate 5 g (34 mmol) of ethyl 2-hydroxyvalerate and 2.85 g (35.9 mmol) of absolute pyridine were dissolved in 100 ml of absolute CH2CI2 under protective gas, the solution 10 was cooled to 0°C and 9.66 g (34 mmol) of trifluoro- methanesuIfonic anhydride were added. The mixture was warmed to room temperature and stirred for 6 hours. The solution was concentrated and the resulting crude product was purified by column chromatography (silica gel, petro-15 leum ether/CHjCljj 6:1). 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-alanine 4.9 g (17.6 mmol) of the trifluoromethanesulfonic ester thus obtained were dissolved, under nitrogen, in 70 ml of absolute CH2CI2 with 4.08 g of the benzyl ester of L-alanine 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 5:1). The yield of each isomer was 500 mg. The diastereomer isolated in the first filtration had the 5.5 configuration. 1H NMR 0*9 (t,CHj), 1.3 (t,CHj), 1.35 (dfCHj), 1.4 (nifCHg), 1.6 (m,CH2), 1.9 (b,NH), 3.3 (t.CH), 3.4 (q,CH), 4«2 (m,CH2)» 5.15 (ifCHg Ph), 7«4 (s, CH arosiErt.) ppm. c) N-(1-vS-Carboethoxybutyl)-S-alanine 600 mg (1.95 mmol) of benzyl ester (diastereomer A) were hydrogenated with Pd on charcoal in 34 ml of ethanol. The catalyst was then filtered off, and the solution was concentrated in vacuo. The product was then obtained as a white solid with a melting point of 137° and a yield of 430 mg. d) 430 mg (1.98 mmol) of N-(1-S-carboethoxybutyl)-S-alanine and 486 mg (1.98 mmol) of benzyl L(-)-octahydrocyclo-pentaCbJpyrrole-2-carboxylate were dissolved, under nitrogen, in 20 ml of dimethylformamide, the solution was cooled to -10°C, and 1.5 ml of triethylamine and 2 ml of n-propylphosphonic anhydride were added. The solution was stirred at -10°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 Na HCO3 solution, 10% aqueous citric acid and saturated aqueous 5 NaCl solution. After the solution had been dried and concentrated, the diastereomeric compounds were separated by column chromatography (silica gel, cyclohexane/ ethyl acetate 9:1). The yield was 360 mg. Both diastereomers were hydrogenated with Pd/C in ethanol as 10 described in Example 94 c) and, after concentration of the solution, they were obtained as -white solids. Example 95: 1-[N-(lS)-Carboxybutyl)-S-alanyl3~(octahydrocyclopenta-Cb]pyrrole)-2-carboxylic acid 15 60 mg (0.17 mmol) of carboxylic acid (Example 94 d) were stirred into 2 ml of 4 N aqueous K0H solution until the substance had completely dissolved. The solution was then applied to a strongly acid ion exchanger and eluted with a 2% strength solution of pyridine in water. The yield after 20 concentration of the solution was 39 mg. o In analogy to the compounds prepared in Examples 94 and 95, it is possible to synthesize the following additional compounds of the formula II h r5ooc -ch-n-c-ch-n-ch (ch2) -r O r4 r5 0 r1 coor2 25 in which, with n = 2, R^ is CH3, R^ is C2H5, R^ * h is H, and R and the part of the molecule r^o0c-ch-n b*r5 are substituted as indicated in the table detailed below. •y » HOOC-CH-NH R4 R5 CH3 a -CH2CH2CH5 a -(CH2)9-CH5 C 2-Naphthyl D 4-Biphenylyl a -(ch2)13-ch3 a EOOC-CH-m R4 R5 ch3 B -ch2ch2ch3 B -(ch2)9-ch3 d 2-Naphthyl p 4-Biphenylyl C —(ch2)j 3—ch3 B ... . j -., | ' ' - • ' •• I o ~i i i . . - 75 - hooc-ch-nh • 4 15 r r o -(ch2)13-ch3 ch3 c -ch2ch2ch5 c -(ch2)9-ch5 G 2-Naphthyl G 4-Biphenylyl D C 2 o o ch3 D -ch2ch2ch3 D -(ch2)9-ch3 h 2-Naphthyl h 4-Biphenylyl h — (ch2)j j-chj D R hooc- ch3 G -ch2ch2ch3 G -(ch2)9-ch5 K 2-Naphthyl I 4-Biphenylyl Ir -(ch2)13-ch3 G hooc-ch-nh r" r5 b4r5 o I ' \ - 76 - hooc-ch-nh • A te R4 R 5 q ch3 h -ch2ch2ch5 h -(ch2)9-ch5 n 2-Naphthyl m 4-Biphenylyl n —(ch2)j3—chj n hooc-ch-nh chj n -ch2ch2ch3 n -(ch2)9-ch3 0 2-Naphthyl n 4-Biphenylyl P -(ch2)13-ch3 0 v. hooc-ch-nh & # ch3 q ^ -ch2ch2ch3 Q -(ch2)9-ch3 p 4-Biphenylyl Q -(ch2)13-ch3 p r\ i - 77 - 21 r hooc-ch-nh n niii ch5 p -ch2ch2ch3 p -(ch2)9-ch3 q 4-Biphenylyl G w -(ch2)13-ch3 q 4-Biphenylyl H a o ^ ... 21D784 - 78 - Reference Example 1: 1) Benzyl 2-(S-aLanyl)-(1S,3S,5S)-2-azabicycloC3.3.0l-octane-3-carboxylate trifluoroacetate 5 1 a) Benzyl 1-(N-tert.butyLoxycarbonyl-S-alanyl?-HS,3S,5S)-2-azabicycloC3.3.Q]octane-3-carboxylate 61.5 g (0.251 mol) of benzyl (1S,3s,5S)-2-azabicycIo-10 C3.3.0 Joetane-3-carboxyI ate, 47.5 g (0.251 mol) of BOC-L-alanine and 173 ml (1.26 mol) of absolute triethylamine are dissolved in 1,025 ml of absolute dimethyLformamide, 252 ml of a 50% strength solution of propanephosphonic anhydride in dichloromethane are added dropwise at -5°C, 15 and the mixture is stirred at -5°C for 30 minutes and at room temperature for four hours. The 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 20 sodium bicarbonate solution, 10% strength citric acid solution water and saturated sodium chloride solution, dried and concentrated. Yield: 93.2 g (89%) of oily product. 25 1b) Benzyl 2-(S-alanyl)-(1S/3S,5S)-2-azabicyclo[3.3.Q]-octane-3-carboxylate trifluoroacetate 235 ml of absolute trifluoroacetic acid are poured over 93.2 g (0.224 mol) of B0C derivative from Reference Exam-30 pie 1a) at 0°C, and the mixture is stirred at 0°C .for 2.5 hours. Excess acid is removed by evaporation in vacuo at 25°C and the residue is crystallized from 1,000 ml of absolute diisopropyl ether. ***-— Yield: 82.6 g (86%), melting point 148—15QC ' V \ J.- <■ S§Sfi£, »" 210 7 G 4 Reference Example 2: 2) n-Octyl (1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy-l a te 2a) Benzyl 2-tert.butyloxycarbonyl-(1S,3S/5S)-2-azabi-cycloC3.3.03octane-3-carboxylate A solution of 39.2 g (0.180 mol) of di-tert.butyl dicarbo-10 nate in 60 ml of absolute methylene chloride is slowly added dropwise at 0°C to a solution of 40.0 g (0.163 mol) of benzyl (1S,3S,5S)-2-azabicyclo[3.3.03octane-3-carboxy-late and 23.4 ml (0.169 mol) of absolute triethylamine in 300 ml of absolute methylene chloride, and the mixture is 15 stirred at 0°C for 15 minutes and at room temperature for one hour. The reaction solution is washed with 10% strength citric acid solution, saturated sodium bicarbonate solution and water, dried and concentrated. Yield: 55.6 g of oily product, 20 CaDp5 = -1.2° (c = 2, methanol). 2b) 2-Tert.butyloxycarbonyl-(1S,,3S/5S)-2-azabicycloC3.3.Q3-octane-3-carboxylic acid 25 55.6 g (0.161 mol) of benzyl ester from Reference Example 2a) are hydrogenated on 4 g of palladium/charcoal (10%) in 2 liters of ethanol at room temperature for 2.5 hours. The catalyst is filtered off with suction, and the filtrate is concentrated. 30 Yield: 37.3 g (90%); Co3^ = +22.7° (c = 1, methanol). 2c) n-Octyl 2-tert.butyloxycarbonyl-(1S,,3S,5S)-2-azabi-cycloC3.3.Q3octane-3-carboxylic acid 35 32.3 g (0.127 mol) of acid from Reference Example 2b) an.d==£SE»s«>- j^x£/y>s 25.3 g (0.253 mol) of potassium bicarbonate are stirre'en P % \ '9fZ81990$ . // 2.19 - 80 - in 500 ml of dimethyLformamide at 40°C for 1.5 hours. After cooling, 48.9 g (0.253 mol) of 1-bromooctane are added dropwise, and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water, extracted three times with ethyl acetate, and the combined organic phases are washed with saturated sodium bicarbonate solution and water, dried and concentrated, and the crude product (44.3 g) is purified by flash chro matography on silica gel (900 g, mobile phase toluene/ ethanol 95:5 or 99.5:0.5) in two portions. Yield: 35.4 g (76%) of oily product, =f +5.7° (c = 1, methanol). The following are obtained in an analogous way: n-octyl 2-tert.butyloxycarbonyl-(1RS,3RS,5RS)-2-azabicyclo-C3.3.QD-7-octene-3-carboxylate; n-octyl ester of N-tert.butyloxycarbonyl-S-proline. 2d) n-Octyl (lS,3S,5S)-2-azabicycloC3.3.03octane-3-car-boxylate 2.6 g (7.0 mmol) of BOC compound from Reference Example 2c) are stirred with 9 ml of trifluoroacetic acid at 0°C for 1.5 hours. The 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 with water, dried and concentrated, and the product is rapidly reacted further. Yield: 1.8 g (95%) of oily product. The following are obtained in an analogous way: n-octyl (1RS,3RS,5RS)-2-azabicycloC3.3.03-7-octene-3-car-b o x y I a t e ; , • ? ^ J n-octyl ester of S-proline. o\ • '•f'm ' *-n'l v* / >kC r._ r- <n J o Reference Example 3: - 81 - 2.10764 3) 3-Octynyl methanesulfonate 5 7.47 g (65 mmol) of methanesulfonyI chloride are added dropwise to a solution of 7.56 g (60 mmol) of 3-octyn-1-ol and 12.45 ml (90 mmol) of triethylamine in 225 ml of methylene chloride at 10°C within 30 minutes, and the mixture is stirred for one hour. The reaction solution 10 is washed with water, saturated sodium bicarbonate solution and again with water, dried and concentrated. Yield: 11.9 g (97%) of oily product. Example 96: 15 n-Octyl 2-cn-(ls-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(lS,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylate 2.07 g (5 mmol) of 2-cn-(1S-ethoxycarbonyI-3-phenyIpropy I)-20 S-aLanyl]-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy-lic acid (ramipril) and 0.50 g (5 mmol) of potassium bicarbonate are stirred in 25 ml of dimethyLformamide at 40°C for 1.5 hours and, after cooling to room temperature, a solution of 1.16 g (6 mmol) of 1-bromooctane in 20 ml 25 of dimethyLformamide is added dropwise, and the mixture is stirred at room temperature overnight. The pH is adjusted to 6 by add it ion of 0.1N HCl, the mixture is diluted with water and extracted three times with methylene chloride, and the combined organic phases are dried, con-30 centrated and purified by column chromatography on. 120 g of silica gel (mobile phase toluene/ethanol 95:5). Yield: 2.35 g (89%) of oily product; C.3» = -23.9° (c = 1, methanol). 35 Example 97: n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ali (1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate y - f ' **TI UT /J 7 219764 - 82 - hydrogen maleate 528 mg (1 mmol) of the ester obtained in Example 96 are dissolved in 20 ml of ether, and a solution of 116 mg (1 mmol) of maleic acid in 4 ml of acetone is added. The solvents are removed by evaporation, and the residue is crystallized with diisopropyl ether. Yield: 0.51 g (79%) of colorless crystals, melting point 89-90°C. Example 98: 2-0ctenyl 2-CN-C1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nyL3-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate hydrogen maleate 2.08 g (5 mmol) of 2-CN-( 1S-ethoxycarbonyl-3-phenyLpropyl)-S-alanyl3-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy-lic acid (ramipril) and 1.00 g (10 mmol) of potassium bicarbonate are stirred in 25 ml of dimethyLformamide at 40°C for 1.5 hours, the mixture is cooled to 0°C, and a solution of 2.3 g (12 mmol) of E-1-bromo-2-octene in 20 ml of dimethyLformamide is added dropwise. The reaction solution is stirred at 0°C for 4 hours, poured in 500 ml of water and extracted 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 purified by flash chromatography on 125 g of silica gel (mobile phase cyclohexane/ethyl acetate 8:2 and 1:1)'. 1.93 g (73%) of an oily product are obtained and converted into the hydrogen maleate in analogy to Example 97. Yield: 2.0 g of colorless crystals, melting point 81-84°C. Example 99: 3-0ctynyl 2-CN-( 1S-ethoxycarbonyl-3-phenylpropyl )-S-ala^^-^ nyl3-(1S,3S,5S)-2-azabicycIoC3.3.0Doctane-3-carboxyl a l'<z L, hydrogen maleate fj / xv- .,, c - 83 - 4.9 g (11.8 mmol) of 2-[N-(lS-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl]-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylic acid (ramipril) and 2.4 g (23.6 mmol) of potassium bicarbonate are stirred in 90 ml of dimethyLformamide at 40°C for 2 hours, and then a solution of 2.41 g (11.8 mmol) of mesylate from Reference Example 3 in 30 ml of dimethyLformamide is added, and the mixture is stirred at 40°C for a further 9 hours. The reaction solution is diluted with 250 ml of water and extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and with water, dried and concentrated, and the crude product (5.6 g) is purified by chromatography on 200 g of silica gel (mobile phase toluene/ethanol 99:1). 3.45 g (56%) 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°C. Example 100: Ethyl 2-CN-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-ala-nyl]-(1S,3S,5S)-2-azabicycloC3.3.0]octane-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 room 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 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 (42%) 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 Example 101: 5-Non/l 2-cn-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylate hydrogen maleate A solution of 1.31 g (7.5 mmol) of diethyl azodicarboxylate in 10 ml of absolute tetrahydrofuran is added dropwise at 0°C to a solution of 1.97 g (7.5 mmol) of triphenyIphos-phine and 0.72 g (5 mmol) of 5-nonanol in 100 ml of absolute tetrahydrofuran, the mixture is stirred for 10 minutes and then, at 0°C, a solution of 2.08 g (5 mmol) of 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylic acid (ramipril) in 25 ml of absolute tetrahydrofuran is added, and the mixture is stirred at 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 2N sodium hydroxide solution and once with water, dried and concentrated, and the crude product (5.0 g) is purified by flash chromatography twice • on 200 g of silica gel (mobile phase a) toluene/ethanol 99:1, b) methylene chloride/ethyl acetate 9:1). 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 (49%); melting point 103-105°C. Example 102: Benzhydryl 2-CN-(1S-menthyloxycarbonyl-3-phenyIpropyl)-S- i alanyl]-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylate 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 violet solution is filtered with suction through C e I i TS"—a-nd— concentrated. The 3 mmol of diphenyldi azomethane obta ine< in this way are dissolved in 32 ml of absolute aceto is \\ ~9FEB1990 X?> - 85 - added dropwise, while cooling in ice, to a solution of 1.31 g (2.5 mmol) of 2-CN-(1S-menthyloxycarbonyl-3-phenyl-propyl)-S-alanyl]-(13,38,55)-2-azabicycloC3.3.Q]octane-3-carboxylic acid (see Example 132) in 32 ml of absolute acetone. The mixture is subsequently 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 cyclohexane/ ethyl acetate 8:2). Yield: 1.63 g (95%) of oily product; Ca3p^ = -57.9° (c = 1, methanol). Example 103: n-Octyl 2-CN-(3-cyclohexyl-1S-ethoxycarbonylpropyl)-S-alanyl]-(1S/3S,5S)-2-azabicycloC3.3.Q]octane-3-carboxylate 1.8 g (6.7 mmol) of octyl ester from Reference Example 2d), 1.92 g (6.7 mmol) of N-(3-cyclohexyl-1S-ethoxycarbon-ylpropyl)-S-alanine and 4.6 ml of absolute triethylamine are dissolved in 30 ml of absolute dimethylformamide, the solution is cooled to -5°C, 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, 10% 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 199:1). Yield: 2.48 g (69%) of colorless oil, CaU^ = -26.4q ( c = 1, methanol). D Example 104: Benzyl 2-CN-C1S-ethoxycarbonyl-1-tridecyl)-S-phenylala-nyl]-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxyLate 3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of a 50% strength solution of propanephosphonic anhydride in methylene chloride are successively added dropwise to a solution of 2.1 g (5 mmol) of N-(1S-ethoxycarbonyI-n-tri-decyI)-S-phenyI a I anine and 1.4 g (5 mmol) of benzyl (1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate in 80 ml of absolute dimethyLformamide, and the reaction solution is stirred at room temperature overnight. It is then poured into water and extracted several times with ethyl acetate, the combined extracts are washed with water, 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, 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 (85%) of oily product Ca3p"* = -8.0° (c = 0.97, ethanol). Example 105: Benzyl 2-CN-(lS-n-octyloxycarbonyl-3-phenylpropyl)-S-alanyl3-(lS,3S,5S)-2-azabieyeLoC3.3.ODoctane-3-carboxylate 6.0 ml (43.4 mmol) of absolute triethylamine and 9.2.g of n-octyl 4-phenyl-2R-trifluorofliethanesulfonyloxybutyrate, dissolved in 20 ml of absolute methylene chloride, are successively added dropwise at 0°C to a solution of 9.3 g (21.7 mmol) of trifluoroacetate from Reference Example 1b) in 100 ml of absolute methylene chloride. The mixture is allowed to reach room temperature, stirred for 2.5 hours, extracted three times with water, dried amd concentrated, and the crude product (11.4 g) is purified by flash chromatography on 450 g of silica gel (mobile .^'V' - 87 - phase cyclohexane/ethyl acetate 9:1, 8:2, 7:3). Yield: 6.95 g (54%) of oily product, CoUp"* = -35.1° (c = 1, methanol). Example 106: Tert. butyl ammoniurn 2-[N-(1S-n-octyloxycarbonyl-3-phenyl-propyl)-S-alanyl3-(1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylate 5.45 g (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. Remov/al of the catalyst by filtration with suction, and concentration result in 4.1 g (89%) of 2-CN-(1S-n-octyIoxycar-bonyl-3-phenylpropyl)-S-alanyl]-(1S,3S,5S)-2-azabicyclo-CS . 3 . 0 Doc tane-3-c a rboxy I i c acid. 190 mg of tert.butyI amine 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 (86%) of colorLess crystals, melting point 141-143°C. Example 107: n-Octyl 2-CN-(1S-carboxy-3-phenyIpropyl)-S-alanyl]-(lS,3S,5S)-2-azabicycloC3.3.03octane-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 neutral ized„.sby 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, jf . *0- the combined organic phases are washed with saturate'^ ^ ** i v fV sodium chloride solution, dried and concentrated, and the crude product (2.05 g) is purified by chromatography on 80 g of silica gel (toluene/ethanol 9:1). The product obtained in this way (1.15 g; 46%) is triturated in 50 ml of petroleum ether, left to stand in the cold, filtered off with suction and dried. Yield: 0.83 g of colorless crystals; melting point 56-61°C. The following compounds according to the invention are additionally obtained by use of suitable starting materials and application of the processes described in Examples 96-107: Example 108: n-Octyl 2-CN-(1S-ethoxycarbonyl-n-heptyl)-S-alanyl1-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate. Example 109: n-Decyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl]-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate; Ca]^ = -25.8° (c = 1, methanol). Example 110: n-Tetradecyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S- alanyl]-(1S,3S,5S)-2-azabicycloC3.3.03octane-3-cartjoxylate; Ca3^ = -19.8° (c = 1, methanol). D Example 111: Example 112: - 89 - 2197G n-Octyl 2-CN-(1S-isobutyloxycarbonyl-3-phenylpropyl)-S-alanyl3-(lS,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate; Ca]^ = -23.7° (c = 1, methanol). Example 113: n-Octyl 2-CN-(1S-n-octyLoxycarbonyl-3-phenylpropyl)-S-alanyl3-(1S,3S,5S)-2-azabicycLoC3.3»03octane-3-carboxylate; Ca]^ = -18.6° (c = 1, methanol). Example 114: n-Octyl 2-CN-(1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanyl3-C1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxy-late; = -15.2° (c = 1, methanol). Example 115: n-Octyl 1'-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala- nyl3spiroCbicycloC3.3.03octane-2,3,S-pyrrolidine3-5lS- carboxylate. Example 116: n-Nonyl I'-CN-flS-ethoxycarbonyl-S-phenylpropyU-S-ala-nyl3spiroCbicycloC2.2.23octane-2,3'S-pyrrolidine3-5,S-carboxylate hydrogen maleate; melting point 110°C. Example 117: n-Decyl 11 — CN— C15-ethoxycarbonyl-3-phenylpropyI)-S-ala- nyl3spiroCbicycloC2.2.23octane-2,3'S-pyrrolidine3-5,S- 1 £ o // 1 f carboxylate hydrogen maleate; melting point 96 C. f(Aj' O't Example 118: - 90 - 2107G4 n-Octyl 2-CN-C1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl3-C1R,3R,5R)-2-azabicycloC3.3.03octane-3-carboxylate; Cot3^ = -7.0° (c = 1.16, methanol). Example 119: n-Octyl 2-CN-C1S-ethoxycarbonyl-3-phenylpropyl)-R-alanylJ-C1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate; Ca3^5 = +18.0° (c = 1, methanol). Example 120: n-Octyl 2-CN-ClR-ethoxycarbonyl-3-phenylpropyl)-R-alanyl 3-C1S,3S/5S)-2-azabicycloC3.3.03octane-3-carboxylate; CaJg"* = +9.4° (c = 1, methanol). Example 121: n-Octyl 2-CN-CIS-ethoxycarbonyl-3-phenylpropyl)-S-alanyl 3-C1S,3S/5S)-2-azabicycloC3.3.03-7-octane-3-carboxylate; Ca3^ = +21.2° Cc = 1, methanol). Example 122: n-Octyl 2-CN-C1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl3-(lR,3R,5R)-2-azab i cycloC3.3.03-7-oc tane-3-c a rboxy I ate; Ca3j|5 = -51.4° Cc - 1, methanol). Example 123: ~ n-Octyl ester of N-CN-C IS-ethoxycarbonyl -3-pheny lpropy I S-alanyI3-S-proline hydrogen maleate; melting point ffA/ ,i?i ii \ -9FEBmoi:, X* a 105—107°C- -91 - Example 124: 2-CN-C1S-Ethoxycarbonyl-n-tridecyl)-S-phenylalanyl]-C1S,3S,5S)-2-azabicycloC3.3.0]octane-3-carboxylic acid; CaD^ = +27.2° (c = 1, methanol). Example 125: Benzyl 2-CN-C1S-ethoxycarbonyl-n-tridecyl)-S-alanylJ-C15,3S,5S)-2-azabicyclo[3.3.QJoctane-3-carboxylate. Example 126: Benzyl 2-CN-C1R-ethoxycarbonyl-n-tridecyl)-S-alanyl]-C1S,35,5S)-2-azabicycloC3.3.0]octane-3-carboxylate. Example 127: Benzyl 2-CN-ClS-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanyl]-C1S,3S,5S)-2-azabicycloC3.3.03octane-3-carboxylate Ca]^ = -28.6° Cc = 1, methanol). Example 128: Benzyl 2-CN-C15-menthyloxycarbonyl-3-phenylpropyl)-S-alanyl]-ClS,3S,5S)-2-azabicycloC3.3.0]octane-3-carl?oxylate Ca Dp"* = -63.2° Cc = 1, methanol). Example 129: 3,3-0 iphenyl-n-propyl 2-CN-C1S-ethoxycarbonyl-3-pheny Ipro-pyD-S-alanylD-CIS^S^SJ^-azabicycloCS.S.OJoctane-S-carboxylate hydrogen maleate; melting point 122-124°C. Example 130: - 92 - 5-Nonyl 1'-CN-C1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nylDspiroCbicycloC2.2.23octane-2,3'S-pyrrolidine3-5,S-carboxylate hydrogen maleate; melting point 121°C. Example 131: Tert.butyI ammonium 2-CN-C1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanyL3-C1S,3S,5S)-2-a2abicycloC3.3.03-octane-3-carboxylate; melting point 133-135°C. Example 132: i Tert.butylammoniurn 2-CN-C1S-menthyloxycarbonyI-3-phenyl-propyl )-S-alany 13-(15,35,5s)-2-azab i eye IoC3.3.03 octane-3-carboxylate; melting point 164-167°C. o - 93 - 219 7 G 4 Compounds of the formula I n R Ri r3 HOOC-CH-N- I I R^ R5 1 Cch2)i0ch3 ch3 c2h5 h d less polar diastereomer [a]^ = +0,5° (c=l, CH3OH); MS (DCI) 481 (M++l) more polar diastereomer [a]20 = -22.5 (c=l, CH3OH); MD (DCI) 481 (M++l) 1 1 CH2)ioCH3 H H D [a]20 = + 52.9° (c=l, ch3oh), MS (DCI) 529 (M++l)- 1 CH(-CH3)2 ' CH3 C2Hs CH2CgH5 D (diastereomers) rfa]20 = -29.8° (c=l, CH3OH), MS (DCI) 459 (M++1) • [a]20 s -0.6° (c=l, CH3OH), MS (DCI) 459 (M++l) 2 CH3 CH3 . c2h5 ch2cgh5 h 1 MS (DCI): 499 (M++l) for both diastereomers 2. CH3 CH3 C2H5 H H . less polar diastereomer = -40.8° (c=l, CH3OH) more polar diastereomer [o]^ = -4.5° (c=l, ch3oh) 2 C6HS CH2-C6H4-0-nC3H7 C2H5 H H rap: 53°C MS (DCI): 605 (M++1) 2 C5H5 *• CH2-C6H4-0-nC3H7 H H . H [a]2^0 = +32.0° (c=l, CH2C12), mp: 120-127°C 2 CsH5 CH2-C6H5 H H H [a]2D° = +32.6° (c=1, CH2Cl2), mp: 145° (decomp.) . Jf v * v e ^ — . 219784 i - 94 - Compounds of the formula I n R R1- R2 . R3 HOOC-CH-N- i ( R4 R5 2 CfiH5 CH2CH(CH3)2 H H H mp: 156°C (decomp.) other diastereomer mp: 137° (decomp.), [o]^ = -*-3.9° (c=l, ch3oh) Z C6H5. CH(CH3)-C2H5 H H H mp: 127°C (decomp.); MS (DCI): 485 (M++l) 2 n-c4h9 CH3 C2H5 CH2-C6H5 D less polar diastereomer [a]^ -51.6° (c-1, CH3OH) .more polar diastereomer [a]^= -26.8° (c-1, ch3oh) 2 11-c4h9 CH3 C2H5 H H less polar diastereomer [a]20= +6.9° (c=l, ch3oh) more polar diastereomer [a]^= +4.4° (c=l, CH3OH); MS+(DCI): 597 2" 11-c4h9 CH3 H H- D 1st diastereomer = +10.4° (c=l, ch3oh) 2nd diastereomer mp: 104-108aC </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 95 - o Ex.22 [b]20 = -21.5° [c 52 [a]c° = -39-3° [c 53 [a]20 = +2.2° [c 78a = *2.7.0° [c malate mp: 118 Table p. 62, 9th. cpd. Table p. 64, 6th cpd. less polar diastereomer more polar diastereomer Table p. 64, 7th cpd. Table p. 65, 9th cpd. Table p. 66, 3rd cpd. 1st diastereomer: 2nd diastereomer (t-BuNH2 salt) Table p. 69, 2nd cpd. = 1, ch3oh] = 1, ch3oh] = 1, CH3OH]; mp: 162-163°C = 1, ch3oh]; •120°C [a]20 = -23.7° [c = 0.152, ch3oh] [a]2D0 = -28.6° [c = i, ch3oh] [a]2D° = +20.7° [c = 1, ch3oh] MS (FAB): 591 (M+ + 1) mp: 53-57°C MS (FAB): 605 (M+ + 1) mp: 142°C [a]2^ = +16.4 (c-[a]2D0 s +29.9 (c 1, ch3oh) 1, CH3OH) [a]20 = -7.3° (c = 1, ch3oh) mp: 117°C o o - 96 - 2.197G4 WHAT WE CLAIM IS: 1. A compound of the formula II * * * R3OOC -"CH-N-C-CH-NH-CH- (CH2)n - R (ii) R4 R5 O R1 COOR2 A. in which I.a) n is 1 or 2; b) R 1. denotes h/drogen; 2. denotes alkyl having 1-18 carbon atoms; 3. denotes an aliphatic acyclic radical of the formula caH C2a—b+13 ^ 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; A. denotes a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula C cH (2 c-d-1)/• "hich is optionally branched, in which c represents an integer 3 to 20, and d represents an even number 0 to (c-2); 5. denotes aryl which has 6-12 carbon atoms and can be mono-, di- or t ri subst i tuted by (C-j-Cg)-a Iky I, (C<j-C4>-a Ikoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C-j-C4)-a Iky I ami no, di (C j-C^ -alkylamino, (C1-C4) -alkanoylaminp, methylenedioxy, carboxyl, cyano and/or sulfamoyl; 6. if n is 2, denotes (C^-C-j~a r? ^1 "^8^"a ^ or di-(C6-C12)-aryl-CC1-C8)-a Iky I, 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. aryloxy which has 6—12 carbon atoms and can bE/v^ substituted as described under I.b)5; v 9. mono- or bicyclic heteroaryloxy or h et e r oa ry l-_ g C c 1 ""C 3) —a I k y L having 5-7 or 8-10 ring atoms "'X! mbkksu. ^-'>» »" i-\,. 2107G4 o o - 97 - respectively, up to 9 of these ring atoms representing carbon and 1 to 2 ring atoms representing sulfur or oxygen and/or 1 to 4 ring atoms representing nitrogen, which can be substituted in the heteroaryl as described under I.b)5; 10. ami no-CC^-C g)-a Iky I; 11. CC^-C^J-a lkanoylamino-(C<|-Cg)-alkyl; 12. (Cy-C-jjJ-aroylamino-CCi-CgJ-alkyl; 13. CC-| —C4> —a lkoxy-carbonylannno-(C<|-Cg)-alkyl; 1 4. CC^-C«i 2)-a ry I — <C1 -C4)~a Ikoxycarbony I a mi no- cc1~c8)-a Iky I; 1 5. CC^-c-j 2^-a ry I-(C-j-C4>-a Iky I ami no-(C<|-Cg)-a Iky I; 16. (C^-C4)-alkylamino-(C^-Cg)-alkyl; 17. di-CC-j-C4)-alkylamino-(C-j-Cg)-alkyl; 18. guanidino-(C")-Cg)-alkyl; 19. imidazolyl; 20. indolyl; 21. (C-j-C4>-a Iky Ithio; 22. if n is 2, (C1 -c4)-a Iky It h i o- (C-j-Cg)-a Iky I; 23. (C6-C<|25-a ry lthio-(C-i-Cg>-a Ikyl which can be substituted in the aryl moiety as described under I.b)5; 24. (C^-C-^2)"3 ry I-(C-j-Cg)-a Iky Ith i o which can be substituted in the aryl moiety as described under I.b)5; 25. if n is 2, carboxy-CC-j-CgJ-alkyl; 26. carboxyl; 27. carbamoyl; 28. if n is 2, carbamoy l-(C<j-Cg)-a Iky I; 29. (C^-C4)-alkoxycarbonyl-(C^-Cg)-a Iky I; 30. if n is 2, CC6-C-j 2)-a ry loxy-CC-j-Cg)-a Iky I which can be substituted in the aryl moiety as described under I.b)5; or . 31. denotes CC^-C-j2^""aryl"^c1""Cg)-a Lkoxy which can be substituted in the aryl moiety as des c r i under I.b)5; ffy c) 1. denotes hydrogen; /[ -Or-- L Lisffltei..-.t ..' .j - '■ •-■ V. ^ - 219764 - 98 - 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 i nteger 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 (c-2); 5. denotes aryl which has 6-12 carbon atoms and can be substituted as described under I.b)5; 6. (C^-C^^'aryl-CC-j-Cgi-a Ikyl or (Cf-C-^-aroyl-<Ci-c8)-alkyl, both of which can be substituted as described for aryl under I.b)5; 7. mono- or bicyclic, optionally partially hydrogenated, heteroaryl or heteroa ry l-CC-j -Cg)-a Iky I 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. - 7., the optionally protected side-chain of a naturally occurring a-amino acid of the formula R^-CH(Nl^J-COOH; d) R^ and R^ are identical or different and /—•s 1. denote hydrogen; i > 2. alkyl having 1-18 carbon atoms; 3. denote an aliphatic acyclic radical of the formula CaH(2a-b+1) 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. a mono-, di-y tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formul^^^MT; CcH(2c-d-1)' which is optionally branched 9FEBI990' 210784 - 99 - in which c represents an integer 3 to 20, and d represents an even number 0 to (c-2); 5. di-(C.j-C4)-alkylaniino-(C.j-Cg)-alkyl; 6. (C-j-C5)-alkanoyloxy-(C^-Cg)-alkyL; 7. (C-j-C^)-alkoxycarbonyloxy-(C-|-C3)-a Ikyl; 8. (Cy-C-j3) —aroy loxy— (C^-Cg)-a Iky L; 9. (C^-C-j2^"ary'-oxycarbonyLoxy-(Ci-Cg)-alkyl; 10. aryl having 6-12 carbon atoms; or 11. denote (C7-C2())-a ra Iky I; it being possible for the radicals mentioned under d) 8., 9., 10. and 11. to be substituted in the aryl moiety as described under I.b)5; and e) 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 and its physiologically tolerated salts. II. excepting compounds of the formula II and their salts, in which a)n is 1 or 2, b) 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, 5. aryl which has 6-12 carbon atoms and can be mono-, di- or t ri s ubst i tuted by (C^-C^-a Iky I, (C<j-C4)-a Ikoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C^ -C^J-a Iky lami no, di-CC-j-C^)-alkytamino, (C^-c^-a Ikanoy lami no, methylene-dioxy, 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) 5; n ^ £ fy v N 8. mono- or bicyclic heteroa ry loxy which has/5-7 or ^ 8-10 ring atoms respectively, 1 to 2 of t:(hese ^ ring atoms representing sulfur or oxygen Nato si i v - 100 - and/or 1 to 4 of these ring atoms representing nitrogen, and which can be substituted as described under II.b)5, 9. ami no-(C<j -C^-a Iky I, 10. (C^-C4)-alkanoylamino-(C'j-C4)-alkyL/ 11. (Cy-C^jJ-aroylamino-CC^-C^i-a Ikyl, 12. (C^-C4)-alkoxycarbonylamino-(Ci-C4)-alkyl/ 13. (C^-C-j 2 )-a ry L- (C-j -C4>-a Lkoxycarbony I ami no-<Ci-C4>-a Ikyl, 14. <C^-Ci2)"aryl-<Ci-C4)-alkylamino-(Ci-C4)-alkyt/ 15. <C^-C4)-alkylamino-(Ci-C4)"-aLkyl/ 16. di-(C<j-C4)-alkylamino-(C<j-C4)-alkyl/ 17. guani di no-(C-|-C4)~a Ikyl, 18. imidazolyl, 19. indoLyI; 20. (C^-C4)-aLkyIthio, 21. CC-j-C4)-a Ikylthi o-(C<j-C4)-a Ikyl, 22. (C^-c-j2^""a rylthio-(C-j-C4)-a Ikyl which can be substituted in the aryl moiety as described under II. b) 5 ; 23. 2?~ary l-(C<j-C4)-alkylthio which can be substituted in the aryl moiety as described under II.b)5; 24. carboxy-CC1-c4)-a Ikyl, 25. carboxyl, carbamoyl, 26. carbamoyl-(C1-C4)-alkyI, 27. (C^-C4)-alkoxycarbonyl-(C-j-C4)-alkyl, 28. (C^-c-j2)~a ry loxy-CC^-C4)-a lky I which can be substituted in the aryl moiety as described under II. b)5; or 29. (C^-c^25~aryl-(C^-C4>-alkoxy uhich can be substituted in the aryl moiety as described under II. b>5; denotes 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, K4.' *-.'i , . i.. . 210 78.1 o - 101 - 4. alkynyl having 2-6 carbon atoms, 5. cycloalkyl having 3-9 carbon atoms, 6. cycloalkenyl having 5-9 carbon atoms, 7. CC3-C9)-cycloalkyl-(C^-C4)-alkyl, 8. (c5-c9)-cycloalkenyl-(c<j-c4)-alkyl, 9. optionally partially hydrogenated aryl which has 6-12 carbon atoms and can be substituted as described under II. b)5, 10. 2^ ~a ry (Cl-C4>-a Iky I or (CyCuJ-aroy I — C C ^ or C25~aLkyl/ both of which can be substituted in the aryl moiety as described under II. b)5; 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 covered by the abovementioned definitions, the optionally protected side-chain of a naturally occurring ot-amino acid -CH (N^^-COOH; © G d) R^ and R^ are identical or different and denote 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 4. di-(C^-C4)-alkylamino-(C-j-C4)-alkyl, 5. (C^-C5)-alkanoyloxy-(C^-C4)~alkyl, 6. (C^-C^)-alkoxycarbonyloxy-CC^-C4)-alkyl, 7. <C7-Ci3)-aroyloxy-<Ci-C4>-aIkyl, 8. (C6-c12)-aryloxycarbonyloxy-(C1-C4)-aIkyl, 9. aryl having 6-12 carbon atoms, 10. (c^-c^2^"aryl-"^c1"c4^~a'-l<yl, 11. CC3-C9)-cyc loa Iky I or 12. <C3-C9)-cycloalkyl-CC1-c4)-alkyl, and e) R^ and R- have the meaning defined under I.e), or B. in which 7 *nu 2197G4 - 102 - o a) n is 1 or 2; b) 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; 5. aryl which has 6-12 carbon atoms and can be mono-, di- or t ri substi tuted by (C1 -C4)-a Iky I, CC-j -C4) — alkoxy, hydroxyl, halogen, nitro, amino, amino-methyl, CC-j-C4>-a Iky I ami no, di — (C-j—C4>—a Iky l-amino, (C^-C4>-a IkanoyI ami no, 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 B. b)5; 8. mono- or bicyclic heteroaryloxy which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 to 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 B. b)5; 9. amino-(01-c4)-aIky I; 10. (c<|-c4)-alkanoylamino-(c'j-c4)~alkyl; 11. (Cy-C^J-a roy Lami no-(C<|-C4)-alkyl; 12. (C<]-C4)-alkoxy-carbonylamino-(Ci-C4)-alkyl; 13. (C6-C12)-aryI-CC^-C4)-aIkoxycarbonylamino-(C-j-C4>-a Iky I; 14. (C£-C<i2>-a ryl-CC^-C4)-alkylami no- (C1-C4) -a Ikyl; 15. (C^-C4>-aIkylamino-(C^-C4)-a IkyI; , 16. di-(C^-C4)-a lkylamino-(C-j-C4)-alkyl; 17. guanidino-(C-j-C4)_a 18. imidazolyl; 19. indolyl; 20. (C.j —C4) —a Iky Ith i o; 21. if n is 2, (C1 -C4)-a Iky Ith i o- (C-,-C4)-a Iky I; 22. (C6-C<|2)~arylthi°"(c1"c4)-a which ca^be substituted in the aryl moiety as described 23. <C6-Ci2>-aryl-(C-j-C4)-a Ikylthio which 219 - 103 - substituted in the aryl moiety as described under B. b)5; if n is 2, ca rboxy-(C-j-C4)-a Iky I; carboxyl; ca rbamoyI; if n is 2/ ca rbamoy I-(C.j-C4)-a Iky I; (C-j-C^J-alkoxycarbonyl-CC-i-C^J-alkyl; if n is 2, (C^-C-j 2>~ary loxy-CC-j-C^-a Iky I which can be substituted in the aryl moiety as described under B. b)5; or (C^-C^ 2^~a ry I-<C-(-C4)-a Ikoxy which can be substituted in the aryl moiety as described under B. b)5; c) R1 represents the side-chain of valine, leucine, norvaline, norleucine/ methionine, ornithine, cyclo-hexyI alanine, 2-thienyI alanine, 3-thienyI alanine, 0-CC3-C5)~aIkyItyrosine, isoleucine, isovaline or C-phenyIglycine; d) and are identical or different and denote 1. hydrogen; 2. alkyl having 1-6 carbon atoms; 3. alkenyl having 2-6 carbon atoms; 4. di-(C^-C4)-alkylamino-<C<j-C4>-alkyl; 5. (C-j-C5)-alkanoyLoxy-(C-j-C4)-alkyl; 6. (C^-C6)-alkoxycarbonyloxy-(C-]-C4)-a Ikyl; 7. (Cy-CijJ-aroyloxy-<C^-04)-a Ikyl; 8. CC^-C-j 2>"*a ry loxycarbony loxy-(C-j-C4)-a Ikyl; 9. aryl having 6-12 carbon atoms; 10. (C^-c<j2^~aryl —^c1"c4)~a Ikyl; 11. (Cj-C^-cycloa Ikyl; or 12. (C3-C9)-cycloalkyl-(C<i-C4)-alkyI, and e) R^ and R^ have the meaning defined under A. I. e), and its physiologically tolerated salts, or C. in which a) n, R, and R^ are as defined above under B. and b) R1 represents the side-chain of alanine, lysine or e -acyllysine, and 24. 25. 26. 27. 28. 29. 30. 2.137 - 104 - c) R^ and r' are identical or different and denote propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl, iso-pentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, cyclooctyl, eyelohexenyI, cycloheptenyI, phenyl, a- or 6 -naphthyI, 2-, 3- or 4-biphenylyI, phenethyl, 3-pheny lpropyI, benzhydryl, a-methyl-benzyl, a-methylenebenzyl, 2-, 3- or 4-phenyIbenzyI, bi benzy l-a-y I, 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 A. II. b) 5, or one of the radicals R^ and R^ denotes hydrogen, and the other is as defined above, or represents benzyl, and R^ represents benzyl, hydrogen or one of the abovementioned definitions, and its physiologically tolerated salts. 2. A compound of the formula II as claimed in claim 1, in which R^ and form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 15 ring carbon atoms and up to 2 ring sulfur atoms and up to 2 ring nitrogen atoms# 3. A compound of the formula II as claimed in claim 1 or 2, in whi ch 219764 - 105 - R denotes 1 . (Cp-C^ g)-alky I; 2. (C7-C-jg)-a Ikenyl; 3. a radical which has 4-18 carbon atoms and is as defined in claim 1 under A. I. b) 3. and in which b ^ 4; 4. a radical which has 4-20 carbon atoms and is defined in claim 1 under A. I. b) 4 and in which d£ 2; 5. is as defined in claim 1 under A. I. b) 5.; 6. heteroarylaIkyl which is as defined in claim 1 under A. I. b) 9.; 7. amino-(C5-Cg)-a Ikyl; 8. (C>j-C4)-alkanoylamino-<C5-Cg)-alkyl; gt (Cy-c^jJ-aroylamino-CCs-CgJ-alkyl; 10. -C^J-a lkoxycarbonylamino-(C5-Cg)-alkyl; 11. *c6~c12>-aryl-CC1-C4)-alkoxycarbonylamino- (C5~Cg)-a Ikyl; 12. (c^-c^2)""aryl-~fc'j-c4)-alkylamino-(c5-cg)-a Ikyl; 13. (C^-C4>-alkylami no-(C5-Cg)-alky I; 14. di-(Ci-C4)-alkylamino-(C5-Cg)-alkyl; 15. guanidino-(C5-Cg)-alkyI; 16. if n is 2, (C^-C4)-alkyIthio-(Cj-Cg)-alky I; 17. ^6"Ci 2) ~a py i o- (C5~Cg>-a lky I which can be substituted in the aryl moiety as described in claim 1 under A. I. b) 5.; 18. (C^-C^ 2>~a ry l-(C5-Cg)-a Ikylthi o which can be substituted in the aryl moiety as described in claim 1 under A. I. b) 5.; 19. if n is 2, carboxy-(C5-Cg)-alkyl; 20. if n is 2, carbamoyl-(C5~Cg)-a lky I; 21. (C^-C4)-alkoxycarbony I - (C5~Cg)-alkyl; 22. if n is 2, <C^-Ci25~aryloxy~^c5"c8'"a ^yl which can be substituted in the aryl moiety as defined in claim 1 under A.I.b)5.; or 23. CC^-C"] 2'~a ry I-(C5~Cg)-a Ikoxy which can be substituted in the aryl moiety as described in cla>mT1 unde r A. I. b), V r> 2.197G4 © - 106 - and its physiologically tolerated salts. 4. A compound of the formula II as claimed in one of claims 1 to 3, in which 1. (C 7 — C -j Ikyl; 2. (Cy-C^8>-aIkenyI; 3. cc7-c18>-aikynyt-; 4. a radical which has 4-18 carbon atoms and is defined as in claim 1 under A. I. c) 3 and in which b > 2 and only double bonds are present; 5. a radical which is as defined in claim 1 under A. I. c) 4./ excepting cycloalkyl and cycloalkenyl having up to 9 carbon atoms; 6. optionally substituted <C6-c-| 2>~a ry I-<C5-C8)-a lky I; 7. optionally substituted (C^-C-jjJ-ar oy l-CCj-Cg)-alkyl or 8. optionally substituted heteroary l-(C.j-Cg)-a lky I, and its physiologically tolerated saLts. 5. A compound of the formula II as claimed in one of claims 1 to 3, in which represents the side-chain of valine, leucine, norvaline, norleucine, methionine, ornithine, eye lohexylalanine, 2-thienylalanine, 3-thienylalanine, 0-(C3-C5)-alkyItyrosine, isoleucine, isovaline or C-phenylglycine, and its physiologically tolerated salts. 6. A compound of the formula II as claimed in one of claims 1 to 5, in which R2 and are identical or different and denote

1. CC7-c

2. (Cy-C^g^-a Ikenyl;

3. a radical which has 4-18 carbon atoms and is as defined in claim 1 under A. I. d) 3. and in which R^ denotes b > 4;

4. a radical which is as defined in claim 1 under A. I. d) 4, excepting (Cj-C^-cyc loa lky I and CCj-C^-cycloalkyl-CCT-C^-alkyl; - 107 -

5. di-CCi-C^J-alkylannno-CCj-Cg^alkyl; 6. (C-j-CgJ-alkanoyloxy-CCg-CgJ-alkyl; 7. CC-j-C^)-alkoxy-carbonytoxy-(C5-Cg)-alkyl; 8. (cy-cijj-aroyloxy-tcs-cgj-alkyi; 9. <c^-c^25-aryloxycarbonyloxy-(c5-cg)-alkyl; 10. (c-j^-c2o)-aralkyl; it being possible for the radicals mentioned under d) 8./ 9. and 10. to be substituted in the aryl moiety as described in claim 1 under A. I. b) 5.; or one of the radicals R2 and R^ denotes hydrogen and the other is as defined above, and its physiologically tolerated salts. 7. A compound of the formula II as claimed in one of claims 1 to 5, in which R2 and r' are identical or different and denote propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl, neopentyl, isopentyl, n-hexyl isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclo-heptyl, cyclooctyl, cyclohexeny I, eyeloheptenyI, menthyl, phenyl, a- or B-naphthyl, 2-, 3- or 4-biphenylyI, phenethyl, 3-pheny lpropy I, benzhydryl, a-methy Ibenzy I, a-methy lenebenzyl, 2-, 3- or 4-phenyIbenzyI, bibenzyl-a-yl, styryl, 1-indenyl or 9-fluorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, optionally being substituted as defined in claim 1 under A. I. b) 5., or one of the radicals R2 and R^ denotes hydrogen and the other is as defined above, or R2 represents benzyl, and R^ represents benzyl, hydrogen or one of the abovementioned definitions, 'and its physiologically tolerated salts. 8. A process for the preparation of a compound as claimed in one of claims 1 to 7, 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, .. ^ , eliminating protective groups which,. r, .. - r*' - v vn •• • ■ m-: v.. 219764 __ - 108 - have been introduced temporarily to protect reacting groups, esterifying/ where appropriate/ compounds of the formula II with free carboxyl groupCs), and converting/ where appropriate/ the resulting compounds into their physiologically tolerated salts. 9. A process for the preparation of a compound as claimed in one of claims 1 to 7, in which at least one of the radicals and R^ does not denote hydrogen, which O comprises esterification of a compound of the formula II in which at least one of the radicals R^ and R^ denotes hydrogen/ and converting, where appropriate, the compound of the formula II thus obtained into its physiologically tolerated salt. 10. A compound as claimed in one of claims 1 to 7 for use as a medicine. 11. A compound as claimed in one of claims 1 to 7 for use as a cognition adjuvant. 12. A pharmaceutical agent containing an effective amount of a compound as claimed in one of claims 1 to 7 and O a physiologically acceptable vehicle. 13. A process for the preparation of an agent as claimed in claim 12, which comprises converting the active compound together with the vehicle and, where appropriate, further additives and/or auxiliaries into a suitable form for administration. 14. An ACE inhibitor comprising a compound of the formula II as claimed in anyone of claims 1-7, or its physiologically tolerated salts, suitable for use as a medicament having a cognition adjuvant action. 15. An ACE inhibitor or its physiologically tolerated salts, having a cognition adjuvant action, wherein the inhibitor is an angiotensin-converting enzyme inhibitor of the formula II A 1 2.13704 - 109 - 3 * * * R OOC - CH - N - C - CH - NH - CH. - (CH' ) -R (II) U l ii ix la 2n R R 0 R COOR 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 4-20 carbon atoms, an optionalty substituted heteroaromatic or hetero-aromati c-(C<j-Cg^-aliphati c radical having 5-12 ring atoms, or a radical 0Ra 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 t having 5-12 ring atoms, r1 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 alicyclic-aliphatic radical having 4-20 carbon atoms, an optionally substituted aromatic radical having 1 o 6-12 carbon atoms, / r i '-9 FEB WO - 110 - 219764 an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic- (C -j-Cg)-a I i ph at i c 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 -amino acid, and 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^ and R^ form, together with the atoms carrying thenr, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms. 16. An ACE inhibitor or its physiologically tolerated salts as claimed in claim 15, wherein the inhibitor is a compound of the formula II in which n, R, R^, R^, R^, R^ and R^ are as defined in claim 1 under A. I. a) - e). 17. An ACE inhibitor or its physiologically tolerated saits as claimed in claim 15 or 16 wherein the inhibitor is a compound of the formula II in which R4 and R5 form, together with the atoms carrying them, a mono-, bi- or tricylic ring system which has 3 to 15 ring carbon atoms and up to 2 ring sulfur atoms and up to 2 ring nitrogen atoms. 2!9764 - m - An ACE inhibitor or its physiologically tolerated salts as claimed in any one of claims 15 to 17 wherein the inhibitor is a 12 3 4 compound of the formula II in which n, R , R , R , R and are as defined in claim 1 under A. II. a) - e). An ACE inhibitor or its physiologically tolerated salts as claimed in any one of claims 15 to 17, wherein the inhibitor is selected from the group comprising: (S,S,S,S,S)-1-CN-(1-carbethoxy-3-phenyl-propyl)-alanyl3-octahydroindole-2-carboxylic acid, 1 - CN - (1 -S-ca rbethoxy-3-phe ny lpropyl5-S-alanyU-(ZS/SaR/TaSJ-octahydroindole-Z-carboxylic acid, (S,S,S,S,S)-2-CN-(1 - ca rbet hoxy-3-pheny lpropyl)-alanylJ-decahydroi soqui noli ne-3-carboxy li c acid, (S,S,S)-2-CK--(1-carbethoxy-3-phenylpropyl)-alanyl]-tetrahydro-isoquinoline-3-carboxyIic acid, (S,S,S,S,S)-2-CN-(1 -carbethcxy-3~phenylpropyl)-alanylD-2-azabi cycloC3.3.0U-octane-3-carboxyIic acid, 2-N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl!l-ci s,endo-2-azabi cycloC3.1 . OD -hexane-3-S-carboxyIic acid and 1-CN-(1 -S-ca rbethoxy-3-phenylpropyl)-S-analyl!]-cis,endo-1 H-2,3 ,3 a,4,5,7 a-hexahydroindo le-2-S- or -2-R-carboxyIic acid. An ACE inhibitor or its physiologically tolerated salts as claimed in any one of claims 15 to 17, wherein the inhibitor is selected from the group comprising: 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylU-exo/endo-spirobicycloC2.2.2Doctane-2,3'-pyrrol-idine-5'-carboxyIic acid, 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl3-(3'S/S'SJ-spirobi cyclo[2.2.2D-octane-2,3'-pyrroIidine-51-carboxyIic acid, 1'-CN-C1-S-carbethoxy-3-pheny lpropyl)-S-alanyl!I-(3,S,5,R)-spi ro-bicycloC2.2.2]-octane-2,3'-pyrrolidine-5*-carboxylie acid, 1 '-CN-C1-S-carbethoxy-3-phenylpropyl)-S -auJL-arnyf-1D-<3,R,5,S>-spirobicycloE2.2.2Doctane-2,3' -py r ro li di ne-L:,'-carboxylic acid, 1 '-CN-(1 -S-ca rbe t ho xy-3-ph e ny Ip r op^l^y— „.C Sv > - 219764 n - 112 - S-alanyl3-(3,R,5,R)-spirobicycloC2.2.23octane-2,3,-pyrro lidine-5'-carboxyIic acid, 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanyl3-(3'S,5'S)-spi robi cyclo-C2.2.23octane-2,3'-pyrrolidine-5'-carboxylic acid, 11 - CN - (1 -R-ca rbet hoxy-3-pheny lpropy I) -S-a Ianyl3-(3'S, 5,R)-spirobicycloC2.2.23oetane-2,3'-pyrrolidine-5,-car-boxylic acid, 11-CN-(1-R-carbethoxy-3-phenylpropy 1)-S-alanyl3-(3,R,5,S)-spirobicycloC2.2.23octane-2,3l-pyrroIidine-5'-carboxy I ic acid, 1 *-CN-(1-R-carbethoxy-(T} 3-pheny I p ropy I) -S-a lanyl3-(3'R,5'R)-spirobicycloC2.2.23- oct ane-2,3 '-pyr ro I i di ne-5 1-ca rboxy li c acid, 1 •—CN — (1 — S-carbethoxy-3-phenylpropyl)-R-alanylD-(3,S,5,S)-spiro-bicycloC2.2.23octane-2,3*-pyrrolidine-5'-carboxylic acid, 1 '-CN -(1-S-ca rbethoxy-3-pheny Ipropyl)-R-alany 13-(3'R,5,S)-spirobicycloC2.2.23octane-2,3 '-pyrrolidine-5'-carboxylic acid, 1,-CN-(1-S-carbethoxy-3-phenyl-propyl)-R-alanylU-(3,S/5,R)-spirobicycloC2.2.23octane-2,3'-pyrrolidine-5'-carboxyIic acid, 1'-CN-C1-S-car-bethoxy-3-phenylpropyl)-R-alanyl3-(3'R,5,R)-spiro-bi cycloC2.2.23octane-2,3'-pyrrolidine-5'-carboxylie acid, 11-CN-(1-R-carbethoxy-3-phenylpropyI)-R-alany13-(3,S,5'S)-spirobicycloC2.2.23octane-2,3'-pyrrolidine-5'-carboxylic acid, 1'-nN-(1-R-carbethoxy-3-phenyl-propyl)-R-alanyl3-(3'R/5'S)-spirobicycloC2.2.23octane-2,3s-pyrrolidine-5'-carboxylie acid, 1 *-CN-(1-R-car-bethoxy-3-phenylpropyl)-R-alanyl3-(3,S,5'R)-spiro-bi eye IoC2.2.23octane-2,3 '-pyrroIidine-5'-carboxyli e acid and 1 '"CN" d -R-c a rbet ho xy-3-ph eny lp ropy I) -R-a I any 13-(3'R,5'R)-spirobi eye IoC2.2.23octan e-2,3'-pyrrolidine-5'-carboxylic acid. 21, An ACE inhibitor or its physiologically tolerated salts as claimed in claim 15, wherein the inhibitor is (S,S,S)-1-methyl-2-(1-carbethoxy-3-phenylpropyl)-2H-undecahydroeye lopentaC4,53pyrroloC1,2-aDpyrazine-3,

8-di one. 22. A pharmaceutical agent containing an effective amount of an ACE inhibitor as claimed in one of claims 1. to 7 ^$1 ,/ 21 97 - 113 - and 15 to 21, or its physiologically tolerated salt. A process for the preparation of a pharmaceutical agent as claimed in claim 22, which comprises converting the active compound with the suitable vehicles, auxiliaries and/or additives into a suitable form for administration A compound according to claim 1 substantially as herein described or exemplified. A process according to claim 8 substantially as herein described or exemplified. HOECHST AKTIENGESELLSCHAFT By Their Attorneys HENRY HUGHES LTD </div>