CA1341064C - Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfunctions - Google Patents

Abstract

Compounds having a coginition adjuvant action, agents containing them and the use thereof in the treatment and prophylaxis of cognitive dysfunctions The invention relates to new compounds having a cognition adjuvant action, to the use of ACE inhibitors as medicaments having a cognition adjuvant action, to agents containing them, and to the use thereof for the treatment and prophylaxis of cognitive dysfunctions.

Description

Compounds having a cognition adjuvant action, agents containing them, and the use thereof for the treatment and prophylaxis of cognitive dysfunctions The invention relateao to the use of angiotensin converting enzyme inhibitors (A(:E inhibitors) or their physiologic-ally tolerated salts as medicaments having a cognition adjuvant action (improving cognitive function) and to the use thereof in the preparation of corresponding pharma-ceutical formulations..
Examples of suitable compounds for this novel use are those of the formula I
X1 - X2 (I) in which 8' denotes R300C - CH - N - C - (CHR~), - , R,~ IRS I I

y' *
..
~'H2 3 or R3 pOC 0 COOK
X2 denotes -CH2SH , -CHI-S-C-R6 , -CA2- -R7 or -y2-(CH2,~P ~H..(CH2)ri R

Y1 represents -S- or -CH2-, Y2 represents -NR9- or -CH2-, m is 0 or 1, n is 0, 1 or 2, p is 0 or 1, R denotes hydrogen, an optional~,ly substituted aliphatic radical having ~ 341 06 4 _ 2 _ 1-21 carbon atoms, an option~~lly substituted alicyclic radical having 3-20 carbon atoms, an optionally substituted aromatic radical having S~ 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted alicyclic-aliphatic radical having 4-2:0 carbon atoms, an optionaU ly substituted heteroaromatic or hetero-aromatic-(C1-Cg;l-aliphatic radical having 5-l2. ring atoms, or a radical ORa or' SRa, in which Ra represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical. having 6-12 carbon atoms, or an optionally substituted heteroaronratic radical 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 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted heteroaromatic or hetero-aromatic-(C1-Cg)-aliphatic radical having 5-12 ring atoms, or, if not already covered by the above definitions, the side-chain, protected where neces-sary, of a naturally occurring a-amino acid, R2 and R3 are identical or different and denote hydro-gen, an optionally substituted aliphatic radical having 1-21 carbon atoms, an optionally substituted alicyclic radical having ~ 341 06 4 3-20 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, R4 represents hydrogen or (C1-C6)-alkyl and RS represents (C1-(:6)-alkyl, (C3-C6)-cycloalkyl or or R4 and RS form, together with the~atoms carrying them, a mono-, bi- or tricyclic, heterocyclic ring system having 3 to 15 ring carbon atoms, R6 denotes hydrogen, amino, (C1-C6)-alkyl, (C6-C12)-aryl or (C7-C13)-aralkyl, R7 denotes (C1-C6)-alkyl or (C~-C13)-aralkyl, preferably -(CHZ,)4-C6H5, R8 denotes (C1-C6)-alkyl, which is optionally mono-substituted by (C1-C6)-alkanoyloxy, preferably 2-methyl-1-propionyloxypropyl, and R9 denotes hydrogen or (C1-C6)-alkyl;
such as compoundls of the formula II, R300C - CH - N ~- C - CH - NH - ~H - (CH2)n R (II) ~4 ~5 ~ ~1 COOR2 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 4-2'0 carbon atoms, an optionally substituted heteroaromatic or hetero-aromatic-(C1-Cg)-aliphatic radical having 5-12 ring atoms, or a radical ORa or' SRa, in which Ra represents an optionally substituted aliphatic radical having 1-4 carbon atoms, an optionally substituted aromatic radical having 6-12 carbon atoms, or an optionally substituted heteroaromatic radical having 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 6-12 carbon atoms, an optionally substituted araliphatic radical having 7-32 carbon atoms, an optionally substituted heteroaromatic or hetero-aromatic-CC1-Cg)-aliphatic radical having 5-12 ring atoms, or, if not already covered by the above definitions, the side-chain, protected where neces sary, of a naturally occurring a-amino acid, R2 and R3 are identical or different and denote hydro-gen, 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 R4 and RS form, together with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring carbon atoms.

~ 341 06 4 An optionally substituted aliphatic radical is understood to be an aliphatic ac;yclic radical, i.e. a radical with an open, straight or branched carbon chain such as, for example, alkyl, alkenyl, alkynyl and corresponding multiply unsatu-rated radicals. It its preferably unsubstituted or, as described below, for example, for carboxyl, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkyl-aminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthio-alkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyloxyalkyl, alkoxycarbonyloxyaUkyl, aroyloxyalkyl or aryloxycarbonyloxyalkyl, monosubstituted.
An optionally substituted alicyclic radical, and the corre-sponding optionally substituted alicyclic-aliphatic radical which is linked via a~n 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 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, cycloalkenyl, cyclo-alkylalkyl, bicycloalkyl, tricycloalkyl and radicals de-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 side-chains are not substituents).
An optionally substituted aromatic radical is preferably aryl such as phenyl, biphenylyl or naphthyl, which is op-tionally mono-, di- or trisubstituted as indicated below for aryl. Radicals derived from aryl, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, can be sub-stituted as for aryl.

An optionally substituted heteroaromatic radical is pref-erably 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-fur or oxygen atoms and/or 1 to 4 of these ring atoms repre-senting nitrogen atoms, and is understood to be, for example, thienyl, benzoCb7thienyl, furyl, pyranyl, benzofuryl, pyr-rolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrid-azinyl, indazolyl, isoindolyl, indolyl, purinyl, quinol-izinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quin-oxalinyl, quinazolyl, cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl. These radicals can also be partially or completely hydrogenated. A hetero-aromatic radical and the corresponding heteroaromatic-aliphatic radical can be substituted as defined below.
An optionally substituted araliphatic radical is under-stood to be, in particular, aralkyl radicals such as aryl-alkyl, diarylalkyl, indanyl or fluorenyl, in which aryl is as defined above and which can be substituted in the manner indicated there.
R4 and R5 can form, with the atoms carrying them, a mono-, bi- or tricyclic heterocyclic ring system which has 3 to 15 ring carbon atoms and preferably has up to 2 sulfur atoms and up to 2 nitrogen atoms in the ring, in particu-lar up to 1 sulfur atom.
Particularly suitable ring systems of these types are those of the following group:
Pyrrolidine (0); thiazolidine (R); tetrahydroisoquinoline (A>;
decahydroisoquinoline (8); octahydroindole (C); indoline (Q>;
octahydrocyclopentaCblpyrrole (D); 2-azaspiroC4.57decane CE>;
2-azaspiroC4.47nonane (F); spiroC(bicycloC2.2.17heptane>-2,3'-pyrrolidineJ (G>; spiroC(bicycloC2.2.2Joctane)-2,3'-pyrrolidineJ (H); 2-azatricycloC4.3Ø16'9Jdecane (I>;
decahydrocycloheptaCb7pyrrole (J); octahydroisoindole (K);

octahydrocyclopentaCc7pyrrole (L>; 2,3,3a,4,5,7a-hexahydro-indole (M>; 2-azabicycloC3.1.OJhexane (N); 1,2,3,3a,4,6a-hexahydrocyclopentaCbJpyrrole (P), all of which can option-ally be substituted. Pyrrolidine (0) and thiazolidine (R);
can be monosubstituted by, for example, (C6-C12)-aryl, (phenyl, 2-hydroxyphenyl etc.), (C6-C12)-arylmercapto (such as phenylmercapto) or (C3-C7>-cycloalkyl (such as cyclo-hexyl). Tetrahydroisoquinoline (A) can carry, for example, in the aryl moiety, up to 2 (C1-C6)-alkoxy radicals, prefer-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 chiral atoms all possible diastereomers, as racemates or enantiomers, or mixtures of various diastereomers are suitable.
The suitable heterocyclic ring systems have the following structural formulae.

_8_ / ' - CooR3 C0op.3 H ,' N' .
)- COORS
' -. C
.. .
. ~COOR3 i ~- CooR3 D ~ ~ ~COOR3 ~'1 -. F 1 t:00R3 ~OOR3 COORS
t G ' ~I I
~..
3 J'-COOR3 3 ~- COOK, '~ COOR
1 1 .
J , x i -COORS COOK
H p ._ -. ---COORS COOR
N
O p I ~- COO;R3 COORS
N
R

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 for-mula 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 tc~ 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 rep-resents an even number 0 to (c-2);
5. denotes aryl which has 6-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-Cg)-alkyl, (C1-C4>-alkoxy, hydroxyl, halogen, vitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4>-alkylamino, (C1-C4)-alkanoylamino, methylene-dioxy, carboxyl, cyano and/or sulfamoyl;
6. if n is 2, dlenotes (C6-C12>-aryl-(C1-Cg>-alkyl or di-(C6-C12)-aryl-(C1-Cg)-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 heteroaryloxy or heteroaryl-(C1-Cg)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms repre-senting carbon and 1 to 2 ring atoms representing sulfur or oxygen and/or 1 to 4 ring atoms repre-senting nitrogen, and which can be substituted in the heteroaryl as described under I.b)5;

10. amino-(C1-C8,)-alkyl;

11. (C1-C4)-alkanoylamino-(C1-C8>-alkyl;

12. (C7-C13)-aroylamino-(C1-Cg)-alkyl;

~3~~ 064 13. (C1-C4>-alkoxycarbonylamino-(C1-Cg)-alkyl;

14. (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C8)-alkyl;

15. (C6-C12)-aryl-(C1-C4)-alkylamino-(C1-Cg)-alkyl;

16. (C1-C4)-alkylamino-(C1-Cg)-alkyl;

17. di-(C1-C4)-ailkylamino-(C1-Cg)-alkyl;

18. guanidino-(C1-Cg)-alkyl, 19. imidazolyl;

20. indolyl;

21. (C1-C4)-alkylthio;

22. if n is 2, (C1-C4>-alkylthio-(C1-Cg>-alkyl;

23. (C6-C12)-arylthio-(C1-C8>-alkyl which can be substituted in the aryl moiety as described under I.b>5;

24. (C6-C12)-aryl-(C1-Cg)-alkylthio which can be substituted in the aryl moiety as described under I.b)5;

25. if n is 2, carboxy-(C1-C8)-alkyl;

26. carboxyl;

27. carbamoyl;

28. if n is 2, carbamoyl-(C1-Cg)-alkyl;

29. (C1-C4)-alkoxy-carbonyl-(C1-C8)-alkyl;

30. if n is 2, (C6-C12)-aryloxy-(C1-Cg)-alkyl which can be~ substituted in the aryl moiety as described under I.b)5; or 31. denotes (C6-~C12)-aryl-(C1-Cg)-alkoxy which can be~ substituted in the aryl moiety as described under I.b)5;

c) R1 denotes hydrogen;
1.

2. denotes alkyl having 1-18 carbon atoms;

3. denotes an aliphatic radical of the formula CaH(2a-b+1) in which double bonds, if their num-ber exceeds 1, are not cumulative, a represents an integer f. 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 and in which c represents an integer 3 to 20 and d rep-resents an even number 0 to (c-2);
5. aryl which has 6-12 carbon atoms and can be sub-s stituted as described under I.b)5;
6. (C6-C12)-aryl-(C1-Cg)-alkyl or (C7-C13)_ aroyl-(C1-C8)-alkyl, both of which can be sub-stituted as described for aryl under I.b)5;
7. mono- or bicyclic, optionally partially hydrogen-ated, heteroaryl or heteroaryl-(C1-Cg)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 or 2 ring atoms representing sulfur or oxygen and/
or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as des-cribed for aryl under I.b>5; or 8. if not already covered by c) 1. - 8., the option-ally protected side-chain of a naturally occurring a-amino acid) of the formula R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and 1. denote hydra~gen;
2. alkyl havingi 1-18 carbon atoms;
3. denote an aliphatic acyclic radical of the for mula CaH(2a-b+1). in which double bonds, if their number exceeds 1, are not cumulative, a represents a~n integer 2 to 18, and b represents an even number 2 to a;
4. a mono-, di-~, tri-, tetra- or pentacyclic, non aromatic hydirocarbon radical of the formula CcH(2c-d-1). which is optionally branched and in which c represents an integer 3 to 20 and d represents a~n even number 0 to (c-2);
5. di-(C1-C4)-a~lkylamino-(C1-Cg>-alkyl;
6. (C1-CS>-alka~noyloxy-(C1-Cg)-alkyl;
7. (C1-C6)-alkoxy-carbonyloxy-(C1-Cg)-alkyl;
8. (C7-C13>-aroyloxy-(C1-Cg>-alkyl;
9. (C6-C12)-aryloxycarbonyloxy-(C1-Cg)-alkyl;
10. aryl having 6-12 carbon atoms; or 11. denote (C7-C20)-aralkyl; it being possible for thc~ radicals mentioned under d) 8., 9., 10.
and 11.. to be substituted in the aryl moiety as described under I.b)5;
and e) R4 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 com-pounds 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 (C1-C4)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl, alkoxy having 1-4 carbon atoms, aryloxy which has 6-12 carbon atoms and can be sub-stituted 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-(C1-C4)-alkyl, (C1-C4)-alkanoylamino-(C1-C4)alkyl, (C7-C13)-aroylamino-(C1-C4)-alkyl, (C1-C4)-alkoxycarbonylamino-(C1-C4>-alkyl, (C6-C12)-aryl-CC1-C4>-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4)-alkylamino-(C1-C4)-alkyl, (C1-C4)-alkylamino-(C1-C4)-alkyl, di-(C1-C4)._alkylamino-(C1-C4)-alkyl, guanidino-(C1-C4)-alkyl, imidazolyl,, indolyl, (C1-C4)-alkylthio, (C1-C4>-alkylthio-(C1-Ct,)-alkyl, (C6-C12)-airylthio-(C1-C4)-alkyl which can be sub-stituted in the aryl moiety as described above for aryl, (C6-C12>-airyl-(C1-C4)-alkylthio which can be substi-tuted in the aryl moiety as described above for aryl, carboxy-(C~-C4)-alkyl, carboxyl, ~.arbamoyl, carbamoyl-(C1-C4>-alkyl, (C1-C4)-alkoxycarbonyl-(C1-C4>-alkyl, (C6-C12)-airyloxy-(C1-C4)-alkyl which can be sub-stituted in the aryl moiety as described above for aryl, or (C6-C12)-airyl-(C1-C4)-alkoxy which can be sub-stituted in the aryl moiety as described above for aryl, R1 denotes hydrogen, alkyl having 1-6 carbon atoms, alkenyl haring 2-6 carbon atoms, alkynyl haring 2-6 carbon atoms, cycloalkyl having 3-9 carbon atoms, cycloalkenyl having 5-9 carbon atoms, (C3-C9)-cy~~loalkyl-(C1-C4>-alkyl, (CS-C9)-cycloalkenyl-(C1-C4)-alkyl, optionally partially hydrogenated aryl which has 6-12 carbon ~~toms and can be substituted as described above for li, (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)~
aroyl-(C1 or C2)-alkyl, both of which can be substi-tuted 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, 1341~~4 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 occurring ~x-amino acid, R1-CH(NH2)-COOH, R2 and R3 are identical or different and denote hydrogen, alkyl having 1-6 carbon atoms, alkenyl having 2-6 carbon atoms, di-(C1-C4>-alkylamino-(C1-C4)-alkyl, (C1-CS>-alkanoyloxy-(C1-C4)-alkyl, (C1-C6>-alkoxycarbonyloxy-(C1-C4>-alkyl, (C7-C13)-aroyloxy-(C1-C4>-alkyl, (C6-C12)-aryloxycarbonyloxy-(C1-C4)-alkyl, aryl having 6-12 carbon atoms, (C6-C12)-aryl-(C1-C4)-alkyl, (C3-Cg>-cycloalkyl or (C3-Cg>-cycloalkyl-CC1-C4)-alkyl, and R4 and RS have the abovementioned meaning, particularly such compounds in which n is 1 or 2, R denotes (C1-C6)-alkyl, (C2-C6)-alkenyl, (C3-Cg)-cycloalkyl, amino-(C1-C4)-alkyl, (C2-CS)-acylamino-(C1-C4>-alkyl, (C7-C13)-aroylamino-(C1-C4>-alkyl, (C1-C4>-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl-(C1-C4)-alkoxycarbonylamino-(C1-C4)-alkyl, (C6-C12)-aryl which can be mono-, di- or tri-substituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hy-droxyl, halogen, vitro, amino, (C1-C4)-alkylamino, di-(C~-C4)-alkylamino and/or methylenedioxy, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert.-butoxycarbonylamino-(C1-C4)-alkyl, benzoyloxy-carbonylamino-(C1-C4>-alkyl, or phenyl which can be mono- or disubstituted, or in the case of methoxy trisubstituted, by phenyl, (C1-C2)-alkyl, (C1 or C2)-alkoxy, hydroxyl, fluorine, chlorine, bromine, amino, (C1-C4)-alkylamino, di-(C1-C4)-alkylamino, - ~ 341 O6 4 nitro and/or methylenedioxy, R1 denotes hydrogen or (C1-C6)-alkyl which can option-ally be substituted by amino, (C1-C6)-acylamino or benzoylamino, or (C2-C6)-alkenyl, (C3-Cg)-cyclo-alkyl, (C5-Cg)-cycloalkenyl, (C3-C7)-cycloalkyl-(C1-C4)-alkyl, (Cb-C12)-aryl or partially hydro-genated aryl, each of which can be substituted by (C1-C4)-alkyl, (C1 or C2)-alkoxy or halogen, or (C6-C12>-aryl-(C1 to C4)-alkyl or (C7-C13)-aroyl-(C1-C2>-alkyl, both of which care 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 particu-lar hydrogen, (C1-C3)-alkyl, (C2 or C3>-alkenyl, the optionally protected side-chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-aminobutyl or benzoylmethyl, R2 and R3 denote identical or different radicals hy-drogen, (C1-C6)-alkyl, (C2-C6)-alkenyl or (C6-C12)-aryl-(C1-C4)-alkyl, but in particular hydrogen, (C1-C4>-alkyl or benzyl, and R4 and RS have the abovementioned meaning.
If R1 represents a side-chain of a protected naturally occurring a-amino acid, such as, for example, protected Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or His, preferred protective groups are the groups customary in peptide chemistry (cf. Houben-Weyl, vol. XV/1 and XV/2). In the case where R1 denotes the pro-tected side-chain of lysine, the known amino protective groups are preferred, but in particular Z, Boc or (C1-C6)-alkanoyl. Suitable and preferred 0-protective groups for tyrosine are (C1-C6)-alkyl, in particular methyl or ethyl.
It is possible and particularly advantageous to use the following compounds according to the invention:
2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl7-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl7-S-1,2, 3,4-tetrahydroisoquinoline-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl7-S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanyll-(3S)-deca-hydroisoquinoline-3-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanyl7-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysyl7-(2S,3aS, 7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-lysyl7-(2s, 3aS,7aS>-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-methyl-S-tyrosylJ-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosyl7-(2S,3aS,7aS>-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-(3,4-dimethylphenylpropyl)-S-ala-nylJ-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-C1-S-carbethoxy-3-(4-fluorophenyl)-propylJ-S-alanylJ-(2S,3aS,7aS>-octahydroindole-2-carboxylic acid 1-CN-C1-S-carbethoxy-3-(4-methoxyphenyl)-propyl7-S-alanylJ-(2S,3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-C1-S-carbethoxy-3-(3,4-dimethoxyphenyl)-propyl7-S-alanylJ-(2S,3aS,,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-cyclopentylpropyl>-S-alanylJ-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aR, 7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-cyclohexylpropyl)-S-alanylJ-(2S, 3aR,7aS)-octahydroindole-carboxylic acid 1-CN-(1-S-carbesthoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR, 7aS>-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbeithoxy-3-cyclohexylpropyl)-S-lysylJ-(2S, 3aR,7aS)-octahydroindole-2-carboxylic~acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-(2S,3aS,7aR)-ocitahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aR, 7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR, 7aS>-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-cyclohexylpropyl)-S-alanylJ-(2S, 3aR,7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-0-ethyl-S-tyrosylJ-(2S,3aR,7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-(2S,3aS, 7aR)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid 1-CN-(1-S-carbevthoxy-3,4-dimethylphenylpropyl>-S-alanylJ-(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid 1-CN-C1-S-carbe~thoxy-3-(4-fluorophenyl)-propylJ-S-alanylJ-(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid 1-CN-C1-S-carbe~thoxy-3-(4-methoxyphenyl)-propylJ-S-alanylJ-(2S,3aS,7aS)-oc~tahydroindole-2-carboxylic acid 1-CN-C1-S-carbe~thoxy-3-(3,4-dimethoxyphenyl)-propylJ-S-alanylJ-(2S,3aS,,7aS)-octahydroindole-2-carboxylic acid 1-CN-(1-S-carbe~thoxy-3-cyclopentylpropyl>-S-alanylJ-(2S, 3aS,7aS)-octahydroindole-2-carboxylic acid 2-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.:5.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbe~thoxy-3-phenylpropyl)-S-lysylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carboxy-3-cyclohexylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-butyl)-S-alanylJ-cis-endo-2-aza-bicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-(3,4-dimethoxyphenylpropyl)-S-ala-nylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclopentylpropyl>-S-alanylJ-cis-endo-azabicyclo-C3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl>-0-methyl-S-tyrosyll-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-(4-fluorophenylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-(4-methoxyphenylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.3.OJoctane-3-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-(2S,3aR, 6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-lysylJ-(2S,3aR, 6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-(2S,3aR,6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyll-2-(2S,3aR, 6aS)-octahydrocyclopentaCbJpyrrole-2-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-2-aza-spiro-C4.SJdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl>-0-ethyl-2-tyrosylJ-2-azaspiro-C4.5Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysyll-2-azaspiro-C4.5Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl7-2-aza-spiroC4.5Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-lysylJ-2-aza-spiroC4.5Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-2-azaspiro-C4.47nonane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-:S-phenylpropyl)-0-ethyl-S-tyrosylJ-2-azaspiroC4.47nonane--3-S-carboxylic acid 2-CN-(1-S-carbethoxy-:S-phenylpropyl>-S-lysyll-2-azaspiro-C4.4Jnonane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-:i-cyclohexylpropyl)-S-alanyl7-2-aza-spiroC4.47nonane-3-S-c;arboxylic acid 2-CN-(1-S-carbethoxy-:S-cyclopentylpropyl)-S-alanylJ-2-aza-spiroC4.47nonane-3-S-c;arboxylic acid 2-CN-(1-S-carbethoxy-:S-cyclopentylpropyl)-S-lysyl7-2-aza-spiroC4.47nonane-3-S-c;arboxylic acid 1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-alanylJ-spiroCbi-cycloC2.2.17heptane-2,,3'-pyrrolidine7-5'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-phenylpropyl)-0-ethyl-S-tyrosyl7-spiroCbicycloC2.2.1Jheaptane-2,3'-pyrrolidinel-5'-S-car-boxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-spiroCbi-cycloC2.2.17heptane-2,.3'-pyrrolidineJ-5'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl)-S-alanylJ-spiro-CbicycloC2.2.17heptane~-2,3'-pyrrolidineJS'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl) -S-lysyl7-spiro CbicycloC2.2.1Jheptane~-2,3'-pyrrolidinel-5'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-alanyll-spiro-CbicycloC2.2.2.7octane~-2,3'-pyrrolidine7-5'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-phenylpropyl)-0-ethyltyrosylJ-spiro-CbicycloC2.2.27octane-2,3'-pyrrolidine7-5'-S-car-boxylic acid 1'-CN-(1-S-carbethoxy--3-phenylpropyl)-S-lysylJ-spiroCbi-cycloC2.2.27octane-2,'_i'-pyrrolidine7-5'-S-carboxylic acid 1'-CN-(1-S-carbethoxy--3-cyclohexylpropyl)-S-alanylJ-spiro-CbicycloC2.2.27octane-2,3'-pyrrolidine7-5'-S-carboxylic acid 2-CN-(1-S-carbethoxy-'_i-phenylpropyl>-S-alanylJ-2-azatri-cycloC4.3Ø16'97decane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-'_i-phenylpropyl)-0-ethyl-S-tyrosylJ-2-azatricycloC4.3Ø1E''9Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-LysylJ-2-azatri-cycloC4.3Ø16'9Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-2-aza-tricycloC4.3Ø16'9Jdecane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-2-aza-tricycloC4.3Ø16'9Jdecane-3-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-decahydro-cycloheptaCbJpyrrole-2-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-0-ethyl-S-tyrosylJ-decahydrocycloheptaCbJpyrrole-2-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-lysylJ-decahydro-cycloheptaCbJpyrrole-2-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl>-S-alanylJ-deca-hydrocycloheptaCbJpyrrole-2-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-deca-hydrocycloheptaCbJpyrrole-2-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-trans-octahydroisoindole-1-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-cis-octa-hydroisoindole-1-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-trans-octahydroisoindole-1-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-octahydroisoindole-1-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-cis-octa-hydrocyclopentaCcJpyrrole-1-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-octahydrocyclopentaCcJpyrrole-1-S-carboxylic acid benzyl ester 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-lysylJ-cis-octahydrocyclopentaCcJpyrrole-1-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-2,3,3a,4, 5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-lysylJ-2,3,3a,4, 5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-LysylJ-2-aza-bicycloC3.1.OJhexane-3-S-carboxylic acid 2-CN-(1-S-carboxy-3-p~henylpropyl>-S-lysylJ-2-azabicyclo-C3.1.OJhexane-cis-endo-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclopentylpropyl)-S-alanylJ-2-azabicycloC3.1.1)Jhexane-3-carboxylic acid 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.l.OJhexane-3-S-carboxylic acid 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-cis-endo-2-azabicycloC3.l.OJhexane-3-S-carboxylic acid 1'-CN-(1-S-carb~ethoxy-3-phenylpropyl>-S-alanylJ-(3'S,5'S)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid ' 1'-CN-(1-S-carb~ethoxy-3-phenylpropyl>-S-alanylJ-3'R,5'S>-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,S'R>-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-S'-carboxylic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'S,5'S)-spiro-bicycloC2.2.2Joctane,2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl>-S-alanylJ-(3'R,5'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl>-R-alanylJ-(3'S,5'S>-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'R,5'S>-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid ~~41 064 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-R-alanyl7-(3'S,5'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-lic acid 1'-CN-(1-S-carbethoxy-3-phenylpropyl>-R-alanyl7-(3'R,S'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-lic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'S,5'S)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-lic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanyl7-(3'R,5'S)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrol~idine-5'-carboxy-lic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'S,5'R>-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-lic acid 1'-CN-(1-R-carbethoxy-3-phenylpropyl)-R-alanylJ-(3'R,5'R)-spiro-bicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxy-lic acid These compounds can be prepared by, for example, the process described in German Patent Application P 33 33 455.2, in which the tert.-butyl or benzyl derivatives de-scribed in the application are converted in a known manner, by acid or alkaline hydrolysis or by hydrogenolysis cata-lyzed with noble metals, into the monocarboxylic acid derivatives. The N~-benzyloxycarbonyl protective group of the lysine derivatives is removed by 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 angio-tensin 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 of 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, European Patent A-79022, European Patent A-49658, European Patent A-51301, US Patent 4,454,292, US
Patent 4,374,847, European Patent A-72352, US Patent 4,350,704, European Patent A-50800, European Patent A-46953, US Patent 4,344,949, European Patent A-84164, US
Patent 4,470,972, European Patent A-65301 and European Patent A-52991. New compounds of the formula I are pre-pared in an analogous. manner.
Orally effective ACE inhibitors (some of the active com-pounds already mentioned above) are also advantageous, such as, for example,. ramipril, enalapril(f), captopril(a), lisinopril(g), cilazapril(o>, RHC 3659, CGS 13945, CGS
13928C(1>, CGS 14824A(h>, CI-906(j), zofenopril(e), foseno-pril(p), alacepril, (:I-925(k>, pentopril(q), CV 3317(m>, indolapril(h>, YS 980(b), fentiapril(c), pivopril(d), perindopril(i), and others. Orally effective ACE inhibi-tors are described in, for example, 8runner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) C19857 2-11.

- .24 -. . ~3 /~. 1~'t3 HS-CHZ CH-CO-N HS-CHZ-CH-CO-N
..
r~ ) t,~02H t b ) p02H
._ S : (ate )3-co-s-cH2-t~-oo- ~ , ta) Qi2-OOZH
tc) lN~ ~2H CH CH
~ 00-S-CN -CH-tb-1~1 ~ CH-NH- ~ 2 2~

p 1 ~ tf) t a 1 ~~2H ~3 ~2p2H5 -N
2H /~2~2 ~ ~ 00 H
~CH-NH -CH . .~
pf 1 1 H ~' 2 Z tJ
(CH2)~-NHZ . GpZH tg) ~i-NH-G' i p ru m r W

n . ~ .
w.
CO H ~~2~2 /

H ~-~-NH-~i 2 .~~3 ~3 2C2 5 ( i ) X~s H (j) X' = 3.4 ~CH3 (k) . . . . / ~ . . . ... . _ t~02H ~~Z~"~2 / ~ ~ ~ ~ .
. . ~'~-~ -'~- ~-NH-CH~~ZCHZ ~
~2C;rH5 ( 1 ) - - p~-pp H I I ~ ~ .
Z , ~ ~2c"ZH5 (m) ~/CN2CH2-~! ~ N .
~N p~
. x,~~ ~~"(Z 2""~
C N
225 . .
QpZH pp2C2H,5 ( o CHZ-OOZH . (n) .. . .
- OOZH , . .
I) . . .
1~1-00-CH -P-( ) ~ ~ ~ I v :, Z !i ~ ~~
.tt . '-_ . ~~ .,-~:~2H
. , ~. yC.CH-GI -CH
H3C~ ~~~i-OCO . . . O I . Z I .
~ ' ~H5 ~ ( ) . .~ , r ~ . ~2CZH5 . CH3 ~ . p (q) ~ X41 O6 4 The ACE inhibit~~rs which are disclosed in European Patent A-79022 and are of the formula III
Coox -N ~ IS) (SI (III) - ~H - 1NH - CH - CH2 - CH

in which R denotes hydro~~en, methyl, ethyl or benzyl, are pre-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 European Patent A-84164 and are of the formula IV
I~
COON (IV) IS) ~S) ~~'~c=c.H-NH-cH-cHZ-cH2 O C~H3 ~OOA~ ' in which R4 denotes hydrogen, (C1-C4)-alkyl or benzyl, in par-ticular the compound of the formula IV in which R4 denotes ethyl.
Furthermore, preference is given to 1'-CN-(1-S-carboethoxy-3-phenylpropyl)-S-alanylJ-exo- or endo-spirobicycLoC2.2.2Joctane-2,3'-pyrrolidin-5'-ylcar-boxylic acid anti isomers, and (S,S,S)-1-methyl-2-(1-car-bethoxy-3-phenyl.propyl)-2H-undecahydrocyclopentaC4.57-pyrroloC1,2-a7p;irazin~e-3,8-dione.
The invention also relates to new compounds of the formula II
~t R300C - ~ H - N' - ~ -~ CH - NH - CH - ( CH2 ) ri R ( I I ) R4 R5 0 R~ COOR2 a. in which 27 1 3 41 d 6 4 ' I.a) n is 1 or 2;
b) R 1. denotes hydrogen;
2. denotes alw;yl having 1-18 carbon atoms;
3. denotes an aliphatic acyclic radical of the for-mula CaH(2ai-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 rep-resents an even number 0 to (c-2);
5. denotes aryl which has b-12 carbon atoms and can be mono-, di- or trisubstituted by (C1-C8)-alkyl, (C1-C4)-alkoxy, hydroxyl, halogen, vitro, amino, aminomethyl, (C1-C4)-alkylamino, di-(C1-C4)-alkytamino, (C1-C4)-alkanoylamino, methylene-dioxy, carboxyl, cyano and/or sulfamoyl;
6. if n is 2, denotes (C6-C12)-aryl-(C1-Cg)-alkyl or di~-(C6-C12)-aryl-(C1-C8)-alkyl, each of which can be substituted in the aryl moiety as described under I.b)5; or 1. alkox;~ having 1-4 carbon atoms;
g, aryloxy which has 6-12 carbon atoms and can be substituted as described under I.b>5;
9. mono- or bicyclic heteroaryloxy or heteroaryl-(C1-Cog)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms repre-senting carbon and 1 to 2 ring atoms representing sulfur or oxygen and/or 1 to 4 ring atoms repre-senting nitrogen, and which can be substituted in the h~~teroaryl as described under I.b)5;
10. amino-(C1-C8)-alkyl;
11. (C1-C,;)-alkanoyl.amino-(C1-Cg)-alkyl;
12. (C7-C~~3)-aroylamino-(C1-Cg)-alkyl;
13. (C1-C,;>-alkoxycarbonylamino-(C1-C8)-alkyl;

14. (C6-C1;>>-aryl-(C1-C4)-alkoxycarbonylamino-(C1-Cg)-alkyl;

15. (C6-C1;~)-aryl-(C1-C4)-alkylamino-(C1-C8)-alkyl;

16. (C1-C4)-alkylamino-(C1-Cg)-alkyl;

17. di-(C1-C4)~alkylamino-(C1-Cg)-alkyl;

18. guanidino-(C1-Cg>-alkyl, 19. imidazolyl;

20. indolyl;

21. (C1-C4)-alkylthio;

22. if n is 2, (C1-C4>-alkylthio-(C1-Cg)-alkyl;

23. (C6-C12)-arylthio-(C1-Cg>-alkyl which can be substituted in the aryl moiety as described under I.b)5;

24. (C6-C12)-aryl-(C1-Cg)-alkylthio which can be substituted in the aryl moiety as described under I.b)5;

25. if n is 2, carboxy-(C1-Cg)-alkyl;

26. carboxyl;

27. carbamoyl;

28. if n is 2, carbamoyl-(C1-Cg)-alkyl;

29. (C1-C4)-alkoxycarbonyl-(C1-Cg)-alkyl;

30. if n is 2, (C6-C12>-aryloxy-(C1-Cg>-alkyl which can be substituted in the aryl moiety as described under I.b)5; or 31. denotes (C~-C12)-aryl-(C1-Cg)-alkoxy which can be substituted in the aryl moiety as described under I.b)5;

c) R1 denotes hydrogen;
1.

2. denotes alkyl having 1-18 carbon atoms;

3. denotes an acyclic aliphatic radical of the for-mula CaH(2a_b+1), in which double bonds, if their number exceeds 1, are not cumulative, a repre-sents 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 which c represents an integer 3 to 20, and d rep-resents an even number 0 to (c-2);
5. aryl which has 6-12 carbon atoms and can be sub-stituted as described under I.b)5;
6. (C6-C1z)-aryl-(C1-Cg)-alkyl or (C7-C13)-aroyl-(C1-Cg>-alkyl, both of which can be substituted as for aryl under I.b)5;
7. mono- or bicyclic, optionally partially hydrogen-ated, heteroaryl or heteroaryl-(C1-Cg)-alkyl which has 5-7 or 8-10 ring atoms respectively, up to 9 of these ring atoms representing carbon and 1 or 2 ring atoms representing sulfur or oxygen and/
or 1 to 4 ring atoms representing nitrogen, and which can be substituted in the heteroaryl as des-cribed for aryl under I.b)5; or 8. if not already covered by c) 1. - 8., the option-ally protected side-chain of a naturally occurring a-amino acid of the formula R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and 1. denote hydrogen;
2. alkyl having 1-18 carbon atoms;
3. denote an aliphatic acyclic radical of the for-mula CaH(2a_b+1), in which double bonds, if their number exceeds 1, are not cumulative, a represents an integer 2 to 18, and b represents an even number 2 to a;
4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula CcH(2c-d-1)~ which is optionally branched and in which c represents an integer 3 to 20, and d represents an even number 0 to (c-2);
5. di-(C1-C4)-a-lkylamino-(C1-Cg)-alkyl;
6. (C1-CS)-alkanoyloxy-(C1-C8)-alkyl;
7. (C1-C6>-alko~xycarbonyloxy-(C1-Cg)-alkyl;
8. (C7-C13)-aro~yloxy-(C1-Cg)-alkyl;
9. (C6-C12)-aryloxycarbonyloxy-(C1-Cg>-alkyl;
10. aryl having b-12 carbon atoms; or 11. denote (C7-G20)-aralkyl; it being possible for they radicals mentioned under d) 8., 9., 10.
and 11.. to be substituted in the aryl moiety as described under I.b)5; and e) R4 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 (C1-C4)-alkyl, (C1-t:4)-alkoxy, hydroxyl, halogen, vitro, amino, aminomethyll, (C1-C4)-alkylamino, di-(C1-C4)-alkyl.amino,, (C1-C4)-alkanoylamino, methylene-diox~~, 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 de-scribed under II.b)5.;
9. amino-(C1-i~4)-alkyl, 10. (C1-t:4)-alkanoylamino-(C1-C4)alkyl, 11. (C7-t:13)-aroylamino-(C1-C4)-alkyl, 12. (C1-C4)-allkoxycarbonylamino-(C1-C4)-alkyl, 13. (C6-t:12)-aryl-(C1-C4)-alkoxycarbonylamino (C1-t:4)-allkyl, 14. lC6-t:12)-aryl-(C1-C4)-alkylamino-(C1-C4>-alkyl, 15. (C1-C4)-alkylamino-(C1-C4)-alkyl, 16. di-(C1-C4)-alkylamino-(C1-C4)-alkyl, 17. guanidino-'(C1-C4)-alkyl, 18. imidazolyl, 19, indolyl;

20. (C1-C4)-alkylthio, 21. (C1-C4)-alkylthio-(C1-C4)-alkyl, 22. (C6-C12)-arylthio-(C1-C4)-alkyl which can be sub-stituted in the aryl moiety as described under II.b>5;

23. (C6-C12)-aryl-(C1-C4)-alkylthio which be can substituted in the aryl moiety as described under II.b)5;

24. carboxy-(C1-C4)-alkyl, 25. carboxyl, 26. carb~~moyl, 27. carb~~moyl-(C1-C4)-alkyl, 28. (C1-~:4)-alkoxycarbonyl-(C1-C4)-alkyl, 29. (C6-I:12>-aryloxy-(C1-C4)-alkyl which be sub-can stituted in the aryl moiety as described under II.b)5; or 30. (C6-I:12)-aryl-(C1-C4)-alkoxy vhich can sub-be stituted in the aryl moiety as described under II.b)5;

c) R1 denotes 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 4. alkyrnyl having 2-6 carbon atoms, 5. cycla~alkyl having 3-9 carbon atoms, 6. cycla~~alkenyl having 5-9 carbon atoms, 7. (C3-C9)-cyc;loalkyl-(C1-C4)-alkyl, 8. (C5-Cg)-cyc:loalkenyl-(C1-C4)-alkyl, 9. optionally partially hydrogenated aryl which has b-12 carbon atoms and can be substituted as de-scribed under II.b)5;
10. (C6-C12)-aryl-(C1-C4)-alkyl or (C7-C13)-aroyl-~ 341 O6 4 (C1 or C2)-alkyl, both of which can be substi-tuted in the aryl moiety as described under II.b)5;
11. mono- or bicyclic, optionally partially hydro-genated heteroaryl which has 5-7 or 8-10 ring atoms respectively, 1 to 2 of these ring atoms representing sulfur or oxygen atoms, and/or 1 to 4 of these ring atoms representing nitrogen atoms, and which can be substituted as described under II.b)5; or 12. if not embraced by the above definitions, the optionally protected side-chain of a naturally occurring a-amino acid of the formula R1-CH(NH2)-COOH;
d) R2 and R3 are identical or different and denote 1. hydrogen, 2. alkyl having 1-6 carbon atoms, 3. alkenyl having 2-6 carbon atoms, 4. di-(C1-C4)-alkylamino-(C1-C4)-alkyl, 5. (C1-C5>-alkanoyloxy-(C1-C4)-alkyl, 6. (C1-C6)-alkoxycarbonyloxy-(C1-C4>-alkyl, 7. (C7-C13)-aroyloxy-(C1-C4>-alkyl, 8. (C6-C12)-aryloxycarbonyloxy-(C1-C4)-alkyl, 9. aryl having 6-12 carbon atoms, 10. (C6-C12)-aryl-(C1-C4)-alkyl, 11. (C3-Cg>-cycloalkyl or 12. (C3-Cg)-cycloalkyl-(C1-C4)-alkyl, and e) R4 and R5 have the meaning defined under I.e), ~8. and compounds of the formula II 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;

_33_ 1341064 ' 5. aryl which has 6-12 carbon atoms and can be mono-, di- or trisub~stituted by (C1-C4)-alkyl, (C1-C4)-alkoxy, hydra~xyl, halogen, vitro, amino, amino-methyl, (C1-C4)-alkylamino, di-(C1-C4)-alkyl-amino, (C1-C4)-alkanoylamino, methylenedioxy, carboxyl, cyano and/or sulfamoyl;

6. alkoxy having 1-4 carbon atoms;

7. aryloxy which has 6-12 carbon atoms and can be sub-stituted as described under e.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 vhich can be substituted as de-scribed under B.b)5;

9. amino-(l:1-C4)~-alkyl;

10. (C1-C4)--alkanoylamino-(C1-C4)-alkyl;

11. (C7-C13)-aroylamino-(C1-C4)-alkyl;

12. (C1-C4)-~alkox;~carbonylamino-(C1-C4>-alkyl;

13. (C6-C12)~-aryl-(C1-C4)-alkoxycarbonylamino-( C 1-C4)-.alkyl ,:

14. (C6-C12)-aryl"(C1-C4)-alkylamino-(C1-C4)-alkyl;

15. (C1-C4)-~alkylamina-(C1-C4)-alkyl;

16. di-<C1-C4)-alkylamino-(C1-C4)-alkyl;

17. guanidino-(C1--C4)-alkyl;

18. imidazolyl;

19. indolyl;

20. (C1-C4)-alkylt:hio;

21. if n is 2, lC~~-C4)-alkylthio-(C1-C4)-alkyl;

22. (C6-C12)-arylt:hio-(C1-C4)-alkyl which can be substituted in the aryl moiety as described under B.b)5;

23. (Cb-C12)-aryl-U C1-C4)-alkylthio which can be substituted in the aryl moiety as described under 8.b)5;

24. if n is 2, carboxy-(C1-C4)-alkyl;

25. carboxyl;

26. carbamo;~l;
27. if n is 2, carbamoyl-(C1-C4)-alkyl;
28. (C1-C4)~-alkoxycarbonyl-(C1-C4)-alkyl;
29. if n is 2, (C6-C12)-aryloxy-(C1-C4)-alkyl which S can be ;substituted in the aryl moiety as described under B.b)5; or 30. (C6-C12)-aryl-(C1-C4)-alkoxy which can be substi-tuted in the aryl moiety as described under B.b>5;
c) R1 represents the side-chain of valine, leucine, norvaline, n~~rleucine, methionine, ornithine, cyclo-hexylalanine, 2-thienylalanine, 3-thienylalanine, 0-(C3-C5)-alkyltyrosine, isoleucine, isovaline or C-phenylglycine;
d) R2 and R3 are identical or different and denote 1. hydrogen;
2. alkyl having 1-6 carbon atoms;
3. alkenyl having 2-b carbon atoms;
4. di-(C1-C4)-alkylamino-(C1-C4>-alkyl;
5. (C1-C5)-alkanoyloxy-(C1-C4)-alkyl;
6. (C1-C6)-alkoxycarbonyloxy-(C1-C4)-alkyl;
7. (C7-C13)-aroyloxy-(C1-C4)-alkyl;
8. (C6-C1Z)-aryloxycarbonyloxy-(C1-C4)-alkyl;
9. aryl having 6-12 carbon atoms;
10. (C6-C12)-aryl-(C1-C4)-alkyl;
11. (C3-C9)-cycloalkyl; or 12. (C3-C9)-cycloalkyl-(C1-C4)-alkyl, and e) R4 and RS have the meaning defined under A.I.e), and their physiologically tolerated salts, or C. in which a) n, R, R4 and RS are as defined above under B. and b) R1 represents the side-chain of alanine, lysine or e-acyllysine, and c) R2 and R3 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, cyclohexenyl, cycloheptenyl, 1 341 06 4 ' phenyl, a- or S-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, benzhydryl, a-methyl-benzyl, a-methylenebenzyl, 2-, 3- or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, being substituted as defined, where appropriate, under A.II.b)5, or one of the radicals R2 and R3 denotes hydrogen, and the other is as defined above, or R2 represents benzyl, and R3 represents benzyl, hydrogen ~or one of the abovementioned definifiions, and their physiologically tolerated salts.
R4 and R5 form, together with the atoms carrying them, preferably a mono-, bi- or tricyclic hetero-cyclic ring system which has 3 to 15 ring carbon atoms and up to 2, preferably up to 1, ring sulfur atoms) and up to 1, preferably no, additional ring nitrogen atom, preferably from the series comprising pyrrol-idine, thiazolidine, tetrahydroisoquinoline, deca-hydroisoquinoline, octahydroindole, indoline, octa-hydrocyclopentaCbJpyrrole, 2-azaspiroC4.5Jdecane, 2-azaspiroC4.4Jnonane, spiroC(bicycloC2.2.1Jheptane)-2,3'-pyrrolidineJ, spiroC(bicycloC2.2.2Joctane-2,3'-pyrrolidineJ, 2-azatricycloC4.3Ø16'9Jdecane, deca-hydrocycloheptaCbJpyrrole, octahydroisoindole, octa-hydrocyclopentaCcJpyrrole, 2,3,3a,4,5,7a-hexahydro-indole, 1,2,3,3a,4,5a-hexahydrocyclopentaCbJpyrrole and 2-azabicycloC3.1.OJhexane.
Suitable salts of the compounds of the formulae I and II
are, depending on the acidic or basic nature of these com-pounds, alkali metal or alkaline earth metal salts or salts with physiologically tolerated amines, or salts with inor-ganic or organic acids such as, for example, HCI, HBr, H2S04, malefic 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 capillaries are surrounded by a layer of endothelial cells which are partic;ularl;y 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 surround-ing tissue than is the case for the remainder of the body.
Hence the preferred compounds of the formula II are those in which at least one of the radicals R, R1, R2 and R3 represents a lipophilic radical, such as a long-chain ali-phatic, alicyclic-aliphatic, araliphatic or heteroaraliph-atic radical, a sufficiently large alicyclic radical, or an appropriately substituted alicyclic, aromatic or hetero-aromatic radica~'~, 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 (C~~-C1g)-alkyl;
1.

2. (C~l-C1g)-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.l.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-(CS-Cg)-alkyl;

8. amino-(C5-Cg>-alkyl;

9. (C1-C4)-alkanoylamino-(CS-Cg)-alkyl;

10. (C7-C13)-aroylamino-(CS-Cg)-alkyl;

11. (C1-C4)-alkoxycarbonylamino-(CS-Cg)-alkyl;

12. (C6-C12>-aryl-(C1-C4)-alkoxycarbonylamino-(CS-C8)-alkyl;

37 - 1 341 06 4, 13. (C6-C12)-aryl-(C1-C4)-alkylamino-(CS-C8)_ alkyl;

14. (C1-C4)-alkylamino-(CS-C8)-alkyl;

15. di-(C1-C4)-alkylamino-(CS-Cg)-alkyl;

16. guanidino-(CS-C8)-alkyl;

17. if n is 2, (C1-C4)-alkylthio-(CS-Cg)-alkyl;

18. (C6-C12)-arylthio-(CS-C8)-alkyl which can be substituted in the aryl moiety as de-s~:ribed above under A.I.b)5;

19. (Cb-C12)-aryl-(CS-Cg)-alkylthio vhich can bra substituted in the aryl moiety as de-scribed above under A.I.b)5;

20. i1f n is 2, carboxy-(CS-Cg)-alkyl;

21. i:E n is 2, carbamoyl-(C5-C$)-alkyl;

22. (I:1-C4)-alkoxycarbonyl-(CS-C4)-alkyl;

23, iif n is 2, (C6-C12)-aryloxy-(C5-C8)-alkyl which can be substituted in the aryl moiety a:. described above under A.I.b>5; or 24. ((:6-C12)-aryl-(CS-C8)-alkoxy Which can be substituted in the aryl moiety as described above under A.I.b)5.

Additional comF~ounds of the formula II which are suitable are those in which R1 denotes 1. (C7-Cl~g)-alkyl;
2. (C7-Cl~g>-alkenyl;
3. (C7-C1~;)-alkynyl;
4. ai radical which has 4-18 carbon atoms and is clefine~i as above under A.I.c)3. and in which 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-a~lkenyl~ having up to 9 carbon atoms;
6. optionally substituted (C6-C12)-aryl-(C5-C8;1-alkyl;
7. optionally substituted (C7-C13)-aroyl-(C3-Cg;l-alkyl or 8. optionally substituted heteroaryl-(C1-C8)-alkyl, and those compounds of the formula II in which R1 represents the side-chain of valine, leucine, norvaline, norleucine, methionine, ornithine, cyclohexylalanine, 2-thienylalanine, 3-thienylalanine, 0-(C3-C5>-alkyltyrosine, isoleucine, isovaline or C-phenylglycine.
R2 and R3 are then identical or different and preferably denote 1. (C7-C1g>--alkyl;
2. (C7-C18)--alkenyl;
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 (C3-C9)-cycloalkyl and (C3-Cg)-cyclo-alkyl-(Cy-C4)-alkyl;
5. di-(C1-Cat)-alk;ylamino-(C5-Cg)-alkyl;
6. (C1-CS>-alkano;yloxy-(C5-Cg)-alkyl;
7. (C1-C6)-alkoxycarbonyloxy-(C5-C8)-alkyl;
8. (C7-C13)--aroyloxy-(C5-Cg)-alkyl;
9. (C6-C12)--arylo:xycarbonyloxy-(C5-C8)-alkyl;
10. (C16-C20%'-arallkyl;
it being possible for the radicals mentioned under d)8., 9.
and 10. to be substituted in the aryl moiety as described above under A.I.~b)5.; or one of the radicals R2 and R3 denotes hydrogen and the other is as defined above.
In addition, preferred compounds of the formula II are those in which F;2 and R3 are identical or different and denote propyl, isopropyl, n-butyl, isobutyl, sec.-butyl, n-pentyl, sec.-pentyl,, isopentyl, neopentyl, n-hexyl, iso-hexyl, cyclobuty~l, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, menthyl, phenyl, a- or S-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, be~nzhydn~yl, a-methylbenzyl, a-methylenebenzyl, 2-, 3- or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl, with phenyl, and phenyl as a part-structure of one of the said radicals, optionally being substituted as defined above under A.I.b)5., or one of the radicals R2 and R3 denotes hyclrogen and the other is as defined above, or R2 represents benzyl, and R3 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 appro-priate 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, elim-inating protective groups which have been introduced tempo-rarity to protect reactive groups, esterifying, where appro-priate, compounds of the formula II having one or more free carboxyl groups, and converting, where appropriate, the re-sulting 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.
R300C-Cli-l~-H HOOC-CH-AH-CH-( CH ) R
R~~ R5 R~ COOR2 2 ri (9) (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, CH2Cl2 or DMA in the pre-sence 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 acti-vated with tetraethyl diphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformic esters), azides or carbo-diimide derivatives and thus activated (cf. Schroder, Lubke, 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.
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-Chi-N-~;-C~Ii-Y1 Y2-CH-(CH2)ri R

(VII) (VIII) ;r, ~h;rh either Y1 represents amino and Y2 represents a leaving group, or Y1 represents a leaving group and YZ
represents amino. Examples of suitable leaving groups are Cl, Br, I, alkylsulfonyloxy or arylsulfonyloxy.
Alkylations of this type are expediently carried out in water or an organic solvent such as a lower aliphatic alcohol (such as ethanol>, benzyl alcohol, acetonitrile, nitromethane or glycol ethers, at a temperature between -20°C and the boiling point of the reaction mixture, in the presence of a base such as an alkali metal hydroxide or an organic amine.
Furthermore, it is possible to condense compounds of the formula IX with compounds of the formula X
R300C-CFi-N-C~-C-=Q~ Q2sC-( CH ) -R
~~~ R5 0 R1 COOR22 n (7:R) (x) in which either 41 represents amino + hydrogen and 42 represents oxo, or 41 represents oxo and 42 represents amino + hydrogen. The condensation is expediently carried out in water or an organic solvent such as a lower alipha-tic alcohol, at a temperature between -20°C and the boiling point of the reactions mixture, in the presence of a reducing ~ 341 O6 4 agent, such as NaBH3CN, compounds of the formula I being obtained directly. However, it is also possible to reduce Schiff's bases or enamines which are produced as inter-mediates, where appropriate after previous isolation, with the formation of compounds of the formula II, for example by hydrogenation in the presence of a transition metal catalyst.
Finally, reaction of compounds of the formula IX (41 -H + NH2) with compounds of the formula XI, or their reac-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, also results in compounds of the formula II (n = 2), R200C~-CH=CH-COR (%I ) .
OCH-C00R2 (%II ) R-CO-t:H3 (%II I ) with Schiff's bases which have been produced as inter-mediates being reduced as described above, and a carbonyl group being converted by reduction (for example with a complex hydride) into methylene.
In the abovementioned formulae V - XIII, R - RS and n are as defined in formula II. Protective groups temporarily introduced to protect reactive groups not involved in the reaction are eliminated in a manner known per se after the reaction is complete (cf. Schroder, Lubke, l~oc. cit., pages 1 - 75 and 24b - 270; Greene, "Protective Groups in Organic Synthesis", New York 1981).
The new compounds of the general formula I or II can also be prepared, for example, using methods of esterification familiar to the expert (see, for example, Buchler, Pearson, Survey of Organic Syntheses, vol. 1, New York 1970, pages 1 341 d6 4 802 - 825; Hoube~n-Weyl, Methoden der Organischen Chemie, (Methods of Organic Clhemistry), volume E5, 1985, pages 656 - 773).
a) Reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R2 and R3 denotes hydrogen with an appropriate alcohol with acid catalysis (mineral acid or acid ion exchanger).
b) Alkylation of a mono- or dicarboxylic acid of the gen-eral formula I or II in which at least one of the radi-cals R2 and F;3 denotes hydrogen with a compound R2Z or R3Z, in which Z denotes a leaving group which can be displaced nuc:leophilically (such as halogen, tosylate>, in a polar erotic or Bipolar 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 formula I or II in which at least one of the radicals R2 and R3 denotes hydrogen with a diazoalkene in an inert organic. solvent such as CH2Cl2.
The cognition adjuvant action of the compounds according to the invention has been tested in the inhibitory (pas-sive) avoidancer test (step-through model) in mice having a body weight of 20-25 g. A modified form of the test method describerd by .J. KOPP, Z. BODANECKY and M.E. JARVIK
has been described by J. BURES, 0. BURESOVA and J. HUSTON
in "Techniques and B~~sic Experiments for the Study of Brain and BehaL~ior", Elsevier Scientific Publishers, Amsterdam (198'_.).
According to the statements in this literature, a sub-stance is said to have cognition adjuvant activity when it is able to abolish the amnesia induced in the experimental animals by an erlectroconvulsive shock or the amnesia in-duced by scopolamine.

1 3t~~ p6 4 The experiments were carried out by modified test methods.
The comparison compound used was the known cognition ad-juvant 2-oxo-1-pyrrolidinylacetamide (piracetam). The marked superiority of the compounds according to the in-s vention over the comparison substance was evident from the fact that the scopolamine-induced amnesia in the inhibi-tory 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-pounds accordin~~ 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 dementia.
Hence the invention also relates to the use of the com-pounds accordin~~ 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 compaunds according to the invention for the preparation of medicaments which can be used for the treatment and prophylaxis of the abovementioned diseases.
It is possible, in practicing the method according to the invention, to u:,e the angiotensin converting enzyme in-hibitors which :ire described above in mammals such as monkeys, dogs, cats, rats, humans etc.
The medicaments are prepared by processes which are known per se and fami~Liar to those skilled in the art. The ~ 341 06 4 ' pharmacologically active compounds (= active compound) according to the invention are used as medicaments either as such or, preferably, combined with suitable pharma-ceutical auxiliaries, in the form of tablets, coated tablets, capsules, suppositories, emulsions, suspensions or solutions, the content of active compound being up to about 95%, preferably between 10 and 75%.
The auxiliaries suitable for the desired medicament for-n~ulation are familiar to those skilled in the art by reason~of their expert knowledge. Apart from solvents, gel-forming agents, suppository bases, tabletting auxi-liaries and other active compound vehicles, it is pos-sible to use, for example, antioxidants, dispersing 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 or subcutaneously>, oral administration being preferred.
For a form for oral use, the active compounds are mixed with the additives suitable for this purpose, such as excipients, stabilizers or inert diluents, and converted by the customary methods into suitable presentations such as tablets, coated tablets, hard gelatin capsules, aqueous, alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. Examples of inert vehicles which can be used are gum arabic, magnesia, magnesium carbonate, lac-tore, glucose or starch, in particular corn starch. This formulation can take the form of dry and of moist gran-ules. Examples of suitable oily excipients or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil.
For subcutaneous or intravenous administration, the active compounds or their physiologically tolerated salts are converted into solutions, suspensions or emulsions, if appropriate with the substances customary for this purpose ~ 349 064 such as solubilizers, emulsifiers or other auxiliaries.
Examples of suitable solvents are water, physiological saline solution or alcohols such as ethanol, propanol, glycerol, and in addition also sugar solutions such as glucose or mannitol solutions, as well as a mixture of the various solvents mentioned.
The following examples 1-6 indicate the forms used for the prophylaxis and treatment of cognitive dysfunctions by the method according to the invention. The compounds accord-ing~to the invention can be converted into the appropriate use forms in analogy to the examples.
Example 1 Preparation of the agent used according to the invention for oral use in the treatment and prophylaxis of cognitive dysfunctions.
1000 tablets each containing 10 mg of 2-CN-(1-S-carbethoxy-3-phenylpropyl>-S-alanylJ-1S,3S,5S-2-azabicycloC3.3.OJ-octane-3-carboxylic acid are prepared using the following auxiliaries:
2-CN-(1-S-carbethoxy-3-phenylpropyl)- 10 g S-alanylJ-(1S,3.S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid corn starch 140 g gelatin 7.5 g microcrystallin~e cellulose ~ 2.5 g magnesium stearate 2.5 g 2-CN-(1-S-Carbethoxy-3-phenylpropyl>-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJactane-3-carboxylic acid and corn starch are mixed with .an aqueous gelatin solution. The mixture is dried and milled to form granules. Microcrystalline cellu-lose and magnesium stearate are mixed with the granules.

~ 341 06 4 The resulting granules are compressed to form 1000 tab-lets, each tablet containing 10 mg of the ACE inhibitor.
These tablets can be used for the treatment and prophy-laxis of cognitive dysfunctions.
Example 2 In analogy to Example 1, 1000 tablets each containing mg of 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-10 (3'S,5'S)-spirobicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid are prepared.
Example 3 Gelatin capsules each containing 10 mg of 1'-CN-(1-S-carb-ethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-spirobicyclo-C2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid are filled with the folla~Wing mixture:
1'-CN-(1-S-Carbethoxy-3-phenylpropyl)-S-alanylJ-(3'R,5'S)-spirobicycloC2.2.2Joctane-2,3'-pyrrolidine-5'-carboxylic acid 10 mg Magnesium stearate 1 mg Lactose 214 mg These capsules can be used for the treatment and prophy-laxis of cognitive dysfunctions.
Example 4 The preparation of an injection solution is described below:
2-CN-(1-S-Carboxy-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-2-carb-oxylic acid 250 mg Methylparaben 5 g Propylparaben 1 9 Sodium chloride 25 g Water for injections 5 l 2-CN-(1-S-Carboxy-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid, the preserva-tives and sodium chloride are dissolved in 3 l of water for injections, and the solution is made up to 5 l with water for injections. The solution is filtered sterile and dispensed aseptically into presterilized vials, which are closed with sterilized rubber caps. Each vial con-tains 5 ml of solution.
Example 5 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-alanylJ-(1S,3S,5S>-2-azabi-cycloC3.3.OJoctane-3S-carboxylic acid use is made of 2-CN-(1-S-carboxy-3-phenylpropyl>-S-alanylJ-(1S,3S,5S)-2-azabi-cycloC3.3.Oloctane-3-carboxylic acid or 1-CN-(1-S-carboxy-3-phenylpropyl)-S-alanylJ-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid or 1-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyll-cis-2,3,3a,4,5,7a-hexahydroClHJindole-2-S-endo-carboxylic acid or 1-tN-(1-S-carboxy-3-phenylpropyl)-S-alanylJ-cis-2,3,3a,4,5,7a-hexahydroClHJindole-2S-endo-carboxylic acid or 2-CN-(1-S-carboxy-3-phenylpropyl)-S-lysylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid or 2-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanylJ-1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid or N-(1-S-carboxy-3-cyclohexylpropyl>-S-lysyl-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid or 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-exo-spirobicyclo-C2.2.2Joctane-2,3'-pyrrolidin-5'-S-ylcarboxylic acid or (S,S,S)-1-methyl-2-(1-carbethoxy-3-phenylpropyl)-2H-un-decahydrocyclopentaC4.5JpyrroloCl,2-aJpyrazine-3,8-dione or 1'-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanylJ-endo-spirobicycloC2.2.2Joctane-2,3'-pyrrolidin-5'-S-ylcarb-oxylic acid.

- ~ 3 4 1 0' 6 4 Example 6 An injection sa~lution is prepared in analogy to the pro-cedure described in Example 4 with the exception that in place of 2-CN-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl7 (1S,3S,5S)-2-azabicyc;loC3.3.07octane-3-carboxylic acid use is made of 2-CN-I.1-S-carboxy-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylic acid or 1-CN-(1-S-carbethoxy-~3-phenylpropyl>-S-alanylJ-(2S,3aR, 7aS)-octahydroindole-~2-carboxylic acid hydrochloride or 1-CN-(1-S-carboxy-3-p~henylpropyl)-S-alanyl7-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid or 1-CN-(1-S-carbethoxy-3-cyclohexylpropyl)-S-alanyl7-cis-2,3,3a,4,5,7a-hexahydro-C1H7indole-2-S-endo-carboxylic acid or 1-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl7-cis-2,3,3a,4,5,7a-hexahydroClH7-indole-2-S-endo-carboxylic acid or 2-CN-(1-carboxy-3-phenylpropyl)-S-lysyl7-(1S,3S,5S)-2-azabicycloC3.3.07-octane-3-carboxylic acid or 2-CN-(1-S-carbethoxy-3-cyclo-hexylpropyl)-S-alanyl7-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylic acid or 2-CN-(1-S-carboxy-3-cyclohexylpropyl>-S-lysyl7-(1S,3S,,5S)-2-azabicycloC3.3.117octane-3-carboxylic acid or 1'-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl7-endo-spirobicycloC2.~?.27octane-2,3'-pyrrolidine-5'-S-carboxylic acid or 1'-CN-(1-S-carboxy-3-phenylpropyl)-S-alanyl7-exo-spirobicycloC2.~'_.27octane-2,3'-pyrrolidine-5'-S-carboxylic acid.
The Examples which now follow are intended to illus-trate the proce::s according to the invention for the prepa-ration of the nelw compounds of the formula I and II , with-out confining the inmention to them.
Example 7:
Octadecyl 2-CN-(1S)-ethoxycarbonyl-3-phenylpropyl-S-alanyl7-cis,endo-2-azabicycloC3.3.07octane-3-S-carboxylate 23 g of octadecyl cis"endo-2-azabicycloC3.3.07octane-3-carboxylate prepared in analogy to European Patent A-79022 are reacted with 6.7 g of H08t, 13.8 g of N-(1S)-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 is filtered off with suction, the filtrate is concentrated, the residue is taken up in 1 l of ethyl acetate, and the solution is extracted by shaking with 3 x 500 ml of 5%
strength NaHC03 solution. The organic phase is concen-trated and chromatographed on a column of 1 kg of silica gel with ethyl ~~cetate/petroleum ether in the ratio 2:1, and in this way is :,eparated into the title compound and the diastereomeric (S,S,R) compound.
Example 8:
1-CN-(1S)-Dodec;~loxycarbonyl-3-phenylpropyl-S-alanyll-2S, 3aR,7aR-octahydn~oindole-2-carboxylic acid a) 8enzyl 1-CN-(1S)-dodecyloxycarbonyl-3-phenylpropyl-S-alanylJ-2S,3~~R,7aR-octahydroindole-2-carboxylate 10 mmol of benzyl S-alanyl-2S,3aR,7aR-octahydroindole-2-carboxylate '(prepared as in European Patent A-84164) are dissolved in 30 ml of anhydrous ethanol. Ethanolic potas-sium hydroxide is used to adjust the pH of the solution to 7.0, and t g of powdered molecular sieve (4A), and then 10 mmol of do~decyl 2-keto-4-phenylbutyrate, are added. A so~'~.utian of 1 g of sodium cyanoborohydride in 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/watei~. After the ethyl acetate phase has been 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 20-25oC undei~ atmospheric pressure. After the catalyst os has been removed, 0.5 N ethanolic hydrogen chloride is added to the solution until it gives an acid reaction.
The solution is concentrated in vacuo, and the residue is crystallized by trituration with diisopropyl ether.
Example 9:
Isobutyl 2-CN-C(2S)-ethoxycarbonyl-3-phenylpropylJ-L-alanylJ-(1S,3S,'.iS>-2-azabicycloC3.3.OJoctane-3-carboxylate 2.00 g (4.80 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-propylJ-L-alanyl~J-(1S,3S,5S>-2-azabicycloC3.3.OJoctane-3-carboxylic acid were dissolved in 100 ml of isobutanol, 0.1 ml of concentrated sulfuric acid was added, and the mixture was boin,ed under reflux for 15 hours. After cool-ing, the solvewt was removed in a rotary evaporator, and the residue was taken up in methylene chloride. This sol-ution was washed once with water, once with saturated aqueous NaHC03 :~oluti~on and again with water, dried over MgS04, and conc~antrat~ed, and impurities were removed by chromatography on 200 g of silica gel (mobile phase methylene chloridelethyl acetate 8:2).
Yield: 51% of theory ~of oily product.
CaJpO = -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-propyl ether.
data on the hydrochloride:
Melting point 1.?3- 124°C
CaJpO = +17.7° '(c - 1, methanol) Example 10:
Benzhydryl 2-CN-C(1S>-ethoxycarbonyl-3-phenylpropylJ-L-alanylJ-(1S,3S,!iS)-2-azabicycloC3.3.OJoctane-3-carboxylate 2.07 g (4.97 mmol) of 2-CN-C(1S)-ethoxycarbonyl-3-phenyl-propylJ-L-alanylJ-(1S,3S,5S>-2-azabicycloC3.3.OJoctane-3-1341064-' carboxylic acid were dissolved in 50 ml of acetone and, while cooling i~n ice, a solution of 1.16 g (5.98 mmol) of diphenyldiazomethane in 50 ml of acetone was added dropwise.
The solution was then stirred at room temperature for 26 hours, the solvent was evaporated off in a rotary evapo-rator, and the residue was purified by flash chromatography on 150 g of silica gel (mobile phase toluene/ethanol 98:2).
Yield: 2.55 g (B8 %) of oily product Ca7p0 - -33.8° Cc - 1, methanol>.
Example 11:
Octadecyl 2-CN-C(1S)-ethoxycarbonyl-3-phenylpropyl7-L-alanyll-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate 2.08 g (5.00 mmol) of 2-CN-C(1S>-ethoxycarbonyl-3-phenyl-propyl7-L-alanyl7-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylic acid were dissolved in 25 ml of absolute dimethyl-formamide, 1.00 g (10.0 mmol) 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-methylformamide 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 or-ganic phase was separated off, dried over MgS04 and concen-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).
Ca7p0 = -19.6° Cc - 1, methanol) Example 12:
8enzyl 2-CN-C(1S)-benzyhydroloxycarbonyl-3-phenylpropyl7-L-alanyl7-(1S,3S,5S)-2-azabicycloC3.3.Oloctane-3-carboxylate a) eenzhydryl (2R)-hydroxy-4-phenylbutyrate A solution of 10.1 g (52.1 mmol) of diphenyldiazomethane in 400 ml of absolute acetone was added dropwise over 20 minutes t~ a solution of 7.40 g (41.1 mmol) of (2R)-hydroxy-4-phenylbutyric acid in 200 ml of absolute ace-tone while cooling in ice, and the reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated off, and the residue was triturated with 100 ml of petroleum ether. 6.4 g of crystalline product were obtained. The mother liquor was concentrated, and a further 6.0 g of the product were isolated by column chromatography on 700 g of silica gel (mobile phase toluene/ethanol 99:1).
Total yield: 12.4 g (87 %).
Melting point 88 - 89°C.
CaJpO - -1.8° (c - 5, methanol).
b) Benzyl 2-CN-C(1S)-benzhydryloxycarbonyl-3-phenylpropylJ-L-alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxy-late b1) 1.80 g (4.33 mmol) of benzyl 2-(N-tert.butoxycarbonyl-L-alanyl)-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-car-boxylate were dissolved in 4.5 ml of trifluoroacetic :ZO 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-ZS alanyl)-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxy-late trifluoroacetate, was dissolved in 10 ml of abso-lute methylene chloride (solution A).
b2) 1.63 g (4.71 mmol) of benzhydryl (2R)-hydroxy-4-phenyl-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 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 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 for 19 hours, then washed three times with water, dried over MgS0~4 and concentrated. The residue was purified by chromatography on 80 g of silica gel (mobile phase cyclohexane/ethyl acetate 8:2 and 7:3), and 0.95 g (30%) of the desired product was obtained.
Melting point 81-85oC.
CaJpO = -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 to that for the compounds of the general formulae I and II):

1~41~64 R300C - ~H - t - C --~H - FA - CH - CH2 - CH2 R4 ~t5 0 CH COOR2 R300C-~A-Nf-E x a m p l a R4 Ft5 R2 R3 13a Ring system- A -C2A5 -CH(CH3)2 14 Ring system H -C2H5 -CH2-CH(CH3)2 15 Ring system C -CH3 -CH2 16 Ring systee C -C2H5 -CH(C6H5)2 1? Ring system D -C2H5 -Q

18 Ring system'D -C2H5 -_ 19 Ring system D -C2H5 _.-_ 20 Ring system D -C2H5 0 21 Ring system D -C2H5 * 22 Ring system D -C2H5 -(CH2)3 23 Ring system E -C2H5 -(CH2)5-CH3 24 Ring system F -CH3 -CH(C6H5)2 25 Ring system d -C2H5 -CH(CH3)2 -_ 26 Ring system t3 -C2H5 CH(C6H5~2 * [a]p= -21.5° [c=1, CH3nH]

R300C - C' H - » - ~~ ~ I H ~ - ~A - CH2 - CH2 /
R4 ~t5 0 CH3 COOR2 R300C-~A-t~-E x a m p l a R4 135 R2 R3 2T Ring systern 0 -C2H5 '(CH2)2~
28 Ring system H C2H5 CH(CH3)2 29 Ring systern H C2H5 CH2 CH(CH3)2 30 Ring system H C2H5 -(CH2)5 CH3 3~ Ring system H C2H5 ~r 32 Ring system H C2H5 -~-CH3 33 Ring systernH C2H5 -34 Ring - H C2H5 0 0 systern 35 Ring systernA H -CH2-O

36 Ring systernH C2H5 CH(C6H5)2 r 3? Ring system H C2H5 -(CH2)8~

38 Ring systam I CH3 39 Ring system J C2H5 -CH(C6H5)2 r 40 Ring system K C2H5 -(CH2)4 CH3 _ 41 Ring systern- C2H5 -C(CH3)3 Ir , 1 341 Ofi 4 _ R300C - C H - 1Q - C ~-CH - NH - ~H - CH2 - CH2 r R4 1~5 ~ CH3 COOR2 R300C-CH-lT-E x a m p l a R4 1~5 R2 R3 42 Ring system M C2H5 -(CH2)2-CH(CH3)3 43 Ring system. A C2H5. -CH(4-F-C6H4)2 44 Ring system_~ 1~ C2H5 -CH(CH3)2 45 Ring system 0 C2H5 -(CHZ)2-46 Ring system p C2H5 --4T Ring system Q C2H5 __ 48 Ring system _ CH2CH(CH3)2 -CH2-~
A

49 Ring system H CH(CH3)2 -C(CH3)3 50 Ring system C CH(C6H5)2 -H

51 R i s y s D CH2 -CH2-n g t a m .

* 52 Ring system D CH2-CH(CH3)2 -CA2 ir*
53 Ring system D CH2 CH(CH3)2 -H
_ 54 Ring system - CH2-CH(CH3)2 -CH(C6H5)2 D

55 Ring system. D CH(C6Ii5)2 -C(CH3)3 56 Ring system D CH(C6A5)2 -H
* [aJ~ _ -39.3° [c=1, CH30H]
** [aJ n° _ +2.2° [c=1, CH~O:H]; mp:162-163°C

R300C - CH - 'N - C -~A - NH - ~H - CA2 - CA2 ~ \
R4' R5 0 CA3 COOR2 R300C-CH-;N-Example 5? Ring system E --~--CA3 -(CA2)5-CH3 58 Ring system E -CAZ CA(CA3)2 -CA(4-F-C6A4)2 59 Ring system G -CA(C6A5)2 -CA2 60 Ring system G -CA(C6A5)2 -C(CA3)3 - _ 61 Ring system A -CA2CA(CA3)2 -CH2-O

62 Ring system H -CH2CA(CA3)2 H

63 Ring system H -CH2CH(CH3)2 -CH(C6A5)2 --64 Ring system H -CH2-O -CH2 _ 65 Ring system - -CH2 -C(CH3)3 H

66 Ring system Ii -CA(C6A5)2 -CH2 6T Ring system H -CA(C6A5)2 -A

68 Ring system A -CH(C6A5)2 -C(CH3)3 69 Ring system A -CA(C6A5)2 -CH(C6H5)2 'l0 Ring system I -~ ~ 0 Z1 Ring system J -(CA2)5-CA3 -CA(CSAS)2 ~ 349 06 4 _ 5g R300C - FA - N - C -CH - NH - ~H - CH2 - CH2 R4 R5 0 CHj COOR2 R300C- 'H-N-E x a m p l a ~~4 R5 R2 Rj ?2 Ring system K ~ -CH2 ?3 Ring system '~ -CH2)2 -(CH2)5-CHj ?4 Ring system M -(CH2)2-CH(CHj)2 -CH(C6H5)Z

75 Ring system. p -CH(C6H5)2 -C(CHj)2-CH2CHj ?6 Ring system 0 -CH(CHj)2 -CA(C6H5)2 ?? Ring system p -CH(CHj)2 -C(CHj)j ?8 Ring system ~ -~(~Hj)j -CH2-~
' * ?8a Ring system D C2H5 Menthyl ?8b Ring system a Menthyl CH2C6H5 * [a]~ _ +27.0° [c=1, CF~30H]; malate mp: 118-120°C

- 58a -"R300C-CH-N-C- CH -X2"
I 4 I S~I
R R 0 CH3 m "Example R300C-~"H-N- R3 X2 m ~4 RS
7 9 Ring system O -CH (C6H5) 2 -C~i25H 1 80 Ring system 0 -(CH2) 5-CH3 -(~i2SH 1 81 R30CC-CH2-N._ -C~i (C6H5) 2 -(~i2-S-OO-~ (CH3) 3 1 82 R300C-C'Fi2-N._ -C~i(CH3) 2 -CH2-S~-(CH3) 3 1-83 CH30 OOR'; .-Cgi (C6H5) 2 -NH~EI-(C~i2) 2 / \

- ~ -59- 1341064 nR300C-CH-N-C- CH -X2n ~ 4 ~ 5~~
R R 0 CH3 m "Example R300C-Cfi-N- R3 X2 m 84 R300C-CHf2-N- -CH ( 4-F-C6H4 ) 2 -NH-i H- ( CH2 ) 2.~ 1 COOCZHS
r 85 R300C-CH2,-1~- -Cg2~ -HH-CH- CH2 ) 2-CC10-CH (C2H5) Z
86 Ring syste~a~ H H 'CH2-b (CHZ)4~
~(CH312CH-CH-O-C-C2H5 0 Y
* ~ NH - ~H - CH2 - CHZ

Example T~ R2 R3 _.
8? CH2 -.C2H5 -CH(C6H5)2 -_ 88 s -~CH(C6H5)2 -(cH2)5-cH3 -_ 89 CH2 -,CH2-CH ( CH3 ) 2 -CH2--60- 1341pfi4 '' rf-'1 J> ~ _ p '~ NH - CH -2CH2 CH2 -O
C OOR
Example R2 R3 90 -CH(C6FI5)2 -C(CH3)3 g1 -CH(C6H5)2 -CH(C6H~)2 Example 92 4-CN-(1S>-Carboethoxy-3-phenylpropyl)-S-benzyl7-exospiro-(bicycloC2.2.27octane-2,3-pyrrolidine)-5-carboxylic acid a) eenzyl ester of N-(1S-carbethoxy-3-phenylpropyl>-S-leucine 3.4 g (10 mmol) of ethyl 2-(D)-trifluoromethylsulfonyl-oxy-4-phenylhutyrate and 5.9 g (15 mmol) of the benzyl ester of L-l~eucine tosylate were mixed in 50 ml of abs.
CH2Cl2 and, .after addition of 4.2 ml of triethylamine, the mixture ~~as stirred at room temperature for 6.5 hours. After concentration of the solution, the pro-duct was isolated by column chromatography (silica gel, cyclohexane/ethyl acetate 9:1). 3.2 g of colorless oil were obtained.
'H ~MR a~ 0.95 (a.. ~3). ~.2 (t, cH3) ~.e (m, CH2) 2.6 (m,. CH2) 3.3 (m. CH) 4.1 (q, CH2) 5.1(s, CH2) 7.3 (e, CH) ppm.
b) N-(1-S-Carboethoxy-3-phenylpropyl)-S-leucine 3.1 g of the benzyl ester obtained in a) were cleaved by hydrogenolys~is with 500 mg of Pt/C (10%) in 200 ml of ethanol. Afr:er removal of the catalyst by filtration and concentr<~tion of the solution, 2.3 g of colorless crystals of l:he carboxylic acid of melting point 120 121°C were obtained.
tg NMR b~ 0.!~ (d, CH3), 1.25 (t, CH3y 1.8-2,1 (m,CH2), 2.~ (~m~ CH2), 3~3 (Q. CR). 4.25 (Q~ CR2~~
?.2 (s, CH) ppm.
c) 4-CN-(1S)-Carbethoxy-3-phenylpropyl)-S-leucylJ-exo-spirobicyclol:2.2.2Joctane-2,3-pyrrolidine-5-carboxylic acid 2 g (6.2 mmol.) of N-(1-S-carboethoxy-3-phenylpropyl)-S-leucine and 1.9 g (3.9 mmol) of benzyl exo-spiro-(bicycloC2.2,.2J-octane-2,3-pyrrolidine)-5-carboxylate were stirred in 100 ml of dimethylformamide with 4.3 ml of triethylarnine and 6.5 ml of n-propylphosphonic 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 NaCI solution. The organic phase was then sep~~rated 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 melt-ing point 131-132°C were obtained.
Rotation CaJp - -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 cata-lyst by filtration and concentration of the solution, the yield was 721) mg.
Melting point: the substance sinters above 65°C
Rotation CaJp - -22.2° (c - 1, methanol) Example 93 4-CN-(1S)-Carboxyl-3-phenylpropyl)-S-leucylJ-exo-spiro-(bicycloC2.2.27octane-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 sub-stance had diss;olved,. The solution was applied to an ion exchanger ((R)Amberlite R 120) and eluted with a 2X strength solution of pyridine in water. The yield was 70 mg.
Rotation Ca7p0 = +3,90 (c - 1, methanol) '10 The following compounds of the formula II are prepared in analogous manner (the designations of the ring systems correspond to tlhose for the compounds of the general for-mulae I and II) s HOOC - C~ - p5- c; - Cg - CH - CH2 - CH2 R 0' R COOC2H5 CH(CH3)Z A

CH ( CI33 ) CH2 CH3 A

CH2-C6H1 > (CH2-Cyclc~heayl) C

CH2-C6H4-OC3H? C

CH2-C6H4-OC4H9 ~ A

* (CH2)4-NH2 D

CH2 )3-HH2 A

CH2~H~- 8 CH3 A

CH- CH
w N

~9~

* [a] p° _ -23.7° [c=0.1.52, CH30H]

- ~ 3t~~ Ofi 4 HOOC - CH - N - h - CH - CH - CH2 - CH2 -R4 R5 0 R~ COOC2H5 R~ HOOC - CH - NH

CH(CH3)2 B

CH(CH3)CH2CH3 B

CH2-C6H4 OCH:3 H

CH2-C6H4 OC2~H5 G

CH2-C6H~-On-~C3H7 G

CH2-C6H4 On-,C4H9 ~ C

( CH2 ) 4..~I2 C

(CH2)3-NH2 G

CH2-CHI s-C~;~3 D

CH - cH

CH C C;A B

~ si - ~34~064 ~ - 64 -HOOC - CH ~- N - ~~ - CH - CH - CH2 - CH2 R4 R5 ~D R~ COOC2H5 R~ HOOC - CH - AH

CH(CH3)2 C

CH ( CH3 ) CH2CH~~ C

CH2-C6H4- OCBj, I

*CH2-C6H4 OC2H',5 H less polar diastereomer [a] _ -28.6 [c=1, CH30H]
o more polar diastereomer [ a _ +20 . 7 [ c=1, ] CH30H ]
p MS
(FAH):591 (M' +
1) CH2-C6H~-On-C-~HT H mp:53-57°C MS ( FAH) :605 (M' + 1 ) CH2-C6H4-On-C,~H9 G
( CHZ ) i-~t G
( CHZ ) 3-~z H

CH - C:fi CH2 - C \ j~H C
S

. ~ 341 06 4 ' - 65 -HOOC - CH - P - ~ - CH - CH - CHZ - CH2 R4 R5 0 R~ COOC2H5 R~ HOOC - CH - NH

CH(CH3)2 D

CH ( CH3 ) CH2CH,3 D

CH2-C6H~ OCH,3 N

CH2-C6H4 OC2;H5 I

CH2--E6H4-On-C3H? I

CH2-C6H4- On-C4H9 H

(CH2)4-NH2 H mp: 142C

(CH2)3-NH2 0 CH2-CHI 8-CH,3 I

CH -Cli mss' ~ 341 06 4 HOOC - CH -~ N - C - CH - CH - CH2 - CHZ -R4 R5 ~D R~ COOC2H5 R~ HOOC - CH - NH

CH(CH3)2 0 CH(CH3)CH2CHj~ E
CH2C6H5 H 1st diastereomer:
[a]n°= +1fi.4 [c=1, CH30HJ
2nd diastereomer:
( t - HuNH2 salt ) (a]~ _ +29.9 [c=1, CH30H]
CHZ-C6H11 C' CH2-C6H,~-OCH3 0 CHZ-C6H4-OCziiS ~ N
CHZ-C6H~-On-CjH~ N
CHZ-C6H~-On-C~Ii9 I
CHZ ) ~-NH2 N
C CHz ) 3-NH2 P

~~H - CIi CHZ - C ~ %H; R
S

. - 67 -R4 R5 0 R~ COOC2H~
R~ HOOC - CH - NH

CH(CH3)2 H
CH(CH3)CH2CH3 F

CH2-C6H4 On-C3H? 0 cH2-C6H4- on-c4H9 N
(CH2)4 NH2 Q
(CH2)3'NH2 Q
CHZ-CH2 s CH3 Q
CH- C:Ei a CH2 - C C:H Q
~s~

_6$_ R4 R5 0 R~ COOC2H5 R~ HOOC - CH - 1QH

CH(CH3)2 I
CH(CH3)CHZCH3 G

CHZ C6H» I

CH2-C6H4-On-C3H7 CH2-C6H4 On-C4H9 0 (CH2)4 NH2 P
CH2-CH2 S-CH;3 N
CH- CH
CH2 - ' j~H H
S

HOOC - CH ~- N - C - CH - CH - CH CH

R4 R5 0 R~ COOC2H5 R~ HOOC - CH - NIi CH(CH3)Z 0 * CH ( CH3 ) CH2CH;f E

cH2 c6H» ~ z CH2-C6H4- OC2~i5 Q
CH2-C6H4 On-~:3H7 Q
CH2~C6A4- On-(:4H9 P
CHI CH2- 8-CH,~ (~
CH- CH
r CH - C CH I

* [a]~ _ -7.3° [c=1, ~CH30H]
mp s 117°C

R4 R5 0 R~ COOC2H5 R~ HOOC - CH - NH

CH(CH3)2 P
CH2- C6H~ P
CH2~C6H~~ M

CH2-C6H4- On-C3H? D
CH2 C6H4-On-C4H9 Q
CH- CH
w N

~S~

HOOC - CH - N - C - CH - CH - CH2 - CH2 ~

CH(CH3)2 N
CH(CH3)CH2CH3 P

CH2-C6H4~ On-C4~H9 D
CH- CH
a a CH C CH P

S
CH(CH3)CH2CH3 Q
CH(CH3)CH3CH3 I

Example 94:
1-CN-(1S)-Carboethoxybutyl)-S-alanyl7-octahydrocyclopenta-Cb7pyrrole)-2-carboxylic acid a) Ethyl DL-2-trifluo~romethylsulfonyloxypentanoate 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 CHZCl2 under protective gas, the solution was cooled to 0°C and 9.66 g (34 mmol) of trifluoro-methanesulfonic 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-leum ether/CH2Cl2 6:1). The yield was 9.3 g of a colorless, slightly viscous liquid.
IR: 2880 -~ 3000 1??0, 1420, 1200 -~ 1220 1150, 620 em 1 b) 8enzyl 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 ~~H2C12 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 concentra-ted, the crude product was taken up in ethyl acetate, and the solution was washed three times with water, dried and concentr;3ted. The diastereomers were separated by column chrom;stography (silica gel, cyclohexane/ethyl acetate 5:1>. The yield of each isomer was 500 mg. The diastereomer isolated in the first filtration had the S,S conf igur~at ion.

a = 0.9 (t.CH3). 1~3 (t.CH3). 1.35 (d.CH3). 1.4 (m,CH2).
1.6 (m,CH2). 1.9 (s.~H). 3.3 (t.CH). 3~4 (Q.CH).
4.2 (m,CH2), 5.15 (q,CH2 Ph), 7.4 (e, CH sromet.) ppm.
c) N-(1-S-Carboethoxybutyl)-S-alanine 600 mg (1.95 mural) of benzyl ester (diastereomer A>
were hydrogenated with Pd on charcoal in 34 ml of etha-nol. The catalyst was then filtered off, and the sol-ution was concentrated in vacuo. The product was then obtained as ~j 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-pentaCb7pyrrole-2-carboxylate were dissolved, under nitro-gen, in 20 m'l of dimethylformamide, the solution was cooled to -11)°C, and 1.5 ml of triethylamine and 2 ml of n-propylphosphonic anhydride were added. The solution 1 X41 Ofi 4 was stirred ~~t -10°C for 1 hour and then at room tem-perature overnight. It was then taken up in 200 ml of ethyl acetate and washed with saturated aqueous NaHC03 solution, 10;K aqueous citric acid and saturated aqueous NaCI solution. After the solution had been dried and concentrated,, the diastereomeric compounds were separa-ted by column chromatography (silica gel, cyclohexane/
ethyl acetate 9:1). The yield was 360 mg. Both dia-stereomers ware hydrogenated with Pd/C in ethanol as described in Example 94 c) and, after concentration of the solution,, they were obtained as~white solids.
Example 95:
1-CN-(1S)-Carbo;Kybutyl)-S-alanyl7-(octahydrocyclopenta-Cb7pyrrole)-2-c~3rboxylic acid 60 mg (0.17 mmol) of carboxylic acid (Example 94 d) were stirred into 2 ml of 4 N aqueous KOH solution until the 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 concentration of the solution was 39 mg.
In analogy to tihe compounds prepared in Examples 94 and 95, it is possible to synthesize the following additional com-pounds of the f~°rmula II
H
R300C - CH - N - C - CIi - N - CH (CH2)ri R
R~ COOR2 in which, with n = 2, R1 is CH3, R2 is C2H5, R3 is H, and R and the part of the molecule R OOC-CH-N

are substituted as indicated in the table detailed below.

R HOOC-CH-NH

-(CH2)9-CH3 C
2-Naphthyl D
4-Biphenylyl A
-(CH2)~3-CH3 A
R HOOC-CH-NH

-CH2CH2CH~~ B
- ( CH2 ) 9-CH3 D
2-Naphthy7.
4-Bipheny7lyl ~ C
- ( cH2 ) ~ 3-c;H3 B

- 7s -R HOOC-CH-NH

-(CH2)9-CH3 G
2-Naphthyl G
4-Biphenylyl D
-(CH2)~3-CH3 C
R HOOC-CH-NH

-(CH2)9-CH3 H
2-Nephthyl H
4-Biphenylyl H
- ( CH2 ) ~ 3-CH,3 D
R HOOC-CH-NH

-(CH2)9-CH3 K
2-Naphthyl I
4-Biphenyly;l Z
- ( CH2 ) ~ 3-CH;3 G

R HOOC-CH-NH

-CH2cH2cH3 H
-(CH2)9-CH3 N
2-Naphthyl M
4-Biphenylyl N
- ( CH2 ) ~ 3-C~3.3 N
R HOOC-CH-PH

-(CH2)9-CH3, 0 2-Naphthyl N
4-Biphenylyl P
- ( CH2 ) ~ 3-CH~3 0 R HOOC-CH-NH

-(CH2)9-CH~~ P
4-Hiphenyl3~l Q
-(CH2)~3-CH3 P

R HOOC-CH-NH

-(CH2)9-CH3 Q
4-Biphenylyl G
-(CH2)~3-CH3 Q
4-Biphenylyl H

Example 96a eenzyl 2-(S-alanyl)~-(1S,3S,SS)-2-azabicycloC3.3.0J-octane-3-carboxylate trifluoroacetate a) Benzyl 1-(N-t:ert.butyloxycarbonyl-S-alanyl)-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate 61.5 g (0.251 mot) of benzyl (1S,3S,SS)-2-azabicyclo-C3.3.OJoctane-3-carboxylate, 47.5 g (0.251 mol) of 80C-l-alanine and 173 ml (1..?6 .mol> of absolute triethylamine are dissolved in 1,025 ml of absolute dimethylformamide, 252 ml of a SOX strength solution of propanephosphonic anhydride in dich~loromethane are added dropwise at -5°C, and the mixture is stirred at -5°C for 30 minutes and at room temperature for four hours. The reaction solution is partitioned be~tveen water and ethyl acetate, the aqueous phase is extracted once more with ethyl acetate, and the combined organic phases are washed With saturated sodium bicarbonate solution, 10X strength citric acid solu-tion Water and saturated sodium chloride solution, dried and concentrated.
Yield: 93.2 g (8S~X) of oily product.
b) eenzyl 2-(S-alanyl)-(1S,3S,SS)-2-azabicycloC3.3.0J-octane-3-carboxylate trifluoroacetate 235 ml of absolute trifluoroacetic acid are poured over 93.2 g (0.224 mol) of 130C derivative from above, at 0°C, wind the mixture is stirred at 0°C for 2.5 hours. Excess acrid 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 (86X), melting point 148-150°C. -I
_ _ ~9 - 1 341 O6 4 Example 966 n-Octyl (1S,3S,,5S)-2-azabicycloC3.3.OJoctane-3-carboxy-late a) eenzyl 2-tert.butyloxycarbonyl-(1S,3S,5S)-2-azabi-cycloC3.3.OJo~:tane-3-carboxylate A solution of 39..? g (0.180 mol) of di-tert.butyl dicarbo-pate 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,'.iS)-2-azabicycloC3.3.OJoctane-3-carboxy-late and 23.4 ml (0.169 mot) of absolute triethylamine in 300 ml of absolute methylene chloride, and the mixture is stirred at 0°C for 15 minutes and at room temperature for one hour. Thin reaction solution is crashed with 10X
strength citric acid solution, saturated sodium bicarbonate solution and Water, dried and concentrated.
Yield: 55.6 g of oily product, CaJpS - -1.20 (c ~_ 2, methanol).
b) 2-Tert.butyloxycarbonyl-(1S,3S,5S)-Z-azabicycloC3.3.OJ-octane-3-carboxylic acid 55.6 g (0.161 mol) of benzyl ester from a) above are hydrogena~:ed on 4 g of palladium/charcoal (10X) in 2 liters of ethanol at room temperature for 2.5 hours.
The catalyst is filtered off vith suction, and the fil-trate is concentrated.
Yield: 37.3 g (90~:);
CaJpS - +22.7° (c - 1, methanol).
c) n-Octyl 2-tert.butyloxycarbonyl-(1S,3S,5S)-2-azabi-cycloC3.3.OJoc:tane-3-carboxylic acid 32.3 g (0.121 mol:n of acid from b) above and 25.3 g (0.253 mol) of potassium bicarbonate are stirred '~41 Os4 in 500 ml of dimethylformamide at 40°C for l.S hours.
After cooling, 48.9 g 00.253 mol) of 1-bromooctane are added dropwise, and they mixture is stirred at room tem-perature 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 (76X) of oily product, Caps = +5.7° (c - 1, methanol).
The following are obtained in an analogous way:
n-octyl 2-tert.butyloxycarbonyl-(1RS,3RS,SRS)-2-azabicyclo-03.3.07-7-octene-3-carboxylate;
n-octyl ester of N-tert.butyloxycarbonyl-S-praline.
d) n-Octyl (1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-car-boxylate 2.6 g (7.0 mmol) of e0C compound from c1 above 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, an~~ the organic phase is washed once more with water, dried and concentrated, and the product is rapidly reacted further.
Yield: 1.8 g (95X) of oily product.
The following are obtained in an analogous way:
n.-octyl (1RS,3RS,:iRS)-2-azabicycloC3.3.OJ-7-octene-3-car-boxylate;
n-octyl ester of :i-praline.

Example 96c ~ ~ t~ ~ 0 6 4 , 3-Octynyl methanesul,fonate 7.47 g (65 mmol) of me!thanesulfonyl chloride are added dropwise to a solution of 7.56 g (60 mmol) of 3-octyn-1-of 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 is washed with water, <.~aturated sodium bicarbonate solu-tion and again with wat:er, dried and concentrated.
lrield: 11.9 g (97X) of oily product.
Example 96d n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate 2.07 g (5 mmol) of 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-~azabicycloC3.3.OJoctane-3-carboxy-lic acid (ramipril> ancf 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 (E~ mmol) of 1-bromooctane in 20 ml of dimethylformamide is. added dropwise, and the mixture is stirred at room temperature overnight. The pH is ad-justed to 6 by addition of 0.1N HCI, the mixture is diluted with water and extracted three times with methylene chloride, and the combiined organic phases are dried, con-centrated and purified by column chromatography on 120 g of silica gel (mobile phase toluene/ethanol 95:5).
Yield: 2.35 g (89X) of oily product;
CaJps - -23.9° (c - 1, methanol>. .. . - .-Example 97:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate ' f .. - 82 -1 341 0~ 4 ~ydrogen maleate 528 mg (1 mmol) of the ester obtained in Example 96d are ;
dissolved in 20 ml of ether, and a solution of 116 mg (1 mmol) of malefic acid in 4 ml.of acetone is added. The solvents are removed by evaporation, and the residue is ~:rystallized With diisopropyl ether.
'field: 0.51 g (79X) of colorless crystals, melting point 89-90oC.
Example 98:
c'.=Octenyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate hydrogen maleate 2.08 g (5 mmol) of 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl>-S-alanyl7-(1S,3S,SS)-2-azabicycloC3.3.07octane-3-carboxy-lic acid (ramipril) and 1.00 g (10 mmol) of potassium bi-carbonate are stirred in 25 ml of dimethylformamide at 40°C
for 1.5 hours, the mixture is cooled to 0°C, and a solu-tion of 2.3 g (12 mmol) of E-1-bromo-2-octene in 20 ml of dimethylformamide is added dropwise. The reaction solu-tion is stirred at O~~C for 4 hours, poured in 500 ml of water and extracted i:hree 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 puri-fied by flash chromat:ograp~hy on 125 g of silica gel (mobile phase cyclohE~xane/~ethyl acetate 8:2 and 1:1).
1.93 g (73X) of an oi~ty product are obtained and converted into the hydrogen mal.eate in analogy to Example-97.
Yield: 2.0 g of colorless .crystals, melting-point.81-84°C. .-.
E;Kample 99:
3-Octynyl Z-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nylJ-(15,3S,5S)-2-azabicycl,oC3.3.OJoctane-3-carboxylate hydrogen maleate . ' ~ 34 ~ os 4 4.9 g (11.8 mmol) of 2-CPS-(1S-ethoxycarbonyl-3-phenyl-propyl)-S-alanyl7-(1S,3S,,SS)-2-azabicycloC3.3.O7octane-3-carboxylic acid (ramiprit.) and 2.4 g (23.6 mmol) of potas-sium bicarbonate are stirred in 90 ml of dimethylformamide S at 40°C for 2 hours, and then a solution of 2.41 g (11.8 mmol) of mesylate i'rom Example 96c in 30 ml of dimethylformamide is added, and the mixture is stirred at 40°C for a further 9 Flours. The reaction solution is diluted with 250 ml oi' 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 (56X) 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-nylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate hydrogen maleate 1.43 g (2.8 mmvl) of carboxylic acid from Example 106 are stirred in 25 ml of ethan~olic hydrochloric acid at room temperature. After 5 days, a further 25 ml of ethanolic hydrochloric acid are addled, the mixture is stirred over-night 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 puri-fled by flash chromatography on 80 g of silica gel -(mobile phase toluene/ethanol 99:1). 0.62 g (42X) 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 _ _.
84-86°C.

Example 101:
5-Nonyl 2-CN-(1S-e~thoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabi~:ycloC3.3.OJoctane-3-carboxylate hydro-gen maleate A solution of 1.31 g (7.5 mmol) of diethyl azodicarboxylate in 10 ml of absolute tetrahydrofuran is added dropwise at 0oC to a solution of 1.97 g (7.5 mmol) of triphenylphos-phine and 0.72 g <.'i mmol) of 5-nonanol in 100 ml of abso-lute tetrahydrofur~rn, the mixture is stirred for 10 minutes and then, at 0°C, a solution of 2.08 g (5 mmol) of 2-CN-(1S-ethoxyc:arbon;yl-3-phenylpropyl)-S-alanylJ-(15,35,5S)-2-azabic:ycloC:3.3.OJoctane-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 con-centrated, the residue is taken up in ethyl acetate, the solution is washed twice with 2N sodium hydroxide solution and once with eater, 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 pro-duct obtained in this way (1.74 g, 64X> is converted into the hydrogen maleal:e in .analogy to Example 97.
Yield: 1.6 g (49X);. melting point 103-105°C.
Example 102:
8enzhydryl 2-CN-(1:~-menthyloxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-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 !~ of nickel peroxide hydrate in 12 ml of ether and,. after stirring for one hour, the vio-let solution is filtered with suction through Celite and concentrated. The 3 mmol of diphenyldiazomethane obtained in this way are dissolved in 32 ml of absolute acetone and _ - 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]-(1S,35,SS)-2-azabicycloC3.3.0]octane-3-carboxylic acid (s~~e 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 (95X) of oily product;
Ca]p5 - -57.9° (c ~- 1, methanol).
Example 103:
n-Octyl 2-CN-(3-cy.lohexyl-1S-ethoxycarbonylpropyl)-S-alanyl]-(1S,3S,SS)-2-azabicycloC3.3.0]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 SOX strength solution of propan~ephosphonic 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 ace-tate, the combined organic phases are washed with water, 10X strength citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solu-tion, 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 (69X) of colorless oil, - _ -[a]25 - -26.40 ( c - 1, methanol).
D

Example 104:
eenzyl 2-CN-(1S-ethoxycarbonyl-1-tridecyl)-S-phenylala-nylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate 3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of a SOX strength solution of propanephosphonic anhydride in methylene chloride are successively added dropwise to a solution of 2.1 g (5 mmol) of N-(1S-ethoxycarbonyl-n-tri-decyl)-S-phenylalanine and 1.4 g (5 mmol) of benzyl (15,3S,5S)-2-azabir:ycloC3.3.OJoctane-3-carboxylate in 80 ml of absolute dimeth;ylformamide, and the reaction solution is stirred at room temperature overnight. It is then poured into waiter and extracted several times with ethyl acetate, the combined extracts are washed with water, lOX citric acid solution, saturated sodium bicar-bonate 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 (85X) of oily product CaJpS - -8.0° (c - 0.97, ethanol).
25. Example 105:
Benzyl 2-CN-(1S-n-o~ctyloxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S>-~?-azabicycloC3.3.OJoctane-3-carboxylate 6.0 ml (43.4 mmol) of absolute triethylamine and 9.2 g of n-octyl 4-phenyl-2R-trifluoromethanesulfonyloxybutyrate, dissolved in 20 ml of absolute methylene chloride, are -successively added dropwiae at 0°C to a-solution of 9.3 g (21.7 mmol) of trifiluoroacetate from Reference Exam- '-ple 1b) in 100 ml of absollute methylene=chloride. The -mixture is allowed to reach room temperature,-stirred for '- w - -;?.5 hours, extracted three times with water, dried-and ' -~:oncentrated, and the crude product (11.4 g)-is purified -' -by flash chromatography on 450 g of silica gel (mobile ~ --8~- 134'p64 phase cyclohexane/ethyl acetate 9:1, 8:2, 7:3).
Yield: 6.95 g (54X) of oily product, CaJpS - -35.1° (c ~- 1, methanol).
Example 106:
Tert.butylammonium 2-CN-(1S-n-octyloxycarbonyl-3-phenyl-propyl)-S-alanylJ-~;1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate 5.45 g (9.2 mmol) of benzyl ester from Example 105 are hydrogenated on 1 c~ of palladium/charcoal (10X) in 300 ml of ethanol at room temperature for 20 minutes. Removal of the catalyst by filtration with suction, and concen-tration result in ~~.1 g (89X) of 2-CN-(1S-n-octyloxycar-bonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicyclo-C3.3.OJoctane-3-carboxylic acid.
190 mg of tert.butylamime 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 (86X) of colorless crystals, melting point 141-143°C.
Example 107:
n-Octyl 2-CN-(1S-carboxy--3-phenylprvpyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC'.S.3.OJoctane-3-carboxylate ' 2.65 g (5 mmol> of ethyl ester from Example 96dare dis-solved in 18 ml of tetrahydrofuran, 7.5 ml of 1N sodium hydroxide solution are added, and the mixture is stirred.
at room temperature for 48 hours. It is neutralized by addition of 7.5 ml of 1N hydrochloric acid. The reaction mixture is concentrated, the residue is suspended. in.
water, the mixture is exi:racted twice with ethyl acetate, the combined organic pha<.ces are washed with saturated__ ~ 349 06 4 _ 88 _ 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; 46X) 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 materi-als and application of the processes described in Examples 96-107:
Example 108:
n-Octyl 2-CN-(1S-ethoxycarbonyl-n-heptyl)-S-alanylJ
(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate.
Example 109:
n-Decyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyll-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJps - -25.8° (c - 1, methanol).
Example 110:
n-Tetradecyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-t15,3S,SS)-2-azabicycloC3.3.Oloctane-3-carboxylate;
CaJpS - -19.8° (c - 1, methanol).
Example 111:
2-Octynyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate hydrogen maleate; melting 70-72°C.

Example 112: ~ ~ 4 1 0 6 n-Octyl 2-CN-(1S-isobutyl.oxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJpS - -23.7° (c - 1, methanol).
Example 113:
n-Octyl 2-CN-(1S-n-octyloxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.Oloctane-3-carboxylate;
CaJpS - -18.6° (c - 1, methanol).
Example 114:
n-Octyl 2-CN-(1S-n-~~ctadecyloxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.OJoctane-3-carboxy-late; CaJps - -15.2" (c - 1, methanol).
Example 115:
n-Octyl 1'-CN-( 1S-e~:hoxyc~arbonyl-3-phenylpropyl )-S-ala-nylJspiroCbicycloC3"3:OJoctane-2,3'S-pyrrolidineJ-5'S-carboxylate.
Example 116:
n-Nonyl 1'-CN-(1S-et:hoxycarbonyl-3-phenylpropyl)-S-ala-nylJspiroCbicycloC2.2.2Joctane-2,3'S-pyrrolidineJ-5'S-carboxylate hydrogen maleate; melting point 110°C.
Example 117:
n-Decyl 1'-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-ala-nylJspiroCbicycloC2.2.2Joc;tape-2,3'S-pyrrolidineJ-5'S-carboxylate hydrogen maleate; melting point 96°C.

Example 118:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-(1R,3R,5R)-2-azabicycloC3.3.07octane-3-carboxylate;
,CaJpS - -7.0° (c - 1.16,. methanol).
Example 119:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-R-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate;
CaJpS - +18.0° (c - 1, methanol).
Example 120:
n-Octyl 2-CN-(1R-ethoxycarbonyl-3-phenylpropyl)-R-alanylJ-(1S,3S,5S)-2-azabicycloC3.3.07octane-3-carboxylate;
Ca7p5 - +9.4° (c - 1, methanol).
Example 121:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyll-(1S,3S,5S>-2-azabicycloC3.3.07-7-octane-3-carboxylate;
CaJpS - +21.2° (c - 1, methanol)., Example 122:
n-Octyl 2-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanyl7-(1R,3R,5R)-Z-azabi~cycloC3.3.07-7-octane-3-carboxylate;
CaJpS - -51.4° (c - 1, methanol).
Example 123:
n-Octyl ester of N~-CN-(1S-ethoxycarbonyl-3-phenylpropyl)-S-alanylJ-S-proline hydrogen maleate; melting point 3 4 ~ 0 6 4 1os-1o7°c.
Example 124:
2-CN-(1S-Ethoxycarbonyl-n--tridecyl)-S-phenylalanylJ-(1S,3S,SS)-2-azabicycloC3..3.OJoctane-3-carboxylic acid;
Ca7p5 - +27.2° (c - 1, methanol).
t:xample 125:
Elenzyl 2-CN-(1S-ethoxycarbonyl-n-tridecyl)-S-alanylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate.
Example 126:
Benzyl 2-CN-(1R-ethoxycarbonyl-n-tridecyl)-5-alanylJ-(1S,3S,SS)-2-azabicyc:loC3.3.OJoctane-3-carboxylate.
Example 127:
8enzyl 2-CN-(1S-n-octadecyloxycarbonyl-3-phenylpropyl)-S-alanylJ-(1S,3S,SS)-2-azabic:ycloC3.3.OJoctane-3-carbvxylate;
CaJpS - -28.6° (c - 1, methanol).
Example 128:
8canzyl 2-CN-(1S-menthyloxycarbonyl-3-phenylpropyl)-S-al.anylJ-(1S,3S,SS)-2-azabicycloC3.3.OJoctane-3-carboxylate;
CaJpS - -63.2° (c - 1, methanol).
Example 129:
3s 3,3-Oiphenyl-n-propyl 2-CN-(1S-ethoxycarbonyl-3-phenylpro-pyl)-S-alanylJ-(1S,3S"sS)-2-azabicycloC3.3.OJoctane-3-carboxylate hydrogen analeate; melting point 122-124°C.

By..~~uitable combinations of the methods described in the foregoing examples, the following additional compounds of the Formula I are prepared:
n, R . ~R1 ' , ~:2 R3 HOOC- CH- N-. . . . R4 R5 1 ~CH2)lpCH3 CH3 C2,H5. H . D
les;S polardiasterevmer~ (a~~D = +0,5 (c=1, CH30H); MS (DCI) 481. (M++1) more= polardiastereomer (a~2D = -22.5('c=1,CH30H) ; (DCI) 481 (M++1 MD ) 1 CH2)lpCH3 H H D
(a~ DO - + 52.9° (c=~1, CH30H), MS (DCI) 529 (M++1)' 1 CH(.CH3)2 ~ CH3 CZH.g ~ CH2C6H5 D (diastereomers;
'?('a~ D~ ~_ -.29.8° (c=1., CH30H), ,MS (DCI) 459 (M++1) ~a~ DO = -0.6° (c=1, CH30H), MS (DCI) 459 (M++1) 2 CH3 ~ CH3 , C2H5 CH2C6H5 H
MS (DCI): 499 (M++:L) for both diastereomers 2. GH3 CH3 . C2H5 ~ H ~ H
less .polar diaster~=omer (a) DO = -40.8° (c=1, CH30H) more polar diastereomen (a~DO = -4.5° (c=l, CH30H) 2 , C6H5 ~CHZ-C6H4-0-»C3H~ C2H5 H . H mp: 53°C
. . MS (DCI): 605 (M++1) 2 .C6H5 ~~ CH2-C6H4-0-nC3H7 H H ~~ . . H
, , (a~ DO - +32.0° (c=l, CH2(:12), mp: 120-127°C
2 C6H5 CH2-C6H5 H . H ' H
+32.6° (c=1, CH2C;12)~ mp: 145° (decamp.) .
. .
.. .. : I
. . . , ~,' . .
' ~ . ..
. . . . , . . , . , ~ . 1 . , ~,~ . - 93 -. . ~ ~ ~ . ~ 1 341 06 4 Compounds of the formula I ' , . n ~ . . R ~ v R1. R2 , R3 HOOC- CH- N-I I

2 C6H5 CH2CH(CH3)2 H H H mp: 156°C
(decamp.) other diastereomer mp: 137° (decamp.), (a~ DO = +3.9° (c=1, CH30H) . 2 C6H5. CH(CH3)-CZHS H H . H
mp: 127°C.(decomp.); M:i (DCI): 485 (M++1) 2 a- C4Hg CH3 C;ZHS CHZ- C6H5 D
less polar diasterevmer (a~DO -51.6° (c=1, CH30H) . t,~
. more polar diastereome:~ (a~2D = -26.8° (c=1, CH30H) 2 a-C4Hg ~ CH3 C:ZHS ~ H H
less polar diastereome=- (a~2D = +6.9° (c=1, CH30H) more polar diastereomer (a~20= +4.4° (c=1, CH30H);. MS (DCI): 597 . D (M++1=
' 2' a- C4Hg CH3 FI H' D
1st diasterevmer (a~DO = +10.4° (c=1, CH30H) 2nd diastereomer mp: 104-108°C
.,..-. .:_ . . . - . . . . ~ . , .
;; ..; . .-,

Claims (3)

1. The use of an angiotension-converting enzyme inhibitor of the formula (II) in which n is 1 or 2;
R denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, an aromatic radical having 6-12 carbon atoms, R1 denotes hydrogen, an aliphatic radical having 1-21 carbon atoms, or, if not already covered by the above definitions, the side-chain, protected where necessary, of a naturally occurring .alpha.-amino acid, R2 and R3 are identical or different and denote hydrogen, an aliphatic radical having 1-21 carbon atoms, an alicyclic radical having 3-20 carbon atoms, an aromatic radical having 6-12 carbon atoms, an araliphatic radical having 7-32 carbon atoms, and R4 and R5 form, together with the atoms carrying them, a heterocyclic ring system selected from pyrrolidine, octahydroindole, and octahydrocyclopenta[b]pyrrole or a physiologically tolerated salt thereof, for the treatment of a cognitive dysfunction in a mammal.

2. The use as clammed in claim 1, wherein the compound of the formula (II) is (S,S,S,S,S)-1-[N-(1-carbethoxy-3-phenylpropyl)-alanyl]-octahydroindole-2-carboxylic acid, 1-[N-(1-S-carbethoxy-3-phenylpropyl)-S-alanyl]-(2S,3aR,7aS)-octahydroindole-2-carboxylic acid, or (S,S,S,S,S)-2-[N-(1-carbethoxy-3-phenylpropyl)-alanyl]-2-azabicyclo[3.3.0]-octane-

3-carboxylic acid.
3. The use of a compound of the formula (II) as defined in claim 1 or 2 in the manufacture of a medicament for the treatment of a cognitive dysfunction in a mammal, whereas said medicament comprises an effective amount of an angiotension-converting enzyme inhibitor of the formula (II) as defined in claim 1 or 2 or a physiologically acceptable salt thereof and a pharmaceutically suitable auxiliary.