DD280765A5 - PROCESS FOR PREPARING NEW COMPOUNDS OF FORMULA II WITH NOOTROPIC EFFECT - Google Patents

Abstract

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

Description

COOR *

or

means.

R ³ OOOC

X ^{2 is} -CH ₂ SH, -CH ^ SCR ⁶ , -CH ₀ -PR ⁷ or

_n -R meant

COOR ²

Y -steht ¹ is-S-or-CH _2, Y -steht by-NR ⁹ -or-CH ₂ CH ^2, m = O odor list, η = O,! Or 2, ρ = O or list, R = Hydrogen,

an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted acyclic radical having 3-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms, an optionally substituted araliphatic radical having 7-32 C. -Atomen, an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms, an optionally substituted heteroaromatic or heteroaromatic (C ₁ -C ₃ ) -aliphatic radical having 5-12 ring atoms, or

a radical OR 'or SR ", wherein R * is an optionally substituted aliphatic radical having 1-4 C atoms, an optionally substituted aromatic radical having 6-12 C atoms or an optionally substituted heteroaromatic radical with

5-12 ring atoms, R 'is hydrogen,

an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted alicyclic radical having 3--20 C atoms, an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms, an optionally substituted aromatic radical having 6-20 carbon atoms, 12 C atoms, an optionally substituted araliphatic radical having 7-32 C atoms, an optionally substituted heteroaromatic or heteroaromatic- (C, -C ₈ ) -aliphatic radical having 5-12 ring atoms or,

if not already covered by the above definitions, the necessarily protected side chain of a natural

occurring α-amino acid, R ² and R ^{3 are the} same or different and

Hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted acyclic radical having 3-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms,

an optionally substituted araliphatic radical having 7-32 C atoms, R ^{4 is} hydrogen or (C, -C ₆ ) -alkyl and R ^{5 is} (C-Ce) -alkyl, (Cj-Cel-cycloalkyl or

stand or

R ⁴ and R ⁵ together with the atoms carrying them form a monocyclic, bicyclic or tricyclic heterocyclic ring system having 3 to 15 ring C atoms,

R ⁶ is hydrogen, amino, (C, -C ₆₎ alkyl, (C ₆ -C ₂ I-aryl or (Cr-Cul-aralkyl, R ⁷ (C | -C _e) alkyl or (Cr-Cultuur Aralkyl, preferably - (CH ₂ I ₄ -C ₆ H ₅ , R ^e (C ₁ -Ce) alkyl, optionally monosubstituted by (C ₁ -C ₆ ) alkanoyloxy, preferably 2-methyl-propionyloxy-propyl,

R ⁹ is hydrogen or (C, -C _e) alkyl; such as compounds of formula II,

R 1 OOC - CH - N - G - CH - NH - CH - (CH ₀ ) - R (M)

Yes Ιςιΐ Η I ο 2 η

IT R ⁵ 0 R ¹ COOR ^

in which

η = 1 or 2, R = hydrogen,

an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted acyclic radical having 3-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms, an optionally substituted araliphatic radical having 7-32 C atoms Atoms, an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms, an optionally substituted heteroaromatic or heieroaromatisch- (C, -C ₈ ) -aliphatic radical having -12 ring atoms, or

a radical OR 'or SR', wherein R "is an optionally substituted aliphatic radical having 1-4 C atoms, an optionally substituted aromatic radical having 6-12 C atoms or an optionally substituted heteroaromatic radical with

5-12 ring atoms, R 'is hydrogen,

an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted acyclic radical having 3-20 C atoms, an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms, an optionally substituted araliphatic radical having 7-32 C atoms, an optionally substituted heteroaromatic or heteroaromatic (C, -C ₈ ) -aliphatic radical having 5-12 ring atoms or,

if not already covered by the above definitions, the necessarily protected side chain of a natural

occurring α-amino acid, R ² and R ^{3 are the} same or different and

Hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms, an optionally substituted acyclic radical having 3-20 C atoms, an optionally substituted aromatic radical having 6-12 C atoms,

an optionally substituted araliphatic radical having 7-32 carbon atoms and R ⁴ and R ⁶ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclischos Rinpcystem having 3 to 15 Rin ^ -C atoms.

By an optionally substituted aliphatic radical is meant an aliphatic acyclic radical, d. H. a radical having an open, straight or branched carbon chain, such as alkyl, alkenyl, alkynyl and corresponding polyunsaturated radicals. It is preferably unsubstituted or, as described below for example in carboxy, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arylalkoxycarbonylaminoalkyl, arylalkylaminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxyalkyl, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyloxyalkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl or aryloxycarbonyloxyalkyl, monosubstituted. An optionally substituted alicyclic radical and the corresponding optionally substituted alicyclic-aliphatic radical linked via an open carbon chain is a preferably mono- to pentacyclic isocyclic, nonaromatic radical having singly or asymmetrically distributed double bonds, which may also be branched (ie carry open-chain aliphatic side chain) and linked via a ring C atom or a side chain C atom. It is preferably unsubstituted. Several rings as components of such residue are condensed, spiro-linked or isolated. Examples of such radicals are cycloalkyl, cycloalkenyl, cycloalkyl, bicycloalkyl, tricycloalkyl and radicals derived from mono-, bi- or oligocyclic terpenes, such as methyl, isomenthyl, bornanyl, bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, menthanyl. Neomenthyl, neoisomenthyl, pinanyl, thujanyl; they are preferably unsubstituted (aliphatic side chains are not substituents as defined herein).

An optionally substituted aromatic radical is preferably aryl, such as phenyl, biphenytyl or naphthyl, which is optionally mono-, di- or trisubstituted as indicated below for aryl. Aryl-derived radicals, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, can be substituted, such as aryl.

An optionally substituted heteroaromatic radical is preferably an aromatic mono- or bicyclic heterocyclic radical having 5 to 7 or 8 to 12, preferably up to 10, ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and / or of which 1 to 4 ring atoms are nitrogen atoms such as thienyl, benzo (b) thienyl, furyl, pyranyl, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolyl, Cinnolinyl, pteridinyl, oxazolyl, isoxazolyl, thiazolyl or isothiazolyl understood. These residues may also be partially or fully hyrdriert. A heteroaromatic radical and the corresponding heteroaromatic-aliphatic radical may be substituted as defined below. By oineni optionally substituted araliphatic radical are especially understood aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or fluorenyl, wherein aryl is as defined above and may be substituted in the manner indicated therein. R ⁴ and R ⁵ can form a mono-, bi- or tricyclic heterocyclic ring system with 3 to 15 ring C atoms with the atoms carrying them, preferably up to 2 S atoms and up to 2 N atoms in the ring, in particular up to 1 S atom.

Suitable ring systems of this kind are, in particular, those from the following group: pyrrolidine (O); Thiazolidine (R); Tetrahydroisoquinoline (A); Decahydroisoquinoline (B); Octahydroindole (C); Indoline (Q); Octa-hydrocyclopenta-1bipyrrole (D); 2-azaspiro | 4.5ldecan (E); 2-azaspiro [4.4] nonane (F); Spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine] (G); Spiro [bicyclo (2.2.2loctane) -2,3'-pyrrolidinyl (H); 2-azatricyclo [4.3.0.1 * ^'9 ldecan (Ii; Decahydrocyclohepta-lblpyrrol (J); octahydroisoindole (K); Octahydrocyclopenta- [c] pyrrole (L); 2,3,3a, 4,5,7a-Hexahydroindo! (M); 2-azabicyclo (3.1.0) hexane (N); 1,2,3,3a, 4,6a-hexahydrocyclopenta [blpytro! (P), all of which may be optionally substituted. Pyrrolidine (O ) and thiazolidine (R) can be replaced by (C ₆ -C ₁₂ I-ArYl, (phenyl, 2-hydroxyphenyl, etc.), (Cf-Cul-arylmercapto (such as phenylmercapto) or (Cj-1-cycloalkyl (such as cyclohexyl) to be monosubstituted. tetrahydroisoquinoline (A) may, for. example, in the aryl moiety of up to 2 (C, -C _e) alkoxy, preferably methoxy wear. the same applies to the other ring systems. However, preferred are the unsubstituted systems.

In the case of compounds of the formula I or II which have a plurality of chiral atoms, all possible diastereomers are grained as racemates

or enantiomers, or mixtures of different diastereomers.

The contemplated heterocyclic ring systems have the following / structural formulas.

COOR. ^J

COOR

-11- 280 7S5

A preferred embodiment is characterized in that compounds of the formula I, preferably those of the formula II are used, in which a) n = 1 or 2isf;

R ¹ IV hydrogen content ^;

2. alkyl having 1-18 carbon atoms;

3. an aliphatic acyclic radical of the formula C ₁ Hi ₂ , - b + ii, wherein double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an integer 2 to a ;

4. a mono-, di-, tri-, tetra-oil pentacyclic, non-aromatic hydrocarbon radical of the formula C _c H | ₂ c - λ - ii, which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 b \ z (c - 2);

5. Aryl with 6-12 C atomon means

by (C, -C _a) alkyl, (C, -C ₄₎ alkoxy, hydroxy, halogen, nitro. Amino, arninomethyl, (C ₁ -C ₄ ) -alkylamino, di (C ₁ -C ₄ ) -alkylamino, (C) -C ₄ ) -alkaioylamino, methylenedioxy, carboxy, cyano, and / or sulfamoyl, m no-, may be di- or trisubstituted;

6. if η = 2, (C, rC ₁₂ ) -aryl (Ci-C ₈ ) -alkyl or di- (C ₆ -C, ₂ ) aryl- (C, -C _e ) -alkyl, which in the aryl part in each case as described under I. b) can be substituted 5; or

7. Alkoxy with 1-4C-AtOi ien;

8. A; yloxymitCKI2C-A. NEN.

which may be substituted as described under I. b) 5.;

9. mono or. bicyclic heteroaryloxy or heteroaryi (C 1 -C 6) -alkyl containing 5-7 or 8-10 ring atomons, of which b i to 9 ring atoms carbon and 1 to 2 ring atoms of heavy! or oxygen and / or 1 to 4 ring atoms represent nitrogen which may be substituted in the heteroaryl as described under I. b) 5;

10. amino (r;, - C ₈ ) alkyl;

11. (C, -C ₄ ) - / 1-alkanoylamino- (C ₁ -C ₁ ) -alkyl;

12. (C ₇ -C ₁₃ ¹ -Aroylamino (C, -C ₈ ) alkyl;

13, (Ci-C ^l ₄ alkoxy-carbonylamino (C, -C _a) alkyl;

14. (. CB-C ₂₎ aryl (Ci-C ₄₎ -alkoxycarbonylamino- (C, -C ₈₎ alkyl;

15. (Ce-Cul-aryl-fct-1-alkylanino-IC-Cel-alkyl;

16. (C, -f; ₄ ) -alkylamino (C, -C ₈ ) -ai. <Yl;

17. di (C 1 -C ₄ ) alkylamino (C 1 -C ₈ ) alkyl;

18. guanidino (C, -C ₈ ) alkyl;

19. imidazolyl;

20. indolyl;

21. (C 1 -C ₄ ) -alkylthio;

22. if η = 2, (C 1 -C ₄ ) alkylthio (C 1 -C ₈ ) alkyl;

23. (Ce-C 1-5 -aryl-thio-C 1 -C 12 -alkyl,

which may be substituted in the aryl part as described under I. b) 5.;

24 (C "-C, ₂₎ aryl (C, -C ₈₎ alkylthio,

which may be substituted in the aryl part as described under I. b) 5.;

25. if η = 2, Corboxy- (C, -C ₈ ) -alky |;

26. carboxy;

27. carbamoyl;

28. if η = 2, carbamoyl-iCr-Cel-alkyl;

29. (C 1 -C ₄ ) alkoxycarbonyl (C 1 -C ₈ ) alkyl;

30. if η = 2, (Ce-C, 2) -aryloxy- (C, -C _e ) -alkyl,

which may be substituted in the aryl part as described under I. b) 5.; or

31. (Ce-Cul-Aryl-IC-CeJ-alkoxy,

which may be substituted in the aryl part as described under I. b) 5 means; c) R ^{1 is} hydrogen;

2. alkyl having 1-18 carbon atoms;

3. an aliphatic radical of formula C, H ₍₂ , - _b * u, wherein double bonds, if their number exceeds 1, are not cumulative, a is an integer 2 to 18 and h is an even number 2 to a;

4. a mono-, di-, tri-, tetra- and pentacyclic, non-aromatic hydrocarbons .offresh of the formula C _c H _(2c, a - », which is optionally branched, where c is an integer from 3 to 20 and d is an even number 0 to (c-2);

5. aryl with 6-12C atoms,

the WiP can be substituted under I. b) 5. described;

6. (Ce-Cijl-aryl-tC ^ Cel-alkyl or (C ₇ -C ₁₃ I-ArOyI- (C ₁ -Ca) -BlkVl,

both of which may be substituted as aryl under I. b) 5. described;

7. mono- or bicyclic, optionally partially hydrogenated heteroaryl or heteroaryl (Ci-C ₈ ) alkyl 5-7 or

8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms nitrogen,

which may be substituted in the heteroaryl as described for aryl under I. b) 5.; or

8. if from c) 1.-8. not yet included, the optionally protected side chain of a naturally occurring a-Aminosäuro the formula R'-CH (NH ₂ ) -COOH means;

d) R ^{2 and} R ^{3 are the} same or different and

1. mean hydrogen;

2. alkyl of 1-18 C atoms;

3. an aliphatic acyclic radical of the formula C _a H ( _2a -b + ti, in which double bonds, if their number exceeds 1, are not cumulative,

a is an integer 2 to 18 and b is an even number 2 to a;

4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula C _C H (2 _C - d - υ, which is branched branched, ν / Οι in c for an integer 3 to 20 and an even number 0 to (c - 2) stand;

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

6. (C 1 -C 12) alkanoyloxy (C 1 -C ₈ ) alkyl;

7. (Ci-Cel-alkoxy-carbonyloxy-ICi-Oel-alkyl;

8. (CT-Cnl-AroyloxylC ^ Csl-alkyl;

9. (Ce-C, ₂ ) -Aryloxycarbonyloxy (C -C _a ) alkyl;

10. aryl with 6-12 C atoms; or

11. (C7-C ₂ o) -aralkyl;

wherein the radicals mentioned under d) 8, 9, 10 and 11 can be substituted in the aryl moiety as described under I. b) 5. in the aryl moiety;

e) R ⁴ and R ⁶ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms.

A particularly preferred embodiment is characterized in that compounds of the formula I, preferably those of the formula II are used, in which η = 1 or 2, R is hydrogen,

Alkyl with 1-8 C atoms,

Alkenyl with 2-6 C atoms;

Cycloalkyl having 3-9 C atoms;

Aryl with 6-12 C atoms,

the (by (Ci-C ^ alkyl, (Ci-C ₄₎ alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (Ci-C ₄₎ alkylamino, di- C, -C ₄₎ alkylamino, (C 1 -C ₄ ) alkanoylamino, methylenedioxy, carboxy and / or sulfamoyl, mono-, di- or trisubstituted,

Alkoxy with 1-4 C atoms,

Aryloxy having 6-12 C atoms,

which may be substituted as described above for aryl,

mono- or bicyclic heteroaryloxy having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and / or 1 to 4 ring atoms nitrogen,

which may be substituted as described above for aryl,

Amino (C 1 -C ₄ ) -alkyl,

(C, _-C4) alkanoylamino (C ₁ -C ₄₎ alkyl,

(C7-C | ₃₎ -Aroylamino- (Ci-C ₄₎ alkyl,

(Ci-C ₄₎ -alkoxy-carbonylamino (C _t -C ₄₎ alkyl,

(C <rC, ₂ ) -aryl (C 1 -C ₄ ) -alkoxycarbonylamino (C 1 -C ₄ ) -alkyl,

(C ₆ -C ₂ ) -aryl (C 1 -C ₄ ) -alkylamino (C 1 -C ₄ ) -alkyl,

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

Di- (Ct-C ₄₎ alkylamino (C, -C ₄₎ alkyl,

Guanidino- (C 1 -C ₄ ) -alkyl,

Imidazofyl.lndolyl,

(C 1 -C ₄ ) -alkylthio,

(C 1 -C ₄ ) -alkylthio (C 1 -C ₄ ) -alkyl,

(C <rC, ₂ ) -arylthio (C, -C ₄ ) -alkyl,

which may be substituted in the aryl part as described above for aryl,

(C ₆ -C ₁₂ ) -aryl (C 1 -C ₄ ) -alkylthio,

which may be substituted in the aryl part as described above for aryl,

Carboxy (C 1 -C ₄ ) alkyl,

Carboxy, carbamoyl,

Carbamoyl (C 1 -C ₄ ) alkyl,

(C 1 -C ₄ ) -alkoxycarbonyl- (C 1 -C ₄ ) -alkyl,

(C <rC, ₂ ) -aryloxy- (C, -C ₄ ) -alkyl,

which may be substituted in the atyl part as described above for aryl or

(C 1 -C 12) -aryl (C 1 -C ₄ ) -alkoxy,

which may be substituted in the aryl part as described above for aryl, R ^{1 is} hydrogen,

Alkyl having 1-6 C atoms, alkenyl having 2-6 C atoms, alkynyl having 2-6 C atoms, cycloalkyl having 3-9 C atoms, cycloalkenyl having 5-9 C atoms,

(C _s -Cg) cycloalkenyl (C 1 -C ₄ ) alkyl,

optionally partially hydrogenated aryl having 6-12 C atoms, which may be substituted as described above for R, (Ce-Ci2) -aryl {C, -C ₄ ) -alkyl or (C ₇ -Cn) -ArOyI- (C ₁ or C ₂ ) alkyl

both of which may be substituted as the above aryl

mono- or bicyclic, optionally partially hydrogenated heteroaryl having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms sulfur or oxygen atoms and / or 1 to 4 ring atoms represent nitrogen atoms, which may be substituted as the above aryl, or

the optionally protected side chain of a naturally occurring α-amino acid H'-CH (NH ₂ > -COOI-I, R ² and R ^{3 are} identical or different and

Hydrogen,

Alkyl with 1-6 C atoms,

Alkenyl with 2-6 C atoms,

Di (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl,

(C 1 -C ₅ ) -alkanoyloxy (C 1 -C ₄ ) -alkyl,

(C | -C _e) alkoxy carbonyloxy (Ci-C ₄₎ alkyl,

(C7-C, 3) -Aroyloxy- (C, -C ₄₎ alkyl,

(C ₆ -C ₁₂ ) -Aryloxycarbonyloxy (C ₁ -C ₄ ) -alkyl,

Aryl with 6-12 C atoms,

(C, rC ₁₂ ) -aryl (C 1 -C ₄ ) -alkyl,

_(C3-C8) -cycloalkyl or

(C ₃ -C 9) -cycloalkyl- (C 1 -C ₄ ) -alkyl

mean and

R ⁴ and R ^{s have} the abovementioned meaning, in particular those compounds in which η = 1 or 2, R (C ₁ -C _e ) -alkvl, (C ₂ -C 6) -alkenyl, (C ₃ -C ₉ ) Cycloalkyl, amino (C ₁ -C ₄ ) alkyl, (C ₂ -C ₆ ) acylamino, (C ₁ -C ₄ ) alkyl, (C 7 -C ₃ ) -acroylamino (C ₁ -C ₄ ) alkyl); ₄₎ alkyl, (C) -C ₄₎ -alkoxy-carbonylamino (C | _-C4) alkyl, (C5 - _Ci2) aryl (Ci-C ₄₎ -alkoxycarbonylamino- (C, - C ₄₎ alkyl, (C5-C _I2) aryl, by (Ci-C ₄₎ alkyl, (C, -C ₄₎ alkoxy, hydroxy, halogen, nitro, amino, (C, -C ₄ ) -Alkyltiino, di- (C, -C ₄ ) alkylamino and / or methylenedioxy mono-, di- or may be trisubstituted, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert. Butoxycarbonylamino- (C 1 -C ₄ ) -alkyl, benzoyloxycarbonylamino- (C ₁ -C ₄ ) -alkyl or phenyl represented by phenyl, (C ₁ -C ₂ -alkyl) (C ₁ -C ₂ ) -alkoxy, hydroxy , fluorine, chlorine, bromine, amino, (C, -C ₄₎ alkylamino, di (C _t -C ₄₎ alkylamino,

Nitro and / or methylenedioxy mono- or di-substituted or in the groove of methoxy, trisubstituted, R 'is hydrogen or (C, -C ₆ ) -alkyl, which may be substituted by amino, (C ^ Cet-acylamino or benzoylamino (C ₂ -C ₆ ) -alkenyl, (Cj-C _e ) -cycloalkyl, (Ce-CnJ-cycloalkenyl, (C ₃ -C ₇ ) -cycloalkyl- (C, -C ₄ ) -alky !, ( Cs-C, ₂ ) -aryl or thiourehydrated aryl, which may each be substituted by (C, CJ-alkyl, (C, or C ₂ ) -alkoxy or halogen, (C ₃ -C, ₂ ) -aryl - (C, to C ₄ ) -alkyl or (C7-C, 3) -royl- (C, -C ₂ ) -alkyl, both of which may be substituted as defined above in the aryl radical, a mono- or bicyclic heterocyclic radical with 5 to 7 or 8 to 10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and / or 1 to 4 ring atoms nitrogen atoms, or one side chain of a naturally occurring, optionally protected α-amino acid, in particular hydrogen, (C, - C ₃ ) alkyl, (C ₂ or C ₃ ) alkenyl, the gen optionally protected side chain of lysine, benzyl, 4-methoxybenzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl

or benzoylmethyl, R ² and R ^{3 are} identical or different radicals hydrogen, (C 1 -C ₆ ) -alkyl, (C ₂ -C ₆ ) - / * 'nyl- or (C ₆ -C ₂ ) -atinyl- C, -C ₄ ) -alkyl,

but especially hydrogen, (C, -C ₄ ) -alkyl or benzyl and R ⁴ and R ^{5 have} the abovementioned meaning.

If R ^{1 is} a side chain of a protected naturally occurring α-amino acid, such as. Protected Ser, Thr, Asp, Asn, Glu, GIn, Arg, Lys, HyI, Cys, Orn, Cit, Tyr, Trp or His are preferred as protecting groups in peptide chemistry common groups (see Houben-Weyl, Bd .XV / 1 and XV / 2). In the case where R ¹ denotes the protected lysine side chain, preference is given to the known amino-protecting groups, but in particular Z, Boc or (C ₁ -C 10 -alkanoyl, preferred as O-protective groups for tyrosine are (C 1 -C ₆ ) -alkyl, in particular methyl or ethyl in question

 Particularly advantageously, the following compounds can be used according to the invention: 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -S-1,2,3,4-tetrahydroisoquinoline-3- carboxylic acid 2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2- | N- (1-S- Carbethoxy-3-phenylpropyl) -S-lysyl] -S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -0 -othyl-S-tyrosyl] -S-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] - (3S) -decahydroisoquinoline-3-carboxylic acid 1- (N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -O-octahydroindole-2-carboxylic acid 1- (N- ( 1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [N - (- S-Carbethoxy-3-phenyl-propyl) -S -lysyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1 [N- (1S-carbethoxy-3-cyclohexyl-propyl) -S-lysyl (2S, 3aS, 7aS) - octahydroindole-2-carboxylic acid i-iN-OS-carbethoxy-S-cyclohexyl-propyl-S-lysyl -ßS.SaSJaSi-octahydroindole ^ -carboxylic

1- [N- (1-S-carbethoxy-3-phenyl ^ -propyl) -0-mβthyl) -S-tyrosyl] - {2S, 3aS, 7aR) -octahydroindol-2-carbonsäurβ

i-IN-dS-Carbethoxy-S-phenyl-propyl-O-ethyl-S-tyrosyl ^ S, aSya-octahydroindole ^ -carboxylic acid 1- [N- (1-S-Carbethoxy-3- (3,4 -dimethylphenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- [NnS-Carbethoxv-3- (4-fluorophenyl) -propyl-S-alanyll- (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-IN-I1-S-Carbethoxy-3- (4-methoxypbenyl) -propyl] -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1- ( N- [1-S-Carbeihoxy-3- (3,4-dimethy <yphenyl) -propyl-S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-iN- (1-S- carbethoxy-3-cyclopentylpropyl) -S-alanyll- (2S, 3aS, 7aS) -octahydroindol-2-carboxylic acid

1- [N- (1-S-C3rbethoxy-3-cyclohexyl-propyl) -S-3-alanyl) - (2S, 3aR, 7aS) -octahydroindole-carboxylic acid 1- [N- (1-S-Carbethoxy-3-phenyl -propyl) -S-lysyl] - (2S, 3aR, 7aS) -octahydroindo! -2-carboxylic acid 1 -IN- (I -S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] - (2S, 3aR, 7 aSi-octahydroindole ^ -carboxylic acid 1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 33S, 7aS) -octahydroindole-2-C3rbonsäure 1- [N- (1-S-Carbetbnxy-3-phenylpropyl) -S-alanyl] - (2S, 3aR, 7aR) -octahydroindole-2-carboxylic acid 1 -IN- (1-S-Carbethoxy-3-) phenyl-propyl) -S-lysyl l (2S, 3 aR, 7 aS) -octahydroindole-2-carboxylic acid 1 -IN-d -S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl- (2 S, 3 aR, 7 aRi-octahydroindole ^ -carboxylic acid 1- [N (1-S-Carbethoxy-3-cyclohexyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 3aR, 7aR) -octahydroindole-2 -carboxylic acid 1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl) - (2S, 3aS _/ 7aR) -oct3hydroindo! -2-c3rbonic acid 1- | N- {1-S- Carbethoxy-3-phenylpropyl) -0-ethyl-S-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-LN- (1-S-Carbethoxy-3,4-dimethylphenyl -propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-IN- (1-S-Carbothoxy-3- (4-fluorophenyl) -propyl] -S-alanyl] - ( 2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-LN- (VS-Carbethoxy-3- (4-methoxyphenyl) -propyl] -S-alanyl- (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1 - [N- (1-S-Carbethoxy-3- (3,4-dimethoxyphenyl) -propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid 1-IN- (1-S -Carbethoxy-3-cyclopentylpropyl) -S-al-3-nyl) - (2S, 33S, 7aS) -octahydroindo! -2-carboxylic acid 2- [N- (IS-Carbethoxy-S-phenyl-propyl-S-alanyl-cis-endo ^ -azabicycloS.S.Ojoctane-SS-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -cis-endo-2-azabicyclo [3.3.0loctan-3-S -carboxylic acid 2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl) - ^< : is-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid 2-IN - (1-S-carboxy-3-cyclohexyl-propyl) -S-alanyl-cis-endo-2-azabicyc! Ol3.3.0] octane-3-S-carboxylic acid 2- [N- (1-S-carbethoxy- butyl) -S-3-aryl] -cis-endo-2-azabicyclo-l3.3.0] octane-3-S-carboxylic acid 2- | N- (1-S-Carbethoxy-3- (3,4-dimethoxyphenylpro pyl) -S-alanyl) -cis-ondo-2-a7a-bicyclo [3.3.0] octane-3-S-carboxylic acid 2- [N- (IS-carbethoxy-S-cyclopentyl-propyl-S-slsyl-cis-endo -azsbicyclo-IS.S.Octane-SS-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-methyl-S-tyrosyl) -cis-endo-2-azabicyclo [3.3. 0] cctane-3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] -cis-endo-2-azabicyclo [3.3.0] octane 3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3- (4-fluorophenyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S -carboxylic acid 2- [N- (1-S-Carbethoxy-3- (4-methoxyph8nyl-propyl) -S-alanyl) -cis-endo-2-azabicyclo [3.3.0-octan-3-S-carboxylic acid 1 [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl) - (2S, 3aR, 6aS) octahydrocyclopenta [blpyrrole-2-carboric acid 1- [N- (1-S-Carboxy! Ioxy 3-cyclohexylpropyl) -lysyl] - (2S, αAr, 6aS) -octahydrocyclopenta [blpyrrole-2-carboxylic acid 1- [N- (1-S-carbethoxy-3-phenyl-propyl) -0-ethyl-S] tyrcsyl) - (2 S, 3a R, 6a) -octahydrocyclopenta [b] pyrrole ·. -carboxylic acid 1- [N- (IS-Carbethoxy-3-phenylpropyl) -S-alanyl] -2- (2S, 3aR, 6aS) -octahydrocyclopenta (b) pyrrole-2-carboxylic acid 2- [N- (1 -S-Carbethoxy-3-phenylpropyl) -S-alanyl-2-3Z3spiro [4.5] decane-3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O- ethyl-2-tyrosyl) -2-azaspiro [4.5] decane-3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] -2-azaspiro [4.5 2-N- (1-S-Carbethoxy-3-cyclohexylpropyl) -S-alanyl] -2-azaspiro ['' oldocane-SS-carboxylic acid 2- [N- (1-) S-Carbethoxy-3-cyclohexylpropyl) -S-lysyl] -2-azaspiro [4 Sjdecan-SS-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl) -2- azaspiro [4.4] nonane-3-3-carbonic acid 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -0-ethyl-S-tyrosyl-2-azaspiro [4.4] nonane-3-S carboxylic acid 2 · [N · (1-S-carboethoxy-3-phylnyl · propyl) -S-lysyl) -2-azaspiro [4.4] nonane-3-carboxylic acid β 2- [N- (1-S-carbethoxy-) 3-cyclohexy! -Propyl) -S-alanyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid 2- | N- (1-S-Carbethoxy-3-cyclopentyl-propyl) -S-alanoyl] - 2-3Z3spiro [4.4lnon An-3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3-cyclopentyl-propyl) -S-lysyl-2-azaspiro [4,4-nonan-3-S-carboxylic acid 1 '- [N- (1 -S-carbethoxy-3-phenyl-propyl) -S-sianyl) -spiro [bicyclo (2,2,1-heptane-2,3'-pyrrolidin-5'-S-carboxylic acid 1 '- [N- (1-S-carbethoxy-) 3-phenyl-propyl) -0-ethyl-S-tyrosyl-spiro [bicyclo [2.2.1] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid V- (N- (1-S-carbethoxy 3-phenyl-propyl) -S-lysyl] -spiro [bicyclo [2.2.1] heptane-2,3'-pyrrolidine) -5'-S-carboxylic acid 1 '- [N- (1-S-carbethoxy-) 3-cyclohexyl-propyl) -S-alanyl] -spiro [bicyclo [2.2.1] hept3n-2,3'-pyrrolidine] 5'-S-carboxylic acid 1 '- [N- (1-S-carbethoxy-3-cyclohexyl- propyl) -S-lysylspiro- [bicyclo [2.2.1] heptane-2,3'-pyrrolidin-5'-S-carboxylic acid V- [N- (IS ^; Carbethoxy-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.21octan-2,3'-pyrrolidin-5'-S-carboxylic acid T- [N- (IS-Caibethoxy-3-phenyl- propyl) -0-8thyl-tyrosyl-spiro- [bicyclo [2.2.2] octane-2,3'-pyrrolidin-5'-S-carboxylic acid V- [N- (1-S-carbethoxy-3-phenyl-propyl ) -S-lysyl] -spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid 1 '- [N- (1-G-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl-spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine | -5'-S-carboxylic acid 2- [N- (1-S-C3rbethoxy-3-phenylpropyl) -S- alanyl) -2-azatricyclo [4.3.0.i ^'9 ldecan-3-S-carboxylic acid 2-iN- (1-S-carbethoxy-3-phenyl-propyl) -0-ethyl-S-tyrosyll-2-azatricyclo [4.3.0.1 ^M- decane-3-S-carboxylic acid 2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -2-azatricyclo [4.3.0.1 ⁶⁹ lecan-3-S -carboxylic acid 2- [N- (1-S-carbethoxy-3-cyclohexyl-propyl) -S-alanyl) -2-azatricyclo [4.3.0.1 ^e - ⁹ ldecan-3-S-carboxylic acid 2- [N- (1 -S-carbethoxy-3-cyclohexyl-propyl) -S-lysyl] -2-az3tricyclo [4.3.0.l ^M | decane-3-S-carboxylic acid 1- [N- (1-S-C3rbethoxy-3-phenyl propyl) -S-alanyl] -decahydrocycl ohepta [b] pyrrole-2-S-carboxylic acid 1- [N- (1-S-Carbethoxy-3-phenylpropyl) -0-ethyl-S-tyrosyl-decahydrocyctohepta [b] pyrrole-2-carboxylic acid 1 - [ N- (I -S-Carbethoxy-3-phenylpropyl) -S-lysyl-decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid 1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) - S-alanyll-decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid

1- [N- (1-S-carbethoxy-3-cyclohexyl-propyl) 'S-lysyl] -decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid

2 - [- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] -trans-octahydroisoindol-1-S-carboxylic acid

2- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl | -cis-octahydro-1-S-carboxylic acid

2- [N- (1-S-carbethoxy-3-cyclohexyl-propyl) -S-alanyll-trans-octahydroisoindol-1-S-carboxylic acid

2- [N- (1-S-carbethoxy-3-cyclohexyl-propyl) -S-alanyl) -cis-octahydroisoindol-1-S-carboxylic acid

2- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl) -cis-octahydrocyclopentalc] pyrrole-1-S-carboxylic acid

2- [N- (1-S-carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-octahydrocyclopenta [c] pyrrole-1-S-carboxylic acid benzylester2- [N- (1-S-carbethoxy 3-cyclohexyl-propyl) -S-lysyl] -cis-octa-hydro-cyclopenta [c) pyrrole-1-S-carbonsäuie

i-IN-ii-S-carbethoxy-S-phenyl-propyll-S-alanyll .S.SaAö ^ ^ a-hexahydro-indole-cis-endo ^ -S-carboxylic acid

1 - [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl) -2,3,3a, 4,5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid

2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl) -2-azabicyclo [3.1.0] hexane-3-S-carboxylic acid

2-) N-i1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl-2-azabicyclo- [3.1.0] hexane-cis endo-3-S-carboxylic acid

2- | N- (1-S-carbethoxy-3cyclopentylpropyl) -S-alanyl] -2-azabicyclo [3.1.0] hexane-3-carboxylic acid

2- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl) -cis-endo-2-azabicyclo | 3.1.0] hexane-3-S-carboxylic acid

2-! N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.1.0] hexane-3-S-carboxylic acid

. I'-IN-dS-carbethoxy-S-S-phenylpropyD-alanyll-O'S.S'SJ-spiro-bicyclo ^^ octane-il ^ .S'-pyrrolidin-ö'-carbonsäure1'- | N- (1 -S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, R'S,) - spiro-bicyclo [2.2.2] octan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'R) -spiro-bicyclo [2.2.2] octan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N - (1-S-carbethoxy-3-phenylpropyl) -S-alanyll- (3'R, 5'R) -spiro-bicyclo [2.2.2ioctan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N - (1-R-carbethoxy-3-phenyl-propyl) -S-alanyl] -3'S, 5'R) -spiro-bicyclo [2.2.2] octan-2,3'-pyrrolidin-5'-carbonsäure1'- [N- (1-R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) -spiro-bicyclo [2.2.2loctan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, 5'S) -spiro-bicyclo [2.2.2loctan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N- ( 1-R-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'R, 5'R) -spiro-bicyclo [2.2.2] octc _l i-2,3'-pyrrolidin] -5'-carbonsäure1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 5'S) -spiro-bicycloI2.2.2] oc tan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -R alanyll- (3'R, 5'S) -spiro-bicycloI2.2.2) octane 2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-S-CarbGthoxy-3-phenylpropyl) -R-alanyl] - (3'S, 5'R) -spiro-bicyclo [2.2.2) octane -2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5'R) -spirc-bicyc o [ 2.2.2loctan-2,3'-pyrrolidin-5'-carbonsäure1 '- [N- (1-R-carbethoxy-3-phenylpropyl) -R-alanyl) - (3'S, 5'S) -.' ipiro-bicyclo [2.2 .2loctan-2,3'-pyrrolidin] -5'-carbonsäure1 '- [N- (1-R-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5'S) -spiro-bicycloI2.2.2 ] octane-2,3'-pyrrolidinl-5'-carbonsäure1 '- [N- (1-R-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'S, 5'R) -spiro-bicyclo [2.2. 2] octan-2,3'-pyrrolidin] -5'-carbonsäure1 '- (N- (1-R-carbethoxy-3-phenylpropyl) -R-alanyl] - (3'R, 5'R) -spiro- [2.2.2 | octane-2,3'-pyrrolidine-5-carboxylic acid

These compounds can be z. B. after the process described in German Patent Application P 3333455.2

prepared by the described in the application tert. Butyl or benzyl derivatives are converted in a known manner by acidic or alkaline hydrolysis or by noble metal-catalyzed hydrogenolysis in the monocarboxylic acid derivatives. The

N'-benzyloxycarbonyl protecting group of the lysine derivatives is removed by noble metal-catalyzed hydrogenolysis. The above

listed compounds can be easily with physiologically acceptable acids or bases (in the case of mono- or

Dicarboxylic acids) into the corresponding salts (eg hydrochlorides, maleate, fumarato, etc.) and as salts the

find use according to the invention.

The compounds of formula I are inhibitors of angiotensin converting enzyme (ACE) or Intermediates in the preparation of such inhibitors and may also be used to combat hypertension

different genesis can be used. The compounds of the formula I and processes for their preparation are known in part, for example from US Pat. No. 4,129,571, US Pat. No. 4,374,829, EP-A-79522, EP-A-79022, EP-A-49658, EP-A-51301, US Pat.

US Pat. No. 4,454,292, US Pat. No. 4,374,847, EP-A-72352, US Pat. No. 4,350,704, EP-A-50800, EP-A-46953, US Pat. No. 4,344,949, US Pat. EP-A-84164, US Pat. No. 4,470,972, EP-A-65301 and EP-A-52991. New compounds of the formula I are prepared in an analogous manner

heigestellt.

Also advantageous are orally active ACE inhibitors (active ingredients z.T. already mentioned above), such as. Ramipril, enalapril (f), Captopril (a), lisinopril (g), cilazapril (o), RHC 3659, CGS 13945, CGS 13928C (I), CGS 14824A (h), CI-906 (j), zofenopril (e), Fosenopril (p), Alacepril CI-925 (k), Pentopril (q), CV 3317 (m), Indolapril (h), YS 980 (b), Fentiapril (c), Pivopril (d), Perindopril (i),

and other. Orally effective ACE inhibitors are described, for example, in Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) 1935

SV-S11 described.

HS-CH

₂ (a)

-CH-CO-N 1

CO ₂ H

CR ₁

j 3 / ^.

HS-CH ₂ -CH-CO-N f

HS-C

^ 9

fa

(CH ₃ ) ₃ -CO-S-CH ₂ -CH-CO-N

(C)

CO ₂ HCH ₂ -CO ₂ H

T ³ / ^

-CH ₂ -CH-CO-N → J

(e) Ο _Λ Η

CO ₂ C ₂ H ₅ If)

C-CH-NH-CH

CH 3 OH (CH ₂ ) -NH ₂ CO H (3)

CFCX

CO ₂ H

- ^ 2

C-CH-NH-CH

O i, l _fH (h) CH ₃ CO ₂ C ₂ H ₅ -

CHNHtt A 1

(I)

X ^ iI

.CO ₂ H

, N

CH-CH, - // ^{z 2} \

C-CH-NH-CH Ί 1 A OCH ₃ CO ₂ C ₂ H ₅

^ CH-CH, - //

,H

.C-CH-NH-CH * CH ₃ CO ₂ C ₂ H ₅ (1)

_k * NH-CH ₂ CO ₀ C,

'2 ^W 2 ^H 5

CH ₂ -CO ₂ H (η)

XsH (j)

X ¹ = 3.4 0CH «(k)

N-CO

CH CH ^{2 2}

(M)

•. CO ₂ H

Cv ^ CH-OCO Hey '«

(Q)

Preferably, the known from EP-A-79022 ACE inhibitors of the formula I c £>

, COOH

- CH - NH - CH - CH ₂ --CH ₂ CH, C ¹ OOR

in which

R is hydrogen, methyl, ethyl or benzyl, in particular the compound of formula III, wherein R = ethyl (ramipril).

Preference is furthermore given to the ACE inhibitors of the formula IV known from EP-A-84164

Φ-

COOH

(S) (S)

CH - NH - CH - CH ₂ - CH ₂

CH, COOR *

in which

R * is hydrogen, (C 1 -C ₄ ) -alkyl or benzyl, especially the compound of formula IV, wherein R ⁴ = ethyl.

Beyond that are preferred

1'-IN- (1-S-carboethoxy-3-phenyl-propyl) -S-alanyl] exo respectively. endo-spirobicyclo [2.2.2loctane-2,3'-pyrrolidine-U'-yl-carboxylic acid and isomers and (SSS1-i-methyl-1-carbethoxy-S-phenyl-propyl-D, H-undecahydro-cyclopenta ^ / rrololi ^ -al-pyrazine-SS

The invention also relates to novel compounds of the formula II,

A. in which

R ³ OOG - CH - Ii - G - GII - iIH - GH - (^ Hg) _n - R

₁₃ 4 T} 5 η r> 1 r \ r>: \ TiC-

O R

COOR '

I. a) η = 1 or 2;

b) R 1 is hydrogen;

2. alkyl having 1-18 carbon atoms;

3. an aliphatic acyl radical of the formula C, H _(2l _ _{b + υ} , wherein double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an integer from 2 to a ;

4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of

Formula C ₀ H ₁ Jr d - υ, which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 ois (c-2);

t ". Aryl of 6-12 carbon atoms, that by (C | -C ₃ ) alkyl, (C | -C ₄ ) alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C, C ₄ ) alkylamino , Di- (C) -C4) -alkylamino, (C 1 -C ₄ -alkanoylamino, methylenedioxy, carboxy, cyano, and / or sulfamoyl may be mono-, di- or trisubstituted;

6. if η = 2, (C6-C, ₂ ) -aryl (C 1 -C 6) -alkyl or di- (C 6 -C 12) -aryl- (C ₁ -C ₈ ) -alkyl, which in the aryl part in each case as described under I. b) can be substituted 5; or

7. Alkoxy with 1-4 C atoms;

8. aryloxy having 6-12 C atoms, since j as described under I. b) 5. substituted

9. mono- or bicylischos heteroaryloxy or heteroaryl-ICt-Cel-alkyl having 5-7 or 8-10 Ringaiomen, of which up to 9 ring atoms are carbon and 1 to 2 ping atoms sulfur or oxygen and / or 1 to 4 ring atoms nitrogen in the heteroaryl as under '. b). 5. may be substituted;

10. amino (C, -C ₈ ) alkyl;

11. (C 1 -C 5) alkanoylamino-C 1 -C 4 -alkyl;

12. _(C7-C13) -Aroylamino- (C, -C ₈₎ alkyl;

13. (Cri-M-Aikoxy-carbonylamino-fCt-CaJ-alkyl;

14. (Cff-CuJ-aryl-C 1 -C 4 -alkoxycarbonylamino-fCt-C

15. (C6-C, 2) aryl (C, -C ₄₎ alkylamino (C, -Ce) alkyl;

16. (C 1 -C 4) alkylamino (C 1 -C ₈ ) -alkyl;

17. di-ICi-CJ-alkylamino-LCH 1 -alkyl;

18. guanidino (C, -C ₈ ) alkyl;

19. imidazolyl;

20. indolyl;

21. (C 1 -C ₄ ) -alkylthio;

22. if η = 2, (C 1 -C ₄ ) -alkylthio (C 1 -C ₄ ) -alkyl;

23. {Ce-C 1-6} arylthio-1-C 1-5 -alkyl,

the substituted in the aryl part as described under I. b) 5. soin can;

24, (Ce-C, ₂₎ alkyl (C, -C ₈₎ alkylthio,

which may be substituted in the aryl part as described under I. b) 5.;

25. if η = 2, carboxy (C 1 -C ₈ ) -alkyl;

26. carboxy;

27. carbamoyl;

28 = 2 is covered, carbamoyl (C, -C ₈₎ alkyl;

29. (C ₁ -C 4) alkoxycarbonyl (C ₁ -C 12) alkyl;

30, if η = 2, (C ₆ -C ₁₂₎ aryloxy (C, -C _e) alkyl,

which may be substituted in the aryl part as described under I. b) 5.; or

31. (C 1 -C 5 -aryl-1-C 1 -C 4 -alkoxy,

which may be substituted in the aryl part as described under I. b) 5. means;

c) R ^{1 is} hydrogen;

2. alkyl having 1-18 J atoms;

3. an aliphatic acyclic radical of the formula

C.H | 2, - b + η means in which double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an even number 2 to a;

4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical

of formula C _c H ( _2c - d - υ, which is optionally branched, wherein c is an integer of 3 to 20 and d is an even number of 0 to (c - 2);

5. aryl having 6-12 C atoms, which may be substituted as described under I. b) 5.;

6. (Ci-CiiJ-AryH ^ -Cal-alkyl or (CT-Cul-aroyl - ^ - Cl-alkyl, which may be substituted both as aryl under I. b) 5. described;

7. mono- or bicyclic, optionally partially hydrogenated heteroaryl or heteroaryl (Ci-C ₈ ) alkyl having 5-7 or 8-10 ring atoms, of which up to 9 ring atoms carbon and 1 to 2 ring atoms sulfur or oxygen and / or Represent 1 to 4 ring atoms sweetener, which may be substituted in the heteroaryl such as aryl under I. b) described 5.; or

8. if from c) 1.-8. not yet covered, the optionally protected side chain naturally occurring α-amino acid and formula R ¹ ^ H (NH ₂ J-COOH means;

d) R ² and R ^{3 are the} same or different and

1. hydrogen means;

2. alkyl of 1-18 C atoms;

3. an aliphatic acyclic radical of the formula C, H ₍₂ , _ _b +1, in which double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an even number 2 to a stand;

4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical

of the formula C _c H _l2c - d - υ, which is optionally branched, in which c is an integer from 3 to 20 and d is an even number from 0 to (c - 2);

5. di (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl;

6. (C 1 -C 5 alkanoyloxy-tC-oalkyl;

7. (C, -Ce) -alkoxycarbonyl- (C, -C,) -alkyl;

8. (CT-Cnl-aroyloxy-iCi-Csl-alkyl;

9. (C 9 -C 12) -Aryloxycarbonyloxy-IC 1 -C 1 -alkyl;

10. aryl with 6-12 C atoms; or

11. _(C7-C20) -aralkyl;

wherein the radicals mentioned under d) 8, 9, 10 and 11 may be substituted as described in I. b) 5. in the aryl moiety and

e) R ⁴ and R ⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms

and their physiologically acceptable salts,

II. Except compounds of formula II and their salts, wherein

a) n = 1 or 2;

b) R 1 is hydrogen;

2. alkyl with 1-8 C atoms;

3. alkenyl with 2-6C atoms;

4. cycloalkyl having 3-9 C atoms;

5. aryl with 6-12 C atoms;

by (C ₁ -C ₄ J--alkyl, (C, -C ₄₎ alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C, -C ₄₎ alkylamino, di- (C | -C ₄ ) -alkylamino, (C 1 -C 6 -alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl may be mono-, di-or trisubstituted;

6. Alkoxy with 1-4 C atoms;

7. aryloxy having 6-12 C atoms,

which may be substituted as described under II. b) 5.;

8. mono- or bicyclic heteroaryloxy having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms sulfur 'or oxygen atoms and / or 1 to 4 ring atoms are nitrogen, which may be substituted as described under II. B) 5. can;

9. amino (C, -C ₄ ) alkyl;

10. (C 1 -C ₄ ) alkanoylamino (C 1 -C ₄ ) alkyl;

11. (C 1 -C 6 -alloylamino-C 1 -C 4 -alkyl;

12. (C ₁ -C ₄ ) alkoxycarbonylamino (C ₁ -C ₄ ) alkyl;

13. (C 9 -C 18) aryl-C 1 -C 4 alkoxycarbonylamino-C 1 -C 4 -alkyl;

14. (Cg -C ₁₂ I-ArYl- (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl;

15. (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl;

16. di (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl;

17. guanidino (C ₁ -C ₄ ) alkyl;

18. imidazolyl;

19. indolyl;

20. (C 1 -C ₄ ) -alkylthio;

21. (C 1 -C ₄ ) -alkylthio! C, C ₄ ) -alkyl;

22. (Ce-Cwl-Arylthic-IC ^ Cil-alkyl;

which may be substituted in the aryl part as described under II. b) 5;

23. (Ce-CuJ-AryMC-C 1 -C 4 alkylthio,

which may be substituted in the aryl part as described under II. b) 5;

24. Carboxy (C, -C ₄ ) alkyl;

25. Carboxy;

26. carbamoyl;

27. carbamoyl-C 1-6 alkyl;

28 (C, -C ₄₎ alkoxy-carbonyl- (C | i -C ₄ alkyl;

29. (C 7 -C 12) aryloxy-iC 1-4 -alkyl,

which may be substituted in the aryl part as described under II. b) 5; or (C ₆ -C ₂ ) -aryl (C 1 -C ₄ ) -alkoxy, which may be substituted in the aryl part as described under II. b) 5;

c) R ¹ 1. hydrogen;

2. alkyl with 1-6C atoms;

3. alkenyl with 2-6 C atoms;

4. Alkynyl with 2-6 C atoms;

5. cycloalkyl having 3 to 9 C atoms;

6. cycloalkenyl having 5-9 C atoms;

7. (C3-C _e) cycloalkyl (C, -C ₄₎ alkyl;

8. (C5-C,) - Cycioalkenyl- (C, -C ₄₎ alkyl;

9. optionally partially hydrogenated aryl having 6-12 C atoms, which may be substituted as described II. B) 5.;

10. (Cg-C ^ aryl-IC-O-alkyl or (C ₇ -C _n I-ArOyI- (C, or C ₂₎ alkyl,

both of which may be substituted as described in the aryl part as described under II. b) 5;

11. mono- or bicyclic, optionally partially hydrogenated heteroaryl having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms, which may be substituted as described under II. B) 5.; or

12. if not covered by the above definitions, the optionally protected side chain means naturally occurring α-amino acid of formula R ¹ - CH (NH ₂ ) -COOH;

d) R ⁷ and R ^{3 are the} same or different and

1. hydrogen;

2. alkylm t1-6c atoms;

3. alkenyl with 2-6C atoms;

4. di- (C, -C ₄₎ -olkylamino- (C ₁ -C ₄₎ alkyl;

5. (C 1 -C 6) alkanoyloxy (C 1 -C ₄ ) alkyl;

6. (C-Cel alkoxy-carbonyloxy-IC-O-alkyl;

7. (C7 -C ₁₃ ) -Aroyloxy- (C, -C ₄ ) alkyl;

8. (Cg-C ₁₂₎ -Aryloxycarbonyloxy (C, -C ₄₎ alkyl;

9. aryl with 6-12 C atoms; 10. (C, r C ₁₂ ) aryl (C, C ₄ ) alkyl; 11. · (C, -C) - cycloalkyl; or

12. (Cj-Cg) -cycloalkyl- (C _r € ₄ ) -alkyl and

e) R ⁴ and R ^{5 have} the meaning defined under I. e),

And compounds of the formula IUN

a) n is 1 or 2;

b) R 1 is hydrogen;

2. alkyl with 1-8 C atoms;

3. alkenyl with 2-6 C atoms;

4 cycloalkyl having 3-9 C atoms;

5. Aryl having 6-12 C atoms, which is represented by (C ₁ -C ₄ -alkyl, (C ₁ -C ₄ -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C ₁ -C ₄ ) - Alkylamino, di- (C ₁ -C ₄ ) -alkylamino, (C ₁ -C ₄ ) -alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl may be mono-, dt- or trisubstituted;

6. Alkoxy with 1-4 C atoms;

7. aryloxy having 6-12 C atoms,

which may be substituted as described by B. b);

8. mono- or bicyclic heteroaryloxy having 5-7 or 8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms are nitrogen, as described under B. b) 5. may be substituted;

9. amino (C, -C ₄ ) alkyl;

10. (C ₁ -C ₄ ) alkanoylamino (C ₁ -C ₄ ) alkyl;

11. (C7-C, 3) -Aroylamino- (C, -C ₄₎ alkyl;

12 (C | -C ₄₎ -alkoxy-carbonylamino (C, -C ₄ i-alkyl;

13. (C ₆ -C, ₂ ) -aryl (C 1 -C ₄ ) alkoxycarbonylamino (C 1 -C ₄ ) alkyl;

14 (C _s -C ₁₂₎ aryl (C, -C ₄₎ alkylamino (C, -C ₄₎ alkyl;

15. (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl;

16. di (C 1 -C ₄ ) alkylamino (C 1 -C ₄ ) alkyl;

17. guanidino (C, -C ₄ ) alkyl;

18. imidazolyl;

19. indolyl;

20. (C 1 -C ₄ ) -alkylthio;

21. if η = 2, (C 1 -C ₄ ) -alkylthio {C, C ₄ ) -alkyl;

22. (Cg-C, ₂ ) arylthio {C, -C ₄ ) -alkyl,

which may be substituted in the aryl part as described under B. b) 5.;

23. (C ₆ -C, ₂ ) -aryl (C 1 -C ₄ ) -alkylthio,

which may be substituted in the aryl part as described under B. b) 5.;

24. if η = 2, cardoxy- (C, -C ₄ ) -alkyl;

25. Carboxy;

26. carbamoyl;

27. if η = 2, carbamoyl (C, -C ₄ ) alkyl;

28. (C 1 -C ₄ ) alkoxy-carbanoyl (C 1 -C ₄ ) -alkyl;

29. if η = 2, (Ce-C, ₂ ) -aryloxy- (C, -C ₄ ) -alkyl,

which may be substituted in the aryl part as described under B. b) 5.; or

30, (Cg-C _I-12 ArVl- (C ₁ -C ₄ I-BIkOXy,

which may be substituted in the aryl part as described under 8. b) 5.;

c) R ¹ for the side chain of valine, leucine, isoleucine, norvaline, norleucine, methionine, ornithine, cyclohexvlalanine, 2-thienylalamine, 3-thienylalamine, O- (Cj-C ₆ ) -alkyl-tyiosine, isovalin or C-phenylglycine stands;

d) R ³ and R ^{3 are the} same or different and

1. hydrogen;

2. alkyl with 1-6 C atoms;

3. alkenyl with 2-6C atoms;

4. di- (C, -C ₄₎ alkylamino (C ₁ -C ₄₎ alkyl;

5. (C-Csl-alkanoyloxy - ^ - C ^ -alkyl;

6. (Ct-Cel alkoxy-carbonyloxy-C 1 -C 4 -alkyl;

7. (C ₇ -C) ₃ I-Aroxyalkyl- (C ₁ -C ₄ -alkyl);

8. (Cg-Cul-Aryloxycarbonyloxy-IC-C ^ -alkyl;

9. aryl with 6-12 C atoms;

10. (Cs-Cwl-AryHC ^ I-alkyl;

11. (C 1 -C 8 -cycloalkyl; or

12. (C 1 -C 5 -cycloalkyl-C 1 -C 8 -alkyl) and

e) R ⁴ and R ^{s have} the meaning defined under AI e) and their physiologically acceptable salts, or

C., in which

a) n, R, R ⁴ and R ^{5 are} as defined above under B. and

b) R ^{1 is} the side chain of alanine, lysine or ε-acyllysine and

c) R ² and R ^{3 are} identical or different and propyl, isopropyl, η-butyl, isobutyl, sec-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, phenyl, α- or β-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, benzhydryl, α-methylbenzyl, α-methylenebenzyl, 2- , 3- or 4-phenylbenzyl, Bibenzy! -A-yl, styryl, 1-indanyl or 9-fluorenyl, where phenyl and phenyl as a substructure of one of the radicals mentioned as defined under A. II. B) 5. Substituted it ' ., or one of the radicals R ² and R ^{3 is} hydrogen and the other is as defined above, or R ^{2 is} benzyl and R ^{3 is} Banzyl, hydrogen or one of the definitions mentioned above and their physiologically compatible salts.

R ⁴ and R ⁵ together with the atoms carrying them is preferably a mono-, bi- or tricyclic ring system having 3 to htiterocyclisches 15Ring-carbon atoms with up to 2, preferably up to 1 ⁿ 'ng-S-atom (s) , and up to 1, preferably, no additional ring N atom, preferably from the series pyrrolidine, T'hzolidin, tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, irdoline, octahydrocyclopentalbjpyrrole, 2-azaspir ^> (4.5) decane, 2-azaspiro [ 4.4) nonane, spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine], spiro [(bicyclo- [2.2.2] octane-2,3'-pyrrolidine], 2-azatricyclo [4.3. 0.1 * ' ⁹ ] decane, decahydro-cyclohepta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [clpyrrole, 2,3,3a, 4,5,7a-hexahydroindole, 1,2,3,3a, 4,5a-hexahydrocyclopenta- [ blpyrrolund2-AzabicycloI3.1.0) hexane.

As salts of the compounds of the formula I and II come, depending on the acidic or basic nature of these compounds, alkali or Alkaline earth salts or salts with physiologically acceptable amines or salts with inorganic or organic acids such as

z. As HCI, HBr, H ₂ SO ₄ , maleic acid, fumaric acid, tartaric acid, citric acid in question.

The capillary structure of the blood vessels of the brain is different from that in other areas of the body. The Brain capillaries are surrounded by a layer of endothelial cells that are particularly tight (due to "tight junctions")

linked together. Brain capillaries also have much less of those pores, through which in others

Blood capillaries, the low molecular weight substances in the surrounding tissue into or out of this can. On

In this way, the property of lipid solubility in the brain capillaries is given a much greater significance for the

Distribution between the blood and the surrounding tissue, as this is the case for the rest of the body. Therefore, compounds of the formula II are preferred in which at least one of the radicals R, R ¹ , R ² and R ^{3 is} a lipophilic Radical, such as a long-chain aliphatic, alicyclic-aliphatic, araliphatic or heteroaraliphatic radical, a

sufficiently large alicyclic radical or an appropriately substituted acyclic, aromatic or heteroaromatic

Rest stands, or contains such as a substructure. It comes ii. In this regard, especially compounds of formula II in question, in which

R1 is (C9-C, _B ) -alkyl;

2. (Cr-Ce) -alkenyl;

3. a residue of 4-18 C-atoms, which is defined as above under A.I. b) 3. and wherein b is> 4;

4. a radical of 4-20 carbon atoms, which is defined as above under A.I. b) 4. and wherein d is> 2;

5. as defined above under A.I. b) 5.;

6. heteroarylalkyl, which is defined as above under A.I. b) 9;

7. amino- _(C6-C8) alkyl;

8. amino-fCu-Cel alkyl;

9. (C 1 -C ₄ ) alkanoylamino (C ₆ -C ₆ ) alkyl;

10. (CT-Cul-aroylamino-ICs-Cil-alkyl;

11. (C 1 -C ₄ ) alkoxycarbonylamino (C 1 -C 12) alkyl;

12. (Q ₅ -C ₁ j) aryl- (C ₁ -C ₄ ) alkoxycarbonylamino- (Cs-C () -alkyl;

13. (C _f r C, ₂ ) aryl (C 1 -C ₄ ) alkylamino (C ₅ -C 12) alkyl;

14. (C 1 -C ₄ ) alkylamino (C ₆ -C ₄ ) alkyl;

15. di (C 1 -C ₄ ) alkylamino (C (rC _e ) alkyl;

16. guanidino-fCs-cal-alkyl;

17. ifn = 2is, (C, -C ₄ ) -alkylthio (Cs-C,) -alkyl;

18. (Cr-CjJ-arylthio-ICs-C.l-alkyl,

which may be substituted in the aryl part as described above under A.I.

19. (Or-CJ-AryMcg-CeJ-alkylthio,

which may be substituted in the aryl part as described above under A.I.

20. if η = 2 , carboxy (Cs-C _e ) -alkyl;

21. Carbamo>: Cs-C _e ) -alkyl;

22. (C 1 -C ₄ ) alkoxycarbonyl (C 6 -C ₄ ) alkyl;

23. if η = 2, (Cg-C.jl-aryloxy-ICg-C.J-alkyl,

which may be substituted in the aryl part as described above under A.I. or

24. (C 1 -C 12) -aryl (C 1 -C 8) -alkoxy which may be substituted in the aryl part as described above under A.I. Furthermore, compounds of the formula II are suitable in which

R ¹ 1. (Cr-CJ-alkyl;

2. (Cr-CJ-alkenyl;

3. (C7 -C ") alkynyl;

4. a radical having 4-18 C atoms, which is defined as above under A.I. c) 3. wherein b 2 is 2 and only double bonds are present;

5. a radical which is defined above under A.I. c) 4. above. Cycloalkyl and cycloalkenyl with up to 9 carbon atoms excluded;

6. optionally substituted (Cg-Cu) AryMCs-Cel alkyl;

Λ optionally substituted (C ₇ -C, al-aroyl-fCr-Csl-alkyl or

8. optionally substituted heteroaryl- (C 1 -C ₆ ) -alkyl,

and those compounds of the formula H in which R ^{1 is} the side chain of valine, leucine, isolsusine, norvaline, norleucine, mothionine, ornithine, cyclohexylalamine, 2-thienylalanine, 3-thiesylalamine, O- (C 3 -C ₆ ) -alkyl tyrosine, Isovalin, or C-phenylglycine. R ² and R ³ are then the same or different and are preferably

1. (Cr-C ") - Alky !;

2. (C _r -C ₁₈₎ alkenyl;

3. a radical of 4-18 C atoms, which is defined as in A.I. d) 3 above, and wherein b is 4;

4. a radical defined as under AI d) 4 above, excluding (C 1 -C 9) cycloalkyl and (C 1 -C ₆ ) cycloalkyl (C 1 -C ₄ ) alkyl;

5. di (C 1 -C ₄ ) alkylamino (C ₆ -C ₆ ) alkyl;

6. (^ -Cyc-alkanoyloxy-ICs-Cel-alkyl;

7. (C, -C ₆ ) alkoxycarbonylcoxy (C ₆ -C _e ) alkyl;

8. (Cr-Cnl-aroyloxy-ICs-Cgl-alkyl;

9. (Ce-Cu-aryloxycarbonyloxy-fCr-Cel-alM; 10. (Cj-C.ol-aralkyl;

wherein the radicals mentioned under d) 8, 9 and 10 can be substituted in the aryl moiety as described above under Al b) 5; or one of R ³ and R ³ is hydrogen and the other is as defined above.

Furthermore, such compounds of formula II are preferred, warin R ² and R ^{3 are} different from each other, and propyl, isopropyl, η-butyl,! Sobut / l, sec-biityi, n-pem A ₁ sec-pentyi, iso-pontyl, Neo-pentyl, n-hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohyxanyl, cycloheptenyl, Menthyl, phenyl, α- or β-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, benzhydryl, α-methylbenzyl,

a-methylenebenzyl, 2-, 4- or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl, wherein phenyl and

Phenyl as a substructure of one of the radicals mentioned, where appropriate, as defined above under A.I.

or one of R ² and R ^{3 is} hydrogen and the other is as defined above, or R ^{2 is} benzyl and R ^{3 is} benzyl, hydrogen or any of the definitions given above.

The invention broadly relates to a process for the preparation of a compound of formula II which is characterized

that their F ^r agmente in a suitable solvent optionally 'r. Presence of a base and / or a

Coupling aid is reacted with each other, optionally intermediately formed unsaturated compounds, such as Schiff bases, reduced, protecting reactive groups from temporarily introduced protecting groups, compounds of the Formula II with free carboxyl group (s) may optionally esterify the compounds obtained into theirs

physiologically acceptable salts.

In the manner mentioned, it is possible, for example, to react compounds of the formula V with compounds of the formula VI.

R ³ OOC-CH HOOC-NH-CH-NH-CH- (CH ₀₎ -R

Il I I <- ''

RR ⁵ R ¹ COOR ²

(V) (VI)

The reaction of these compounds can be carried out, for example, in analogy to known peptide coupling processes in an organic solvent such as DMF, CH ₂ Cl ₂ , DMA in the presence of coupling aids such as carbodiamides (eg dicyclohexylcarbodiimide), diephenylphosphoryl azide, alkanehorphoric acid anhydrides, dialkylphosphinic anhydrides or N, N-succinimidyl carbonate in a solvent as CH ₃ CN are performed. Amino groups in compounds of formula V can be activated with tetraethyldiphosphite. The compounds of the formula VI can be converted into active esters (for example with 1-hydroxybenzotriazole), mixed anhydrides (for example with chloroformates), azides or carbodiimide derivatives and activated therewith (compare Schröder, Lübke, 3 Peptides , Volume 1, Nsw York 1965, pages 76-136). The reaction is preferably carried out between -2O ⁰ C and the boiling point of the reaction mixture.

Likewise lasson, also compounds of formula VII with compounds of formula VII! react to form compounds of formula II,

R ⁵ OOC-CH-NC-CH-Y ¹ Y ² -CH- (CH _O ) -R

ι α ς I 'I ι! 2 * ⁿ

R ⁴ R ⁵ 0 R ¹ COOR ^

(VII) (VIII)

wherein either Y 'is Amihu and Y ^{2 is} a leaving group or Y ^{1 is} a leaving group and Y ^{2 is} amino.

Suitable leaving groups are for. B. Cl, Br, I, alkylsulfonyloxy or Ary ulfonyloxy. Alkylation of this type is conveniently carried out in water or an organic solvent such as a lower one

aliphatic alcohol (such as ethanol), benzyl alcohol, acetonitrile, nitromethane or glyme at a temperature between 2O ⁰ 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 through.

Furthermore, compounds of the formula IX can be condensed with compounds of the formula X, R ³ OOC-CH-NCC- = G ¹ Q ² = C- (CHj-R

U Ir il h ι ο ^{2 η}

R * R 'OR ¹ COOR ^

(IX) (X)

where either Q 'is amino + hydrogen and Q ² is oxo or Q ^{1 is} oxo and Q ^{2 is} amino + hydrogen. The condensation is conveniently carried out in water or an organic solvent such as a lower aliphatic alcohol at a temperature between -20 ° C and the boiling point of the reaction mixture in the presence of a reducing agent such as NaBH ₃ CN to give compounds of formula I directly , However, it is also possible to reduce the Schiff's bases or enamines formed as intermediates, if appropriate after prior isolation, to form compounds of the formula II, for example by hydrogenation in the presence of a transition metal catalyst.

Finally, the implementation of verbin '· leads to such. that of the formula IX (Q ¹ = H + NH ₂ ) with compounds of the formula XI or their reaction with compounds of the formulas X><and XIII, suitably in the presence of a base, such as sodium alcoholate, in an organic solvent, such as a lower alcohol a temperature between -10 ⁰ C and the boiling point of Raaßgemisches to compounds of formula II (n = 2 /,

R ² OOC-CH = CH-COR (XI)

OCH COOR ² (XII)

R-CO-CH _{3 t} (XIII)

whereby intermediately formed Schiff bases are reduced as described above and a carboxyl group is reduced (for example with a complex hydride) to methylene.

In the above formulas V-XIII, RR ⁶ and η are as defined in Formula II. Protective group temporarily introduced to protect non-reactive reactive groups) *; After termination of the reaction, they are split off in a manner known per se (see Schröder, Lübke, loc cit., Pages 1-75 and 246-270, Greene, "Protective Grups in Organic Synthesis", New

The novel compounds of the general formula I or II can also be prepared, for example, using esterification methods which are familiar to the person skilled in the art (see, for example, Buchler, Pearson, Survey of Organic Syntheses, Vol 1, New York 1970, pp. 802-825; Houben-Weyl, Methods of Organic Chemistry, Volume E5, 1985, pp. 656-773).

a) The reaction of a mono- or dicarboxylic acid of the general formula I or II in which at least one of the radicals R ² and R ^{3 is} hydrogen, with a corresponding alcohol under acid catalysis (mineral acid or acidic ion exchanger).

b) The alkylation of a mono- or dicarboxylic acid of the general formula I or II, wherein at least one of R ² and R ^{3 is} hydrogen, with a compound R ² Z or R ³ Z, wherein 7. a nucleophilically displaced leaving group (such as Halogen, tosylate) in a polar protic or dipolar aprotic solvent in the presence of a base such as alkali metal hydroxide or alcoholate.

c) The reaction of a mono- or dicarboxylic acid of the general formula I or II, wherein at least one of the radicals R ² and R ^{3 is} hydrogen, with a diazoalkene in an inert organic solvent such as CH ₂ Cl ₂ .

The ncotropic effect of the compounds according to the invention was tested on mice having a body weight of 20-25 g in the inhibitoiy (passive) avoidance test (step-through mode). A modified form of the methods described by J. KOPP, Z. BODAL ^ CKY and M.E. JARVIK's test method has been described by J. BURES, O. BURESOVA and J. HUSTON in "Techniques and Basic Experiments for the Study of Brain and Behavior", Elsevier Scientific Publishers, Amsterdam (1983) According to these references, a substance is then designated as nootropic effective if it is capable of reversing the amnesia or scopolamine-induced amnesia induced by electroconvulsive shock in the experimental animals.

The experiments were carried out according to modified test methods. As a comparative compound, the known nootropic 2-oxc-i-pyrrolidinylacetic acid amide (piracetam). The clear consideration of the compounds according to the invention over the comparison substance was demonstrated by the fact that the scopolamine-induced amnesia in the inhibitory avoidance test met with a MED (minimally effective dose) of 1-30 mg / kg p. o. can pick up. The reference substance has a med of about 500-1000 mg / kg p.o.

The compounds of the invention usually have only a low toxicity.

The compounds of the invention are due to their pharmacological properties in addition to the treatment of hypertension for the treatment of cognitive dysfunctions of different origins, as they are, for. B. Alzheimer's disease or senile dementia occur (suitable.

The invention therefore further relates to the use of the compounds according to the invention in the treatment and prophylaxis of cognitive dysfunctions in hypertensive patients.

The invention further comprises medicaments containing said compounds, processes for their preparation and the use of the compound genes according to the invention in the preparation of medicaments used for the treatment and prophylaxis of the abovementioned diseases.

In practicing the method of the present invention, the above-described angiotensin converting enzyme inulin may be applied to mammals such as monkeys, dogs, cats, rats, humans, etc.

The medicaments are prepared by methods which are known per se and familiar to the person skilled in the art. The medicaments which are used according to the invention are pharmacologically active compounds (= active ingredient) either as such or preferably in combination with suitable pharmaceutical excipients in the form of tablets, drakes, capsules, suppositories, emulsions, suspensions or solutions, the active substance content being up to about 95%, advantageously between 10 and 75%.

Which excipients are suitable for the desired drug formulation is familiar to the skilled person due to his expertise. In addition to solvents, gelling agents, suppository bases, tablet excipients and other drug carriers, it is possible to use, for example, antioxidants, dispersants, emulsifiers, defoamers, flavoring agents, preservatives, solubilizers or dyes.

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

For an oral application form, the active compounds are mixed with the appropriate additives such as carriers, stabilizers or inert diluents and brought by the usual methods in suitable dosage forms such as tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions , As inerto carrier z. Gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, especially corn starch. The preparation can be carried out both as a dry and as a wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils such as sunflower, oil or cod liver oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, if desired with the customary substances such as solubilizers, emulsifiers or other excipients in solution,

Brought suspension or emulsion. The solvents are ζ. B. in question water, physiological saline or alcohols, eg. As ethanol, propanol, glycerol, besides sugar solutions such as glucose or mannitol or a mixture of the various solvents mentioned.

embodiment

The invention is explained in more detail below with reference to some examples. The following Examples 1-6 indicate the use forms for the prophylaxis and treatment of cognitive dysfunctions according to the method according to the invention. The compounds according to the invention can be brought into the corresponding use forms analogously to the examples.

example 1

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

1000 tablets each containing 10 mg of 2- [N- (1-S-carbethoxy-S-phenyl-propyl-S-alanyl-i S, 3S, 5S-2-azabicyclo [3.3.0] octane-3-carboxylic acid are manufactured with the following tools:

2-lN - (] - S-carbethoxy-3-phenyl-propyl) -S-alanyl] -

(1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid 10g

Cornstarch 140g

Gelatin 7.5g

Microcrystalline cellulose 2,5g

Magnesium Stearate 2.5g

2- [N- (1-S-Cerbethoxy-3-phenylpropyl) -S-alanylj- (1S, 3S, 5S) -2-ozabicycyclo [3.3.0loctan-3-carboxylic acid and cornstarch are mixed with a mixed gelatinous gelatin solution. The mixture is dried and ground into granules. Microcrystalline cellulose and magnesium stearate are mixed with the granules. The resulting granules are compressed into 1000 tablets, each tablet containing 10 mg of the ACE inhibitor. These tablets can be used to treat and prevent cognitive dysfunction.

Example i

In analogy to Example 1, 1000 tablets are prepared, each containing 10 mg of 1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) -spirobicyclo [2.2.2] octane. 2,3'-pyrrolidine-5'-carboxylic acid.

Example 3

Gelatin capsules each containing 10 mg of 1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyll (3'R, 5'S) -spirobicyclo (2.2.2] octane-2,3' pyrrolidine-5'-ca.bonsäure are included

1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyll (3'R, 5'S) -spirobicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-carboxylic acid 10mg Magnesium stearate 1 mg

Lactose 214 mg

These capsules can be used to treat and prevent cognitive dysfunction.

Example 4

The preparation of an injection solution is described below:

2- [N- (1-S-Carboxy-3-phenyl-propyli-S-alanyl] -

(1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid 250 mg

Methylparaben 5g

Propylparaben 1 g

Sodium chloride 25g

Water for injection 51

2- [N- (1-S-carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicycloI3.3.0-octane-3-carboxylic acid, the preservatives and sodium chloride are reported in FIG Dissolve water for injection and make up to 51 with water for injection. The solution is sterile filtered and aseptically filled into pre-sterilized bottles which are sealed with sterilized rubber caps. Each bottle contains 5ml solution.

Example 5

Tablets which may be used for the treatment or prophylaxis of cognitive dysfunctions are prepared as described in Example 1, except that instead of 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyll - (1S, 3S, 5S) -2-azabicyc! O [3.3.0] octane-3S-carboxylic acid

2- (N- (1-S-carboxy-3-phenylpropyl) -S-alanyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or 1- (N- (1 -S-carboxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid or i-tN-dS-carbethoxy-S-phenyl-propyl-S-alanylloxy .S.SaASJa-hexahydroilHlindol ^ -S-endo-carboxylic acid or

i-fN-dS-carboxy-S-phenyl-propyD-S-alanyll-cis ^^. aaASJa-hexahydrodHjindol ^ S-eodo-carbonsaureoder2- [N- (1-S-Carboxy-3-phenyl-propyl) -S -ly6yl] - (1S, 3S, 5S) -2-azableyclo [3.3.0] octane-3-carbonsäureoder2- | N- (1S-carboethoxy-3-cycloliexyl-propyl) -S-alanyl] - (1 S , 3S, 5S) -2-ajabicyclo [3.3.0] octane-3-carboxylic acid or

N- (1S-Carboxy-3-cyclohexyl-propyl) -S-lysyl (1S, 3S, 5S) -2-azabicyclo [3.3.0Joctan-3-carbonsäurooder

1 '- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] -exo-spirobicyclo [2.2.2loctan-2,3'-pyrrolidin-5'-S-yl-carboxylic acid or (SS SJ-i-methyl ^ -d-carbethoxy-S-phenyl-propyD ^ H-undecahydro-cyclopenta ^ ^ .Blpyrroloti -alpyrazin-Se-dionoder1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -S alanyl) -endo-spirobicyclo [2.2.2] octane-2,3-pyrrolidinyl-5'-S-carboxylic acid.

Example β

An injection solution is prepared analogously to the procedure described in Example 4, with the exception that instead of

2- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0loctan-3-carbonsäure2- [N- (1- S-carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0loctan-3-carbonsäureoder1- [N- (1S-carboethoxy-3-phenyl- propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindol-2-carbonsäurehydrochloridoder1- [N- (1-S-carboxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS ) octahydroindole-2-carboxylic acid or 1 - [NCS-carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-2,3,3a, 4,5,7a-hexahydro [1H] indole-2-S -din-carboxylic acid or 1 - [N - (- S-carboxy-3-phenyl-propyl-S-alanyl-cis ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ -3-phenyl-propyl) -S-lysyll- (1S, 3S, 5S) -2-nzabicyclo [3.3.0] octan-3-carbonsäureoder2- [N- (1S-carboethoxy-3-cyclohexyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octan-3-carbonsäureoder2- [N- (1S-carboxy-3-cyclohexyl-propyl) -S-lysyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octan-3-carbonsäureoder1 '[N- (1S-carboxy-3-phenylpropyl) -S-alanyl | -endo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidin in-5'-S-carbonsäure1'IN-! 1-S-Carboxy-3-phenylpropyl) -S-alanyl) -exo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidin-5'-S be applied carboxylic acid.

The following examples 7-95 should! the inventive method for preparing the novel compounds of formula I.

or Il explain, without the invention would be limited thereto.

Example 7

2- [N- (1S) -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -cis, endo-2-a7abicyclo [3.3.0] ocane-3-S-carboxylic acid octadecyl ester 23g of cis prepared analogously to EP-A-79022 , endo-2-azabicyclo | 3.3.0] octane-3-carboxylic acid octadecyl esters are reacted with 6.7 g of HOBt, 13.8 g of N- (1S) -carbethoxy-3-phenylpropyl) -S-alanine, and 10.2 g of dicyclohexylcarbodiimide in 200 ml Dimethylformamide reacted. After stirring for 3 hours at room temperature, it is filtered off from precipitated dicyclohexylurea, concentrated, taken up in 11 ethyl acetate and shaken with 3x 500 ml of 5% NaHCO ₃ solution. The organic phase is concentrated, chromatographed with ethyl acetate / petroleum ether in the ratio 2: 1 on a column of 1 kg of silica gel and thus separated into the title compound and the diastereomeric (S, S, R) compound.

Example 8 1- [N- (1S) -Dodecyloxycarbonyl-3-phenylpropyl) -S-alanyl] -2S, 3aR, 7aR-octohydrolndole-2-carboxylic acid

a) 1- [N- (1S) -dodecyloxycarbonyl-3-phenylpropyl) -S-silanyl] -2S, CR, 7aR-octahydroindole-2-carboxylic acid benzyl ester 1OmMoI S-alanyl-2S, 3aR, 7aR-octahydroindole-2 B6nzyl carboxylic acid esters (prepared according to EP-A-84164) are dissolved in 30 ml of anhydrous ethanol. The solution is adjusted to a pH of 7.0 by means of ethanolic potassium hydroxide and 1 g of powdered molecular sieve (4 A) and then 10mMoI 2-keto-4-phenyl-butyric acid dodecyl ester are added. A solution of 1 g of sodium cyartoborohydride in 10 ml of anhydrous ethanol is slowly added dropwise. After a reaction time of 20 hours at 20 to 25 ⁰ C, the reaction solution is filtered and the solvent abd6still> ert. The residue is taken up in ethyl acetate / water. After evaporating the ethyl acetate phase, the residue is chromatographed on silica gel with ethyl acetate / cyclohexane (1: 4).

b) The compound obtained according to a) is hydrogenated in ethanol in the presence of palladium-charcoal (10%) at 20-25 ° C under atmospheric pressure. After separation of the catalyst, the solution is mixed with 0.5 η ethanolic hydrogen chloride until acidic reaction. The solution is concentrated in vacuo and the residue triturated with diisopropyl ether for crystallization.

Example 9

2- [N - [(2 S) -ethoxycarbonyl-3-phenylpropyl] -L-alanylI- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octan-3-carbonsäureisobutylester2,0Cg (4,80mmol) 2 - [N - [(1S) -cthoxycarbonyl-3-phenylpropyl] -L-alanyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid was dissolved in 100 ml of isobutanol, 0.1 ml of concentrated sulfuric acid added and the mixture was refluxed for 15 hours. After cooling, the solvent was removed on a rotary evaporator and the residue was evaporated in a rotary evaporator

Added methylene chloride. This solution was once each with water, saturated aqueous NaHCO ₃ solution and again Water, dried over MgSO ₄ , concentrated and purified by chromatography on 200 g of silica gel (eluent Methylene chloride / ethyl acetate 8: 2) separated from impurities. Yield: 51% of theory oily product. Ia] J ⁰ = -28.2 "(c = 1, methanol). This product was dissolved in ether, adjusted to pH 2 with saturated ethereal hydrochloric acid, the solvent was evaporated and

the residue crystallized from diisopropyl ether.

Hydrochloride data:

M.p. 123-124 ⁰ C

[a) S ° = + 17.7 ° (c = 1, methanol)

Example 10

2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] (1S, S, 5S) -2-azablcyclo [3.3.0] octane-3-carboxylic acid benzhydryl ester, 2.07g (4, 97 mmol) of 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid were dissolved in 50 μl of acetone and, with ice-cooling, a solution of 1.16 g (5.98 mmol) of diphenyldiazomethane in 50 ml of acetone was added dropwise. The solution was then stirred for 26 hours at room temperature, the solvent was evaporated on a rotary evaporator and the residue was purified by flash chromatography on 150 g of silica gel (mobile phase: toluene / ethanol 98: 2)

 Yield: 2.55 g (88%) oily product

la] g ° = -33.8 ° (c = 1, methanol).

Example 11

2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S,) - 2-aznblcyclo [3.3.0] octane-3-carboxylic acid octadecyl ester 2.08g ( 5.00 mmol) 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid were dissolved in 25 ml dissolved absolute dimethylformamide, 1.00 g (lO.Ommoi / potassium hydrogen carbonate was added and stirred for 90 minutes at 40 ⁰ C. After cooling to room temperature a solution of 4.00 g (12.0 mmol) of 1 -Bromoctadecan in 20 ml of absolute dimethylformamide was added dropwise and Stirred for 4 hours at 40 ⁰ C.

The solution center! was removed on a rotary evaporator at about 1 Torr and the residue partitioned between water and methylene chloride. The organic phase was separated, dried over MgSO ₄ and concentrated. From the crude product (5.40 g) were isolated by column chromatography on 200 g of silica gel (eluent toluene / ethanol 99: 1) 3.05 g (92%) of the product.

[a] g ° = -19.6 ° (c = 1, methanol)

Example 12 2- [N - {(1S) -benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-oza-cyclic [3.3.0-octan-3-carboxylic acid benzyl ester

a) (2R) -hydroxy-4-phenylbutyric acid benzyl ester

To a solution of 7.40 g (41.1 mmol) of (2R) -hydroxy-4-phenylbutyric acid in 200 mL of absolute acetone was added, while cooling with ice for 20 minutes, a solution of 10.1 g (52.1 mmol) of diphenyldiazomethane in 400 mL of absolute acetone was added dropwise and the reaction mixture stirred for 20 hours at room temperature. The solvent was evaporated and the residue triturated with 100 ml of petroleum ether. There were obtained 6.4 g of crystalline product. The mother liquor was evaporated and isolated by column chromatography on 700 g of silica gel (eluent toluene / ethanol 99: 1) further 6.0 g of the product

 Total yield: 12.4g (87%)

 Mp 88-8. 'C.

 [a] g ° = -1.8 ° (c = 5, methanol).

b) 2- [N - [(1 S) -benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] -dodan-3-carboxylic acid benzyl ester b |) 1, 80 g (4.33 mmol) of 2- (N-tert-butoxycarbonyl-L-alanyl) - (1S, 3S, 5S) -2-azabicyclo [2.3.0] rctan-3-carboxylic acid benzyl ester were dissolved in 4.5 ml of trifluoroacetic acid and Stirred for 90 minutes at room temperature. The reaction solution was evaporated and stripped with toluene three times on a rotary evaporator to remove trifluoroacetic acid esters. Dor residue, consisting of 1.90 g of 2- (L-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester trifluoroacetate, was dissolved in 10 ml of absolute methylene chloride (solution A). ,

bj) 1.63 g (4.71 mmol) of (2R) -hydroxy-4-phenyl-butyric acid benzhydryl ester from example 12a) were dissolved together with 0.4 ml of absolute pyridine in 25 ml of absolute methylene chloride and at -10 ° C. within 20 minutes of 1 , 41 g (5.00 mmol) Trifluormethansulfonsaureanhydrid added dropwise. Subsequently, the cooling bath was removed and after reaching room temperature, the solvent was evaporated. The residue was filtered through 50 g of silica gel with methylene chloride and concentrated. There were obtained 1.70 g of 4-phenyl- (2R) -trifluoromethylsulfonyloxy-butyric acid benzhydryl ester and dissolved in 10 ml of absolute methylene chloride (solution B).

b ₃ ) To solution A was added 1.0 ml (7.40 mmol) of triethylamine and then slowly added dropwise at ⁰ ° C. solution B. The cooling bath was removed and the reaction solution stirred at room temperature for 19 hours, then washed three times with water, dried over MgSO ₄ and evaporated. 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 were obtained. Mp 81-85 ° C Ia] I ⁰ -55.2 ° (c =!, Methanol)

By suitable combinations of the methods described in the preceding examples, the following further compounds are prepared (the designation of the ring systems corresponds to that for the compounds of general formulas I and II):

R- ⁷ OOC-CH-NCR ⁴ R ⁵ 0

cn - m:

OH _n

CH - CH,

¹ 2 '

- CH,

For example, R ³ UOG-CH-IT-iH5

R-

13 ring system A -C ₂ H ₅ -c, (CH ₃ ) ₂ 14 ring system B -C ₂ H ₅ -0112-011 (0113) 2 15 ring system G -Clio -CH ₂ -Q 16 ring system G -C ₂ H ₅ -CH (C ₆ V ₂ 17 ring system D -C ₂ H ₅ 18 ring system D -C ₂ H ₅ 19 ring system D -C ₂ H ₅  Ο 20 ring system D ^ ₂ H ₅ OO 21 ring system D -C ₂ H ₅ ΌΟ 22 Λ ingsystem Ώ -C ₂ H ₅ - <CH ₂ > 3 ^ Q 23 ring system -C ₂ H ₅ - (CH ₂ ) ₅ -CH ₃ 24 ring system F -CH ₃ -UII (C ₆ H ₅ ) ₂ 25 ring system G -C ₂ H ₅ -Cli (CH ₃ ) ₂

m G

-cmc ₆ ii ₅ ) ₂

R ⁵ OOC - CH - II - G - CH

¹ A 'h "' R ^ R ^J 0 CH, CII - CII ₀ ~ CH ₀ - // \

I ρd ά

COOR ^

Ex "

R ³ OOC-CH-Ii-R ⁴ IP

Ring system G

Ring system H

Ring system HG ₂ H ₅

R ³

CH ₂ -GH

Ring system H

Ring system II

Ring system H

Ring system JI G ₂ H ₅ G ₂ H ₅ ^C 2 ^H 5

OIL ·

Ring system H

Ring system II

Ring system I

Ringo system LG ₂ H ₅

C ₂ H ₅

C ₂ H ₅

-CIL

36 Ring system H C ₂ H ₅ -CiI (C ₆ H ₅ J ₂ 37 Ring system H C ₂ H ₅ - < ^c " ₂ > 8 <3> 38 ling system I CH, 39 Ring system J C ₂ H ₅ -CH (C ₆ H ₅ ) J,

R ³ OOC

- GU

Ii - C R °

 f

GII - ΙΠΙ

GK - GII _n ι ⁿ <^ COOR

R ³ OOC-CH-N-

42 Ringaystem Li C ₂ H ₅ - (CH ₂ ) ₂ -CH (CH ₃ ) ₃ 43 ring system ii C ₂ H ₅ -GH (4-P-CgIL) ₂ 44 ring system ii G ₂ H ₅ -CII (CH ₃ ) ₂ 45 ring system O C ₂ H ₅ - (OH ₂ > ₂ -0 46 ring system P C ₂ H ₅ Ό 47 ring system Q C ₂ H ₅ ring system A GH ₀ GIi (GH-,),

Ring system B ClI

Ring system D

GIL · -

-G (CII ₃ ) ₃

Ring system C CI-I (CgH ₅ ) ₂ -II

52 ring system D CH ₂ -GH (GH ₃ ) 2 -GII (C ₆ H ₅ ) > 53 Ringaystem D Cn ₂ -GIi (GII ₃ ) 2 -H 54 ring system D GII ₂ -CH (GII) 2 -GIi 2

Ring system D

GH (G ₆ H ₅ )

Ring system D UH (CgII _n ) ₂ -H

R- ³ OOC-CII-H-C-CiI-1IH-CiI-CIU-CH,

CH-

co jir

Ex.

R ³ OOC-CH-HR-

Ringaystem E

Ring system E

Ring system G

-CH ₂ -CJH (CiI ₃

Ring system G -CH - (CII ₂ ) -CH ₃

-CIL

-C

Ring system H-CH ₀ CH (CIU)

Ring system H -CH ₂ CiI (CH ₃ )

Ring system H

CligCH (CIU -CH,

-II

-CiI (CgIU) ₂

Ring system H-CH,

Ring system H-CIL

-CIL

O)

C (CH ₃ J ₃

Ring system II -CH (CgIU) ₂ -CH,

Ring system H

-CH (CgH ₅ ) ₂ -H

Ringsysteji II

-CH (C ₆ H ₅ ) ₂

Ring system II -CH (CGH _{r) 2} -C (CI

Ring system I

-O

Ring System J - (CIU) ^ -

R-OOC - CH ι λ

R ⁴

N - GR ⁵

II - IYH GH.

CII - CH ₀ - CII ₀

cooir

Ex,

R ^ OOC-CH II

11-

R ⁴ R VJL K O -CH ₂ -Q 72 ring system L -CV ₂ -Q - (CH ₂ ) ₅ -CH ₃ 73 ring system U - (CIU) ₀ -UH (GH. <- <- ₃ ) ₂ -CH (CH ₆ H ₅ ) ₂ 74 ring system Ν -CH (C ₆ II ₅ ) ₂ -C (CIV ₂ -OH ₂ CH ₃ 75 ring system O -cn (CH ₃ ) ₂ -GH (C ₆ H ₅ ) 2 76 ring system P -CII (CH ₃ ) ₂ -C (CH ₃ J ₃ 77 ring system Q -C (CH ₃ ) ₃ -CH ₂ -Q 78 ring system D C ₂ H ₅ I.ienthyl 78a ring system G j.lentliyl CH _o CH _r 2 ο 5 78b ring system

R ³ OOC-ClI

r ⁴

Ii-G

ii

(CH - YY 3 / m

Ex.

R- ³ OOC-CH-II-

R ³

R-OOC-CH ₂ -II-CII (CgH ₅ )

82 'R ³ OOG-GH ₂ -IJ-

-Chg-S-CO-C

Ringsys R ⁴ R ⁵ -CH (C ₆ H ₅ J ₂ -CH ₂ SH 1 79 Ring3yc tem O - (CH ₂ J ₅ -CH ₃ -CH ₂ SH 1 80 tem O

-GH (GIL ·).

-CHP-S-UO-C- (CH ₃ )

InI-CH- (GH ₂ )

R ³ 0OC -CH-Ii G - Il 0 * GH CH, X ² m X ² m Ex " R ³ OJC-CiI-Ji R ³ InI-CH- (GH ₂ ) ₂ ~ ζ ~ j) ¹ 84 R ³ OOG-GH ₂ -Ii -CHU-FC ₆ HJ ₂

CH,

-HH-GiI- (CH ₂ ) ₂

86 Ring system H H

-CH ₂ -P- (CH ₂ ) ₄

0 ι

0K

Ho

GH ₂ -COOR

GII - CH ₂ - GH, _v COJR ^

Ex. Y ¹ -CH (C II) 2 R ³ 6 ¹ V 2 ' 87 GH ₂ -GH ₂ -GII (G. H ₃ ) ₂ - Uli \ U > ₅ -oii ₃ 88 O O - (UH ₂ O 39 -CH ₂ -,

, w NH-CH- CH ₀ - CH R ^ OOC '_ ^

COOR

Example 92 4- [N- (1S) -carboethoxy-3-phenylpropyl) -S-b8nzyl] exo-spiro (blcyclo [2.2.2] octane-2,3-pyrrolidine) -5-carboxylic acid

a) N-β-carethoxy-S-phenylpropyl-S-laurylbenzyiester

3.4 g (10 mmol) of ethyl 2- (D) -trifluoromethylsulfonyloxy-4-phenylbutyrate and 5.9 g (15 mmol) of L-leucine benzyl ester tosylate were dissolved in 50 ml of abs. CH ₂ CI ₂ mixed and stirred for 6.5 hours at room temperature after addition of 4.2 ml of triethylamine. After concentrating the solution, the product was isolated by column chromatography (silica gel, cyclohexane / ethyl acetate 9: 1). There were obtained 3.2 g of colorless oil. ¹ H-NMR δ = 0.95 (d, CH _3), 1.2 (t, CH ₃₎ 1.8 (m, CH ₂₎ 2.6 (m, _CH2) 3.3 (m, CH ) 4.1 (q, CH ₂ ) 5.1 (s, CH ₂ ) 7.3 (s, CH) ppm.

b) N- (1-S-Carboethoxy-3-phenylpropyl) -S-leucln

3.1 g of the benzyl ester obtained in a) were hydrogenolytically cleaved with 500 mg of Pt / C (10%) in 200 ml of ethanol. After filtration of catalyst and concentration of the solution, 2.3 g of colorless crystals of the carboxylic acid of melting point 120-121 ⁰ C were obtained

'H-NMR δ = 0.9 (d, CH _3), 1.25 (t, CH _3), 1.8-2.1 (m, CH _2), 2.7 (m, CH _2), 3.3 (q, CH), 4.25 (q, CH ₂ ), 7.2 (s, CH) ppm.

c) 4- [N- (1S) -carbethoxy-3-phenylpropyl) -S-leucyl] exo-spiroblcyclo [2.2.2] octane-2,3-pyrrolidine-5-carboxylic acid 2g (6.2 mmol) N- (1S-Carboethoxy-3-phenylpropyl) -S-leucine and 1.9 g (3.9 mmol) of exo-spiro (bicyclo [2.2.2] octane-2,3-pyrrolidine) -5-carboxylic acid benzyl ester were dissolved in 100 ml of dimethylformamide with 4, Triethanolamine and 6.5 ml of n-propylphosphonic anhydride are stirred overnight at room temperature. The reaction solution was taken up in ethyl acetate and washed twice with aqueous NaHCO ₃ solution and once each with aqueous 10% citric acid, aqueous sat. NaHCOj solution and sat. shaken aqueous NaCl solution. The organic phase was then separated, dried and concentrated. The crude product with a yield of 2.8 g was separated by column chromatography (silica gel, toluene / ethyl acetate 95: 5) in the two diastereomers. From each benzyl ester, 1 y pure product was obtained.

1 g of the first diastereomer was hydrogenated with Pd / C in 40 ml of ethanol. There were obtained 780 mg of crystalline carboxylic acid of melting point 131-132 ° O.

Rotation value (a] ₀ ° = -2,8 ° ic = 1, methane!)

860 mg of the second diastereomer were hydrogenated with Pd / C in 35 ml of ethanol and the yield after removal from the catalyst and concentration of the solution was 720 mg.

Melting point: The substance sinters from 65 ⁶ C

Rotation value [a] g ° = -22,2 ° (c = 1, methanol)

Example 93

4- [N- (1S) -Car.boxyl-3-phenylpropyl) -S-leucyl] -exo-splo (bicyclo [2.2.2] octane-2,3-pyrrolidinyl) - 5-carboxylic acid 102 mg (0.2 mmol) of the carboxylic acid from Example 92c) were stirred in aqueous 4N KOH solution until the entire substance had dissolved. The solution was placed on an ion exchanger ("" Amberlite R 120) and eluted with aqueous 2% pyridine solution. The yield was 70 mg.

Rotation value Ia] I " = + 3.9 ° (c = 1, methanol)

The following compounds of the formula II are prepared in an analogous manner (the designations of the ring systems correspond to those for the compounds of the general formulas I and II):

C00C _o H _K ά b

-35- 280; n5

R ¹ HOOC - CH - NH

Π ⁴ R ⁵

CH (CH ₃ ) CH ₂ CH ₃ A

CH ₂ C ₆ H ₅ A

CH ₉ -CfH ₁₁ (CH 2 -Cyclohexyl) C

CH ₂ -C ₆ H ₄ OCH ₃ G

CH ₂ -C ₆ H ₄ OC ₂ H ₅ C

CH ₂ -C ₆ H ₄ -OC ₃ H ₇ C

CH ₂ -C ₆ H ₄ -OC ₄ H ₉ A

(CH ₀ ) ^ - NH ₀ D

CH ₂ -CH ₂ -SCH ₃ A

CH CH

  I Il

CH_ - Π CH

HOOC -

CH-N-C

'4 {, 5 A R RO

-CH-CH- CH. - CH

A ¹

ι COOC ₂ H ₅

R ¹

HOOC - CH - NH π π

CH (CH ₅ ) ₂

CH (CH ₅ ) CH ₂ CH ₃

CH ₂ C ₆ H ₅

CH ₂ -C ₆ H ₁₁

CH ₂ -C ₆ H ₄ -OCH ₃

CH ₂ -C ₆ H ₄ -OC ₂ H ₅

CH ₂ -C ₆ H ₄ -On-C ₃ H ₇

CH ₂ -C ₆ H ₄ -On-C ₄ H ₉

(CH ₂ ) ₄ -NH ₂

(CH ₂ ) ₃ -NH ₂

CH ₂ -CH ₂ -S-CH ₃

CH

- C

CH

Il

CH

B B B D H G

η U

C G D

HOOC "CH-N-C -

U _R 5 A η π υ

CH-CH-CH ₀ - CH ₀ mi ά ά R ¹ COOC ₂ H ₅

HOOC - CH - NH R ⁴ R ⁵

CH (CH ₃ ) ₂

CH (CH ₅ ) CH ₂ CH ₅ CH ₂ C ₆ H ₅

CH ₂ -C ₆ H ₁₁

CH ₂ -C ₆ H ₄ -OCH ₅ CH ₂ -C ₆ H ₄ - OC ₂ H ₅ CH ₂ -C ₆ H ₄ -On-C ₅ H ₇ CH ₂ -C ₆ H ₄ -CN C ₄ H ₉

₂₄ (CH ₂ J ₅ -NH ₂ CH ₂ -CH ₂ -S-CH ₅

CH ₉ - C

CH-CH CH

C C C E H H G G H H

HOOC -

CH-N-C

¹ R ' R ^J O

Ä *

CH-CH-CH ₀ -CH ₀ I ₁ I 2 I

R ¹ COOC ₂ H ₅

R ¹

HOOC - CH - NH R ⁴ R ⁵

CH (CH ₅ ) CH ₂ CH ₅ CH ₂ C ₆ H ₅ CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₄ -OCH ₅ CH ₂ -C ₆ H ₄ -OC ₂ H ₅ CH ₂ -C ₆ H ₄ -On-C ₅ H ₇

CH ₂ - ^C 6 ) nC ₄ H _g -CH (CH 2> 4 -NH ₂ Il CH ₂ -CH ₂ -s CH CH- M CH ₂ - C

D D D P N I I H H 0 I

HOOC - CH - N - C - CH - CH - CH ₀ --CH ₀ I ₄ ICi I ₁ ι ² R ⁴ R ^ OR ¹ C00C _o H _K

R ¹ HOOC - CH - NH

R ⁴ R ⁵

₅ J ₂ G

CH (CH ₅ ) CH ₂ CH ₅ E

CH ₂ CgHc; H

CHp-Cz Hi 4G

CH ₂ -C ₆ H ₄ -OCH ₅ O

CH ₂ -C ₆ H ₄ -OC ₂ H ₅ N

CH ₂ -C ₆ H ₄ -On-C ₅ H ₇ N

CH ₂ -C ₆ H ₄ -On-C ₄ H ₉ I

(CH ₂ J ₄ -NH ₂ N

(CHO) ₅ -NH ₂ P

CH ₂ -CH ₂ -S-CH ₅ P

CH- CH

CH ₉ - C CH K

HOOC -

* CH

R ⁴

NC R ⁵

CH-CH-CH ₀ -CH ¹

COOC ₂ H ₅

R ¹

HOOC - CH - NH

CH (CH ₃ ) ₂ CH (CH ₅ ) CH ₂ CH ₅ CH ₂ C ₆ H ₅ CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₄ --OCH ₅

CH ₂ -C ₆ H ₄ -On-C ₅ H ₇ CH ₂ -C ₆ H ₄ -On-C ₄ H ₉ (CHg) ₂ NK ₄ (CH _{2) 5} -NH ₂ CH ₀ ^- CHp "S

CH,

CH-CH

II

-C CH

H P I H P 0 0 N Q Q Q

HOOC -

* CH

NC ι κ> ι CH-CH-CH ₀ - CH ₀ J V

R ¹ COOC ₂ H ₅

R ¹

HOOC - CH - NH

CH (CH ₅ ) ₂

CH (CH ₅ ) CH ₂ CH ₅ CH ₂ C ₆ H ₅

UH ₂ ^ ₆ M ₁₁

CHg-C ₆ H ₄ -OCH ₅ ^ 2 "^ 6 ^ 4 ~ ^ 2 ^ 5 CH ₂ -C ₆ H ₄ -On-C ₅ H ₇ CH ₂ -C ₆ H ₄ -On-C ₄ H ₉ ( CH ₂ J ₄ -NH ₂ CHp-CHp-S-CH-Z

CH ₂ - C

CH- CH

11 ι

CH I G N I Q P P 0 P N

HOOC - CH - N - C r4 r5 CH - CH - CH ₀ - CH,

ill ^ά '

R ¹ C00C _o H _c

R ¹

HOOC - CH - NH

R '

R-

CH (CH ₅ ) CH ₂ CH ₅ CH ₂ C ₆ H ₅

CHg-C ₆ H _n CH ₂ -C ₆ H ₄ -UC ₂ H ₅ CH ₂ -C ₆ H ₄ -On-C ₅ H ₇ CH ₂ -C ₆ K ₄ -O-C ₄ H ₉ CHp-CHg- S-CH-I CH-CH

Il

CHo - C CH 0 H 0 L Q Q P G

HOOC -

CH-NO A * R ⁵

- CH - CH R ¹ COOC,

CH ₂ - CH ₂

R ¹

HOOC - CH - NH R ⁴ R ⁵

CH (CH ₃ ) ₂ CH ₂ -C ₆ H ₅ CH ₂ -C ₆ H ₁₁ CH ₂ -C ₆ H ₄ -OCH ₅ CH ₂ -C ₆ H ₄ -OC ₂ H ₅ CH ₂ -C ₆ H ₄ - On-C ₅ H ₇ GH ₂ -C ₆ H ₄ -On-C ₄ H ₉ CH-CH

M il

CH ₀ - C CH

P P M D D D Q

HOOC - CH - N - C - CH - CH - CH ₂ -

R ⁵ OR ¹

COOC ₂ H ₅

HOOJ - CH - NH

R "

CH (CH ₃ J ₂

CH (CH ₃ ) CH ₂ CH ₃

CH ₂ -C ₆ H ₅

^CH 2 " ^C 6 ^H 11 CH ₂ -C ₆ H ₄ -On-C ₄ H ₅

CH

CH ₂ - C,

CH

ii

CH

N P

N D

CH (CH ₃₎ CH ₂ CH ₃ CH (CH _{3) 3} CH ₃ CH

Q I O Q

Example 94 HN- (1S) -carboethoxybutyl) -S-alanyl] -octahydrocyclopenta [b] pyrrole) -2-carboxylic acid

a) DL-2-trifluoromethylsulfonyloxy-pentanoic acid ethyl ester

5 g (34 mmol) of 2-hydroxyvaleric acid ethyl ester and 2.8 g (35.9 mmol) of abs. Pyridine was dissolved in 10OmI abs. CH] CI _{2 dissolved} under inert gas, cooled to 0 ° C and treated with 9.66 g (34 mmol) of T.ifluormethansulfonsäureanhydrid. After warming to room temperature, it was stirred for 6 hours. After concentrating the solution, the crude product obtained was purified by column chromatography (silica gel, petroleum ether / CH ₂ Cl ₂ 6: 1). The yield was 9.3 g of a colorless, slightly viscous liquid

IR: 2880-3000 1770,1420, 1200-1220 1150,620cm " ¹

b) N- (1-S-Carboethoxybutyl) -S-alanine benzyl ester

4.9 g (17.6 mmol) of the Trifluormethansulfonsäureesters thus obtained were under nitrogen in 70ml CH ₂ Cl ₂ abs. with 4.08 g of L-AlaninbenTylester hydrochloride (19 mmol) with the addition of 5.4 ml of triethylamine and stirred for 3 hours at room temperature. The solution was concentrated, the crude product taken up in ethyl acetate and washed three times with water, dried and concentrated. The diastereomers were separated by column chromatography (silica gel, cyclohexane / ethyl acetate 5: 1). The yield was 500 mg per isomer. The diastereomer isolated in the first filtration has the S ₁ S configuration

¹ H-NMR

δ = 0.9 (t, CH _3), 1.3 (t.CHj), 1.35 (d, CH _3), 1.4 (m, CH _2), 1.6 (m, CH ₂₎ , 1.9 (s, NH), 3.3 (t, CH), 3.4 (q, CH), 4.2 (m, CH ₂ ), 5.15 (q, CH ₂ Ph), 7 , 4 (s, CH aromat.) Ppm.

c) N- (1-S-Carboethoxybutyl) -S-alanine

600 mg (1.95 mmol) of benzyl ester (diastereomer A) were hydrogenated in 34 ml of ethanol with Pd on carbon. The catalyst was then filtered off and the solution was concentrated in vacuo. The product then precipitated as a white solid with a melting point of 137 ⁰ C and a yield of 430mg.

d) 430 mg (1.98 mmol) of N- (1-S-carboethoxybutyl) -S-alanine and 486 mg of gemmoDLM-octahydrocyclopenta-lbl-pyrrolecarboxylic acid benzyl ester were dissolved under nitrogen in 20 ml of dimethylformamide, cooled to -10 ° C., with 1, 5 ml of triethylamine and 2 ml of n-Propylphosphonsäureanöydrid ver. «P'zt. It was stirred for 1 hour at -1O ⁰ C and then at room temperature overnight. The solution was taken up in 200 ml of ethyl acetate and washed with sat. aqueous NaHCO ₃ solution, 10% aqueous citric acid and sat. washed aqueous NaCl solution. After drying and concentrating the solution, the diastereomeric compounds were separated by column chromatography (silica gel, cyclohexane / ethyl acetate 9: 1) The yield was 360 mg Both Oiastereomere be hydrogenated as described in Example 94c) with Pd / C in ethanol and fell after Einongen the Solution as a white solid on.

Example 95

1- [N- (1S) -carboxylbutyl) -S-alanyl] - (octahydrocyclopenta- [b] pyrrole) -2-carboxylic acid 60mg (0.17mmol) carboxylic acid (Example 94d) was dissolved in 2ml of 4N aqueous KOH solution stirred until complete dissolution of the substance. Thereafter, the solution was added to a strongly acidic ion exchanger and eluted with aqueous 2% pyridine solution. After concentration of the solution, the yield was 39 mg.

Analogously to the compounds prepared in Examples 94 and 95, according to the formula II,

CH - N - C - CH- H CH (C Il • N - R ⁴ R ⁵ 0 R ¹ COOR ² R 0OC - where n = 2 R ': R ² : R ³ : = CH ₃ = C ₂ H ₆ = H

3 ^H

Bowie R and the molecular moiety ITOOC-CH-N

R ⁴ R ⁵

are substituted according to the table below, synthesize the following further compounds.

R HOOC-CH-ItH

CH ₃ A

-CH ₂ CH ₂ CH ₃ A

- (CHO) q-CH-2C

2-naphthyl D

4-biphenylyl A

) nr-CH · * A

HOOC-CH-NH R ⁴ R ⁵

CH ₃ B ^ ^m wll ^ j VyJl 0 V / Jl ¹ X B - (CH ₂ ) Q-CH ₃ D 2-Napht.iyl F 4-biphenylyl C - (CHp) ^ 3-CH ₃ B

HOOC-CH-NH R ⁴ R ⁵

-CHpCHpCH,

2-naphthyl 4-biphenylyl - (CHg) ^ ₃ -CH ₃

C C O G D C

R CH ₅ KOOC-CH-NH D -CHpCHpCH, R ⁴ R * D - (CHgJg-CH ₃ H 2-naphthyl H 4-biphenylyl H - (CH 2 L, -CH, D

R CH ₅ HOOC-CH-NH G -CHpCHpCH, i «R ⁵ G - (CHg) ₉ -CH ₃ K 2-naphthyl I 4-biphenylyl L - (CHg) ₁₃ -CH, G

HOOC-CH-NH R ⁴ r5

-CHpCHpCH, - (CH ₂ J ₉ -CH 2-naphthyl 4-biphenylyl - ^ CHp ^ 4, -CH,

H H N M N N

HOOC-CH-NH

-CHpCHpCH, - (CH ₂ J ₉ -CHj 2-naphthyl 4-biphenylyl - (CHpJ *, - CH,

N N 0 N P 0

HOOC-CH-NH R ⁴ R ⁵

-C HoC HoCH-i

4-biphenylyl

j-CHj

Q Q P Q P

HOOC-CH-NH

-CHpCHpCH-r (J

₉ j 4-biphenylyl- (CH 2) 3-CH, 4-biphenylyl

P P Q G Q H

Reference Example 1:

1) 2- (S-Alanyi) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl trifluoroacotate

1a) 2- (W-tert -butyloxycarbonyl-sialyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid isobutyl ester 61.5 g (0.251 mol) (1S, 3S, 5S) -2-A * abicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, 47.5 g (0.231 mol) of BOC-L-alanine and 173 ml (1.26 mol) of absolute triethylamine are dissolved in 1025 ml of absolute dimethylformamide, 252 ml of a 50 weight%

Propanephosphonsäureanhydridlösung in dichloromethane at -5 ⁰ C added dropwise, 30 minutes at -5'C and four hours at Room temperature stirred. The reaction solution is distributed between water and Essigertor, the aqueous phase still

once extracted with ethyl acetate, the combined organic phases with saturated sodium bicarbonate solution, 10%

Citric acid solution, water and saturated Nstriumchloridlösung, dried and concentrated. Yield: 93.2 g (89%) oily product.

1b) 2- (S-Alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carbo, isoic acid benzyl ester trifluoroacetate 93.2g (0.224mol) BOC derivative from Reference Example 1 a) (at ⁰ ° C with 235ml of absolute Trifluoressi (doused acid and 2.5 hours at O ⁰ C stirred. Excess acid is evaporated in vacuo at 25 ⁰ C and the crystallized ind Residues from 1000mlabsolutem diisopropyl ether.

Yield: 82.6 g (86%), m.p. 148-15O ⁰ C. Reference Example 2:

2) (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

2 a) 2-tert-Butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester

To a solution of 40.0 g (0.163 mol) of (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid'oenzyl ester and 23.4 ml (0.166 mol)

of absolute triethylamine in 300 ml of absolute methylene chloride is added dropwise at ⁰ C a solution of 39.2 g (0,180mol) Ditert.butyldicarbonat in 60ml of absolute methylene chloride was slowly added for 15 minutes at ⁰ ° C and one hour at

Room temperature stirred. The reaction solution is washed with 10% citric acid solution, saturated Sodium bicarbonate solution and water, dried and concentrated. Yield: 55.6 g of oily product, Ia) I ⁶ = -1.2 ° (c = 2, methanol).

2 b) 2-tert-Butyloxycarbonyl- (1S, 3S, 5S) -2-azablycryl [3.3.0] octane-3-carboxylic acid 55.6 g (0.161 mol) of beruylestor from Reference Example 2a) are dissolved in 21% ethanol at room temperature 4g palladium / carbon (10%) hydrogenated for 2.5 hours. The catalyst is filtered off with suction and the filtrate is concentrated.

Yield: 37.3 g (90%);

[aYe ⁶ = + 22.7 ° (c = 1, methanol).

2c) 2-tert-butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester 32.3 g (0.127 mol) of acid from Reference Example 2b) and 25.3 g ( 0.253 mol) of potassium bicarbonate are in 500ml

Dimethylformamide for 1.5 hours at 4O ⁰ C stirred. After cooling, 48.9 g (0.253 mol) of 1-bromooctane are iugefopft and

stirred overnight at room temperature. The reaction mixture is added to water, extracted three times with ethyl acetate, the combined organic phases washed with saturated sodium bicarbonate solution and water, dried, concentrated and the crude product (44.3g) by flash chromatography on silica gel (900g, eluent toluene / ethanol 95 :. or 99.5: 0.5) in two portions.

Yield: 35.4 g (76%) oily product,

[ate ⁵ = + 5.7 ° (c = 1, methanol).

Obtained in an analogous way:

2-tert-butyloxycarbonyl (1RS, 3RS, 5RS) -2-azabicyclo (3.3.0) -7-octen-3-carboxylic acid n-octyl ester,

N-t-butyloxycarbonyl-S-proline-n-octylsster.

2d) (1S, 3S, 5S) -2-Azablcyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

i, 6 g (7.0 mmol) of BOC compound from Reference Example 2c) are stirred in 9 mL of trifluoroacetic acid for 1.5 hours.

The excess acid is evaporated in vacuo, the residue taken up in water, basic with sodium bicarbonate

, extracted with ethyl acetate, the organic phase washed once more with water, dried, concentrated and the

Pro iukt quickly implemented. From actual: 1.8 g (95%) oily product. In an analogous way we obtain:

(1RS, 3RS, 5RS) -2-azabicyclo [3.3.0] -7-octen-3-carboxylic acid-n-octyloster,

S-proline n-octyl ester. Reference Example 3:

3) methanesulphonic acid (3-octynyl) ester

To a solution of 7.56 g (60 mmol of 3-octyn-1-ol and 12.45 ml (90 mmol) of Trie'iiylai.iin in 225 ml of methylene chloride are added

10'C within 30 minutes 7.45 g (65 mmol) of methanesulfonyl chloride first and then stirred for one hour. Dio

Reaction solution is washed with water, saturated sodium bicarbonate solution and again with water, dried and

concentrated.

Yield: 11.9 g (97%) oily product. Example 96

2- (N- (1S-ethoxycarbonyl-S-phenylpropyl-S-alanyl-dS.SS.SSJ ^ -azabicycloIS.S-octane-S-carboxylic acid n-octyl ester, 2.07g (5mmol) 2- | N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0-octane-3-carboxylic acid (ramipril) and 0.50 g (5 mmol) of potassium bicarbonate are dissolved in 25 ml Dimethylformamide stirred for 1.5 hours at 4O ⁰ C, after

Cooled to room temperature, a solution of 1.16 g (6 mmol) of 1-bromooctane in 20 ml of dimethylformamide was added dropwise and over Stirred at room temperature overnight. By adding 0.1 N HCl is adjusted to pH 6, diluted with water, three times with Extracted Metnylenchlorid and the combined organic phases dried, concentrated and purified by column chromatography

on 120 g of silica gel (eluent toluene / ethanol 95; 5).

Yield: 2.3Eg (89%) oily product. Ia] J ⁵ = -23.9 ° (c =!, Methanol). Example 97

2-IN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0 | octan-3-carboxylic acid n-octylesterhydrogenmal inat '.'

528 mg (1 mmol) of an amine obtained according to Example 96 are dissolved in 20 ml of ether and treated with a solution of 116 mg (1 mmol) of maleic acid in 4 ml of acetone. The solvents are evaporated and the residue is crystallized with diisopropylethor.

Yield: 0.5 g (79%) of colorless crystals, mp 89-90 ° C.

Example 98

2- (N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octan-3-carbunsäure- (2-octenyl) esterhydrogenmaleinat

2.08 g (5 mmol) of 2 [N- (1S-ethoxycarbonyloxypropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid ( Ramipril) and 1.00 g (10 mmol) of potassium bicarbonate are stirred in 25 ml of dimethylformamide for 1.5 hours at 40X, cooled to ⁰ ° C., and a solution of 2.3 g (12 mmol) of E-1-bromo-2-octene in 20 ml Dimethylformamide added dropwise. The reaction solution is stirred for 4 hours at ⁰ ° C, added to 500 ml of water, extracted three times with Essigester, the combined extracts were concentrated, twice with saturated sodium bicarbonate solution and washed three times with water, dried and the crude product (3.4 g) by flash chromatography on 125 g of silica gel (mobile phase cyclohexane / ethyl acetate 8: 2 and 1: 1).

This gives 1.93 g (73%) of an oily product, which is converted into the hydrogen maleate analogously to Example 97.

Yield. 2.0 g colorless crystals, mp 81-34 ⁰ C.

Example 99

2- [N- (1S-Eihoxycarbonyl-3-phenylpropyl} -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (3-octynyl) esterhydrogenmaleinat

4.9 g (11.8 mmol) of 2- [NO.sup.-S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (ramipril) and 2.4 g (23.6 mmol) of potassium hydrogen carbonate are stirred in 90 ml of dimethylformamide for 2 hours at 40 ° C, then a solution of 2.41 g (11.8 mmol) of mesylate from Reference Example 3 in 30 ml of dimethylformamide was added and more

Stirred for 9 hours at 40 ° C. The reaction solution is diluted with 250 ml of water, extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and with water, dried, concentrated and the crude product (5.6 g) is purified by chromatography on 200 g of silica gel (eluent toluene / ethanol 99: 1). cleaned. This gives 3.45 g (56%) of oily product, of which 1.3 g are converted into the hydrogen maleate analogously to Example 97.

Yield: 0.8 g of colorless crystals, mp 68-7O ⁰ C.

Example 100

2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid ehtylesterhydrogenmaleinat

1.43 g (2.8 mmol) of carboxylic acid from Example 106 are stirred in 25 ml of ethanolic hydrochloric acid at room temperature. After 5 days, another 25 ml of ethanolic hydrochloric acid are added, stirred overnight, the residue taken up in ethyl acetate, washed three times with saturated sodium bicarbonate solution and once with water, dried, concentrated, and the crude product (1.16 g) purified by flash chromatography on 80 g of silica gel (Eluent toluene / ethanol 99: 1). This gives 0.62 g (42%) oily product, which is converted into the hydrogen maleate analogously to Example 97.

Yield: 0.50 g colorless crystals, mp 84-86 ⁰ C..

Example 101

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (5-nonyl) esterhydrogenmaleinat

To a solution of 1.97 g (7.5 mmol) of triphenylphosphiri and 0.72 g (5 mmol) of 5-nonanol in 100 ml of absolute tetrahydrofuran at ⁰ ° C., a solution of 1.31 g (7.5 mmol) of diethyl azadicarboxylate in 10 ml added dropwise to absolute tetrahydrofuran,

Stirred for 10 minutes, then at 0 ° C, a solution of 2.08g (5 mmol) of 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2- azabicyclo [3.3.0] octane-3-carboxylic acid (ramipril) in 25 ml of absolute tetrahydrofuran, stirred at ⁰ ° C. for ¹ hour and at room temperature overnight. The reaction solution is concentrated, taken up in ethyl acetate, washed twice with 2N sodium hydroxide solution and once with water, dried, concentrated by evaporation and the crude product (5.0 g) is purified twice by flash chromatography on 200 g of silica gel (Laufiittei a) toluene / ethanol 99: 1, b) methylene chloride / ethyl acetate 9: 1). The product thus obtained (1.74 g, 64%) is converted into the hydrogen maleate analogously to Example 97.

Yield: 1.6g (49%); M.p. 102-105 ° C.

Belt game 102

2- [N- (1S-menthyloxycarbonyl-3-phenylpropyl) -S-ala; iyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0-octan-3-carboxylic acid benzhydryl ester To a suspension of 2.95 g of nickel peroxide hydrate in 12 ml of ether is added dropwise at room temperature, a solution of 0.59g (3 mmol) Benzophenonhydrazon in 12 ml of ether, stirred for one hour, the violet solution filtered through Celite and concentrated. The 3 mmol of diphenyldiazomethane thus obtained are dissolved in 32 ml of absolute acetone and added with ice cooling to a solution of 1.31 g (2.5 mmol) of 2-iN- (1S-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S. 3S, 5S) -2-azabicyclo (3.3.0) octane-3-carboxylic acid (see Example 132) in 32 ml of absolute acetone is then added, followed by stirring for 38 hours at room temperature, concentrated and the crude product by column chromatography on kieselgol (eluent toluene / ethanol 99.5: 0.5 or cyclohexane / ethyl acetate 8: 2)

Yield: 1.63 g (95%) of oily product; (ali ⁶ - -57.9 ° (c = 1, methanol).

Example 103

2- [N- (3-Cyclohexyl-1S-ethoxycarbonyl-propyl! -S-alanyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester 1.8g ( 6.7 mmol) octyl ester from Reference Example 2d), 1.92 g (6.7 mmol) of N- (3-cyclohexy! -1 S-ethoxycarbonyl-propyD-S-alanine and 4.6 ml of absolute triethylamine are dissolved in 30 ml of absolute dimethylformamide , cooled to -5 ⁰ C, and slowly added dropwise 6.7 ml of a 50% solution of Propanphosphonsäureanhydnd in methylene chloride. the reaction solution is stirred overnight at room temperature, added to 200 rnl of water, extracted three times with Essigester, the combined organic phases with water, 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, concentrated and the crude product (3.1 g) purified by flash chromatography on 120 g silica gel (eluent toluene / ethanol 199: 1) yield: 2.48 g (69%). colorless oil, (a) g ⁶ = -26.4 ° (c = 1, methanol).

Example 104

2- [N- (1S-Ethoxycarbpnyl-n-tridecyl) -S-phenyialanyl] - (1S, 3S, 5S) -2-azabicycloI3.3.0] octane-3-carboxylic acid benzyl ester

To a solution of 2.1 g (5 mmol) of N- (1S-ethoxycarbonyl-n-tridecyl-S-phenylalanine and 1.4 g (5 mmol) (1S, 3S, 5S) -2-

azabicycloI3.3.0] octane-3-carboxylic acid benzyl ester in 80 ml of absolute dimethylformamide, 3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of a 50% solution of propanephosphonic anhydride in methylene chloride are successively added dropwise and the reaction solution is stirred at room temperature overnight. Then it is added to water, repeatedly Tiit

Essigester extracted, the combined extracts with water, 10% citric acid solution, saturated sodium bicarbonate solution and

washed saturated sodium chloride solution, dried, concentrated and the crude product (3.15 g) by flash chromatography on silica gel (mobile phase cyclohexane / ethyl acetate 7: 3).

Yield: 2.76 g (85%) oily product

[a] g ° = -8.0 ° (c = 0.97, ethanol).

Example 105

2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester

To a solution of 9.3 g (21.7 mmol) of trifluoroacetate from Reference Example 1b) in 100 ml of absolute methylene chloride at O ⁰ C successively 6.0 ml (43.4 mmol) of absolute triethylamine and 9.2 g of 4-phenyl-2R

(trifluoromethanesulfonyloxy) butanoic acid-n-octyl ester, dissolved in 20 ml of absolute methylene chloride, added dropwise. One lets up

Room temperature, stirred for 2.5 hours, extracted three times with water, dried, concentrated and purified the crude product

(11.4 g) by flash chromatography on 4GOg silica gel (mobile phase cyclohexane / ethyl acetate 9: 1.8: 2.7: 3).

Yield: 6.95 g (54%) oily product. Ia] I * = -35.1 ° (c = 1, methanol). Example 106 Tert.butylammonium- [2- [N- (iS-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl) - (1S, 3S, 5S) -2-azabicyclol3.3.0] octan-3-

carboxylate] 5.45 g (9.2 mmol) of benzyl ester from Example 105 are hydrogenated in 300 ml of ethanol at room temperature 1 g of palladium / carbon (10%) for 20 minutes. After suctioning off the catalyst and concentrating, 4.1 g (89%) of 2- (N-O-Sn) are obtained.

Octyloxycarbonyl 3-phenylpropy) - S-alanyl] - (1S, 3S, 5S) -2azabicyclo [3.3.0] octane-3-carboxylic acid.

1.3 g of this acid are tert in ethanol with 190mg tert. Butylamine was added, the solvent evaporated and the residue with

Diisopropyl ether crystallizes. Yield: 1.27 g (86%) of colorless crystals.

M.p. 141-143-C

Example 107

2- [N- (1S-carboxy-3-phenylpropyl) -S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid nC; ctyl ester 2.65g (5 mmol ) Ethyl ester from Example 96 are dissolved in 18 ml of tetrahydrofuran, 7.5 ml of 1 N sodium hydroxide solution and stirred for 48 hours at room temperature. It is neutralized by adding 7.5 ml of 1 N hydrochloric acid. The reaction mixture was concentrated, the residue suspended in water, extracted twice with ethyl acetate, the combined organic phases washed with saturated sodium chloride solution, dried, concentrated and the crude product (2.05 g) purified by chromatography on 80 g of silica gel (toluene / ethynol 9: 1). The product thus obtained (1.15 g, 46%) is triturated in 50 ml of petroleum ether, cooled, filtered off with suction and dried.

Yield: 0.83 g of colorless crystals; Mp. 56-61 ° C. Using appropriate starting materials and using those described in Examples 96-107 Methods are also obtained the following compounds according to the invention:

Example 1CB 2- [N- (1S-ethoxycarbonyl-n-heptyl) -S-alanyl) - (1S, 3S, 5S) -2-aiabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

Example 109

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl | - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane S-carboxylic acid n-decyl ester; (ag ⁶ = - 2'5.8 ° (c = 1, methanol).

Example 110

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -Salanyl | - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-tetradecyl ester;

(ajj ⁶ = -19.8 ° (c = 1, methanol).

Example 111

2- | N- (13-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclol3.3.0] octan-3-carboxylic acid (2-oxtinyl) esterhydrogenmaleinat; M.p. 70-72 ⁰ C.

Example 112

2- [N- (1S-lsobutyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0loctan-3-carboxylic acid n-octyl ester; [ate ⁶ = -23.7 ° (c = 1, methanol).

Example 113

2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0loctan-3-carboxylic acid n-octyl ester; (a ⁶ = -18.6 ° (c = 1, methanol).

Example 114

2- [N- (1S-n-octadecyloxycarbonyl-3-phenylpropyl) -S-alanylj- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester; [ate ⁶ = -15.2 ° (c = 1, methanol).

Example 115 1 '- [N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl-spiro-lbicyclo [2.2.2-octo-2,3'S-pyrrolidine] -5'S-carboxylic acid n-octyl ester;

Example 116

Mp 11O ⁰ C.; V- [N- (I S-ethoxycarbonyl-S-S-phenylpropyD-alanyll-spirolbicycloU ^^ loctan ^ .S'S-pyrrolidinl-S'S-carboxylic acid n-nonylesterhydrogenmaleinat.

Example 117

V- [N- (I S-ethoxycarbonyl-S-S-phenylpropyD-alanyll-spiroIbicyclo ^^^ ^ .a'S loctan-pyrrolidinl-ö'S-carboxylic acid n-decylesterhydrogenmaleinat; m.p. 96 ^0C.

Example 118 2- (N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyll (1R, 3R, 5R) -2-azabicyclo [3.3.0-octan-3-carboxylic acid n-octyl ester; (a) g ⁵ = -7.0 "(C = 1.16, methanol).

Example 119

2-IN- (1S-ethoxycarbonyl-3-phenylpropyl) -R alanyll- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester; [a ⁶ = + 18.0 ° (c = 1, methanol).

Example 120

2- [N- (1R-ethoxycarbonyl-3-phenylpropyl) -R-alany l (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester!; [al ₀ ^B = +9.4 "(C = 1, methanol).

Example 121

2- | N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyi] - (1S, 3S, 5S) -2-azabicyclo [3.3.0l-7-octen-3-carbcnsäure n-octyl; (alo ⁶ = + 21.2 ° (c = 1, methanol).

Example 122

2- | N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1R, 3R, 5R) -2-azabicyclo [3.3.0) -7-ocien-3-carboxylic acid n-octyl ester; [ate ⁶ = -51.4 ° (c = 1, methanol).

Example 123

N-lN'-IIS-ethoxycarbonyl-S-S-phenylpropyD-alanyll-S-proline-n-octyl-hydrogen maleate; M.p. 100-107 ⁰ C.

Example 124

2- (N- (1S-ethoxycarbonyl-n-tridecyD-S-phenylalanyl-d S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid; [aβ ⁰ = + 27.2 ° (c = 1, Mothanol).

Example 125 2- [N- (1S-Ethoxycarbonyl-n-tridecyl) -S-alanyl l (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester

Example 126 2- [N- (1R-ethoxycarbonyl-n-tride-1-yl) -S-alanyl | - (1S, 3S, 5S) -2-azabicycloI3.3.0] octane-3-carboxylic acid benzyl ester

Example 127

2- [N- (1S-n-Octadecyloxycarbo'l-3-phenyl-pentyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester;

[a \ l * = -28.6 "(c = 1, methanol)!

Example 128

2- [N- (1S-Mentliyloxyrarbonyl-3-Phei) lpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester; [a | J ⁶ = ·· -63.2 ° (c = 1, methanol).

Example 129

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0loctan-3-carbonsäufe- (3,3-diphenyl-npropyDester-hydrogen maleate m.p. = 122-124 ⁰ C..

Example 130 V- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl) -spiroIbicyclo] 2.2.2) octane-2,3'-S-pyrrolidine] -5'-S-carboxylic acid (5-nonyl) ester

hydrogen maleate, mp 121 ° C.

Example 131 Tert. butylammonium ^ -In-dS-n-octadecyloxycarbonyl-S-S-phenylpropyD-alanyll-azabicyclo ^ dS.SS.BSJ-O.S.Oloctan-S-

carboxylate mp. 133-135 ^C C.

Example 132 Tert. butvlc.moniumU-IN-dS-menthyloxycarbonyl S-phenylpropyD S alanyll-dS.SS.SSl ^ -azabicycloO.S.Oloctan-S-

carboxylate); M.p. 164-167 ° C.

Claims (8)

1. (C ₇ -C ₁₈ J alkyl group; 1. hydrogen; 1. hydrogen; 1. mean hydrogen; 1. A process for the preparation of a compound of formula II R ³ OOG - GH - H - G - CII - NH - GII - (GH ") _O - R" _n ι Λ / r. Il I ₁ i ρ ^{22 w} R ⁴ R ^J 0 R ¹ COOP / Α., In which I. a) η = 1 or 2; b) R 1 is hydrogen; 2. (Cr-C, ₈ ) -alkenyl; 2 {C7-C ₁₈₎ alkenyl; 2. (C ₇ -C ₁₈ J -alkenyl; 2. The method according to claim 1, characterized in that one prepares a compound of formula II in which R ⁴ and R ⁵ together with the atoms carrying them a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C Atoms, up to 2 ring S atoms and up to 2 ring N atoms preferably from the series pyrrolidine, thiazolidine, tetrahydroisoquinoline, Decf / hydroisoquinoline, octahydroindole, indoline, octahydrocyclopenta / bApyrrol, 2-azaspiro / 4.5 / decane, 2 -Azaspiro / 4.4 / nonane, spiro / (bicyclo / 2.2.1 / heptane) -2,3'-pyrrolidine /, spiro / (bi-cyclo- / 2.2.2 / octane) -2,3'-pyrrolidine /, 2-azatricyclo- / 4.3.0.1 ⁶ⁱ⁹ / decane, decahydrocyclohepta / b / pyrrole, octahydroisoindole, octahydrocyclopenta / c / pyrrole, 2,3,3a, 4,5,7a-hexahydroindole 1,2,3,3a-4,5a -H x ^ hydrocyclopenta / b / pyrrole and 2-azabicyclo / 3.1.0 / hexane or their physiologically acceptable salt. 2. Alky! with 1-6 C atoms; 2. alkyl with 1-8 C atoms; 2. alkenyl with 1-6 C atoms; 2. alkyl with 1-6 C atoms; 2. alkyl with 1-8 C atoms; 2. alkyl of 1-18 C atoms; 2. Alkyi having 1-8 carbon atoms; 2. alkyl having 1-18 carbon atoms; 3. a radical having 4-18 C atoms, which is defined as in claim 1 under A. I. d) 3. and wherein b is 2: 4, 3. (Cy-CJ-Alkmyl; 3. a radical having 4-18 C-atoms, which is defined as in claim 1 under A.I. b) 3. and wherein b is> 4; 3. The method according to claim 1 or 2, characterized in that one prepares a compound of formula II, in which R 1. (C 1 -C 4) alkyl; 3. alkenyl with 2-6 C atoms; 3. alkenyl with 2-6 C atoms; 3. alkenyl with 2-6 C atoms; 3. alkenyl with 2-6 C atoms; 3. alkenyl with 2-6 C atoms; 3. an aliphatic acyclic radical of formula C _a H ( _2a b + n, wherein double bonds, if their number exceeds 1, are not cumulative, a is an integer 2 to 18 and b is an integer 2 to a; 3. An aliphatic acyclic radical of the formula C _a H (2 _a - b + n, in which double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an integer 2 to a stand; 3. an aliphatic, acyclic radical of the formula C _a H ( _2a -b + d, wherein double bonds, if their number exceeds 1, are not cumulated, a is an integer 2 to 18 and b is an integer 2 to a stand; 4. a radical which is defined as in claim 1 under AI d) 4th, (Ca-C ^ -cycloalkyl and (C ₃ -C9) -cycloalkyl (C ₁ -C ₄ ) alkyl except; 4. a radical having 4-18 C atoms, which is defined as in claim 1 under A. I. c) 3. wherein b is> 2 and only double bonds are present; 4. The method according to any one of claims 1 to 3, characterized in that one prepares a compound of formula II in which R ¹ 4. a radical of 4-20 carbon atoms, as defined in claim 1 under A.I. b) 4. and wherein d is> 2; 4. di- (C, -C ₄ ) -alky! Amin o '(C ₁ -C ₄ ) -alkyl; 4. cycloalkyl having 3-9 C atoms; 4. di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl; 4. Alkynyl with 2-6 C atoms; 4. cycloalkyl having 3-9 C atoms; 4. a mono-, di-, tri-, tetra- or pentacyclic non-aromatic hydrocarbon radical of the formula C _c H | _2c - d - n is optionally branched wherein c is an integer of 3 to 20 and even an integer of 0 to (c - 2); 4. a mono-, di-, tri-, tetra- or pentacyclic non-aromatic hydrocarbon radical of the formula C _c H | _2c - d - η which is optionally branched, wherein c is an integer of 3 to 20 and d is an even number of 0 to (c - 2); 4. a mono-, di-, tri-, tetra- or pentacyclic non-aromatic hydrocarbon radical of the formula C _c H ( _2c -a - κ, which is optionally branched, wherein c is an integer from 3 to 20 and even an integer from 0 to (c - 2); 5. di (C 1 -C ₄ ) alkylamino (C ₅ -C ₈ ) alkyl; 5. The method according to any one of claims 1 to 3, characterized in that one prepares a compound of formula II in which R ^{1 is} the side chain of valine, leucine, isoleucine, norvaline, norleucine, methionine, ornithine, cyclohexylalanine, 2-thienylalanine , 3-thienylalanine, O- (C ₃ -C ₅ ) -alkyl tyrosine, isoleucine, isovalin or C-phenylglycine, or their physiologically acceptable salt. 5. a radical which is defined as in claim 1 under A. I. c) 4. except cycloalkyl and cycloalkenyl having up to 9 carbon atoms; 5. as defined in claim 1 under A.I. b) 5.; 5. (CH 1 -j-alkanoyloxy - ^ - CO-alkyl; 5. aryl with 6-12 C atoms, that represented by (C ₁ -Cj) -alkyl, (C ₁ -Gj) -alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C ₁ -C ₄ -alkylamino, di (C ₁ -C ₄ ) -alkylamino, ( C ₁ -C ₄ ) alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl may be mono-, di- or trisubstituted; 5. (C-CBl alkanoyloxy-fCr-Q-alkyl; 5. cycloalkyl having 3-9 C atoms; 5. aryl with 6-12 C atoms, that represented by (C ₁ -Cj) -alkyl, (C ₁ -C ₄ ) -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C ₁ -C ₄ -alkylamino, di (C ₁ -C ₄ ) -alkylamino, (C 1 -C 6) -alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl may be mono-, di- or trisubstituted; 5. di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₈ ) alkyl; 5. aryl having 6-12 carbon atoms, which may be substituted as described under I. b) 5.; 5. aryl having 6-12 carbon atoms, that represented by (C ₁ -C ₈ ) -alkyl, (C ₁ -C ₄ ) -alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C ₁ -C ₆ -alkylamino, di (C ₁ -C ₄ ) -alkylamino , (Ci-GjJ-alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl can be mono-, di- or trisubstituted; 6. (C 1 -C ₅ ) alkanoyloxy (C ₅ -C ₈ 5 -alkyl; 6. The method according to any one of claims 1 to 5, characterized in that one prepares a compound of formula II, in which R ² and R ^{3 are the} same or different and 1. (C ₇ -C ₁₈ I-AIkYl; 6. optionally substituted (C 1 -C 12) aryl-iCs-Cel alkyl; 6. Heteroaryl-alkyl which is defined as in claim 1 under A.I. b) 9; 6. (C 1 -C 6) alkoxy-carbonyloxy-1CH 1 -alkyl; 6. Alkoxy with 1-4 C atoms; 6. (C 1 -C 6 -alkoxy-carbonyloxy-C 1 -C 6 -alkyl; 8. (Cs-C ^ -aryloxycarbonyloxy-id-CJ-alkyl; 9. aryl with 6-12 C atoms; 10. (CfT-C ^ -aryl-id-C ^ -alkyl; 11. (Cr-Cgj-cycloalkyl or 12. (C ₃ -C ₉ ) -cycloalkvl (C ₁ -C ₄ ) -alky! mean and e) R ⁴ and R ^{5 have} the meaning defined under I. e); or B., in which a) η = 1 or 2 b) R 1 is hydrogen; 6. cycloalkenyl having 5-9 C atoms; 7th 9. optionally partially hydrogenated aryl having 6-12 C atoms, which may be substituted as described under II. B); 10. (Ce-CuJ-aryl-ICr-CJ-alkyl or (C ₇ -C ₁₃ J-ArOyI- (C ₁ or C ₂ ) -alkyl, both of which may be substituted in the aryl part as described under II. b) 5; 11. mono- or bicyclic, optionally partially hydrogenated heteroaryl having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms represent sulfur or oxygen atoms and / or 1 to 4 ring atoms nitrogen atoms, as in II. B). 5. may be substituted, or 12. if not covered by the above definitions, the optionally protected side chain of a naturally occurring α-amino acid R ^{1 represents} -CH (NH ₂ ) -COOH, d) R ² and R ^{3 are the} same or different and 6. Alkoxy with 1-4 C atoms; 6. (C 1 -C 5 -alkanoyloxy-C 1 -C 6 -alkyl; 6. (Ce-C 1-4 -aryl-ICn-CAL-alkyl or (CT-C 1-4 -acryloyl-C 1 -C 12 -alkyl, both of which may be substituted as aryl under i.b.); 6. if η · = 2, (Cβ-C ^ -aryl-tC ^ Cei-alkyl or di-ICg-C ^ -aryl-iCH ^ -alkyl, which in the aryl moiety in each case as in I. b) 5. may be substituted; or 7. The method according to any one of claims 1 to 5, characterized in that one prepares a compound of formula II in which R ² and R ^{3 are the} same or different and propyl, isopropyl, η-butyl, isobutyl, sec-butyl, n-pentyl, sec-pentyi, isopentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, menthyl, phenyl, α- or β-naphthyl, 2-, 3- or 4-biphenylyl, phenethyl, 3-phenylpropyl, benzhydryl, α-methylbenzyl, α-methylenebenzyl, 2-, 3- or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indenyl or 9-fluorenyl, wherein phenyl and phenyl as a partial structure the radicals mentioned are optionally substituted as defined in claim 1 under Al b) 5. or one of the radicals R ² and R ^{3 is} hydrogen and the other is as defined above or R ^{2 is} benzyl and R ^{3 is} benzyl, hydrogen or one of the above or their physiologically acceptable Salt. 7. (C 1 -C 4 -alkoxy-carbonyloxy-C 1 -C 5 -alkyl; 9. (C 6 -C ₁₂ ) -Aryloxycarbonyloxy- (C ₅ -C ₈ ) alkyl;
10 represents (C ₁₆ -C ₂ o) aralkyl; wherein the radicals mentioned under d) 8, 9 and 10 may be substituted in the aryl part as described in claim 1 under Al b) 5. or one of the radicals R ² and R ^{3 is} hydrogen and the other is as defined above , or their physiologically acceptable salt. 7. optionally substituted (C ₇ -C ₃ ) -royl- (C 1 -C ₈ ) -alkyl or 8. optionally substituted heteroaryl (C, -C ₈ ) alkyl, or their physiologically acceptable salts. 7. amino (C ₅ -C ₈ ) alkyl; 8. amino- _(C5-C8) alkyl; 9. (C 1 -C 4) alkanoylamino-ICs-CeJ-alkyl; 10. (CT-C 1 -C 6) -acryloylamino-C 1 -C 6 -alkyl; 11. (C 1 -C ₄ ) alkoxycarbonylamino (C ₆ -C ₈ ) alkyl; 12 (C _s -C ₁ 2) -Ary - (C ₁ -C 4) alkoxycarbonylamino (C ₅ -C ₈₎ -alkyl!; 13. (C ₆ -C, 2) aryl- (C 1 -C 4) alkylamino {C ₅ -C _B ) -acyl; 14. (C) C 15. Di-iCT 16. guanidino-iCs-CeJ-alkyl; 17. if η = 2, (C ₁ -C ₄₎ -alkylthio (C ₅ -C ₈ ) -alkyl; 18. _(C6-C12) -Arylthio- _(C5-C8) alkyl, in the aryl moiety as in claim 1 under A.I. b) 5. may be substituted; 19. (Cg-C ^ -AryMCs-CaJ-alkylthio, which may be substituted in the aryl part as described in claim 1 under A.I. 20. if η = 2, carboxy-ICg-C ^ -alkyl; 21. if η = 2, carbamoylC-C ^ alkyl; 22. (C 1 -C 4) alkoxycarbonyl (C ₅ -C ₈ ) alkyl; 23. if η = 2, (Cff-C ^ J-aryloxy-C 1 -C 10 -alkyl, which may be substituted in the aryl part as described in claim 1 under A.I. or 24. (C 1 -C 4) 1-aryl-ICr-Cel-alkoxy, which may be substituted in the aryl moiety as in claim 1 under A.I. b) means, or their physiologically acceptable salt. 7. (C ₇ -C ₁₃ J-Aryloxy- (C ₁ -C ₄ ) alkyl; 8. (C 9 -C 12) arylcycloxyphenyloxy-C 1 -C 4 -alkyl; 9. aryl with 6-12 C atoms; 10. (cerium-C 1-4 aryl-CJ-alkyl; 11. (Qr-Cj-cycloalkyl or 12. (C ₃ -C ₉ ) -Cycioalkyl- (C ₁ -C ₄ ) -alkyl and a) R ⁴ υ .id R ^{5 have} the meaning defined under AI e) and their physiologically acceptable Salts, or
C ₁ in which a) n, R, R ⁴ and R ^{5 are} as defined above under B. and b) R ^{1 is} the side chain of alanine, lysine or e-acyllysine and c) R ² and R ^{3 are} identical or different and propyl, isopropyl, η-butyl, isobutyl, sec-butyl, n-pentyl, sec-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, cyclobutyl, Cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclohexenyl, cycloheptenyl, phenyl, α- or β-naphthyl, 2-, 3- or 4-biphenyl, phenethyl, 3-phenylpropyl, benzhydryl, α-methylbenzyl, α-methylenebenzyl, 2-, 3-or 4-phenylbenzyl, bibenzyl-a-yl, styryl, 1-indanyl or 9-fluorenyl, where phenyl and phenyl as a substructure of one of the radicals mentioned are optionally substituted as defined under A.II.b) 5. or one of the R ² and R ^{3 is} hydrogen and the other is as defined above, or R ^{2 is} benzyl and R ^{3 is} benzyl, hydrogen or one of the definitions mentioned above and, where appropriate, their pharmaceutical administration form, characterized in that their fragments in a optionally occurring solvent, if appropriate in the presence of a base and / or e Inte coupling agent is reacted with each other, optionally intermediately formed unsaturated compounds such as Schiff's bases, reduced, protecting protecting groups temporarily introduced protective groups, compounds of formula II mitfreier (en) carboxyl group (s) optionally esterified and the resulting compounds optionally in their physiologically acceptable salts and, if appropriate, bring the compounds prepared by this process together with the carrier and optionally further additives and / or excipients into a suitable administration form. 7. aryloxy having 6-12 C atoms, which may be substituted as described in B. b) 5.; 8. mono- or bicyclic heteroaryloxy with 5-7 or 8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms are nitrogen, as described in B. b ) 5. may be substituted; 9. amino (C, -C ₄ ) alkyl; 10. (C ₁ -C ₄ ) alkanoyl-amino (C ₁ -C ₄ ) -alkyl; 11. (CT-C3 -acylamino-fCr-C, J-alkyl; 12. (Cr-GjJ-alkoxycarbonylamino-iCr-C ^ -alkyl; 13. (Ce-C 1-4 -aryl- ^ -Q-alkoxycarbonylamino-C 1-4 -alkyl; 14. (C ₆ -C ₁₂ ) aryl (C ₁ -C ₄ ) alkylamino {C ₁ -C ₄ ) alkyl; 15 (C, -C ₄₎ alkylamino (C ₁ -C ₄₎ alkyl; 16. di- (C, -C ₄₎ alkylamino (C ₁ -C ₄₎ alkyl; 17. guanidino-C 1 -C 12 alkyl; 18. imidazolyl; 19. indolyl; 20. (C-O-alkylthio; 21. ifn = 2, (C ₁ -C ₄ ) -alkylthio (C ₁ -C ₄ ) -alkyl; 22. (C 6 -C ₁₂ ) arylthio (C 1 -C ₄ ) -alkyl, which may be substituted in the aryl part as described under B. b) 5.; 23. (C 6 -C ₁₂ ) -aryl (C 1 -C ₄ ) -alkylthio, which may be substituted in the aryl part as described under B. b) 5.; 24. if η = 2, carboxy (C 1 -C ₄ ) alkyl; 25. Carboxy; 26. caroamoyl; 27. if η = 2, carbamoyl (C ₁ -C ₄ ) alkyl; 28. (C 1 -C 12) alkoxy-carbonylMCi-CJ-alkyl; 29. if η = 2, (C ₆ -C ₁₂ -alkyl-C ₁ -C ₄ -H) yl, which may be substituted in the aryl part as described under B. b) 5. or 30. (C ₆ -C, 2) -aryl (C ₁ -C ₄ ) -alkoxy _f which may be substituted in the aryl part as described under B. b) 5. means; c) R ¹ for the side chain of valine, leucine, isoleucine, norvaline, norleucine, methionine, ornithine, cyclohexylalanine, 2-thienylalanine, 3-thienylalanine, O- (C ₃ -C ₅ ) -alkyl-tyrosine, isovalin or C-phenylglycine stands; d) R ^{2 and} R ^{3 are the} same or different and 7. aryloxy having 6-12 C atoms; which may be substituted as described under II. b) 5.; 8. mono or. bicyclic heteroaryloxy having 5-7 or 8-10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and / or 1 to 4 ring atoms are nitrogen; which may be substituted as described under II. b) 5.; 9. amino - ^ - O-alkyl; 10. (C ₁ -C ₄ ) alkanoylamino (C ₁ -C ₄ ) alkyl; 11. (CT-C 1-6) -Aroylamino-C 1-10 -O-alkyl; 12. (C ₁ -C ₄ ) alkoxycarbonylamino (C ₁ -C ₄ ) alkyl; 13. (C ₆ -C 12) aryl- (C ₁ -C 4) alkoxycarbonylamino (C ₁ -C 4) alkyl; 14. (C ₆ -C ₁₂ ) aryl (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl; 15. (d -Q-alkylamino-iC ^ -alkyl; 16. di (C ₁ -C ₄ ) alkylamino (C ₁ -C ₄ ) alkyl; 17. guanidino (C, -C ₄ ) alkyl; 18. imidazolyl; 19. indolyl; 20. (C, -C ₄ ) alkylthio; which may be substituted in the aryl part as described under II. b) 5; 23. (Ce-Czl-aryl-ICr-OO-alkylthio, which may be substituted in the aryl part as described under II. b) 5; 24. Carboxy-KVCJ-alkyl; 25. Carboxy, carbamoyl; 26. carbamoyl-iCr-CJ-alkyl; 27. (C 1 -C 4 -cycloxycarbonyl-IC ^ alkyl; 28. (C 1 -C 4 -Aryloxy - ^ - CJ-alkyl; which may be substituted in the aryl moiety as described under II. b) 5 29. (C 9 -C 12 aryl-ICr-CJ-alkoxy; which may be substituted in the aryl moiety as described under II. b) 5. c) R ¹ 1. hydrogen; 7. (C ₁ -C 6) -alkoxy-C 1-8 -aryloxy (C ₁ -C ₈ ) -alkyl; 8. (C 1 -C 8 -Aroyloxy - ^ - OO-alkyl; 9. (C 1 -C 4) 5-aryloxycarbonyloxy-tC 1 CeJ-alkyl; 10. Aryi with 6-12 C atoms or 11. _(C7-C20) -aralkyl; wherein the radicals mentioned under d) 8, 9, 10 and 11 may be substituted as described in I. b) 5. in the aryl moiety and e) R ⁴ and R ⁵ together with the atoms carrying them form a monocyclic, bicyclic or tricyclic heterocyclic ring system having 3 to 15 R ring C atoms and their physiologically acceptable salt, excluding compounds of the formula II and their salts, in which a) η = 1 or 2 b) R 1 is hydrogen; 7. mono- or bicyclic, optionally partially hydrogenated heteroaryl or heteroaryl-KM-CaJ-alkyl having 5-7 or 8-10 ring atoms, of which up to 9 ring atoms carbon and 1 to 2 ring atoms sulfur or oxygen and / or 1 to 4 Ring atoms are nitrogen, which may be substituted in the heterocaryl such as aryl under I. b) 5., or 8. if from c) 1.-7. not yet covered, the optionally protected rope chain of a naturally occurring α-amino acid of the formula R ¹ -CH (NH ₂ ) -COÜH Dedeutet; d) R ² and R ^{3 are the} same or different and 7. Alkoxy with 1-4 C atoms; 8. aryloxy having 6-12 C atoms; which may be substituted as described under I b) 5.; 9. mono or. bicyclic heteroaryloxy or heteroaryMC.-CaJ-alkyl having 5-7 or 8-10 ring atoms, of which up to 9 ring atoms are carbon and 1 to 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms are nitrogen, which in the heteroaryl as under I. b) 5. may be substituted; 10. amino-iCr-QO-alkyl; 11. (C 1 -C 5) alkanoylamino-C 1 -C 6 -alkyl; 12. (CT-C 1 -j-aroylamino-iCT-CaJ-alkyl; 13. (C ₁ -C ₄ ) alkoxycarbonylamino (C ₁ -C ₈ ) alkyl; 14. (C ₆ -C ₁₂ ) -aryl (C ₁ -C ₄ ) -alkoxycarbonylamino (C ₁ -C ₈ ) -alkyl, 15. (Cg-Cii 16. (C ^ a 17. Di-iCr 18. Guanidino-fCr-Col-alkyl; 19. imidazo'.yl; 20. indolyl; 21. (Cr-CJ-alkylthio; 22nd fa !! , n = 2 is, (C 1 -C ₄ ) -alkylthio (C 1 -C ₈ ) -alkyl; 23. (C 1 -C 4 -arylthio-F C 1 -CfO-alkyl; which may be substituted in the aryl part as described under I. b) 5.; 24. (Cg-C ^ -AryMCr-CeJ-alkylthio; which may be substituted in the aryl part as described under I. b) 5.; 25. if η = 2, carboxy (C ₁ -C ₈ ) alkyl; 26. carboxy; 27. carbamoyl; 28. if η = 2, carbamoyl (C ₁ -C ₈ ) alkyl; 29. (Ct-CJ-alkoxycarbonyl-l ^ -CaJ-alkyl; 30. if η = 2, (Cg-C ^ -Aiyloxy - ^ - C ^ -alkyl, which may be substituted in the aryl moiety as described under I. b) 5.; or 31 (C6-C ₁₂ ) -aryl (Ci-C ₈ ) -alkoxy, which in the aryl part as described under I. b) 5. substituted can be means; c) R ^{1 is} hydrogen; A process according to any one of claims 1 to 7, in which the radicals are as previously defined, wherein at least one of R ² and R ^{3 is} not hydrogen, characterized in that a compound of formula II in which at least one of R ² and R ^{3 is} hydrogen , esterified, and optionally converted the resulting compound of formula II into its physiologically acceptable salt. Field of application of the invention The invention relates to a process for the preparation of compounds of formol II with valuable pharmacological properties, in particular with nootropic effect for the treatment and prophylaxis of cognitive dysfunctions. The invention further relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically acceptable salts as drugs with nootropic (the cognitive function improving) effect and their use in the preparation of corresponding pharmaceutical preparations. Characteristic of the known state of the art About the use of compounds of formula II for the treatment and prophylaxis of cognitive dysfunctions are not known. Object of the invention The aim of the invention is to provide new compounds with a nootropic effect, which are suitable for the treatment and prophylaxis of cognitive dysfunctions. Presentation of the essence of the invention Dor invention is the object of finding new compounds with the desired properties and methods for their preparation. For example, compounds of the formula I are suitable for this novel use, X ¹ -X ² in which X ¹ R ³ OOC -CH-NC- (CHR ¹ J ₁₁₁ -, ni R ⁵ 0