DE3901291A1 - Compounds with psychotropic action, compositions containing these and the use thereof for the treatment and prophylaxis of central nervous system disorders - Google Patents

Abstract

The invention relates to the use of angiotensin converting enzyme inhibitors as pharmaceuticals with psychotropic, in particular anxiolytic, action, compositions containing these and to the use thereof for the treatment or prophylaxis of central nervous system disorders, in particular of anxiety states. The invention furthermore relates to compounds of the formula <IMAGE> in which R<2> is hydrogen or ethyl and R<3> is n-octyl, to processes for their preparation, to compositions containing these and to the use thereof as pharmaceuticals.

Description

Compounds with psychotropic action, these containing Means and their use in the treatment and Prophylaxis of disorders of the central nervous system.

The invention relates to the use of angiotensin Converting enzyme inhibitors (ACE inhibitors) or their Physiologically acceptable salts as a drug with psychotropic, especially anxiolytic action, these containing agents and their use in the manufacture corresponding pharmaceutical preparations.

For example, come for this novel use Compounds of the formula I into consideration,

X¹-X² (I)

in which

means

means
Y¹ is -S- or -CH₂-,
Y² is -NR⁹ or -CH₂-,
m = 0 or 1,
n = 0, 1 or 2,
p = 0 or 1,
R = hydrogen,
an optionally substituted aliphatic radical having 1 to 21 C atoms,
an optionally substituted alicyclic 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,
an optionally substituted alicyclic aliphatic radical having 4-20 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) aliphatic radical having 5-12 ring atoms, or
a radical ORa or SRa means in which
Ra 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 having 5-12 ring atoms,
R¹ 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 6-12 C atoms,
an optionally substituted araliphatic radical having 7-32 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) -aliphatic radical having 5-12 ring atoms or,
if not already covered by preceding definitions, the necessary protected side chain of a naturally occurring α- amino acid,
R² and R³ are the same or different and are hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
a remainder of the formula

wherein R¹⁰ is hydrogen, an aliphatic radical of 1-6 C atoms or an optionally substituted means aromatic radical having 6-12 C atoms, a remainder of the formula

wherein R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
mean,
R⁴ is hydrogen or (C₁-C₆) alkyl and
R⁵ is (C₁-C₆) -alkyl, (C₃-C₆) -cycloalkyl or

stand or
R⁴ and R⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms,
R⁶ is hydrogen, amino, (C₁-C₆) -alkyl, (C₆-C₁₂) -aryl or (C₇-C₁₃) -aralkyl,
R⁷ is (C₁-C₆) -alkyl or (C₇-C₁₃) -aralkyl, preferably - (CH₂) ₄-C₆H₅,
R⁸ is (C₁-C₆) alkyl which is optionally monosubstituted by (C₁-C₆) alkanoyloxy,
preferably 2-methyl-1-propionyloxy-propyl,
and
R⁹ is hydrogen or (C₁-C₆) alkyl;
in particular compounds of the formula II,

in which
n = 1 or 2,
R = hydrogen,
an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
an optionally substituted alicyclic-aliphatic radical having 7-14 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) aliphatic radical having 5-12 ring atoms, or
a radical ORa or SRa means in which
Ra 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 having 5-12 ring atoms,
R¹ 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 6-12 C atoms,
an optionally substituted araliphatic radical having 7-32 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) -aliphatic radical having 5-12 ring atoms or,
if not already covered by preceding definitions, the necessary protected side chain of a naturally occurring α- amino acid,
R² and R³ are the same or different and are hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
a remainder of the formula

wherein R¹⁰ is hydrogen, an aliphatic radical of 1-6 C atoms or an optionally substituted means aromatic radical having 6-12 C atoms, a remainder of the formula

wherein R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
mean,
and
R⁴ and R⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms.

Under an optionally substituted aliphatic Rest means an aliphatic acyclic radical, d. H. a remainder with an open, straight or branched Carbon chain, such as alkyl, Alkenyl, alkynyl and corresponding polyunsaturated Residues. It is preferably unsubstituted or, as below for example in the case of 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 bound via an open carbon chain corresponding optionally substituted alicyclic aliphatic radical is a preferably mono- to pentacyclic isocyclic, non-aromatic radical with Single or asymmetrically distributed double bonds, the also be branched (i.e., open-chain aliphatic Can carry side chains), and that via a ring C atom or a side chain C atom is linked. He is preferably unsubstituted. Several rings as components such a residue is condensed, spiro-linked or isolated. Examples of such radicals are cycloalkyl, Cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and of mono-, bi- or oligocyclic terpenes derived radicals, such as menthyl, isomenthyl, Bornyl, caranyl, epibornyl, epiisobornyl, isobornyl, 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, biphenylyl or naphthyl, the optionally as indicated below in aryl (b) 5.) mono-, di- or trisubstituted. Aryl-derived residues, such as aralkyl, aryloxy, arylthio or aroyl, preferably Benzoyl, may be substituted 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 to  10 ring atoms, of which 1 to 2 ring atoms sulfur or Oxygen gases and / or from which 1 to 4 ring atoms Represent 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. These radicals may also be partially or completely hydrogenated his. A heteroaromatic radical and the corresponding heteroaromatic-aliphatic radical can be defined as below, be substituted.

Under an optionally substituted araliphatic In particular, aralkyl radicals such as arylalkyl, diarylalkyl, Indanyl or fluorenyl understood, wherein aryl as defined above and in the manner indicated there may be substituted.

An optionally substituted acyl radical is one straight-chain or branched, saturated or unsaturated aliphatic radical, preferably a unsubstituted saturated or unsaturated alkanoyl Radicals such as formyl, acetyl, propionyl, butyryl, isobutyryl, Valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, Palmitoyl, stearoyl, caprinoyl, caproyl, capryloyl, Arachidonoyl, sorboyl, angeloyl, acryloyl, propiolyl, Methacryloyl, crotonoyl, isocrotonoyl, oleoyl, elaidoyl or ricinoleoyl. Preference is given to fatty acid residues, as they are in natural triglycerides occur.

R⁴ and R⁵ can be a mono-, with the atoms carrying these atoms bicyclic or tricyclic heterocyclic ring system with 3 form up to 15 ring C atoms, preferably in the ring up to to 2 S atoms and up to 2 N atoms, in particular up to 1 S atom has.  

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 (O), octa-hydrocyclopenta- [b] pyrrole (D); 2-azaspiro [4.5] decane (E); 2-azaspiro [4.4] nonane (F); Spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine] (G); Spiro [(bicyclo [2.2.2] octane) -2,3'-pyrrolidine] (H); 2-azatricyclo [4.3.0.1 ^6,9 ] decane (I); Decahydrocyclohepta- [b] pyrrole (J); Octahydroisoindole (K); Octahydrocyclopenta [c] pyrrole (L); 2,3,3a, 4,5,7a-hexahydroindole (M); 2-azabicyclo [3.1.0] hexane (N); 1,2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole (P), all of which may be optionally substituted. Pyrrolidine (O) and thiazolidine (R) may e.g. Example, by (C₆-C₁₂) -aryl (phenyl, 2-hydroxyphenyl, etc.), (C₆-C₁₂) -Arylmercapto (such as phenylmercapto) or (C₃-C₇) cycloalkyl (such as cyclohexyl) monosubstituted. Tetrahydroisoquinoline (A) may, for. B. in the aryl moiety up to 2 (C₁-C₆) alkoxy, preferably carry methoxy. The same applies to the other ring systems. However, the unsubstituted systems are preferred.

The suitable heterocyclic ring systems have the following structural formulas:  

Naturally occurring amino acids are a, for example, Ala, Ser, Thr, Val, Leu, Ile, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Orn, Cit, Tyr, Phe, Trp and His.

If R¹ is a side chain of a protected naturally occurring a-amino acid is such. Protected groups such as protected Ser, Thr, Asp, Asn, Glu, Gln, Arg, Lys, Hyl, Cys, Orn, Cit, Tyr, Trp or His, are the usual groups in peptide chemistry preferred (see Houben-Weyl, Volumes XV / 1 and XV / 2). In the case where R¹ is the protected lysine side chain, the known amino-protecting groups, but especially Z, Boc or (C₁-C₆) - alkanoyl are preferred. As O-protecting groups for tyrosine are preferably (C₁-C₆) alkyl, in particular methyl or ethyl in question.

The compounds of the formula I or II have asymmetric Carbon atoms and can therefore be used as enantiomers and Diastereomers occur. The invention includes both pure enantiomers as well as the racemates.

For compounds of formula I or II, the more chiral Atoms have all kinds of diastereomers Racemates or enantiomers, or mixtures of various Diastereomers into consideration.

A preferred embodiment is characterized that compounds of the formula I, preferably those of Formula II, can be used in which

• a) n = 1 or 2;
• b) R
  • 1. hydrogen means;
  • 2. alkyl having 1-18 carbon atoms;
  • 3. an aliphatic acyclic radical of the formula C _a H _{(2 a-b +1)} , wherein double bonds, if their number exceeds 1, are not cumulated, a is an even number 2 to 18 and b is an integer 2 to a ;
  • 4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula C _c H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to ( c -2) stand;
  • 5. aryl having 6-12 carbon atoms,
    by (C₁-C₈) alkyl, (C₁-C₄) alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C₁-C₄) alkylamino, di (C₁-C₄) alkylamino, (C₁-C₄ ) Alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl, mono-, di- or trisubstituted;
  • 6. if n = 2, (C₆-C₁₂) -aryl (C₁-C₈) -alkyl or di- (C₆-C₁₂) -aryl- (C₁-C₈) -alkyl,
    which may each be substituted in the aryl part as described under b) 5; or
  • 7. Alkoxy with 1-4 C atoms;
  • 8. aryloxy having 6-12 C atoms;
    which may be substituted as described under b) 5.;
  • 9. mono- or bicyclic heteroaryloxy or heteroaryl (C₁-C₈) -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 may be substituted in heteroaryl as described under b) 5.;
  • 10. amino (C₁-C₈) alkyl;
  • 11. (C₁-C₄) alkanoylamino (C₁-C₈) alkyl;
  • 12. (C₇-C₁₃) -Aroylamino- (C₁-C₈) alkyl;
  • 13. (C₁-C₄) alkoxy-carbonylamino (C₁-C₈) alkyl;
  • 14. (C₆-C₁₂) -aryl (C₁-C₄) alkoxycarbonylamino (C₁-C₈) alkyl;
  • 15. (C₆-C₁₂) -aryl (C₁-C₄) -alkylamino (C₁-C₈) alkyl;
  • 16. (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 17. di (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 18. guanidino (C₁-C₈) alkyl;
  • 19. imidazolyl;
  • 20. indolyl;
  • 21. (C₁-C₄) alkylthio;
  • 22. if n = 2, (C₁-C₄) alkylthio (C₁-C₈) alkyl;
  • 23. (C₆-C₁₂) arylthio (C₁-C₈) alkyl;
    which may be substituted in the aryl part as described under b) 5.;
  • 24. (C₆-C₁₂) -aryl (C₁-C₈) -alkylthio,
    which may be substituted in the aryl part as described under b) 5.;
  • 25. if n = 2, carboxy (C₁-C₈) alkyl;
  • 26. carboxy;
  • 27. carbamoyl;
  • 28. if n = 2, carbamoyl (C₁-C₈) alkyl;
  • 29. (C₁-C₄) alkoxy-carbonyl (C₁-C₈) alkyl;
  • 30. if n = 2, (C₆-C₁₂) -aryloxy- (C₁-C₈) -alkyl,
    which may be substituted in the aryl part as described under b) 5.; or
  • 31. (C₆-C₁₂) -aryl (C₁-C₈) alkoxy,
    which may be substituted in the aryl moiety as described under b) 5.;
• c) R¹
  • 1. hydrogen means;
  • 2. alkyl having 1-18 carbon atoms;
  • 3. an aliphatic radical of formula C _a H _{(2 a-b +1)} , wherein 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 the formula C _c H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to ( c -2) stand;
  • 5. aryl with 6-12 C atoms,
    which may be substituted as described under I. b) 5.;
  • 6. (C₆-C₁₂) -aryl (C₁-C₈) -alkyl or (C₇-C₁₃) -royl (C₁-C₈) -alkyl,
    both of which may be substituted in the aryl moiety as described under b);
  • 7. mono- or bicyclic, optionally partially hydrogenated heteroaryl or heteroaryl (C₁-C₈) 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 up to 4 ring atoms represent nitrogen,
    which may be substituted in the heteroaryl as described under aryl b) 5.; or
  • 8. if from c) 1.-8. not yet included
    the optionally protected side chain of a naturally occurring α- amino acid of the formula R¹-CH (NH₂) -COOH means;
• d) R² and R³ 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 _a H _{(2 a-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 ;
  • 4. a mono-, di-, tri-, tetra- or pentacyclic, non-aromatic hydrocarbon radical of the formula C _c H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to ( c -2) stand;
  • 5. di (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 6. (C₁-C₅) alkanoyloxy (C₁-C₈) alkyl;
  • 7. (C₁-C₆) alkoxy-carbonyloxy (C₁-C₈) alkyl;
  • 8. (C₇-C₁₃) -Aroyloxy- (C₁-C₈) alkyl;
  • 9. (C₆-C₁₂) -Aryloxycarbonyloxy- (C₁-C₈) alkyl;
  • 10. aryl with 6-12 C atoms;
  • 11. (C₇-C₂₀) aralkyl;
  • 12. phthalidyl;
  • 13. a remainder of the formula means
    in which R¹⁰ is hydrogen, (C₁-C₆) -alkyl or aryl having 6-12 C atoms,
  • 14. a remainder of the formula in which R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
• where the radicals mentioned under d) 8, 9, 10 and 11 as described under b) 5. substituted in the aryl moiety could be; and
• e) R⁴ and R⁵ together with the atoms carrying them mono-, bi- or tricyclic heterocyclic ring system with 3 to 15 ring carbon atoms.

A particularly preferred embodiment is characterized in that compounds of the formula I, preferably those of the formula II are used, in which
n = 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,
by (C₁-C₄) alkyl, (C₁-C₄) alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C₁-C₄) alkylamino, di (C₁-C₄) alkylamino, (C₁-C₄ ) Alkanoylamino, methylenedioxy, carboxy, cyano 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 (C₁-C₄) alkyl,
(C₁-C₄) alkanoylamino (C₁-C₄) alkyl,
(C₇-C₁₃) -Aroylamino- (C₁-C₄) alkyl,
(C₁-C₄) alkoxy-carbonylamino (C₁-C₄) alkyl,
(C₆-C₁₂) -aryl- (C₁-C₄) alkoxycarbonylamino (C₁-C₄) alkyl,
(C₆-C₁₂) -aryl- (C₁-C₄) alkylamino (C₁-C₄) alkyl,
(C₁-C₄) alkylamino (C₁-C₄) alkyl,
Di- (C₁-C₄) alkylamino (C₁-C₄) alkyl,
Guanidino (C₁-C₄) alkyl,
Imidazolyl, indolyl,
(C₁-C₄) alkylthio,
(C₁-C₄) alkylthio (C₁-C₄) alkyl,
(C₆-C₁₂) -Arylthio- (C₁-C₄) alkyl,
which may be substituted in the aryl part as described above for aryl,
(C₆-C₁₂) -aryl- (C₁-C₄) alkylthio,
which may be substituted in the aryl part as described above for aryl,
Carboxy (C₁-C₄) alkyl,
Carboxy, carbamoyl,
Carbamoyl (C₁-C₄) alkyl,
(C₁-C₄) -alkoxy-carbonyl- (C₁-C₄) alkyl,
(C₆-C₁₂) -aryloxy (C₁-C₄) alkyl,
which may be substituted in the aryl part as described above for aryl or
(C₆-C₁₂) -aryl- (C₁-C₄) alkoxy,
which may be substituted in the aryl part as described above for aryl,
R¹ is hydrogen,
Alkyl with 1-6 C atoms,
Alkenyl with 2-6 C atoms,
Alkynyl with 2-6 C atoms,
Cycloalkyl having 3-9 C atoms,
Cycloalkenyl having 5-9 C atoms,
(C₃-C₉) -cycloalkyl- (C₁-C₄) alkyl,
(C₅-C₉) cycloalkenyl (C₁-C₄) alkyl,
optionally partially hydrogenated aryl having 6-12 C atoms,
which may be substituted as described above in R,
(C₆-C₁₂) -aryl (C₁-C₄) -alkyl or (C₇-C₁₃) -royl- (C₁ or C₂) -alkyl,
both of which may be substituted like 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 represent sulfur or oxygen atoms and / or 1 to 4 ring atoms nitrogen atoms,
which may be substituted as the above aryl or
the optionally protected side chain of a naturally occurring α- amino acid R¹-CH (NH₂) -COOH,
R² and R³ are the same or different and are hydrogen,
Alkyl with 1-12 C atoms,
Alkenyl with 2-12 C atoms,
Di- (C₁-C₄) alkylamino (C₁-C₈) alkyl,
(C₁-C₅) alkanoyloxy (C₁-C₈) alkyl,
(C₁-C₆) alkoxy-carbonyloxy (C₁-C₈) alkyl,
(C₇-C₁₃) -Aroyloxy- (C₁-C₈) alkyl,
(C₆-C₁₂) -Aryloxycarbonyloxy- (C₁-C₈) alkyl,
Aryl with 6-12 C atoms,
(C₆-C₁₂) -aryl- (C₁-C₈) alkyl,
(C₃-C₉) -cycloalkyl or
(C₃-C₉) -cycloalkyl- (C₁-C₈) alkyl
mean and
R⁴ and R⁵ have the meaning given above.

A very particularly preferred embodiment is characterized in that compounds of the formula I, preferably those of the formula II, are used, in which
n = 1 or 2,
R (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₃-C₉) cycloalkyl, amino (C₁-C₄) alkyl, (C₂-C₅) acylamino (C₁-C₄) alkyl , (C₇-C₁₃) -Aroylamino- (C₁-C₄) -alkyl, (C₁-C₄) -alkoxycarbonylamino- (C₁-C₄) -alkyl, (C₆-C₁₂) -aryl (C₁-C₄) -alkoxycarbonylamino- C₁-C₄) alkyl, (C₆-C₁₂) -aryl, substituted by (C₁-C₄) alkyl, (C₁-C₄) alkoxy, hydroxy, halogen, nitro, amino, (C₁-C₄) alkylamino, di - (C₁-C₄) - alkylamino and / or methylenedioxy mono-, di- or may be trisubstituted, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert. Butoxycarbonylamino- (C₁-C₄) alkyl, Benzoyloxycarbonylamino- (C₁-C₄) alkyl or phenyl, which by phenyl, (C₁-C₂) alkyl, (C₁ or C₂) alkoxy, hydroxy, fluorine, chlorine, bromine, Amino, (C₁-C₄) -alkylamino, di- (C₁-C₄) alkylamino, nitro and / or methylenedioxy mono- or disubstituted or in the case of methoxy, may be trisubstituted means
R¹ is hydrogen or (C₁-C₆) -alkyl, which may optionally be substituted by amino, (C₁-C₆) -acylamino or benzoylamino, (C₂-C₆) -alkenyl, (C₃-C₉) -cycloalkyl, (C₅-C₉) -Cycloalkenyl, (C₃-C₇) -cycloalkyl- (C₁-C₄) alkyl, (C₆-C₁₂) -aryl or partially hydrogenated aryl, each by (C₁-C₄) alkyl, (C₁ or C₂) - alkoxy or halogen (C₆-C₁₂) -aryl (C₁-C₄) -alkyl or (C₇-C₁₃) -acroyl- (C₁-C₂) -alkyl, both of which may be substituted as defined above in the aryl radical, a mono- or bicyclic heterocyclic radical having 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 a side chain of a naturally occurring, optionally protected α- amino acid, in particular but hydrogen, (C₁-C₃) alkyl, (C₂ or C₃) alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxy nzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl or benzoylmethyl,
R² and R³ represent the same or different radicals hydrogen, (C₁-C₁₂) -alkyl, (C₂-C₁₂) -alkenyl or (C₆-C₁₂) -aryl (C₁-C₈) -alkyl, and
R⁴ and R⁵ have the meaning given above.

Particularly advantageous may be the following compounds used according to the invention:

2- [N- (1-S-Carbethoxy-3-phenylpropyl) -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-phenylpropyl) -O-ethyl-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-phenylpropyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-methyl-S-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3- (3,4-dimethylphenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- [1-S-Carbethoxy-3- (4-fluorophenyl) -propyl] -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- [1-S-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- [N- (1-S-Carbethoxy-3-cyclopentylpropyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] - (2S, 3aS, 7aR) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] - (2S, 3aR, 7aR) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (2S, 3aR, 7aR) -octahydroindole-2-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-phenyl-propyl) -S-alanyl] - (2S, 3aS, 7aR) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3,4-dimethylphenyl-propyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3- (4-fluorophenyl) -propyl] -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
1- [N- [1-S-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- [N- (1-S-Carbethoxy-3-cyclopentylpropyl) -S-alanyl] - (2S, 3aS, 7aS) -octahydroindole-2-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-butyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3- (3,4-dimethoxyphenylpropyl) -S-alanyl] - cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclopentyl-propyl) -S-alanyl] -cis-endo-azabicyclo [3.3.0] octane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-methyl-S-tyrosyl] -cis-endo-2-azabicyclo [3.3.0] octane-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-methoxyphenyl-propyl) -S-alanyl] - cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] - (2S, 3aR, 6aS) octahydrocyclopenta [b] pyrrole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexylpropyl) -S-lysyl] - (2S, 3aR, 6aS) -octahydrocyclopenta [b] pyrrole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] - (2S, 3aR, 6aS) -octahydro-cyclopenta [b] pyrrole-2-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -2- (2S, 3aR, 6aS) -octahydro-cyclopenta [b] pyrrole-2-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-ethyl-2-tyrosyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexylpropyl) -S-alanyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexylpropyl) -S-lysyl] -2-azaspiro [4.5] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclopentyl-propyl) -S-alanyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclopentyl-propyl) -S-lysyl] -2-azaspiro [4.4] nonane-3-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -spiro [bicyclo [2.2.1] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenyl-propyl] -O-ethyl-S-tyrosyl] spiro [bicyclo [2.2.1] heptane-2,3'-pyrrolidine] -5'- S-carboxylic acid
1 '- [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] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] -spiro [bicyclo [2.2.1] heptane-2,3'-pyrrolidine] -5'-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-ethyl-tyrosyl] spiro- [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] spiro [bicyclo] [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -spiro [bicyclo [2.2.2] octane-2,3'-pyrrolidine] -5'-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] -2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] -2-azatricyclo [4.3.0.1 ^6,9 ] decane-3-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] decahydrocyclohepta [-b] pyrrole-2-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -O-ethyl-S-tyrosyl] decahydrocyclohepta [b] pyrrole-2-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-lysyl] -decahydrocyclohepta [p-] pyrrole-2-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -decahydrocyclohe-pta [b] pyrrole-2-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] -decahydrocyclohep-ta [p] pyrrole-2-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -trans-octahydroisoine-dol-1-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -cis-octahydroisoindol-1-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -transoctahydrois-oindole-1-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-octahydroisoindole-1-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-octahydrocyclopentane [c] pyrrole-1-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis-octahydro-cyclopenta [c] pyrrole-1-S-carboxylic acid benzyl ester
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-lysyl] -cis-octahydro-cyclopenta [c] pyrrole-1-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] -2,3,3a, 4, 5,7a-hexahydroindole-cis-endo-2-S-carboxylic acid
1- [N- (1-S-Carbethoxy-3-phenyl-propyl) -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- (1-S-Carbethoxy-3-phenylpropyl) -S-lysyl] -2-azabicyclo [3.1.0] hexane-cis-endo-3-S-carboxylic acid
2- [N- (1-S-Carbethoxy-3-cyclopentylpropyl) -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-cyclohexyl-propyl) -S-alanyl] -cis-endo-2-azabicyclo [3.1.0] hexane-3-S-carboxylic acid
1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) spiro-bicyclo [2.2.2] octane-2,3'-pyrrolidine -5'-carboxylic acid
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid octyl ester
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octan-3-S-carboxylic acid decyl ester
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octan-3-S-carboxylic acid (5-nonyl) ester
2- [N- (1-S-octyloxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid octyl ester
2- [N- (1-S-menthyloxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid benzhydryl ester

These compounds can be z. B. according to the process described in German Patent Application P 33 33 455.2 prepare 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 ^ε -benzyloxycarbonyl protecting group of the lysine derivatives is removed by noble metal-catalyzed hydrogenolysis.

The preparation of the compounds of general formula I. or II, for example, also using the Professional familiar esterification methods are carried out (see z. Buehler, Pearson, Survey of Organic Syntheses, Vol. 1, New York 1970, pp. 802-825; Houben-Weyl, Methods of Organic Chemistry, Vol. E5, 1985, pp. 656-773), for example by

• a) reaction of a mono- or dicarboxylic acid of general formula I or II, wherein at least one of R² and R³ is hydrogen, with a corresponding alcohol under acid catalysis (mineral acid or acidic ion exchanger).
• b) alkylation of a mono- or dicarboxylic acid of general formula I or II, wherein at least one of R² and R³ is hydrogen, with a Compound R²Z or R³Z, wherein Z is a nucleophilic to displacing leaving group (such as halogen, tolysate) means in a polar protic or dipolar  aprotic solvent in the presence of a base such as Alkali metal hydroxide or alcoholate.
• c) reaction of a mono- or dicarboxylic acid of general formula I or II, wherein at least one of R² and R³ is hydrogen, with a Diazoalkane in an inert organic solvent like CH₂Cl₂.

The compounds listed above are easy with Physiologically acceptable acids or bases (in the case of Mono- or dicarboxylic acids) into the corresponding salts (eg, hydrochlorides, maleinates, fumarates, etc.) and as salts find the use according to the invention.

The compounds of the formula I and II are inhibitors of Angiotensin converting enzyme (ACE) or intermediates in the manufacture of such inhibitors and can also be used to combat high blood pressure Genesis be used. The connections of the Formula I and II and methods for their preparation are partially known, for example, from US Patent 41 29 571, US Patent 43 74 829, EP-A-79 522, EP-A-79 022, EP-A-49 658, EP-A-51 301, US Pat. No. 4,454,292, US Pat. No. 4,374,847, EP-A-72352, US Patent 4350704, EP-A-50800, EP-A-46953, US Pat. No. 4,344,949, EP-A-84164, US Pat. No. 4,470,972, EP-A-65 301 and EP-A-52 991. Novel compounds of the formula I and II are prepared in an analogous manner.

Advantageous are also orally active ACE inhibitors (active ingredients sometimes already mentioned above), such as. Ramipril, enalapril (f), captopril (a), lisinopril (g), cilazapril (o), RHC 3659, CGS 13 945, CGS 13 928C (l), CGS 14 824A (h), CI-906 (j ), Zofenopril (e), fosenopril (p), alacepril CI-925 (k), pentorpil (q), CV 3317 (m), indolapril (h), YS 980 (b), fentiapril (c), pivopril (i.e. ), Perindopril (i), MDL 27 088 (r), MDL 27 788 (s), RS-5142 (t) and others. Orally effective ACE inhibitors are described, for example, in Brunner et al., J. Cardiovasc. Pharmacol. 7 (Suppl. I) [1985] S2-S11.

From the u. a. from EP-A-2 43 645 known ACE inhibitors of formula III

in which
R² and R³ are the same or different and denote hydrogen, an aliphatic radical having 1-21 C atoms, an alicyclic radical having 3-20 C atoms or an araliphatic radical having 7-32 C atoms,
those are preferred in which
R² is hydrogen, methyl, ethyl, benzyl, menthyl or n-octyl and
R³ is hydrogen, benzhydryl, n-octyl, n-decyl or 5-nonyl.

Furthermore, from EP-A-84 164 and EP-A-2 43 645 known ACE inhibitors of the formulas IVa and IVb

in which R² and R³ are as defined above in formula III, those in which
R² is hydrogen, (C₁-C₈) alkyl, benzyl or menthyl and
R³ is hydrogen, benzhydryl or (C₁-C₁₀) -alkyl.

In addition, preferred are those of US Patent 46 20 012 and EP-A-2 43 645 known ACE inhibitors of the formula V.

in which
R¹ is hydrogen, (C₁-C₈) alkyl, benzyl or menthyl and
R² is hydrogen, benzhydryl or (C₁-C₁₀) -alkyl and their isomers.

From EP-A-2 43 645 it is also known that the Compounds of formula I and II also a nootropic (the cognitive function improving) effect and therefore also for the treatment of cognitive dysfunctions different genesis, as z. B. in the Alzheimer's disease or senile dementia occur, are suitable.

It has now surprisingly been found that the compounds of Formula I and II a psychotropic, especially one  have anxiolytic effect. They are therefore for the Treatment and prophylaxis of disorders of the central Nervous system, especially of anxiety, suitable.

The anxiolytic effect was demonstrated in different test models checked so, z. B. in Lick-shock-conflict test for birds and in the "Geller-Soifter Conflict Test" after GELLER and SOFT.

Lick-shock-conflict test Method (VOGEL, J.R., Psychopharmacologia 21 (1971), 1-7)

Male Wistar Rats from own rearing (SPF Hattersheim) in the weight between 90 and 120 g used. The animals will be tested for 48 hours before the test the drinking water withdrawn. The animals are tested in the test a plastic box (14 × 12 × 28 cm, W × D × H) set with a Water bottle is equipped with metal drinking tube and which also allows, via an electronic circuit the Number of contacts of the tongue of the animal with the drinking tube to eat. The bottom of the box is made of metal rods that be powered by the control electronics can.

The animals have 5 minutes after insertion into the box, to find the drinking tube and lick it 50 times. Animals that do not drink the drinking tube within this time have not been used for the trial. After these 50 leakages (lickungs) become drinking tube and ground bars energized for 5 seconds each (DC 300 μA) and then for another 5 sec again Approved. This episode will be alternating for a time continued for 5 minutes, with the number of drinking tube Contacts of the animal during the stimulation current and the Stimulus-free phase on various electronic Counters are registered.  

Groups of eight animals per dose are used with the Test substances, on different routes of application, z. As oral, intraperitoneal or subcutaneous, treated. at oral administration by gavage will be the Test substances suspended in a 1% Tylose gel and 5 ml / kg body weight administered via the gavage. The exam in the obg. Test apparatus is oral Administration 1 hour, subcutaneous or intraperitoneal administration 30 minutes after application of the test substances. The number the drinking tube contacts in the stimulation current phase serves as Test variable. The average number of contacts in this Phase in the control group is set to 100% and or decrease in the number of contacts in those with test substance treated animals is given in percentage terms with respect to Control group expressed.

Anxiolytics usually cause one in this test significant increase in water absorption (lickings) in the Stimulation current phase compared to the untreated controls.

If a linear or logarithmic relationship between Given dose and effect, an ED + 100 (i.e., the Dose that is an increase in water intake by 100% caused by the control group) by means of Regression analysis calculated. Is a linear one Dose dependence is not given, so a minimal effective dose (MED), d. i. the lowest dose the test substance, which is still a statistically significant Increase in water intake compared to the control group effects (p = 0.05, DUNNETT test).  

Number of drinking tube contacts in the stimulation current phase 30 minutes after administration of the test substance compared to the control group

Geller-Seifter Conflict Test Method (Geller, I. and Seifter, J., Psychopharmacologia 1 (1962), 482)

Male Wistar Rats from own rearing (SPF Hattersheim) in weight between 240 and 370 g used and assigned to experimental groups of 8 animals each. 4 animals each are kept in plastic cages (56 × 38 × 20 cm) assembled and weighed by weighing 80% of their normal body weight.  

The animals are trained, in a SKINNER box a button to squeeze to get a reward in the form of sweetened To obtain condensed milk. The box contains two buttons Microswitches, a loudspeaker, a house light, two Signal lights above the keys as well as a floor Metal rods. The training scheme became the work of GELLER and SEIFTER (1962) in the modification of DAVIDSON & COOK (Psychopharmacologia 15 (1969), 159-168) borrowed: Each session consists of four 15-minute sections, the all from a 12 minute "Variable Interval" (VI) phase and a 3-minute fixed ration (FR) phase are composed. During the VI phase, the Animals at the touch of a button milk rewards in one by one Random-controlled interval of 10-110 sec an average of 60 ± 15 sec. during the FR phase the animals receive a reward for each press of the button, in addition, however, every third press of a button will turn it on painful electrical stimulus over the floor bars administered to create a conflict situation. The current of the electrical stimulus will be for each Animal individually adjusted (0.3-0.6 mA) that the Key press rate in the entire FR phase between 5 and 15 lies.

The training takes place 5 days a week, experiments with test substances are carried out once a week. As the animals serve as their own control, they become available each trial with test substance has at least two initial values performed without test substance. The to be tested Compounds are in a 1% Tylose gel suspended and orally by gavage 30 min before the start of the test administered in a volume of 2 ml / kg. Changes in the Keystroke rate in the VI phase are used as an influence motor activity and increases in the Keystroke rate in the FR phase is used as an indication of evaluated an "anticonflict" or "anxiolytic" effect.  

Usually, the minimum effective dose (MED) of the test substance is determined, ie the lowest tested dose which causes a statistically significant change in the button pressure rate ( P = 0.05, WILCOXON matched pairs signed rank test).

The meds determined in these two experimental models after intraperitoneal administration are between 0.1 and 30 mg / kg Experimental animal.

The invention therefore further relates to the application of Compounds of the invention in the treatment and Prophylaxis of disorders of the central nervous system, especially from anxiety.

The invention also relates to novel compounds of Formula III

in which the five chiral C atoms (*) each have the S configuration,
R² is ethyl or hydrogen and
R³ is n-octyl,
and their physiologically tolerated salts, preferably maleinates.

An inventive method for producing this new compounds is characterized in that one

• a) a compound of the formula III in which the five chiral C atoms (*) each have the S configuration, R² is ethyl or a basic, acid or hydrogenolytically readily removable carboxyl protective group and R³ is hydrogen, with n-octanol preferably using well-known esterification methods (see, for example, Buehler, Pearson, Survey of Organic Synthesis, Vol 1, New York 1970, pp. 802-825; Houben-Weyl, Methods of Organic Chemistry, Volume E5, 1985, pp. 656-773), e.g. B. under acid catalysis or after activation of the carboxylic acid function of III (R³ = H) or the hydroxyl function of n-octanol, especially under the conditions of a Mitsunobu reaction, in a suitable solvent at a temperature up to the boiling point of the reaction mixture,
  or that one
• b) a compound of formula III in which the configuration and R² and R³ are as defined above under (a), with a compound of formula VI H₃C- [CH₂-] ₇X (VI) in the X is a leaving group which displaces nucleophilic may be, in particular a Cl, Br, I atom or a sulfonic acid residue, under conditions of nucleophilic substitution, preferably in a polar organic solvent such as an alcohol, preferably methanol, ethanol, propanol or isopropanol or a lower ketone, preferably acetone , Methyl ethyl ketone or methyl isobutyl ketone or in acetonitrile, dimethylformamide, dimethyl sulfoxide or sulfolane or a hydrocarbon, preferably toluene, with or without the presence of an auxiliary base to scavenge the forming acid, preferably in the presence of potassium bicarbonate, sodium carbonate, triethylamine, pyridine, 1,5-diazabicyclo [5.4.0] undec-5-ene or 1,5-diazabicyclo [4.3.0] non-5-ene, and with or without the presence of an alkali halide enids, preferably sodium iodide or potassium iodide, at a temperature of between -50 and + 100 ° C, preferably between -20 and + 60 ° C,
  or that one
• c) reacting a compound of the formula III which is as described above under (a) and in which R² is hydrogen and R³ is n-octyl, with ethanol as described under process variant (a),
  or that one
• d) a compound of formula III in which the configuration, R² and R³ are as defined above under (c), with a compound of formula VII H₃C-CH₂-X (VII) in the X is a leaving group which can be displaced nucleophilic , means, as described under process variant (b), implements,
  or that one
• e) a compound of the formula VIII in which R² is as defined above under (a), with a compound of the formula IX in which the four chiral C atoms (*) each have the S configuration, z. B. analogously to the procedure described in US Patent 45 25 301 in a suitable solvent at a temperature up to the boiling point of the reaction mixture,
  or that one
• f) a compound of the formula X. in which the three chiral C atoms (*) each have the S configuration and R³ is n-octyl, with a compound of the formula XI in which R² is as defined under (a) above, for example in analogy to known peptide coupling methods in an organic solvent such as DMF, CH₂Cl₂, DMA in the presence of coupling aids such as carbodiimides (eg dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphonic anhydrides, dialkylphosphinic anhydrides or N , N-Disuccinimidoylcarbonat in a solvent such. As acetonitrile or after activation of the compounds of formula X, z. By reaction with tetraethyl diphosphite or after conversion of the compounds of the formula XI into active esters (for example with 1-hydroxybenzotriazole), into mixed anhydrides (for example with chloroformates), into azides or into carbodiimide derivatives (compare Schröder , Lübke, The Peptides, Volume 1, New York 1965, pages 76-136) at temperatures preferably between -20 ° C and the boiling point of the solvent, if necessary, in a resulting compound of formula III (R = protective group) the protective group R in in a manner known per se, for example using saponification methods familiar to the person skilled in the art (such as acidic or alkaline hydrolysis) or hydrogenation methods in a suitable solvent at a temperature up to the boiling point of the reaction mixture, and the compound of the formula III (R 2 = ethyl or Hydrogen) optionally converted into its physiologically acceptable salt, wherein, if used as starting materials of the method nsvarianten (a) - (f) stereoisomer mixtures are used, then in a further separation step, the all-S-isomer of the formula III (R² = hydrogen or ethyl, R³ = n-octyl) is separated.

A hydrogenolytically removable carboxyl protective group, like Bzl, is preferably hydrogenolysed on a suitable catalyst such. B. palladium on activated carbon at a pressure of 0.2 to 10 bar and a temperature between 0 ° C and 100 ° C in an organic Solvent split off.

Easily saponifiable aliphatic radicals, such as (C₁-C₆) -alkyl, are the preferred basic or acid cleavable  Carboxyl-protecting groups. They are using the Skilled in the art of saponification methods (see eg Houben / Weyl, Methods of Organic Chemistry, Volume E 5/1, page 223-255), z. B. by acid or alkaline Cleaved off hydrolysis.

The compounds of formula III (R² = hydrogen or Ethyl, R³ = hydrogen) are known (see, for example, EP-A- 79,022, US Patent 45 87 258).

Compounds of formula VI and VII are known and mostly available for purchase.

Compounds of formula VIII are selected from the corresponding Hydroxyl compounds by conversion of the hydroxyl group obtained in the -OSO₂CF₃ group according to common methods.

From Diastereomeren- or Enantiomerengemischen the above-mentioned new all-S compounds Recrystallize or by chromatography, for. B. on Silica gel, or by salt formation with optically active Excipients are separated.

The invention also relates to intermediates of formula XII

in which the three chiral C atoms in each case the S configuration and Q is hydrogen or the rest XIII

means and mixtures of compounds of the formula XII and their stereoisomers, as well as a method for the preparation these compounds, which is characterized in that one

• a) a compound of formula XIV in which Q is hydrogen or -CO-CH (CH₃) -NH₂, with n-octanol or H₃C- [CH₂] ₇-X as in process variant (a) or (b) above or
• b) a compound of the formula XV as above in process variant (f) with an amino-protected, for example, protected with Z or Boc alanine and then splits off the amino protecting group and, if desired, the all-S-isomer of formula XII isolated.

Compounds of formula XIV are for example EP-A-79 022 or US Patent 45 87 258 known.

The new all-S compounds of formula III (R² = H or Ethyl, R³ = n-octyl) and their physiologically acceptable Salts have, in addition to the above-mentioned psychotropic and particular anxiolytic effect a strong nootropic, d. H. the cognitive function improving, effect on. you are therefore for the treatment of cognitive dysfunctions different genesis, as z. B. in the  Alzheimer's disease or senile dementia occur, suitable. The nootropic effect of Compounds of the invention have been used in mice that have a Body weight of 20-25 g possessed, in the inhibitory (passive) avoidance test (step-through model) checked. A modified form of J. Kopp, Z. Bodanecky and M.E. Jarvik's test method was 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 then referred to as nootropic effective, when at the Experimental animals by means of an electroconvulsive shock produced amnesia or those induced by scopolamine Can lift amnesia.

The experiments were based on modified test methods carried out. As a comparative compound served the known Nootropic 2-oxo-1-pyrrolidinylacetic acid amide (piracetam). The clear superiority of the invention Compounds via the comparison substance were found in that scopolamine-induced amnesia is inhibitory avoidance test with a MED (minimum effective dose) from 0.03-30 mg / kg p. o. can pick up. The Comparative substance has a med of about 500-1000 mg / kg p. O.

The invention therefore further relates to the application of Compounds of the invention in the treatment and Prophylaxis of cognitive dysfunctions.

The invention further comprises the said new ones Drugs containing active substances, process for their Production and use of the invention Compounds in the manufacture of medicaments intended for Treatment and prophylaxis of the above Diseases in mammals such as monkeys, dogs, cats, rats, People etc. are used.  

The invention further comprises the compounds mentioned of the formulas I and II their production and the use of Compounds according to the invention in the preparation of Medicines used for the treatment and prophylaxis of Disorders of the central nervous system, in particular of Anxiety, are suitable.

In practice of the method according to the invention, the above described angiotensin converting enzyme inhibitors of Formula I and II to mammals such as monkeys, dogs, cats, Rats, humans etc. are used.

The drugs are known per se, the Expert familiar procedures. As a medicine are the pharmacologically active Compounds (= active substance) either as such or preferably in combination with suitable pharmaceutical Excipients in the form of tablets, dragees, capsules, Suppositories, emulsions, suspensions or solutions used, wherein the active ingredient content to about 95%, advantageously between 10 and 75%.

Which excipients for the desired Medicament formulation are suitable, the expert due to his expertise. In addition to solvents, Gelling agents, suppository bases, tablet Excipients and other drug carriers can for example, antioxidants, dispersants, Emulsifiers, defoamers, flavoring agents, Preservatives, solubilizers or dyes be used.

The active ingredients may be, for example, orally, rectally or parenteral (eg, intravenous or subcutaneous) with oral administration being preferred.  For an oral form of application, the active Compounds with the appropriate additives such as Carriers, stabilizers or inert Diluents mixed and by the usual Methods in appropriate dosage forms such as Tablets, dragees, capsules, aqueous, alcoholic or oily suspensions or aqueous, alcoholic or oily solutions. As inert carrier can z. Gum arabic, magnesia, magnesium carbonate, lactose, glucose or starch, especially corn starch. The preparation can be used both as dry and as Wet granules take place. As 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 as solubilizers, emulsifiers or others Excipients in solution, suspension or emulsion brought. As a solvent come z. In question water, physiological saline or alcohols, e.g. Ethanol, Propanol, glycerin, in addition also sugar solutions such as Glucose or mannitol solutions or else a mixture of the various solvents mentioned.

The following examples are intended to illustrate the invention Explain compounds and methods without the invention to the substances mentioned here by way of example or Restrict procedures. Next are forms of application for the prophylaxis and treatment of disorders of the central Nervous system indicated by the method according to the invention.

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

2.07 g (5 mmol) of 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 stirred in 25 ml of dimethylformamide for 1.5 hours at 40 ° C, after cooling to room temperature, a solution of 1.16 g (6 mmol) of 1-bromooctane in 20 ml of dimethylformamide added dropwise and stirred overnight at room temperature. By addition of 0.1 N HCl is adjusted to pH 6, diluted with water, extracted three times with methylene chloride and the combined organic phases were dried, concentrated and purified by column chromatography on 120 g of silica gel (eluent toluene / ethanol 98: 2).
Yield: 2.35 g (89%) oily product;
[ α ] = -23.9 ° ( c = 1, methanol)

Example 2 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -1 S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octylester- hydrogen maleate

528 mg (1 mmol) of an amine obtained according to Example 1 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 diisopropyl ether.
Yield: 0.51 g (79%) of colorless crystals, mp. 89-90 ° C

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

To a solution of 1.97 g (7.5 mmol) of triphenylphosphine and 0.65 g (5 mmol) of n-octanol in 100 ml of absolute Tetrahydrofuran is added at 0 ° C a solution of 1.31 g (7.5 mmol) Diethyl azodicarboxylate in 10 ml absolute Dropped tetrahydrofuran, stirred for 10 minutes, then at 0 ° C a solution of 2.08 g (5 mmol) 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid (ramipril) in 25 ml absolute tetrahydrofuran added, one hour at 0 ° C. and stirred overnight at room temperature. The Reaction solution is concentrated, taken up in ethyl acetate, twice with 2 N sodium hydroxide solution and once with water washed, dried, concentrated and the crude product (5.0 g) by flash chromatography on 200 g of silica gel (mobile phase Methylene chloride / ethyl acetate 9: 1). 0.83 g is obtained (31%) of the title compound.

Example 4 2- [N- (1S-Carboxy-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2- azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

2.65 g (5 mmol) of ethyl ester from Example 1 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 is 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) by chromatography on 80 g of silica gel (toluene / ethanol 9: 1 ) cleaned. 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

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

1.40 g (2.8 mmol) of carboxylic acid from Example 4 are dissolved in 25 ml ethanolic hydrochloric acid at room temperature for 3 days touched. Then it is concentrated, the residue in ethyl acetate taken up, three times with saturated sodium bicarbonate solution and once washed with water, dried, concentrated and the crude product by column chromatography (eluent Toluene / ethanol 98: 2). 850 mg (57%) are obtained the title link.

Example 6 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [30.3] octane-3-carboxylic acid n-octyl ester

2.50 g (5 mmol) carboxylic acid from Example 4 and 1.00 g (10 mmol) Potassium bicarbonate are in 25 ml Dimethylformamide stirred for one hour at 40 ° C, after Cool to room temperature a solution of 0.66 g (6 mmol) Added dropwise bromoethane in 20 ml of dimethylformamide and over Stirred at room temperature overnight. You give up water, extracted three times with ethyl acetate, washed the combined organic phases several times with water, dried, concentrated and purifies the crude product by column chromatography Silica gel (mobile phase toluene / ethanol 98: 2). 210 g are obtained (80%) of the title compound.

Example 7 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester 7a) 2-tert-butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylate

To a solution of 40.0 g (0.163 mol) of (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester and 23.4 ml (0.169 mol) of absolute triethylamine in 300 ml of absolute methylene chloride at 0 ° C, a solution of 39.2 g (0.180 mol) of di-tert-butyl dicarbonate in 60 ml of absolute methylene chloride is slowly added dropwise, stirred for 15 minutes at 0 ° C and one hour at room temperature. 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
[ α ] = -1,2 ° ( c = 2, methanol)

7b) 2-tert-butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid

55.6 g (0.16 mol) of benzyl ester from Example 7a) are hydrogenated in 2 l of ethanol at room temperature over 4 g of palladium / carbon (10%) for 2.5 hours. The catalyst is filtered off with suction and the filtrate is concentrated.
Yield: 37.3 g (90%)
[ α ] = + 22.7 ° ( c = 1, methanol)

7c) 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 Example 7b) and 25.3 g (0.253 mol) of potassium hydrogen carbonate are stirred in 500 ml of dimethylformamide at 40 ° C for 1.5 hours. After cooling, 48.9 g (0.253 mol) of 1-bromooctane are added dropwise and the mixture is stirred overnight at room temperature. The reaction mixture is poured into water, extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and water, dried, concentrated and the crude product (44.3 g) is purified by flash chromatography on silica gel (900 g g; eluent toluene / ethanol 95: 5 or 99.5: 0.5) in two portions.
Yield: 35.4 g (76%) oily product
[ α ] = + 5.7 ° ( c = 1, methanol)

7d) (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n- octyl

2.6 g (7.0 mmol) of BOC compound from Example 7c) are stirred at 0 ° C. with 9 ml of trifluoroacetic acid for 1.5 hours. The excess acid is evaporated in vacuo, the residue taken up in water, basified with sodium bicarbonate, extracted with ethyl acetate, the organic phase washed once more with water, dried, concentrated and the product is reacted rapidly.
Yield: 1.8 g (95%) oily product

7e) 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid-N- octyl

To a solution of 1.76 g (6.6 mmol) of amine from example 7d) in 10 ml of methylene chloride at -10 ° C in succession 6.44 g (56 mmol) of N-ethylmorpholine, 1.84 g (6.6 mmol) of N- (1S- Ethoxycarbonyl-3-phenylpropyl) -S-alanine and 4 ml Propanephosphonic anhydride (50% in methylene chloride) dropwise. The mixture is stirred for 3 hours at 0 ° C and 3 hours Room temperature after, concentrated, gives up the residue Water, extracted with ethyl acetate and washed the organic Phase with water, 25% sodium bisulfate solution and saturated sodium bicarbonate solution. The solution will be dried, concentrated and purified by column chromatography Silica gel (mobile phase toluene / ethanol 98: 2). you receives 2.47 g (71%) of the title compound.  

Example 8 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octylester- hydrogen maleate 8a) (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n- octyl ester hydrochloride

To a suspension of 10 g (64 mmol) of (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid in 100 ml of distilled n-octanol is added dropwise at 40 ° C 16.3 g (150 mmol) of distilled trimethylsilyl chloride and stirred overnight at 40 ° C. The volatiles are removed on a rotary evaporator, the octanol is removed by short path distillation in a high vacuum, the distillation residue taken up in methylene chloride, concentrated and triturated twice with diisopropyl ether. This gives 14.6 g (75%) of the title compound.
M.p. 87-78 ° C
[ α ] = -23.7 ° ( c = 1, methanol)

8b) 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid-N- octyl-hydrogen maleate

2.0 g (6.6 mmol) of amine hydrochloride from Example 8a) suspended in 30 ml of methylene chloride and 10 ml of water and the pH by adding saturated potassium carbonate solution set to 9-10. Then 1.84 g (6.6 mmol) of N- (1S- Ethoxycarbonyl-3-phenylpropyl) -S-alanine and a solution of 4.1 ml of methyl ethylphosphinic anhydride, in 4 ml Methylene chloride added successively. You stir over Night at room temperature, diluted with methylene chloride and Water, the organic phase is washed with a potassium sulfate / Potassium bisulfate buffer, sodium bicarbonate solution and  Sodium chloride solution, dries, narrows and drops out of the Crude product (2.92 g) by dissolving in 33 ml of diisopropyl ether and adding a solution of 766 mg of maleic acid in 4 ml Acetone the title compound. This gives 2.50 g (67%).

Example 9 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester 9a) 2- [N-tert -butyloxycarbonyl-S-alanyl] - (1S, 3S, 5S) -2- azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

To a mixture of 2.67 g (10 mmol) of the amine from Example 7d), 1.89 g (10 mmol) of BOC-S-alanine and 1.00 g (10 mmol) of triethylamine in 50 ml of absolute dimethylformamide is added dropwise in an ice bath slowly add 10 ml of a propanephosphonic anhydride solution (50% in methylene chloride) and stir at room temperature for 4 hours. The solution is mixed with 200 ml of water, extracted twice with ethyl acetate, 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 by column chromatography on silica gel (eluent toluene / ethanol 99 :. 1) cleaned. 3.05 g (70%) of the title compound are obtained.
[ α ] = -39.9 ° ( c = 1, methanol)

9b) 2- (S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3 carboxylic acid n-octyl ester

6.70 g (15.9 mmol) BOC compound from Example 9a) are in 30 ml of trifluoroacetic acid for 90 minutes at 0 ° C stirred. The Solvent is evaporated, the residue in ethanol  taken up, neutralized by adding potassium carbonate, filtered and concentrated. This gives 5.3 g (98%) of Title compound.

9c) 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid-N- octyl

To a solution of 1.35 g (4.0 mmol) of amine from Example 9b) in 25 ml of absolute methylene chloride are added at 0 ° C. successively 0.8 g (8 mmol) of triethylamine and a solution of 1.36 g (4 mmol) of ethyl 4-phenyl- (2R) -trifluoromethylsulfonyloxybutyrate in 10 ml of absolute methylene chloride and stir overnight at room temperature. The reaction solution is washed with water, dried, concentrated and the Crude product by column chromatography on silica gel (Eluent toluene / ethanol 99.5: 0.5, 99: 1). you receives 0.28 g (13%) of the title compound.

Example 10

Preparation of the agent used according to the invention oral use in the treatment and prophylaxis cognitive Dysfunctions, as well as for the treatment and prophylaxis of Disorders of the central nervous system.

1000 tablets each containing 10 mg of 2- [N- (1-S-Carbethoxy-3-) phenyl-propyl) -S-alanyl] -1 S, 3S, 5S-2-azabicyclo [3.3.0] octan-3-carboxylic acid n-octyl ester are included with the following tools:

2- [N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid | 10 g n-octyl @ corn starch 140 g gelatin 7.5 g Microcrystalline cellulose 2.5 g magnesium stearate 2.5 g

2- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester and Corn starch are mixed with an aqueous gelatin solution mixed. The mixture is dried and turned into a Milling granules. Microcrystalline cellulose and Magnesium stearate are mixed with the granules. The resulting granules are pressed into 1000 tablets, wherein Each tablet contains 10 mg of the active substance. These tablets can be used for the above indications be used.

Example 11

Analogously to Example 10, 1000 tablets are prepared which each 10 mg of 1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) -Spirobicyclo [2.2.2] octane-2,3'-pyrrolidin-5'- contain carboxylic acid.

Example 12

Gelatin capsules 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 are included filled with the following mixture:

1 '- [N- (1-S-carbethoxy-3-phenylpropyl) -S-alanyl] - (3'S, 5'S) -spirobicyclo [2.2.2] octane-2,3'-pyrrolidine 5'-carboxylic acid | 10 mg Magnesium stearate | 1 mg lactose 214 mg

These capsules can be used for the treatment and prophylaxis of Disorders of the central nervous system are used.

Example 13

The preparation of an injection solution is described below described:

2- [N- (1-S-Carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid | 250 mg methylparaben 5 g Propylparaben 1 g sodium chloride 25 g Water for injection | 5 l

2- [N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2- azabicyclo [3.3.0] octane-3-carboxylic acid, the Preservatives and sodium chloride are added in 3 l Dissolve water for injection and dilute to 5 l with water for Injection filled. The solution is sterile filtered and Aseptically filled in pre-sterilized bottles with sterilized rubber caps are sealed. each Bottle contains 5 ml of solution.

Example 14

Tablets which may be used for the treatment or prophylaxis of central nervous system disorders are prepared as described in Example 10, except that instead of 2- [N- (1-S-carbethoxy-3-phenyl-propyl) - S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3S-carboxylic acid n-octyl ester 2- [N- (1-S-carboxy-3-phenyl-propyl) -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
1- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-2,3,3a, 4,5,7a-hexahydro [1H] indole-2-S-endo carboxylic acid or
1- [N- (1-S-carboxy-3-phenyl-propyl) -S-alanyl] -cis-2,3,3a, 4, 5,7a-hexahydro [1H] indole-2S-endo-carboxylic acid or
2- [N- (1-S-carboxy-3-phenylpropyl) -S-lysyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
N- (1-S-carboxy-3-cyclohexyl-propyl) -S-lysyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] exo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-S-carboxylic acid or
(S, S, S) -1-methyl-2- (1-carbethoxy-3-phenyl-propyl) -2H-undecahydro-cyclopenta [4.5] pyrrolo [1,2-a] pyrazine-3,8-dione or
1 '- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -endo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidinyl-5'-S-carboxylic acid or
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid n-octyl ester or
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octan-3-S-carboxylic acid decyl ester or
2- [N- (1-S-Carbethoxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid (5-nonyl) ester or
2- [N- (1-S-octyloxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid octyl ester or
2- [N- (1-S-menthyloxy-3-phenylpropyl) -S-alanyl] -cis-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid benzhydryl ester
be used.

Example 15

An injection solution is prepared analogously to the procedure described in Example 13, except that instead of 2- [N- (1-S-Carbethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) 2-azabicyclo [3.3.0] octane-3-carboxylic acid or
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-Carbethoxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid hydrochloride or
1- [N- (1-S-carboxy-3-phenyl-propyl) -S-alanyl] - (2S, 3aR, 7aS) -octahydroindole-2-carboxylic acid or
1- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] -cis- 2,2,3a, 4,5,7a-hexahydro [1H] indole-2-S-endo carboxylic acid or
1- [N- (1-S-carboxy-3-phenyl-propyl) -S-alanyl] -cis-2,3,3a, 4, 5,7a-hexahydro [1H] indole-2-endo-carboxylic acid or
2- [N- (1-carboxy-3-phenylpropyl) -S-lysyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
2- [N- (1-S-Carbethoxy-3-cyclohexyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
2- [N- (1-S-carboxy-3-cyclohexyl-propyl) -S-lysyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid or
1 '[N- (1-S-carboxy-3-phenylpropyl) -S-alanyl] -endo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-S-carboxylic acid
1 '[N- (1-S-carboxy-3-phenylpropyl) -S-alanyl] exo-spirobicyclo [2.2.2] octane-2,3'-pyrrolidine-5'-S-carboxylic acid
be applied.

Example 16

Preparation of the agent used according to the invention oral use in the treatment and prophylaxis cognitive Dysfunctions, as well as for the treatment and prophylaxis of Disorders of the central nervous system.

1000 tablets each containing 15 mg of 2- [N- (1-S-Carbethoxy-3-) phenyl-propyl) -S-alanyl] -1 S, 3S, 5S-2-azabicyclo [3.3.0] octan-3-carboxylic acid n-octyl ester maleate made with the following tools:

2- (N- (1-S-carbethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane - 3-carboxylic acid | 15g n-octyl-maleate @ corn starch 200 g gelatin 10 g Microcrystalline cellulose 4 g magnesium stearate 4 g

2- [N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octylester- Maleate and corn starch are mixed with an aqueous gelatine Solution mixed. The mixture is dried and turned into a Milling granules. Microcrystalline cellulose and  Magnesium stearate are mixed with the granules. The resulting granules are pressed into 1000 tablets, wherein each tablet contains 15 mg of the active substance. These tablets can be used for the above indications be used.

Example 17

Preparation of the agent used according to the invention oral use in the treatment and prophylaxis cognitive Dysfunctions, as well as for the treatment and prophylaxis of Disorders of the central nervous system.

1000 tablets each containing 8 mg of 2- [N- (1-S-carboxy-3-) phenyl-propyl) -S-alanyl] -1 S, 3S, 5S-2-azabicyclo [3.3.0] octan-3-carboxylic acid n-octyl ester are included with the following tools:

2- [N- (1-S-Carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid @ n-octyl 8 g corn starch 120 g gelatin 7 g Microcrystalline cellulose 2 g Magnesium stearate | 2 g

2- (N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) - 2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester and Corn starch are mixed with an aqueous gelatin solution mixed. The mixture is dried and turned into a Milling granules. Microcrystalline cellulose and Magnesium stearate are mixed with the granules. The resulting granules are pressed into 1000 tablets, wherein each tablet contains 8 mg of the active substance. These tablets can be used for the above indications be used.

Claims (20)

1. Use of an ACE inhibitor for the production of a Drug with a psychotropic effect. 2. Use of an ACE inhibitor for the preparation of a Drug with anxiolytic effect. 3. Use according to claim 1 or 2, characterized in that angiotensin converting enzyme inhibitors of the formula I X¹-X² (I) in which means means
Y¹ is -S- or -CH₂-,
Y² is -NR⁹- or -CH₂-,
m = 0 or 1,
n = 0, 1 or 2,
p = 0 or 1,
R = hydrogen,
an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
an optionally substituted alicyclic-aliphatic radical having 4-20 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) aliphatic radical having 5-12 ring atoms, or
a radical ORa or SRa means in which
Ra 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 having 5-12 ring atoms,
R¹ 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 6-12 C atoms,
an optionally substituted araliphatic radical having 7-32 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) -aliphatic radical having 5-12 ring atoms or,
if not already covered by preceding definitions, the necessary protected side chain of a naturally occurring α- amino acid,
R² and R³ are the same or different and are hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
a remainder of the formula wherein R¹⁰ is hydrogen, an aliphatic radical having 1-6 C atoms or an optionally substituted aromatic radical having 6-12 C atoms,
a remainder of the formula wherein R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
mean,
R⁴ is hydrogen or (C₁-C₆) alkyl and
R⁵ is (C₁-C₆) -alkyl, (C₃-C₆) -cycloalkyl or stand or
R⁴ and R⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms,
R⁶ is hydrogen, amino, (C₁-C₆) -alkyl, (C₆-C₁₂) -aryl or (C₇-C₁₃) -aralkyl,
R⁷ is (C₁-C₆) -alkyl or (C₇-C₁₃) -aralkyl, preferably - (CH₂) ₄-C₆H₅,
R⁸ is (C₁-C₆) alkyl which is optionally monosubstituted by (C₁-C₆) alkanoyloxy,
preferably 2-methyl-1-propionyloxy-propyl, and
R⁹ is hydrogen or (C₁-C₆) alkyl;
or their physiologically acceptable salts are used. 4. Use according to claim 1 or 2, characterized in that the angiotensin converting enzyme inhibitors of the formula II in which
n = 1 or 2,
R = hydrogen,
an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
an optionally substituted alicyclic-aliphatic radical having 7-14 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) aliphatic radical having 5-12 ring atoms, or
a radical ORa or SRa means in which
Ra 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 having 5-12 ring atoms,
R¹ 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 6-12 C atoms,
an optionally substituted araliphatic radical having 7-32 C atoms,
an optionally substituted heteroaromatic or heteroaromatic (C₁-C₈) -aliphatic radical having 5-12 ring atoms or,
if not already covered by the above definitions, means the necessarily protected side chain of a naturally occurring α- amino acid,
R² and R³ are the same or different and are hydrogen, an optionally substituted aliphatic radical having 1-21 C atoms,
an optionally substituted alicyclic 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,
a remainder of the formula wherein R¹⁰ is hydrogen, an aliphatic radical having 1-6 C atoms or an optionally substituted aromatic radical having 6-12 C atoms,
a remainder of the formula wherein R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
mean,
and
R⁴ and R⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms,
or their physiologically acceptable salts are used. 5. Use according to one or more of claims 1 to 4, characterized in that compounds of the formula I, preferably those of the formula II are used, in which

• a) n = 1 or 2;
• b) R
  • 1. hydrogen means;
  • 2. alkyl having 1-18 carbon atoms;
  • 3. an aliphatic acyclic radical of the formula C _a H _{(2 a-b +1)} , 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- or pentacyclic, non-aromatic hydrocarbon radical of the formula C _k H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to (C-2);
  • 5. aryl having 6-12 carbon atoms,
    by (C₁-C₈) alkyl, (C₁-C₄) alkoxy, hydroxy, halogen, nitro, amino, aminomethyl, (C₁-C₄) alkylamino, di (C₁-C₄) alkylamino, (C₁-C₄ ) Alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl, mono-, di- or trisubstituted,
  • 6. if n = 2, (C₆-C₁₂) -aryl (C₁-C₈) alkyl or di- (C₆-C₁₂) -aryl- (C₁-C₈) alkyl, which in the aryl moiety in each case as under b ) 5. may be substituted; or
  • 7. Alkoxy with 1-4 C atoms;
  • 8. aryloxy having 6-12 C atoms,
    which may be substituted as described under b) 5.;
  • 9. mono- or bicyclic heteroaryloxy or heteroaryl (C₁-C₈) 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 Represent nitrogen, which may be substituted in the heteroaryl as described under b) 5.;
  • 10. amino (C₁-C₈) alkyl;
  • 11. (C₁-C₄) alkanoylamino (C₁-C₈) alkyl;
  • 12. (C₇-C₁₃) arylamino (C₁-C₈) alkyl;
  • 13. (C₁-C₄) alkoxy-carbonylamino (C₁-C₈) alkyl;
  • 14. (C₆-C₁₂) -aryl (C₁-C₄) alkoxycarbonylamino (C₁-C₈) alkyl;
  • 15. (C₆-C₁₂) -aryl (C₁-C₄) -alkylamino (C₁-C₈) alkyl;
  • 16. (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 17. di (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 18. guanidino (C₁-C₈) alkyl;
  • 19. imidazolyl;
  • 20. indolyl;
  • 21. (C₁-C₄) alkylthio;
  • 22. if n = 2, (C₁-C₄) alkylthio (C₁-C₈) alkyl;
  • 23. (C₆-C₁₂) arylthio (C₁-C₈) alkyl,
    which may be substituted in the aryl part as described under b) 5.;
  • 24. (C₆-C₁₂) -aryl (C₁-C₈) -alkylthio,
    which may be substituted in the aryl part as described under b) 5.;
  • 25. if n = 2, carboxy (C₁-C₈) alkyl;
  • 26. carboxy;
  • 27. carbamoyl;
  • 28. if n = 2, carbamoyl (C₁-C₈) alkyl;
  • 29. (C₁-C₄) alkoxy-carbonyl (C₁-C₈) alkyl;
  • 30. if n = 2, (C₆-C₁₂) -aryloxy- (C₁-C₈) -alkyl,
    which may be substituted in the aryl part as described under b) 5.; or
  • 31. (C₆-C₁₂) -aryl (C₁-C₈) alkoxy,
    which may be substituted in the aryl moiety as described under b) 5.;
• c) R¹
  • 1. hydrogen means;
  • 2. alkyl having 1-18 carbon atoms;
  • 3. an aliphatic radical of formula C _a H _{(2 a-b +1)} , wherein 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 the formula C _c H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to ( c -2) stand;
  • 5. aryl with 6-12 C atoms,
    which may be substituted as described under b) 5.;
  • 6. (C₆-C₁₂) -aryl (C₁-C₈) -alkyl or (C₇-C₁₃) -royl (C₁-C₈) -alkyl,
    both of which may be substituted in the aryl moiety as described under b);
  • 7. mono- or bicyclic, optionally partially hydrogenated heteroaryl or heteroaryl (C₁-C₈) 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 up to 4 ring atoms represent nitrogen,
    which may be substituted in the heteroaryl as described under aryl b) 5.; or
  • 8. if from c) 1.-8. not yet included
    the optionally protected side chain of a naturally occurring α- amino acid of the formula R¹-CH (NH₂) -COOH means;
• d) R² and R³ are the same or different and
  • 1. hydrogen means;
  • 2. alkyl of 1-18 C atoms;
  • 3. an aliphatic acyclic radical of formula C _a H _{(2 a-b +1} ), wherein 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 the formula C _c H _{(2 c-d -1)} , which is optionally branched, wherein c is an integer from 3 to 20 and d is an even number 0 to ( c -2) stand;
  • 5. di (C₁-C₄) alkylamino (C₁-C₈) alkyl;
  • 6. (C₁-C₅) alkanoyloxy (C₁-C₈) alkyl;
  • 7. (C₁-C₆) alkoxy-carbonyloxy (C₁-C₈) alkyl;
  • 8. (C₇-C₁₃) -Aroyloxy- (C₁-C₈) alkyl;
  • 9. (₆-C₁₂) -Aryloxycarbonyloxy- (C₁-C₈) alkyl;
  • 10. aryl with 6-12 C atoms;
  • 11. (C₇-C₂₀) aralkyl;
  • 12. phthalidyl;
  • 13. a remainder of the formula means
    in which R¹⁰ is hydrogen, (C₁-C₆) -alkyl or aryl having 6-12 C atoms,
  • 14. a remainder of the formula in which R¹¹ and R¹², identically or differently independently of one another, denote hydrogen, an optionally substituted alkyl radical having 1-23 C atoms or an optionally substituted acyl radical having 1-23 C atoms,
• wherein the radicals mentioned under d) 8, 9, 10 and 11 may be substituted in the aryl part as described under b) 5; and
• e) R⁴ and R⁵ together with the atoms carrying them form a mono-, bi- or tricyclic heterocyclic ring system having 3 to 15 ring C atoms.

6. Use according to one or more of claims 1 to 5, characterized in that compounds of the formula I, preferably those of the formula II are used, in which
n = 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 having 6-12 C atoms, which is represented by (C₁-C₄) -alkyl, (C₁-C₄) -alkoxy, hydroxyl, halogen, nitro, amino, aminomethyl, (C₁-C₄) -alkylamino, di- (C₁-C₄) -alkyl C₄) -alkylamino, (C₁-C₄) alkanoylamino, methylenedioxy, carboxy, cyano and / or sulfamoyl, mono-, di- or may be 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 are sulfur or oxygen atoms and / or 1 to 4 ring atoms are nitrogen, which may be substituted as described above for aryl,
Amino (C₁-C₄) alkyl,
(C₁-C₄) alkanoylamino (C₁-C₄) alkyl,
(C₇-C₁₃) -Aroylamino- (C₁-C₄) alkyl,
(C₁-C₄) alkoxy-carbonylamino (C₁-C₄) alkyl,
(C₆-C₁₂) -aryl- (C₁-C₄) alkoxycarbonylamino (C₁-C₄) alkyl,
(C₆-C₁₂) -aryl- (C₁-C₄) alkylamino (C₁-C₄) alkyl,
(C₁-C₄) alkylamino (C₁-C₄) alkyl,
Di- (C₁-C₄) alkylamino (C₁-C₄) alkyl,
Guanidino (C₁-C₄) alkyl,
Imidazolyl, indolyl,
(C₁-C₄) alkylthio,
(C₁-C₄) alkylthio (C₁-C₄) alkyl,
(C₆-C₁₂) -arylthio (C₁-C₄) -alkyl which may be substituted in the aryl part as described above for aryl,
(C₆-C₁₂) -aryl (C₁-C₄) -alkylthio which may be substituted in the aryl part as described above for aryl,
Carboxy (C₁-C₄) alkyl,
Carboxy, carbamoyl,
Carbamoyl (C₁-C₄) alkyl,
(C₁-C₄) -alkoxy-carbonyl- (C₁-C₄) alkyl,
(C₆-C₁₂) -Aryloxy- (C₁-C₄) alkyl, which may be substituted in the aryl moiety as described above in aryl, or
(C₆-C₁₂) -aryl (C₁-C₄) -alkoxy which may be substituted in the aryl part as described above for aryl,
R¹ is hydrogen,
Alkyl with 1-6 C atoms,
Alkenyl with 2-6 C atoms,
Alkynyl with 2-6 C atoms,
Cycloalkyl having 3-9 C atoms,
Cycloalkenyl having 5-9 C atoms,
(C₃-C₉) -cycloalkyl- (C₁-C₄) alkyl,
(C₅-C₉) -cycloalkenyl- (C₁-C₄) -alkyl, optionally partially hydrogenated aryl having 6-12 C-atoms, which may be substituted as described above in R,
(C₆-C₁₂) -aryl (C₁-C₄) -alkyl or (C₇-C₁₃) -acroyl- (C₁ or C₂) -alkyl, both of which may be substituted as 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 R¹-CH (NH₂) -COOH,
R² and R³ are the same or different and
Hydrogen,
Alkyl with 1-12 C atoms,
Alkenyl with 2-12 C atoms,
Di- (C₁-C₄) alkylamino (C₁-C₈) alkyl,
(C₁-C₅) alkanoyloxy (C₁-C₈) alkyl,
(C₁-C₆) alkoxy-carbonyloxy (C₁-C₈) alkyl,
(C₇-C₁₃) -Aroyloxy- (C₁-C₈) alkyl,
(C₆-C₁₂) -Aryloxycarbonyloxy- (C₁-C₈) alkyl,
Aryl with 6-12 C atoms,
(C₆-C₁₂) -aryl- (C₁-C₈) alkyl,
(C₃-C₉) -cycloalkyl or
(C₃-C₉) -cycloalkyl- (C₁-C₈) alkyl
mean and
R⁴ and R⁵ have the meaning given above. 7. Use according to one or more of claims 1 to 6, characterized in that compounds of the formula I, preferably those of the formula II are used, in which
n = 1 or 2,
R (C₁-C₆) alkyl, (C₂-C₆) alkenyl, (C₃-C₉) cycloalkyl, amino (C₁-C₄) alkyl, (C₂-C₅) acylamino (C₁-C₄) alkyl , (C₇-C₁₃) -Aroylamino- (C₁-C₄) -alkyl, (C₁-C₄) -alkoxycarbonylamino- (C₁-C₄) -alkyl, (C₆-C₁₂) -aryl (C₁-C₄) -alkoxycarbonylamino- C₁-C₄) alkyl, (C₆-C₁₂) -aryl, substituted by (C₁-C₄) alkyl, (C₁-C₄) alkoxy, hydroxy, halogen, nitro, amino, (C₁-C₄) alkylamino, di - (C₁-C₄) - alkylamino and / or methylenedioxy mono-, di- or may be trisubstituted, or 3-indolyl, in particular methyl, ethyl, cyclohexyl, tert. Butoxycarbonylamino- (C₁-C₄) alkyl, Benzoyloxycarbonylamino- (C₁-C₄) alkyl or phenyl, which by phenyl, (C₁-C₂) alkyl, (C₁ or C₂) alkoxy, hydroxy, fluorine, chlorine, bromine, Amino, (C₁-C₄) - alkylamino, di (C₁-C₄) -alkylamino, nitro and / or methylenedioxy mono- or disubstituted or in the case of methoxy, may be trisubstituted, means
R¹ is hydrogen or (C₁-C₆) -alkyl, which may optionally be substituted by amino, (C₁-C₆) -acylamino or benzoylamino, (C₂-C₆) -alkenyl, (C₃-C₉) -cycloalkyl, (C₅-C₉) -Cycloalkenyl, (C₃-C₇) -cycloalkyl- (C₁-C₄) alkyl, (C₆-C₁₂) -aryl or partially hydrogenated aryl, each by (C₁-C₄) alkyl, (C₁ or C₂) - alkoxy or halogen (C₆-C₁₂) -aryl (C₁-C₄) -alkyl or (C₇-C₁₃) -acroyl- (C₁-C₂) -alkyl, both of which may be substituted as defined above in the aryl radical, a mono- or bicyclic heterocyclic radical having 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 a side chain of a naturally occurring, optionally protected α- amino acid, in particular but hydrogen, (C₁-C₃) alkyl, (C₂ or C₃) alkenyl, the optionally protected side chain of lysine, benzyl, 4-methoxy nzyl, 4-ethoxybenzyl, phenethyl, 4-amino-butyl or benzoylmethyl,
R² and R³ represent the same or different radicals hydrogen, (C₁-C₁₂) -alkyl, (C₂-C₁₂) -alkenyl or (C₆-C₁₂) -aryl (C₁-C₈) -alkyl, and
R⁴ and R⁵ have the meaning given above. 8. Use according to one or more of claims 1 to 7, characterized in that compounds of the formula II are used, wherein R⁴ and R⁵ together with the atoms carrying them a mono-, bi- or tricyclic 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, tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, indoline, octahydrocyclopenta [b] pyrrole, 2-azaspiro [4.5] decane, 2- Azaspiro [4.4] nonane, spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidine], spiro [(bicyclo [2.2.2] octane) -2,3'-pyrrolidine], 2- Azatricyclo [4.3.0.1 ^6,9 ] decane, decahydrocyclohepta [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, 2,3,3a, 4,5,7a-hexahydroindole, 1,2,3,3a, 4,6a Hexahydrocyclopenta [b] pyrrole and 2-azabicyclo [3.1.0] hexane. 9. Use in a process for the preparation of a Pharmaceutical agent according to one or more of Claims 1 to 8, characterized in that the Active substance with the appropriate carrier, auxiliary and / or Add additives in a suitable dosage form. 10. Compound of formula III in which the five chiral C atoms (*) each have the S configuration,
R² is ethyl or hydrogen and
R³ is n-octyl,
and their physiologically acceptable salts. 11. A compound of formula III according to claim 10, wherein R² Ethyl, as well as their physiologically acceptable Salts. 12. A compound of formula III according to claim 10, wherein R² Hydrogen means, as well as their physiological compatible salts. 13. Maleinate of the compound according to claim 11. 14. A process for preparing a compound of formula III according to any one of claims 10 to 13, characterized in that

• a) a compound of the formula III in which the five chiral C atoms (*) each have the S configuration, R² is ethyl or a basic, acid or hydrogenolytically readily removable carboxyl protective group and R³ is hydrogen, with n-octanol implements,
  or that one
• b) a compound of formula III in which the configuration and R² and R³ are as defined above under (a) with a compound of formula VI H₃C- [CH₂-] ₇X (VI) in the X is a leaving group which displaces nucleophilic means under conditions of nucleophilic substitution,
  or that one
• c) reacting a compound of the formula III which is as described above under (a) and in which R² is hydrogen and R³ is n-octyl, with ethanol as described under process variant (a),
  or that one
• d) a compound of formula III in which the configuration, R² and R³ are as defined above under (c), with a compound of formula VII H₃C-CH₂-X (VII) in the X is a leaving group which can be displaced nucleophilic , means, as described under process variant (b), implements,
  or that one
• e) a compound of the formula VIII in which R² is as defined above under (a), reacted with a compound of formula IX in which the four chiral C atoms (*) each have the S configuration,
  or that one
• f) a compound of the formula X. in which the three chiral C atoms (*) each have the S configuration and R³ is n-octyl, and reacted with a compound of the formula XI in which R² is as defined above under (a), if necessary in an obtained compound of the formula III (R² = protective group), the protective group R² is split off in a manner known per se and the compound of the formula III (R² = ethyl or hydrogen ) optionally converted into its physiologically acceptable salt,
  if, as starting materials of process variants (a) - (f) stereoisomer mixtures are used, then in a further separation step, the all-S-isomer of formula III (R² = hydrogen or ethyl, R³ = n-octyl) is separated.

15. Compound of formula XII in which the three chiral carbon atoms each have the S configuration and Q is hydrogen or the radical XIII means. 16. Stereoisomer mixture containing a compound according to Claim 15. 17. A process for preparing a compound according to claim 15 or 16, characterized in that

• a) a compound of formula XIV in which Q is hydrogen or -CO-CH (CH₃) -NH₂, reacting with n-octanol or H₃C- [CH₂] ₇-X according to claim 14, process variant (a) or (b) or
• b) a compound of the formula XV analogously to claim 14, process variant (f) is reacted with an amino-protected alanine and then cleaved off the amino protecting groups and, if desired, the all-S-isomer of formula XII isolated.

18. A compound according to any one of claims 10 to 13 for Application as a remedy. 19. A compound according to claim 18 for use as Nootropic. 20. A compound according to claim 18 for use Psychotropic, preferably anxiolytic.