PT89537B - PROCESS FOR THE PREPARATION OF SUBSTITUTED DERIVATIVES OF N-OCTILO AZABICYCLO- {3.3.0} OCTANO-3-CARBOXYLATE WITH PSYCHOTROPIC ACTION - Google Patents

Abstract

(A) n-Octyl 2-alanyl-2-azabicyclo (3,3,0)octane-3- carboxylate derivs. of formula (Ia), in which all five chiral C atoms are in the S configuration, and their salts are new: R'2 = H or Et; R'3 = n-octyl. (B) Intermediates of formula (IX) and (X) in all-S isomer form are also new (see 'Preparation'). (C) ACE inhibitors (I) are used to prepare medicaments with psychotropic, esp. anxiolytic, activity. Pref (I) have min effective doses of 0.1-30 mg/kg in the 'lick-shock' and 'Geller-Seifter' conflict tests.

Description

The invention relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically acceptable salts, as drugs with psychotropic action, especially anxiolytic action, to drugs containing these compounds, as well as their use in preparation of the corresponding pharmaceutical compositions.

For this new use, for example compounds of formula I x -x (i)

R

ch ₂

COOR ⁵

O

X ² represents -CH9SH, -CH9-SCR ⁶ , -CH9-PR ⁷ or ² II ² I ₈

OR

-Y ² - (CH ₂ ) _p -CH- (CH ₂ ) _n -R

I 2

COOR ^

Y ¹ represents -S- or -CH ₂ ~,

Q

Y represents -NR - or -CH ₂ , m is 0 or 1, n is 0, 1 or 2, p is 0 or 1,

R represents hydrogen, an aliphatic radical possibly substituted with 1 to 21 carbon atoms, an alicyclic radical possibly substituted with 3 to 20 carbon atoms, an aromatic radical possibly substituted with 6 to 12 carbon atoms, an araliphatic radical possibly substituted with 7 to 32

carbon atoms, an alicyclic-aliphatic radical evetually substituted with 4 to 20 carbon atoms, a heteroaromatic or heteroaromatic-aliphatic radical with 1 to 8 carbon atoms in the aliphatic part with 5 to 12 ring atoms, possibly substituted, or a radical 0R ^a or SR ^a , where

R ^a represents an optionally substituted aliphatic radical, with 1 to 4 carbon atoms, an optionally substituted aromatic radical, with 6 to 12 carbon atoms, or an eventually substituted beoaromatic radical, with 5 to 12 ring atoms,

R ^ represents hydrogen, an aliphatic radical eventually substituted, with 1 to 21 carbon atoms, an alicyclic radical possibly substituted, with 3 to 20 carbon atoms, an alicyclic-aliphatic radical eventually substituted, with 4 to 20 carbon atoms, an optionally substituted aromatic radical, with 6 to 12 carbon atoms, an optionally substituted araliphatic radical, with 7 to 32 carbon atoms, an optionally substituted heteroaromatic or heteroaromatic-aliphatic radical, with 1 to 8 carbon atoms in the aliphatic part and 5 to 12 ring atoms, or if it is not yet covered by the above definitions, the side chain that is eventually blocked from a naturally occurring c <-amino acid,

3

R or R are the same or different and represent hydrogen, an aliphatic radical possibly substituted with 1 to 21 carbon atoms, an alicyclic radical possibly substituted with 3 to 20 carbon atoms, an aromatic radical possibly substituted with 6 to 12 carbon atoms, an araliphatic radical eventually substituted with 7 to 32 carbon atoms, a radical of formula

in which R ¹⁰ represents hydrogen, an aliphatic radical with 1 to 6 carbon atoms or an aromatic radical eventually substituted with 6 to 12 carbon atoms, a radical of formula

-ch ₉ -ch-ch ₉ -or ¹² or ch ₉ -or ¹³ ·

I ll I

OR -CH ¹ 12 ch ₂ -or

12 in which R and R are the same or different and independently of each other represent hydrogen, an alkyl radical optionally substituted with 1 to 23 carbon atoms or an acyl radical possibly substituted with 1 to 23 carbon atoms,

R ^ represents hydrogen or alkyl with 1 to 6 carbon atoms and

R ^ represents alkyl with 1 to 6 carbon atoms, cycloalkyl with 3 to 6 carbon atoms or or

5

R and R ^y together with the atoms to which they are attached form a monocyclic, bicyclic or tricyclic heterocyclic ring system with 3 to 15 ring carbon atoms,

R represents hydrogen, amino, alkyl with 1 to 6 carbon atoms, aryl with 6 to 12 carbon atoms or aralkyl with 7 to 13 carbon atoms,

R represents alkyl with 1 to 6 carbon atoms or aralkyl with 7 to 13 carbon atoms, preferably - (CHp) /} ^- CgH ^,

R® represents alkyl having 1 to 6 carbon atoms which is eventually monosubstituted by alkanoyloxy having 1 to 6 carbon atoms, preferably 2-methyl-1-propionyloxy-propyl, and

represents hydrogen or alkyl having 1 to 6 carbon atoms;

especially.the compounds of formula II, x * *

R ^? OOC - CH - N - C - CH - RH - CH - (CH?) -R (II) i ₅ b ι 2

R ⁴ R ^? 0 R COOR where n is 1 or 2,

R represents hydrogen, an aliphatic radical possibly substituted with 1 to 21 carbon atoms, an alicyclic radical possibly substituted with 3 to 20 carbon atoms, an aromatic radical possibly substituted with 6 to 12 carbon atoms, an araliphatic radical possibly substituted with 7 at 32 carbon atoms, an alicyclic-aliphatic radical eventually substituted with 7 to 14 carbon atoms, a heteroaromatic or heteroaromatic-aliphatic radical possibly substituted with 1 to 8 carbon atoms in the aliphatic part and 5 to 12 ring atoms, or 0R ^to a radical or SR ^a, in which

R ^a represents an aliphatic radical eventually substituted with 1 to 4 carbon atoms, an aromatic radical eventually substituted with 6 to 12 carbon atoms or a hetero aromatic radical eventually substituted with 5 to 12 ring atoms, r! represents hydrogen, an aliphatic radical possibly substituted with 1 to 21 carbon atoms, an alicyclic radical possibly substituted with 3 to 20 carbon atoms, an alicyclic-aliphatic radical possibly substituted with 4 to 2 carbon atoms, an aromatic radical possibly substituted with 6 to 12 carbon atoms, an araliphatic radical eventually substituted with 7 to 32 carbon atoms, a heteroaromatic or heteroaromatic-aliphatic radical

te substituted with 1 to 8 carbon atoms in the aliphatic part and 5 to 12 ring atoms, or if they are not yet covered by the previous definitions, the side chain possibly blocked by a naturally occurring o -amino acid,

R ^ and R ⁹ are identical or different and represent hydrogen, an optionally aliphatic radical substituted with 1 to 21 carbon atoms, an alicyclic radical optionally substituted 3 to 20 carbon atoms, a eventualmen aromatic radical substituted te 6 to 12 atoms carbon, an araliphatic radical eventually substituted with 7 to 32 carbon atoms, a radical of formula

in which R ^ represents hydrogen, an aliphatic radical with 1 to 6 carbon atoms or an aromatic radical eventually substituted with 6 to 12 carbon atoms, a radical of formula

-ch ₅ -ch-ch ₂ -or ¹²

CHp-OR ¹¹ or j

-CH ¹ 12 CH ₂ -0R ^x

12 in which R and R are the same or different and independently of each other represent hydrogen, an alkyl radical possibly substituted with 1 to 23 carbon atoms or an acyl radical possibly substituted with 1 to 23 carbon atoms, and

5. ,

R and R together with the atoms to which they are attached form a monocyclic, bicyclic or tri-cyclic heterocyclic ring system, with 3 to 15 ring carbon atoms.

An optionally substituted aliphatic radical is understood to mean an aliphatic acyclic radical, that is, a radical with an open, linear or branched carbon chain, such as alkyl, alkenyl, alkynyl, and the corresponding polyunsaturated radicals. It is preferably unsubstituted or monosubstituted as earlier described mind for example for carboxy, carbamoyl, aminoalkyl, alkanoylaminoalkyl, alkoxycarbonylaminoalkyl, arilalcoxicarbonilaminoalquilo, arilalquilaminoalquilo, alkylaminoalkyl, dialkylaminoalkyl, alkylthioalkyl, arylthioalkyl, carboxialcuilo, carbamoylalkyl, alkoxycarbonylalkyl, alkanoyloxy alkyl, alkoxycarbonyloxyalkyl, aroyloxyalkyl or aryloxycarbonyloxyalkyl.

An eventually substituted alicyclic radical and the corresponding eventually substituted alicyclic-aliphatic radical attached via an open carbon chain, is a non-aromatic radical, preferably monocyclic to isocyclic pentacyclic, with double asymmetrically distributed single or multiple bonds, which can also be branched (i.e., carrying open aliphatic side chains) and that is coupled through a ring carbon atom or a side chain carbon atom. It is preferably unsubstituted. The various rings as components of a radical of this nature are condensed, coupled by spiro bond or isolated. Examples of such radicals are cycloalkyl, cycloalkenyl, cycloalkylalkyl, bicycloalkyl, tricycloalkyl and radicals derived from monocyclic, bicyclic or oligocyclic terpenes, such as menthyl, isomentyl, boronyl, ceranyl, epibornyl, epiisobornyl, isobornyl, neomilyl, neomilyl, neomilyl, neomilyl, neomilyl, neomilyl, ninomino, ; they are preferably unsubstituted (aliphatic side chains according to the present definition are not considered substitutes).

An optionally substituted aromatic radical is preferably aryl such as phenyl, biphenylyl or naphthyl, which is optionally monosubstituted, disubstituted or tri-substituted as previously indicated for aryl (b) 5.). Aryl-derived radicals, such as aralkyl, aryloxy, arylthio or aroyl, preferably benzoyl, _L

may be substituted as the aryl radical.

An optionally substituted heteroaromatic radical is preferably a heterocyclic mono or bicyclic aromatic radical with 5 to 7 or, respectively, 8 to 12 ring atoms, preferably up to 10 ring atoms, of which 1 to 2 ring atoms are sulfur atoms or oxygen, and / or of which 1 to 4 ring atoms represent nitrogen atoms, such as for example thienyl, benzo / b / thienyl,. furyl, pyre nile, benzofuryl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyridazinyl, indazolyl, isoindolyl, indolyl, purinyl, quinolizinyl, isoquinolinyl, phthalazinyl, naphthyrinyl, quinoxyazyl, quinoline isothiazolyl. These radicals can also be partially or totally hydrogenated. A heteroaromatic radical and the corresponding 'heteroaromatic -aliphatic radical' may be substituted as defined above.

An optionally substituted araliphatic radical is understood to mean in particular aralkyl radicals such as arylalkyl, diarylalkyl, indanyl or fluorenyl, being aryl defined as above and may be substituted as indicated.

An optionally substituted acyl radical is a straight or branched, saturated or unsaturated aliphatic radical, preferably an unsubstituted, saturated or unsaturated alkanoyl radical, such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, lauroyl, myristoyl, palmitoyl, stearoyl, caprineyl, caproyl, capryloyl, arachidonoyl, sorboyl, angeloyl, acryloyl, propiolyl, methacryloyl, crotonoyl, isocrotonoyl, oleoyl, elaidoyl or ricinoleoyl. Fatty acid radicals, such as those occurring in natural triglycerides, are preferred.

5

R and R together with the atoms to which they are attached form a monocyclic, bicyclic or tricyclic heterocyclic ring system, with 3 to 15 ring carbon atoms, which preferably has up to 2 atoms of. sulfur and up to 2 nitrogen atoms, especially up to 1 atom _ o _

sulfur.

As such ring systems are of particular interest to those in the following group:

pyrrolidine (0); thiazolidine (R); tetrahydroisoquinoline (A); decahydroisoquinoline (B); octahidroindol (C); indoline (Q); octahidrocyclopenta / b_ / pyrrole (D); 2-aspasospiro / 4.5 / dean (E);

2- ^aspasospiro / ^ 4.47 ^monarto (F); spiro / Xbicyclo / 2.2.l / heptane) -2,3 -pyrrolidine / (G); spiro / Cbicycle / 2.2.2 / octane) -2,3'-pyrrolidine / (H); 2-azathricycle /? · 3 · 0.1θ '\ _ / dean (I); decahydrocyclohepta / T) _J7pyrrole (J); octahidroisoindo (K); octahydrocyclopene / c / pyrrole (E); 2,3,3a, 4,5,7a-hexahydroindole (M); 2-aza-biciclo / 3.Ι.θ / hexane (N); 1,2,3,3a, 4, oa-hexahydrocyclopenta / ^ bJZpirrol (P), which may all be eventually replaced. Pyrrolidine (0) and thiazolidine (R) can be monosubstituted, for example, by aryl with 6 to 12 carbon atoms (phenyl, 2-hydroxyphenyl, etc.), arylmercapto with 6 to 12 carbon atoms (as phenylmercapto) or by cycloalkyl with 3 to 7 carbon atoms (like cyclohexyl). Tetrahydroisoquinoline (A) can carry, for example, in the aryl part up to 2 alkoxy radicals with 1 to 6 carbon atoms, preferably methoxy radicals. The same is valid for the other ring systems. However, unsubstituted systems are preferable.

The heterocyclic ring systems that are of interest in the present case have the following structural formulas:

Μ Ν

fi 2

Naturally occurring d -amino acids are for example Ala, Ser, Thr, Val, leu, Ile, Asp, Asn, Glu, Gin, Arg, Lys, Hyl, Orn, Cit-, Tyr, Phe, Trp and His.

In the case of R ^ representing the side chain of a naturally occurring '/ -amino acid

protected, such as Ser, Thr, Asp, Asn, Glu,

Blocked Gin, Arg, Lys, Hyl, Gys, Orn, Cit, Tyr, Trp or His are the preferred groups in current groups in peptide chemistry (see Houben-Weyl, vol XV / 1 and XV / 2). In the case of R1 representing the lysine blocked side chain, known amino blocking groups are preferred, but especially Z, Boc or alkanoyl with 1 to 6 carbon atoms. As oxygen-blocking groups for tyrosine, preferably alkyl having 1 to 6 carbon atoms, especially methyl or ethyl, is of interest.

The compounds of formulas I or II have asymmetric carbon atoms and can therefore occur as enantiomers and diastereomers. The invention encompasses both pure enantiomers and racemates.

In compounds of formulas I or II which have several chiral atoms, all possible diastereomers, such as racemates or enantiomers, or mixtures of the various diastereomers, are of interest.

A preferred embodiment is characterized by the fact that compounds of formula

1, preferably those of formula II, which

a) n is 1 or 2;

b) R represents 12 hydrogen;

2. alkyl with 1 to 18 carbon atoms;

5. an aliphatic acyclic radical of formula C, in which the double bonds, if their number exceeds 1, are not accumulated, a represents an integer from 2 to 18 and b represents an integer from 2 to a;

4. a non-aromatic, monocyclic, di-cyclic, tricyclic, tetracyclic or pentacyclic radical of formula ^C and ^H (2c-dl) ^{which is} eventually branched, in which £ is an integer from 3 to 20 ed is an integer from 0 to (c-2);

5. aryl with 6 to 12 carbon atoms, which may be monosubstituted, disubstituted or tri-substituted with alkyl with 1 to 8 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy, halogen, nitro, amino, aminomethyl, alkylamino with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms

in each part alkyl, alkanoylamino with 1 to 4 carbon atoms, methylenedioxy, carboxy, cyano and / or sulfamoyl;

6. if n is 2, it represents aryl-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part, or diaryl-alkyl with 6 to 12 carbon atoms in each aryl part and 1 to 8 carbon atoms in the alkyl part, which may be substituted in the aryl part, each, as described above in b) 5 ·; or

7. alkoxy with 1 to 4 carbon atoms;

8. aryloxy with 6 to 12 carbon atoms, which may be substituted as above in b) 5;

9. heteroaryloxy or heteroaryl-monocyclic or bicyclic alkyl, with 1 to 8 carbon atoms in the alkyl part and with 5 to 7 or respectively 8 to 10 ring atoms, of which up to 9 ring atoms are carbon atoms and 1 to 2 ring atoms are sulfur or oxygen atoms, and / or 1 to 4 ring atoms represent nitrogen atoms, which can be substituted on the heteroaryl part as described in b) 5;

10. aminoalkyl having 1 to 8 carbon atoms;

11. alkanoylamino-alkyl having 1 to 4 carbon atoms in the alkanoyl part and 1 to 8 carbon atoms in the alkyl part;

12. aroylamino-alkyl with 7 to 15 carbon atoms in the aromatic part and 1 to 8 carbon atoms in the alkyl part;

13 · alkoxycarbonylamino-alkyl with 1 to 4 carbon atoms in the alkoxy part and 1 to 8 carbon atoms in the alkyl part; aryl-alkoxycarbonylamino-alkyl having 6 to 12 carbon atoms in the aryl part, 1 to 4 carbon atoms in the alkoxy part and 8 carbon atoms in the alkyl part;

15 · aryl-alkylamino-alkyl with 6 to 12 carbon atoms in the aryl part, 1 to 4 carbon atoms in the alkylamino part and 1 to 8 carbon atoms in the alkyl part;

16. alkylamino-alkyl having 1 to 4 carbon atoms in the alkylamino part and 1 to 8 carbon atoms in the alkyl part;

17. dialkylamino-alkyl with 1 to 4 carbon atoms in each alkylamino part and 1 to 8 carbon atoms in the alkyl part;

18. guanidino-alkyl having 1 to 8 carbon atoms in the alkyl part;

19 · imidazolyl;

i 9

20. indolyl;

21. alkylthio with 1 to 4 carbon atoms;

22. if n is 2, it represents alkylthioalkyl having 1 to 4 carbon atoms in the alkylthio part and 1 to 8 carbon atoms in the alkyl part;

23. arylthioalkyl with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part;

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

24. aryl-alkylthio having 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part, which can be substituted in the aryl part as described in b) 5 .;

25. if n is 2, it represents carboxy-alkyl having 1 to 8 carbon atoms in the alkyl part;

26. carboxy;

27 · carbamoyl;

28. if n is 2, it represents carbamoyl-alkyl having 1 to 8 carbon atoms in the alkyl part;

29. alkoxycarbonyl-alkyl having 1 to 4 carbon atoms in the alkoxy part and 1 to 8 carbon atoms in the alkyl part;

30. if n is 2, it represents aryloxy-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the non-alkyl part, which can be substituted in the aryl part as described in b) 5. or

31. aryl-alkoxy having 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkoxy part, which may be substituted in the aryl part as described in b) 5 .;

c) R '· represents 1. hydrogen;

2. alkyl with 1 to 18 carbon atoms;

3. an aliphatic radical of formula C _to H (2 _to _t> ₊ i)> ^{in which the} double bonds, if their number exceeds 1, are not accumulated, a represents an integer from 2 to 18 and b represents a integer from 2 to a;

4. a non - aromatic hydrocarbon radical, monocyclic, dicyclic, tricyclic, tetracyclic or pentacyclic, ^G is of formula ^H (2c-d) ^everrt ualmente is branched, where c is an integer from 3 to 20 and B is a number from 0 to (c-2);

5. aryl with 6 to 12 carbon atoms, which can be substituted as described in I.b) 5 ·;

6. aryl-alkyl with 6 to 12 carbon atoms in the aryl part and 8 carbon atoms in the alkyl part, or aroyl-alkyl with 7 to 13 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part , which can both be substituted on the aryl part as described in b) 5 ·;

7. heteroaryl or heteroaryl-monocyclic alkyl.or bicyclic, possibly partially hydrogenated, having 1 to 8 carbon atoms in the alkyl part and having 5 to 7 or respectively 8 to 10 ring atoms, of which up to 9 ring atoms are d atoms carbon and 1 or 2 ring atoms are sulfur or oxygen atoms, and / or 1 to 4 ring atoms represent nitrogen atoms, which can be substituted on the heteroaryl radical as described for aryl in b) 5 ·; or

8. if it is not yet covered by c) 1.-8., The possibly blocked side chain of a naturally occurring amino acid of formula r1-CH (NH ₉ ) -COOH;

3 ^z

d) R and R are the same or different and represent

1. hydrogen;

2. alkyl with 1 to 18 carbon atoms;

3 · a non - cyclic aliphatic radical, the CH / _O formula. _n χ, in which the double bonds, if their number exceeds 1, are not accumulated, a represents an integer from 2 to 18 and b represents an integer from 2 to a;

4. a monocyclic, dicyclic, tricyclic, tetracyclic or pentacyclic non-aromatic hydrocarbon radical, of formula ^ 2 ^ (2c-dl) '9- ^ue eventually ® branched, where £ represents an integer from 3 to 20 and d represents an integer from 0 to (c-2);

5. dialkylamino-alkyl with 1 to 4 carbon atoms in each alkylamino group and 1 to 8 carbon atoms in the alkyl group;

6. alkanoyloxy-alkyl having 1 to 5 carbon atoms in the alkanoyl part and 1 to 8 carbon atoms in the alkyl group;

7 · alkoxycarbonyloxy-alkyl having 1 to 6 carbon atoms in the alkoxy group and 1 to 8 carbon atoms in the alkyl group,

8. aroyloxy-alkyl with 7 to 13 carbon atoms in the aryl group and 1 to 8 carbon atoms in the alkyl group; ______

9. aryloxycarbonyloxy-alkyl with 6 to 12 carbon atoms in the aryl group and 1 to 8 carbon atoms in the alkyl group;

10. aryl with 6 to 12 carbon atoms;

11. aralkyl with 7 to 20 carbon atoms;

12. phthalidyl;

13. a formula radical

where R ¹⁰ represents hydrogen, alkyl of 1 to 6 carbon atoms or aryl of 6 to 12 carbon atoms,

14. a formula radical

C ^ -OR ¹¹

-Ch

I ₁₂ ch ₂ -or

12 in which R and R are the same or different and independently of each other represent hydrogen, an alkyl radical optionally substituted with 1 to 23 carbon atoms or an acyl radical possibly substituted with 1 to 23 carbon atoms, the radicals mentioned in d ) 8., 9 ·, 10. and 11. are substituted in the aryl part as described in b) 5 .; e \ 4 5

e) R and R together with the atoms to which they are attached form a monocyclic, bicyclic or tricyclic heterocyclic ring system with 3 to 15 ring carbon atoms.

A particularly preferred embodiment is characterized by the use of compounds of formula 1, preferably those of formula II where n is 1 or 2,

R represents hydrogen, alkyl having 1 to 8 carbon atoms,

-15alkenyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 9 carbon atoms, aryl with 6 to 12 carbon atoms that can be monosubstituted, disubstituted or trisubstituted with alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy, halogen, nitro, amine, aminomethyl, alkylamino with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms in each alkyl group, alkanoylamino with 1 to 4 carbon atoms, methylenedioxy, carboxy, cyano and / or sulfamoyl, alkoxy with 1 to 4 carbon atoms, aryloxy with 6 to 12 carbon atoms, which can be substituted as described above for aryl, monocyclic or bicyclic heteroaryloxy, with 5 to 7 or respectively 8 to 11 carbon atoms ring, of which 1 or 2 ring atoms are sulfur or oxygen atoms and / or 1 to 4 ring atoms represent a nitrogen atom, which can be substituted as described above for aryl, aminoalkyl with 1 to 4 carbon atoms , alkanoylamino-alkyl c om 1 to 4 carbon atoms in each alkyl part, aroylamino-alkyl with 7 to 13 carbon atoms in the aryl part it 4 carbon atoms in the alkyl part, alkoxycarbonylamino-alkyl with 1 to 4 carbon atoms in each group alkyl, aryl-alkoxycarbonylamino-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 4 carbon atoms in each alkyl part, aryl-alkylamino-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 4 atoms carbon in each alkyl group, alkylamino-alkyl with 1 to 4 carbon atoms in each alkyl group, dialkylamino-alkyl with 1 to 4 carbon atoms in each alkyl group, guanidino-alkyl with 1 to 4 carbon atoms in the alkyl group, imidazolyl, indolyl, alkylthio with 1 to 4 carbon atoms, alkylthio-alkyl with 1 to 4 carbon atoms in each alkyl group, arylthio-alkyl with 6 to 12 carbon atoms in the aryl group and 1 to 4 carbon atoms in the alkyl group, which may be substituted on the aryl part as described above ma for aryl, aryl-alkylthio having 6 to 12 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl part, which can be substituted in the aryl part as described above for aryl,.

carboxyalkyl with 1 to 4 carbon atoms in the alkyl group, carboxy, carbamoyl, carbamoyl-alkyl with 1 to 4 carbon atoms in the alkyl, alkoxycarbonyl-alkyl group with 1 to 4 carbon atoms in each alkyl, aryloxy-alkyl group 6 to 12 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl group, which can be substituted in the aryl part as described above for aryl, or aryl-alkoxy with 6 to 12 carbon atoms in the part, aryl it 4 carbon atoms in the alkoxy group, which may be substituted on the aryl part as described above for aryl, r! represents hydrogen, alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, alkynyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 9 carbon atoms, cycloalkenyl with 5 to 9 carbon atoms, cycloalkyl- alkyl with 5 to 9 carbon atoms in the cycloalkyl group and 1 to 4 carbon atoms in the alkyl, cycloalkenyl-alkyl group with 5 to 9 carbon atoms in the 'cyclalkenyl group and 1 to 4 carbon atoms in the alkyl group, possibly hydrogenated aryl partially with 6 to 12 carbon atoms, which can be replaced as described above in

R, aryl-alkyl with 6 to 12 carbon atoms in the aryl part it 4 carbon atoms in the alkyl group or aryl-alkyl with 7 to 13 carbon atoms in the aryl part and 1 or 2 carbon atoms in the alkyl part, which can both are substituted as described above for aryl, monocyclic or bicyclic heteroaryl, possibly partially hydrogenated, with 5 to 7 or 6 to 10 ring atoms, of which 1 or 2 ring atoms are sulfur or oxygen and / or 1 to 4 ring atoms represent azo atoms, which may be substituted with the previous aryl group, or the side chain possibly protected from a naturally occurring d-amino acid, of the formula R ^ -CH (NH _O ) -COOH,

3 5,

R and R are the same or different and represent hydrogen, alkyl with 1 to 12 carbon atoms, alkenyl with 2 to 12 carbon atoms, dialkylamino-alkyl with 1 to 4 carbon atoms in each alkylamino group and 1 to 8 carbon atoms in the alkyl group, alkanoyloxy-alkyl with 1 to 5 carbon atoms in the group

7 alkanoyl powder and 1 to 8 carbon atoms in the alkyl, alkoxycarbonyloxy-alkyl group with 1 to 6 carbon atoms in the alkoxy group and 1 to 8 carbon atoms in the alkyl group, aroyloxyalkyl with 7 to 15 carbon atoms in the aryl group and 1 to 8 carbon atoms in the alkyl, aryloxycarbonyloxy-alkyl group with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part, aryl with 6 to 12 carbon atoms, aryl-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part, cycloalkyl with 5 to 9 carbon atoms or cycloalkyl-alkyl with 5 to 9 carbon atoms in the cycloalkyl part and 1 to 8 carbon atoms in the alkyl group and 4 5

R and R have the meanings indicated above.

A very particularly preferred embodiment is characterized by the fact that compounds of formula 1 are used, preferably compounds of formula II, in which n is 1 or 2,

R represents alkyl with 1 to 6 carbon atoms, alkenyl with 2 to 6 carbon atoms, cycloalkyl with 5 to 9 carbon atoms, aminoalkyl with 1 to 4 carbon atoms, acylamino-alkyl with 2 to 5 carbon atoms in the group acyl and 1 to 4 carbon atoms in the alkyl, aroylamino-alkyl group with 7 to 15 carbon atoms in the aryl group and 1 to 4 carbon atoms in the alkyl group, alkoxycarbonylamino-alkyl with 1 to 4 carbon atoms in each alkyl group , aryl-alkoxycarbonylamino-alkyl with 6 to 12 carbon atoms in the aryl group and 1 to 4 carbon atoms in each alkyl group, aryl with 6 to 12 carbon atoms, which can be monosubstituted, disubstituted or trisubstituted by alkyl with 1 to 4 carbon atoms, alkoxy with 1 to 4 carbon atoms, hydroxy, halogen, nitro, amino, alkylamino with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms in each alkyl group and / or by methylenedioxy, or represents 5-indolyl, especially methyl, ethyl lo, cyclohexyl, t-butoxycarbonylamino-alkyl with 1 to 4 carbon atoms in the alkyl part, benzoyloxycarbonylamino-alkyl with 1 to 4 carbon atoms in the alkyl part, or phenyl which may be monosubstituted or disubstituted by phenyl, alkyl with 1 or 2 carbon atoms, alkoxy with 1 or 2 carbon atoms, hydro

xi, fluorine, chlorine, bromine, amino, alkylamino with 1 to 4 carbon atoms, dialkylamino with 1 to 4 carbon atoms in each alkyl, nitro and / or methylenedioxy group, or in the case of methoxy it may be tri-substituted,

R ¹ represents hydrogen or alkyl with 1 to 6 carbon atoms which may be substituted by amino, acylamino with 1 to 6 carbon atoms or by benzoylamino, represents alkenyl with 2 to 6 carbon atoms, cycloalkyl with 3 to 9 carbon atoms, cycloalkenyl with 5 to 9 carbon atoms, cycloalkyl-alkyl with 3 to 7 carbon atoms in the cycloalkyl part and 1 to 4 carbon atoms in the alkyl part, aryl with 6 to 12 carbon atoms or partially aryl hydrogenated. which may be substituted each by alkyl with 1 to 4 carbon atoms, alkoxy with 1 or 2 carbon atoms or by halogen, represents aryl-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 4 carbon atoms in the alkyl or aralkyl part with 7 to 13 carbon atoms in the aryl part and 1 or 2 carbon atoms in the alkyl part, which can both be substituted in the aryl radical as defined above, a monocyclic or bicyclic heterocyclic radical with 5 to 7 or respectively 8 to 10 ring atoms, of which 1 to 2 ring atoms are sulfur or oxygen atoms and / or 1 to 4 ring atoms represent nitrogen atoms, or a side chain of a naturally occurring αί-amino acid , optionally blocked, especially, however, hydrogen, alkyl having 1 to 3 carbon atoms, alkenyl having 2 or 3 carbon atoms, the possibly blocked methyl chain of lysine, benzyl, 4-methoxybenzyl, phenethyl, 4-ethoxybenzyl, 4 -amino-buti lo or benzoylmethyl,

3

R and R are the same or different and represent hydrogen, alkyl with 1 to 12 carbon atoms, alkenyl with 2 to 12 carbon atoms or aryl-alkyl with 6 to 12 carbon atoms in the aryl part and 1 to 8 carbon atoms in the alkyl part, and Â. R _Λ

R and R have the meanings indicated above.

The following compounds can be used in a particularly advantageous manner according to the invention:

- 19 2- / N- (1-S-Carboethoxy-3-phenyl-propyl) -S-alanyl / -S-1,2,3,

4-tetrahydroisoquinoline-3-carboxylic acid 2- / N- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl / -S-l,

2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2 - ^ / N- (1-S-Carbo and toxi-3-phenyl-propyl) -S-lysyl / -Sl, 2,3,4tetrahydroisoquinoline-3- 2- _t / N- (1S-Carboethoxy-3-phenyl-propyl) -0-ethyl-S-tyrosyl7 ~ S -1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid 2- / N- ( lS-Carboethoxy-3-phenyl-propyl) -S-alanyl / - (3S) -decahydroisoquinoline-3-carboxylic acid l- / N- (lS-Carboethoxy-3-phenyl-propyl) -S-alanyl / - ( 2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- ^ N- (lS-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl7- (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- / N- (lS-Carboethoxy-3-phenyl-propyl) -S-lysi] J7- (2s, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- / N- (lS-Carboethoxy-3-cyclohexyl-propyl ) -S-lysyl7 ~ (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / ΊΪ- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-lysyl / ~ (2S, 3aS, 7aS ) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) -0-methyl-S-tyrosyl7 ~ (2s, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- ^ N- (1-S-Carboethoxy-3 -phenyl-propyl) -0-ethyl-S-tyrosyl / (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3- (3,4-dimethylphenyl-propyl) - S-alanyl / - (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / -1- / 1S-Carboethoxy-3- (4-fluorophenylJ-propyl ^ -S-alanyl / (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / N- / 1S-Carboethoxy-3- (4-methoxyphenyl) -propyl7 ~ S-alanyl7 (2s, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- / N- / lS-Carboethoxy-3- (3,4-dimethoxyphenyl) -propyl7-S-alanyl7 ~ (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / N- (lS-Carboethoxy-3-cyclopentylpropyl) -S -alanyl7 ~ (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 1 ^ 47- (ls-Carboethoxy-3-phenyl-propyl) -S-alanyl7- (2S, 3aR, 7aS) -octahidroindol-2- carboxylic acid l- / N- (lS-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl7 ~ (2S, 3aR, 7aS) -octahidroindol-2-carboxylic

1- / ΪΊ- (1-S-Carboethoxy-3-phenyl-propyl j-S-lysyl / - acid (2S, 3aR,

7aS) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-cyclohexyl-propyl) -S-lysyl / - (2S, 3aR, 7aS) -octahidroindol-2-carboxylic acid 1- / N- (lS-Carboethoxy-3-phenyl-propyl) -O-ethyl-S-tyrosyl / (2S, 3aS, 7aR) -octahidroindol-2-carboxylic acid l- / Tl- (lS-Carboethoxy-3-phenyl-propyl ) -S-alanyl7 ~ (2S, 3aR, 7aR) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-lysyl7- (2S, 3aR,

7aS) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-eiclohexyl-propyl jS-alanily ⁷ - (2S, 3aR, 7aR) -octahidroindol-2-carboxylic acid 1- / N- (lS -Carboethoxy-3-cyclohexyl-propyl) -0-ethyl-S-tyrosyl / - (2S, 3aR, 7aR) -octahidroindol-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) - S-alanylJ7- (2S, 3aS,

7aR) -octahidroindol-2-carboxylic acid 1- / ΪΤ- (1-S-Carboet oxy-3-phenyl-propyl) -0-ethyl-S-tyrosyl7 (2s, 3aS, 7aS) -octahidroindol-2-carboxylic acid

1- / N- (ls-Carboethoxy-3> 4-dimethylphenyl-propyl) -S-alanylJ7- (2S, 3aS 7aS) -octahidroindol-2-carboxylic acid l- / N- / lS-Carboethoxy-3- (4 -fluorfenyl) -propyl / -S-alanyl7 (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid l- / N- / lS-Carboethoxy-3- (4-methoxyphenyl j-propid ^ -S-alanidJT (2S , 3aS, 7aS) -octahidroindol-2-carboxylic acid 1- / II- / IS-Carboethoxy-3- (3,4-dimethoxyphenyl) -propyl7 ~ S-alanyl / - (2S, 3aS, 7aS) -octahidroindol-2 -carboxylic acid 1- / N- (1S-Carboethoxy-3-cyclopentylpropyl) -S-alanyl / - (2S, 3aS, 7aS) -octahidroindol-2-carboxylic acid 2- / N- (ls-Carboethoxy-3-phenyl) -propyl-S-alanid ^ -cis-endo-2-azabicyclo / 3.3.0 / octane-3-S-carboxylic acid 2- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-lysyl / - cis-endo-2azabicycles / 3.3.O / octane-3-S-carboxylic acid 2- / N- (1S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl / -cisendo-2-azabicycles _i /3.3.O / octane-3-S-carboxylic acid 2- / N- (ls-Carboxy-3-cyclohexyl-propyl) -S-alani] 7-cis-eno-2-azabicyclo / 3.3 · O / octane-3- S-carboxylic acid 2- / N- (1S-Carboethoxy-butyl) -S-al anil7-cis-endo-2-azabicic 3.o7octane-3-S-carboxylic

2- / n- (1S-Carboethoxy-3- (3,4-dimethoxyphenylpropyl) -S-alanyl / '- cis-endo-2-azabicycloyl · 3.07 octane-3-S-carboxylic acid 2 - / ^ - ( lS-Carboethoxy-3-cyclopentyl-propyl) -S-alanyl7-cisendo-azabicyclo- / 3 · 3.θ / octane-3-S-carboxylic acid 2- _< / N- (lS-Carboethoxy-3-phenyl-propyl ) -O-methyl-S-tyrosyl / cis-endo-2-azabicyclo3 · 3.θ / octane-3-S-carboxylic acid 2- _z / N- (1S-Carboethoxy-3-phenyl-propyl JO-ethyl -S-tyrosyl / ⁷ cis-endo-2-azabicyclo / 3 · 3.θ / octane-3-S-carboxylic acid 2- / N- (1S-Carboethoxy-3- (4-fluorophenyl-propyl) -S- alanyl7 ~ cis-endo-2-azabicyclo / 3.3.O / octane-3-S-carboxylic acid 2- ₍ / N- (1S-Carboethoxy-3 ~ (4-methoxyphenyl-propyl) -S-alanyl / ~ cis- endo-2-azabicyclo / 3 · 3.θ / octane-3-S-carboxylic acid l- _< / N- (lS-Carboethoxy-3-yenyl-propyl) -S-lysyl / ~ (2S, 3aR,

6aS J-octahidrocyclopenta / ^- b_J7pyrrole-2-carboxylic acid l - / ^ - (lS-Carboethoxy-3-cyclohexylpropyl) -S-lysyl / - (2S,

3aR, 6aSJ-octahidrocyclopenta / ^- b_7pyrrole-2-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) -0-ethyl-S-tyrosyl / (2s, 3aR, 6aSí-octahidrocyclopentaíb_ypirrol-2-carboxylic l- / N- (lS-Carboethoxy-3-phenyl-propyl) -S-alanyl / -2- (2S, 3aR,

6aS J-octahidrocyclopentaí ^- 2-7-pyrrole-2-carboxylic acid 2- _z / N- (ls-Carboethoxy-3-phenyl-propyl) -S-alanyl / -2-azospiro / 4.57decane-3-S-carboxylic acid 2- / N- (1S-Carboethoxy-3-phenyl-propyl) -0-ethyl-2-tyrosyl / 2-aspasospiro- / 4 ^and barrel-3-S-carboxylic acid 2- / N- (1-S-Carboethoxy- 3-phenyl-propyl) -S-lysyl / -2-aspasospiro / 4.5 / decane.-3-S-carboxylic acid 2- _z ^ - (1S-Carboethoxy-3-cyclohexylpropyl) -S-alanyl / -2 -azaospiro / 2-z-decane-3-S-carboxylic acid 2- _z / N- (ls-Carboe-foxy-3-cyclohexylpropyl) -S-lysyl / -2-azospiro / 4. ^ decane-3-S-carboxy 2- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-alanyl7-2-aspasospiro / 4 · 47honan-3-S-carboxylic acid 2- / N- (1S-Carboethoxy-3-phenyl) -propyl) -0-ethyl-S-tyrosyl / -2azaospiro / 4.4 / nonane-3-S-carboxylic acid 2- / N- (ls-cafcboe-toxi-3-phenyl-propyl) -S-lysyl / - 2-aspasospiro /4.4/nonano-3-Sc arb oxy acid 2- / N- (1S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl / -2-aza spiro ^ ?. 4 / nonane-3- S-carboxylic

2- ^ N- (1S-Carboethoxy-3-cyclopentyl-propyl) -S-alanyl / -2-aspasospiro ^ / Ã. jy ⁷ nonane-3-S-carboxylic acid 2- _z / N- (1S-Carboethoxy-3-cyclopentyl-propyl) -S-lysyl / -2-aza-spiro / 4.47nonane-3-S-carboxylic acid 1 '-7N- (1S-Carboethoxy-3-phenyl-propyl) -S-alanyl / -spiro ^ / bicycle / 2.2. iyheptane-2,3 ¹ -pyrrolidinyl / 7-5 ¹ -S-carboxylic acid 1 '/ N- (1S-Carboethoxy-3-phenyl-propyl-0-ethyl-S-tyrosyl / -es piro / bicic 10 ^ 2.2 ./7heptane-2,3 '-pyrrolidinyl / -5 ¹ - S-carboxylic acid 1' - / N- (1S-Carboethoxy-3-phenyl-propyl) -S-lysyl-spiro / bιοί clo / ^ 2. 1 / heptane-2,3'-pyrrolidine / -5'-carboxylic acid 1 '- / N- (1S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl7 ~ spiro / bicycle / 2.2. / ⁷ heptane-2 , 3 ^1- pyrrolidine / 5'-S-carboxylic acid 1 ¹ - / N- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-lysyl7-spiro-bicycle / 2.2.l / Zheptane-2, 3'-pyrrolidine7 ~ 5 ¹ -S-carboxylic acid 1 '- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-alanyl / -spiro / bicycle / 2.2.2 / octane-2,3 ¹ - pyrrolidine / -5'-S-carboxylic acid 1 '- ^ - (1S-Carboethoxy-3-phenyl-propyl) -0-ethyl-tyrosyl / ^-and £ pyro - ^ / bicycle / L 2.27octane-2,3' -pyrrolidine / -5'-S-carboxylic acid 1 '- / N- (1-S-Carboethoxy-3-phenyl-propyl) -S-lisily ⁷ -spiro _i / bi, cycle / 2.2.2 / octane-2 , 3 ^1- pyrrolidine / -5'-S-carboxylic acid 1 '- ^ - (1S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl7 ~ spiro / bicycle / 2.2.2 / octane-2,3'-pyrrolidine / -5'-S-carboxylic acid 2 - ^ - (1-S-Carboet oxy-3-phenyl-propyl) -S-alanyl 2-azatγιο iclo / 4 .3.0.l6 '9 / çj ecano-3-S-carboxylic acid 2- / n- (1-S-Carboethoxy-3-phenyl-propyl) -0-ethyl-S-tyrosyl7— f Q

-2-azathricycle / 4.3 · 0.1 '* ^, _ / decane-3-S-carboxylic acid 2- / n- (1-S-Carbo et oxy-3-phenyl-propyl) -S-lyse] J7- 2-azatr Ισιο lo ^ Ã · 3.Ο.ΐ6 ' _9/7 ^ _ecan0 _ ^ _ g_ _car - | _{; i0X} ^ 2 ₀ 2- / n- (1S-Carboethoxy-3-cyclohexyl-propyl) -S-alani] / - 2-azatricylT? · 3-0.16 '^ _ / decano-3-S-carboxylic acid 2- / Ν- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-lisi] / - 2-azatriciblo / 4.3.0.I ⁶ ' ⁹ _7decane-3-S-carboxylic acid l-7N- (lS-Carboethoxy-3-phenyl-propyl) -S-alanyl7-decahydro cyclohepta / ^- b_7pyrrole-2-S-carboxylic acid l- / N- (lS-Carboethoxy-3-phenyl-propyl) -0-ethyl-S -tyrosi / 7-decahydrocyclohepta / “b_7pyrrole-2-S-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-lysyl / -decahydro23 cyclohepta / ^- b_ypirrol-2-S-carboxylic acid (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl / -decahydrocyclohepta / ^- b _- 7pyrrole-2-S-carboxylic acid 1 - </ ~ N— (lS-Carboethoxy-3-cyclohexyl-propyl ) -S-lysyl / -deca hydrocyclohepta _z / ^_ b_7pyrrole-2-S-carboxylic acid 2- _z / N- (lS-Carboethoxy-3-phenyl-propyl) -S-alanyl / -trans-octahidroisoindol-lS-carboxylic 2 - ^ / N- (1S-Carboethoxy-3-phenyl-propyl) -S-alanyl7-cis-octahydroisoindol-1S-carboxylic acid 2- ^ N- (1-S-Carboethoxy-3-cic) lohexyl-propyl) -S-alanyl / -traps octahidroisoindol-1S-carboxylic acid 2 - ^ / n- (1-S-Carboet oxy-3-cyclohexyl-propyl) -S-alanyl / -cisoctahidroisoindo1-1-S-carboxylic 2- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-alani] J7-cis-octahidrocyclopenta / ^- c_ / pyrrole-1S-carboxylic acid 2- _< / N- (1S-Carboethoxy-3- cyclohexyl-propyl) -S-alanyl / -cisoctahidrocyclopenta _i / ^- 2- _i / N- benzyl pyrrole-1S-carboxylate (lS-Carboethoxy-3-cyclohexyl-propyl) -S-lysyl7-cis-octahidrocyclopenta ^ c_ / pyrrole-1S-carboxylic acid 1- / N- (1S-Carboethoxy-3-phenyl-propyl) -S-alanyl7,2,3,3a, 4,

5,7a-hexahidroindol-cis-endo-2-S-carboxylic acid 1- / N- (1-S-Carboethoxy-3-phenyl-propyl) -S-lysyl7-2,3,3a, 4,5, 7a -hexahidroindol-cis-endo-2-S-carboxylic acid

2- / N- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-lysyl7-2-azabicyclo / 3 · 1.O / hexane-3-S-carboxylic acid 2- / N- (1S-Carboxy -3-phenyl-propyl) -S-lysylJ7-2-azabicyclo / 3.10 / hexane-cis-endo-3-S-carboxylic acid 2- _< / N- (1S-Carboethoxy-3-cyclopentylpropyl) -S- alanyl / -2-azabicycles / 3 · 1.0 / hexane-3-carboxylic acid 2- / n- (ls-Carboethoxy-3-phenyl-propyl) -S-alanyl / -cis-endo-2-azabicycles / 3.1.0 / hexane-3-S-carboxylic acid 2- / Ê- (1-S-Carboethoxy-3-cyclohexyl-propyl) -S-alanyl / -cisendo-2-azabicyl / 3 · 1.07hexane-3-S-carboxylic acid 1 '- / ÍT- (1S-Carboethoxy-3-phenylpropyl) -S-alanyl / - (3' S, 5 ¹ S} spiro-bicyl / 2.2.2 / -octane-2,3'-pyrrolidine-5 ' -carboxylic acid 2 - ^ / n- (1S-Carboethoxy-3-phenylpropyl) -S-alanyl7-cis-endo-2-azabicyclo / 3 · 3 · 0 / octyl acid octane-3-S-carboxylate 2- ^ N- (1-S-Carboethoxy-3-phenylpropyl) -S-alanyl / -cis-en-

do-2-azabicyclo / 3.3 · O / dicyclo-octane-3-S-carboxylate 2- / N- (1S-Carboethoxy-3-phenylpropyl) -S-alanylJ7-cis-endo-2-azabicyl / 3 · 3.0 / 5-nonyl acid 2- / N- (1-S-Oethyloxy-3-phenylpropyl) -S-alanyl / -cis-endo-2azabicyclo3 / octane-3-S-carboxylate / 3 · 3.0 / octane-3- Octyl acid 2- / N- (1S-Mentyloxy-3-phenylpropyl) -S-alanyl / -cis-endo-2azabicyclo / 3 · 3'0 / octane-3-S-carboxylate

These compounds are prepared, for example, by the process described in the German patent application P 3 333 455 · 2, the derivatives in t-butyl or benzyl being transformed in a known manner, as described in the patent application, in the derivatives of monocarboxylic acids by acidic or alkaline hydrolysis, or by hydrogenolysis catalyzed by noble metals. The N- ^and benzyloxycarbonyl blocking group of the lysine derivative is eliminated by noble metal-catalyzed hydrogenolysis.

The preparation of the compounds of general formula I or II can be carried out, for example, using also esterification methods which are in the domain of the experts (see for example Buehler, Pearson, Survey of Organic Syntheses, Vol. 1, New York 1970 , page 802-325; Houben-Weyl, Methoden der Organischen Chemie, volume E5, 1985, page 656-773), for example by

a) reaction of a monocarboxylic or dicarboxylic acid of form

3 general mule I or II in which at least one of the radicals R and R represents hydrogen, with a corresponding alcohol by acid catalysis (mineral acids or acid ion exchangers)

b) alkylation of a monocarboxylic or dicarboxylic acid of general formula I or II, in which at least one of the radicals r and

R represents hydrogen, with a compound of formula R Z or 3

R Z in which Z represents a leaving group which can be removed under nucleophilic conditions (such as halogen or tosylate) in a polar protic or dipolar aprotic solvent, in the presence of a base such as an alkali metal hydroxide or alcoholate.

c) the reaction of a monocarboxylic or dicarboxylic acid of the general formula I or II, in which at least one of the radicals R1 and R5 represents hydrogen, with a diazoalkane in a solvent

- 25 inert organic, such as dichloromethane.

The aforementioned compounds can be easily transformed into the corresponding salts with acid

of the physiologically acceptable or with bases (in the case of monocarboxylic or dicarboxylic acids) (for example hydrochlorides, maleates, fumarates, etc.) and are applied according to the invention in the form of salts.

The compounds of formulas I and II are inhibitors of the angiotensin converting enzyme (ACE) or are intermediate products for the preparation of those inhibitors, and can also be used to fight blood hypertension of different genesis. The compounds of formulas I and II and the process for their preparation are partly known, for example from US patents 4,129,571, 4,374,829, EP-A-79 522, EP-A-79 022, EP-A- 49658 EP-A-51 301, American patents 4,454,292, 4,374,847, EP-A-72 352 US patent 4,350,704 EP-A-50 800, EP-A-46 953, American patent 4,344,949, EP-A-84 164, US patent 4 470 972, EP-A-65 and EP-A-52 991. The new compounds of formula I and II are prepared in an analogous manner.

They are also advantageously used as orally effective ACE inhibitors (active substances, as already described above) such as ramipril, enalapril (f), captopril (a), lisinopril (g), cilazapril (o),

RHC 3 659, CGS 13 945, CGS 13 9280 (1), CGS 14 824A (h),

CI-906 (j), zofenopril (e), fosenopril (p), alacepril CI-925 (k), pentopril (q), CV 3317 (m), indolapril (h), YS 980 (b), fentiapril (c ), pivopril (d), perindopril (i), MDI 27 088 (r), MDL 27 788 (s), RS-5 142 (t) and others. Orally effective ACE inhibitors are described for example in Brunner et al,

J. Cardiovasc. Pharmacol, 7 (supplement I) / 1985 / pags. 2-11.

co ₂ h co ₂ h (k)

CH,

II (CH ₅ ) ₅ -CO-S-CH ₂ -CK-CO-N (d).

CH ₂ -C0 ₂ H

CH,

V

C0-S-CH ₂ -CH-C0-II

co ₂ h .CHgCHgc-ch-hh-ch '

(e) lX ^> CO ₂ H

G-CH-NH »Ί

CH (CH _{2) 4} -NH ₂ CO ₂ H (£)

• C-CH-NH-CH '' i I

CH, C (co ₂ h

H ₅ CO ₂ C ₂ H ₅ (f)

H / CH ₂ CH ₂

CO ₂ H, _/ ch ₂ ch ₂ ^H O-CH-NH-CH '</ 1 I

CH ₃ co ₂ c ₂ h ₅ (h)

, ch ₂ ch ₂ ch ₅

X

i I

CH, C (ch ₃ co ₂ c ₂ h ₅ ch ₅ co ₂ c ₂ h ₅ (i)

co ₂ h

C-CH-NH-CH

0 ^ Á i

x '= H (j)

X '= 3.4 OCH ₃ (k)

CH ₅ C0 ₂ C ₂ H ₅

CH ₂ -C0 ₂ H CH ₅ /

CH-KH-CH i I

CH ₂ CH2 ^

(1) co ₂ c ₂ h ₅ (m)

co ₂ h p- “

H, C .CH-OCO ³ \ κΖ I

CHN-C0-CH? -P- (CH ₂ ) ₄ -

c ₂ h ₅ (£)

Oa

N C0 ₂ H ch ₃ c-ch-ch ₉ -ch ^x i 1

CH ₃ co ₂ c ₂ h ₅ (a)

HOOO Ο

NH-CH i

COOH (£)

COOH nh-ch-ch ₂ -ch ₂

COOC ₂ H ₅

Of known ACE inhibitors, among others, of the EP-A-243 645 specialty, of formula III

H

CCó COOR ⁵ (III)

H 1 ^(S) o ^z GH-NH-CH-CH ₉ -CH ₉ G \ S

A 1 ₂

CH ₅ COOR in which

R and R are the same or different and represent hydrogen, an aliphatic radical with 1 to 21 carbon atoms, an alicyclic radical with 5 to 20 carbon atoms or an araliphatic radical with 7 to 32 carbon atoms, those where

R represents hydrogen, methyl, ethyl, benzyl, menthyl or n-octyl, and 3

R is hydrogen, benzhydryl, _F n octyl, n-decyl or 5-nonyl.

In addition, from the ACE inhibitors known from EP-A-84 164 and EP-A-243 645, formulas IVa and IVb • N

COOR '

THE.

(IVa)

CH-NH-CH-0H ₂ -0H ₂ -ó / Vi

A A

CH ₅ COOR

(IVb)

- -

3 in which R and íc are defined as in formula III above, those in which

R represents hydrogen, alkyl having 1 to 8 carbon atoms, benzyl or menthyl and

R4 represents hydrogen, benzhydryl or alkyl having 1 to 10 carbon atoms.

Also preferred are ACE inhibitors known from U.S. Patent 4 620 012 and EP-A-243 645, of formula V

in which

R ^ represents hydrogen, alkyl having 1 to 8 carbon atoms, benzyl or menthyl and

R represents hydrogen, benzhydryl or alkyl having 1 to 10 carbon atoms, and their isomers.

It is also known from EP-A-243645 that the compounds of formula I and II additionally have a nootropic action (which improves cognitive function) and are therefore also suitable for the treatment of cognitive dysfunctions of different genres, such as those for example in Alzheimer's disease or senile dementia.

It has now surprisingly been found that the compounds of formula I and II have a psycho-tropic action, especially an anxiolytic action. They are also useful for the treatment and prophylaxis of disorders of the central nervous system, especially anxiety states.

Anxiolytic action has been proven in several test models and thus, for example, in the VOGED lick-shock conflict test and in the conflict test

Geller-Seifter according to GELLER and SEIETER.

Lick-shock conflict test Method (VOG-EL, JR, Rsychopharmacology 21, (1971) 1-7) Male, self-cultured Wistar rats (SPP Hattersheim) weighing between 90 and 120 g, are the animals used in this assay .

The animals were drinking water 48 hours before the start of the test. For the test, the animals were placed in a plastic box (14 x 12 x 28 cm, width x depth x height) which was equipped with a water bottle with a metal drinking tube and which also allowed, by means of an electronic device, count the number of contacts of the animals' tongue with the drinking tube.

The bottom of the box consisted of metallic vareats that could be put under tension by means of control electronics.

The animals, after being placed in the box, had 5 minutes to discover the drinking tube and lick it 50 times. Animals that at the end of this time had not found the drinking tube were not used in this test. After this phase of licking 50 times, the drinking tube and the bottom rods were put under tension each for 5 seconds (direct current 300 uA) and then left inactive for another 5 seconds. This sequence was repeated alternately over a period of 5 minutes, recording the number of contacts with the animals' drinking tube during the phases of on and off current, over several electronic meters.

Groups of 8 animals are treated each, and per dose, with the test substances, by several routes of application, orally, intraperitoneally or subcutaneously. In oral application by esophageal tube, the test substances are pasted with a 1% carboxymethyl cellulose gel and applied through the esophagus tube at a rate of 5 ml / kg of body weight. The test on the aforementioned test apparatus is performed by oral administration after 1 hour, and by subcutaneous or intraperitoneal administration 30 minutes after application of the test substances. The number of contacts with the drinking tube in the connected current phase serves as a variable of / en-_

I go out. The average number of contacts at this stage, for the control group, is set to 100 / and the increase or decrease in the number of contacts for animals treated with the test substances is expressed as a percentage in relation to the control group.

In this test, anxiolytics generally cause a marked increase in water absorption (lick contacts) in the on-current phase, compared to untreated controls.

In the case of a linear or logarithmic relationship between dose and action, an ED + 100 value (ie the dose that causes an increase in water absorption of 100 ^ relative to the control groups) is calculated by regression analysis. If there is no linear relationship depending on the dose, a minimum effective dose (MED) is determined, that is, the lowest dose of the test active substance which still causes a significant increase in water absorption compared to the control group ( p = 0.05, DUNNETT test).

Number of contacts with the baby tube in the connected current phase, 30 minutes after the administration of the test substances, in comparison with the control groups

Compound Dose (mg / ί · Ρ ·) 0.1 0.3 1 3 10 30 Captopril + 46 4- 109 + 117 * Analapril + 42 + 114 + 130 * Ramipril + 88 + 148 * + 113 THE + 1 + 32 + 65 B + 53 + 116 * + 176 * Ç +16 + 36 / + 73 / + 124 + 28 + 108 *

p 0.05 (Dunnett test)

R ³ OOC - CH - N - C - CH - NH - CH - (CH ₂ ) _n -R (II)

5 1 2 item R ^J 0 R COOR _

-CH-N-

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

Male Wistar rats of their own culture (SPP Hattersheim) weighing between 240 and 370 g, were used as test animals and test groups of 8 animals each were established. Each 4 animals are collected in plastic cages (56 x 38 x 20 cm) and, using previously weighed rations, are kept at about 80% of their normal body weight.

The animals are trained in a SKINNER box to press a key in order to receive a reward in the form of sweetened condensed milk. The box contains two keys with microswitches, a loudspeaker, a light, two light signals on the keys, as well as a bottom consisting of metal rods. The training scheme was inspired by the work of GELLER and SEIFTER (1962) according to the modification of DAVILSOM & COOK (Psychopharmacologia 15 (1969) 159-168); each section consists of 4 15-minute sections that all consist of a 12-minute Variable Interval (VI) phase and a 3-minute Pixed ration (PR) phase. During phase VI the animals receive the milk reward for pressing the key in an interval of 10 to 110 seconds, controlled by a randomized generator with an average value of 6o + 15 seconds. During the PR phase, the animals receive a compensation for each press of the button, but additionally, for each 3 presses of the button, they receive a painful electric shock through the bottom rods to

To _ produce a conflict situation. The current intensity of the electric shock is individually adjusted for each animal (0.3 - 0.6 mA) so that the rate of pressure on the key throughout the PR phase is between 5 θ 15 times.

5 training takes place in ^{two days} of the week and testing with the test substances are carried out once a week. As the animals serve as their own controls, before each test with the test substance, at least two previous tests are carried out without the test substance. The compounds to be tested are suspended in a 1% carboxymethylcellulose gel and are administered 30 minutes before the start of the test, orally, through an esophagus probe, in a volume of 2 ml / kg. Variations in the rate of pressure of the key in phase VI are assessed as the influence of motor activity, and the increase in the rate of pressure in the key in phase PR is assessed as an indicator for an anti-conflict or anxiolytic action. The minimum effective dose (MED) of the test substance is pre-determined, that is, the lowest test dose which still causes a statistically significant variation in the key pressure rate (p = 0.05; matched pairs signed rank test of WIICOXON).

The MED values determined in these two test models after intraperitoneal administration are between 0.1 and 30 mg / kg in test animals.

The invention therefore also relates to the use of the compounds according to the invention in the treatment and prophylaxis of disorders of the central nervous system, especially of anxiety states.

The invention also relates to the new compounds of formula III

H

COOR

OH, COOR '(III)

in which the 5 chiral carbon atoms (*) each have the S configuration,

R represents ethyl or hydrogen and

R represents n-octyl, as well as its physiologically acceptable salts, preferably maleates.

process according to the invention for the preparation of these new compounds is characterized by the fact that

(a) reacting with n-octanol a compound of formula III in which the 5 chiral carbon atoms (*) each have the 2 configuration S, R represents ethyl or a carboxyl blocking group easily dissociable in an acid or basic medium, or hydrogenolytically, and R R represents hydrogen, preferably using the esterification methods known to those skilled in the art (see for example Buehler, Rearson, Survey of Organic Synthesis, Vol. 1, New York 1970, pages 802-825; Houhen-Weyl , Methoden der Organischen Chemie, vol. E5, 1985, pp. 656-773), for example by acid catalysis or after activation of the III carhoxyl acid function (R ^ = = hydrogen) or the hydroxy function of n-octanol, especially under the conditions of a Mitsunobu reaction, in an appropriate solvent, at a temperature up to the boiling point of the reaction mixture, or by

b) reacting a compound of formula III in which the configuration ~ 2 3 ~ - race, as well as R and R are defined as above in (a), with a compound of formula VI h ₃ c- (ch ₂ ) ₇ x (VI) in which X represents a leaving group that can be displaced nucleophilically, especially a chlorine, bromine or iodine atom, or a sulfonic acid radical, under the conditions of a nucleophilic substitution, preferably in a polar organic solvent, such as for example an alcohol, preferably methanol, ethanol, propanol or isopropanol, or an infertile ketone

above, preferably acetone, methyl ethyl ketone or methyl isobu tileetone, or in acetonitrile, dimethylformamide, dimethyl sulfoxide or sulfolane, or a hydrocarbon, preferably toluene, with or without the presence of an auxiliary base for fixing the acids formed, preferably na preser. potassium hydrogen carbonate, sodium carbonate, triethylamine, pyridine, 1,5-diazabicyclo / 5 · 4.0 / undeca-5-ene or 1,5-diazabicyclo / 4.3.0 / nona-5-ene, as well as in the presence or absence of an alkali halide, preferably sodium iodide or potassium iodide, at a temperature between -50 and + 100 ° C, preferably between -20 and + 60 ° C, or

c) to react with ethanol a compound of formula III that p

has the configuration described above in (a) and in which R represents • 2 sits hydrogen and R ^p represents n-octyl, as described in process variant (a), or

d) reacting a compound of formula III in which the configuration, R and R are defined as above in (c), with a compound of formula VII

(VII) in which X represents a leaving group that can be displaced nucleophilically, as described in process variant (b), or by

e) if a compound of formula VIII is reacted

(AND)

CH ₂ -CH ₂ -CH-0S0 ₂ CP ₅

COOR ² (VIII)

in which the 4 chiral carbon atoms (*) each have the s configuration, for example analogously to the process path described in U.S. Patent 4,525,301, in an appropriate solvent, at a temperature up to the boiling point of the reaction mixture, or by

f) a compound of formula X is reacted

H *

COORH H (x) in which the 3 chiral carbon atoms (#) an S and R configuration represent n-octyl, to formula XI * *

HOOC-CH-NH-CH-CHp-CHpI I 2

CH ₅ coor each have a compos (XI)

_z in which R is defined as previously in (a)., for example by analogy with known peptide coupling processes, in an organic solvent such as dimethylformamide, dichloromethane, dimethylacetamide, in the presence of auxiliary coupling agents, such as carbodiimides (for example dicyclohexylcarbodiimide) of diphenylphosphorylazide, or anhydrides of alkanophosphonic acids, anhydrides of dialkylphosphonic acids or N, N-disuccinimidoyl carbonate,

in a solvent such as acetonitrile, or after the activation of the compounds of formula X, for example by reaction with tetraethyl diphosphite, or after the transformation of the compounds of formula XI into activated esters (for example with 1-hydroxybenzotriazole) in mixed anhydrides ( eg with chloroformates) in azides or in carbodiimide derivatives (see Schröder, liibke, The Peptides, vol. 1,

New York, 1965, p. 76-136) at temperatures preferably between -20 ° C and the boiling point of the solvent, if necessary dissociate in a compound of formula o

III thus obtained (R = blocking group) the blocking group R in a manner known per se, for example using saponification methods known to those skilled in the art (such as acid or alkaline hydrolysis) or hydrogenation methods, in an appropriate solvent, at a temperature up to the boiling point of the reaction mixture, and eventually transform the compound of formula III thus obtained (R = = ethyl or hydrogen) into its physiologically acceptable salt, then separating in another separation step, in the case mixtures of stereoisomers, the isomer of formula III in which all chiral atoms have the S configuration (R = hydrogen or ethyl, R ^? = n-octi) are used as starting products for the process variants (a) - (f) it).

A hydrogenolytically dissociable carboxyl blocking group, such as Bzl, is preferably dissociated by hydrogenolysis with an appropriate catalyst, such as palladium on activated carbon, at a pressure of 0.2 to 10 bar and at a temperature between 0 ° C and 100 ° C, in an organic solvent.

Aliphatic radicals that are easily available, such as alkyl with 1 to 6 carbon atoms, are the preferred acid or basic dissociable carboxyl blocking groups. They are dissociated using saponification methods known to those skilled in the art (see for example Houben / Weyl, Methoden der Organischem Chemie, vol E 5/1, pp. 223-255) for example by acid or alkali hydrolysis

, 2

The compounds of formula III (R = hydrogen or ethyl, R4 = hydrogen) are known (see for example ER-A-79022 U.S. Patent 4,587,258).

The compounds of formulas VI and VII are known and are mostly obtained commercially.

The compounds of formula VIII are obtained from the corresponding hydroxyl compounds, by transforming the hydroxyl group into the -SO ₂ CP2 group according to standard procedures.

From the mixtures of diastereomers or enantiomers, the new compounds mentioned above can be obtained in which all chiral atoms have the S configuration, by separation by recrystallization or by chromatography, for example on silica gel, or by formation of salts with optically active auxiliary substances.

The invention also relates to intermediate products of formula XII

coo (ch ₂ ) ₇ ch ₅ (XII) in which the 3 chiral carbon atoms each have the S and Q configuration represents hydrogen or 0 radical XIII (S)

-ç-ch-nh ₉

II ² 0 CH2 (XIII) and mixtures of compounds of formula XII and their stereoisomers, as well as a process for the preparation of these compounds, which is characterized by the fact that

a) if a compound of formula XIV is reacted

COOH (XIV)

- 40 in which Q represents hydrogen or -C0-CH (CH ^) - UH ₂ , with n-octa nol or Η ^ 0- (0Η ₂ ) γ-Χ, as described above in variant (a) or (h) of the process, or

h) reacting a compound of formula XV with coo / ch ₂ _7 ₇ -ch ₅ (XV) as described above in the process variant (f), with alanine blocked at the amino group, for example with Z or Boc, and then It is possible to dissociate the amino blocking group and, if desired, to isolate the isomer of formula XII in which all chiral lytic atoms have the S configuration.

The compounds of formula XIV are known, for example, from EP-A-79 022 or from US Patent 4,587,258.

The new compounds in which all chiral atoms have the S configuration, of formula III (R = = hydrogen or ethyl, R ^ = n-octyl) and their physiologically acceptable salts, in addition to the above mentioned psychotropic and especially anxiolytic action, they have a strong nootropic action, that is, they improve cognitive function. They are appropriate supports for the treatment of dysfunctions of different genres, such as those that occur for example in Alzheimer's disease, or in senile dementia. The nootropic action of the compounds according to the invention was confirmed in rats that had a body weight of 2 to 25 g, in the inhibitory (passive) leak test (step-through model). A modified form of the test method described by J. KOPP, Z. BODANECKY and Μ. E. JARVIK, was described by J. BURES, 0. BURESOVA and J. HUSTON in Thechniques and Basic Experiments for the Study of Brain and Behavior Elsevier Scientific Publishers, Amsterdam (1983).

According to the literature data, a substance is then classified as effective as nootropic if, in the test animals, it allows the amnesia produced by electroconvulsive shock or a to be suppressed.

amnesia induced by scopolamine.

The tests were carried out according to the modified test method. As a comparison compound, the known nootropic 2-oxo-1-pyrrolidinylacetamide (pyramid ketame) was seen. The clear superiority of the compounds according to the invention over the comparison substance is proven by the fact that scopolamine-induced amnesia is suppressed in the inhibitory leak test with a MED value (mini effective dose) of 0.03 to 30 mg / kg po The comparison substance had a MED value of about 500 to 1000 mg / kg p.o. '

The invention therefore also relates to the use of the compounds according to the invention in the treatment and prophylaxis of cognitive disorders.

The invention also comprises the drugs containing the new active compounds mentioned, the process for their preparation, as well as the use of the compounds according to the invention in the preparation of drugs that are used for the treatment and prophylaxis of diseases mentioned above, in mammals such as monkeys, dogs, cats, rats, in humans, etc.

The invention further comprises drugs containing the compounds of formulas I and II already mentioned, the process for their preparation, as well as the use of the compounds according to the invention in the preparation of drugs which are suitable for the treatment and prophylaxis of disorders of the body. central nervous system, especially that of anxiety.

In the practice of the methods according to the invention, the angiotensin converting enzyme inhibitors, of formulas I and II described above, can be applied to mammals, such as monkeys, dogs, cats, rats, in man, etc.

Medicines are prepared according to conventional methods known to you and those skilled in the art. As medicaments, the pharmacologically effective active compounds according to the invention (= active substance) are either used as they are, or are preferably used in combination with suitable pharmaceutical auxiliary substances, and are for example in the form of tablets, dragees, capsules , suppositories, emulsions, suspensions or solutions, the content of the active substance being up to about 95%, being more advantageously between 10 and 75%.

The choice of the most appropriate active substance for the intended drug formulation is within the scope of the experts, based on their professional experience. In addition to solvents, gelling agents, suppository bases, auxiliary substances for tablets and other carrier substances of the active substance, they can also be used, for example, anti-oxidants, dispersants, emulsifiers, defoamers, flavor correctors, preservatives, solution or dyes.

The active substances can be applied, for example, orally, rectally or parenterally (for example intravenously or subcutaneously), oral application being preferred.

For an oral application form the active compounds are mixed with the appropriate auxiliary substances for the purpose, such as carrier substances, stabilizers or inert diluents, and by means of current methods are put in the appropriate dosage form, such as tablets, dragees , filler capsules, both aqueous and alcoholic or oily suspensions, or both aqueous and alcoholic or oily solutions. As inert carrier substances, for example, gum arabic, magnesia, magnesium carbonate, lactose, glucose or starches, especially corn starch, can be used. In this case the preparation can be carried out both in the form of wet granules as well as dry granules. As oily or solvent carrier substances, for example, vegetable or animal oils such as sunflower oil or cod liver oil are of interest.

For subcutaneous or intravenous application, the active compounds, or their physiologically acceptable salts, are put in the form of a solution, suspension or emulsion, possibly using common auxiliary substances for the purpose, such as dissolution aids, emulsifiers and other auxiliary substances. As solvents, for example, water, saline or alcohols, for example, ethanol, propanol, glycerin, and in addition to sugar solutions, such as glucose or mantain solutions, or a mixture of the various solvents mentioned, are of interest.

The following examples make it possible to elucidate in more detail the compounds and processes according to the invention, without however limiting the invention to the substances or processes specifically described herein. Application forms for the prophylaxis and treatment of disorders of the central nervous system are also presented, according to the method according to the invention.

Example 1

2- / N- (1S-ethoxycarbonyl-3-phenylpropyl-3-phenylpropyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo _z / 3 · 3 · O / octane-3-carboxylate -octyl

2.7 g (5 mmoles) of 2- / È- (1S-ethoxycarbonyl-3-phenylpropyl ^ -S-alanyl / - (1S, 3S, 5S) -2-azabicyclo / 3 · 3.θ / octane- 3-carboxylic (ramipril) and 0.50 g (5 mmoles) of potassium hydrogen carbonate are stirred in 25 ml of dimethylformamide 1.5 at 40 ° C, after cooling to room temperature a solution is added dropwise 1.16 g (6 mmoles) of 1-bromooctane in 20 ml of dimethylformamide and stir at room temperature overnight Adding hydrochloric acid 0.1 N, adjust the pH to 6, dilute with water, extract 3 times with methylene chloride and the organic phases after being combined are dried, concentrated and purified by column chromatography using 120 g of silica gel (eluent toluent / ethanol 98: 2).

Yield: 2.35 g (89%) of an oily product;

/ 7 * 7 ^ = -23.9 ° (c = 1, methanol)

Example 2

2- / È- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo _i / 3 · 3 · 07octane-3-carboxylate hydrogen maleate

528 mg (1 mmole) of the amine obtained according to example 1 are dissolved in 20 ml of ether and mixed with a solution of 116 mg (1 mmole) of maleic cadium in 4 ml of acetone. The solvent is evaporated and the residue is crystallized with diisopropyl ether Yield: 0.51 g (79%) of colorless crystals, mp. 89 ~ 90 ° C. Example 3

2- / È- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl7- (1S, 3S, 5S) -2azabicyl / 3.3-0 / n-octyl-octane-3-carboxylate

To a solution of 1.97 g (7.5 mmoles) of triphenylphosphine and 0.65 g (5 mmoles) of n-octanol in 100 ml of absolute tetrahydrofuran is added dropwise, at 0 ° C, a solution 1.31 g (7.5 mmoles) of diethyl azodicarboxylate in 10 ml of absolute tetrahydrofuran. Stir repeatedly for 10 min, then add a solution of 2.08 g (5 mmol) of acid at 0 ° C

2- / ΪΤ- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo / 3 · 3.0 / -octane-3-carboxylic (ramipril) in 25 ml of tetrahydrofuran absolute. Stir one hour at 0 ° C and then overnight at room temperature. The reactive solution is concentrated, taken in ethyl acetate and washed twice with 2IT caustic soda and once with water, dried, concentrated and dried. crude product (5.0 g) is purified by flash chromatography on 200 g of silica gel (eluent methylene chloride / ethyl acetate 9: 1). 0.83 g (31%) of the title compound are obtained.

Example 4

2- / S- (n-octyl-1S-carboxy-3-phenylpropyl-S-alanyl / - (IS, 3S, 5S) -2-azabicyclo / 3 · 3.0 / octane-3-carboxylate

2.65 g (5 mmoles) of ethyl ester of example 1 are dissolved in 18 ml of tetrahydrofuran, 7.5 ml of 1N caustic soda are added thereto and stirred at room temperature 48 h. Neutralize by adding 7.5 ml 1N hydrochloric acid. The reaction mixture is concentrated, the residue is suspended in water, extracted twice with ethyl acetate, the organic phases are then washed with saturated sodium chloride solution, dried, concentrated and the crude product (2.05 g) is finally purified by chromatography on 80 g of silica gel ς

(toluene / ethanol 9: 1) · The product thus obtained (1.15 g; 46%) is crushed in 50 ml of petroleum ether, alkalized, filtered and dried.

Yield: 0.83 g of colorless crystals; mp, 56-6 ° C.

Example 5

2- n-octyl 2- / N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (IS · 3S, 5S) -2-azabicyclo / 3.3.0 / octane-3-carboxylate

1.40 g (2.8 mmoles) of the carboxylic acid of example 4 are stirred in 25 lm of ethanolic hydrochloric acid at room temperature for 3 days. Then concentrate, take the residue in ethyl acetate, wash 3 times with saturated sodium bicarbonate solution and 1 time with water, dry, concentrate and purify the crude product by chromatography. in column (eluent toluene / ethanol 98: 2). 850 mg (57%) of the title compounds are obtained.

Example 6

2- / ΪΤ- (1S-ethoxycarbonyl-3-phenylpropyl JS-alanyl / ⁷ - (IS, 3S, 5S) -2-azabicyl / 3 · 3.0 / n-octyl octane-3-carboxylate

2.50 g (5 mmoles) of the carboxylic acid of example 4 θ 1.00 g (10 mmoles) of potassium hydrogen carbonate are stirred in 25 ml of dimethylformamide for 1 h at 40 ° C, after cooling to room temperature add drop them a solution of 0.66 g (6 mmoles) of bromeethane in 20 ml of dimethylformamide and stir for a further night at room temperature. Pour over water, extract 3 times with ethyl acetate, wash the combined organic phases several times with water, dry, concentrate and purify the crude product by column chromatography on silica gel (eluent toluene / ethanol 98: 2). 210 g (80%) of the title compound are obtained. Example 7

2- / N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl7- (1S, 3S, 5S) -2-azabicyclo / 3 · 5.0 / n-octyl octane-3-carboxylate _ A a

7a) 2-t-butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo _z / 3. 3 · O / oobano

-3-benzyl carboxylate

To a solution of 40.0 g (0.163 mmol) of benzyl (IS, 3S, 5S) -2-azabicyclo / 3.3 · 07octane-3-carboxylate and 23.4 ml (0.169 moles) of absolute triethylamine in 300 ml of methyl chloride in absolute, a solution of 39.2 g (0.180 mole) of di-t-butyl dicarbonate in 6 ml of absolute methylene chloride is added dropwise at 0 ° C continuously 15 min at 0 ° C and then 1 h at room temperature. The reactive solution is washed with 10% citric acid solution, with saturated sodium bicarbonate solution and with water, dried and concentrated.

Yield: 55.6 g of the oily product = -1.2 ° (c = 2, methanol)

7b) 2-t-butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo / 3.3.0 / · octane-3-carboxylic acid

55.6 g (0.16 moles) of the benzyl ester of example 7a) are hydrogenated in 2 l of ethanol at room temperature with 4 g of palladium / carbon (10%) for 2.5 h. The catalyst is removed by filtration and the filtrate is concentrated.

Yield: 37.3 g (90%) / ckJ7 ² 5 = + 22.7 ° C, c = 1, methanol)

7c) 2-t-butoxyoxycarbonyl- (1S, 3S, 5S) -2-azabicyclo / 3 · 3.0 / n-octyl octa no-3-carboxylate

32.3 g (0.125 moles) of the acid of example 7b) and 25.3 g (0.253 moles) of potassium hydrogen carbonate are stirred in 500 ml of dimethylformamide for 1.5 h and 40 ° C. After cooling, 48.9 g (0.253 moles) of 1 bro mooctane are added dropwise and stirred overnight at room temperature. The reaction mixture is poured into water, extracted 3 times with ethyl acetate, the organic phases after being combined are washed with saturated sodium hydrogen carbonate solution and water, dried, concentrated and the crude product (44.3 g) is purified by flash chromatography on silica gel (900 g; 95: 5 or 99.5: 0.5 toluene / ethanol) in 2 portions. , _____ '. .

Yield: 35.4 g (76%) of the oil product / 0/7 ^ 5 _ ₊ 5 _} γ ° (c = 1, methanol)

7d) (IS.3S, 5S) -2-azabicyclo / 3.3.0 / n-octyl octane-3-carboxylate

2.6 g (7.0 mmol) of the BOC compound of example 7c) are stirred at 0 ° C with 9 ml of trifluoroacetic acid for 1.5 h. The excess of the acid is evaporated in vacuo, the residue is taken up in water, it is made alkaline with sodium bicarbonate, it is extracted with ethyl acetate, the organic phase is washed once more with water, it is dried, concentrated and the product is subjected quickly to the next reaction.

Yield: 1.8 g (95 $) oily product

7θ) 2- / N- (lS-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (lS, 3S,

5S) -2-azabicyclo / 3.3.07octane-3-n-octyl carboxylate

To a solution of 1.76 g (6.6 mmoles) of the amine of example 7d) in 10 ml of methylene chloride are added dropwise at -10 ° C and successively 6.44 g (56 mmoles) of M-ethylmorpholine, 1.84 g (6.6 mmol) of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine and 4 ml of propanophosphonic acid anhydride (50% in methylene chloride). Stir 3 h at 0 ° C and another 3 h at room temperature, concentrate, pour the residue over water, extract with ethyl acetate and wash the organic phase with water, with 25% solution sodium hydrogensulfate and saturated sodium hydrogen carbonate solution. The solution is dried, concentrated and purified by column chromatography over silica gel (eluent toluene / ethanol 98: 2). 2.47 g (71%) of the title compound are obtained

Example 8

2- / Ê- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (1S, 3S, 5S) -2-azabicyclohydrate / 3.3 · O / n-octyl octane-3-carboxylate

8a) (IS, 3S, 5S) -2-azabicyclohydrate / 3.3.0 / n-octyl octane-3-carboxylate _ / 1 P _

To a suspension of 10 g (64 mmoles) of acid (IS, 3S, 5S) -2-azabicyclo / 3 · 3 · octane-3-carboxylic acid in 100 ml of distilled n-octanol is added dropwise to 40 ° C, 16.3 g (150 mmol) of distilled trimethylsilyl chloride, and stirred overnight at 40 ° C. The volatile components are eliminated in a rotary evaporator, the octane is separated by rapid distillation in high vacuum, the residue of the distillation is taken up in methylene chloride, it is concentrated and triturated 2 times with ether, diisopropyl. 14.6 g (75%) of the title compound are obtained.

mp 76 - 78 ° C (c = 1, Methanol)

8b) 2- / N- (1S-ethoxycarbonyl-3-phenylpropyl} -S-alanyl / - (1S, 3S, 5S) -2-azabicyl / 3 · 3.0 / octane-3-carboxylate hydrogen maleate

2.0 g (6.6 mmoles) of the amine hydrochloride of example 8a) are suspended in 30 ml of methylene chloride and 10 ml of water and the pH is adjusted to 9 to 10 by the addition of a saturated solution of potassium carbonate. Then, 1.84 g (6.6 mmoles) of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanine are successively added and a solution of 4.1 ml of methyl ethyl phosphine acid anhydride in 4 ml of chloride methylene. Stir overnight at room temperature, dilute with methyl chloride and water, wash the organic phase with a potassium sulphate / potassium hydrogen sulphate buffer, with sodium bicarbonate solution and sodium chloride solution dry, concentrate and precipitate the title compound from the crude product (2.92 g) by dissolving it in 33 ml of diisopropyl ether and adding a solution of 766 mg of maleic acid in 4 ml of acetone. 2.50 g (67%) are obtained.

Example 9

2- / ΊΪ- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo / 3.3.0 / n-octyl octane-3-carboxylate

9a) 2- _</ Nt-butyloxycarbonyl-S-alanyl/-(lS,3S,5S)-2-azabicil/3.3.07octane-3- n-octyl carboxylate _ λ o _

2,6 a mixture of 2.67 g (10 moles) of the amine of example 7d),

1.89 g (10 mmoles) of BOC-S-alanine and 1.00 g (10 mmoles) of triethylamine in 50 ml of absolute dimethylformamide, are added dropwise in an ice bath and slowly, 10 ml of a solution of propanophosphonic acid anhydride (50% in methylene chloride) and stir for 4 hours at room temperature. The solution is mixed with 200 ml of water, extracted twice with ethyl acetate, the organic phases after being combined are washed with water, with 10% citric acid solution, with saturated sodium hydrogen carbonate solution and with solution. saturated sodium chloride, dried, concentrated and the crude product is purified by column chromatography using silica gel (eluent toluene / ethanol 99: 1) · 3.05 g (70%) of title compound = -59.9 ° (c = 1, methanol)

9b) 2- (S-alanyl- (1S-3S, 5S) -2-azabocycle / 3 · 3-07 octane-3-carboxylate n-octyl.

6.70 g (15.9 moles) of the BOC compound of example 9a) 3 m 30 ml of trifluoroacetic acid are stirred for 90 minutes at 0 ° C. The solvent is evaporated, the residue is taken up in ethanol, neutralized by the addition of potassium carbonate, filtered and concentrated. 5.3 g (98%) of the title compound are obtained.

9c) 2- / ΪΪ- (1S-ethoxyearbonyl-3-phenylpropyl) -S-alanyl / - (IS, 3S,

5S) -2-azabicycle _z is3.3 · 0 / n-octyl octane-3-carboxylate

To a solution of 1.35 g (4.0 moles) of the amine of example 9b) in 25 ml of absolute methylene chloride are added at 0 ° C and successively 0.8 g (8 moles) of triethylamine and a 1.36 g (4 moles of ethyl 4-phenyl- (2R) -trifluoromethylsulfonyloxy-butyrate in 10 ml of absolute methylene chloride and stir overnight at room temperature. The reactive solution is washed with water, it is dried and concentrated and the crude product is purified by column chromatography using silica gel (eluent toluene / ethanol 99.5: 0.5, 99: 1). 0.28 g (13%) of the compound are obtained of title.

Example 10

Preparation of compositions used according to the invention for oral application in the treatment and prophylaxis of cognitive disorders, 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-carboethoxy-3-phenyl-propyl) -S-alanyl / -lS, 3S, 5S-azabicycles / 3.3 · 0 / octa no-3 -n-octyl carboxylate, are prepared using the following auxiliary substances;

2- / N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl / - (1S, 3S, 5S) -2-azabicyclo / 3.3.07octane-3-carboxylate of n-oethyl 10 g cornstarch 140 g gelatin 7.5g microcrystalline cellulose 2.5g magnesium stearate 2.5g

2- / N- (1S-carboethoxy-3-phenyl-propyl) -S-alanyl / - (1S, 3S, 5S-2-azabicyclo / 3 · 3.0 / n-octyl octane-3-carboxylate and the starch of corn are mixed with an aqueous gelatin solution.

The mixture is dried and ground into a granulate. The granulate is mixed with microcrystalline cellulose and magnesium stearate. The granulate thus obtained is molded by compression into 1000 tablets, each tablet containing 10 mg of the active substance. These tablets can be used for the above mentioned indications.

Example 11

Analogously to example 10, 1000 tablets were prepared, each containing 10 mg of 1 '- / N- (ls-carbethoxy-3-phenylpropyl) -S-alani37 ~ (3' S, 5 'S) -spirobicycle ₍ /2.2.2/octane-2,3'- pyrrolidino-5'- carboxylic.

Example 12

Gelatin capsules each containing 10 mg of 1 '- / Ê- (1S-carbethoxy-3-phenylpropyl) -S-alanyl / - (3'S, 5'S) -spirobicyclo / 2.2.2 / octane-2, 3'-pyrrolidine-5'-carboxylic, are filled with the following mixture;

1 '- / N- (1S-carboethoxy-3-phenylpropyl) -S-alanyl / - (3' S, 5 'S) · -spirobicyclo / 2.2.2 / octane-2,3'-pyrrolidine-5' -carboxylic 10 mg j _ laugh _

magnesium stearate lactose

214 mg.

The capsules can be analyzed for the treatment and prophylaxis of disorders of the central nervous system.

Example 13

The preparation of a solution for injection is then described: 2- / N- (1S-carboxy-3-phenyl-propyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo / 3 · 3 · 0 / octane-3-carboxylic 250 m methylparaben 5 g propylparaben 1 g sodium chloride 25 water for injections 5 1.

2- / N- (1S-carboxy-3-phenyl-propyl) -S-alanyl / - (IS, 3S, 5S) -2-azabicyclo / 3.3 'θ / octane-3-carboxylic acid, preservative and chloride of sodium are dissolved · in 1 water for injections and the volume is adjusted to 5 1 with water for injections. The solution is sterilized by filtration and is packaged, under aseptic conditions, in previously sterilized bottles that are closed with sterile rubber stoppers. Each vial contains 5 ml of the solution.

Example 14

As described in example 10, tablets are prepared that can be used for the treatment and prophylaxis of disorders of the central nervous system, with the exception that instead of using 2- / N- (1S-carbethoxy-3-phenyl- propyl) -S-alanyl7- (IS, 3S, 5S) -2-azabicyclo / 3.3.07octane-3S-carboxylate of n-octyl, 2- / N- (1S-Carboxy-3-phenyl- propyl) -S-alanyl / - (IS, eS, 5S) -2-azabicyclo / 3 · 3.07octane-3-carboxylic or 1- / ΪΤ- (1S-Carboxy-3-phenyl-propyl) -S- alaniX7- (2S, 3aR, 7aS> -octahidroindol-2-carboxylic or 1- / N- (1S-Carbetoxy-3-phenyl-propyl) -S-alani2j7-cis-2,3,

3a-4,5,7a-hexahydro / 1H7indol-2-S-end o-carboxylic or 1- / N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl / -cis-2,3 , 3a,

4,5,7a-hexahydro _</ lH / -indol-2S-endo-carboxylic acid or 2- / N- (l-carboxy-3-phenylpropyl) -S-lysyl / - (lS, 3S, 5S) ~

-2-azabicil / 3.3 · O / octane-3-carboxylic or 2- / N- (1S-Carbaetoxy-3-cyclohexyl-propyl) -S-alanyl / ~ (IS, 3 S, 5S) -2-azabicyclo _i / 3 · 3 · O / octane-3-carboxylic or N- (lS-Carboxy-3-cyclohexyl-propyl) -S-lysyl- (lS, 3S, 5S) -2-azabicyclo / 3 · 3 · 0 / octane-3-carboxylic or 1 '- / N- (1S-Carbetoxy-3-phenyl-propyl) -S-alanyl7-exo-spirobicyclo / 5.2.2 / octan>-2,3'-pyrrolidin-5' -S-carboxylic or (S, S, S) -1-methyl-2- (1-carbethoxy-3-phenyl-propyl) -2H-undecahydro-cyclopenta / 4.5 / pyrrole / 1,2-a7pyrazine-3,8 -dione or 1 '- / N- (1S-Carbetoxy-3-phenylpropyl) -S-alanyl / -endo-spirobicyclo / 2.2.2 / octane-2,3' -pyrrolidinyl-5 '-S-carboxylic or 2 - / N- (1-S-Carbetoxy-3-phenylpropyl) -S-alanyl / -cis-endo-2-azabicyclo / 3.3.0 / octan> n-octyl 3-S-carboxylate or 2- / N- (lS-carbethoxy-3-phenylpropyl) -S-alanyl ^/> cis-endo-2-azabicyclo / 3.3 · O / S octane-3-carboxylate or 2-decyl / n (1-S-carbethoxy -3-phenylpropyl) -S-alanyl / -cis-endo-2-azabicyclo / 3.3.07octane-3-S-carboxylate of 5-nonyl or 2- _z / N- (lS-0ctiloxy-3-fen ilpropyl) -S-alanyl7-cis-endo-2-azabicyclo / 3.3.07octane-3-S-carboxylate octyl or 2- / IT- (1S-Mentyloxy-3-phenylpropyl) -S-alanyl / -cis- endo-2-azabicyclo ^. Benzhydryl O / octane-3-S-carboxylate Example 15

An injectable solution is prepared analogously to the procedure described in example 13, with the difference that instead of using 2- _z / N- (1S-carboxy-3-phenyl-propyl) -S-alanyl / - (1S , 3S, 5S) -2-azabicyclo _i /3.3.07octane-3- carboxylic, if 2- / N- (1S-Carbetoxy-3-phenyl-propyl) -S-alani] y- (lS, 3S, 5S) -2-azabicyclo / 3.3.o7octane-3-carboxylic or 2- / Ê- (1S-Carboxy-3-phenyl-propyl) -S-alanyl / - (1S, 3S, 5S) -2azabicyl ^ 3.3. 7, ctane-3-carboxylic or 1- / N- (1S-Carbetoxy-3-phenyl-propyl) -S-alanyl7 ~ (2S, 3aR,

7aS) -octahidoindol-2-carboxylic hydrochloride or 1- / N- (1S-Carboxy-3-phenyl-propyl) -S-alanyl7 ~ (2S, 3aR, 7aS) octahidroindol-2-carboxylic acid or l- / N- (1S-Carbetoxy-3-cyclohexyl-propyl) -S-alanyl / -cis2,3,3a, 4,57a-hexahydro / 1H / indole-2-S-endo-carboxylic or l - ^ / ii- ( 1S-Carboxy-3-phenyl-propyl) -S-alanyl / -cis-2,3,3a.

4,5,7a-hexahydro / 1H7indol-2-S-endo-carboxylic or 2- / N- (1-Carboxy-3-phenyl-propyl) -S-lysyl / - (IS, 3S, 5S) -2azabicyl /3·3.0/octane-3- carboxylic or 2- / N- (1S-Carbetoxy-3-cyclohexyl-propyl) -S-alanyl / - (IS, 33.5S) -2-azabicycles / 3 · 3 · 07octano-3-carboxylic acid or 2- / N- (l ^_ S-Carboxy-3-cyclohexyl-propyl) -S-lisil7 "(IS, 3S, 5S) -2-azabicyclo / 3.3.07octano-3-carboxylic acid or 1 ¹ / N- (1S-Carboxy-3-phenylpropyl) -S-alanyl7-ethyl ⁽ 3rd aspirin / 2.2.2 / octane-2,3'-pyrrolidin-5 '-S-carboxylic acid or 1' / N- ( 1S-Carboxy-3-phenylpropyl TS-alanyl;

Example 16

Preparation of a usable composition according to the invention for oral application in the treatment and prophylaxis of cognitive disorders, as well as for the treatment and prophylaxis of disorders of the central nervous system.

1000 tablets' each containing 15 mg of 2- / N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl7-1S, 3S, 5S-2-azabicycle / 3.3-0 / octane maleate -3-n-octyl carboxylate, are prepared together with the following auxiliary substances: 2- / N- (1S ~ carbethoxy-3-phenyl-propyl) maleate -S-alanyl7 ~ (1S, 3S, 5S) -2 -azabicycle _< / 3 · 3.0 / n-octyl octane-3-carboxylate g

cornstarch 200 g gelatin 10 g microcrystalline cellulose 4 g magnesium stearate 4 g 2- / N- (1S-carbethoxy-3-phenyl-propyl) -S-alanyl7 ~ (1 S, 3S, 5S) -2 -azabicycle / 3.3.07octane-3-carboxylate of n-octyl and corn starch are mixed with an aqueous gelatin solution. The mixture is dried and ground into a granulate. Microcrystalline cellulose and this magnesium arate are added to this granulate, mixing well. The granulate obtained is molar in the form of 1000 tablets, each tablet containing 15 mg of the active substance.

These pills can be used for the above mentioned indications. ....

- ..... there--.··- - ........

- 54 Example 17

Preparation of compositions used according to the invention for oral application in the treatment and prophylaxis of cognitive disorders, as well as for the treatment and prophylaxis of disorders of the central nervous system.

1000 tablets each containing 8 mg of 2 - ^ / ϊί- (1-S-carboxy-3-phenyl-propyl-S-alanyl7 ~ 1S, 3S, 5S-2-azabicycles / 3 · 3 · 07 ~ 3-carboxylate of n-octyl, are prepared using 'the following auxiliary substances:

2 - ^ / N- (1-S-carboxy-3-phenylpropyl) -S-alanyl / - (1S, 3S, 5S) -2-azabicycloyj · 3.0 / n-octyl octane-3-carboxylate 8 g starch corn 120 g gelatin 7 g crystalline cellulose 2 g magnesium stearate 2 g

2- / n- (1S-carboxy-3-phenylpropyl) -S-alanyl7 ~ (1S, 3S, 5S) -2-azabicyclo / 3.3 · N-octyl octane-15-carboxylate and corn starch are mixed with an aqueous gelatin solution. The mixture is dry and ground into a granulate. Microcrystalline cellulose and magnesium stearate are mixed with this granulate. The resulting granulate is molded into the form of 1000 tablets each containing 8 mg of the active substance. These tablets can be used for the above mentioned indications.

Claims (1)

- reads Process for the preparation of a compound with formula III (III) in which the 5 chiral carbon atoms (*) each have the S configuration, R represents ethyl or hydrogen and 3 R represents n-octyl, as well as its physiologically acceptable salts, characterized by the fact that a) reacting with n-octanol a compound of formula III in which the 5 chiral carbon atoms (*) each have „2 conformation S, R represents ethyl du a carboxyl blocking group easily dissociable in acid or basic medium , or Z hydrogenolithically, and Ir represents hydrogen, or by b) reacting a compound of formula III in which configuration, as well as R and R are defined as above in (a) with a compound of formula VI h ₃ c- (ch ₂ ) ₇ x (VI) in which X represents a leaving group that can be displaced nucleophilically, under the conditions of a nucleophilic substitution ^a 'or by c) reacting with ethanol a compound of formula III which has the configuration described above in (a) and in which R represents hydrogen and R ⁷ represents n-octyl, as described in process variable (a), or per d) reacting a compound of formula III in which the configuration ~ 2 3 ~ - race, R and R are defined as above in (c), with a compound of formula VII (VII) H ₅ C-GH ₂ -X in which X represents a leaving group that can be displaced from the nucleophilically, as described in variant (b) of the process, or by e) reacting a compound of formula VIII (R) Ç VcHo-CHo-CH-OSOoCP (VIII), 2 z COOR in which R is defined as previously in (a), with a composition of formula IM // i 0 ^z CH, (IX) in which the 4 chiral carbon atoms (*) each have the S configuration, or by f) a compound of formula X is reacted COOR '(X) in which the 3 chiral carbon atoms (*) each have the S and R configuration represents n-octyl, with a compound of formula XI * * HOO C-CH-NH-CH-CH ₂ -CH ₂ , 2 // \\ (XI) COOR p in which R is defined as previously in (a), if necessary _z 2 dissociates into a compound of formula III thus obtained (R = group 2 po blocking) the blocking group R in a manner known to itself, and eventually transforming the compound of formula III thus obtained (R = ethyl or hydrogen) in a physiologically acceptable salt thereof, and, if the mixtures of the stereoisomers are used as starting products of the process variants (a) - (f), in another separation step, the isomer of formula III in which all chiral atoms have the S configuration (R = z = hydrogen or ethyl, R = n-octyl). 28. A process according to claim 1, characterized in that a compound of formula 2 is obtained in which R represents ethyl, or its physiologically acceptable salts. 3. A process according to claim 1, characterized in that a compound of formula III is obtained in which R ₂ represents hydrogen, or its physiologically acceptable salts. _ 4th _ Process according to claim 2, characterized in that a maleate is obtained. Process for the preparation of a compound of 'formula XII coo (ch ₂ ) ₇ ch _s (XIL) in which the 3 chiral carbon atoms each have the S and Q configuration representing hydrogen or the radical of the formula XIII ( $) -c-ch-nh ₉ II I 0 CH ₃ characterized by the fact that a) a compound of formula XIV (XIII) is reacted 00H (xiv) in which Q represents hydrogen or -C0-CH (CH ₃ ) -NH ₂ , with n-octanol or with H ₂ C- / CH ₂ _ / ₇ ~ X analogously to claim 1, variants (a) or (b) the process, or b) reacting a compound of formula XV σοο / 0Η ₂ _7γ-θΗ ₃ (XV) analogously to claim 1, variant (f) of the process, with alanine blocked in the amino group, and then dissociating the blocking group from amino and, if desired, isolating the isomer of formula XII in which all atoms have S configuration. 6. A process according to claim 5, characterized in that, starting from a mixture or mixtures of stereoisomers of compounds XIV or XV, a mixture of stereoisomers containing a compound of formula XII is obtained. - 7fi Process for the manufacture of pharmaceutical compositions with psychotropic action and in particular with anxiolytic action, characterized by being incorporated as an additive ingredient in a compound when prepared, according to the preceding claims in combination with pharmaceutically acceptable vehicles. The applicant declares that the first applications for this patent were filed in the German Federal Republic, on January 27, 1988, January 30, 1988 and on April 22, 1988, under the nos. P 38 02 302.2, P 38 02 760.7 and P 38 13 819.0, respectively.