CS276385B6 - Process for preparing compounds with nootropic effect - Google Patents

Abstract

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

Description

(57)

The present invention relates to a process for the preparation of compounds having a nootropic action of the general formula (II) and their physiologically tolerable salts, with the exception of the compounds mentioned above, which comprises treating a compound of the formula III with a compound of formula IV or compounds IVa and IVb in the presence of a base. in an organic solvent at a temperature between -10 ° C and the boiling point of the reaction mixture, whereupon optionally intermediate intermediates of unsaturated compounds such as Schiff bases are reduced, protecting groups temporarily introduced to protect the reactive groups are cleaved, compounds of formula II with a free carboxyl group; with free carboxyl groups are optionally esterified and the resulting compounds are optionally converted into their physiologically tolerable salts. The compounds produced are used as ACE inhibitors as medicaments with nootropic effect.

I I »

K ³ OOC - CH - Ji - C - CH - KH - CH - (CH ₂ ) _n - R

1.1. ; i, I,

R ⁵ R ¹ COOR *

K 2 OOC -CH-NC-CH-HH ₂

CH-X ² CH-COR

I Z> 4

000R ² X ⁴ (IVa) (IVb)

CS 276 335 B6

CS 276 385 B6

The invention relates to a process for the preparation of compounds having a nootropic effect, as well as their salts, which are physiologically useful. In particular, the invention relates to the use of angiotensin converting enzyme inhibitors (ACE inhibitors) or their physiologically acceptable salts as medicaments having a nootropic (i.e., memory-enhancing) effect. The compounds produced are used to produce the respective pharmaceutical preparations.

The present invention provides a process for preparing the novel compounds of formula (II)

R ³ 00C CH - CH - R ⁴ X K - CH - CH. 1 »» 0 NH - CH - (CH ₂ ) _ft - R COOR ² (II) R ⁵ R ¹ in which AND. n means a number 1 or 2,

R represents an alkyl group having 1 to 15 carbon atoms, a cyclohexyl group, a cyclohexylmethyl group, an aryl group having 6 to 12 carbon atoms or an arylmethyl group having 6 to 12 carbon atoms in the aryl moiety,

R ¹ is the side chain of alanine, lysine, leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, C 1 -C 4 alkyltyrosine, ornithine, methionine or 2-thienylalanine,

R represents a hydrogen atom, a C 1 -C 18 alkyl group, a C 5 -C 6 cycloalkyl group, a tolyl group, a C 1 -C 2 mono- or diphenylalkyl group or a menthyl group,

R ³ represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, an octenyl group, an octinyl group, a cycloalkyl group having 5 to 6 carbon atoms, an aryl group having 6 to 12 carbon atoms optionally substituted by a methyl or halogen atom, mono - or a diphenylalkyl group having 1 to 8 carbon atoms in the alkyl moiety, wherein the phenyl moiety is optionally substituted by halogen, or represents a menthyl group,

R 1 and R 2 together with the atoms to which they are attached represent a residue of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 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, 4'-pyrrolidine] 3,0, ¹⁶ ' ⁹ ] decane, decahydrocyclohepta [b] pyrrole, hexahydrocyclopropa [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, 2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2 3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole, indoline, or their physiologically tolerable salts,

II.

with the exception of compounds of formula (II) and salts thereof, in which n is simultaneously 1 or 2,

R represents an alkyl group having 1 to 8 carbon atoms, a cyclohexyl group or an aryl group having 6 to 12 carbon atoms; represents a C1-C4 alkyl group, a cyclohexylmethyl group, a phenylmethyl group, the phenyl being optionally substituted by a C1-C4 alkoxy group or, if not included in the above definitions, an optionally protected naturally occurring < amino acid of formula R ³ -CH (NH ₂₎ -C00H,

CS 276 385 B6

3

R and R are the same or different and are hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, arylalkyl of 6 to 12 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl moiety or (C 5 -C 6) cycloalkyl;

R ⁴ and R ⁴ have the meaning defined in ad I.

Preferably, the process of the present invention provides compounds of formula Π in which n is 1 or 2,

R is C 1 -C 6 alkyl, C 10 -C 15 alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 2-naphthyl, 2-naphthylmethyl, 4-biphenylyl or t-biphenylmethyl group

R ¹ represents the side chain of alanine, lysine, leucine, tartrate, isoleucine, phenylalanine, cyclohexylalanine, C 1 -C 4 -alkyltyrosine, ornithine, methionine or 2-thisnylalanine,

R represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, an octadecyl group, a cyclopentyl group, a cyclohexyl group, a tolyl group, a benzyl group, a phenylethyl group, a benzhydryl group or a menthyl group,

R ^ represents a hydrogen atom, an alkyl group having 1 to 10 carbon atoms, a tetradecyl group, an octadecyl group, an octenyl group, an octinyl group, a cyclopentyl group. a cyclohexyl group, a phenyl group, a benzyl group, a phenylethyl group, a phenylpropyl group, a 3,3-diphenylpropyl group, a phenylactyl group, a tolyl group, a benzhydryl group,

4,4'-difluorobenzhydryl, 4-fluorophenyl, 4-biphenylyl, 2-naphthyl or menthyl,

5 R and R together with the atoms to which these radicals are attached form a radical of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 2-azaspiro [4.5] decane, 2-azaspirc [4.4] ] nonane, spiro [bicyclo [2.2.2] octane] -2,3 '-pyrrolidine, 2-azatricyclo [4,3,0, l ^6' decane, decahydrocyclohepta [b] pyrrole, hexahydrocyklopropa [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, spiro (bicyclo [2.2.1] heptane) -?, 3-pyrrolidine, 2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2,3,3a, 4 , 6α-hexahydrocyclopenta [b] pyrrole, indoline, or a physiologically tolerable salt thereof.

A particularly preferred embodiment of the invention is a process for the preparation of 2- [h1- (1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] benzhydryl ester (1S, 3S, 5S; -2-azabicyclo). 3,0] octane-3-carboxylic acid 2- [2- [X1S] -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane octadecyl ester -3-carboxylic acid 2- [Nf (1S) -benzhydryloxycarbonyl-3-phenylpropyl] -1-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-slanyl] - (1S, 3S, 5S-2-azabicyclo [3.3.0] octane-3-carboxylic acid, n-octyl ester, 2- [1M- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo L3,3,0] octane-3 hydrogen maleate n-octyl ester 2-{N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, -

3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid),

CS 276 385 86 2- [1H-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, n-octyl ester 2- [N- (1S-carboxy-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, n-decyl ester of 2- [ N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 2- [N- (n-octyl) ester (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] -ClS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 2- [N- (1S) n-octyl ester -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] -7-octene-3-carboxylic acid 2- [M- (1S) -benzyl ester -ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid and 2- [N- (1R-ethoxycarbonyl) -n-benzyl ester -1ridecyl) -S-alanyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid.

Suitable ring systems consisting of R ⁴ and R ³ together with the atoms to which the R ⁵ and R ³ substituents are bonded are in particular those of the following group:

pyrrolidine group (0), tetrahydroisoquinoline group (A), decahydroisoquinoline group (B), octahydroindole group (C), indoline group (Q), octahydro cyclopenta [blpyrrole group ¢ 0], 2-azaspiro [4,5] dean group (E), 2-azaspiror 4,4] nonane group (F), spiro [(bicyclo [2.2.1] heptane) -2,3'-pyrrolidin] (0), spiro [(bicyclo [2 2,2joktan) -2,3'-pyrrolidine] group (H) of 2-azatricyclo [4,3,0, l ^6,9] decanoic group (I), decahydrocyclohepta [b] pyrrclová group (J) oktahydroisoindolová (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 (R).

For compounds of the formula II which contain several chiral atoms, all possible diastereomers, such as racemate or enantiomers or mixtures of different diastereomers, are suitable.

Relevant heterocyclic ring systems have the following structural formulas:

CD)

CC)

CS 276 385 B6

CS 276 385 86

N

COOH, 3

(Q)

Suitable salts of the compounds of the formula (II) are, depending on the acidic or basic nature of the compounds, alkali metal or alkaline earth metal salts or salts with physiologically usable amines or salts with inorganic or organic acids such as hydrochloric acid acid, hydrobromic acid, sulfuric acid, maleic acid, fumaric acid, tartaric acid and citric acid.

The capillary structure of the blood vessels of the brain differs from the capillary structure of the blood vessels in other parts of the body. Cerebral vascular capillaries are surrounded by a layer of endothelial cells that are particularly closely connected to each other (by tight junctions). In addition, the brain capillaries have far fewer pores through which other blood capillaries can enter the surrounding tissue or, on the contrary, low molecular weight substances can escape from the tissue. Thus, in brain capillaries, the ability of lipid solubility is much more important for the distribution between blood and surrounding tissue than in the rest of the body.

The present invention provides a process for the preparation of compounds of formula (II) which comprises reacting fragments of these compounds with one another in a suitable solvent, optionally in the presence of a base and / or a coupling reagent, or an unsaturated intermediate containing intermediate, such as Schiff's bases. The compounds of formula (II) with a free carboxyl group or free carboxyl groups are optionally esterified and the resulting compounds are optionally converted into their physiologically acceptable salts.

The compounds of formula (II) according to the invention are prepared by the preparation of a compound of formula (III)

E ³ 00C-CH-N-C-CH-NH ₂ (III)

CS 276 385 86 (IV), in which:

R ^1, R ^3, R ⁴ and R ⁵ are as defined above, with a compound of formula IV or compounds of the formulas IVa and IVb

CH - X ² CH - COS i ₂ L cocsr X * (IVa) (IVb) in which 2

R and R are as defined above and

2 4

X and X as X X and X represent a chemical bond or

2

X and X together represent oxo and

X ³ and X ⁴ represent each hydrogen atom, in the presence of a base in an organic solvent at a temperature between -10 ° C and the boiling point of the reaction mixture, whereupon optionally interroedially unsaturated compounds such as Schiff bases are reduced, protecting groups temporarily introduced to protect reactive The compounds of formula II having a free carboxyl group or free carboxyl groups are optionally esterified and the resulting compounds are optionally converted into their physiologically tolerable salts.

Thus, compounds of formula IX can be reacted

R ³ O0C-CH-N-C-CHNH _?

III r5 o _r 1 in which 13 4 5

R, R, R and R are as defined above, with compounds of formula XI

R @ ² OOC - CH = CH - COR (IX), (XI), wherein Fe 2 i and R have the meanings given above, since the compounds of the formulas XII and XIII

OCH - COOR ²

R-CO-CH3 (XII), (XIII),

CS 276 385 B6 in which

R and R have the above meanings, suitably in the presence of a base such as sodium alkoxide, in an organic solvent, at temperatures between -10 ° C and the boiling point of the reaction mixture, to give compounds of formula II wherein n is 2, the intermediate Schifi bases are reduced and the carbonyl group is converted to a methylene group by reduction, for example by treatment with a complex hydride.

The intermediate Schifi bases can also be reduced after prior isolation, for example by hydrogenation in the presence of a transition metal catalyst, to give compounds of formula II.

In the above formulas III, IV, IVa, IVb, IX, XI, XII and XIII, the general substituents R 1 to R 2 and n have the meanings defined above for the substituents II.

Protective groups that are introduced temporarily to protect non-reactive groups are cleaved after the reaction is completed in a manner known per se (cf. Schröder, Lubke, supra, pp. 1-75 and 246-270; Greene, Protective Groups in Organic Synthesis, New York 1981).

The novel compounds of formula (II) can also be prepared, for example, using well-known esterification methods (cf., for example, Buchler, Pearson, Survey of Organic Syntheses, Vol. 1, New York 1970, pp. 802-825; Houben-Weyl, Methoden der organischen). Chem., Vol. E5, 1985, pp. 656-773).

a) Reaction of a mono- or ricarboxylic acid of formula II, wherein at least one of the radicals R @ 3 and R @ 2 is hydrogen, with the corresponding alcohol under acid catalysis (mineral acid or acidic ion exchanger).

b) Alkylation of a mono- or dicarboxylic acid of formula II, wherein at least one? R @ 2 and R @ 2 are hydrogen, with a compound of the formula R @ 2 or R @ 2 in which Z is a nucleophilically removable leaving group (such as a halogen or tosylate residue) in a polar protic or dipolar aprotic solvent in the presence of a base such as hydroxide or an alkali metal alkoxide.

c) Reactions of a mono- or dicarboxylic acid of the general formula II, in which at least one of

R 3 and R 3 are hydrogen, with diazoalkene in an inert organic solvent such as methylene chloride.

The nootropic effect of the compounds of the invention was tested in mice weighing 20-25 g using a step-through-model inhibition test. Modified method of the method described by 3. Kopp, Z. Bohdanecky and Μ. E. jarvik, I describe 3. Bureš, Q. Burešová and 3. Huston in Techniques and Basic Experiments for the Study of Brain and Behavior, Elsevier Scientific Publishers, Amsterdam (1983).

In accordance with these literature data, a substance is said to be neootropically effective if it allows suppression of amnesia in experimental animals caused by electroconvulsive shock or scopolamine.

The experiments were carried out according to modified test methods. The known nootropic, i.e. 2-oxo-1-pyrrolidinylacetamide (Piracotam), serves as the comparative compound. The obvious superiority of the compounds of the invention over the comparator is that scopolaroin-induced amnesia can be suppressed in the defense inhibition test using a minimum effective dose (MED) of 1.0 to 30 mg / kg p.o. The reference substance has a MED value of about 500 to 1000 mg / kg p.o.

In general, the compounds according to the invention have only low toxicity.

In addition to the treatment of high blood pressure, the compounds according to the invention are also suitable for the treatment of cognitive dysfunctions of various origins, such as Alzheimer's disease or senile dementia, because of their pharmacological properties.

EN 276 385 86

The invention further relates to the use of the compounds of the invention for the treatment and prophylaxis of cognitive dysfunctions in patients with high blood pressure.

The invention further includes medicaments comprising said compounds, a process for their manufacture, as well as the use of the compounds of the invention for the manufacture of medicaments which are used for the treatment and prophylaxis of the above diseases.

Using the method of the invention, the above angiotensin converting enzyme inhibitors can be used in mammals such as monkeys, dogs, cats, rats, humans, etc.

The medicaments are prepared by methods known to those skilled in the art. The medicaments used are the pharmacologically active compounds according to the invention (= 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, the active substance content being up to about 95 %, preferably between 10 and 75%.

Which excipients are suitable for the desired pharmaceutical preparations will be apparent to those skilled in the art on the basis of his knowledge. In addition to solvents, gelling agents, suppository bases, tablet excipients and other active compound carriers, for example, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, cosolvents or colorants can be used.

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

For an oral dosage form, the active compounds are mixed with suitable excipients such as carriers, stabilizers or inert diluents and converted into dosage forms such as tablets, dragees, push-fit capsules, aqueous alcoholic or oily suspensions, or aqueous, alcoholic or oily solutions. As inert carriers, for example, gum arabic, magnesium oxide, magnesium carbonate, lactose, glucose or starch, in particular corn starch, can be used. In this case, the preparation can be produced in both dry and wet granules. Suitable oily carriers or solvents are, for example, vegetable or animal oils, such as sunflower oil or fish oil.

For subcutaneous or intravenous administration, the active compounds or their physiologically acceptable salts, optionally together with substances customary for this purpose, such as co-solvents, emulsifiers or other auxiliaries, are brought into solution, suspension or emulsion. Suitable solvents are, for example, water, physiological sodium chloride solution or alcohols, for example ethanol, propanol, glycerin, furthermore sugar solutions, such as glucose or mannitol solutions, or else a mixture of the various solvents mentioned.

The compounds of the invention can be converted into the corresponding dosage forms analogously to these examples.

The following examples serve to illustrate the process of the invention in more detail to produce the novel compounds of formula (II) without, however, limiting the scope of the invention in any way.

Example 1

1- [N- (1S) -dodecyloxycarbonyl-3-phenylpropyl) -S-alanyl] -2S, 3aR, 7aR-octahydroindole-2-carboxylic acid

a) 1- [N- (1S) -Dodecyloxycarbonyl-3-phenylpropyl) -S-alanyl] -2S, 3aR, 7aR-octahydroindole-2-carboxylic acid benzyl ester mmol of S-alanyl-2S, 3aR, 7aR-octahydroindole benzyl ester The 2-carboxylic acid (produced according to EP-A-84164) is dissolved in 30 ml of anhydrous ethanol. The solution was adjusted with ethanolic potassium hydroxide to pH 7.0 and then 1 g of powdered molecular sieves (4 × iq ^- m ^), and then 10 mmol of 2-dodecyl Koto-4-phenylbutyric kyselí9

CS 276 385 B6 {i

I i

<

i í

í i í i

.} .í ': í ny. A solution of 1 g of sodium cyanoborohydride in 10 ml of anhydrous ethanol is then slowly added dropwise.

After a reaction time of 20 hours at 20-25 ° C, the reaction solution is filtered and the solvent is distilled off. The residue was taken up in ethyl acetate / water. After evaporation of the ethyl acetate phase, the residue is chromatographed on silica gel with ethyl acetate / cyclohexane (1: 4).

b) The compound obtained under a) is hydrogenated in ethanol in the presence of 10% palladium on carbon at 20-25 ° C and at atmospheric pressure. After separation of the catalyst, a solution of 0.5 N ethanolic hydrogen chloride is added to the filtrate until an acidic reaction is obtained. The solution was concentrated in vacuo and the residue triturated with diisopropyl ether until crystallization.

Example 2

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

2.00 g (4.80 mmol) of 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -1-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] The octane-3-carboxylic acid is dissolved in 100 ml of isobutyl alcohol, 0.1 ml of concentrated sulfuric acid is added to the solution, and the mixture is refluxed for 15 hours. After cooling, the solvent was removed by rotary evaporation and the residue was taken up in methylene chloride. This solution is washed once with water, saturated aqueous sodium bicarbonate solution and again with water, dried over magnesium sulphate, concentrated and chromatographed on 200 g of silica gel (solvent system: methalene chloride / ethyl acetate 8: 2) to remove impurities.

Yield: 51% of theory as an oil.

[.alpha.] D @ 20 = -28.2 DEG (c = 1, methanol).

This product was dissolved in ether, adjusted to pH 2 by addition of saturated ethereal hydrogen chloride, the solvent was evaporated and the residue was crystallized from diisopropyl ether.

Hydrochloride:

mp 123-124 ° C

[.Alpha.] D @ 20 = + 17.7 DEG (c = 1, methanol).

Example 3

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

2.07 g (4.97 mmol) of 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- The 3-carboxylic acids are dissolved in 50 ml of acetone, and a solution of 1.16 g (5.98 mmol) of diphenyldiazomethane in 50 ml of acetone is added dropwise under ice-cooling. After the solution was stirred at room temperature for 26 hours, the solvent was removed by rotary evaporation and the residue was purified by flash chromatography on 150 g of silica gel (solvent system: toluene / ethanol 98: 2).

Yield: 2.55 g (88% of theory) of an oily product.

[.Alpha.] D @ 20 = -33.8 DEG (c = 1, methanol).

Example 4

2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octadecyl ester i

'and

CS 276 365 B5

2.08 g (5.00 mmol) of 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -1-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane The 3-carboxylic acid was dissolved in 25 ml of absolute dimethylformamide, treated with 1.00 g (10.0 mmol) of potassium bicarbonate and stirred at 40 ° C for 90 minutes. After cooling to room temperature a solution of 4.00 g (12.0 mmol) of L-bromcktsdskanu in 20 ml of absolute dimethylformamide and stirred for 4 hours at 40 ^Q C. The solvent is then evaporated on a rotary evaporator at 133.3 Pa and the residue was partitioned between water and methylene chloride. The organic phase is separated, dried over magnesium sulphate and concentrated. 3.05 g (92% of theory) of the crude product were isolated from the crude product (5.40 g) by column chromatography on 200 g of silica gel (toluene / ethanol 99: 1).

₌ -19.6 ° (c = 1, methanol).

The following compounds are prepared by a suitable combination of the methods described in the above examples (the designation of the ring systems corresponds to the designation of the ring systems for compounds of formula II):

R ³ OOC - CH-K-C- * CH 1 CH ₃ t / NH - CH - CH, - CH, - C. V) i ₂ '\ _y COOR' ---- ' R ⁴ i _c R ' II i ⁰ Example R ³ OOC-CH-K- R ² R ³ physical 1, L R ⁴ R ⁵ data

ring system

-c ₂ h ₅ ring system B

-c ₂ h ₅

-CH (CH _{3) 2}

-CK ₂ -CH (CH ₃ ) ₂ ring system C -CK ₃ θ ring system C ^_ ^ 2 ^H 5 g ring system 3 ^ 2 ^ 5 ring system 3 ^_C 2 ^K 5 ring system 3 ^-C 2 ^ 5 ring system 3 ' ^C 2 ^H 5 ring system 3 ^_C 2 ^H i>

r ³ ooc-ch-n-ring system D ring system E ring system F ring system G ring system G ring system G ring system H ring system H ring system H ring system H ring system H ring system H ring system H

CS 276 385 B6

-c ₂ to ₅

-c ₂ h ₅

-CH,

-c ₂ h ₅

- ^C 2 ^H 5 ^C 2 ^H 5 ^C 2 ^H 5 ^c 2 ^h 5 ^C 2 ^H 5 c ₂ h ₅ ^C 2 ^H 5 c ₂ h ₅

- (CH ₂ ) ₅ -CH ₃

-CH (C ₆ H ₅ ) ₂

-CH (CH _{3) 2}

-CH (C ₆ H ₅ ) ₂

-CH (CH _{3) 2}

-CH ₂ -CH (CH ₃ ) ₂

- (CH ₂ ) ₅ -CH ₃

[α] ²⁰ = -21.5 ° (o = 1; CH 3 OH)

E 276 385 86 Example R ³ OOC-CH = N-R ² "I ₅

R ⁴ Ir physical data

27 Mar: circular ayatém: H H 28 circular system H ^C 2 ^H 5 29 circular system H ^C 2 ^H 5 30 circular system AND ch ₃ 31 circular system J ^C 2 ^K 5 32 circular system TO ^C 2 ^H 5 33 circular system L ^C 2 ^H 5 34 circular system M ^C 2 ^H 5 35 circular system N c ₂ h ₅ 36 circular system N ^C 2 ^H 5 37 circular system 0 c ₂ h ₅

-ch (c ₆ h ₅ ) ₂ · '

- (ch ₂ ) ₄ -ch ₃

-C (CH ₃ ) ₃

- (CH ₂ ) ₂ -CH (CH ₃ ) j

CH (4-FC ₆ H _{4) 2}

-CH (CH _{3) 2}

CS 276 385 B6 physical data

example iPooc-ch-n- 1 ₄ 1 ₅ E ⁴ R? R ² 38 circular system ^C 2 ^H 5 39 circular system Q ^C 2 ^H 5 ⁴⁰ ring system ch ₂ ch (ch ₃ ) ₂ 41 ring system CH _{(CH3) 2} 42 ring system CH (C ₆ H ₅ ) ₂ 43 ring system ch ₂ - 44 ring system CH ₂ -CH (CH ₃ > 2 45 ring system CH ₂ -CH (eH ₃ ) ₂ . 46 ring system CH ₂ -CH (CH ₃ ) ₂ 47 ring system CH (C ₆ H ₅ ) ₂

O> - ^r

-H

(c = 1, CH-OH)

m.p. 162 to 163

-ch (c ₆ h ₅ ) ₂

-C _{(CH3) 3}

CS 276 385 86 Example R ³ OOC-CH-NR ⁴ R ⁵ Physical data Ring system D ch (c ₆ h ₅ ) ₂ Ring system E Ring system B

- <CH ₂ ) ₅ -CH ₃ ring system G

-ck (c ₆ h ₅ ) ₂ ring system G ring system H

-CH ₂ CH (CH ₃ ) ₂ ring system H ring system H

-CH, CH _{(CH3) 2}

-ch ₂ ch (ch ₃ ) ₂ ring system H ring system H

-CH (4-EC ₆ H ₄ ) ₂

-C (CH ₃ ) ₃

R ³ 00C-CH-N ring system H ring system H ring system H ring system H ring system I ring system J ring system K ring system L ring system M ring system N

EN 276 385 86

-ch (c ₆ h ₅ ) ₂

-ch (c ₆ h ₅ ) ₂

-ch (c ₆ h ₅ ) ₂

-ch (c ₆ h ₅ ) ₂

- (CH ₂ ) ₂ -CH (CH ₃ ) ₂

-ch (c ₆ h ₅ ) ₂

- (οη ₂ ) ₅ -οη ₃

-ch (c ₆ h ₅ ) ₂

-C (CH ₃ ) ₂ -C ₁₂ CH ₃ physical data

CS 276 305 B6

R ^J-CH-00C data Nfyzikální

R ⁴ R ⁵ an example O-CH (CH ₃ ) ₂ -CH ₂ CH ₂ CH ₃ ring system P-CH ₂ CH ₃ ring system Q -C (CH ₃ ) ₃ ring system D. GgH4 ring system O menthyl

R ^J OOC - CH - N - C - / CH 1 - X i, LO

R ⁴ R ⁵ ' ^3ί 3' ^m

-C (CH ₃ ) ₃

-CHment, hyl

CH ₂ C ₆ H _f [<x] 2 ° = + 27.0 ° (c = 1; CH 3 OH) molate: mp 118-120 ° C Example

R ^J OOC-CH-NH * 5

R ⁴ R ⁵ ring system ring system

R ^J-00C CH - N

- (CH ₂ ) ₅ -CH ₃ -CH ₂ 3H

-ch (c ₆ h ₅ ) ₂ -ch ₂ -s-co-c (ch ₃ ) ₃

CS 276 385 86 Example R ³ OOC-CH-Nm

R ⁴ R ⁵

OOR-CH (C ₆ H ₅ ),

-CH (CH ₃ ) ₂ -CH ₂ -S-CO-C (CH ₃ ) ₃ 1

R ^j _00C-CH2 -N

ring system H (CH _{3) 2} CH ₂ CH ₂ -p-ICH) ₄ ° ol

CH - O - C - C, H

CS 276 385 B6 example example

CHCH-CH (C ₆ H ₅ ) ₂

-CH ₂ -CH (CH ₃ ) ₂

-CH (C ₆ H ₅ ) ₂ -c (CH ₃ ) ₃

-ch (c ₆ h ₅ ) ₂ -ch <c ₆ h ₅ ) ₂

-CH (C ₆ H ₅ ) ₂

- (CH 2) -CH ₃

EN 276 385 86

Example 86

4- [N- (1S) -carboxy-3-phenylpropyl) -S-leucyl] -exo-spiro (bicyclo [2.2.2] octane-1,2,3-pyrrolidine) -5-carboxylic acid

102 mg (0.2 mmol) of the carboxylic acid of Example 88c) is stirred in a 4N aqueous potassium hydroxide solution and stirring is continued until the substance is completely dissolved. The solution obtained is then filtered through an ion exchanger (Araberlite ® ¹ R 120) and eluted with a 2¾ aqueous pyridine solution. Yield: 70 mg.

[λ. [α] D = + 3.9 ° (c = 1, methanol).

The following compounds of formula II are prepared in an analogous manner:

HOCC-CH-N- physical j, 4 1? data

eH (CH3) ₂ ch (ch ₃ ) ch ₂ ch ₂ ch ₆ ^c ₅

CH ₂ -C 8 H 4 (CK ₂ -cyclohexyl)

CH, -C.H. CCH-, o 4 3

CH ₀ -C, H. ΟΟ, Η.

o 4 2 5

C 3 -C 8 _and H- _O C, H ₇

6 4 3 6

CH, -C-OC H H ₀ 2 4 4 9 _{(CH2) 4} -NH ₂

C

G

C

C

AND

D [α] J 0 = -23.7 ° (c = 0.152; C 11 -JOH) (ck ₂ ) ₃ -n ^h 2

AND

CS 276 385 B6

R ¹ HOOC-CH-N- Physical i L Duta R ⁴ R ³ ck ₂ -ch ₂ -s ch ₃ λ CH - CH η tt CH -. - CH ² AND CH (CH-j) ₂ H nonpolar diastersomer mp 132-133 ° C diastsreomer polar (AL ²⁰ = -22.2 ° c = 1, CH ₃ OH] CH, -C _N HD of 0 H non-polar diasterecmer [α] β ° = + 16.4 ° [C = 1, CH ₃ OH] polar disstereomer [α3β ° = + 29.9 ° [C = 1, CH ₃ OH] CH _{(CH3) 2} (B) CH (CH ₃ ) CH ₂ CH ₃ (B) ch ₂ c ₆ h ₅ (B) ^{C C} 6 ^H 11 D ^CH 2 ' ^C 6 ^H 4 ~ ^OCH 3 H ^CH 2 ^-C 6 ^H 4 ^QC 2 ^H 5 G 2 ^^ ^- ^ 6 ^ ^{_ θ} Π- 4 N 4 O 7 G ^CH 2 ' ^C 6 ^H 4 ^O 4 ^C 4 ^H 9 C (ch ₂ ) ₄ -nh ₂ C (CH ₂ ) ₃ -NH ₂ G CH ₂ -CH ₂ -S-CH ₃ 0

CH - CH CH II Η CH ₂ --C 8 CH _{(CH3) 2} C

ch (ch ₃ ) ch ₂ ch ₃

CH ₂ C _s ^H 5 ^CH 2 ^C 6 ^H 11

CH ₂ -C ₆ H ₄ -OCH ₃ ^CH 2 ^-C 6 ^H 4 ° ^C 2 ^H 5

EN 276 385 86

^HOŮC-CH-CH2 Nfyzikální data ^-C 6 ^H 4 ^{'0N C} 3 ^H 7 ^CH 2 -C 6 ^H 4-0n-C ₄ H _g (CH _{2) 4} NH ₂ (CH _{2) 3} -NH ₂

CH ₂ -CH ₂ -S-CH ₃

CH - CH

CH ² -C CH ²

CH _{(CH3) 2}

CH (CH ₃ ) CH ₂ CH ₃ ch ₂ c ₆ h ₅

CH ₂ -C ₆ H _n ^CH 2 ^C 6 ^H 4 ^OCH 3 ^CH 2 ^-C 6 ^H 4 ^_C 2 ^H 5 ^CH 2 ^-C 6 ^H 4 ^{-0n C} 3 ^H 7

CH ₂ -C ₆ H ₄ -O ₄ -C ₄ H _g

C c

E

AND

H, nonpolar diastereomer [<ύ] ^θ θ = -28.6 ° (c = l, CH ₃ 0H] polar diastereomer ÍcCJd = ^{+20 0} - ⁷ ° ^C t ^{= 1} 'CHjOH] MS (FAB) 591 (M ⁺ + (l)

H, m.p. Mp 53-57 ° C

MS (FAB) 605 (M @ ⁺ +1)

G

G

H

H

C

D

D

F

N

AND

H

EN 276 385 86

R ¹ HOOC-CH-N- Physical Data R ⁴ R ⁵ (CH ₂ ) ₄ -NH ₂ H, m.p. 142 [deg.] C (ch ₂ ) ₃ n ₂ 0 CH ₂ -CH ₂ -S-CH ₃ AND CH - CH t (It CH _n -C CH 3 - / S D CH _{(CH3) 2} G CH (CH ₃ ) CH ₂ CH ₃ E CH ₂ C _s H ₅ Η 1. diastereomer [cC] g ° = + 16.4 ° [C = 1, CH3GH] 2. diastereomer (tert-BuNH ₉ -salt) _{= +29) 9} o [ _{C = 1> CH} } _GH j CH ₂ -C ₆ H _n G CH ₂ -C ₆ H ₄ ^H 3 -0C C CH ₂ -C ₆ ^h 4-CC ₂ ^h 5 N CH-C, H, -On-C, H-, 2 6 4 j N CH ₂ -C ₆ H ₄ -O ₄ -C ₄ H ₉ AND

(CH ₂ ) ₄ -NH ₂

(CH _{2) 3 -NH?} P CH ₂ -CH ₂ -S-CH ₃ O

CH - CH II (1 CH, -CCH ² X / S TO

. CH _{(CH3) 2} H CH (CH ₃ ) CH ₂ CH ₃ F ch ₂ c ₆ h ₅ AND

CS 276 385 B6

HOOC-CH-Physical data

R ⁴ R ^{5 CH} 2 ^-C 6 ^H 4 ^-0CH 3 ch ₂ -c ₆ h ₄ -oc ₂ h ₅ ^CH 2 ^-C 6 ^H 4 ^On_C 3 ^H 7

CH ₂ -C ₆ ^H 4 ° ⁿ -C 4 ^H 9 (CH ₂ ) ₄ -NH ₂ (CH ₂ ) j -NH ₂

CH ₂ -CH ₂ -S-CH ₃

CH - CH

II 11

CH ₉ -C CH ^{2 '}

CH _{(CH3) 2}

CH (CH ₃₎ CH ₂ CH CH ₂ C ₆ H ₅ ^CH 2 ^C 6 ^H IL ^CH 2 O ^{C H} 4 ^-OCH 3

CH _o -CH-OC ₉ H.

6 4 2 5

CH ₂ -C ₆ H ₄ -On-C ₃ H ₇ ^CH 2 ' ^C 6 ^H 4 ^O 4 ^C 4 ^H 9 (ch ₂ ) ₄ -nh ₂ ch ₂ -ch ₂ -s-ch ₃

CH - CH

II II

CH ² -C CH ²

WITH

CH _{(CH3) 2}

H

P

O

O

N

Q

Q

Q

G

N

AND

Q

P

P

O

P

N

CS 276 385 B6

R ¹ HOCC-CH-N- Physical 1 data R ⁴ R ⁵ ch (ch ₃ ) ch ₂ ch ₃ HU] g ⁰ = -7.3 ° (c = 1, _CH3 0H), mp 117 ° C ^CH 2 ^C 6 ^H 5 0 CH ₂ -C ₆ H _n L ch ₂ -c ₆ h ₄ -oc ₂ h ₅ Q ^CH 2 ' ^C 6 ^H 4 ^-On_C 3 ^H 7 q CH ₂ C _s H ₄ -0n-C ₄ H ₉ P ch ₂ ~ ch ₂ -s-ch ₃ G CH - CH fl II CH, -C ² CH \ Z I ’ CH _{(CH3) 2} P ch ₂ -c ₆ h ₅ P • ^CH 2 ^C 6 ^H 11 M ^CH 2 ' ^C 6 ^H 4 ^OCH 3 0 ch ₂ -c ₆ h ₄ -oc ₂ h ₅ D ^CH 2 ” ^C 6 ^H 4 ' ^{On C} 3 ^H 7 0 CH ₂ -C ₆ ^H 4 -O ⁿ -C ₄ H ₉ Q

CH - CH II II CH, -C CH2 ² / S N

CH _{(CH3) 2} N CH (CH ₃ ) CH ₂ CH ₃ P CH ₂ -C 8 ^H 5 Q ^CH 2 ^C 6 ^H 11 N ^^ ^ 2 ^_ 4 ^_ θ6 ^θ η- ^ 4 ^ 9 0

CS 276 385 B6

R ¹

HOOC-CH-Physical data

R ⁴ R ⁵

CH - CH

II II

CH ² -C CH ²

CHCCHjlCHjCH ^ CH _(CH3) CH ₂ CH ₃ ^'C 2 ^C 6 ^H n

CH ₂ -c ₆ H _n

AND

O

Q

Example 87

1- [N- (1S) -carboxybutyl) -S-alanyl] - (octahydrocyclopentatt (1-pyrrole) -2-carboxylic acid) mg (0.17 mmol) of carboxylic acid (Example 90d) was stirred into 2 ml of 4N aqueous hydroxide solution The solution was transferred to a strongly acidic ion exchanger and eluted with a 2% aqueous pyridine solution to give a yield of 39 mg.

MS: (DCI) 327 (M ^& lt ^; + &^gt; +1).

Other compounds of formula II can be synthesized in an analogous manner to those described in Examples 90 and 91

r ³ ooc - ch - N-C-CH i ”i H - N - CH (CH 2) -R 11; AND ⁰ R ⁴ * 5 R R ¹ COOR ^

in which n is the number 2, r! represents a methyl group,

R is ethyl and

R ³ 'represents a hydrogen atom, wherein R and part of the molecule of the formula R ^{3 have} OOC-CH-N-

R ⁴ R ^{5 the} meanings given in the tables below.

EN 276 385 86

R HOOC-CH-N- 11 R ⁴ R; CHj AND -ch ₂ ck ₂ ch ₃ AND - (ch ₂ ) ₉ -ch ₃ C 2-Naphthyl 0 4-biphenylyl AND - (ch ₂ ) ₁₃ -ch ₃ AND R HOOC-CH-N- 1 R ⁴ R ⁵ ch ₃ (B) -CH ₂ CK ₂ CH ₃ 8 - (CH _{2) g} -CH ₃ θ 2-naphthyl F 4-bifsnylyl C - (ch ₂ ) ₁₃ -ch ₃ (B) R HCOC-CH-N- R ⁴ R ⁵ ch ₃ C -ch ₂ ch ₂ ch ₃ C - (ck,) ₉ -ch ₃ G- 2-Naphthyl G 4-biphenylyl D - (ch ₂ ) ₁₃ -ch ₃ C

CS 276 385 B6

R HOOC-CH-N- 1 R ⁴ R ⁵ CHj 0 -ch ₂ ch ₂ ch ₃ 0 - <ch ₂ ) ₉ -ch ₃ H 2-Naphthyl H 4-biphenylyl H - (ch ₂ ) ₁₃ -ch ₃ D R HOOC-CH-N- R ⁴ R ⁵ CHj G -ch ₂ ch ₂ ch ₃ G - (ch ₂ ) ₉ -ch ₃ TO 2-Naphthyl AND 4-biphenylyl L - (CH ₂ ) ₁₃ -CH ₃ G R HOGC-CH-N- II R ⁴ R ⁵ ch ₃ H -CH ₂ CH ₂ CH ₃ H - (CH ₂ ) ₉ -CH ₃ N 2-Naphthyl M 4-biphenylyl N ^(CH 2 ⁾ 13 ' ^CH 3 N

EN 276 385 86

R HOOC-CH-N- 1 1 R ⁴ R ⁵ CHj N -ch ₂ ch ₂ ch ₃ N - (CH _{2) g} -CH ₃ 0 2-Naphthyl N 4-biphenylyl P ^(CH 2 ⁾ 13 ' ^CH 3 0 R HOOC-CH-N- i i 1 1 R ⁴ R ⁵ CHj Q -CH ₂ CH ₂ CH ₃ Q -CCH ₂ ) ₉ -CH ₃ P 4-biphenylyl Q - (CHPii-CH 3 P R HOOC-CH-N- physical 1 1 R ⁴ R ⁵ data Cl-ij P -ch ₂ ch ₂ ch ₃ P - (ch ₂ ) ₉ -ch ₃ Q 4-biphenylyl G - (ch ₂ ) ₁₃ -ch ₃ Q 4-biphenylyl H

EN 276 385 86

Also in an analogous manner to the compound of formula (II) as described in Example 87, the following may be prepared.

E ^J OCC-CH-N - C - u ⁰ CH - N - CH (CH3) - Ei 14 n (II) »4 E ⁴ | _c E ^J É ¹ 1 2 COCw R ¹ R ² R ³ HOOC-CH-N- physical data

i (ch ₂ ) _1q ch ₃ ch ₇ c ₂ h ₅ (CH ₂ ) ₁₀ CH ₃ ^ch 2 ^C 6 ^H 5 less polar diastereomer = +0) 5 ° (c = 1, CH ₃ OH);

MS (DCI) 481 (M ⁺ +1) more polar diastereomer [?] ²⁰ = -22.5 ° (c = 1, CH ₃ OH); MS (DCI) 481 (M ⁺ +1) [α] D = + 52.9 ° (c = 1, CH 3 OH);

MS (DCI) 529 (M ⁺ l) i CH (CH _{3) 2} CH ₃

C ₂ H ₅ ^ch 2 ^C 6 ^H 5 ⁰ diastereomers [ ²⁰ = -29.8 ° (C = 1, CH ₃₀ OH);

MS (DCI) 459 (M ⁺ +1) = -0.6 ° (c = 1, CH 3 OH); MS (DCI) 459 (M @ ⁺ +1)

Cll ₃ Cll ₃ c ₂ h ₃

CH 2 C, H _r 26;

MS (DCI): 499 (M ⁺⁺ 1) for both diastereomers ^{2 CH} 3 CH ₃ C ₂ H _s h

C _s H ₅ CH ₂ C _s H ₄ -0-nC ₃ H ₇ H ^H C ^ less polar diastereomer [C6] = 40.8 g of DEG (c = 1, CHjOH) "polar diastereomer [<C] ^2Q = -4.5 ° (c = 1, CH ₃ OH)

H, m.p. High: 34 ° C

MS (DCI): 605 (M ⁺ +1) ^C 6 ^H 5 ^CH 2 ^C 6 ^H 4 ° ^C 3 ^H 7 [α] ²⁰ = + 32.0 ° (c = 1, CH ₂ Cl ₂ ) mp 120-127 ° C

EN 276 385 86

R ¹

R ² R ⁵ H00C-CH-N- Physical data

R ⁴ R ⁵

2 ^C 6 ^H 5 CH ₂ -C _^H5 H H H [ΰθ] θ ° = + 32.6 ° (c = 1, CH ₂ Cl ₂ ) tt 145 ^Q C (decomposition) 2 ^C 6 ^H 5 CH ₂ CH (CH ₃ ) ₂ H H H mp 156 ° C (decomposition) another diastereomer: mp 137 ° C (decomposition), [?] ²⁰ = + 3.9 ° (c = 1 CH 3 OH) 2 ^C 6 ^H 5 CH (CH ₃ ) -C ₂ H ₅ H H H mp 127 ° C (dec.); MS (OCI): 485 (M @ ⁺ +1)

nC ^ Hg CH ₃ c ₂ h ₅ ch ₂ -c ₆ h ₅ D nC ₄ Hg CH ₃ c ₂ h ₅ HH nC ₄ Hg CH ₃ less polar diastereomer [£ 1d ° ^{= _51} > ^é ° ^(c = ^ch 3 ^{0h )} more polar diastereomer [<- -26.8 ° (c = 1, CH 3 OH) less polar diastereomer []] g ⁰ = + 6.9 ° (c = 1, CH 3 OH) more polar diastereomer [ώ] θ ° = ⁺ M ° (c = 1, CH 3 OH); MS (OCI): 597 (M + +1)

1. diastereomer = + 10.4 ° (c = 1, CH 3 OH)

2. diastereomer m.p. Mp 104-108 ° C

Comparative Example 1

1) 2- (S-alanyl) - (1S, 3S, 55) -2-azabicyclo-3,3,10-octane-3-carboxylic acid benzyl ester trifluoroacetate 1a) 2- (N-tert-Butyloxycarbonyl-S-alanyl) benzyl ester - ( 1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid

61.5 g (0.251 mol) of (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, 47.5 g (0.251 mol) of BOC-L-alanine and 173 ml (1 (26 mol) of absolute triethylamine is dissolved in 1,025 ml of absolute dimethylformamide, a 50¾ solution of propanephosphonic anhydride in dichloromethane is added thereto at -5 ° C (dropwise), and the reaction mixture is further stirred at -5 ° for 30 minutes. C and 4 hours at room temperature. The reaction solution was then partitioned between water and ethyl acetate, the aqueous phase was extracted once more with ethyl acetate, the combined organic phases were washed with saturated sodium bicarbonate solution, 10% citric acid solution, water and saturated sodium chloride solution, dried and concentrated. Yield: 93.2 g (89% of theory) of an oily product.

1b) 2- (S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester trifluoroacetate

93.2 g (0.224 mol) of the BOC derivative from Comparative Example 1a) was poured at 0 ° C with 235 ml of absolute trifluoroacetic acid and stirred at 0 ° C for 2.5 hours. The excess acid is evaporated under reduced pressure at 25 ° C and the residue is crystallized from 1000 ml of absolute diisopropyl ether.

Yield: 82.6 g (86% of theory).

M.p. 148-150 ° C.

Comparative Example 2

(2) (15,3S, 5S) -2-Azabickylo [3.3.0] octane-3-carboxylic acid n-octyl ester

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

To a solution of 40.0 g (0.163 mol) of (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester and 23.4 ml (0.169 mol) of absolute triethylamine in 300 ml of absolute of methylene chloride, a solution of 39.2 g (0.180 mol) of di-tert. butyldicarbonate in 60 ml of absolute methylene chloride, and the reaction mixture was further stirred at 0 ° C for 15 minutes and at room temperature for 1 hour. The reaction solution was then washed with 10% citric acid solution, saturated sodium bicarbonate solution and water, dried and evaporated.

Yield: 55.6 g of an oily product.

[α] D ⁵ = 1.2 ° (c = 2, methanol).

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

55.6 g (0.161 mol) of the benzyl ester of Comparative Example 2a) is hydrogenated in 2 liters of ethanol at room temperature in the presence of 4 g of palladium on carbon (10%) for a period of time.

2.5 hours. The catalyst is filtered off and the filtrate is concentrated.

Yield: 37.3 g (90% of theory).

[.alpha.] D @ ²⁵ = + 22.7 DEG (c = 1; methanol).

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

32.3 g (0.127 mol) of the acid of Comparative Example 2b) and 25.3 g (0.253 mol) of potassium hydrogen carbonate are stirred in 500 ml of dimethylformamide for 1.5 hours at 40 ° C. After cooling, 1-bromooctane (48.9 g, 0.253 mol) was added dropwise and the reaction mixture was stirred at room temperature overnight. 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 in two portions by flash chromatography on silica gel ( 900 g, solvent system: 95: 5 or 99.5: 0.5 toluene / ethanol).

Yield: 35.4 g (76% of theory) of the oily product.

[.Alpha.] D @ ²⁵ = + 5.7 DEG (c = 1, methanol).

The following compounds were prepared in an analogous manner:

CS 276 385 2-tert-Butyloxycarbonyl- (1RS, 3RS, 5RS) -2-azabicyclo [3.3.1] -7-octene-3-carboxylic acid 6-octyl ester;

N-tert-butyloxycarbonyl-S-proline n-octyl ester.

2d) (1S, 3S, 5S) -2-Azabicyclol-3,3,0] octane-3-carboxylic acid n-octyl ester

2.6 g (7.0 mol) of the 80C-derivative of Comparative Example 2c) are stirred at 0 ° C with 9 ml of trifluoroacetic acid for 1.5 hours. The excess acid is evaporated under reduced pressure, the residue is taken up in water, basified with sodium bicarbonate, extracted with ethyl acetate, the organic phase is washed once more with water, dried, concentrated and the product obtained is reacted quickly.

Yield: 1.8 g (95% of theory) of an oily product.

The following compounds were obtained in an analogous manner: (1RS, 3RS, 5RS) -2-Azabicyclo [3.3.0} -7-octene-3-carboxylic acid n-octyl ester; n-octyl ester of S-proline.

Comparative example

3) methanesulfonic acid (3-octynyl) ester

To a solution of 3-octin-1-ol (7.56 g, 60 mmol) and triethylamine (12.45 mL, 90 mmol) in methylene chloride (225 mL) at 10 ° C was added dropwise 7.47 g (65 mmol) of chloride over 30 minutes. of methanesulfonic acid and the reaction mixture is further stirred for 1 hour. The reaction solution was washed with water, saturated sodium bicarbonate solution and again with water, dried and concentrated.

Yield: 11.9 g (97% of theory) of the oily product.

Example 88. 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- of carboxylic acid (Ramipril) and 0.50 g (5 mmol) of potassium bicarbonate were stirred in 25 ml of dimethylformamide at 40 ° C for 1.5 hours, after cooling to room temperature a solution of 1.16 g (6 mmol) of 1- of bromooctane in 20 ml of dimethyl formamide and the reaction mixture is stirred overnight at room temperature. The pH is adjusted to 6 by addition of 0.1N hydrochloric acid solution, diluted with water, extracted three times with methylene chloride and the combined organic phases are dried, concentrated and purified by column chromatography on 120 g of silica gel using toluene / ethanol 95: 5 as eluent. . Yield: 2.35 g (89% of theory) of the oily product.

[Α] D = -23.9 ° (c = 1, methanol).

Example 89

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

528 mg (1 mmol) of the amine obtained according to Example 92 were dissolved in 20 ml of ether and a solution of 116 mg (1 mmol) of maleic acid in 4 ml of acetone was added. The solvent was evaporated and the residue was crystallized from diisopropyl ether.

CS 276 385 B6

Yield: 0.51 g (79% of theory) of colorless crystals.

Melting point: 89-90 ° C.

Example 90

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, ethoxycarbonyl-3-phenylpropyl) ester, 2-octenyl) hydrogen maleate

35.55) -2-azabicyclo [3.3.0] octane-3-carboxylic acid

2.08 g (5 mmol) of 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3- of carboxylic acid (Ramipril) and 1.00 g (10 mmol) of potassium bicarbonate are stirred in 25 ml of dimethylformamide at 40 ° C for 1.5 hours, then the reaction mixture is cooled to 0 ° C and a solution of 2.3 is added dropwise. g (12 mmol) of N-bromo-2-octene in 20 ml of dimethylformamide. The reaction solution is stirred at 0 ° C for 4 hours, then poured onto 500 ml of water, extracted three times with ethyl acetate, the combined extracts are washed twice with saturated sodium bicarbonate solution and washed three times with water, then dried, concentrated and the crude product is dried. Purification by flash chromatography on 125 g silica gel using cyclohexane / ethyl acetate (8: 2, 1: 1) as solvent. The crude product yield was 3.4 g, while the pure product yield was 1.93 g (73%). An oily product is obtained, which is converted to the hydrogen maleate analogously to Example 93.

Yield: 2.0 g of colorless crystals, m.p. 81-84 ° C.

Example 91

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-3- (1S, ethoxycarbonyl-3-phenylpropyl) ester, hydrogen maleate (3-octinyl) ester

35.55) -2-azabicyclo [3.3.0] octane-3-carboxylic acid

4.9 g (11.8 mmol) of 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- Of 3-carboxylic acid (Ramipril) and 2.4 g (23.6 mmol) of potassium hydrogen carbonate were stirred in 90 ml of dimethylformamide at 40 ° C for 2 hours. A solution of 2.41 g (11.8 mmol) of the mexylate of Comparative Example 3 in 30 ml of dimethylformamide is then added and the reaction mixture is stirred for a further 9 hours at 40 ° C. The reaction solution is diluted with 250 ml of water, extracted three times with ethyl acetate, the combined organic phases are washed with saturated sodium bicarbonate solution and water, dried, concentrated and the crude product (5.6 g) is purified by chromatography on 200 g of silica gel using toluene and ethanol in a ratio of 99: 1 as eluent. 3.45 g (56% of theory) of an oily product are obtained, from which 1.3 g are converted in analogy to Example 93 to hydrogen maleate. Yield: 0.8 g of colorless crystals.

Melting point 68-70 ° C.

Example 92

2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] ethyl ester hydrogen maleate - (1S,

35.55) -2-azabicyclo [3.3.03 octane-3-carboxylic acid

1.43 g (2.8 mmol) of the carboxylic acid of Example 102 was stirred in 25 ml of ethanolic hydrogen chloride at room temperature. After five days, an additional 25 ml of ethanolic hydrogen chloride is added, the mixture is stirred overnight, concentrated, the residue is taken up in ethyl acetate, washed three times with saturated sodium bicarbonate solution and once with water, dried, concentrated and the crude product (1.16). g) was purified by flash chromatography on 80 g of silica gel using a 99: 1 mixture of toluene and ethanol as the solvent system. 0.62 g (42%) of an oily product is obtained, which is converted in analogy to Example 93 to the hydrogen maleate.

Yield: 0.50 g of colorless crystals.

Mp 84-86 ° C.

CS 276 385 B6

Example 93

(5-Nonyl-2- [thi- (1S-ethoxycarbonyl-3-phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid hydrogen maleate

To a solution of 1.97 g (7.5 mmol) of triphenylphosphine and 0.72 g (5 mmol) of 5-nonanol in 100 ml of absolute tetrahydrofuran at 0 ° C was added dropwise a solution of 1.31 g (7.5 mmol) of azadicarboxylic acid diethyl ester. of acid in 10 ml of absolute tetrahydrofuran, the reaction mixture is further stirred for 10 minutes and then a solution of 2.08 g (5 mmol) of 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] is added at 0 ° C. 1 - (1S, 3S, 5S) -2-azabickylo [3.3.0] octane-3-carboxylic acid (Ramipril) in 25 mL of absolute tetrahydrofuran and stirred at 0 ° C for 1 hour and then at room temperature overnight room temperature. The reaction solution was concentrated, the residue was taken up in ethyl acetate, washed twice with 2N sodium hydroxide solution and once with water, dried, concentrated and the crude product (5.0 g) was purified by flash chromatography on silica gel (200 g) by flash chromatography. (b) a mixture of toluene and ethanol (99: 1); and (b) a mixture of methylene chloride and ethyl acetate (9: 1) as the solvent system. The product so obtained (1.74 g, 64% of theory) was converted to the hydrogen maleate in an analogous manner to that described in Example 93.

Yield: 1.6 g (49% of theory).

Melting point 103-105 ° C.

Example 94

2- [N- (1S-Menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 55) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester

A solution of 0.59 g (3 mmol) of benzophenone hydrazone in 12 ml of ether was added dropwise at room temperature to a suspension of 2.95 g of nickel peroxide hydrate in 12 [mu] l ether, the mixture was further stirred for 1 hour. thicken. The thus obtained 3 mmol of diphenyldiazomethane is dissolved in 32 ml of absolute acetone, and the solution obtained is added dropwise to a solution of 1.31 g (2.5 mmol) of 2- [N- (1S-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] under ice-cooling. 1 - (15,3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (cf. Example 128) in 32 mL absolute acetene. The reaction mixture was further stirred at room temperature for 38 hours, concentrated and the crude product was purified by column chromatography on silica gel using toluene / ethanol (99.5: 0.5) or cyclohexane / ethyl acetate (8: 2) as solvent. system.

Yield: 1.63 g (95 L of theory) of an oil.

[.alpha.] D @ ³ = -57.9 DEG (c = 1, methanol).

Example 95

Tert-Butylammonium [2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-a-lanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octyne-3-carboxylate

5.45 g (9.2 mmol) of the benzyl ester of Example 101 was hydrogenated in 300 mL of ethanol at room temperature to 1 g of palladium on carbon (10¾) for 20 minutes. After filtering off the catalyst and concentrating, 4.1 g (89%) of 2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo are obtained. [3,3,10] octane-3-carboxylic acid.

1.3 g of this acid in ethanol are mixed with 190 mg of tert-butylamine, the solvent is evaporated off and the residue is crystallized from diisopropyl ether.

Yield: 1.27 g (86% of theory) of colorless crystals.

M.p .: 141-143 ° C.

CS 276 385 B6

Example 96 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 the ethyl ester of Example 92 was dissolved in 18 ml of tetrahydrofuran, 7.5 ml of 1 N sodium hydroxide solution were added thereto, and the mixture was stirred at room temperature for 48 hours. The reaction mixture was neutralized by the addition of 7.5 ml of 1N hydrochloric acid. The reaction mixture is concentrated, the residue is suspended in water, extracted twice with ethyl acetate, the combined organic phases are washed with saturated sodium chloride solution, dried, concentrated and the crude product (2.05 g) is purified by chromatography on silica gel with toluene and ethanol, 9: 1. The product thus obtained (1.15 g;

% of theory) is triturated in 50 ml of petroleum ether, left to stand in the cold, filtered and dried.

Yield: 0.83 g of colorless crystals, m.p. 56-61 ° C.

In addition, using the appropriate starting materials and following the procedures described in Examples 88 to 96, the following compounds of the invention were obtained:

Example 97 2- [N- (1S-Ethoxycarbonyl-n-heptyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester.

Example 98 2- [h '- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3 n-decyl ester -carboxylic acids;

[α] D = -25.8 ° (c = 1, methanol).

Example 99 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-tetradecyl ester acids;

[Α] D = -19.8 ° (c = 1, methanol).

Example 100

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, ethoxycarbonyl-3-phenylpropyl) ester, hydrogen maleate (2-octinyl) ester

3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid; mp 70-72 ° C.

Example 101 2- [ii- (1S-Isobutyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] n-octyl ester octane-3-carboxylic acid;

[Α] ²⁵ = -23.7 ° (c = 1, methanol).

CS 276 385 Bo

Example 102 2- [N- (1S-n-Octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester acids;

= -18.6 ° (c = 1, methanol).

Example 103 2- [N- (1S-n-Octadecyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (15,3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid π-octyl ester acids;

[.Alpha.] D @ 15 = -15.2 DEG (c = 1, methanol).

Example 104 1 [N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane-2,3'S-pyrrolidine] -5'S-carboxylic acid n-octyl ester.

Example 105

1 * - [N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane-2,3'S-pyrrolidine] -5S-carboxylic acid, n-nonyl ester hydrogen maleate; melting point 110 ° C,

Example 106

1 '- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane-2,3'S-pyrrolidine] -5'S n-decyl ester hydrogen maleate -carboxylic acids; mp 96 ° C.

Example 107 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1R, 3R, 5R) -2-azabicyclo [3.1.1] n-octyl ester

3,0) octane-3-carboxylic acid;

[Α] D ²⁵ = -7.0 ° (c = 1.16, methanol).

Example 108 2- [N- [1S-ethoxycarbonyl-3-phenylpropyl] -R-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid π-octyl ester;

[.alpha.] D @ 20 = + 18.0 DEG (c = 1, methanol).

Example 109 2- [N- (1R-Ethoxycarbonyl-6-phenylpropyl) -R-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid n-octyl ester;

[.Alpha.] D @ 20 = + 9.4 DEG (c = 1, methanol).

Example 110 n-octylter 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [[3,3,3]] -7 -octene-3-carboxylic acids;

[.alpha.] D @ ²⁰ = + 21.2 DEG (c = 1, methanol).

CS 276 385 B6

Example 111 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1R, 3R, 5R) -2-azabicyclo [3.3.0] -7-octen-3- n -yl ester carboxylic acids;

[.Alpha.] D @ ²⁰ = -51.4 DEG (c = 1, methanol).

Example 112

N- [N '- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -S-proline n-octylester maleate;

mp 105-107 ° C.

Example 113

2- [N- (1S-ethoxycarbonyl-n-tridecyl) -S-phenylalanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid;

[.Alpha.] @ ²⁰ = + 27.2 DEG (c = 1, methanol).

Example 114

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

Example 115

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

Example 116

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

[.alpha.] D @ ²⁰ = -28.6 DEG (c = 1, methanol).

Example 117

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

[.alpha.] D @ ²⁰ = -63.2 DEG (c = 1, methanol).

Example 118

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] hydrogen maleate (3,3-diphenyl-n-propyl) ester octane-3-carboxylic acid; mp 122-124 ° C.

Example 119

1'- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane-2,3S-pyrrolidine] -5S- carboxylic acids; mp 121 ° C.

EN 276 385 86

Example 120

Tert-Butylammonium [2- [N- (1S-n-octadecyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylate ]; mp 133-135 ° C.

Example 121

Tert-Butylammonium [2- (6S-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylate]; mp 164-167 ° C.

Example 122 2-N - (1-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester mmol n S-alanyl- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octyl ester, together with 10 mmol of 3-benzoylacrylic acid ester and 10 mmol of triethylamine, are dissolved in 100 ml of anhydrous ethanol and the reaction mixture is stirred at 20-25 ° C for 24 hours. The reaction mixture was neutralized with 1N hydrochloric acid, evaporated to dryness and the residue was taken up in ethyl acetate / water. The ethyl acetate phase was dried and evaporated.

The oily crude product thus obtained is dissolved in 100 ml of ethyl acetate and hydrogenated at 0.3 MPa at room temperature in the presence of 5% palladium on carbon catalyst.

Claims (3)

PATENT CLAIMS 1 2 X and X together represent oxo and 3 4 X and X represent each hydrogen atom, in the presence of a base in an organic solvent at a temperature between -10 ° C and the boiling point of the reaction mixture, whereupon any intermediate intermediates which are formed, such as Schiff's bases, are reduced, protecting groups temporarily introduced to protect the reactive groups. If desired, the compounds of formula II having a free carboxyl group or free carboxyl groups are esterified and the resulting compounds are optionally converted into their physiologically tolerable salts. A process for the preparation of compounds having a nootropic effect of the general formula II O R, 1 COOR '(II) in which AND. denotes 1 or 2, denotes an alkyl group having from 1 to 15 carbon atoms, a cyclohexyl group, a cyclohexylmethyl group, an aryl group having 6 to 12 carbon atoms or an arylmethyl group having 6 to 12 carbon atoms in the aryl moiety; leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, O-alkyltyrosine having up to 4 carbon atoms in the alkyl moiety, ornithine, methionine or 2-thienylalanine, CS 276 385 B6 O R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, a tolyl group having a mono- or diphenylalkyl having 1 to 2 carbon atoms in the alkyl moiety or a menthyl group, R ⁵ is hydrogen, C 1 -C 18 alkyl, octenyl, octinyl, C 5 -C 6 cycloalkyl, C 6 -C 12 aryl optionally substituted by methyl or halogen, a mono- or diphenylalkyl group having 1 to 8 carbon atoms in the alkyl moiety wherein the phenyl moiety is optionally substituted by halogen or is a menthyl group, R 1 and R 2 together with the atoms to which they are attached represent a residue of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 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, l ^{E, 9]} decane, decahydrocyclohepta [b] pyrrole, hexahydrocyklopropafb] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, 2,3,3a, 4,5,7a-hexahydro , pyrrolidine, 1,2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole, indoline, or physiologically tolerable salts thereof. IX with the exception of compounds of formula (II) and salts thereof, in which n is simultaneously 1 or 2, R represents an alkyl group having 1 to 8 carbon atoms, a cyclohexyl group or an aryl group having 6 to 12 carbon atoms, R ¹ represents a C 1 -C 4 alkyl group, a cyclohexylmethyl group, a phenylmethyl group, the phenyl being optionally substituted with a C 1 -C 4 alkoxy group or, if not included in the above definitions, an optionally protected side chain of a naturally occurring cC -amino acid of formula R 1 -CH (NH ₂₎ -COOH, 2. A process according to claim 1, wherein the corresponding compounds of the formulas III and IV or IVa and IVb are used as starting materials to give compounds of the formula II in which n is 1 or 2, R is C 1 -C 6 alkyl, C 1 -C 15 alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 2-naphthyl, 2-naphthylmethyl, 4-biphenylyl or 4-biphenylmethyl a group; R ¹ represents the side chain of alanine, lysine, leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, C 1 -C 4 -alkyltyrosine, ornithine, methionine or 2-thienylalanine, R is hydrogen, alkyl. C1-C10, octadecyl, cyclopentyl, cyclohexyl, tolyl, benzyl, phenylethyl, benzhydryl or menthyl, R ³ represents a hydrogen atom, a C 1 -C 10 alkyl group, a tetradeoyl group, an octadecyl group, an octenyl group, an octinyl group, or an alkenyl group; cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, phenylpropyl, 3,3-diphenylpropyl, phenyloctyl, tolyl, benzyl, 4,4'-difluorobenzhydryl, 4-fluorophenyl, 4- biphenylyl, 2-naphthyl or menthyl, CS 276 385 B6 R ⁴ and R ⁵ together with the atoms to which these radicals are attached form a radical of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 2-azaspiro [4.5] decane, 2-azaspiro [ 4,4] nonane, spiro [bicyclo [2.2.2] octane] -2,3'-pyrrolidine, 2-azatricyclo [4.3.0.1 &lt; 2,7 &gt;] decane, decahydrocyclohepta [b] pyrrole, hexahydrocyclopropa [b] pyrrole, octahydroisoindole, octahydrocyclopenta [c] pyrrole, spiro (bicyclo [2.2.1] heptane) -2,3-pyrrolidine, 2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1, 2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole, indoline, or a physiologically tolerable salt thereof. 2 4 X and X represent a chemical bond or 2 3 R and R are the same or different and are hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 12 carbon atoms, arylalkyl of 6 to 12 carbon atoms in the aryl moiety and 1 to 4 carbon atoms in the alkyl moiety or (C 5 -C 6) cycloalkyl; 4 5 R and R are as defined in ad I, characterized in that the compound of formula III is reacted R ³ 00C - CH - N - C - CH - NH ² (ΠΙ) in which 13 4 5 R, R, R and R are as defined above, act with a compound of formula IV or a compound of formulas IVa and IVb CS 276 385 B6 CH - X ² CH - COR | | ^(IV) > COOR ² X ⁴ (IVa) (IVb) in which R and R are as defined above and X ³ and X ³ as well as 3. Process according to claim 1 or 2, characterized in that the corresponding compounds of the formulas III and IV or IVa and IVb are used as starting materials to give 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] benzhydryl ester. -L-alanyl] (15,3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid 2- [2 - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L- alanyl] (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid 2- [1 - [(1S) -benzhydryloxycarbonyl-3-phenylpropyl] -yl benzyl ester -L -alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 2-N - (1S-ethoxycarbonyl-3-phenylpropyl) n-octyl ester - S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) n-octyl ester hydrogen maleate -alanyl] - [1S, 3S, 55] -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -hydrogen maleate (5-nonyl) ester -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, benzhydryl 2- [N- (lS-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (lS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, ^e n-octyl 2- [N- (15-carboxy-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, n-decyl ester of 2- [1 '- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, n 2- [li- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octyl ester, n - 2- [1 - (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] -7-octene-3-carboxylic acid octyl ester, 2- [N- (1S-ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.1] benzyl ester O] octane-3-carboxylic acid and 2- [li- (1R-ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- 3-carboxylic acids.