CS276179B6 - Process for preparing compounds with nootropic activity - 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

BACKGROUND OF THE INVENTION The present invention relates to a process for the preparation of compounds having nootropic activity, as well as their salts, which are physiologically useful. In particular, the invention relates to the use of an angiotensin converting enzyme inhibitor (ACE-inhibitor) or a physiologically acceptable salt thereof as a medicament having a nootropic (i.e., memory-enhancing) effect. The compounds produced are used to produce the respective pharmaceutical preparations.

The present invention relates to new compounds of the general formula II R ³ 00C-NC-CH-CH-NH-CH (CH) - R (II), and ₄ i; ki

R ⁴ r 'R ^and C00R ₂ in which

I.

n is 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 represents 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, an alkyl group having 1 to 18 carbon atoms, a cycloalkyl group having 5 to 6 carbon atoms, a tolyl group, a mono- or diphenylalkyl group having 1 to 2 carbon atoms in the alkyl moiety or a methyl 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, the phenyl residue being optionally substituted by halogen, or a methyl group,

5

R and R together with the atoms to which they are attached represent a residue of tetrahydroisoquinoline. decahydroisoquinoline, octahydroindole, 2-azabicyclo, 3, ioctane, 2-azaspiro [4.5] decane, 2-azaspiro [1,4] nonane, spiro (bicyclo [2.2.1] heptane) -2,3'-pyrrolidine, spiro (bicyclo [2.2.2] octane-2,3'-pyrrolidine, 2-azatricyclo [4.3.0.1 < 2,7 >] decane, decahydrocycloheptaphylpyrrole, hexahydrocyclopropa [b] pyrrole, octahydroisoindole, octahydrocyclopentylpyrrole,

2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole, indoline, or their physiologically tolerable salts,

CS 276179 Βδ

II.

with the exception of compounds of formula II and their salts, in which n: simultaneously denotes 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; is C1-C4alkyl, cyclohexylmethyl, phenylmethyl, the phenyl being optionally substituted with C1-C4 alkoxy or, if not included in the above definitions, optionally protected naturally occurring side chain. - amino acids of the formula r ¹ -ch (nh ₂ ) -cooh,

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 ^ and R ^ are as defined in ad I.

Preference is given to the preparation of compounds of formula II in which n is 1 or 2, is C1 -C6 alkyl, C1 -C6 alkyl, cyclohexyl, cyclohexylmethyl, phenyl, benzyl 2-naphthyl, 2-naphthylmethyl, 4-biphenylyl or 4-biphenylmethyl means the side chain of alanine, lysine, leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, C 1 -C 4 alkyltyrosine ornithine, methionine or 2-thienylalanine, represents a hydrogen atom, an alkyl group of 1 to 10 carbon atoms, an octadecyl group, a cyclopentyl group, a cyclohexyl group, a tolyl group, a benzyl group, a phenylthyl group, a benzhydryl group or a menthyl group. , alkyl. (C 10-C 10) group, tetradecyl, octadecyl, octeryl, ectinyl, cyclopentyl, cyclohexyl, phenyl, benzyl, phenylethyl, phenylpropyl, 3,3-diphenylpropyl, phenyloctyl, tolyl a benzhydryl group, a 4,4-difluorobenzhydryl group, an N-fluorophenyl group, a 4-biphenyl group, a 2-naphthyl group or a menthyl group,

5 __ _ -

R and R together with the atoms to which they are attached form a residue of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 2-azaspirof 4,5] decane, 2-azaspiro-4 4] nonane, spiro (bicyclo [2.2.2] ok3

CS 276179 Bg tan) -2,3-pyrrolidine, 2-azatricyclophyl, 3,0, 11'-dececane, decahydrocyclohepta [b] pyrrole, hexahydrocyclopropa [b] -pyrrole, octahydroisoindole, octahydrocyclopenta (clpyrole, spiro (bicyclo £ 2)) (2, 1] Heptane) -2,3-pyrrolidine, E, 2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2,3,3a, 4,6a-hexahydrocyclopentaflpyrrole, indoline, or their physiologically compatible salts.

More particularly, the present invention provides a process for the preparation of 2- [n - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, 2- [2 - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octadecyl ester, 2-IFN- C (1S) -Benzhydryloxycarbonyl-3-phenylpropyl-1-L-alanyl-4- (1S, 3S, 5S) -2-azabicyclo [2,3.0] octane-3-carboxylic acid, 2- (N- (1S-) - ethoxycarbonyl-3-phenylpropyl) -S-alanyl-1- (1S, 3S, 5S-2-azabicyclo [3.3.1] octane-3-carboxylic acid, 2- [n- (1S-ethoxycarbonyl) n-octyl ester hydrogen maleate) 3-Phenylpropyl) -S-alanyl-4- (1S, 3S, 5S) -2-azabicyclo (3,3,0) -octane-3-carboxylic acid 2- (N- (1S) -alkyl maleate (5-nonyl) ester) ethoxycarbonyl-3-phenylpropyl) -S-alanylJ- (1S, 3S, 5S) -2-azabicyclo (3,3,0j _{octane-7-carboxylic} acid 3, benzhydryl 2 - (Ti- (lS-menthyloxykarbony1-3- phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo (3,3,10-octane-3-carbo) xylic acid, 2- [N- (1S-carboxy-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabieyclo [3.3.0]] octane-3-carboxylic acid n-octyl ester 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, n-octyl, n-decyl ester 2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl) - (1S, 35,5S) -2-azabicyclo-β, 3,0-octane-3-carboxylic acid, n-octyl ester 2- N - (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-4- (1S, 3S, 5S) -2-azabicyclo-3,3,10-7-octene-3-carboxylic acid benzyl ester 2- [n- (1S-ethoxycarbonyl-n-tridecyl) -S-alanyl-1- (1S, 3S, 5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid and 2- [n- (1R-ethoxycarbonyl) -n- tridecyl) -S-anynyl] - (1S, 3S, 5S) -2-azabicyclo [2,3- b] octane-3-carboxylic acid.

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

li pyrrolidine group (0), tetrahydroisoquinoline group (A), decahydroisoquinoline group (8), octahydroindole group (C), indoline group (Q), octahydrocyclopenta [b] pyrrole group (D), 2-azaspiro [li, 5] decane group (E), 2-azaspiro | 4,

4] nonano group (F), spirof (bicyclo £ 2.2, 1] heptane) -2,3'-pyrrolidine group (G), spiro f (bicyclo (2,2,2 octane) -2,3-pyrrolidinone) - (H), 2-azatricyclo [4.3.0.1 < >] decane (I), decahydrocyclohepta (b) pyrrole (J), octahydroisoindole (K), octahydrocyclopentafc] -pyrrole (L), 2,3,3a, 4,5,7a-hexahydroindole (M), 2-azabicyclo [3.1.1.0] hexane (N), 1,2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole group (P).

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

Possible heterocyclic ring systems have the following structural formulas:

(A) (B)

(E) (F)

C5 276179 B6

COOR ³ (L) (M)

N

(P)

--COOR ', 3

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 acceptable amines or salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid 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, 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, lipid solubility is much more important for 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) by 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 such as a Schiff base. the protecting groups introduced temporarily to protect the reactive groups are cleaved, 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 reacting a compound of formula (III).

R ³ OOC - CH - N - Al 1

R ⁴ R ³ (III) in which it represents

i) hydrogen ii) a group -CO-CH-i ¹ γΙ or iii) a group -CO-C = O, and

L

R ⁴ , R ⁴ and R ⁴ have the meanings given above, with compounds of formula IV

C- (CH_) -R Zn (IV),

COOR wherein in i) B ^ is HOOC-CH-NHB is hydrogen,

In the case of ii) B is Y and B is hydrogen or

2 in the case of iii) B and B 'together mean Q,

2 n, R, R and R are as defined above,

2

Y is amino and Y is a leaving group or vice versa and

is amino + hydrogen and Q is oxo or vice versa, in an organic solvent at a temperature between -20 ° C and the boiling point of the reaction mixture, wherein in the case of i) a coupling aid is present and in iii) the reaction is optionally carried out in water and / or optionally in the presence of a reducing agent, whereupon optionally intermediate unsaturated compounds such as Schiff bases are reduced, the protecting groups temporarily introduced to protect the reactive groups are cleaved, the compounds of formula II with a free carboxyl group or free carboxyl groups are optionally esterified and the compounds obtained are optionally converted into their physiologically tolerated salts.

For example, compounds of formula V may be reacted in this manner

R is GOC-CH-N-H

14,

R ⁴ R ⁵ in which

6 5 ^y

R, R and R R are as defined above, (V), with compounds of formula VI

HOOC-CH-NH-CH- (CH 2) -R 12 n (VI),

R ¹ COOR ² in which

2

R; R, R and n are as defined above

The reaction of these compounds can be carried out, for example, analogously to known methods of coupling peptides in an organic solvent such as dimethylformamide, methylene chloride, dimethylamide in the presence of co-coupling agents such as carbodiimides (e.g. dicyclohexylcarbodiimide), diphenylphosphoryl azide, alkanephosphoric anhydride N-siccinimidyl carbonate in a solvent such as methyl cyanide. The amino groups in the compounds of formula (V) may be activated with tetraethyldiphosphite. Compounds of formula (VI) can be converted to activated esters (e.g., 1-hydroxybenzotriazole), mixed anhydrides (e.g., chloroformic acid esters), azides or carbodiimide derivatives and thereby activated (cf. Schroder, Liibke, The Peptides, Vol. 1). , New York 1965, pp. 76-156). The reaction is preferably carried out at temperatures between -20 ° C and the boiling point of the reaction mixture.

The compounds of formula (VII) can also be reacted with one another

R ³ 00C-CH-N

C-CH-Y ¹ (VII) wherein

4 5

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

Y ² -CH- (CH ² ) -R 1 'COOR (VIII) in which R, R ^{2 and} an are as defined above, and bu3 v ¹ means amino and - - - Y ² means a leaving group, - or . - , 2 - Y means amino and '1 - Y - means a leaving group.

CS 276179 86

Suitable leaving groups are, for example, chlorine, bromine, iodine, alkylsulfonyloxy or arylsulfonyloxy.

The alkylation of this type is conveniently carried out in water or in an organic solvent such as a lower aliphatic alcohol, for example ethanol, benzyl alcohol, acetonitrile, nitromethane or glycol ether at a temperature between -20 ° C and the boiling point of the reaction mixture in the presence of a base such as alkali metal hydroxide; of an organic amine.

Further, compounds of formula IX can be condensed,

R ³ 006

CH-N-C (IX),

R 'in which

R ¹ , R ⁵ , R 6 and R 6 are as defined above, with compounds of formula C

Q ² = C- (CH ² ) -R 1 ^{2 n} (X)

COOR ² in which 2

R, R and n have the above meanings, and either

Q ¹ is amino + hydrogen; and

Q is oxo, or

Q ¹ is oxo and

Q is amino + hydrogen.

The condensation is conveniently carried out in water or in an organic solvent, such as a lower aliphatic alcohol, at a temperature between -20 ° C and the boiling point of the reaction mixture in the presence of a reducing agent such as NaBH 4 CN to directly obtain compounds of formula I.

However, it is also possible to reduce the Schiff bases or intermediate intermediates after prior isolation to give compounds of formula II, for example by hydrogenation in the presence of a transition metal catalyst.

In the above formulas V ^; to X have the general substituents -R to R 6 and n as defined above under formula II. ______ -

Protective groups that are temporarily introduced to protect non-reactive reactive groups are cleaved off in a manner known per se. (Cf. Schrider, Lubke, cited above, pp. 1-75 and 246-270; Greene, Protective Groups in Organic Synthesis, New York 1981).

CS 276179 Bo

The novel compounds of the formula (II) can also be prepared, for example, using generally 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 Chemie, vol. E5, 1985, pp. 656-773).

a) Reaction of a mono- or dicarboxylic acid of general formula II, wherein at least one of the radicals and R 6 represents a hydrogen atom, with the corresponding alcohol under acid catalysis (mineral acid or acidic ion exchanger).

b) Alkylation of a mono- or dicarboxylic acid of the formula II in which at least 93 days of R and R is a hydrogen atom with a compound of the formula R 2 or R ⁵ Z in which Z is a nucleophilically removable leaving group (such as halogen or a tosylate residue), in a polar protic or dipolar aprotic solvent in the presence of a base such as an alkali metal hydroxide or alkoxide.

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

3 of the radicals R and R represents a hydrogen atom, 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. A modified method of the method described by J. Kopp, Z. Bohdanecký and M.E. Jarvik, describe J. Bures, 0. Buresova and J. 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 nootropically 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 (Piracetam), serves as the comparative compound. The obvious superiority of the compounds of the invention over the comparator is that amnesia induced by scopolamine 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.

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

The invention further includes medicaments comprising said compounds, processes for their preparation, 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 aforementioned diseases. Utilizing the method of the invention can overcome the aforementioned inhibitors of angiotensin-converting enzyme used on mammals such as apes, dogs, kočěách, ^rats: humans etc. Z

1

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, antioxidants, dispersants, emulsifiers, antifoams, flavorants, preservatives, co-solvents or colorants can be used.

For example, the compounds may be administered orally, rectally, or parenterally (e.g., intravenously or subcutaneously), with oral administration being preferred.

For an oral dosage form, the active compounds are admixed with excipients suitable for this purpose as carriers, stabilizers or inert diluents and are converted into dosage forms such as tablets, dragees, push-fit capsules, aqueous alcoholic or oily suspensions or aqueous solutions by conventional methods. 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 1-89 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.

He did

2- [N- (1S) -ethoxycarbonyl-3-phenylpropyl) -S-alanyl] -is-endo-2-azabicyclo [3.3.0] octane-3-S-carboxylic acid octadecyl ester g cis-endo-2 octaecyl ester -azabicyclo-1,3,3-octane-3-carboxylic acid prepared analogously to EP-A-79022 is reacted with 6.7 g of HOBt, 13.8 g of N- (1S) -ethoxycarbonyl-3-phenylpropyl) -S-alanine and 10.2 g of dicyclohexylcarbodide in 200 ml of dimethylformamide. After stirring at room temperature for 3 hours, the precipitated dicyclohexylurea is filtered off, the filtrate is concentrated, the residue is taken up in 1 l of ethyl acetate and the ethyl acetate solution is extracted three times with 500 ml of 5% sodium hydrogen carbonate solution each time. The organic phase is concentrated, the residue is chromatographed on a 1 kg silica gel column using a 2: 1 mixture of ethyl acetate and petroleum ether to give the title compound and the diastereomeric (S, S, R) derivative.

Example 2 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 S-alanyl-2S, 3aR, 7aR-octahydroindole-2 benzyl ester -carboxylic acids (produced according to EP-A-84164) are 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 x 10 ^- m ^), and then 10 mmoles of dodecyl 2-keto-4-phenylbutyric acid. 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 to 25 ° C, the reaction solution is filtered and the solvent is distilled off. The residue was taken up in a mixture of ethyl acetate and 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 3

2-N-2S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl- (15,3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid xsobutyl ester

2.00 g (4.80 mmol) of 2-N-I (1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl-1- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- The 3-carboxylic acids are 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 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: 8: 2 methalene chloride / ethyl acetate).

Yield: 51% of theory as an oil.

Hš

-28.2 ⁰ (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

CS 276179 Βδ of diisopropyl ether.

Hydrochloride:

mp: 123-124 ° C + 17.7 ^° (c = 1, methanol).

Example 4

2- [n - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclop, 3θ] 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-3-carboxylic acid were dissolved in 50 ml of acetone and to this solution under ice cooling, a solution of 1.16 g (5.98 mmol) of diphenyldiazomethane in 50 ml acetonu.Potom r ₀ ztok stirred for 26 hours at room temperature, the solvent The residue is 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.

= -33.8 ⁰ (c-1, methanol).

Example 5 y

2- [N - [(1S) -ethoxycarbonyl-4-phenylpropyl] -1-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid octadecyl ester

2.08 g (5.00 mmol) of 2- [N - ((S) -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 dimethyl formamide, 1.00 g (10.0 mmol) of potassium bicarbonate was added thereto, and the mixture was stirred at 40 ° C for 90 minutes. After cooling to room temperature, a solution of 4.00 g (12.0 mmol) of 1-bromo-octadecane in 20 ml of absolute dimethylformamide was added dropwise and the mixture was stirred at 40 ° C for 4 hours. The solvent was then removed on a rotary evaporator at 1 mmHg and the residue was partitioned between water and methylene chloride. The organic phase is separated, taken up with 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 with toluene / ethanol (99: 1).

[Α] D = -19.6 ^° (c = 1, methanol).

EXAMPLE 6 2- [Κ - [(1S) -Benzhydryloxycarbonyl-3-phenylpropyl] -1-alanyl] - (1S, benzyl) -benzhydryloxycarbonyl ester 3S, 5S) -2-azabicyclo [3.3.1.0] octane-3-carboxylic acid

(a) (2R) -Hydroxy-4-phenylbutyric acid benzhydryl ester

To a solution of 5 -, 40 g (41.1 mmol) - (2R) -hydroxy-4-phenylbutyric acid in 200 ml of absolute acetone under ice-cooling, dropwise a solution of 10.1 g (52.1 mmol) over 20 minutes.

Δδ of diphenyldiazomethane in 400 ml of absolute acetone and the reaction mixture was stirred at room temperature for 20 hours. The solvent was evaporated and the residue was triturated with 100 ml of petroleum ether. 6.4 g of crystalline product are obtained. The mother liquor was evaporated and a further 6.0 g of product was isolated by column chromatography on 700 g of silica gel using toluene / ethanol (99: 1) as eluent.

Total yield: 12.4 g (87% of theory).

Mp 88-89 ° C.

⁰ = -1.8 (c = 5, methanol).

b) 2- (n - [(1S) -Benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester bj ) 1.80 g (4.33 mmol) of 2- (N-tert-butoxycarbonyl-L-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3- benzyl ester The carboxylic acids are dissolved in 4.5 ml of trifluoroacetic acid and stirred at room temperature for 90 minutes. The reaction solution was evaporated and, in order to remove the trifluoroacetic acid esters, three times with toluene on a rotary evaporator. The residue, consisting of 1.90 g of 2- (L-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, is dissolved in 10 ml of absolute methylene chloride (solution A ).

b) 1.63 g (4.71 mmol) of (2R) -hydroxy-4-phenylbutyric acid benzhydryl ester of Example 6a) was dissolved together with 0.4 ml of absolute pyridine in 25 ml of absolute methylene chloride and at -10 ° C. C was added dropwise over 20 minutes 1.41 g (5.00 mmol) of trifluoromethanesulfonic anhydride. The cooling bath was then removed and the solvent was evaporated after reaching room temperature. The residue was filtered through 50 g of silica gel using methylene chloride and the methylene chloride solution was concentrated. 1.70 g of 4-phenyl- (2R) -trifluoromethylsulphonyloxybutyric acid benzhydryl ester is obtained and this product is dissolved in 10 ml of absolute methylene chloride (solution B). b) 1.0 ml (7.40 mmol) of triethylamine was added to solution A and then solution B was slowly added dropwise at 0 ° C. The cooling bath was removed and the reaction solution was stirred at room temperature for 19 hours. washed three times with water, dried over magnesium sulphate and evaporated. The residue was purified by chromatography on 80 g of silica gel using cyclohexylene / ethyl acetate (8: 2 and 7: 3) as eluent. 0.95 g (30% of theory) of the desired product is obtained.

Melting point: 81-85 ° C.

= -55.2 ⁰ (c = 1, methanol).

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

CS 276179 BG

5 5 ^{µ 1} 2 RR CH 3 COOR

Example R 00C-CH ³ N 1 1 R ² ' R ³ physical data

ring system

- ^C 2 ^K 5 ring system 8

- ^C 2 ^H 5

-CH (CH _{3) 2}

-CH ₂ -CH (CH ₃ ) ₂ ring system C

-CH,

-CH.

ring system

-c ₂ h ₅

-CH (C _Fi H _{5) 2}

11 ring system -C ₂ ^H 5 12 circular system 0 -c, h ₅ 13 ring system -c ₂ h ₅ 14 ring system -c ₂ h ₅ 15 Dec ring system - ^C 2 ^H 5 16 ring system “ ^C 2 ^H 5 17 ring system -c ₂ h ₅ 18 ring system F -CHj ⁼ 19 Dec ring system -c ₂ h ₅ 20 May ring system -c ₂ h ₅

- (CH 2 - CH 2

-CH (C ₆ H ₅ ) 2

-CH (CH _{3) 2}

- CH (C ₆ H ₅ ) ₂

R ³ physical data

example R ³ 00C-CH- -N- R ² í 4 R R 21 circular system G -C ₂ ^h 5 22nd circular system H c ₂ h ₅ 23 circular system H ^C 2 ^H 5 24 circular system H ^C 2 ^H 5 25 circular system H ^ 2 ^ 5 26 circular system H c ₂ h ₅ 27 Mar: circular system H C ₂ n ₅ 28 circular system H ^C 2 ^H 5 29 circular system H H 30 circular system H ^C 2 ^H 5 31 circular system H ^C 2 ^H 5 32 circular system AND ch ₃ 33 circular system J c ₂ h ₅ 34 circular system TO - c ₂ h ₅ 35 circular system L ^C 2 ^H 5 36 circular system M ^C 2 ^H 5 37: circular system N c ₂ h ₅

-ch ₂ -ch (ch ₃ ) ₂

O-

- ©

-CH 2 (C ₆ K ₅ ) ₂

- (CH ₂ ) ₄ -CH ₃

-C (CH ₃ ) ₃

- (CH ₂ ) ₂ -CH (CH ₃₎

CH (4-FC ₆ H _{4) 2}

E 276 179 86 Example R ³ OOC-CH-N physical data

Ø ⁴ Ø ⁵ ring system N ring system 0 ring system P ring system Q ring system A c ₂ h ₅ -ch (ch ₃ ) ₂

circular system 8 · ch (ch ₃ ) ₂ circular system C ^CH <W ₂ circular system D CH ₂ - circular system 0 ch ₂ -ch (ch ₃ ) ₂ circular system D CH ₂ -CH (CH ₃ ) ₂

-C _{(CH3) 3}

-H

(c = 1, CH ₃ OH) mp 162-163 ° C

ring system CH ₂ -CH (CH ₃ ) -CH (C _s H _{5) 2} ring system CH (C ₆ H ₅ ) ₂ -C _{(CH3) 3} ring system CH (C H _{NO 5) 2} -H circular system ..-. \ Or3 -CH ₂ ) ₅ -CH ₃

ring system

-CH ₂ -CH (CH ₃ -) 2

CH (4-FC _s H _{4) 2} Physical data Example

R00C-CH-NLI

R ⁴ R ⁵ ring system G ring system 0 ring system H ring system H ring system H ring system H ring system H ring system H ring system H ring system H ring system H ring system I ring system J ring system K ring system L

-CH (C h _{No. 5) 2}

-ClKC.il ,. )

7 Z

-CK ₂ CH (CH ₃ ) ₂

-CK ₂ CK (CH ₃ ) ₂

-CH ₂ CH (CH 3) ₂

-H

-CH (C ₆ ^H 5) ₂

-ch (c ₆ ^h 5) ₂

-ch (c ₆ h ₅ ) ₂

-CH (C H _{NO 5) 2}

-H

-C (CH ₃ ) ₃

- (CH ₂ ) ₅ -CH ₃

Example R OOC-CH-Ni, I,

R ⁴ R ⁵ physical data ring system M - (CH 2) ₂ -CH (CH ₂ ) ₂ -CH ₂ Cl 2 H 2) 6 5 2 ring system N -CH (C, H ₂ ) ₂

-c (ch ₃ ) ₂ -ch ₂ ch ₃ ring system 0

-ch (ch _? ) ₂

-ch (c ₆ h ₅ ) ₂ ring system P

-ch (ch _? ) ₂

-c (ch ₃ ) ₃ ring system Q

-C _{(CH3) 3}

-CH

ring system D ^ 2 ^ 5 menthyl [<= + ²⁷ ° C (c = 1; CH 3 OH) maleate: mp 118-120 ° C ring system G menthyl CH ₂ CgH ₃

R ³ 00C - CH - N - C - / CH - X ^Z

R ⁴ R ⁵

CH, Example R 00C-CH-NR ⁴ R ⁵ ring system 0 ring system 0

-ch (c ₆ h ₅ ) ₂ - (ch ₂ ) ₅ -ch ₃

- ^c HfC ₆ H ₅ ) ₂

-CH (CH _{3) 2}

-ch ₂ sh

-ch ₂ sh

-CH ₂ -S-CO-C (CH ₃ )

-CH ₂ -S-C0-C (CH ₃₎ ³ Example R 00C-CH-N R ³

CH (4-FC ₆ H _{4) from}

AND

C00C ₂ H ₅

-NH-CH (CH _{z) 2}

ring system H example

C00-CH (C ₂ H _{5) 2}

(CH ₃ ) ₂ CH-CH-O-CC ₂ H ₅

CH,

CH,

-ch (c ₆ h ₅ ) ₂

-CH ₂ -CH (CH ₃ ) ₂

-CH (C _s H _{5) 2}

Example R

-CH (C ₆ H ₅ ) ₂ -C (CH ₃ ) ₃

-CH (C ₆ H ₅ ) ₂ -CH (C ₆ H ₅ ) ₂

Example 88

4- [N- (1S) -ethoxycarbonyl-3-phenylpropyl) -S-leucyl] exoppiro (bicyclo [2.2.2] octane-2,3'-pyrrolidine) -5-carboxylic acid

h) N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-leucylbenzyl ester

3.4 g (10 mmol) of 2- (D) -trifluoromethylsulfonyloxy-4-phenylbutyric acid ethyl ester and 5.9 g (15 mmol) of L-leucine benzyl ester oxalate are combined in 50 ml of absolute methylene chloride and after addition of 4.2 ml of triethylamine was stirred at room temperature for 6.5 hours. P _by concentrating the solution, the product was isolated by column chromatography on silica gel using cyclohexane: ethyl acetate 9: 1 as eluent. 3.2 g of a colorless oil are obtained.

1 H-NMR Spectrum:

Δ = 0.95 (d, CH ₃ ), 1.2 (t, CH ₃ ), 1.8 (m, CH ₂ ), 2.6 (m, Cl · 4), 3.3 (m, CH),

4.1 (q, CH ₂ ), 5.1 (s, CH ₂ ), 7.3 (s, CH) ppm.

b) N- (1-S-ethoxycarbonyl-3-phenylpropyl) -S-leucine

3.1 g of the benzyl ester obtained according to a) is hydrogenolytically cleaved by treatment with 500 mg of platinum on carbon (103) in 200 ml of ethanol. After filtering off the catalyst and concentrating the solution, 2.3 g of a colorless carboxylic acid crystalline product having a melting point of 120 DEG-121 DEG C. are obtained.

¹ H-NMR Spectrum: ...

0.9 Cd, CH ₃ ), 1.25- (t, CH ₃ k, 1.8-2.1 tm, CH 3), 2.7 (my CH 3, 3.3 (q, CH) 4.25 (q, CH ₂ ), 7? 2 (s, CH) ppm.

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

2g (6.2 mmol) of N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-leucine and 1.9 g (3.9 mmol) of exo-spiro benzyl ester (bicyclo [2.2.23 octane-2,3- pyrrolidine) -5-carboxylic acid is stirred overnight in 100 ml of dimethylformamide with 4.3 ml of triethylamine and 6.5 ml of n-propylphosphonic anhydride at room temperature. The reaction solution is taken up in ethyl acetate and extracted twice with aqueous sodium bicarbonate solution and then once with aqueous 10% citric acid solution, aqueous saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution. The organic phase is then separated, dried and concentrated. The crude product obtained in a yield of 2.8 g was separated by column chromatography on silica gel using toluene / ethyl acetate (95: 5) as the eluent to give both diastereomers. 1 g of pure product was obtained from each benzyl ester. 1 g of the solid diastereomer is hydrogenated in 40 ml of ethanol in the presence of palladium on carbon. 780 mg of crystalline carboxylic acid of melting point 131 DEG-132 DEG C. are obtained.

= -2.8 ° (c = 1, methanol).

860 mg of the second diastereomer was hydrogenated in 35 ml of ethanol in the presence of palladium on carbon and the yield after filtration of the catalyst and concentration of the solution was 720 mg.

Melting point: The substance is south of 65 ° C.

[.alpha.] D @ 20 = -22.2 DEG (c = 1, methanol).

Example 89

4- [N- (1S) -carboxy-3-phenylpropyl) -S-leucyl] -exo-spiro (bicyclo [2.2.2] octane-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 was then filtered through an ion exchanger (Amberlite R 120) and eluted with a 2% aqueous pyridine solution. Yield: 70 mg.

Θρθ = +3.9 ⁰ (c-1, methanol).

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

CS 276179 Bg

HOOC - CH - N - C - CH - CH - CH ₂ - CH ₂ cooc ₂ h ₅

HOOC-CH-N b

R R

physical data ch (ch ₅ ) ₂ ch (ch ₃ ) ch ₂ ch ₃ ^CH 2 ^C 6 ^H 5

CH ₂ ^-C 6 ^H 4 O (CH ₂ -cyclohexyl) ^CH 2 ^-C 6 ^H 4 ^OCH 3 ^CH 2 ^-C 6 ^H 4 ^OC 2 ^H 5 ^CH 2 ^-C 6 ^H 4 ° ^C 3 ^H 7 ch ₂ -c ₆ h ₄ -oc ₄ h ₉ (CH ₂ ) ₄ -NH ₂ (CH ₂ ) ₃ -NH ₂

CH ₂ -CH ₂ -S CH ₃

CH - CH

CH .CH ^X S C (c = 0.152, CH? OH) CH (CH _{3) 2} nepoláťní diastereomer, mp 132-133 ° C, polar diastereomer I /] ²⁰ = -22.2 ° [c = 1, CH ₃ 0h ] ^CH 2 ^_C 6 ^H 5 nonpolar diastereomer = +16.4 DEG / c = 1, CH ₃ 0h] polar diastereomer = +29.9 DEG {c = CH 0h7

CS 276179 Βδ

HOQC-CH-Physical data

R * R ⁵ ch (ch ₃ ) ₂

ClKCIljíCI ^ C ^ CH ₂ C ₆ ^H 5 ^CH 2 ^C 6 ^H 11 CH ₂ -C ₆ H ₄ -OC ₂ ^H 3 CH -C ₆ ^H 4 -OC ₂ ^H 5 ^CH 2 ^C 6 ^H 4 ^N ° ^C 4 ^H 7 (CH ₂ ) ₄ -nh ₂ (CH ₂ ) ₃ -NH ₂

CH-CH ₂ -S-CH ₃

CH - CH

CH _O C ^CH2 \ S

WITH

(B)

(B)

D

H

C

G

C

C

G

D

(B)

CH _{(CH3) 2}

CH (CH ₃ ) CH ₂ CH ₃ ch ₂ c ₆ h ₅ ^CH 2 ^C 6 ^H 4 ^-0CH 3 ^CH 2 ^C 6 ^H 4 ° ^C 2 ^H 5 ^CH 2 ^C 6 ^H 4 ° ⁿ - ^C 3 ^H 7

AND

Η non-polar diastereomer = -28.6 ° C = 1, CH ₃ 0H] polar diastereomer Hd ° = +25.7 {C = 1, C ^ OH]

MS (FAB) 591 (M &^lt; + &^gt; + 1)

Mp: 53-57 ° C - MS (FAB) 605 (M ⁺ : +1) 25

HOOC-CH-Physical data

CH - CH, -On-C, H, Z 6 4 4 5 (ch ₂ ) ₄ -nh ₂ (ch ₂ ) ₃ -nh ₂ ch ₂ -ch ₂ -s-ch ₃

CH

CH

CH ² -C CH ²

WITH

CH _{(CH3) 2}

CH (CH ₃ ) CH CH ₂ C ₆ h ₅ ^CH 2 ^-C 6 ^H 11

CH ₇ -C ₆ H ₄ -OCH ₃ c ^h 2-c ₆ h ₄ ° C ₂ ^h 5

CH.-CH, -Οη-Γ H., Z o 4 it ^CH 2 ^-C 6 ^H 4 ° ⁿ - ^C 6 ^H 9 (CH ₂ ) ₄ -nh.

(CH _{2) 3} -NH _from

CH ₂ -CH ₂ -S-CH ₃

CH - CH o

CH-C-CH ² 's

ch (ch ₃ ) ₂

I 4 15 R D

G

G

H

H

D

D

O

E

N

AND

AND

H

H, m.p. 142 [deg.] C

O

AND

D

G - ·

E _; CH (CH ₃ ) CH ₂ CH ₃

CS 276179 Β6 ·

HOOC-CH-Physical data

ch ₂ c ₆ ^h 5

Diastereomer fz] ²⁰ = + 16.4 ^° [C = 1, CH ₃ OH]

2nd diastereomer (t BuNH _2-sulphonyl) jý_j20 = +29,9 ⁰ [c = CH ₃ ^CH 2 0HJ ^C 6 ^H 11 ^CH 2 ^_C 6 ^H 4 ^OCH 3 CH ₂ -C ₆ H ₄ - oc ₂ h ₅

C ^H 2 -C ^H _é 4-0n-C ₃ ^H 7 ^CH 2 ^C 6 ^H 4 ° ⁿ - ^C 4 ^H 9 (εΗ _{2) 4} -ΝΗ ₂ (CH _{2) 3} -NH _2, -CH ₂ CH ₂ -s-ch ₃

CH-CH II u

CH ² -C ² CH ² CH ² (CH ₃ ) ₂

CH (CH ₃ ) CH ₂ CH ₃ ^CH 2 ^C 6 ^H 5 ^CH 2 ^-C 6 ^H 11

-C 2 ^{H oc-C6H4-} H 3 ^CH 2 ^C 6 ^H 4 ^C 2 ^H 5

G

O

N

N

AND

N

P

P

TO

Η

F

AND

Η

P

O ^CH 2 ^C 6 ^H 4 ° ⁿ - ^C 3 ^H 7

O

CS 276179 Bu

R ¹ HOOC-CH-N- physical data U ₅ RR ¹ ' ^Μ 2 ^{_ (} ' 6 ^ 4 ^_ θ ^{η 2} 4 ^ 9 ') N (CH ₂ ) ₄ -NH ₂ Q (CH ₂ ) ₃ -N'H ₂ Q CH ₂ -CH ₂ -S-CH ₃ Q CH - CH 11 CH three "C ^CH2 \ / S G CH _{(CH3) 7} AND CH (CH ₃ ) CH ₂ CH ₃ G ch ₂ c ₆ h ₅ N ^CH 2 ^-C 6 ^H 11 AND ^CH 2 ^-C 6 ^H 4 ° ^CH 3 0 ^CH 2 ^C 6 ^H 4 ° ^C 2 ^H 5 P CH ₀ -C, H, -On-CH. Of o - her P ^CH 2 ^C 6 ^H 4 ⁰ⁿ " ^C 4 ^H 9 0 (ch ₂ ) ₄ -nh ₂ P CH ₂ -CH ₂ -S-CH ₃ N

CH - CH • 11 CH 2 -CCH H CH (CH ₃ ) ₂ - θ CH (CH ₃ ) CH ₂ CH ₃ "- MP ° = -7.3 ⁰ (c = 1, CH ₃ 0H)"'Z_ tt .13 7 ° C CH ₂ C ₆ H ₅ 1S ^CH 2 ^-C 6 ^i! ll - L J

CS 276179 Ββ

R ¹ HOOC-CH-N- physical data 4 * 5 R R ^CH 2 ^C 6 ^H 4 ° ^C 2 ^H 5 Q ^CH 2 ' ^C 6 ^H 4 ⁿ ° ^C 3 ^H 7 Q C ^H 2 -C ₆ H ₄ -0 _n -C ₄ ^H g P CII ₂ -CH ₂ -5-CII ₃ C CH-CH ₂ M CH ₂ -CCH AND ch (ch ₃ ) ₂ P ch ₂ -c ₆ ^h 5 P ^CH 2 ^-C 6 ^H 11 M ^CH 2 ^_C 6 ^H 4 ^-0CH 3 D CH ₂ -C ₆ H ₄ -0 2 ^H 5 ^C D CH ₂ -C ₆ H ₄ -On-C ₃ H ₇ D C 1 -C 4 H 4 -On-C 4 H 8 Q CH - CH II CH ^{2 -} CH ^{2 S} _S ' N ch (ch ₃ ) ₂ N CH (CH ₃ ) CH ₂ CH ₃ P ch ₂ -c ₆ h ₅ Q ^CH 2 ^-C 6 ^H 11 N ^c H ₂ - ^C 6 ^H 4 ° ⁿ - ^C 4 ^H 9 D

CH - CH II II CH-c CH \ / 'S P 7 - - CH (CH ₃ ) CH ₂ CH ₃ Q · 4-, · CH (CH ₃ ) CH ₂ CH ₃ AND

HOOC-CH-Ni for physical data ^CH 2 ' ^C 6 ^H 11 ^CH 2' ^C 6 ^H 11

Example 90 1- [N- (1S) -ethoxycarbonylbutyl) -S-alanyl] octahydrocyclopenta [b] pyrrole) -2-carboxylic acid

a) DL-2-Trifluoromethylsulfonyloxypentanoic acid ethyl ester g (34 mmol) of 2-hydroxy-valeric acid ethyl ester and 2.85 g (35.9 mmol) of absolute pyridine are dissolved in 100 ml of absolute methylene chloride under shielding gas, cooled to 0 ° C and 9.66 g (34 mmol) of trifluoromethanesulfonic anhydride were added. After warming to room temperature, the reaction solution was stirred for 6 hours. After concentrating the solution, the crude product obtained is purified by column chromatography on silica gel using petroleum ether / methylene chloride (6: 1) as eluent. 9.3 g of a colorless, slightly viscous liquid are obtained

IR: 2880-3000, 1770, 1420,

1200-1220 1150, 620 cm ^-1

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

The trifluoromethanesulfonic acid ester thus obtained (4.9 g, 17.6 mmol) was dissolved in 70 ml of absolute methylene chloride under a nitrogen atmosphere, with 4.08 g of L-alanine benzyl ester hydrochloride (19 mmol) and 5.4 ml of triethylamine and reaction mixture. the solution was stirred at room temperature for 3 hours. The solution is concentrated, the crude product is taken up in ethyl acetate and washed three times with water, dried and concentrated. The diastereomers were separated by column chromatography on silica gel (cyclohexane / ethyl acetate 5: 1). The yield per isomer is 500 mg. The diastereomer isolated in the first filtrates has an S, S-configuration.

1 H-NMR Spectrum:

0.9 (t, CH ₃ ), ~ 1.3 (t * CH ₃ ), 1.35 (d, CH ₃ ), 1.4 (m, CH ₂ ), 1.6 (m, CH ₂ ), 1.9 (s, NH), 3.3 (t, CH), 3.4 (q, CH), 4.2 (m, CH ₂ ), 5.15 (q, C 1-4 -phenyl), 7 4 (s, CH aromatic) ppm.

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

600 mg (1.95 mmol) of benzyl ester (diastereomer A) was hydrogenated in 34 ml of ethanol in the presence of palladium on charcoal _{. The} catalyst was then filtered off and concentrated under reduced pressure. The product precipitated as a white solid, mp 137 ° C. Yield: 430 mg. : Σ

CS 276179 Bo

d) 430 mg (1.98 mmol) of N- (1-S-ethoxycarbonylbutyl) -S-alanine and 486 mg (1.98 mmol) of L (-) - octahydrocyclopentafl) pyrrole-2-carboxylic acid benzyl ester are dissolved under The mixture was cooled to -10 [deg.] C. under a nitrogen atmosphere in 20 ml of dimethylformamide. To the cooled solution was added 1.5 ml of triethylamine and 2 ml of n-propylphosphonic anhydride. The reaction mixture was stirred at -10 ° C for 1 hour and then at room temperature overnight. The solution was taken up in 200 mL of ethyl acetate, and then the ethyl acetate solution was washed with a saturated aqueous sodium bicarbonate solution, a 10X aqueous citric acid solution, and a saturated aqueous sodium chloride solution. After drying and concentration of the solution, the diastereomeric compounds were separated by column chromatography on silica gel using cyclohexane / ethyl acetate 9: 1.

Yield: 360 mg.

Non-polar diastereomer - -27.3 ° [c = 1, CH 2 OH], polar diastereomer = -61.6 ⁰ [C = 1, CH 3 OH] MS (F-AB) 445 (M ⁺ +1) each.

Both diastereomers are hydrogenated in ethanol in the presence of palladium on carbon as described in Example 90c) and precipitated as a white solid upon concentration of the solution.

(MS (DCI): 355 (M ⁺ +1) for both diastereomers).

Example 91

1- [N- (1S) -carboxybutyl) -S-alanyl] - (octahydrocyclopenta [b] pyrrole) -2-carboxylic acid mg (0.17 mmol) of carboxylic acid (Example 90d) was stirred into 2 ml of 4N aqueous hydroxide solution potassium and stirring is continued until the substance is completely dissolved. The solution was then transferred to a strongly acidic ion exchanger and eluted with a 2SS aqueous pyridine solution. After concentration of the solution, the yield is 39 mg.

MS: (DCI) 327 (M ⁺ +1).

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

H

00C R - CH - N - C - CH - N - CH _(O) -R

L U o fi i

R R R COOR

In which

n means number 2, R ¹ means methyl, R ² means ethyl and R ³ means hydrogen atom,

wherein R and a portion of the R ³ 90C-CH-N- molecule have the meanings given in the tables below. Ια I c

--------. R ⁴ R

R hooc-ch-n-. ... ch ₃ AND -CH ₂ CH ₃ AND - (ch ₂ ) ₉ -ch ₃ C 2-to phtyl D 4-biphenylyl AND - (ch,) ₁₃ -ch ₃ AND

R HOOC-CH N U L ₅ RR CH _? (B) -CH ₂ CH ₂ CH ₃ (B) - (ch ₂ ) ₉ -ch ₃ D 2-to phtyl F 4-Biphenylyl C - (CH ₂ ) ₁₃ -CH ₃ (B) R HOOC-CH-N- I 1 kb R ⁴ R ch ₃ C -CH ₂ CH ₂ CH ₃ C - (ch ₂ ) ₉ -ch ₃ G 2-to phtyl G 4-biphenylyl D - (CH ₂ ) ₁₃ -CH ₃ C

CS 276179 BfS

R 7 HOOC-CH-N-

CHj D -ch ₂ ch ₂ ch ₃ D - (CH _{2) g} -CH ₃ H 2-Naphthyl H 4-biphenylyl H - (ch ₂ ) ₁₃ -ch ₃ D

R HOOC-CH-N- '4 1 5 R R ch ₃ 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 HOOC-CH-N- G G R R CHj H -ch ₂ ch ₂ ch ₃ H - (ch ₂ ) ₉ -ch ₃ N 2-Naphthyl M 4-bi-phenyl N - (ch ₂ ) ₁₃ -ch ₃ N

CS 276179 Βδ

HOOC-CH-N4

R-R

-CH ₂ CH ₂ CH ₃

- (ch ₂ ) ₉ -ch ₃

2-to phtyl

4-biphenylyl '

- (ch ₂ ) ₁₃ -ch ₃

HOOC-CH-N * 45 R

-ch ₂ ch ₂ ch ₃

- (ch ₂ ) ₉ -ch ₃

4-biphenylyl

- (ch ₂ ) ₁₃ -ch ₃

Q

Q

P

Q

P

R

HOOC-CH-Physical data

Ø ⁴ R ⁵

CH ₃ 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 Also following analogous compounds procedure common as described in of formula II Examples 90 a 91 can prepare R ³ OOC - CH 1 R ⁴ - N - Cl; R ⁵ - CH ¹ R ¹ H - N - CH (CH ₂ CO ² R ² > n - ^R (II) n R R ¹ R ^Z R ³ HOOC-CH-N / R ⁴ R ⁵ physical data

c ₂ h ₅ i ch (ch ₂ ) _1q ch ₃ ch ₃ i (ch ₂ ) _1q ch ₃ ch ₂ c ₆ h ₅ i ch (ch ₃ ) ₂ ch ₃

C ₂ H ,. ^CH 2 ^C 6 ^H 5 ^D less polar diastereomer

Wq ⁰ = + 0.5 ° (c = 1, CH ₃ · OH5,

MS (DCI) 481 (M ⁺ l) f polar diastereomer / -J ² ° = -22.5 ⁰ (c = 1, CH ₃ 0H); MS (DCI) 481 (M ⁺ +1) ° + 52.9 ° (c = 1, CH ₃ OH);

MS (DCI) 529 (M ⁺ +1) diastereomers = -29.8 ^° (c = 1, CH ₃ OH) _;

MS (DCI) 459 (M ⁺ +1) = -0.6 ° (c = 1, CH ₃₀ OH);

MS (DCI) 459 (M @ ⁺ +1)

n R r ¹ R ^Z R ³ HOOC -ČH-N- * 4 ‘5 R R physical data 2i “CHy CHj ^C 2 ^H 5 ^CH 2 ^C 6 ^H 5- H MC (DCI): 499 (M @ ⁺ +1) for both diastereomers 2 ch ₃ ch ₃ ^C 2 ^H 5 H H less polar diastereo- ^: mer j>] J ° = -40.8 ° (c = 1, . CHjOH) more polar diastereomer Hd ° ⁼ ' ⁴ ' ⁵ ° ( ^{c = 1} > ch ₃ oh) 2 ^C 6 ^H 5 C ^H 2 -C ₆ H ₄ -O-n ^C 3 ^H 7 ^C 2 ^H 5 M H mp 53 ° C MS (DCI): 605 (M ⁺ +1) 2 ^C 6 ^H 5 CH ₂ -C ₆ H ₄ -0-nC ₃ H ₇ H H TO Wo ° ^{= + 32} > ° ° (c = i, ch ₂ or ₂ ) m.p. Mp 120-127 ° C 2 ^C 6 ^H 5 ^CH 2 ^C 6 ^H 5 H H H Λ / ·] θ ° = + 32.6 ° (c = 1, CH ₂ Cl ₂ ) mp 145 ° C (decomposition) 2 ^C 6 ^H 5 ch ₇ ch (ch ₃ ) ₂ H H H mp 156 ° C (decomposition) another diastereomer: mp 137 ° C (decomposition) = + 3.9 ⁰ (c = 1, CH ₃ 0H) 2 ^C 6 ^H 5 CH (CH ₃₎ -C ₂ H ₅ H H H mp 127 ° C (dec.); MS (DCI): 485 (M @ ⁺ +1) 2 nC ₄ H ₉ CHj ^C 2 ^H 5 ^CH 2 ^-C 6 ^H 5 D less polar diastereo- mer [] = -51.6 ° ^Ζ ° (c = CH ₃ 0H) more polar diastereomer G] D = -26.8 ° (c = 1, CH ₃ 0H) 2 ^! -c ₄ h ₉ ch ₃ c ₂ h ₅ H H less polar diastereomer

[^ = + 6.9 ° (CZL, CH ₃ 0H) polar diastereomer "

Wq ° = +4.4 ⁰ (c = 1, CH ₃₀ OH) _from MS (DCI): 597 (M ⁺ +1)

CS 276.179 Βδ n R

R ²

HOOC-CH-N> 4h

RR physical data nC ₄ H ₉

CH,

H D 1st diastereomer - °

(c = 1.CHjOll)

2. diastereomer m.p. Mp 104-10 ° C

Comparative Example 1

1) 2- (S-alanyl) - (1S, 35,5S) -2-azabicyclo-3,3,3-ooctane-3-carboxylic acid benzyl ester trifluoroacetate 1a) 2- (N-tert-butyloxycarbonyl-S-alanyl) benzyl ester - (1S, 3S, 5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid

61.5 g (0.251 mol) of benzylestel (JS, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, 47.5 g (0.251 mol) of BOC-L-alanine and 173 ml (1.26 mol) of absolute triethylamine is dissolved in 1025 ml of absolute dimethylformamide, a 50% solution of propanephosphonic anhydride in dichloromethane at -5 ° C (dropwise) is added thereto, and the reaction mixture is further stirred for 30 minutes at -5 ° 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, sodium citric acid solution, water and saturated sodium chloride solution, dried and concentrated. Yield: 93.2 g (89% of theory) of an oily product.

lb) 2- (S-alanyl) - (1S, 3S, 5S) -2-azabicyclo (3.3.0 .mu.-octane-3-carboxylic acid benzyl ester trifluoroacetate)

93.2 g (0.224 mol) of the BOC derivative from Comparative Example 1a) are poured at 0 ° C with 235 ml of absolute trifluoroacetic acid and the mixture is 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) (1S, 35,5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid n-octyl ester

2a) 2-tert-Butyloxycarbonyl- (1S, 3S, 5S) -2-azabicyclo [2,3.0] octane-3-carboxylic acid benzyl ester

To a solution of (1S, 3S, 5S) ± -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester (40.0 g, 0.163 mol) and absolute triethylamine (23.4 µl, 0.169 mol) in 300 mL of absolute A solution of 39.2 g (0.180 mol) of di-tert-butyl dicarbonate in 60 µL of absolute methylene chloride was slowly added dropwise at 0 ° C, and the reaction mixture was further stirred for 15 minutes at 0 ° C for 3 hours. 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.

£ «] ²⁵ = - 1.2 ⁰ (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) was hydrogenated in 2 L of ethanol at room temperature in the presence of 4 g of palladium on carbon (10%) for 2.5 hours. The catalyst is filtered off and the filtrate is concentrated.

Yield: 37.3 (90% of theory).

[et] ²³ - + 22.7 ⁰ (c = 1, methanol).

2c) 2-tert-Butyloxycarbonyl- (1S, 35,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

32.3 g (0.127 mol) of the acid of Comparative Example 2b) and 25.3 g (0.253 mol) of potassium bicarbonate 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 was poured into water, extracted three times with ethyl acetate, the combined organic phases were washed with saturated sodium bicarbonate solution and water, dried, concentrated and the crude product (44.3 g) was purified in two portions by flash chromatography on silica gel. (900 g, solvent system: toluene / ethanol 95: 5 or 99.5: 0.5).

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

⁰ = +5.7 (c - 1, methanol).

The following compounds were prepared in an analogous manner: 2-tert-Butyloxycarbonyl- (1RS, 3RS, 5RS) -2-azabicyclo-β, 3θ] -7-octene-3-carboxylic acid n-octyl ester;

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

38

2d) (2S, 3S, 5S) -2-azabicyclo β, 3, θ] octane-5-carboxylic acid n-octyl ester

2.6 g (7.0 mol) of the BOG derivative from Comparative Example 2c) are stirred at 0 DEG 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 are obtained in an analogous manner:

(1RS, 3RS, 5RS) -2-Azabicyclo [eta] &lt; 3 &gt; -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 then 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 92 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, 35,55) -2-azabicyclo [3.3.0] octane-3- of carboxylic acid (Ramipril) and 0.50 g (5 mmol) of potassium hydrogen carbonate are stirred in 25 ml of dimethylformamide at 40 DEG C. for 1.5 hours, after cooling to room temperature a solution of 1.16 g (6 mmol) is added dropwise. Of 1-bromooctane in 20 ml of dimethylformamide and the reaction mixture is stirred overnight at room temperature. The pH is adjusted to 6 by addition of 0.1 N hydrochloric acid, the mixture is 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. in a ratio of 95: 5 as eluent.

Yield: 2.35 g (89% of theory) of the oily product.

= -23.9 ^° (c = 1, methanol).

CS 276179 Βδ

EXAMPLE 93:

2 - [. N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl-3- (1S, 3s75 = S =) - 2-azabicyclo [3.3.1] octane-3-carboxy n-octyl ester, maleate 1b of the acid

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.

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

Melting point: 89-90 ° C.

Example 94

2- [1- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl-1- (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- (2-octenyl) ester, hydrogen maleate 3-carboxylic acids

2.08 g (5 mmol) of 2-CN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-3- (1S, 3S, 5S) -2-azabicyclo-3,3,3-octane-3-carboxylic acid (Ramipril) and 1.00 g (10 mmol) of potassium bicarbonate were stirred in 25 ml of dimethylformamide at 40 ° C for 1.5 hours, then the reaction mixture was cooled to 0 ° C and a solution of 2.3 g (12 mmol) was added dropwise. 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 95

2- [N- (IS-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo- (3,3, θ) octane-3- (3-octinyl) ester, hydrogen maleate carboxylic acids

4.9 g (11.0 mmol) of 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo-3,3,3,0-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 was then added and the reaction mixture was stirred at 40 ° C for a further 9 hours. 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 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 to hydrogen maleate analogously to Example 93.

Yield: 0.8 g of colorless crystals.

Melting point 68-70 ° C.

CS 276179 86

Example 96

2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-slanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.1.0] octane-3-carboxylic acid ethyl ester hydrogen maleate.

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) Purified by flash chromatography on 80 g of silica gel using toluene / ethanol (99: 1) as the solvent system. 0.62 g (42S) of an oily product is obtained, which is converted in analogy to Example 93 to hydrogen maleate.

Yield: 0.50 g of colorless crystals.

Mp 84-86 ° C.

Example 97

2- (N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl) - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3- (5-nonyl) ester, hydrogen maleate k arboxylic acids

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. acid in 10 ml of absolute tetrahydrofuran, the reaction mixture is further stirred for 10 minutes and then a solution of 2, D8 g (5 mmol) of 2-CN- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - is added at 0 ° C. (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid (Ramipril) in 25 mL of absolute tetrahydrofuran, and the mixture was stirred at 0 ° C for 1 hour and then overnight at 0 ° C. rooms. 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 200 g of silica gel using a) toluene mixture (a) and 99: 1 ethanol and b) 9: 1 methylene chloride: ethyl acetate 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), m.p. 103-105 ° C.

Example 98

2- [N- (1S-Menthyloxycarbonyl-3-phenylpropyl) -1S-alan-5-yl] - (1S, 3S, 5S) -2-azabicyclo [3.3.1] 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 nickel peroxide hydrate (2.95 h) in 12 ml of ether, the mixture was further stirred for 1 hour, then the violet solution was filtered through the diatomite and the filtrate are concentrated. 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 - (18-mentyhloxycarbonyl-3-phenylpropyl) - S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [5.3.0] octane-3-carboxylic acid (cf. Example 128) in 32 mL of 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) for cyclohexane / ethyl acetate (8: 1). 2 as a solvent system.

Yield: 1.63 g (95% of theory) of an oily product;

L <= -57.9 ⁰ (c - 1, methanol).

Example 99 2-N- (3-Cyclohexyl-1S-ethoxycarbonylpropyl) -S-alanyl} - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

1.8 g (6.7 mmol) of the octyl ester of Comparative Example 2d), 1.92 g (6.7 mmol) of N- (3-cyclohexyl-15-ethoxycarbonylpropyl) -S-alanine and 4.6 ml of absolute triethylamine were added. Dissolve in 30 ml of absolute dimethylformamide, cool to -5 ° C and slowly add dropwise 6.7 ml of a 50% solution of propanephosphonic anhydride in methylene chloride. The reaction solution is stirred overnight at room temperature, then poured onto 200 ml of water, extracted three times with ethyl acetate, the combined organic phases are washed with water, 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, concentrate, and the crude product (3.1 g) is purified by flash chromatography on 120 g of silica gel using toluene / ethanol (199: 1) as the solvent system.

Yield: 2.48 g (69% of theory) of a colorless oil.

[/] _ ^ ³ -26.4 ⁰ (c = 1, methanol).

Example 1 a d 100

2- [N- (1S-ethoxycarbonyl-n-tridecyl) -S-phenylalanyl] - (1S, 35,5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester

To a solution of 2.1 g (5 mmol) of N- (1S-ethoxycarbonyl-n-tridecyl) -S-phenylalanine and 1.4 g (5 mmol) of (1S, 3S, 5S) -2-azabicyclo [3.3] benzyl ester of octane-3-carboxylic acid in 80 ml of absolute dimethylformamide is gradually added dropwise 3.5 ml (25 mmol) of absolute triethylamine and 5.0 ml of a 50% solution of propanephosphonic anhydride in methylene chloride and the reaction is stirred overnight at room temperature. The reaction solution was poured into water, extracted several times with ethyl acetate, the combined extracts were washed with water, 10% citric acid solution, saturated sodium bicarbonate solution and saturated sodium chloride solution, dried, concentrated and the crude product (3.15 g) was added. Purification by flash chromatography on silica gel using cyclohexane / ethyl acetate 7: 3 as the solvent system.

Yield: 2.76 g (85% of theory) of an oily product;

---- -8.0 ° (c = 0.97, ethanol). '-

CS 276179 86

and..

Example 101

2-N - (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo (3,3,0,4} octane-3-carboxylic acid benzyl ester

To a solution of 9.3 g (21.7 mmol) of the trifluoroacetate of Comparative Example 1b) in 100 ml of absolute methylene chloride at 0 ° C was gradually added dropwise 6.0 ml (43.4 mmol) of absolute triethylamine and 9.2 g of n- 4-phenyl-2R- (trifluoromethanesulfonyloxy) -butyric acid octyl ester dissolved in 20 mL of absolute methylene chloride. The reaction mixture was allowed to warm to room temperature, stirred for 2.5 hours, extracted three times with water, dried, concentrated and the crude product (11.4 g) purified by flash chromatography on 450 g silica gel cyclohexane and ethyl acetate in a ratio of 9: 1, 8: 2 and 7: 3 as solvent system.

Yield: 6.95 g (54% of theory);

[α] ²⁵ = -35.0 ⁰ (c = 1, methanol).

Example 102

Tert-Butylammonium [2- [h- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylate2

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 (103) for 20 minutes. After filtering off the catalyst and concentrating, 4.1 g (89% of theory) of 2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl- (1S, 3S, 5S) -2-azabicyclo] -3 are obtained. 3, Ooctane-3-carboxylic acids.

1.3 g of this acid in ethanol were mixed with 190 mg of a target. butylamine, the solvent was evaporated and the residue was crystallized from diisopropyl ether.

Yield: 1.27 g (86% of theory) of colorless crystals, m.p. 141-143 ° C.

EXAMPLE 103 2-N- (1S-Carboxy-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo {3,3,

O] octane-3-carboxylic acid

2.65 g (5 mmol) of the ethyl ester of Example 92 are dissolved in 18 ml of tetrahydrofuran, 7.5 ml of 1N sodium hydroxide solution are added to the obtained solution, and the mixture is 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 using toluene / ethanol. 9: 1 as eluent. The product obtained (1.15 g; 45% of theory) is triturated in 50 ml of petroleum ether, left to cool in the cold, filtered off and dried.

Yield: ^0.83 g of colorless crystals melting at 56-61 ° C.

CS 276179 Be

In addition, using the appropriate starting materials and following the procedures described in Examples 92 to 103, the following compounds of the invention were obtained:

Example 104 2- [N- (1S-ethoxycarbonyl-n-heptyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester

EXAMPLE 105 2- [N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3- n -yl ester carboxylic acids;

[α] ⁵ - -25.8 ⁰ (c = 1, methanol).

Example 106 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-tetradecyl ester;

= - 19.8 ⁰ (c = 1, methanol).

Example 107

2- (N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [2,3.0] octane-3-carboxylic acid, 2-octinyl) ester, maleate; mp 70-72 ° C.

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

(AJG ⁵ = -23.7 ° (c = 1, methanol).

Example 109-2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-aza-bicyclo [3.3.0] n-octyl ester octane-3-carboxylic acid;

(. ** · 3β5 = -18.6 ° (c. = 1, methanol). ......- ----- - - ..........-

Example 110 ..

2- [N- (1S-n-octadecyloxycarbonyl-3-phenylpropyl) -Salanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl; '

H ⁰ = -15.2 (c = 1, methanol). CS 276179 B6 ·.

Example 111 1 '- (N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane + 2,3'S-pyrrolidine] -5S-carboxylic acid n-octyl ester.

Example 112

1 '- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro {bicyclo [2.2.2] octane-2,3'S-pyrrolidine] -5'S-carboxylic acid n-nonyl ester hydrogen maleate;

mp 110 ° C.

Example 113

1 '- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiro [bicyclo [2.2.2] octane-2,3'S-pyrrolidine] -5'S- m.p. 96 ° C.

Example 114 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1R, 3R, 5R) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-octyl ester;

_ -7.0 ⁰ (c = 1.16, methanol).

EXAMPLE 115 2- [N- [1S-Ethoxycarbonyl-3-phenylpropyl] -R-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- 3-carboxylic acids;

I /.] P5 = ⁰ +18,0 (c = 1, methanol).

EXAMPLE 116 2- [N- (1R-Ethoxycarbonyl-3-phenylpropyl) -R-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane- 3-carboxylic acids,

ΙΧ] θ ⁵ = ⁰ + 9.4 (c = 1, methanol).

Example 117 ad 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] n-octyl ester -7-octene-3-carboxylic acid;

CA 1? ³ = + 2? ¹ (c = 1, methanol). EXAMPLE 118 2- [N- (1S-Ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1R, 3R, 5R) -2-azabio n-octyl45

B6cyclo [3.3.0] -7-octene-3-carboxylic acid;

[.Alpha.] D ^{= 51.4} DEG ( ^c = 1, methanol).

Example 119

N-Jn '- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl-5-proline N-octyl ester, maleate;

mp 105-107 ° C.

Example 120

2- [n- (1S-ethoxycarbonyl-n-tridecyl) -S-phenylalanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid;

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

Example 121

2- [1- (1S-Ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [10.3.0] octane-3-carboxylic acid benzyl ester.

Example 122

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

Example 123

2- [N- (1S-n-octadecyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [1,3.0] octane-3-carboxylic acid benzyl ester;

= -28.6 ⁰ (c = 1, methanol).

Example 124

2- [N- (1S-Menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2+ cyclo [3,3,0-octane-3-carboxylic acid benzyl ester;

⁰ ₌ -63.2 (c = 1, methanol).

Example 125

2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S, 5S-2-azabicycloyl) -3,3-octane-3-methyl maleate (3,3-diphenyl-n-propyl) ester 122 DEG-124 DEG.

CS 276179 Bo

Example 126

1 '- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] spiroXbicyclo [2.2.2] octane-2,3'S-pyrrolidine] 5'S-carboxylic acid (5-nonyl) ester hydrogen maleate; mp 121 ° C.

Example 127

Tert-Bulamylammonium [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 128

Tert-Butylammonium [2- [N- (1S-menthyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.1] octane-3-carboxylate]; mp 164-167 ° C

Claims (2)

1 2 HOOC-CH (R) -NH- and B represents a hydrogen atom, carried out in the presence of a coupling reagent. The method of claim 1 wherein the reaction of compounds of formula (IXI) wherein A is -CO-C (R 6) = q \ with compounds of formula (IV) wherein B and B are together Q , optionally also in water and / or optionally in the presence of a reducing agent. 5. The method of claim 1, wherein the corresponding starting material is used. compounds of formula (III) and (IV) to form compounds of formula (II) in which n is 1 or 2, R is C 1 -C 6 alkyl, C 10 -C 6 alkyl; 15 carbon atoms, cyclohexyl, cyclohexylmethyl, phenyl, benzyl, 2-naphthyl, 2-naphthylmethyl, 4-biphenylyl or 4-biphenylmethyl; R ¹ is the side chain of alanine, lysine, leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, o-alkyltyrosinu having 1 to 4 carbon atoms in the alkyl part, ornithine, methionine, or 2-thienylalanine, R ⁷ is hydrogen, alkyl of 1 up to 10 carbon atoms, octadecyl, cyclopentyl, cyclohexyl, tolyl, benzyl, phenylethyl, benzhydryl or menthyl, R ³ represents a hydrogen atom, a C 1 -C 10 alkyl group, a tetradecyl group, an octadecyl group, an octenyl group, an octinyl group, an octinyl group, a cyclopentyl group, a cyclohexyl group, a phenyl group, a benzyl group, a phenylethyl group, a phenylpropyl group, 3,3- diphenylpropyl, phenyloctyl, tolyl, benzyl, 4,4'-difluorobenzhydryl, 4-fluorophenyl, 4-biphenylyl, 2-naphthyl or menthyl, 4 5 R and R together with the atoms to which they are attached form a residue of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo [3.3.0] octane, 2-azaspiro [4,5]] decane, 2-azaspiro [4, 4] nonane, spiro [bicycle [2,2, 1 2 2 B is Y and B is hydrogen or B and B are together Q, n, R, '1 and R are as defined above means amino and Y is amino + hydrogen and Q is a leaving group or vice versa, and is oxo or vice versa, in an organic solvent at a temperature between -20 And the boiling point of the reaction mixture, whereupon any intermediate unsaturated compounds such as Schiff bases are reduced, the protecting groups temporarily introduced to protect the reactive groups are cleaved, the compounds of formula XI with a free carboxyl group or free carboxyl groups are optionally esterified _and recovered the compounds are optionally converted into their physiologically tolerable salts. A method according to claim 1, wherein the reaction of compounds of formula III in which A represents a hydrogen atom with compounds of formula IV in which 8 represents a group 1. n is the 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 represents the side chain of bacon, lysine, leucine, valine, isoleucine, phenylalanine, cyclohexylalanine, C 1 -C 4 -alkyltyrosine, ornithine, methionine or 2-thynylalanine, .......... ........... 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, a mono- or diphenylalkyl group having 1 to 2 carbon atoms in the alkyl moiety or a menthyl group; . R represents a hydrogen atom, an alkyl group having 1 to 18 carbon atoms; octenyl, octinyl, C 5 -C 6 cycloalkyl, Is a C 6 -C 12 aryl group optionally substituted by a methyl or halogen atom, a C 1 -C 8 mono- or diphenylalkyl group wherein the phenyl moiety is optionally substituted by halogen, or is a menthyl group, R ⁴ and R ⁵ together with the atoms to which they are attached represent a radical of tetrahydroisoquinoline, decahydroisoquinoline, octahydroindole, 2-azabicyclo-β 3, 3 θ] octane, 2-azaspiro [4,5] decane, 2-azaspiro [4, 4] nonane, spiro (bicyclo [2.2.1] heptane-2,3'-pyrrolidine, spirobicyclo [2.2.2] octane) -2,3'-pyrrolidine, 2-azatricyclo [4.3.0] , 1 ^6,9 ] decane, decahydrocyclohepta [b] pyrrole, hexahydrocyclohepta [b | pyrrole, octahydroisoindole octahydrocyclopenta [b] pyrrole, 2,3,3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2,3,3a, 4,6a-hexahydrocyclopenta [b] pyrrole, indoline, or their physiologically compatible salts, with the exception of the compounds of formula (II) and their salts, 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 ³ is C 1 -C 4 alkyl, cyclohexylmethyl, phenylmethyl, the phenyl being optionally substituted with C 1 -C 4 alkoxy or, if not included in the above definitions, optionally protected naturally occurring side chain » 4-amino acid of the formula R ³ -CH _(NH2) -C00H, 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 and R ^{4 and} R ⁵ are as defined in ad I, characterized in that R ³ 00C reacting compounds of formula III - CH - N - A in which And it means i) hydrogen, - ii) a group -CO-Y-CH ^3; or (III), And (iii) a group -CO-CxQ ¹ R and R 'are as defined above, with compounds of Formula IV C- (CH 2) -R I ₂ COOR (IV) in which, in case of (i) B is HOOC-CH-NHb in case ii) iii) B represents a hydrogen atom, A method for producing compounds R ³ 00C. Claims with nootropic effect of formula II CH - N - C - CH - NH - CH - (CH) - R (II), i; i i 4 S ^{u 1} 2 R * RR COOR ^Z in which 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, 12.3, 3a, 4,5,7a-hexahydroindole, pyrrolidine, 1,2,3,3a, 4,6a-hexahydrocyclopenta [phi] pyrrole, indoline, or their physiologically tolerable salts. A method according to any one of claims 1 to 4, wherein the corresponding starting materials of formulas III and IV are used to form 2- [N - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanylJ (1S, 3S) benzhydryl ester. 5S) 2- [2 - [(1S) -ethoxycarbonyl-3-phenylpropyl] -L-alanyl] (1S, 3S, 5S) -2-azabicyclo [3.3.1] octane-3-carboxylic acid, octadecyl ester -azabicyclo D, 3,0] octane + 3-carboxylic acid 2- [N - [(1S) -benzhydryloxycarbonyl-3-phenylpropyl] -L-alanyl] - (1S, 3S, 5S) -2 · -abicyclo [benzoate] 3,3, θ] octane-3-carboxylic acid, 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3, 3, θ] octane-3-carboxylic acid, 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [1,3] n-octyl ester hydrogen maleate θ] -octane-3-carboxylic acid 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] (15,3S, 5S) -2-azabicyclo [d] -maleinate (5-nonyl) ester 3, O] -octane-3-carboxylic acid 2- [N- (1S-menthyloxycarbonyl-3) benzhydryl ester -phenyl-propyl) -S-alanyl] - (1S, 3S, 5S) = 2-azabicyclo [3.3.0] octane-3-carboxylic acid 2- [thi- (1S-carboxy-3-) n-octyl ester phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo-5,3,10-octane-3-carboxylic acid, CS 276179 2- [li- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid n-decyl ester 2- [N- (1S-n-octyloxycarbonyl-3-phenylpropyl) -S-alanyl] - (15,3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid, n-octyl ester 2- [N- (1S-ethoxycarbonyl-3-phenylpropyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] -7-octen-3-, n-octyl ester carboxylic acid, 2- {n - (15-ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester, and 2- [N- (1R-ethoxycarbonyl-n-tridecyl) -S-alanyl] - (1S, 3S, 5S) -2-azabicyclo [3.3.0] octane-3-carboxylic acid benzyl ester.