EP0823912A1

EP0823912A1 - Azacycloalcane derivatives, preparation thereof and their applications in therapy

Info

Publication number: EP0823912A1
Application number: EP96913576A
Authority: EP
Inventors: Manuel Bedoya Zurita; Juan Antonio Diaz Martin; Gregorio Del Sol Moreno; Ulpiano Martin Escudero Perez; Maria Dolores Jimenez Bargueno; Magali Romanach Ferrer
Original assignee: Synthelabo SA
Current assignee: Synthelabo SA
Priority date: 1995-05-03
Filing date: 1996-04-12
Publication date: 1998-02-18
Also published as: US5869518A; FR2733750A1; AU699120B2; TR199701287T1; IL118119A0; CO4750652A1; PL323177A1; HUP9903886A2; FR2733750B1; EE9700288A; JPH11504913A; NZ307230A; KR19990008276A; BR9608309A; WO1996034870A1; ZA963485B; HUP9903886A3; AU5652096A; NO975020D0; MX9708322A

Abstract

Azacycloalcane derivatives having general formula (I) wherein R1 and R2 represent a hydrogen atom, an alkyl group or a phenyl group, or R1 and R2 form together an oxo group, R3 is a hydrogen atom or an alkyl group, or R3 forms a methylene group, R4 is an aromatic group or, when R3 forms a methylene group, R4 is a phenylene group of which a carbon atom is bound to Y and another carbon atom adjacent to the former carbon atom is bound to said methylene group, R5 is either a group OR7 where R7 is a hydrogen atom or a benzyl group, or a group N4-methyl-piperazinyl, or else a group NHR8 wherein R8 is a hydroxyl, pyridinylmethyl or phenylmethyl group, A is an optionally substituted aromatic cycle, n is 1 or 2, X is CH, O or N, and Y is CH2, O or S, their preparation process and their applications in therapy.

Description

AZACYCLOALCAN DERIVATIVES, THEIR PREPARATION AND THEIR

THERAPEUTIC APPLICATIONS

The present invention relates to derivatives

of azacycloalkanes, their preparation and their therapeutic applications, in particular in the treatment of diabetes, obesity and hyperglycemia.

The azacycloalkane derivatives of the invention correspond to the general formula (I)

in which:

* R ₁ and R ₂ , identical or different, each represent a hydrogen atom, an alkyl group, linear, branched or cyclic, comprising from 1 to 6 carbon atoms, or a phenyl group optionally substituted by an alkyl group, linear or branched, comprising from 1 to 6 carbon atoms, by one or two halogen atoms or by a COOR ₆ group, R ₆ being a hydrogen atom or an alkyl group, linear or branched, comprising from 1 to 6 atoms of carbon,

or R ₁ and R ₂ together form an oxo group,

* R ₃ represents a hydrogen atom or an alkyl group, linear or branched, comprising from 1 to 4 carbon atoms, or else R ₃ forms a methylene group,

* R ₄ represents an aromatic group chosen from a phenyl, naphthyl or pyridinyl group, optionally substituted by an alkyl group, linear or branched, comprising from 1 to 6 carbon atoms, by one or two halogen atoms, by a nitro group , or by a COOR ₆ group, R ₆ being as defined above,

or, when R ₃ forms a methylene group, then R ₄ represents a phenylene group in which a carbon atom is linked to Y and another carbon atom, adjacent to the preceding one, is linked to said methylene group,

* R ₅ is either an OR ₇ group, where R ₇ is a hydrogen atom or a benzyl group, or an N ₄ - ethyl-piperazinyl group, or also an NHR ₈ group where R ₈ is a hydroxyl group,

pyridinylmethyl or phenylmethyl. n is 1 or 2,

* A is an aromatic ring, optionally substituted by one or two halogen atoms, one or two alkyl groups, linear or branched, comprising from 1 to 4 carbon atoms, by a nitro group, by a COOR ₆ , R _{6 group} being as defined above, by one or two alkoxy groups, linear or branched, comprising from 1 to 6 carbon atoms or by a methylenedioxy group,

* X is CH, O or N, and * Y is CH ₂ , O or S.

The compounds of formula (I) form with the pharmaceutically acceptable acids and bases salts which form part of the invention. According to the present invention, the preferred salts are the sodium and calcium salts, which are such that R ₇ represents a sodium or calcium atom.

The compounds of formula (I) have an asymmetric carbon atom. They can therefore exist in the form enantiomers. These enantiomers and their mixtures, including the racemic mixtures, form part of the invention.

In the context of the present invention, the following terms have the following meanings:

* an oxo group represents a group = O.

* an aromatic group consists of an unsaturated ring comprising from 3 to 14 carbon atoms, as well as, optionally, a heteroatom chosen from the group consisting of sulfur, oxygen and nitrogen, said cycle having a maximum number of 'unsaturations, taking into account its possible substitutes. Furthermore, it can be noted that when n is equal to 1 or 2, this means that the number of carbon atoms included in the parenthesis is equal to 1 or 2. When n is equal to 1, the azacycloalkane derivative according to the invention is a dihydro-1H-pyrrole derivative. When n is equal to 2, the azacycloalkane derivative according to the invention is a tetrahydropyridine derivative.

According to a preferred embodiment of the invention, A is chosen from the group consisting of thiophene, benzene, furan and naphthalene, these aromatic groups being or not substituted as indicated above.

According to another advantageous aspect of the invention, n is equal to 1 and R ₅ is a hydroxyl group. Furthermore, R ₄ is

preferably an unsubstituted phenyl group.

As a subgroup of compounds according to the invention, mention may in particular be made of the derivatives of y-oxo-α- (phenylmethyl) -5,6-dihydro-4H-thieno acid [3,4- c] pyrrole-5-butanoic formula II

in which R ₅ is as defined for formula (I) and R ₉ and R ₁₀ , identical or different, represent an atom

hydrogen, a halogen atom or an alkyl group, linear or branched, comprising from 1 to 4 carbon atoms.

Pure enantiomers, mixtures of enantiomers, including racemic mixtures, as well as the pharmaceutically acceptable salts of the compounds of formula (II), form part of the invention.

The compounds of formula (I) can be prepared according to the process represented in scheme 1 in Annex 1. According to this process, a compound of formula (III) is reacted

in which R ₁ , R ₂ , A and n are defined as in formula (I), with a compound of general formula (IV)

in which R ₃ , R ₄ , X and Y are defined as in formula (I), R ₁₁ represents a halogen atom or a hydroxyl group and R ₁₂ is an alkoxy group comprising from 1 to 4 carbon atoms, linear or branched, or a phenylalkoxy group, the alkoxy part of which comprises from 1 to 4 carbon atoms, such as the benzyloxy group.

This reaction can be carried out in a solvent such as dichloromethane, in the presence of triethylamine and / or an agent activating the acid function such as chloroformate.

isobutyl or carbonyldiimidazole (CDI). Compounds of formula (la) are thus prepared in which R ₁ , R ₂ , R ₃ , R ₄ , R ₁₂ A, n, X and Y have the meanings mentioned above.

The compounds of formula (I) for which R ₅ is a benzyloxy group can thus be directly obtained by choosing R ₁₂ as being a benzyloxy group.

The compounds of the invention of formula (Ib), for which R ₅ is a hydroxyl group, can be obtained by hydrogenolysis or hydrolysis of the compounds of formula (la), using for example sodium hydroxide or hydrochloric acid.

The compounds of the invention of formula (I) where R ₅ is either an N ₄ -methyl-piperazinyl group or an NHR ₈ group where R ₈ is a hydroxyl, pyridinylmethyl or phenylmethyl group, can be prepared by reacting the compounds of formula (la) with an amine of formula HZ in which Z represents an N ₄ -methyl-piperazinyl group or an NHR ₈ group as defined above, in the presence of carbonyldiimidazole.

The compounds of formula (III) can be prepared according to methods well known to those skilled in the art, in particular according to the methods described in the French patent application.

93 07538, or according to methods described in the literature, such as for example in Tetrahedron Letters, 36, 5877-5880

(1995).

More particularly, the compounds of formula (III), in which A is an optionally substituted benzene group, n is equal to 1, R ₁ and R ₂ each represent a hydrogen atom, can in particular be prepared according to the two methods represented in diagrams 2 and 3 of Annex 2. According to the method of diagram 2, a compound of formula (V), in which R ₁₃ represents a halogen atom, an NO ₂ group, linear or branched alkyl, comprising from 1 to 4 carbon atoms, with urea to prepare an imide compound of formula ( VI) where R ₁₃ has the meaning indicated above. The imide function of the compound of formula (VI) is then reduced using sodium borohydride, in the presence of

boron trifluoroetherate, to obtain the compounds of formula (IIIa) where R ₁₃ has the meaning indicated above. According to scheme 3, a compound of formula (VII) is reacted successively, in which R14 represents an atom

halogen, with a strong base such as n-butyllithium in a solvent such as tetrahydrofuran, then with N, N-dimethylformamide, then with sodium borohydride, then finally with hydrochloric acid to obtain a compound of formula (VIII). This is subjected to the action of sodium hydride, then to that of potassium tert-butoxide in the presence of water to obtain the compounds of formula (Ilb) where R14

represents a halogen atom.

The compounds of formula (IV) can be prepared according to methods described in the literature, as for example in J. Am. Chem. Soc, 90, 3495-3502 (1968) or in J. Med. Chem., 36, 2788-2797 (1993).

The following examples illustrate the invention.

The analyzes confirm the structure of the compounds.

Example 1. γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H- furo [3,4-c] pyrrole-5-butanoic acid.

1.1.- Furan-3,4-dimethanol. To 95 ml (95 mmol) of a 1 M solution of lithium aluminum hydride in tetrahydrofuran, a solution of 7.2 g (39 mmol) of furan-3,4 is added at 0 ° C. -diethyl dicarboxylate in 95 ml of tetrahydrofuran. We stir at

room temperature for 16 h then added at 0 ° C, 3.8 ml of water and 3.8 ml of a 15% sodium hydroxide solution. The precipitate formed is filtered, washed with three times 100 ml of

tetrahydrofuran, then the combined organic phases are washed with brine, dried over sodium sulfate, filtered and evaporated to dryness. 4.26 g of an oily product are obtained. 85% yield.

1.2.- 3,4-Bis (chloromethyl) furan.

To a solution of 5.3 g (41.36 mmol) of furan-3,4-dimethanol in 30 ml of chloroform, a solution of 7.5 ml (105.3 mmol) of chloride is added at 0 ° C. of thionyl in 30 ml of chloroform. The mixture is stirred for 2 h at room temperature then the mixture is poured into 100 ml of ice water. The organic phase is decanted, washed with twice 50 ml of cold water, dried over sodium sulfate and then evaporated to dryness. 3.97 g of an oily product are obtained. Yield 58%.

1.3.- 5-Benzoyl-5,6-dihydro-4H-furo [3,4-c] pyrrole.

To a solution of 0.75 g (6 mmol) of benzamide in 20 ml of N, N-dimethylformamide, 0.72 g (18 mmol) of a dispersion of sodium hydride in water is added at 0 ° C. oil; stirred at room temperature for 90 min., then a solution of 1 g (6 mmol) of 3,4-bis (chloromethyl) furan in 20 ml of N, N-dimethylformamide is added. The mixture is stirred for 2.5 h, cooled to 0 ° C., 50 ml of water are added and the mixture is extracted with three times 50 ml of ethyl acetate; the combined organic phases are washed with brine, dried over sodium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the eluent mixture ethyl acetate / hexane 1/4. 0.42 g of a solid is obtained White. Yield 32%.

Melting point: 84.5-85.5 ° C.

1.4.- 5,6-Dihydro-4H-furo [3,4-c] pyrrole. To a solution of 2.7 g (12.6 mmol) of 5-benzoyl-5,6-dihydro-4H-furo [3,4-c] pyrrole in 20 ml of ethanol, 30 ml is added (67, 5 mmol) of a 2.5 M aqueous solution of sodium hydroxide. The mixture is stirred at reflux for 6.5 h; the ethanol is distilled and then extracted with three times 30 ml of dicloromethane. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. 1.25 g of an oily product are obtained, which is used as it is for the following reaction.

1.5.- Phenylmethyl γ-Oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H-furo [3,4- c] pyrrole-5-butanoate.

To a solution of 2.5 g (8.3 mmol) of 3-carboxy-2 (R, S) - (phenylmethyl) -1-phenylmethyl propanoate in 40 ml of tetrahydrofuran is added at 0 ° C, 1.48 g (9 mmol) of

carbonyldiimidazole; stirred for 90 min. at room temperature then a solution of 1 g (9 mmol) of 5,6-dihydro-4H-furo [3, 4-c] pyrrole in 40 ml of tetrahydrofuran is added; after 2 h the mixture is poured into ice water and stirred for 30 min. The precipitate formed is filtered, washed with twice 20 ml of water and dried under vacuum. 2.85 g of a white solid are obtained. Yield 88%.

Melting point: 101-102 ° C.

1.6.- γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H- furo [3,4-c] pyrrole-5-butanoic acid. To a solution of 1 g (2.56 mmol) of γ-oxo-α (R, S) -

(phenylmethyl) -5,6-dihydro-4H-furo [3,4-c] phenylmethyl pyrrole-5-butanoate in 10 ml of tetrahydrofuran is added 10 ml of ethanol, then, at 0 ° C, a solution of 0.308 g (7.7 mmol) of sodium hydroxide in 10 ml of water. We stir the mixture for 2 h at 0 ° C, then for 2 h at room temperature. The solution obtained is concentrated, 30 ml of water are added and the mixture is washed with twice 35 ml of diethyl ether. The aqueous phase is cooled, then a 2 M acid solution is added

hydrochloric until pH 2. The precipitate formed is filtered, washed with twice 20 ml of water and dried under vacuum. 0.47 g of a white solid is obtained. Yield 61%.

Melting point: 135-137 ° C.

Example 2. 5-Fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.

2.1.- N - [(4-Fluoro-2-formylphenyl) methyl] -2,2- dimethylpropanamide.

To a solution of 5 g (23.9 mmol) of N - [(4-fluorophenyl) methyl] -2,2-dimethylpropanamide in 60 ml of tetrahydrofuran, 22.9 ml (57, 3 mmol) of a solution of 2.5 M n-butyllithium in hexane. Stirred 1 h at 0 ° C, cooled to -78 ° C and then added 2 ml of N, N-dimethylformamide and stirred for 2 h at 0 ° C. 20 ml of a saturated ammonium chloride solution are added, the mixture is stirred for 30 min at room temperature and then 50 ml of water and 100 ml of ethyl acetate are added. The organic phase is washed with brine, dried over sodium sulfate and then evaporated to dryness. The residue crystallizes from an ethyl acetate / hexane mixture. 3 g of a white solid are obtained. Yield 53%.

Melting point: 62-64 ° C.

2.2.- N - [[4-Fluoro-2- (hydroxymethyl) phenyl] methyl] -2,2- dimethylpropanamide.

To a solution of 0.5 g (2.1 mmol) of N - [(4-fluoro-2-formylphenyl) methyl] -2,2-dimethylpropanamide in 15 ml of methanol, the following is added at 0 ° C, 0, 08 g (2.1 mmol) sodium borohydride. Stir for 4 h at room temperature, then removes the solvent. 20 ml of a saturated sodium hydrogencarbonate solution are added and the mixture is extracted with twice 30 ml of dichloromethane. The combined organic phases are washed with brine, dried over sodium sulfate, then evaporated to dryness. The product crystallizes from an ethyl acetate / hexane mixture in the form of a white solid. 0.27 g is obtained. Yield 54%.

Melting point: 102-103 ° C.

2.3.- N - [[2-Chloromethyl) -4-fluorophenyl] methyl] -2,2- dimethylpropanamide.

A mixture of 2.77 g (11.57 mmol) of N - [[4-fluoro-2- (hydroxymethyl) phenyl] methyl] -2,2-dimethylpropanamide and 20 ml of acid is heated to 60 ° C. concentrated hydrochloric acid for 20 h; the solvent is removed and 3 g of a white solid are obtained.

Quantitative yield.

Melting point: 99-103 ° C.

2.4.- 2- (2,2-Dimethyl-1-oxopropyl) -5-fluoro-2,3-dihydro-1H- isoindole. To a solution of 2.9 g (11.25 mmol) of N - [[2-chloromethyl) - 4-fluorophenyl] methyl] -2,2-dimethylpropanamide in 70 ml of N, N-dimethylformamide, the following is added to 0 ° C, 0.49 g (12.3 mmol) of a 60% dispersion of sodium hydride in oil. Stir at 0 ° C for 1 h, then add 2ml of acid

hydrochloric 6N. The solvent is eliminated and the residue is purified by chromatography on a column of silica gel using the eluent mixture ethyl acetate / hexane 1/9. 2.1 g of a white solid are obtained. 85% yield.

Melting point: 80-82 ° C.

2.5.- 5-Fluoro-2,3-dihydro-1H-isoindole.

To a suspension of 6.6 g (54 mmol) of tert-butylate potassium in 140 ml of tetrahydrofuran, 0.3 ml (16.7 mmol) of water is added, the mixture is stirred for 5 min, then 1.8 g (8.13 mmol) of 2- (2.2-) are added dimethyl-1-oxopropyl) -5-fluoro-2,3-dihydro-1H-isoindole. The mixture is stirred at 70 ° C. for 48 h, filtered through celite, washed with twice 50 ml of

tetrahydrofuran, then the filtrates are evaporated to dryness. 20 ml of 6N hydrochloric acid are added, the solution obtained is washed with twice 20 ml of ethyl acetate, then the aqueous phase is basified with 6N sodium hydroxide until pH 14 and it is extracted with three times 30 ml of ethyl acetate. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. 0.69 g of an oily product is obtained.

Yield 61%.

2.6.- 5-Fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- phenylmethyl isoindole-2-butanoate.

This compound was obtained in the form of an oil, according to the process described in step 1.5 of Example 1, from phenylmethyl-3-carboxy-2 (S) - (phenylmethyl) -1-propanoate and 5-fluoro-2,3-dihydro-1H-isoindole.

2.7.- 5-Fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic acid.

To a solution of 1.18 g (2.83 mmol) of 5-fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoate

phenylmethyl in 5 ml of ethyl acetate, 150 mg of 10% palladium on carbon are added and hydrogenation is carried out at a pressure of 20 psi (137,921 Pa) for 2.5 h. After filtration on celite and then evaporation of the solvent, the product is crystallized from diethyl ether. 0.6 g of a white solid is obtained.

Yield 65%.

Melting point: 136-138 ° C.

Example 3 5-methyl-γ-oxo-α (S) - (phenylmethyl) -2,3- acid dihydro-1 H-isoindole-2-butanoic.

3.1.- 5-Methyl-1H-isoindole-1,3- (2H) -dione. A mixture of 8.1 g (50 mmol) of 5-methylisobenzofuran-1,3-dione and 6 g (100 mmol) of urea is heated at 170 ° C for 45 min. The molten mixture is poured onto water, the precipitate formed is filtered, dissolved in 250 ml of dichloromethane and then washed successively with a saturated solution of sodium hydrogen carbonate, with water and with brine. Finally, it is dried over sodium sulfate and evaporated to dryness. 5.7 g of a slightly yellow solid are obtained. Yield 71%.

Melting point: 196-197 ° C.

3.2.- 5-Methyl-2,3-dihydro-1H-isoindole.

To a suspension of 2 g (12.4 mmol) of 5-methyl-1H-isoindole-1,3- (2H) -dione in 50 ml of tetrahydrofuran, 1.87 g (49.6 mmol) of borohydride are added. sodium. The mixture is cooled to 0 ° C and a solution of 6.25 ml (49.6 mmol) of boron trifluoride etherate in 15 ml of tetrahydrofuran is added. The mixture is refluxed for 5 h, cooled, 25 ml of methanol are added, the mixture is stirred for 1 h at room temperature, then 25 ml of 6N hydrochloric acid is added and the mixture is refluxed for 1 h. The mixture is filtered, the filtrate is concentrated, washed with twice 40 ml of diethyl ether and evaporated to dryness. 20 ml of a 5N sodium hydroxide solution are added and the mixture is extracted with twice 100 ml of dichloromethane. The organic phases are washed with brine, dried over sodium sulfate and then evaporated to dryness. 0.65 g of an oily product is obtained.

3.3.- 5-Methyl-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- phenylmethyl isoindole-2-butanoate.

This compound was obtained in the form of an oil, according to the process described in step 1.5 of Example 1, from phenylmethyl-3-carboxy-2 (S) - (phenylmethyl) -1-propanoate and 5-methyl-2,3-dihydro-1H-isoindole.

3.4.- 5-methyl-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic acid.

This compound was obtained in the form of an oil, according to the process described in step 2.7 of Example 2, from 5-methyl-γ-oxo-α (S) - (phenylmethyl) -2.3 -dihydro-1H-isoindole-2-phenylmethyl butanoate.

The sodium salt of this compound has a melting point above 250 ° C.

By reproducing this example using as starting material 1H-isoindole-1,3 (2H) -dione, it was possible to prepare the acid γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro -1H-isoindole-2- butanoic, γ-oxo-α (R) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic and γ-oxo-α (R, S) - (phenylmethyl) -

2,3-dihydro-1H-isoindole-2-butanoic.

Example 4. α (R, S) - [[(2, 3-dihydro-1H-isoindol-2-yl) carbonyl] aminolbenzenepropanoic acid.

4.1.- α (R, S) - [[(2,3-Dihydro-1H-isoindol-2-yl) carbonyl] amino] phenylmethyl benzenepropanoate.

To a solution of 0.71 g (4.39 mmol) of carbonyldiimidazole in 10 ml of tetrahydrofuran is added a solution of 1.09 g (4.26 mmol) of phenylmethyl α-amino-benzenepropanoate in 10 ml of tetrahydrofuran . After 30 min, a solution of 0.45 g (3.76 mmol) of 2,3-dihydro-isoindole in 5 ml of tetrahydrofuran is added and the mixture is stirred for 16 h at 60 ° C. The solvent is removed, the residue is dissolved in 100 ml of dichloromethane, washed with 2N hydrochloric acid, dried over sodium sulfate and then evaporated to dryness. The residue is purified by chromatography on a silica gel column using the eluent mixture of ethyl acetate / hexane: 1/4. 1.25 g of an oily compound are obtained. Yield: 83%. 4.2.- α (R, S) acid - [[(2,3-dihydro-1H-isoindol-2-yl) carbonyl] amino] benzenepropanoic acid.

This compound was obtained in the form of a white solid, according to the process described in step 2.7 of Example 2, from α (R, S) - [[(2,3-dihydro-1H-isoindol -2- yl) carbonyl] amino] benzenepropanoate of phenylmethyl.

Melting point: 185-187 ° C.

Example 5. Trans-3 - [(2,3-dihvdro-1H-isoindol-2-yl) carbonyl] -1,2,3,4-tetrahydronaphthalene-2-carboxylic acid.

5.1.- ethyl and phenylmethyl trans-1,2,3,4-Tetrahydronaphthalene-2,3-dicarboxylate.

To a suspension of 1.84 g (45 mmol) of chromium chloride in a mixture of 20 ml of tetrahydrofuran and 20 ml of hexamethylphosphoramide, a solution of 1.32 g (5 mmol) of 1 is added for 1 h , 2-bis (bromomethyl) benzene and 3.42 g (15 mmol) of ethyl phenylmethyl E-but-2-enedioate in 20 ml of tetrahydrofuran. The mixture is stirred for 48 h and then the mixture is poured into 100 ml of 1N hydrochloric acid and extracted with four times 50 ml of ethyl acetate. The combined organic phases are washed successively with 100 ml of water, 100 ml of a 5N solution of lithium chloride, 100 ml of water and finally with brine. Dried over sodium sulfate, evaporated to dryness and the residue is chromatographed on a column of silica gel using the eluent mixture ethyl acetate / hexane: 5/95. 0.91 g of an oily product is obtained. Yield 47%.

5.2.- 2-ethyl-1,2,3,4-Tetrahydronaphthalene-2,3-dicarboxylate.

A solution of 0.9 g (2.7 mmol) of ethyl phenylmethyl trans-1,2,3,4-tetrahydronaphthalene-2,3-dicarboxylate is hydrogenated in the presence of 0.4 g of palladium on carbon at 10%, at a pressure of 20 psi (137,921 Pa) for 5 h. We filter the mix on celite and evaporate to dryness. 0.65 g of a white solid is obtained. Yield 97%.

Melting point: 100-103 ° C.

5.3.- ethyl trans-3 - [(2,3-Dihydro-1H-isoindol-2-yl) carbonyl] -1,2,3,4- tetrahydronaphthalene-2-carboxylate.

To a solution of 0.65 g (2.6 mmol) of trans-1,2,3,4-tetrahydronaphthalene-2,3-dicarboxylate in 10 ml of dichlorometane is added at 0 ° C 0.38 ml (5.2 mmol) of thionyl chloride. Stirred at room temperature for 2 h and evaporated to dryness. The residue is dissolved in 10 ml of dichloromethane and the solution obtained is added to a solution of 0.31 g (2.6 mmol) of 2, 3-dihydro-1H-isoindole in 10 ml of dichloromethane and 0.72 ml (5.2 mmol) of triethylamine, cooled to 0 ° C. The mixture is stirred for 4 h at room temperature, 10 ml of water are added, the organic phase is decanted, washed with brine, dried over sodium sulfate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the eluent mixture ethyl acetate / hexane 1/4. 0.55 g of a white solid is obtained. Yield 61%.

Melting point: 119-121 ° C.

5.4.- Trans-3 - [(2,3-dihydro-1H-isoindol-2-yl) carbonyl] - 1,2,3,4-tetrahydronaphthalene-2-carboxylic acid.

This compound is obtained in the form of a white solid, according to the method described in step 1.6 of Example 1, from trans-3 - [(2,3-dihydro-1H-isoindol-2-yl) carbonyl] -1,2,3,4- ethyl tetrahydronaphthalene-2-carboxylate.

Melting point: 224-226 ° C (this compound is listed in the Table below, under No. 23).

Example 6: phenylmethyl γ-oxo-α- (phenylmethyl) -5,6-dihydro-4H-thieno [3.4- c] pyrrole-5-butanoate

6.1. 2- (Phenylmethyl) -1,4-butanedioate of phenylmethyl and 1,1 dimethylethyl

To a solution of 1.66 ml (12 mmol) of diisopropylamine in 1 ml of dry tetrahydrofuran, 5 ml (12 mmol) of a 2.5 M solution of butyllithium in hexane are added at -5 ° C. After 30 min. at this temperature, it is cooled to -70 ° C. and then a solution of 2.40 g (10 mmol) of 3-phenylpropionate is added

phenylmethyl in 15 ml of tetrahydrofuran. After 30 minutes, 2.26 ml (14 mmol) of 1,1-dimethylethyl bromoacetate are added, then the mixture is stirred at O ° C for 2 h and poured into 10 ml of a saturated chloride solution. 'ammonium. The organic phase is decanted, washed with saturated sodium chloride solution, dried over sodium sulfate and then evaporated to dryness. The residue is chromatographed on a silica column using the eluent mixture ethyl acetate / hexane 1/10. 2 g of an oily product are obtained.

6.2. Phenylmethyl 3-Carboxy-2- (phenylmethyl) -1-propanoate To a solution of 2 g (5.6 mmol) of phenylmethyl and 1,1-dimethylethyl 2- (phenylmethyl) -1,4-butanedioate in

16 ml of dichloromethane, 8 ml of acid are added at 0 ° C.

trifluoroacetic. After 7 h at room temperature, evaporated to dryness and then crystallized from cyclohexane.

1.05 g of a white product are obtained.

Melting point: 86-87 ° C.

6.3. γ-Oxo-α- (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5 butylate phenylmethyl

To a solution of 1.01 g (3.4 mmol) of phenylmethyl 3-carboxy-2- (phenylmethyl) -1-propanoate in 15 ml of dichloromethane, 0.49 ml is added at 0 ° C. 8 mmol) of thionyl chloride then two drops of N, N-dimethylformamide. After

2 h at room temperature, evaporated to dryness and the residue is dissolved in 25 ml of dichloromethane. The solution is cooled to 0 ° C. and then a solution of 0.81 g (3.4 mmol) of

5,6-dihydro-4H-thieno [3,4-c] pyrrole trifluoroacetate and 1.4 ml (10.2 mmol) of triethylamine in 25 ml of dichloromethane. After 16 h at room temperature, 25 ml of water are added, the organic phase is decanted, washed with a saturated solution of sodium chloride and then dried over sodium sulfate and evaporated to dryness. The residue is chromatographed on silica gel using the eluent mixture ethyl acetate / hexane 3/7. 0.52 g of a white solid is obtained.

Melting point: 122-124 ° C.

Example 7: γ-oxo-α- (phenylmethyl) -5,6-dihydro-4H- thieno [3,4-c] pyrrole-5-butanoic acid

To a solution of 1.22 g (3 mmol) of γ-oxo-α- (phenyl

methyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoate of phenylmethyl in 15 ml of tetrahydrofuran, we add

15 ml of ethanol then, at 0 ° C, a solution of 0.36 g

(9 mmol) sodium hydroxide. After 1 h at room temperature, the medium is concentrated to about 15 ml, 15 ml of water are added, then acidified with 2N hydrochloric acid to pH 2 and extracted with 3 times 25 ml of ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is triturated with diethyl ether to provide 0.71 g of a white solid.

Melting point: 161-163 ° C.

Example 8: 5- [4- (4-methylpiperazin-1-yl] -1,4-dioxo-3- (phenylmethyl) butyl] -5,6-dihydro-4H-thieno [3,4-c] pyrrole

To a solution of 1 g (3.17 mmol) of γ-oxo-α- (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid in 15 ml of dry tetrahydrofuran, 0.55 g (3.39 mmol) of carbonyldiimidazole is added. The mixture is stirred at room temperature for 1 h and then 0.42 ml (3.8 mmol) of 4-methylpiperazine is added and the mixture is stirred at room temperature for 20 h The mixture is evaporated to dryness, the residue is dissolved in 50 ml of dichloromethane , then the solution obtained is washed successively with 2 times 50 ml of a saturated solution of sodium hydrogencarbonate and 20 ml of a saturated solution of sodium chloride, dried over sodium sulfate and then evaporated to dryness. After crystallization from ethanol, 1 g of a white solid is obtained. Melting point: 156-158 ° C.

The compounds of the invention are collated in the following table with their physical characteristics. They could have been prepared according to the methods described above.

The compounds of the invention have been tested in various biological tests.

In particular, they were subjected to an activity test

hypoglycemic in rats.

This test is carried out on rats fasted for 20 h. The products to be tested are administered orally. Blood samples are taken from the tail 0.5, 1, 2, 3, 5 and 7 h after administration of the product, according to the method described by H. OHNOTA in The Journal of Pharmacology and Experimental Therapeutics, 269, nδ 2, 489-495 (1994).

The compounds of the invention reduce the basal blood sugar by 30 to 40% at doses between 1 and 10 mg / kg.

The results show that the compounds of the invention

exhibit "in vivo" hypoglycemic properties. They can therefore be used as a medicine in the treatment of hyperglycemia, diabetes and obesity.

The compounds of the invention can be presented, in

combination with any suitable excipient, in any pharmaceutical form or composition suitable for oral or parenteral administration, for example, in the form of tablets, capsules, dragees, or oral solutions or

injectables.

The compounds of the invention can be administered in daily doses of between approximately 5 and 100 mg in adults by the oral route, or between approximately 1 and 100 mg by the parenteral route.

Claims

1. Azacycloalkane derivatives of general formula (I)

in which:

* R ₁ and R ₂ , identical or different, each represent a hydrogen atom, an alkyl group, linear, branched or cyclic, comprising from 1 to 6 carbon atoms, or a phenyl group optionally substituted by an alkyl group, linear or branched, comprising from 1 to 6 carbon atoms, by one or two halogen atoms, a COOR ₆ group, R ₆ being a hydrogen atom or an alkyl group, linear or branched,

comprising from 1 to 6 carbon atoms,

or R ₁ and R ₂ together form an oxo group,

* R ₃ represents a hydrogen atom or an alkyl group, linear or branched, comprising from 1 to 4 carbon atoms, or else R ₃ forms a methylene group, * R ₄ represents an aromatic group chosen from a phenyl or naphthyl group or pyridinyl, optionally substituted by an alkyl group, linear or branched, comprising from 1 to 6 carbon atoms, by one or two halogen atoms, by a nitro group, or by a COOR ₆ group, R ₆ being as defined above,

or, when R ₃ forms a methylene group, then R ₄ represents a phenylene group in which a carbon atom is linked to Y and another carbon atom, adjacent to the preceding one, is linked to said methylene group, * R ₅ is either an OR ₇ group, where R ₇ is a hydrogen atom or a benzyl group, or an N ₄ -methyl-piperazinyl group, or also an NHR ₈ group where R ₈ is a hydroxyl group,

pyridinylmethyl or phenylmethyl,

* n is equal to 1 or 2,

* A is an aromatic ring, optionally substituted by one or two halogen atoms, one or two alkyl groups, linear or branched, comprising from 1 to 4 carbon atoms, by a nitro group, by a COOR ₆ , R _{6 group} being as defined above, by one or two alkoxy groups, linear or branched, comprising from 1 to 6 carbon atoms or by a methylenedioxy group, * X is CH, O or N, and

* Y is CH ₂ , O or S, in the form of pure enantiomers or mixtures of enantiomers, including racemic mixtures, and their addition salts with acids and with pharmaceutically acceptable bases.

2. Derivatives according to claim 1, characterized in that A is an aromatic ring, whether or not substituted, chosen from the group consisting of thiophene, benzene, furan and naphthalene.

3. Derivatives according to one of claims 1 and 2, characterized in that n is equal to 1 and R ₅ is a hydroxyl group.

4. Derivatives according to one of claims 1 to 3, characterized in that they consist of the derivatives of formula II wherein R5 is as defined in claim 1 and R ₉ and R ₁₀ , identical or different, represent a hydrogen atom, a halogen atom or an alkyl group, linear or branched, comprising from 1 to 4 atoms carbon.

5. Derivatives according to one of claims 1 to 4, characterized in that they are in the form of a sodium or calcium salt, so that R7 represents a sodium or calcium atom.

6. γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.

7. γ-oxo-α (R) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.

8. γ-oxo-α (R, S) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic acid.

9. 5-Fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic acid.

10. 4-Fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H- isoindole-2-butanoic acid.

11. γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4H-furo [3,4- c] pyrrole-5-butanoic acid.

12. γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H- furo [3,4-c] pyrrole-5-butanoic acid.

13. γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid.

14. γ-oxo-α (R) - (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid.

15. γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H- thieno [3,4-c] pyrrole-5-butanoic acid.

16. Phenylmethyl γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4tf-thieno [3,4- c] pyrrole-5-butanoate.

17. Process for preparing the compounds according to one of claims 1 to 16, characterized in that it comprises the following steps: i) reacting a compound of formula (III)

in which R ₁ , R ₂ , A and n are as defined in claim 1,

with a compound of formula (IV)

wherein R ₃ , R ₄ , X and Y are as defined in claim 1, R ₁₁ represents a halogen atom or a hydroxyl group and R ₁₂ ^{is an} alkoxy group comprising from 1 to 4 carbon atoms, linear or branched, or a group

phenylalkoxy, of which the alkoxy part comprises from 1 to 4 atoms of carbon, such as the benzyloxy group,

so as to obtain a compound of formula (la)

in which R ₁ , R ₂ , R ₃ , R ₄ , R ₁₂ , A, n, X and Y have the

meanings mentioned above, ii) where appropriate, hydrogenolysis or hydrolysis of the group R ₁₂ of the compound of formula (la) to prepare the compounds of formula (I) in which R ₅ represents a hydroxyl group, iii) then, as the case may be where appropriate, the compounds of formula (I) are prepared where R ₅ is either an N ₄ -methyl-piperazinyl group or an NHR ₈ group where R ₈ is a hydroxyl, pyridinylmethyl or phenylmethyl group, by reacting the compounds of formula ( I) where R ₅ is a hydroxyl group, with an amine of formula HZ in which Z represents an N ₄ -methyl-piperazinyl group or an NHR ₈ group as defined above, in the presence of

carbonyldiimidazole.

18. Medicament characterized in that it comprises at least one azacycloalkane derivative according to one of claims 1 to 16.

19. Pharmaceutical composition characterized in that it comprises at least one azacycloalkane derivative according to one of claims 1 to 16, in combination with any suitable excipient.

20. Use of an azacycloalkane derivative according to one of claims 1 to 16, for the preparation of a medicament intended for the treatment of diabetes, hyperglycemia or obesity.