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

Azacycloalcane derivatives, preparation thereof and their applications in therapy

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EP0823912A1
EP0823912A1 EP19960913576 EP96913576A EP0823912A1 EP 0823912 A1 EP0823912 A1 EP 0823912A1 EP 19960913576 EP19960913576 EP 19960913576 EP 96913576 A EP96913576 A EP 96913576A EP 0823912 A1 EP0823912 A1 EP 0823912A1
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ml
group
phenylmethyl
dihydro
acid
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German (de)
French (fr)
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Zurita Manuel Bedoya
Sol Moreno Gregorio Del
Martin Juan Antonio Diaz
Bargueno Maria Dolores Jimenez
Escudero Perez Ulpiano Martin
Ferrer Magali Romanach
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Synthelabo
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Synthelabo
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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D491/00Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04Ortho-condensed systems
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D209/00Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44Iso-indoles; Hydrogenated iso-indoles
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D217/00Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/06Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with the ring nitrogen atom acylated by carboxylic or carbonic acids, or with sulfur or nitrogen analogues thereof, e.g. carbamates
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D495/00Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04Ortho-condensed systems

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

Azacycloalkanes DERIVATIVES, THEIR PREPARATION AND THEIR

THERAPEUTIC APPLICATIONS

The present invention relates to derivatives

of azacycloalkanes, their preparation and their applications in therapy, especially in the treatment of diabetes, obesity and hyperglycemia.

Derivatives of azacycloalkanes 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 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 group COOR 6, R 6 being a hydrogen atom or an alkyl group linear or branched comprising from 1 to 6 carbon 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 R 3 form a methylene group,

* R 4 represents an aromatic group selected from phenyl, naphthyl 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 nitro , or COOR 6, R 6 being as defined above,

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

* R 5 is either OR 7, wherein R 7 is a hydrogen atom or a benzyl group, or a group N 4 - ethyl-piperazinyl, or else NHR 8 wherein 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, a nitro group, a COOR 6, R 6 being as defined above, with 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) formed with acids and pharmaceutically acceptable base salts which are part of the invention. According to the present invention, preferred salts are the sodium and calcium salts, which are such that R 7 is a sodium or calcium atom.

The compounds of formula (I) contain an asymmetric carbon atom. They can therefore exist as enantiomers. These enantiomers and mixtures thereof, including 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, and, optionally, a heteroatom selected from the group consisting of sulfur, oxygen and nitrogen, said ring having a maximum number of unsaturations, given its optional substituents. Furthermore, it is noted that when n is 1 or 2, this means that the number of carbon atoms included in the brackets is 1 or 2. When n is equal to 1, the azacycloalkane derivative according to 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 selected from the group consisting of thiophene, benzene, furan and naphthalene, these aromatic groups being substituted or not as indicated above.

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

preferably an unsubstituted phenyl group.

As subgroup of compounds according to the invention, we may notably mention the one consisting of acid derivatives .gamma.-oxo-α- (phenylmethyl) -5,6-dihydro-4H-thieno [3,4- c] pyrrole-5- butanoic acid of formula II

wherein 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.

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

The compounds of formula (I) may be prepared according to the process shown in Scheme 1 in Appendix 1. In this method, reacting a compound of formula (III)

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

wherein 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 1 to 4 carbon atoms, linear or branched, or a phenylalkoxy group whose alkoxy part has from 1 to 4 carbon atoms, such as benzyloxy.

One can carry out this reaction in a solvent such as dichloromethane, in the presence of triethylamine and / or an activating agent for the acid function as chloroformate

isobutyl or carbonyldiimidazole (CDI). Thus preparing compounds of formula (Ia) wherein 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) wherein R 5 is a benzyloxy group can thus be directly obtained by selecting R 12 as a benzyloxy group.

The compounds of the invention of formula (Ib), wherein R 5 is hydroxyl, may be obtained by hydrogenolysis or hydrolysis of the compounds of formula (la), for example by means of sodium hydroxide or hydrochloric acid.

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

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

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

(1995).

More particularly, the compounds of formula (III), wherein A is a benzene group optionally substituted, n is 1, R 1 and R 2 each represent a hydrogen atom, can especially be prepared according to the two processes represented in schemes 2 and 3 of Annex 2. According to the method of scheme 2, reacting a compound of formula (V), wherein R 13 represents a halogen atom, an NO 2 group, linear or branched alkyl, comprising 1 to 4 carbon atoms, with urea to prepare an imide compound of formula (VI) wherein R 13 has the meaning indicated above. Is then reduced the imide compound of formula (VI) with sodium borohydride in the presence of

boron trifluoride etherate, to obtain the compounds of formula (IIIa) wherein R 13 has the meaning indicated above. According to Scheme 3, successively reacting a compound of formula (VII) wherein 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, and then finally with hydrochloric acid to obtain a compound of formula (VIII). The latter is subjected to the action of sodium hydride, and then to that of potassium tert-butoxide in the presence of water to obtain the compounds of formula (IIb) wherein R14

represents a halogen atom.

The compounds of Fomule (IV) may be prepared according to methods described in the literature, eg 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 acid (R, S) - (phenylmethyl) -5,6-dihydro-4H-furo [3,4-c] pyrrole-5-butanoic acid.

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

room temperature for 16 h and 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 100 ml

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

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

To a solution of 5.3 g (41.36 mmol) furan-3,4-dimethanol in 30 ml of chloroform was added at 0 ° C, a solution of 7.5 ml (105.3 mmol) of thionyl in 30 ml of chloroform. 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 sulphate and then evaporated to dryness. Was obtained 3.97 g of an oily product. 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 was added at 0 ° C, 0.72 g (18 mmol) of a dispersion of sodium hydride in oil; at room temperature was stirred for 90 min., then a solution of 1 g (6 mmol) of 3,4-bis (chloromethyl) furan in 20 ml of N, N-dimethylformamide. Stirred for 2.5 h, cooled to 0 ° C was added 50 ml of water and extracted with three times 50 ml of ethyl acetate; the combined organic phases are washed with brine, dried over sodium sulfate then evaporated to dryness. The residue is purified by chromatography on silica gel using the eluent mixture ethyl acetate / hexanne 1/4. 0.42 g of a white solid is obtained. Yield 32%.

Melting point: 84.5 to 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 (67, 5 mmoles) of an aqueous solution 2.5 M sodium hydroxide. The mixture was stirred at reflux for 6.5 h; the ethanol is distilled and extracted with three 30 ml diclorométhane. The combined organic phases are washed with brine, dried over sodium sulfate and evaporated to dryness. 1.25 g is obtained as an oily product which is used as such for the next reaction.

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

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

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

Melting point: 101-102 ° C.

1.6.- γ-oxo-α acid (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] pyrrole-5-phenylmethyl butanoate in 10 ml of tetrahydrofuran 10 ml of ethanol is added, then at 0 ° C, a solution of 0.308 g (7.7 mmol) of sodium hydroxide in 10 ml of water. The mixture was stirred for 2 h at 0 ° C, then for 2 hours at room temperature. Concentrating the solution obtained, 30 ml of water was added and washed with twice 35 ml of diethyl ether. The aqueous phase is cooled, and then a 2M solution of acid

hydrochloric acid until pH 2. The precipitate was filtered formed, 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 is added at -78 ° C, 22.9 ml (57 3 mmol) of a solution of n-butyllithium 2.5M in hexane. Stirred 1 h at 0 ° C, cooled to -78 ° C and then 2 ml of N, N-dimethylformamide and stirred for 2 h at 0 ° C. 20 ml of a saturated solution of ammonium chloride, stirred 30 min at room temperature and then 50 ml of water and 100 ml of ethyl acetate. the organic phase is washed with brine, dried over sodium sulfate then evaporated to dryness. The residue crystallized from ethyl acetate / hexane. 3 g of a white solid is 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 is added at 0 ° C, 0, 08 g (2.1 mmol) of sodium borohydride. Stirred for 4 h at room temperature, then the solvent is removed. 20 ml of a saturated solution of sodium hydrogencarbonate and extracted with twice 30 ml of dichloromethane. Washed the organic layers with brine, dried over sodium sulfate and then evaporated to dryness. The product crystallized from ethyl acetate / hexane as a white solid. There is obtained 0.27 g. 54% yield.

Melting point: 102-103 ° C.

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

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

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-diméthyIpropanamide in 70 ml of N, N-dimethylformamide is added at 0 ° C, 0.49 g (12.3 mmol) of a dispersion of sodium hydride 60% in oil. Stirred at 0 ° C for 1 h, then 2 ml of acid is added

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

Melting point: 80-82 ° C.

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

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

tetrahydrofuran, then dry the filtrates evaporated. 20 ml of hydrochloric acid 6N was added, washing the resulting solution with twice 20 ml of ethyl acetate and then basified the aqueous-phase with 6 N sodium hydroxide to pH 14 and is extracted with three times 30 ml of ethyl acetate. Washed the organic layers with brine, dried over sodium sulfate and the evaporated to dryness. Was obtained 0.69 g of an oily product.

Yield 61%.

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

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

2.7.- acid 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 was added 150 mg palladium on charcoal 10% and hydrogenated 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 was crystallized in diethyl ether. Is obtained 0.6 g of a white solid.

Yield 65%.

Melting point: 136-138 ° C.

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

3.1.- 5-Methyl-1H-isoindole-1,3 (2H) -dione. A mixture of 8.1 g (50 mmol) of 5- méthylisobenzofuranne-1,3-dione and 6 g (100 mmol) of urea at 170 ° C for 45 min. Pouring the molten mixture into water, filter the precipitate formed, dissolved in 250 ml of dichloromethane and then washed successively with a saturated solution of sodium hydrogencarbonate, with water and with brine. Finally dried over sodium sulphate and evaporated to dryness. 5.7 g of a slightly yellow solid. 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 is added 1,87g (49.6 mmol) of sodium borohydride sodium. The mixture was cooled to 0 ° C and a solution of 6.25 ml (49.6 mmol) of boron trifluoride etherate in 15 ml of tetrahydrofuran. is refluxed for 5 h, cooled, 25 ml of methanol, stirred for 1 h at room temperature, then 25 ml of hydrochloric acid 6N was added and heated at reflux for 1 h. The mixture was filtered, the filtrate is concentrated, washed with twice 40 ml of diethyl ether and evaporated to dryness. 20 ml of a sodium hydroxide solution 5 N and extracted with twice 100 ml of dichloromethane. Washed the organic layers with brine, dried over sodium sulfate then evaporated to dryness. Was obtained 0.65 g of an oily product.

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

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

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

This compound was obtained as an oil according to the method described in step 2.7 of Example 2, from 5-methyl-γ-oxo-α (S) - (phenylmethyl) -2,3 dihydro-1H-isoindole-2- butanoate phenylmethyl.

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

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

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

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

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

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

Melting point: 185-I87 ° C.

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

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

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 was added for 1 h, a solution of 1.32 g (5 mmol) of 1 , 2-bis (bromomethyl) benzene and 3.42 g (15 mmol) of ethyl E-but-2-énedioate and phenylmethyl in 20 ml of tetrahydrofuran. Stirred for 48 h and then poured into 100 ml of 1N hydrochloric acid and extracted with four times 50 ml of ethyl acetate. Wash the combined organic phases successively with 100 ml of water, 100 ml of a 5 N 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 silica gel column using the eluent mixture ethyl acetate / hexane: 5/95. Was obtained 0.91 g of an oily product. Yield 47%.

5.2.- trans-1,2,3,4-tetrahydronaphthalene-2,3-dicarboxylic acid 2-ethyl.

A solution of 0.9 g (2.7 mmol) of trans-1,2,3,4-tetrahydronaphthalene-2,3-dicarboxylate ethyl and phenylmethyl, in the presence of 0.4 g palladium on charcoal to 10% at a pressure of 20 psi (137,921 Pa) for 5 h. The mixture was filtered through celite and evaporated to dryness. Was obtained 0.65 g of a white solid. Yield 97%.

Melting point: 100-103 ° C.

5.3.- 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-dicarboxylic acid 2-ethyl ester in 10 ml of dichlorométane is added at 0 ° C 0.38 ml (5.2 mmol) of thionyl chloride. at room temperature was stirred for 2 h and evaporated to dryness. The residue was dissolved in 10 ml of dichloromethane and the resulting solution into 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 was stirred for 4 h at room temperature, 10 ml of water is added, the organic phase decanted, washed with brine, dried over sodium sulphate and then evaporated to dryness. The residue is purified by chromatography on silica gel using the eluent mixture ethyl acetate / hexane 1/4. Was obtained 0.55 g of a white solid. Yield 61%.

Melting point: 119-121 ° C.

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

This compound was obtained as 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-tetrahydronaphthalene-2-carboxylate.

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

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

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

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

phenylmethyl in 15 ml of tetrahydrofuran. After 30 min., 2.26 ml (14 mmol) of 1,1-dimethylethyl bromoacetate and the mixture was 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 a saturated solution of sodium chloride, dried over sodium sulfate then evaporated to dryness. The residue is chromatographed on a column of silica with the eluent mixture ethyl acetate / hexane 1/10. Is obtained 2 g of an oily product.

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

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

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

Was obtained 1.05 g of a white product.

Melting point: 86-87 ° C.

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

To a solution of 1.01 g (3.4 mmol) of 3-carboxy-2- (phenylmethyl) -1-propanoate phenylmethyl in 15 ml of dichloromethane was added at 0 ° C, 0.49 ml (6, 8 mmol) of thionyl chloride and 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 was cooled to 0 ° C then a solution of 0.81 g (3.4 mmol) of

trifluoroacetate 5,6-dihydro-4H-thieno [3,4-c] pyrrole and 1.4 ml (10.2 mmol) of triethylamine in 25 ml of dichloromethane. After 16 h at room temperature, 25 ml of water, the organic phase 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. It obtien 0.52 g of a white solid.

Melting point: 122-124 ° C.

Example 7: acid 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-phenylmethyl butanoate in 15 ml of tetrahydrofuran was added

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

(9 mmol) of sodium hydroxide. After 1 h at room temperature, the medium is concentrated to about 15 ml, adding 15 ml of water and then acidified with 2N hydrochloric acid to pH 2 and extracted 3 times with 25 ml of ethyl acetate. the organic phases are combined, washed with a saturated solution of sodium chloride, dried over sodiu sulfate and evaporated to dryness. The residue was 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- acid (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid in 15 ml of dry tetrahydrofuran was added 0.55 g (3.39 mmol) of carbonyldiimidazole. Stirred at room temperature for 1 h then 0.42 ml (3.8 mmol) of 4- methylpiperazine and stirred at room temperature for 20 h The mixture was evaporated to dryness, the residue is dissolved in 50 ml of dichloromethane then the solution obtained is washed successiveme 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 sulphate and then evaporated to dryness. After crystallization from ethanol, 1 g of a white solid. Melting point: 156-158 ° C.

The compounds of the invention are summarized in the following table with their physical characteristics. They have been prepared by the methods described above.

The compounds of the invention were tested in various bioassays.

In particular, they were subjected to activity test

hypoglycemic rats.

This test is performed on rats fasted for 20 hours. The test products are administered orally. Blood samples are made at the tail 0.5, 1, 2, 3, 5 and 7 hours after dosing, as described by H. OHNOTA in The Journal of Pharmacology and Experimental Therapeutics, 269, nδ 2 489-495 (1994).

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

The results show that the compounds of the invention

present "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 form or pharmaceutical composition suitable for oral or parenteral administration, for example in the form of tablets, capsules, coated tablets, or drinkable solutions or

injectables.

The compounds of the invention may be administered at daily doses between about 5 and 100 mg in adults orally, or between about 1 and 100 mg parenterally.

Claims

1. azacycloalkanes 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 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 group COOR 6, R 6 being a hydrogen atom or an alkyl group, linear or branched,
comprising 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 R 3 form a methylene group, * R 4 represents an aromatic group selected from phenyl, naphthyl or pyridinyl, optionally substituted by an alkyl group, linear or branched comprising from 1 to 6 carbon atoms, by one or two halogen atoms, nitro, or COOR 6, R 6 being as defined above,
or, when R 3 form a methylene group, then R 4 represents a phenylene group in which one carbon atom is linked to Y and another carbon atom, adjacent to the previous one, is bonded to said methylene group, * R 5 is either a group oR 7, wherein R 7 is a hydrogen atom or a benzyl group, or a group N-methyl 4-piperazinyl, or else NHR 8 wherein 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, a nitro group, a COOR 6, R 6 being as defined above, with 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 pharmaceutically acceptable bases.
2. Derivatives according to Claim 1, characterized in that A is an aromatic ring, subtitué or not, selected 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 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 carbon 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, such that R7 represents a sodium or calcium atom.
6. γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.
7. The γ-oxo-α (R) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.
8. The γ-oxo-α (R, S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.
9. The acid 5-fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.
10. The acid 4-fluoro-γ-oxo-α (S) - (phenylmethyl) -2,3-dihydro-1H-isoindole-2-butanoic acid.
11. The γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4H-furo [3,4-c] pyrrole-5-butanoic acid.
12. The γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H-furo [3,4-c] pyrrole-5-butanoic acid.
13. The γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid.
14. The γ-oxo-α (R) - (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid.
15. The γ-oxo-α (R, S) - (phenylmethyl) -5,6-dihydro-4H-thieno [3,4-c] pyrrole-5-butanoic acid.
16. The γ-oxo-α (S) - (phenylmethyl) -5,6-dihydro-4Tf-thieno [3,4-c] pyrrole-5-butanoate phenylmethyl.
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)
wherein 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 1 to 4 carbon atoms, linear or branched, or a group
phenylalkoxy, the alkoxy part comprises from 1 to 4 carbon atoms, such as benzyloxy,
so obtaining a compound of formula (Ia)
wherein R 1, R 2, R 3, R 4, R 12, A, n, X and Y have the
meaning mentioned above, ii) if desired, hydrogenolysis or hydrolyzing the R 12 group of the compound of formula (Ia) to prepare compounds of formula (I) wherein R 5 represents a hydroxyl group, iii) then, if desired, prepare the compounds of formula (I) wherein R 5 is either an N-methyl 4-piperazinyl, or NHR 8 wherein R 8 is a hydroxyl group, pyridinylmethyl, or phenylmethyl, by reacting the compounds of formula ( I) where R 5 is a hydroxyl group, with an amine of formula HZ in which Z represents N-methyl-piperazinyl or 4 NHR 8 as defined above, in the presence of
carbonyldiimidazole.
18. Medicament, characterized in that it comprises at least one derivative of azacycloalkane derivative according to one of claims 1 to 16.
19. Pharmaceutical composition characterized in that it comprises at least one derivative of azacycloalkane derivative according to one of claims 1 to 16, in association with any suitable excipient.
20. Use of a derivative of azacycloalkane derivative according to one of claims 1 ttoo 16, for the preparation of a medicament for the treatment of diabetes, hyperglycemia or obesity.
EP19960913576 1995-05-03 1996-04-12 Azacycloalcane derivatives, preparation thereof and their applications in therapy Withdrawn EP0823912A1 (en)

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FR9505260 1995-05-03
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