EP0923567A1

EP0923567A1 - Benzylamine derivatives, their preparation and their application in therapeutics

Info

Publication number: EP0923567A1
Application number: EP97937650A
Authority: EP
Inventors: Christophe Philippo; Marie-Claire Orts; Olivier Crespin; Philippe Bovy
Original assignee: Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1996-08-29
Filing date: 1997-08-22
Publication date: 1999-06-23
Also published as: US6060508A; WO1998008834A1; AU4020097A; FR2752839B1; ZA977767B; JP2000516945A; AR009468A1; FR2752839A1

Abstract

Compounds of general formula (I) in which: A represents either one hydrogen atom, one hydroxyl, one C1-6 hydroxyalkyl group, one thiol, one C1-6 alkylsulphanyl group, one amine group, one C1-6 alkylamine group, one di (C1-6 alkyl) amine group, one C1-6 alkyl hydroxylamine group, one C1-6 alcoxy group, one hydroxylamine group, one C1-6 N, O-dialkyl hydroxylamine group, one azide, one halogen such as fluorine, chlorine or bromine, B represents one hydrogen atom, one C1-6 alkyl, branched or linear, one C2-6 alkenyl group, one C1-6 fluoroalkyl group, one C1-2 perfluoroalkyl group, one C1-6 alcoxy group, one phenyl group, or one oxo group, X represents one oxygen or sulphur atom. The invention is useful in therapeutics.

Description

BENZYLAMINE DERIVATIVES, THEIR PREPARATION AND THEIR APPLICATION

IN THERAPEUTICS

The compounds of the present invention correspond to the general formula (I)

in which :

A represents either a hydrogen atom, a hydroxyl, a C _{λ 6} hydroxyalkyl group, a thiol, a C _xs alkylsulfanyl group, an amino group, a C _{x 6} alkylammo group, a di (C _{x 6} alkyl) amino group, a group C _{λ 6} alkyl hydroxylamine, a group C _{,. 6} alkoxy, a hydroxylamine group, a Cj ₆ N group, 0-dιalkyl hydroxylamine, an azido, a halogen such as fluorine, chlorine or bromine, B represents a hydrogen atom, a C _{: s} alkyl group, linear or branched, a group C ₂ . ₆ alkenyl, a Ci ₆ fluoroalkyl group, a Cj ₂ perfluoroalkyl group, a C, _ ₆ alkoxy group, a phenyl group, or an oxo group, X represents an oxygen or sulfur atom, Rj _. and R ₂ represent, independently of one another, a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano, a carboxamide, a C _{l 6} alkyl group, linear or branched, a group C ₂ . ₆ alkenyl, a C _{3 6} cycloalkyl group, a C _1-s alkoxycarbonyl group, a C _{x 6} hydroxyalkyl group, a C _{λ 6} alkoxy group, a C _1-6 alkoxyalkyl group, a C _1-6 fluoroalkyl group, a group C _{1 2} perfluoroalkyle or R _x and R ₂ together form, with the double bond to which they are attached, a C _{3 6} cycloalkenyl ring, a C _{4 6} cycloalkdienyl ring, or an aryl in

R ₃ and R ₄ represent, independently of one another, a hydrogen atom, a C _1-β alkyl group, a C _{2 6} alkenyl group, C _3-6 cycloalkyl, C _{3 6} cycloalkenyl, a group C ₁₆ fluoroalkyle, a group C _{l 2} perfluoroalkyle or R ₃ and R ₄ together form a group C _{2 6} alkylene, C _{2 6} alkenylene, to give for example a piperidyle, azétidinyle or pyrrolidyl, or R ₃ and R ₄ together, with the nitrogen to which they are attached, a heterocycle, saturated or unsaturated, comprising 3 to 6 carbon atoms and a second nitrogen atom, this nitrogen atom being optionally substituted by a C ^ ,, alkyl group, to give for example a piperazyl or imidazyl, or an oxygen atom, to give for example a morpholinyl; and

R ₅ represents a hydrogen atom or a halogen, such as fluorine, chlorine or bromine.

The compounds of general formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers, as well as their mixtures, including racemic mixtures are part of the invention.

The compounds of general formula (I) can be in the form of a free base or of addition salts with pharmaceutically acceptable acids, which also form part of

1 invention.

The compounds of the invention can be prepared by methods illustrated by the schemes which follow.

The compounds of formula (I), in particular those for which A represents a hydroxyl group, can be prepared according to the process described in scheme 1.

According to this process, an ethenyl derivative of formula IV is reacted with an oxidant such as sodium periodate, osmium tetroxide or metachloroperbenzoic acid in basic or acidic medium so as to form a diol of formula III. The hydroxyl group twinned with group B is selectively protected by a protective group P, in a manner known to a person skilled in the art, for example by formation of a silylated ether, so as to obtain the compound of formula II. The hydroxyl group carried by the alpha carbon of the heterocyle of the compound thus obtained, can then optionally be activated, in a manner known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyle group or a bromine atom. The compound of formula (I) according to the invention is then prepared from this compound by reacting it with an amine HR ₃ R ₄ , followed by deprotection by methods known to those skilled in the art. The meanings of X, R _lt R ₂ , R ₃ , R ₄ , R ₅ and B in each of the compounds of formulas II, III and of the amine NHR ₃ R ₄ , are those indicated for formula (I).

Diagram 1

The ethenyl derivative of formula IV can itself be prepared from a bro derivative of formula V as defined above, by palladic coupling of Stille with a compound of formula X, under the conditions defined by Me Kean, DR; Parinello, G. Renaldo, AF; Stille, JK, J. Org. Chem. , 52, 1987, 492.

Alternatively, the ethenyl derivative of formula IV can be prepared from an aldehyde derivative of formula XI, by a Wittig reaction under conditions standard for a person skilled in the art. The compounds of formula XI can themselves be prepared by formylation of a bro derivative of formula V in the presence of N, N-dimethylformamide and butyl lithium. The formylation reaction can be carried out in an organic solvent such as tetrahydrofuran, N, N-dimethylformamide or a mixture of these solvents, according to the following reaction scheme (2):

Diagram 2

V XI IV

The compounds of formula V can themselves be prepared from β-phenoxyketones or β-thiophenoxyketones of formula

VI which is reacted with an acid, preferably a mineral acid, such as polyphosphoric acid or sulfuric acid (scheme 1). The meanings of X, R _{1 (} R ₂ and R ₅ for the compounds of formulas V and VI are those indicated for formula (I).

The compounds of formula VI can be obtained directly from the corresponding phenols or thiophenols of formula

VII which is reacted with an α-haloketone of formula VIII, preferably an α-chloroketone. This reaction can be carried out in an organic solvent, such as N, N-dimethylformamide, in the presence of potassium carbonate and an iodide such as potassium iodide (scheme 1). The meanings of X, R _lr R ₂ and R ₅ for compounds of formulas VI and VII, are those indicated for formula (I).

The compounds of formula VI can also be prepared in two stages, by reaction of a compound of formula VII as defined above, with an α-haloester of formula VIII, where R _j has the meaning indicated for formula I , in an organic solvent such as N, N-dimethylformamide, in the presence of potassium carbonate and an iodide such as potassium iodide followed, after saponification, by the transformation of intermediate IX thus obtained into said compound of formula VI. This transformation is effected by the action of thionyl chloride followed or not by the amine of einreb (SO ₂ C1 ₂ / NH (CH ₃ ) (OCH ₃ )), under the conditions described by Nahm and Weinreb, Tet. Lett., 22, 3815, 1981, followed by the reaction with an organometallic of formula R ₂ MY for which R _{2 has} the meaning indicated for formula I, M represents a metal and Y represents a halogen such as chlorine or bromine . This organometallic is preferably an organomagnesium.

In addition to the process described above, the compounds of formula V, for which X represents an oxygen, in particular those for which R _: is a methyl group and R ₂ is a hydrogen atom, can be prepared according to the reaction scheme ( 3) following:

Diagram 3

According to this process, a compound of formula VII is reacted as defined above, with propargyl bromide. This reaction can be carried out in an organic solvent such as N, N-dimethylformamide, in the presence of potassium carbonate and an iodide such as potassium iodide. The phenoxypropargyl derivative of formula XII thus obtained is then reacted with diethylaniline in the presence of cesium fluoride, this under the conditions described by Ishi, H. et al., Chem. Pharm. Bull., 40, 1992, 1148.

Furthermore, the compounds of formula XI, in particular those for which R _λ and R ₂ each represent a hydrogen atom, can be prepared according to the following reaction scheme (4):

Diagram 4

According to this process, a 2,3-dihydrobenzofuran or 2,3-dihydrobenzothiophene of formula XIII is reacted with n-butyl lithium in an organic solvent such as N, N-dimethylformamide, tetramethylene diamine (TMEDA) or their mixtures . An aldehyde derivative of formula XIV is then obtained which is treated with 2, 3-dichloro-5, 6-dιcyanocyclohexa- 2, 5-diene-1,4-dione (DDQ). The compound of formula XI obtained is then recovered which can be used to prepare the compound of formula (I) according to the process described above.

The compounds of formula (I) according to the invention, for which A is a hydroxyl group, can also be prepared according to the following reaction scheme (5):

XV |

According to this process, the compound of formula (I) is prepared by reacting an oxirane derivative of formula XV with an amine NHR ₃ R ₄ . The meanings of X, Rj, R ₂ , R ₃ , R 2, R ₅ and B of the oxirane derivative of formula XV and of said amine, are those indicated for formula (I).

The oxirane derivative of formula XV can be prepared either by reaction of trimethylsulfonium iodide on the aldehyde of formula XI described above, or by the action of a peracid such as metachloroperbenzoic acid on the ethenyl derivative of formula IV in conventional conditions for those skilled in the art.

It is also possible to obtain oxirane from a ketone of formula XVI.

XVI

In this case, the ketone is halogenated in the α position, and reduced to halohydrin which, treated with a base, is converted into oxirane XV.

Alternatively, the compounds of formula (I), in which A is a C _1-6 alkoxy group and B an oxo group according to the invention, can be prepared according to the scheme reaction (6) next

Diagram 6

HNR ₃ R ₄

Reduction

(D (I)

According to this process, a metallation of a bromine derivative of formula V as defined above is carried out, for example by means of butyl lithium or preferably by action of magnesium, by forming the corresponding Gπgnard reagent, then reacting this produced with alkyl glyoxylate of formula XVII. The reaction can be carried out in an organic solvent such as tetrahydrofuran. The hydroxyl group of the compound of formula XVIII can be activated by methods known to those skilled in the art, so as to obtain a nucleophuge group, such as a mesyl, tosyl group or a bromine atom, and it is then reacted with a amine NHR ₃ R ₄ , as defined above.

Alternatively, the compounds of formula (I), in which A is a C _{x 6} alkoxy group and B an oxo group according to the invention, can be prepared by reaction of an organozmic or an organomagnesium compound of the bromine derivative of formula V with a compound obtained by reaction of a secondary amine of formula HNR ₃ R ₄ , for which the meanings R ₃ and R ₄ are those indicated for the formula (I) except the hydrogen atom, the benzotriazole and the alkyl glyoxylate of formula XVII or the monoacetal of glyoxale according to the process described by Katrizky et al. (Synthesis 1989, 323; synthesis 1990, 1173).

The compound of formula (I), in which A is a C _{x 6} alkoxy group and B an oxo group, can be reduced, by conventional methods known to those skilled in the art, to give the compounds of formula (I) in which A is a hydroxyl group and B is a hydrogen.

The compound of formula (I) according to the invention, for which A is not a hydroxyl group, can also be prepared from the compound of formula I, where A is a hydroxyl group, by activating this group, so known to a person skilled in the art, so as to obtain a nucleophuge group W, such as a mesyl, tosyle group or a bromine atom and from this compound by reacting it with a nucleophilic group A according to the reaction scheme ( 7) following:

Diagram 7

XIX (l)

(I)

Alternatively, the compounds of formula (I) according to the invention, for which A is a hydrogen atom, can also be prepared by dehydroxylation of a corresponding compound of formula (I), where A is a hydroxyl group. The dehydroxylation reaction can be carried out, in a manner known to those skilled in the art, by reaction with triethylsilane and trifluroacetic acid.

The compounds of formula (I) according to the invention, for which A is a hydrogen atom, can also be prepared according to the following reaction scheme (8):

Diagram 8

XI XX (D

According to this process, the compound of formula (I) is prepared by reacting a nucleophilic derivative of formula B-CH ₂ MY for which M represents a metal, Y represents a halogen and B has the meaning indicated for formula (I), such as for example an organomagnesium or an organolithium, with an imine derivative of formula XX obtained by reaction of a secondary ine of formula NHR ₃ R ₄ , for which the meanings of R ₃ and R ₄ are those indicated for the formula ( I) except the hydrogen atom, with an aldehyde of formula XI. The meanings of X, R _1f R ₂ , R ₅ and B are those indicated for formula (I).

The starting materials for the syntheses of the compounds of formula (I) are directly commercially available, are known in the literature or can be synthesized by conventional methods known to those skilled in the art.

The following examples illustrate the methods and techniques suitable for the preparation of this invention, without however limiting the scope of the claim. Microanalyses and NMR and IR spectra confirm the structures of the compounds. Example 1: 2, 3 -Dimethyl -7- (ld ethylamιno-2 -hvdroxyethyl) - benzofuran. hydrochloride

(1) 3- (2-bromo-phenoxy) -2-butanone

60 g (347 mmol) of 2-bromo-phenol, 57.43 g (416 mmol) of potassium carbonate, 57 g (347 mmol) of iodide are introduced into a 1 liter three-necked flask fitted with a condenser. potassium, 600 ml of N, N-dimethylformamide and 4.34 g (416 mmol) of 3-chloro-2-butanone. The mixture is heated at 80 ° C for 16 hours. 1500 ml of water are added and then extraction is carried out with ethyl acetate (3 x 400 ml). The organic phases are combined, washed with a molar sodium hydroxide solution (2 x 500 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent cyclohexane: ethyl acetate 9: 1).

75.07 g are obtained (yield: 89%) of 3 - (2-bromo-phenoxy) - 2-butanone (yellow oil).

(2) 2,3-methyl-7-bromo-benzofuran

25 ml of concentrated sulfuric acid are introduced into a 100 ml three-necked flask fitted with a thermometer and a 10 ml addition funnel and cooled to between -15 and 0 ° C. by a dry ice bath in 'acetone. 3- (2-bromo-phenoxy) -2 -butanone (5 g, 20.6 mmol) is added dropwise and stirring is continued for 5 min. The mixture is poured onto crushed ice and then extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: cyclohexane). 4.24 g (yield: 91%) of 2-methyl-3-methyl-7-bro o-benzofuran are obtained. F = 33 ° C

(3) 2,3-dimethyl-7-ethenyl -benzofuran

In a 1 liter three-necked flask fitted with a refrigerant, introduced 32 g (142 mmol) of 2, 3-methyl-7-bromo-benzofuran, 3.3 g (2.84 mmol) of tetrakis-triphenylphosphine-palladium, 300 ml of toluene and 50 g (156.2 mmol) of tributyl-vinyl-stannane. The mixture is heated to reflux for 3 hours, 1 g of tetrakis-triphenylphosphine-palladium is added and the heating is continued for 2 hours. The reaction mixture is allowed to return to ambient temperature, then 500 ml of ethyl acetate and 500 ml of sodium hydroxide are added. The organic phase is washed with brine, dried over magnesium sulfate and concentrated. The residue is distilled under a vacuum of 0.03 mm Hg (4 Pa). The fraction passing between 60 and 78 ° C. is collected which is then purified by chromatography on a silica column (elution solvent 1% ethyl acetate in cyclohexane). 23.5 g are obtained (Yield: 96%) of 2,3-dimethyl-7-ethenyl -benzofuran in the form of a colorless oil.

(4) 2, 3-dimethyl-7- (1, 2 -dihydroxyethyl) -benzofurane

3.86 g (28.6 mmol) of N-methyl-N-oxide-morpholine, 10 ml of water and 20 ml of acetone are placed in a 100 ml three-necked flask. 2.1 ml of a 1% solution by mass of osmium tetroxide in tert-butanol are added dropwise, followed by a solution of 5.2 g (26 mmol) of 2, 3-dimethyl- 7-ethenyl-benzofuran in 10 ml of acetone. The reaction mixture is stirred for 5 hours at room temperature. 100 ml of water are added and extraction is carried out with ethyl acetate (3 × 150 ml). The organic phases are combined, washed with 100 ml of a 1% solution of sodium bisulfite and 100 ml of a 1% solution of sodium bicarbonate, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 35% ethyl acetate in cyclohexane). 4.2 g (yield: 85%) of 2, 3-dimethyl-7- (1, 2-dihydroxy ethyl) - benzofuran are obtained in the form of a white solid. Mp 93-95 ° C.

(5) 2, 3-dimethyl-7- (1-hydroxy-2 - [tert-butyldimethyl silyloxy] -ethyl) -benzofuran 3.1 g (19.3 mmol) of 2, 3-dimethyl-7- (1,2-dihydroxy-ethyl) -benzofuran, 200 ml of N, N-dimethylformamide and 2 are placed in a 500 ml flask. , 36 g (34.8 mmol) imidazole. The mixture is cooled to 0 ° C., 2.63 g (17.4 mmol) of tert-butyl dimethyl chlorosilane are added and the mixture is stirred for 2 hours at 0 ° C. 800 ml of water are added and extraction is carried out with ethyl acetate (3 x 400 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 10% ethyl acetate in hexane). 4.9 g (yield: 83%) of 2.3 dimethyl -7- (2- [tert-butyl dimethyl silyloxy] -1-hydroxyethyl) benzofuran are obtained in the form of an oil.

(6) 2,3-dimethyl-7- (1-diethylamino-2- [tert-butyl dimethyl silyloxy] -ethyl) -benzofuran

3 g (9.82 mmol) of

2,3-dimethyl-7-1-hydroxy-2- [tert-butyl dimethyl silyloxy] -1- hydroxyethyl) -benzofuran, 50 ml of ethyl ether and 2.2 ml

(15.7 mmol) of triethylamine. The mixture is cooled to -

30 ° C with a dry ice bath in acetone and 1.24 ml (15.7 mmol) of mesyl chloride are added. The cooling bath is removed and the reaction mixture is allowed to return to room temperature for 30 minutes. 200 ml of water are added and extraction is carried out with ethyl ether (3 x 150 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is transferred without further purification into a 100 ml three-necked flask fitted with a condenser. 20 ml (190 mmol) of diethylamine, 3 ml of chloroform are added and the mixture is heated at reflux for 16 hours. The reaction mixture is cooled to room temperature, concentrated in vacuo, 150 ml of water are added and extraction is carried out with ethyl ether (3 x 200 ml). The organic phases are combined, dried over magnesium sulfate, and concentrated under vacuum. The residue is purified by chromatography on a silica column (elution solvent 10% methanol in dichloromethane). We obtain 2.77 g (Yield 78%) of 2, 3 -dimethyl- 7- (1 -diethylamιno-2 - [but - butyl -dimethyl silyloxy] ethyl) -benzofuran in the form of an oil. (0.5 g of 2,3-dimethyl-7- [1-hydroxy-2 [tert-butyldimethyl -silyloxy] -ethyl) -benzofan unreacted is recovered.

(7) 2, 3-Dimethyl-7- [1-diethylamino-2-hydroxyethyl) - benzofuran.

2.77 g (7.68 mmol) of 2,3-dimethyl-7- [1-diethylammo-2 - [tert-butyldimethyl silyloxy] -ethyl] -benzofuran and 30 ml of are introduced into a 250 ml flask. tetrahydrofuran. The mixture is cooled to 0 ° C. in an ice bath and a solution of 2.9 g (9.21 mmol) of tert-butylammonium fluoride trihydrate in 10 ml of tetrahydrofuran is added. The reaction mixture is stirred at 0 ° C for 1 hour and at room temperature for 16 hours. 150 ml of water are added and extraction is carried out with ethyl ether (3 x 200 ml). The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% methanol in dichloromethane). 1.6 g are obtained (Yield: 80%) of 2, 3-methyl-7- (1-diethylamino-2-hydroxyethyl) -benzofuran in the form of an oil.

(8) 2,3-dimethyl-7- (1-diethylamino-2-hydroxyethyl) -benzofuran hydrochloride

0.55 mg of 2, 3-methyl-7- is placed in a 100 ml flask

(1-diethylamino-2-hydroxyethyl) -benzofuran and 100 ml of a 0.1N solution of hydrochloric acid in isopropanol. The salt is concentrated in vacuo and recrystallized from ethyl acetate. 0.561 g of 2,3-dimethyl-7- (1-diethylamino-2-hydroxyethyl) -benzofuran hydrochloride are obtained. Mp 160-161 ° C.

Example 2: Asymmetric Synthesis

Using essentially the same process as that of Example 1, using for step (4) AD mix for isomer (+), according to the procedure described by Sharpless, KB; et al J. Org. Chem. 1992, 57, 2768, (AD mix β for the (-) isomer), chiral compounds of formula (I) according to the invention were prepared. These compounds are those having the numbers 5 to 10 in the table below.

Example 3

Using essentially the same method as that of Example 1, using an adequate amine in step (6), other compound of formula (I) according to the invention was prepared. These compounds are those having the numbers 10 to 24 in the table below.

Example 4: 2,3-Dimethyl-7,1,2-di-(diethylamino) ethyl] -benzofuran hydrochloride.

(1) 2, 3-dimethyl-7- [1, 2-di- (diethylamino) ethyl] -benzofuran

0.8 g (2.7 mmol) of 2,3-dimethyl-7- [1-diethylamino-2-hydroxyethyl] benzofuran hydrochloride, 2.67 ml (19.2 mmol) are placed in a 100 ml flask ) of triethylamine and 50 ml of dichloromethane. The solution is cooled to -30 ° C, with the acid of a dry ice bath, and 99 ml (12.8 mmol) of mesyl chloride are added dropwise. The temperature is allowed to return to 0 ° C. and the solution is concentrated under vacuum. 20 ml of diethylamine are added to the residue and the solution obtained is heated to reflux for 16 hours. The reaction mixture is cooled to ambient temperature, it is concentrated under vacuum, 50 ml of water are added and extraction is carried out with ethyl acetate. The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent: 10% methanol in dichloroethane). 0.434 g is obtained (yield = 55%) of 2,3 dimethyl-7- [1,2-di- (diethylamino) ethyl] -benzofuran in the form of an oil. (2) 2,3 dimethyl -7- [1,2-di - (diethylamino) ethyl] -benzofuran hydrochloride.

400 mg of 2, 3-dimethyl-7- [1, 2-di- (diethylamino) -ethyl] -benzofuran and 10 ml of a hydrochloric acid solution in isopropanol are placed in a 100 ml flask . The salt is concentrated in vacuo and recrystallized from ethyl acetate. 400 mg are obtained (yield = 88%) of 2,3 dimethyl hydrochloride -7- [1,2-di- (diethylamino) ethyl] -benzofuran. Mp 183 ° C.

Example 5

Using essentially the same method as that of Example 4, using the appropriate nucleophile, other compounds of formula (I) according to the invention were prepared. These compounds are those having the numbers 27 to 34 in the table below.

Example 6: 2,3-dimethyl -7- (1-diethylamino-2-fluoroethyl) -benzofuran hydrochloride.

(1) 2, 3 -dimethyl -7- (1 -diethylamino-2 - fluoroethyl) -benzofurane

0.664 ml (3.72 mmol) of diethylaminosulfide trifluoride (DAST) and 5 ml of dichloromethane are placed in a 50 ml flask. The mixture is cooled to -78 ° C by a dry ice bath in acetone and a solution of 0.877 g (3.38 mmol) of 2.3 dimethyl -7- (1- diethylamino-) is added dropwise. 2-hydroxyethyl) benzofuran in 5 ml of dichloroethane. Stirring is continued for 90 minutes at this temperature, before allowing the reaction mixture to return to room temperature. 10 ml of water are added and extraction is carried out with dichloroethane (3 x 15 ml). The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% methanol in dichloromethane) 700 mg (yield = 62%) of hydrochloride of 2,3-dimethyl -7- are obtained. (1-diethylamino-2-fluoroethyl) -benzofuran in the form of a colorless oil.

Example 7 2-Ethyl-3-methyl-7- (1-diethylammo- 2-hydroxyethyl) hydrochloride-benzofuran.

(1) 2-Ethyl-3-diethyl-7- (N, N '-diethyl ethyl glycinate) benzofuran.

This compound is prepared from 2 -ethyl -3 -methyl -7- bromobenzofuran according to the procedure of Katrizky, A.R .; Urogdi, L.; Mainz, A. Synthesis 1989, 323.

(2) 2-Ethyl-3-methyl-7- (1-diethylamino-2-hydroxyethyl) - benzofuran.

300 mg (7.87 mmol) of mixed aluminum and lithium hydride and 10 ml of anhydrous tetrahydrofuran are introduced into a 100 ml flask. This suspension is cooled to 0 ° C. in an ice bath and a solution of 1 g (3.15 mmol) of 2-ethyl-3-methyl -7- (N, N '- diethyl glycinate) is added dropwise. ethyl) -benzofuran in 20 ml of tetrahydrofuran. The reaction medium is stirred for 1 hour at ambient temperature then hydrolysis by the successive addition of 0.3 ml of water, 0.3 ml of a 15% sodium hydroxide solution and 0.9 ml of water. A white precipitate is formed which is filtered and washed with 50 ml of ether. The filtrate is washed with 50 ml of water, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 2% methanol in dichloromethane). 0.83 g is obtained (yield = 96%) of 2-ethyl-3-methyl-7- (1-diethylamino-2-hydroxyethyl) -benzofuran in the form of a yellow oil.

(3) 2-Ethyl-3-methyl-7- (1-diethylamino-2 - hydroxyethyl) -benzofuran hydrochloride

0.79 g (2.86 mmol) of 2 - ethyl -3-methyl -7- (1-diethylamino-2-hydroxyethyl) -benzofuran is placed in a 100 ml flask and 50 ml of a 0.1 N solution of hydrochloric acid in isopropanol. The salt is concentrated in vacuo. 0.29 g of 2-ethyl-3-methyl-7- (1-dιethylamιno- 2-hydroxyethyl) -benzofuran hydrochloride is obtained in the form of a white wax.

EXAMPLE 8 2.3-dimethyl-7- (1-methylethylenomethyl) -benzofuran hydrochloride

(1) 2, 3 -dimethyl -7-formyl -benzofuran

17 g (75.6 mmol) of 2-methyl -3-methyl -7-bromo-benzofuran and 250 ml of tetrahydrofuran are introduced into a 1 liter flask under an inert atmosphere. The mixture is cooled to -78 ° C by a dry ice bath in acetone. 60 ml of tert-butyl lithium (1.4 M in pentane) are added dropwise and the mixture is left to stir for 10 minutes. 17.5 ml of N, N-dimethylformamide (227 mmol) are then added dropwise, and the reaction mixture is allowed to return to ambient temperature. 100 ml of water are added, followed by extraction with ethyl acetate (3 x 80 ml). The organic phases are combined, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent cyclohexane: ethyl acetate 9: 1). 11.97 g are obtained (Yield: 91%) of 2,3-dimethyl-7-formylbenzofuran. Mp 56-58 ° C.

(2) 2, 3-dimethyl-7- (1-diethylaminoethyl) -benzofuran

1.8 g (10.3 mmol) of 2, 3-dimethyl-7-formyl -benzofuran, 80 ml of benzene, molecular sieve 4A and 3 are introduced into a 250 ml three-necked flask fitted with a condenser. 19 ml (30.8 mmol) of diethylamine. The mixture is heated at reflux for 16 hours, cooled to room temperature and then filtered to remove the molecular sieve. The filtrate is concentrated under vacuum and is introduced with 100 ml of anhydrous tetrahydrofuran into a 250 ml three-necked flask fitted with a condenser. The solution is cooled to 0 ° C. in an ice bath and 20 ml of a 3.0 molar solution of methyl magnesium bromide in tetrahydrofuran. The reaction mixture is heated to reflux for 26 hours, 8 ml of a 3.0 molar solution of methylmagnesium bromide in tetrahydrofuran are added again and stirring is continued under reflux for 12 hours. The mixture is cooled by an ice bath, 50 ml of a saturated ammonium chloride solution are added and extraction is carried out with ethyl acetate (3 x 200 ml). The organic phases are combined, dried over magnesium sulfate and concentrated in vacuo. The residue is purified by chromatography on a silica column (elution solvent 5% methanol in dichloromethane). 0.281 g is obtained (Yield = 11%). of 2,3 dimethyl - 7- (1 -diethylaminoethyl) - benzofuran in the form of a colorless oil.

(3) 2,3-dimethyl -7- (1-diethylaminoethyl) hydrochloride - benzofuran

0.2 g (0.81 mmol) of 2,3-dimethyl - 7- (1-diethylaminoethyl) -benzofuran and 2 ml of a 6N solution of hydrochloric acid in 1 'are placed in a 100 ml flask isopropanol. The salt is concentrated under vacuum and recrystallized from ethyl acetate and di-isopropyl ether. 0.142 g is obtained (Yield = 61%) of 2,3-dimethyl-7- (1-diethylaminoethyl) -benzofuran hydrochloride in the form of a solid. M = 28-30 ° C.

Example 9: (+) -2 -Ethyl -3 -methyl -7- (1-diethylamino-2 - hydroxyethyl) -benzothiophene, hydrochloride

(1) (2-Bromo-thiophenoxy) -acetone

20 g (105.7 mmol) of 2-bromo-thiophenol, 19 g (137.5 mmol) of potassium carbonate, 27.8 g (165.5 mmol) of iodide are introduced into a 500 ml three-necked flask potassium, 200 ml dimethylformamide and 14.68 g (158.6 mmol) of chloroacetone. The mixture is stirred for 2 hours at room temperature then is poured into 800 ml of water. An extraction is carried out with ethyl acetate (3 x 400 ml). The phases organics are combined, washed with a molar solution of sodium hydroxide (2 x 400 ml), dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent 10% ethyl acetate in cyclohexane). 24.1 g are obtained (yield: 93%) of (2-bromothiophenoxy) -acetone (yellow oil).

(2) 3-Methyl-7-bromo-benzothιophene

140 g of polyphosphoric acid (PPA) and 14.4 g (58.7 mmol) of (2-bromothiophenoxy) acetone are placed in a 500 ml three-necked flask. The mixture is heated at 100 ° C for 40 minutes and then cooled in an ice bath. Crushed ice is added and extraction is carried out with ethyl acetate (3 x 300 ml). The organic phases are combined, washed with water (200 ml) then with a molar solution of sodium hydroxide (200 ml), dried over magnesium sulphate and then concentrated. The residue is purified by chromatography on a silica column (elution solvent: cyclohexane). 11.86 g are obtained (yield: 89%) of 3-methyl-7-bromo-benzothιophene in the form of an oil.

(3} 2 -Acetyl -3 -methyl -7 -bromo-benzothiophene

7.6 g (39.46 mmol) of 3-methyl-7-bromo-benzothιophene (previously dried under vacuum over phosphoπque anhydride) and 70 ml of dichloromethane are placed in a 250 ml three-necked flask fitted with a thermometer. The mixture is cooled to 0 ° C in an ice bath, 2.89 g (36.8 mmol) of acetyl chloride are added and then the mixture is stirred for 5 minutes at 0 ° C. 5 g of aluminum chloride are then added in small portions, checking that the temperature does not exceed 7 ° C and stirring is continued at 0 ° C for 45 minutes. The reaction mixture is poured onto crushed ice and extraction is carried out with ethyl acetate (3 × 150 ml). The organic phases are combined, washed with saturated sodium bicarbonate solution (200 ml) and water (200 ml), dried over magnesium sulphate and then concentrated. The residue is purified by chromatography on a silica column (elution solvent 5% ethyl acetate in petroleum ether). 8.55 g (yield: 95%) of 2-acetyl-3-methyl-7-bromo-benzothiophene are obtained in the form of a white solid. Mp: 105-107 ° C.

(4) 2-Ethyl - 3-methyl - 7 -bromo-benzothiophene

8.6 g (32 mmol) of 2-acetyl-3-methyl-7-bromo-benzothiophene and 175 ml of diethylene glycol are placed in a 500 ml three-necked flask fitted with a distillation system. The mixture is stirred at 30 ° C for 5 minutes and 4.2 ml (56 mmol) of hydrazine monohydrate are added dropwise. The mixture is heated at 40 ° C for 5 minutes and 4.3 g (76.6 mmol) of potassium hydroxide powder is added. The temperature is brought to 110 ° C for 40 minutes and then to 160 ° C for 100 minutes to allow the water present in the reaction mixture to distill. The mixture, once cooled, is then poured onto crushed ice and extraction is carried out with ethyl acetate (3 × 200 ml). The organic phases are combined, washed with 200 ml of a saturated sodium bicarbonate solution and 2 x 200 ml of water, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (cyclohexane elution solvent). 7.62 g (yield: 84%) of 2-ethyl - 3-methyl -7-bromo-benzothiophene are obtained in the form of a yellow oil.

Using essentially the same method as that of steps (4) to (8) of Example 1 and using for step (4) AD mix α for (+) isomer, according to the procedure described by Sharpless, KB; et al J. Org. Chem. 1992, 57, 2768, the benzothiophene chiral compounds of formula (I) according to the invention were prepared.

In this table :

- "-" represents a compound in free form,

In addition, compounds whose number is accompanied by a "*" are in the form (+), those accompanied by a "" are in the form (-). The [α] _D ²⁰ (c = l) of the compounds 5, 6, 7, 8, 9, 10, 49, 50, 51, 52, 61, 62, 63 and 64 are respectively +24.7 _(CH2CL2;,

+3, 0 ( _M e _OH ) '"24.7 ( _CH2 C2) t" 3.5 (MeOH)' ~ 23.9 (CH2C2 '/ +29.0 (CH2 L2)> - _16.6 ( _{CH2C 2} ) ι +78.9 ( _CH2CL2 ) '+19.5 (CH2CL2)'"29.5 (CH2C12:» "15.9 (CH2C2) (+22.7

(απc _ω +15.22 ( _CH2CL2 +16.3 _(C H2C2) - All the other compounds in the table are racemates. The compounds of the invention were subjected to biological tests intended to demonstrate their contractile activity on the urethral and arterial smooth muscles.

1. The in vi o activity of the compounds of the invention has been studied on the urethral and arterial smooth muscles. These tests were carried out on female New Zealand rabbits weighing 3 to 3.5 kg. The animals were killed by vertebral dislocation, and then rings of tissue from the mesenteric arteries and urethra were removed. These tissue rings were immersed in a modified Krebs solution, oxygenated by a mixture of 95% of 0 ₂ and 5% of CO ₂ . Each tissue sample was subjected to a tension of 1 g and then phenylephrine was introduced at cumulative doses and the dose / response curve was established. After rinsing the samples, the compound to be studied was introduced at cumulative doses and the dose / response curve established. The contractile effect of each compound is evaluated by calculating the pD ₂ (negative logarithm of the agonist concentration which induces 50% of the maximum contraction) as well as by the maximum effect representing the percentage of the maximum contraction obtained with the phenylephrine (% E _max ).

The results obtained show that the compounds in accordance with the invention have:

* a pD ₂ urethra, usually between 4 and 9

* a pD ₂ artery usually less than 3,

* a% E _raax urethra greater than 30, usually between 40 and 90,

* a% E _roax artery usually less than 5.

2. The in vitro activity of the compounds of the invention was studied on the saphenous veins of Yucatan micro-pigs. The tissue is cut in a helix and is mounted in a tank with organs isolated in an oxygenated modified Krebs solution by a mixture of 95% 0 ₂ and 5% C0 ₂ maintained at 37 ° C. The vessel is connected to an isometric sensor at a basal voltage of 1 g and is connected to a polygraph allowing the recording of blood pressure variations. The viability of each preparation is tested by pre-stimulation with noradrenaline 3μM. After rinsing, the compound to be studied is introduced and its concentration-response curve constructed cumulatively until a maximum response is obtained. The contractile effect of each compound is evaluated by calculating the EC _S0 (concentration producing 50% of the maximum response).

The compounds of the invention have made it possible to obtain a vemoconstrictor activity with an EC ₅₀ value usually between 1 μM and 100 μM.

The compounds of the invention can be used in the treatment of venous insufficiency and venous ulcer.

3. The in vivo activity of the compounds of the invention on the blood and urethral pressure was studied in the amyele rat and the rabbit, according to the following protocols:

* Demedulated rats

Wistar rats are anesthetized and demedulated (according to the technique described by Gillespie, MacLaren A. and Polock D., A method of stimulatmg different segments of the autonomy outflow from the spinal column to vaπous organs m the pithed cat and rat; Br. J Pharmacol., 1970, 40: 257-267).

The catheters are introduced through the femoral artery and a jugular vein. Another catheter is introduced into the urethra through an incision made in the bladder. The test compounds are administered in increasing doses by intravenous infusion.

The results are expressed in doses (μg / kg) necessary to increase the urethral pressure by 10 cm of water (PU ₁₀ ) or the blood pressure of 10 mm Hg (PA _l0 ) or 50 mm Hg (PA ₅₀ ).

The compounds of the invention thus tested, made it possible to obtain:

- PU ₁₀ with doses less than 500 μg / kg, usually between 5 and 200 μg / kg,

- a PA ₁₀ with doses greater than 600 μg / kg, usually between 600 and 2000 μg / kg,

- PA _S0 could not be reached.

* Awake rabbits

The experiments are carried out on female New Zealand rabbits weighing between 3 and 4 kg, anesthetized with a mixture of Ketamine and Xylazine. The catheters are introduced for the descending aorta into the femoral artery, into a jugular vein and into the urethra (1.5 cm below the neck of the bladder).

The test compounds are administered 5 to 15 days after the operation, by intravenous (i.v.) administration in 5 minutes, and in a single dose (10 or 100 μg / kg). The compounds to be tested orally are administered by gavage at a single dose (10, 30, 100, 300 or 1000 μg / kg).

We measured here the increase in urethral pressure (PU) and blood pressure (PA), compared to basal pressure, urethral and arterial respectively. The results obtained are expressed as a percentage of premedication values 5 minutes after intravenous administration (i.v.) and 30 minutes after gavage (p.o.).

The compounds of the invention thus tested, allowed an increase in the PU greater than 50%, usually between 50 and 350% after intravenous administration. venous, and usually between 50 and 200% after force-feeding. The increase in BP was always less than 10%, usually it is 0%.

All of the above results show that the compounds of the invention have a strong urethral contractile action and a weak arterial contractile action.

They can be used as a medicament, in particular as a contracting agent for smooth muscles, and more particularly still, in the treatment of stress urinary incontinence. In this indication, the compounds according to the invention have good efficacy and, usually, less side effects than the drugs conventionally used for such treatment, in particular as regards the side effects affecting the cardiovascular system, in particular the arterial beds.

The compounds according to the invention can also be used for the treatment of venous insufficiency, migraine, gastrointestinal disorders and as a vasoconstrictor of the nasal mucosa.

The compounds according to the invention can be presented in different pharmaceutical forms suitable for administration by the digestive or parenteral route, if necessary by combining with at least one pharmaceutical excipient. Suitable pharmaceutical forms are for example tablets, capsules, dragees, capsules, oral or injectable solutions, syrups, suppositories.

These pharmaceutical forms can be dosed to allow a daily dose of 0.1 μg / kg to 50 mg / kg.

Claims

claims

1. Compound of formula (I)

in which :

A represents either a hydrogen atom, a hydroxyl, a C _1-6 hydroxyalkyl group, a thiol, a C _1-6 alkylsulfanyl group, an amino group, a C _1-6 alkylamino group, a di (C _{1- 6} alkyl) amino, a group C ₁ . ₆ alkyl hydroxylamine, a group C _1-6 alkoxy, a group hydroxylamine, a group C _1-6 N, 0-dialkyl hydroxylamine, an azido, a halogen such as fluorine, chlorine or bromine, B represents an atom d hydrogen, a linear or branched C _1-6 alkyl group, a C ₂ group. ₆ alkenyl, a C _1-6 fluoroalkyl group, a C _1-2 perfluoroalkyl group, a C _1-6 alkoxy group, a phenyl group, or an oxo group, X represents an oxygen or sulfur atom, R _x R _: and R ₂ represent, independently of each other, a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano, a carboxamide, a C _{1 -f} alkyl group, linear or branched, a group C ₂ . ₆ alkenyl, a C _3.6 cycloalkyl group, a C _1-6 alkoxycarbonyl group, a C _1-6 hydroxyalkyl group, a C _1-6 alkoxy group, a C _1-6 alkoxyalkyl group, a C _1-6 fluoroalkyl group, a C _1-2 perfluoroalkyl group or R _x and R ₂ together form, with the double bond to which they are attached, a C ₃ ring. _€ cycloalkenyl, a C _4-6 cycloalkienenyl ring, or a C _5-6 aryl, R ₃ and R ₄ represent, independently of one another, a hydrogen atom, a C _1-6 alkyl group, a C _2.6 alkenyl group, C ₃ . ₆ cycloalkyl, C ₃ . ₆ cycloalkenyl, a C _1-6 fluoroalkyl group, a C _1-2 perfluoroalkyl group or R ₃ and R ₄ together form a C ₂ group. ₆ alkylene, C ₂ . ₆ alkenylene, or R ₃ and R ₄ together form with the nitrogen to which they are attached, a heterocycle, saturated or unsaturated, comprising 3 to 6 carbon atoms and a second nitrogen atom, this nitrogen atom being optionally substituted by a group C _{3 4} alkyl, or an oxygen atom, and

R ₅ represents a hydrogen atom or a halogen, such as fluorine, chlorine or bromine, such as fluorine, chlorine or bromine, in the form of an enantiomer, of diastereoisomer, or of a mixture of these different forms , including racemic mixture as well as their addition salts with pharmaceutically acceptable acids.

2. Process for the preparation of compounds according to claim 1, for which A is a hydroxyl group, characterized in that a compound of formula II is reacted

in which R _x , R ₂ , R ₅ are as defined in claim 1 and P is a protective group, with a love of formula HNR ₃ R ₄ in which R ₃ and R ₄ are as defined in claim 1, followed by deprotection, or else a compound of formula XV is reacted

in which R _lt R ₂ , R ₅ and B are as defined in claim 1, with an amine of formula HNR ₃ R ₄ in which R ₃ and R ₄ are as defined in claim 1, or alternatively a compound of formula XVIII is reacted

XVIII

in which R _lt R ₂ and R ₅ are as defined in claim 1 and B represents a C _{x 6} alkoxy group, with an amine of formula HNR ₃ R ₄ in which R ₃ and R „are as defined in claim 1.

3. Process for the preparation of compounds according to claim 1, for which A is not a hydroxyl group, characterized in that a compound of formula XIX is reacted

wherein R _1f R ₂ , R ₃ , R ₄ and R ₅ are as defined in claim 1 and W is a nucleophuge group, with a nucleophilic group A as defined in claim 1.

4. Process for the preparation of compounds according to claim 1, for which A is a hydrogen atom, characterized in that a compound of formula XX is reacted

in which R ₁ , R ₂ , R ₃ , R ₄ and R _s are as defined in claim (1), with a nucleophilic group B-CH ₂ MY, in which B is as defined in claim 1, Y represents a halogen, such as chlorine or bromine, and M represents a metal.

5. Medicament characterized in that it consists of a compound according to claim 1.

6. Pharmaceutical composition characterized in that it comprises a compound according to claim 1 and one or more suitable excipients.