WO1998033793A1

WO1998033793A1 - α-AZACYCLOMETHYL BENZOTHIOPHENE AND α-AZACYCLOMETHYL BENZOFURANE DERIVATIVES, PREPARATION AND THERAPEUTIC APPLICATION

Info

Publication number: WO1998033793A1
Application number: PCT/FR1998/000135
Authority: WO
Inventors: Christophe Philippo; Stéphanie AUBOUSSIER; Olivier Crespin; Philippe Bovy; Gilles Courtemanche
Original assignee: Sanofi-Synthelabo
Priority date: 1997-01-30
Filing date: 1998-01-27
Publication date: 1998-08-06
Also published as: AU6218598A; AR011578A1

Abstract

The invention concerns compounds of formula (I) in which A represents either a hydrogen atom or a hydroxyl group, R1, R2, R4, identical or different, each represent a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano group, a C1-6 alkyl group, a C2-6 alkenyl group, a C3-6 cycloalkyl group, a C3-6 cycloalkenyl group, a C6-14 aryl, a C1-6 alcoxycarbonyl group, a C1-6 hydroxyalkyl group, a C1-6 alcoxy group, a C1-6 alcoxyalkyl group, a C1-6 fluoroalkyl group, a C1-2 perfluoroalkyl group, or R1 and R2 together form, with the benzothiophene or benzofurane carbons bearing R1 and R2, a phenyl; R3 represents a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C1-6 fluoroalkyl group, a C1-2 perfluoroalkyl group, C3-6 cycloalkyl group, C3-6 cycloalkenyl group, a phenyl or a benzyl, a C1-6 alcoxycarbonyl group; R5 represents a hydrogen atom or a halogen such as fluorine, chlorine or bromine; and n represents a whole number from 1 to 6. The invention is applicable in therapy.

Description

DERIVATIVES OF α-AZACYCLOMETHYL BENZOTHIOPHENE AND α-AZACYCLOMETHYL BENZOFURANE, THEIR PREPARATION AND THEIR THERAPEUTIC APPLICATION

The present invention relates to derivatives of α-azacyclomethyl benzothiophene and α-azacyclomethyl benzofuran, their preparation and their therapeutic application.

The compounds correspond to the general formula (I):

in which :

A represents either a hydrogen atom or a hydroxyl group,

X represents a sulfur atom or an oxygen atom,

R _L , R ₂ , R ₄ , identical or different, each represent a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano group, a C _x _ ₆ alkyl group, a C ₂ group . ₆ alkenyl, C ₃ _ ₆ cycloalkyl, C _3. ₆ cycloalkenyl, C ₆ aryl. _14r a C _1-6 alkoxycarbonyl group, a C _ ₆ hydroxyalkyl group, a C _x _ ₆ alkoxy group, a C ₁ „ _β alkoxyalkyl group, a C ₁ _ ₆ fluoroalkyl group, a C ₁ _ ₂ perfluoroalkyl group, R _x and R ₂ can also form, together, a chain C _x _ ₆ alkylene, a chain C ₃ . ₅ alkenylene, or R _x and R ₂ together form, with the carbons of benzothiophene or of benzofuran carrying R _x and R ₂ , a phenyl,

R ₃ represents a hydrogen atom, a group C ₁ . ₆ alkyl, a C ₂ _ ₆ alkenyl group, a C _λ _ ₆ fluoroalkyl group, a C ₁ group. ₂ perfluoroalkyl, C ₃ . ₆ cycloalkyl, C ₃ . ₅ cycloalkenyl, phenyl, benzyl or a Cι_ _c alkoxycarbcnyle group, R ₅ represents a hydrogen atom or a halogen such as fluorine, chlorine or bromine,

"a" and "c" represent 0 or l, "b" represents 0, 1 or 2, and n defines the size of the cycle and can be between 1 and 6. This cycle consists of a nitrogen heterocycle, saturated or unsaturated or aromatic, comprising 2 to 7 carbon atoms, and, as heteroatom, the nitrogen atom carrying R ₃ . Such a ring can for example consist of a piperidyl, pyrrolidyl, azetidyl or pyridinyl group.

In the context of the present invention, the term C ^ g alkyl is understood to mean a saturated, linear or branched aliphatic group comprising from 1 to 6 carbon atoms, such as for example a methyl, ethyl, propyl or isopropyl group, butyl, isobutyl, tert-butyl, etc. The term C ₁ . ₆ alkylene denotes a group C ₁ . ₆ divalent alkyl.

The term C ₂ . ₆ alkenyl denotes a linear or branched mono- or polyunsaturated aliphatic group comprising from 2 to 6 carbon atoms. An alkenyl group according to the invention preferably comprises 1 or 2 ethylenic unsaturations. The term C ₂ . ₆ alkenylene denotes a C ₂ group. ₆ divalent alkenyl.

The terms C _1-6 alkoxy, C _ ₆ alkoxycarbonyl, C ₁ _ ₆ hydroxyalkyl and C ₁ _ ₆ alkoxyalkyl denote, respectively, alkoxy, alkoxycarbonyl, hydroxyalkyl and linear or branched, saturated or unsaturated alkoxyalkyl groups, comprising from 1 to 6 carbon atoms.

The term C _λ _ ₆ fluoroalkyle designates a group C ₁ . ₆ alkyl as defined above, substituted by at least one fluorine atom, it being understood that all the hydrogen atoms are not substituted by fluorine atoms.

The term C ₁ _ ₂ perfluoroalkyle designates an alkyl group comprising 1 to 2 carbon atoms, each hydrogen atom of which is substituted by a fluorine atom. The term aryl in C ₆ . ₁₄ denotes a mono-, bi- or tricyclic aliphatic system having at least one aromatic ring, comprising from 6 to 14 carbon atoms, such as for example the phenyl and naphthyl groups.

The term C ₃ . ₆ cycloalkyl denotes a saturated cyclic aliphatic system comprising from 3 to 6 carbon atoms.

The term C ₃ . ₆ cycloalkenyl denotes a cyclic unsaturated aliphatic system comprising from 3 to 6 carbon atoms.

According to the invention, a group C ₃ . ₆ cycloalkenyl preferably comprises 1 or 2 unsaturations.

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 an addition salt with pharmaceutically acceptable acids, which also form part of the invention.

According to a preferred embodiment of the invention,

A represents a hydroxyl group,

X represents a sulfur atom or an oxygen atom,

R ₁₇ R ₂ , R ₄ , identical or different, each represent a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a C _λ _ ₆ alkyl group, a C ₂ _ ₆ alkenyl group, a C ₁ _ ₆ hydroxyalkyl group, a C _τ _ ₆ fluoroalkyl group, a C _x _ ₂ perfluoroalkyl group, or R _λ and R ₂ may together form a C _λ _ ₆ alkylene chain, a C ₃ chain. ₆ alkenylene, or R _± and R ₂ together form, with the carbons of the benzothiophene or of the benzofuran carrying R _x and R ₂ , a phenyl,

R ₃ represents a hydrogen atom, a C _] __ ₆ alkyl group, a C ₂ _g alkenyl group, a C ₁ group. ₆ fluoroalkyl, one perfluoroalkyl group C _x _ ₂ , or a group C ₁ . ₆ alkoxycarbonyl,

R ₅ represents a hydrogen atom or a halogen such as fluorine, chlorine or bromine, "a" and "c" represent 0 or 1, "b" represents 0, 1 or 2, and n represents an integer of 1 to 6, preferably 2 to 5.

The compounds derived from α-azacyclomethyl benzothiophene and -azacyclomethyl benzofuran of formula (I) according to the invention, can be prepared according to different processes. These processes are described in Figure 1.

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

According to this process, the compounds of formula (I) can be obtained by the reaction of an aldehyde of formula (II), in which Pg represents a protective group, known to a person skilled in the art, with a derivative (III ') obtained by metallation of the bromine derivative of formula (III). The meanings of X, R _x , R ₂ , R ₄ , R _{5 /} a, b, c and n of the compounds of formula (II), (III) and (III '), are those indicated in formula (I) . The metallation reaction can be carried out in an organic solvent such as tetrahydrofuran by formation of the Grignard reagent of the bromine derivative of formula (III), or more advantageously by reaction of the bromine derivative of formula (III) in the presence of n-butyllithium, the term "metal" in formula (III ') representing MgBr or Li respectively.

For example, compounds of formula (I) wherein R ₃ represents a C ₁ _ ₆ alkoxycarbonyl group can be obtained by reacting an aldehyde of formula (II), respectively wherein Pg represents a group C _1. ₆ alkoxycarbonyl with a derivative of formula (III '). Diagram 1

The compounds of formula (I) for which R ₃ represents a hydrogen atom are obtained by deprotection of the protective group Pg from the nitrogen of the compound of formula (I), according to methods known to those skilled in the art. Such a protective group can for example be a C _x _ ₆ alkoxycarbonyl group such as tert-butyloxycarbonyl (tBoc).

The secondary amine thus obtained can then be functionalized, according to methods known to those skilled in the art, for example by reductive amination to give a compound of formula (I) in which R ₃ is not hydrogen.

The aldehydes of formula (II) can be obtained by reduction, for example according to the method described by

Jurczack J. et al., Chem. Rev (1989), ___, 149, from the corresponding N-protected α-amino acid derivatives of formula (VII) themselves originating from the α-amino acids of formula (VIII). R ₄ , a, b, c and n have the meanings indicated in formula (I). Pg is defined as above and B represents a group, known to those skilled in the art, among others, N-methyl - O-methyl-hydroxyamine (Νahm and einreb (1981), Tet. Lett., 22., 3815 ), allowing a controlled reduction and which stops at the formation of an aldehyde.

The compounds of formula (III) can themselves be prepared from α-phenylthioketones or α-phenoxyketones of formula (IV), depending on whether X represents respectively a sulfur atom or an oxygen atom. The compounds of formula (IV) are reacted with an acid, preferably a mineral acid, such as sulfuric acid or polyphosphoric acid (PPA). The meanings of X, R _x , R ₂ and R ₅ for the compounds of formulas (III) and (IV) are those indicated in formula (I).

The compounds of formula (IV) can be obtained directly from the thiophenols or the corresponding phenols, of formula (V), depending on whether X represents respectively a sulfur atom or an oxygen atom. We react the compounds of formula (V) with an α-haloketone of formula (VI). 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. Said α-haloketone is usually an α-chloroketone. The meanings of X, R _x , R ₂ and R ₅ for the compounds of formulas (V) and (VI), are those indicated in formula (I) •

The compounds of formula (I) according to the invention, for which A is a hydrogen atom, can also be prepared by dehydroxylation of a compound of corresponding 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.

In addition, the following reaction scheme can be used to synthesize the compounds of formula (IV): scheme 2

(IX)

Thus, according to this scheme 2, the compounds of formula (IV) can be prepared by reaction of a compound of formula (V) as defined above, with an α-haloester of formula (IX) where R _x has the meaning indicated in formula (I). This reaction can be carried out in an organic solvent such as N, N-dimethyl formamide, in the presence of potassium carbonate and an iodide such as potassium iodide. The reaction product of formula (X), obtained by this reaction, can then be transformed into said compound of formula (IV) by reaction with an organometallic of formula (R ₂ ) MY for which R _{2 has} the meaning indicated in the formula ( I), M represents a metal and Y a halogen. This organometallic is preferably an organomagnesium. The reaction is carried out in the presence of acid chloride or Weinreb amide (S0 ₂ C1 ₂ / NHCH ₃ 0CH ₃ ), under the conditions described by Nahm and Weinreb, Tet. Lett. (1981), ___, 3815.

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

figure 3

According to this process, a compound of formula (V) as defined above is reacted 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 (XI) 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. (1992), 4_0, 1148.

The following examples illustrate the methods and techniques suitable for the preparation of this invention, without however limiting the scope of the claim. The elementary analyzes and NMR and IR spectra confirm the structures of the compounds.

Example 1: (R. R) -2 - \ (2-ethyl-3-methylbenzo fjol thien-7-yl) 1,1-dimethylethyl hydroxymethyllpyrrolidine-1-carboxylate and (R. S) -2 - \ (2 -ethyl-3-methylbenzo rjbl thien-7-yl) hydroxymethyll pyrrolidine-1-carboxylate of 1.1-dimethylethyl

(1) 1- [(2-Bromophenyl) thio] propan-2-one.

20 g (105.7 mmol) of 2-bromothiophenol, 19 g (137.5 mmol) of potassium carbonate, 27.8 g (165.5 mmol) of potassium iodide are introduced into a 500 ml three-necked flask , 200 ml of 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 organic phases 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 chromatographic column on silica (elution solvent 10% ethyl acetate in cyclohexane). 24.1 g (yield: 93%) of 1- [(2-bromophenyl) thio] propan-2-one (yellow oil) are obtained.

(2) 7-Bromo-3-methylbenzo [b] thiophene.

140 g of polyphosphoric acid and 14.4 g (58.7 mmol) of 1- [(2-bromophenyl) thio] propan-2-one 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 then added thereto and extraction is carried out with ethyl acetate (3 × 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 on a chromatographic column on silica (elution solvent: cyclohexane). 11.86 g are obtained (yield: 89%) of 7-bromo-3-methylbenzo [b] thiophene in the form of an oil.

(3) 1- (7-Bromo-3-methylbenzo [b] thien-2-yl) ethanone.

7.6 g (39.46 mmol) of 7-bromo-3-methylbenzo [b] thiophene (previously dried under vacuum over phosphoric anhydride) and 70 ml of dichloromethane. 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 a saturated solution of sodium bicarbonate (200 ml) and water (200 ml), dried over magnesium sulfate and then concentrated. The residue is purified by chromatographic column on silica (elution solvent 5% ethyl acetate in petroleum ether). 8.55 g (yield: 95%) of 1- (7-bromo-3-methyl benzo [b] thien-2 -yl) ethanone are obtained in the form of a white solid. Mp: 105-107 ° C.

(4) 7-Bromo-2-ethyl-3-methylbenzo [b] thiophene.

8.6 g (32 mmol) of 1- (7-bromo-3-methylbenzo [Jb] thien-2 -yl) ethanone and 175 ml of are placed in a 500 ml three-necked flask fitted with a distillation system. diethylene glycol. 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 solution of sodium bicarbonate and 2 x 200 ml of water, dried over magnesium sulfate and concentrated. The residue is purified by a chromatographic column on silica (cyclohexane elution solvent). 7.62 g (yield: 84%) of 7-bromo-2-ethyl-3-ethylbenzo [b] thiophene are obtained in the form of a yellow oil.

(5) (R) -2 - [(Methoxyτnéthylamino) carbonyl] pyrrolidine-1- carboxylate of 1, 1-dimethylethyl.

13.0 g (56.8 mmol) of (R) -2-carboxypyrrolidine-l-carboxylate of 1 are placed in a 500 ml three-necked flask, fitted with a thermometer and a 250 ml addition funnel , 1-dimethylethyl and 190 ml of dichloromethane. The mixture is cooled to -20 ° C by a dry ice bath, and 7.91 ml (57 mmol) of triethylamine is added followed by 7.01 ml (56.8 mmol) of pivaloyl chloride. The mixture is vigorously stirred for 15 minutes at -10 ° C., then the temperature is allowed to rise to 0 ° C., and a solution of 11.07 g (113 mmol) of N, O hydrochloride is added dropwise - dimethylhydroxamine and 17.4 ml (125 mmol) of triethylamine in 160 ml of dichloromethane. The reaction mixture is allowed to return to ambient temperature in 120 minutes, then it is cooled to 0 ° C. in an ice bath and 100 ml of a 0.1 Ν solution of hydrochloric acid are added. The organic phase is washed successively with 100 ml of a 0.2 M sodium hydroxide solution, and with 200 ml of brine, then dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: 50% ethyl acetate in cyclohexane). 14.26 g (yield: 92%) of (R) -2 - [(methoxymethylamino) carbonyl] pyrrolidine-1-carboxylate of 1,1-dimethylethyl are obtained in the form of a colorless oil.

(6) {R) -2-Formylpyrrolidine-1-1,1-dimethylethylcarboxylate.

In a 125 ml flask, 0.80 g (21 mmol) of lithium aluminum hydride and 25 ml of ethyl ether are placed. The suspension is cooled to -10 ° C by an ice bath and a solution of 4.57 g (16.8 mmol) of (R) -2- [(methoxymethylamino) carbonyl] pyrrolidine-1 is added dropwise - 1, 1-dimethylethyl carboxylate in 25 ml of ethyl ether. The reaction mixture is stirred for 45 minutes at -10 ° C, then a solution of 3.43 g (25.2 mmol) of potassium bisulfate in 50 ml of water is added. An extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, washed with 120 ml of a molar hydrochloric acid solution, 120 ml of a saturated sodium bicarbonate solution, 120 ml of water, 120 ml of brine, dried over magnesium sulfate and concentrated. . 3.03 g (yield: 84.5%) of (i?) - 2-formylpyrrolidine-1-carboxylate of 1,1-dimethylethyl are obtained in the form of a colorless oil.

(7) (R, R) -2 - [(2-ethyl-3-methylbenzo [Jb] thien-7- yl) hydroxymethyl] pyrrolidine-1-1,1-dimethylethyl and {R, S) -2 carboxylate - [(2-ethyl-3-methylbenzo [b] thien-7-yl) hydroxymethyl] pyrrolidine-1-1,1-dimethylethylcarboxylate.

5.76 g (22.6 mmol) of 7-bromo-2-ethyl-3-methylbenzo [b] thiophene and 45 ml of anhydrous tetrahydrofuran are placed in a 150 ml three-necked flask. The solution is cooled to -78 ° C. by a dry ice bath in acetone, and 9.7 ml (24.1 mmol) of a 2.5 M solution of n-butyl lithium are added dropwise. in hexane. The reaction mixture is stirred for 25 minutes at -78 ° C. and then a solution of 3.0 g (15.1 mmol) of (R) -2-formylpyrrolidine-1-carboxylate of 1.1 is added dropwise -dimethylethyl in 15 ml of anhydrous tetrahydrofuran. The reaction mixture is stirred for 15 minutes at -78 ° C. then it is allowed to return to ambient temperature and 100 ml of water are added. An extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, washed with 120 ml of water, 120 ml of brine, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: 20% ethyl acetate in the cyclohexane) to give 2.03 g of (R, R) -2 - [(2, 3-dimethyl benzo [Jb] thien-7-yl) hydroxymethyl] pyrrolidine-1-1, 1-dimethylethyl carboxylate ([α ] ²⁰ _D = -62.8 ° (CH ₂ C1 ₂ )) (yield: 36%) in the form of a white solid - F: 55 ° C - and 2.32 g of (R, S) - 2 - [(2-ethyl-3-methylbenzo [b] thien-7-yl) hydroxymethyl] 1,1-dimethylethyl pyrrolidine-1-carboxylate ([α] ²⁰ _D = + 53.9 ° (CH ₂ C1 ₂ )) (yield: 41%) in the form of a colorless wax.

Example 2: (R, S) -a- (2-ethyl-3-methylbenzo Tbl thien-7-yl) pyrrolidine-2-methanol hydrochloride

2.18 g (5.82 mmol) of {R, S) -2 - [(2-ethyl-3-methylbenzo [b] thien-7 -yl) hydroxymethyl] pyrrolidine- are placed in a 250 ml flask 1, 1-dimethylethyl 1-carboxylate, 27 ml of dichloromethane and 3 ml of a solution of 5 M hydrochloric acid in isopropanol. The mixture is stirred for 16 hours at room temperature and then concentrated in vacuo. The residue is dissolved in 100 ml of water and extraction is carried out with ethyl ether (3 x 50 ml). 30 ml of a molar sodium hydroxide solution are added to the organic phase and extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, dried over magnesium sulfate and 2 ml of a solution of 5 M hydrochloric acid in isopropanol are added. The mixture is concentrated in vacuo and the residue is recrystallized from ethyl acetate to give 1.31 g of (R, S) -2 - [hydroxy (2-ethyl-3-methylbenzo thiophene-7 -yl) hydrochloride ) methyl] pyrrolidine ([α] ²⁰ _D = + 47.9 ° (methanol)) (yield: 72%) in the form of a white solid - F: 176 ° C.

Example 3: (R, S) -α- (2-ethyl-3-methylbenzo b ^~ \ thien-7-yl) -1-ethylpyrrolidine-2-methanol hydrochloride

1.07 g (3.43 mmol) of (R, S) -2 - [hydroxy (2-ethyl-3-methylbenzothiophene -7 -yl) methyl] pyrrolidine hydrochloride is placed in a 100 ml flask ml methanol, 0.91 g (20.6 mmol) acetaldehyde and 0.43 g (6.87 mmoles) of sodium cyanoborohydride. The reaction mixture is stirred at room temperature for 24 hours and then 10 ml of a molar solution of sodium hydroxide are added. An extraction is carried out with ethyl acetate (3 × 10 ml). The organic phases are combined, dried over magnesium sulfate and concentrated to give 1.03 g of {R, S) -2- [hydroxy (2-ethyl -3-methylbenzothiophene-7-yl) methyl] -1-ethylpyrrolidine ( [α] ²⁰ _D = + 92.9 ° (dichloromethane)) (yield: 98%) in the form of an oil. A solution of 0.95 g (3.13 mmol) {R, S) -2 - [hydroxy (2-ethyl-3-methylbenzothiophene-7-yl) methyl] - 1-ethylpyrrolidine in 27 ml of dichloromethane and 3 ml of a solution of 5M hydrochloric acid in isopropanol is stirred at room temperature for 30 min. The mixture is concentrated under vacuum and the residue is recrystallized from ethyl acetate to give 0.595 g of {R, S) -α- (2-ethyl-3-methylbenzo [Jb] thien-7 hydrochloride hydrochloride - yl) pyrrolidine-2 -methanol ([α] ²⁰ _D = -57 ° (dichloromethane)) (yield: 56%) in the form of a white solid - F: 140 ° C.

Example 4: Syn and Anti 2 - fhydroxy (2, 3-dimethylbenzofuran- 7 - yl) methyl l piperidine-1-carboxylate of 1. 1-dimethylethyl

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

60 g (347 mmol) of 2-bromo-phenol, 57.43 g, are introduced into a 1 liter three-necked flask fitted with a condenser.

(416 mmol) of potassium carbonate, 57 g (347 mmol) of potassium iodide, 600 ml of 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 (cyclohexane elution solvent: ethyl acetate 9: 1).

75:07 g are obtained (yield: 89%) of 3- (2-bromo-phenoxy) - 2-butanone (yellow oil).

(2) 2, 3-Dimethyl-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 are obtained (yield: 91%) of 2-methyl-3-methyl-7-bromo-benzofuran - mp: 33 ° C.

(3) N- (1, 1-Dimethylethyloxycarbonyl) -pipécolic-N, O-dimethyl-hydroxamide

13.0 g (56.8 mmol) of N-tert-butoxycarbonyl-pipecolic acid and 190 ml of dichloromethane are placed in a 500 ml three-necked flask, fitted with a thermometer and a 250 ml addition funnel. . The mixture is cooled to -20 ° C by a dry ice bath, and 7.91 ml (57 mmol) of triethylamine is added followed by 7.01 ml (56.8 mmol) of pivaloyl chloride. The mixture is vigorously stirred for 15 minutes at -10 ° C., then the temperature is allowed to rise to 0 ° C., and a solution of 11.07 g (113 mmol) of N, O hydrochloride is added dropwise -dimethylhydroxamine and 17.4 ml (125 mmol) of triethylamine in 160 ml of dichloromethane. The reaction mixture is allowed to return to ambient temperature in 120 minutes then it is cooled to 0 ° C. in an ice bath and 100 ml of a 0.1 Ν solution of hydrochloric acid are added. The organic phase is washed with 100 ml of 0.2 M sodium hydroxide solution, then with 200 ml of brine, dried over magnesium sulphate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: 50% ethyl acetate in cyclohexane). 14.26 g are obtained (Yield: 92%) of N- (1,1-dimethylethyloxycarbonyl) -pipecolic-Ν, O-dimethyl-hydroxamide in the form of a colorless oil. (4) N- (1, 1-Dimethylethyloxycarbonyl) -pipécolic-aldehyde

In a 125 ml flask, 0.80 g (21 mmol) of lithium aluminum hydride and 25 ml of ethyl ether are placed. The suspension is cooled to -10 ° C by an ice bath and a solution of 4.57 g (16.8 mmol) of N-tert-butoxycarbonyl-pipecolic-N, O-dimethyl- is added dropwise. hydroxamide in 25 ml of ethyl ether. The reaction mixture is stirred for 45 minutes at -10 ° C, then a solution of 3.43 g (25.2 mmol) of potassium bisulfate in 50 ml of water is added. An extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, washed with 120 ml of a molar hydrochloric acid solution, 120 ml of a saturated sodium bicarbonate solution, 120 ml of water, 120 ml of brine, dried over magnesium sulphate and concentrated. . 3.03 g are obtained (Yield: 84.5%) of N- (1,1-dimethylethyloxycarbonyl) - pipecolic-aldehyde in the form of a colorless oil.

(5) Syn and Anti 2- [Hydroxy (2,3-dimethylbenzofuran-7-yl) methyl] 1,1-dimethylethyl piperidine-1-carboxylate

8.55 g (38.1 mmol) of 2,3-dimethyl-7-bromo-benzofuran and 80 ml of anhydrous tetrahydrofuran are placed in a 250 ml three-necked flask. The solution is cooled to -78 ° C by a dry ice bath in acetone, and 15.2 ml (36.6 mmol) of a 2.4 M solution of lithium n-butyl is added dropwise. in hexane. The reaction mixture is stirred for 25 minutes at -78 ° C. and then a solution of 6.5 g (30.5 mmol) of N-tert-butoxycarbonyl-pipecolic-aldehyde in 25 ml of anhydrous tetrahydrofuran is added dropwise. . The reaction mixture is stirred for 15 minutes at -78 ° C. then it is allowed to return to ambient temperature and 100 ml of water are added. An extraction is carried out with ethyl acetate (3 x 80 ml). The organic phases are combined, washed with 120 ml of water, 120 ml of brine, dried over magnesium sulfate and concentrated. The residue is purified by chromatography on a silica column (elution solvent: 10% ethyl acetate in cyclohexane). We obtains 7.75 g (Yield: 80%) of Syn and Anti of 2- [hydroxy (2,3-dimethylbenzofuran-7-yl) methyl] piperidine-1- carboxylate of 1,1-dimethylethyl in the form of an oil colorless.

Example 5: Syn α- (2,3-Dimethylbenzofuran-7-yl) -piperidin-2-methanol, hydrochloride and Anti α- (2,3-dimethylbenzofuran-7-yl) -piperidin-2-methanol, hydrochloride

In a 250 ml flask, 3.0 g (9.32 mmol) of Syn and Anti 2- [hydroxy (2,3-dimethylbenzofuran-7-yl) methyl] piperidine-1-carboxylate are placed. dimethylethyl, 45 ml of dichloromethane and 5 ml of a solution of 5 M hydrochloric acid in isopropanol. The mixture is stirred for 4 hours at room temperature and then concentrated in vacuo. The residue is dissolved in 100 ml of water and extraction is carried out with ethyl ether (3 x 50 ml). 30 ml of a molar solution of sodium hydroxide are added to the organic phase and extraction is carried out with ethyl acetate (3 ×

80 ml). The organic phases are combined, dried over magnesium sulfate and 2 ml of a solution of 5M hydrochloric acid in isopropanol are added. The mixture is concentrated in vacuo and the residue is recrystallized from ethyl acetate to provide 310 mg of anti α- (2,3-dimethylbenzofuran-7-yl) -piperidin-2-methanol hydrochloride in the form d '' a white solid (mp: 247 ° C). The mother liquors are concentrated in vacuo and the residue obtained is recrystallized from ethyl ether to give 1.15 g of Syn α- (2,3-dimethylbenzofuran-7-yl) -piperidin-2-methanol hydrochloride under form of a white solid (mp: 118-128 ° C).

Example 6: Syn α- (2,3-Dimethylbenzofuran-7-yl) -1- methylpiperidin-2-methanol, hydrochloride

In a 100 ml flask, 120 mg (0.41 mmol) of syn α- (2, 3-dimethylbenzofuran-7-yl) - piperidin-2-methanol hydrochloride, 8 ml of methanol, 120 mg (4 mg) are placed. , 1 mmol) of paraformaldehyde and 80 mg (1.22 mmol) of cyanoborohydride sodium. The reaction mixture is stirred at room temperature for 24 hours and then 10 ml of a molar solution of sodium hydroxide are added. An extraction is carried out with ethyl acetate (3 × 10 ml). The organic phases are combined, dried over magnesium sulphate and 0.5 ml of a solution of 5M hydrochloric acid in isopropanol is added. The mixture is concentrated in vacuo and the residue is recrystallized from ethyl ether to give 69 mg of syn α- (2,3-dimethylbenzofuran-7-yl) 1-methylpiperidin-2-methanol hydrochloride in the form of a white solid (mp: 178-180 ° C).

Example 7:

By essentially reproducing the same process of Example 6, with the appropriate starting materials, other compounds of formula (I) according to the invention were prepared. These compounds are those having the numbers 19 to 24 in the table below.

Example 8: (.R, R) - (2) - [Hydroxy (2, 3-dimethylbenzofuran-7-yl) methyl] 1,1-dimethylethyl and (R, 5) - (2) pyrrolidine-1-carboxylate - [hydroxy (2,3-dimethylbenzofuran-7-yl) methyl] 1,1-dimethylethyl pyrrolidine-1-carboxylate

(1) {2R) - (N, O-dimethylhydroxylamine carboxylate) 1, 1-dimethylethyl pyrrolidin-1-carboxylate

By reproducing the process described in step (3) of Example 4, and using 1- (1, 1-dimethylethyl) - (R) -proline carboxylate as starting material, we obtain (2R) - (N, O-dimethylhydroxylamine carboxylate) 1, 1-dimethylethyl pyrrolidin-1-carboxylate in the form of a colorless oil.

(2) (2R) -Formyl-pyrrolidin-1-carboxylate of 1, 1-dimethylethyl

By reproducing the process described in step (4) of Example 4, and using {2R) as starting material ~ (N, O-dimethylhydroxylamine carboxylate) 1, 1-dimethylethyl pyrrolidin-1-carboxylate, 1, 1-dimethylethyl (2R) -formyl-pyrrolidin-1-carboxylate is obtained in the form of a colorless oil.

(3) (R, R) - (2) - [Hydroxy (2, 3-dimethylbenzofuran-7-yl) methyl] 1,1-dimethylethyl pyrrolidin-1-carboxylate and (R, S) - (2) - [hydroxy (2,3-dimethylbenzofuran-7-yl) methyl] 1,1-dimethylethyl pyrrolidin-1-carboxylate

By reproducing the process described in step (5) of Example 4, and using as starting material the (2R) -formyl-pyrrolidin-1-carboxylate of 1, 1-dimethylethyl, one obtains, after purification by chromatography on a silica column (elution solvent: 30% ethyl acetate in cyclohexane), {R, R) - (2) - [hydroxy (2, 3-dimethylbenzofuran-7-yl) methyl] pyrrolidin -1,1-dimethylethyl-1-carboxylate ([α] ²⁰ _D = -14.9 ° (CH ₂ C1 ₂ )) (yield: 30%) in the form of a colorless oil and (R, S) - ( 2) - [hydroxy (2, 3-diméthylbenzofuran- 7-yl) methyl] pyrrolidin-l-carboxylate 1,1-dimethylethyl ([] ²⁰ _D = + 85.5 ° (CH ₂ C1 ₂₎₎ (yield: 33%) as a colorless oil.

The other compounds in the table are synthesized in an analogous manner from the appropriate starting materials.

The following table gathers the compounds of the invention, as well as their physical characteristics.

BOARD

In this table :

- HC1 represents a hydrochloride

- t-Boc represents an N-tert-Butoxycarbonyl

Furthermore, stereochemistry is specified in the order in which it appears in the nomenclature of compounds. Compounds whose number is accompanied by a "*" are in the form of a pair of diastereoisomers. All the other compounds in the Table, apart from compounds n ° 62 and 63 which are racemic, are chiral. Compounds whose ring size "n" is accompanied by "**" have an aromatic nitrogen ring. 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 vitro 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 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 _raax ).

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

* a pD ₂ urethra, usually between 4 and 8

* a pD ₂ artery usually less than 3,

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

* a% E _max artery usually equal to zero.

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 calculation of the EC ₅₀ (concentration producing 50% of the maximum response).

The compounds of the invention have made it possible to obtain a venoconstrictor 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 yelated rats and rabbits, according to the following protocols:

* Demedulated rats

Istar rats are anesthetized and demedulated (according to the technique described by Gillespie, MacLaren A. and Polock D., A ethod of stimulating different segments of the autonomy outflow from the spinal column to various organs in the pithed cat and rat; Br. J Phar acol., 1970, 40: 257-267).

The catheters are introduced through the aorta 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 ₁₀ ) 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 50 and 200 μg / kg,

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

- PA ₅₀ could not be reached.

* Vigilant conscious rabbits

The experiments are carried out on female New Zealand rabbits weighing between 3 and 4 kg, anesthetized with pentobarbital. 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 (100 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 at 5 minutes after dosing.

The compounds of the invention thus tested, allowed an increase in the PU greater than 70%, usually between 90 and 25%. The increase in BP was always less than 10%, usually it was 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.

It could be determined that the compounds of the invention are ligands for the α-adrenergic receptors.

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

1. Compound of formula (I)

in which :

A represents either a hydrogen atom or a hydroxyl group,

X represents a sulfur atom or an oxygen atom,

R ₁₇ R ₂ , R ₄ , identical or different, each represent a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a cyano group, a C ₁ group. ₆ alkyl, one group

C ₂ . ₆ alkenyl, a C ₃ group. ₆ cycloalkyl, a group C ₃ . ₆ cycloalkenyl, aryl C ₆ _ ₁₄₎ a group C _x _ _g alkoxycarbonyl, a group C ₁ _ ₆ hydroxyalkyl, a group C _ ₆ alkoxy, a group C ₁ . ₆ alkoxyalkyl, a C- _L group. _g fluoroalkyle, a group C ₁ . ₂ perfluoroalkyl, or R _± and R ₂ together form a chain C ₁ . ₆ alkylene, a C ₃ chain. ₆ alkenylene, or R _x and R ₂ together form, with the carbons of benzothiophene or benzofuran carrying R _± and R ₂ , a phenyl,

R ₃ represents a hydrogen atom, a group C ₁ . ₆ alkyl, a group C ₂ _ ₆ alkenyl, a group C- ^ g fluoroalkyle, a group C _ ₂ perfluoroalkyle, C ₃ . ₆ cycloalkyl, C ₃ _ ₆ cycloalkenyl, phenyl, benzyl or a group C ₁ _ ₆ alkoxycarbonyl,

R ₅ represents a hydrogen atom or a halogen such as fluorine, chlorine or bromine, "a" and "c" represent 0 or 1, "b" represents 0, 1 or 2, and n represents an integer from 1 to 6, in the form of an enantiomer, a diastereoisomer, or a mixture of these different forms, including racemic mixture as well as their addition salts with pharmaceutically acceptable acids.

2. Compound according to claim 1, characterized in that A represents a hydroxyl group, X represents a sulfur atom or an oxygen atom,

R- _L , R ₂ , R ₄ , identical or different, each represent a hydrogen atom, a halogen such as fluorine, chlorine or bromine, a C _] __g alkyl group, a C ₂ group. ₆ alkenyl, a C ^ g hydroxyalkyl group, a C ^ g fluoroalkyl group, a C _x _ ₂ perfluoroalkyl group, or R _λ and R ₂ together form a C- ^ g alkylene chain, a C ₃ chain. ₆ alkenylene, or R _x and R ₂ together form, with the carbons of benzothiophene or benzofuran carrying R _x and R ₂ , a phenyl, R ₃ represents a hydrogen atom, a group C- ^ g alkyl, a group C ₂ . ₆ alkenyl, a group C ₁ . ₆ fluoroalkyle, a group C ₁ _ ₂ perfluoroalkyle, or a group C ^ galcoxycarbonyle, R ₅ represents a hydrogen atom or a halogen such as fluorine, chlorine or bromine, "a" and "c" represent 0 or 1 , "b" represents 0, 1 or 2, and n represents an integer from 1 to 6, preferably 2 to 5.

3. Process for the preparation of a compound according to claim 1, characterized in that an aldehyde of formula (II) is reacted

with an organometallic derivative of benzothiophene or benzofuran of formula (III ')

in which the meanings of X, R _{1 #} R ₂ , R ₄ , R ₅ , a, b, c and n of the aldehyde of formula (II) and of the benzofuran or benzothiophene derivative of formula (III ') are those defined for the compound of formula (I) according to claim 1 and Pg represents a protective group.

4. Medicament, characterized in that it consists of a compound according to claim 1 or 2.

5. Pharmaceutical composition characterized in that it comprises at least one compound, according to claim 1 or 2, and one or more suitable excipients.