EP0891358A1

EP0891358A1 - Oxazolidin-2-one derivatives, preparation method therefor and therapeutical use thereof

Info

Publication number: EP0891358A1
Application number: EP96932663A
Authority: EP
Inventors: Samir Jegham; Frédéric Puech; Philippe Burnier; Danielle Berthon; Odile Leclerc
Original assignee: Synthelabo SA
Current assignee: Sanofi Aventis France
Priority date: 1995-10-11
Filing date: 1996-10-08
Publication date: 1999-01-20
Also published as: WO1997013768A1; AU7135996A; US5969146A; JPH11513400A; TW336234B

Abstract

Oxazolidin-2-one derivatives of general formula (I), wherein R1 is a hydrogen atom, an alkyl, hydroxyalkyl, fluoroalkyl, hydroxyfluoroalkyl, cyanoalkyl, optionally substituted phenyl or optionally substituted phenylmethyl group, or a group R3A- where R3 is a cycloalkyl or cyclooxyalkyl group optionally substituted by a hydroxy group, and A is a -CH2 or -CH2-CH2 radical, R2 is a hydrogen atom or a methyl group, X is an oxygen or sulphur atom or a group NR4 where R4 is an alkyl group, and Z is an oxygen atom or a group -CH=CH or -CH2-CH2, a method for preparing said derivatives, and the therapeutical uses thereof, are disclosed.

Description

COMPOUNDS DERIVED FROM OXAZOLIDIN-2-ONE, THEIR PREPARATION PROCESS AND THEIR THERAPEUTIC APPLICATION

The subject of the present invention is compounds derived from oxazolidin-2-one of general formula (I)

in which:

R ₁ represents a hydrogen atom, an alkyl group,

hydroxyalkyle, fluoroalkyle, hydroxyfluoroalkyle,

cyanoalkyl, phenyl substituted or not substituted by a halogen atom or by an alkoxy, nitrile or nitro group, phenylmethyl substituted or not by a halogen atom or by an alkoxy, nitrile or nitro group, or a group R ₃ A- in which R ₃ is a cycloalkyl or cyclooxyalkyl group, substituted or not substituted by a hydroxy group, and A is a radical -CH ₂ or -CH ₂ -CH ₂ , R ₂ represents a hydrogen atom or a methyl group, X represents a oxygen, sulfur atom or a group

NR ₄ where R ₄ is an alkyl group or a hydrogen atom, and Z represents an oxygen atom or a group -CH = CH or

-CH ₂ -CH ₂ ,

their preparation process and their applications

therapeutic.

In the context of the present invention, and unless otherwise indicated, the following terms have the meanings

following:

* an alkyl group is an aliphatic group, saturated,

linear or branched, comprising 1 to 5 carbon atoms,

an alkoxy group is an OR ₅ group, where R ₅ is an alkyl group as defined above, a fluoroalkyl group is an alkyl group as defined above, in which at least one of the carbon atoms is substituted by one or more fluorine atoms,

a hydroxyfluoroalkyl group is a fluoroalkyl group as defined above, one of the carbon atoms of which is substituted by a hydroxy group,

* a cycloalkyl group is a radical derived from a

cycloalkane, comprising from 3 to 6 carbon atoms,

* a cyclooxyalkyl group is a cycloalkyl group as defined above in which one of the carbon atoms is replaced by an oxygen atom as the hereroatom; the perhydrofuranyl and perhydropyranyl groups are representative of such a cyclooxyalkyl group,

* a cyanoalkyl group is an alkyl group as defined above, in which at least one of the carbon atoms is substituted by a nitrile group.

The compounds of formula (I) where R ₂ is a methyl group are preferred. Among these latter compounds, those where X represents an oxygen atom are very particularly preferred.

When X represents an oxygen atom, the group R _{j ^} Z advantageously represents:

or, i) a group R _a O, where R _a has one of the meanings of R _x chosen from a hydrogen atom an alkyl, fluoroalkyl, hydroxyfluoroalkyl, cyanoalkyl, R ₃ A-, phenyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy and phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group.

More preferably, R _a is a hydrogen atom or a phenylmethyl, butyl, 4, 4, 4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl, 3,3,3-trifluoro-2-hydroxypropyl group, 3-cyanopropyl, p-fluorophenylmethyl, cyclopropylmethyl or 2- (1-hydroxycyclopentyl) ethyl. or, ii) a group R _b Z, where Z is a group -CH = CH- or

-CH ₂ -CH ₂ - and R _b has one of the meanings of R ₁ chosen from a hydrogen atom or an alkyl, fluoroalkyl, hydroxyalkyl, hydroxyfluoroalkyl, phenyl substituted or unsubstituted group by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group.

More preferably, R _b Z is chosen from the group ethenyl, 2-phenylethenyl, 2-phenylethyl, 5,5,5-trifluoropentyl, 5,5,5-trifluoropentenyl, 5,5,5-trifluoro-4-hydroxypentyl and 5 , 5,5-trifluoro-4-hydroxypentenyl.

When X represents a sulfur atom, the group R ₁ Z advantageously represents a group R _c O, where R _c has one of the meanings of R ₁ chosen from an alkyl, hydroxyalkyl, fluoroalkyl, hydroxyfluoroalkyl, phenyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom or by an alkoxy, nitrile or nitro group. According to a preferred aspect of the invention, R _c is chosen from the group consisting of butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl and the phenylmethyl group.

When X represents a group NR ₄ , R ₄ is preferably a methyl group and the group R ₁ Z advantageously represents a group R _d O, where R _d has one of the meanings of R ₁ chosen from a fluoroalkyl or hydroxyfluoroalkyl group, a phenyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group.

According to a preferred aspect of the invention, R _d is chosen from the group consisting of 4,4,4-trifluorobutyl,

4,4,4-trifluoro-3-hydroxybutyl and the phenylmethyl group.

The compounds of formula (I) have one or two asymmetric carbon atoms. They can therefore exist in the form of enantiomers or pure diastereoisomers or as a mixture of these different forms, including as a racemic mixture. These different forms and their mixtures are part of the invention. The compounds of formula (I) in which R ₁ Z represents a group R ₁ -CH = CH-, with the exception of the compounds in which R ₁ is a hydrogen atom, exist in the form of cis or trans isomers. These forms, as well as their mixtures, form part of the invention.

The compounds of the invention of formula (I) can be prepared according to the methods described in appendices 1 and 2. The compounds of formula (la), (Ib), (le), (Id) and (le), which are compounds of formula (I) according to the invention where Z represents an oxygen atom, can be prepared according to the process represented in appendix 1. In these compounds, X has one of the meanings given in formula (I ).

According to this process, an ethyl carbamate derivative of formula (II) is reacted with 4- (methoxymethyl) -1,3-dioxolan-2-one of formula (III) in the presence of potassium carbonate. In formula (II), R ₁ and X have one of the meanings given in formula (I) with the exception, as regards R ₁ , of hydrogen. This reaction makes it possible to obtain a compound of formula (la), which is a compound of formula (I) for which R ₂ represents a methyl group and R ₁ has one of the meanings given for formula (I), with the exception of hydrogen.

The compounds of formula (la) where R ₁ represents a phenylmethyl group can be used to prepare the compounds of formula (Ib). The latter are compounds of formula (I) for which R ₂ represents a hydrogen atom and R ₂ represents a methyl group. To this end, the phenylmethyl group is removed from said compound of formula (la), for example by means of dimethylphenylamine and aluminum chloride or by catalytic hydrogenation in the presence of palladium on carbon.

The compounds of formula (Ib) can be used to prepare the compounds of formula (Ic). The latter are compounds of formula (I) for which R ₁ and R ₂ each represent a hydrogen atom. To do this, demethylation of a compound of formula (Ib) is carried out using a Lewis acid, such as boron tribromide, in a solvent such as dichloromethane. The compounds of formula (Ic) can in turn be used to prepare the compounds of formula (Id). The latter are compounds of formula (I) for which R ₁ has one of the meanings given in formula (I), with the exception of the hydrogen atom, and R ₂ is a hydrogen atom. To do this, it is possible to react a compound of formula (Ie) with a compound of formula R ₁ Y, where R ₁ has one of the meanings given in formula (I), with the exception of hydrogen, and Y is a halogen atom or a leaving group such as methylsulfonyloxy (mesyloxy) or p-toluenesulfonyloxy (tosyloxy). This reaction can be carried out in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile, N, N-dimethylformamide or a mixture of these solvents. The

reaction temperature may be the reflux temperature of the solvent.

According to an advantageous aspect of the invention, the compounds of formula (Ib) can be used to obtain compounds of formula (le) according to the invention for which R _{1 has} one of the meanings given in formula (I), except for the meaning hydrogen atom. To this end, a compound of formula (Ib) is reacted with a compound of formula R ₁ Y, where R ₁ has one of the meanings given in formula (I), with the exception of an atom of hydrogen, and Y is as defined above. This reaction can be carried out in the presence of a base such as potassium carbonate, in a solvent such as acetonitrile. The reaction temperature can be the reflux temperature of the solvent.

The compound of formula (Ie) thus obtained can then be demethylated to prepare a compound of formula (Id). Demethylation can be carried out under the conditions indicated above as regards the demethylation of the compound of formula (Ib).

Of course, a compound (la) which already has the desired meaning of R ₁ does not have to be transformed into a compound (le); such a compound of formula (la) can itself be demethylated to directly obtain a compound of formula (Id).

According to another aspect of the invention, the compounds of formula (I) for which the group R ₁ is a group comprising a hydroxyl function, can be prepared by reacting a compound of formula (II) comprising such a group R ₁ with a compound of formula (III), said hydroxyl function being previously protected in a conventional manner for a person skilled in the art, by a protective group such as t-butyldimethylsilyl. After preparation of the compound of formula (la), the protective group of the hydroxyl function can be eliminated by means, for example, of tetra-n-butylammonium fluoride, in an organic solvent such as tetrahydrofuran.

The compounds of formula (If) and (Ig), which are compounds of formula (I) according to the invention where Z represents,

respectively, a group -CH = CH or -CH ₂ -CH ₂ , can be prepared according to the process represented in appendix 2. In these compounds, X has one of the meanings indicated in formula (I).

According to this process, a compound of formula (Ib) as mentioned above is reacted with anhydride

trifluoromethanesulfonic (Tf ₂ O) to obtain a trifluoromethanesulfonate derivative of formula (IV).

The compound of formula (IV) can then be reacted with palladium acetate in the presence of carbon monoxide and methanol to prepare a methoxycarbonyl derivative of formula (V), which is in turn treated using 'a

borane-dimethylsulfide complex (BH ₃ .S (CH ₃ ) ₂ ) to obtain a hydroxymethyl derivative of formula (VI). The latter can then be treated with oxalyl chloride and

dimethyl sulfoxide to prepare a formyl derivative of formula (VII). This treatment can be carried out at a temperature of around -70 ° C.

The formyl derivative of formula (VII) can then be reacted with a triphenylphosphonium salt of formula

R ₁ CH ₂ P ⁺ (C ₆ H ₅ ) ₃ W-, in particular a halide of

triphenylphosphonium, such as a triphenylphosphonium bromide, where R ₁ has one of the meanings given in formula (I) and W- represents the anion of a halogen atom. This reaction can be carried out in the presence of a base such as potassium carbonate. It is thus possible to prepare a compound according to the invention of formula (If), in which Z represents a group -CH = CH-.

The compound of formula (If) can then be reduced to prepare a compound according to the invention of formula (Ig). This reduction can be carried out using hydrogen in the presence of a catalyst such as palladium on carbon.

In the compounds of formula (IV), (V), (VI) and (VII), X has one of the meanings given in formula (I).

The compounds of formula (If) and (Ig) can be demethylated to yield the corresponding compounds of formula (I) where R ₂ represents a hydrogen atom. This demethylation can be done using a Lewis acid such as boron tribromide.

According to an advantageous aspect of the invention, it is possible to

directly prepare the compounds of formula (If) for which R ₁ is a hydrogen atom, by reacting the compound of formula (IV), mentioned above, with

tributylvinyltin, in the presence of lithium chloride and tetrakis (triphenylphosphine) palladium.

The compounds of formula (II) can be prepared according to the process represented in appendix 3, by reacting a compound of formula (VIII) with a compound of formula R ₁ Y, in which R ₁ is defined as in formula (I) and Y is a halogen atom, in particular bromine, or a labile group such as methylsulfonyloxy (mesyloxy) or p-toluenesulfonyloxy (tosyloxy). This reaction can be carried out in the presence a base such as potassium carbonate, in a solvent such as acetonitrile. The reaction temperature can be the reflux temperature of the solvent. The compound of formula (VIII) can be prepared from a compound of formula (IX), where R ₆ is a protecting group for the hydroxy group, in particular a methyl or phenylmethyl group. To this end, said protective group R ₆ is eliminated by conventional means for those skilled in the art. Thus, when R ₆ is a methyl group, the compound of formula (IX) is demethylated using a Lewis acid such as boron tribromide, in an organic solvent such as dichloromethane. The temperature used during this treatment can be between -20 ° C and 20 ° C.

When R ₆ is a phenylmethyl group, this protective group can be removed by catalytic hydrogenation.

Of course, when the protective group R ₆ has one of the desired meanings of R ₁ , the compound of formula (IX) can be directly used as the compound of formula (II).

The compound of formula (IX) can be prepared by

decarboxylation of a compound of formula (X), by heating to a temperature close to the melting point of the latter compound, or even to a temperature above said melting point.

The compound of formula (X) can be prepared by

saponification of a compound of formula (XI), using a base such as potassium hydroxide in an alcoholic medium. The saponification reaction can be carried out at a

temperature between 0 ° C and the reflux temperature of the solvent. In formula (XI), R ₇ represents a methyl or ethyl group.

The compound of formula (XI) can be prepared by reacting a compound of formula (XII), where R ₇ represents a methyl or ethyl group, with ethyl chloroformate. This reaction can be carried out in the presence of a base such as potassium carbonate, in a solvent such as toluene. This reaction can be carried out at the reflux temperature of the solvent. In each of the compounds of formula (VIII), (IX), (X), (XI) and (XII), X has one of the meanings given in formula (I).

The compounds of formula (XII) can be prepared according to various synthetic routes according to the nature of X. These synthetic routes are represented in Annex 4.

The compounds of formula (XII) where X is a sulfur atom and R ₆ and R ₇ each represent a methyl group, can be prepared by reacting 3-nitro-4-cyanoanisole with methyl thioglycolate. This reaction can be carried out in the presence of a base such as potassium hydroxide, in a solvent such as N, N-dimethylformamide. This reaction can be carried out at 0ºC.

3-nitro-4-cyanoanisole is a known compound. It can be prepared according to the method described by A.H. Cook et al., J.

Chem.Soc, 1945, 68, 861. The compounds of formula (XII) for which X is an oxygen atom or ΝR ₄ , can be prepared by a process according to which a compound of formula (XIII) is treated, either by sodium ethylate when X represents an oxygen atom, or by potassium tert-butoxide when X represents NR ₄ .

The compound of formula (XIII) can be prepared by reacting a compound of formula (XIV), where X is an oxygen atom or NR ₄ , with sodium hydride then bromoacetate

ethyl.

A compound of formula (XIV) where X is an oxygen atom, can be prepared by reacting 2-hydroxy-4- (phenylmethoxy) benzaldehyde with nitroethane or hydroxylamine and ethyl formate. 2-hydroxy-4- (phenylmethoxy) benzaldehyde is a known compound, which can be prepared according to JSH Davies (J. Chem. Soc. 1950, 3206). A compound of formula (XIV) where X is an NR ₄ group, can be prepared by reacting a compound of formula (XV) with a compound of formula R ₄ NH ₂ , such as methylamine. The compound of formula (XV) can itself be obtained by reacting commercially available 2-fluoro-4- (hydroxy) benzonitrile with benzyl bromide. In the compounds of formula (XIV) and R ₄ NH ₂ , R ₄ has one of the meanings given for formula (I).

The enantiomers 5 (R) and 5 (S) of the compounds of formula (I) are prepared respectively from the enantiomers (S) and (R) of 4-methoxymethyl-1,3-dioxolane-2-one of formula ( III), according to the method described above.

(S) -4-methoxymethyl-1,3-dioxolane-2-one is a known compound, the preparation of which is described in the patent

EP 0511 031.

(R) -4-methoxymethyl-1,3-dioxolane-2-one is prepared according to the same method, starting from (R) -2,2-dimethyl-1,3-dioxolan-4-methanol.

The following examples are intended to illustrate the

preparation of some compounds of the invention. The

elementary microanalyses, and the R.M.N. confirm the structures of the compounds obtained.

In the names of the compounds, the dash "-" is part of the word, and the dash "-" is only used for the break at the end of the line; it must be deleted in the absence of a break, and must not be replaced either by a normal dash or by a space.

Example 1: (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one

1.1. (R) -4- (methoxymethyl) -2,2-dimethyl-1,3-dioxolane In a 6 liter reactor fitted with a rigorous ref, a temperature probe and an addition funnel, one

introduced 420 ml of demineralized water and 420 g (10.5 mol) of sodium hydroxide in pellets. To the solution stirred at 20 ° C., 2.3 l of dichloromethane, 396 g (3.00 mol) of (R) -2, 2-dimethyl-1,3-dioxolane-4-methanol ([α]) are added. ²⁰ _D = - 11 °; c = 4; methanol) and 20.5 g (0.090 mol) of chloride

benzyltriethylammonium. Then 567 g (4.50 mol) of dimethyl sulphate are added over 50 minutes, keeping the temperature below 30 ° C. The mixture is stirred for 18 hours and then 1 liter of water is added. The organic phase is separated and washed with 0.5 l of water. The aqueous phases are re-extracted with 3 l of dichloromethane and then the organic phases are combined, filtered and concentrated by

distillation under reduced pressure. 496 g of product are obtained.

1.2. (S) -3-methoxypropane-1,2-diol A mixture of the 496 g of product obtained in the previous step in 220 ml of water is heated to 60 ° C. with stirring

demineralized, then 1.5 ml of 36% hydrochloric acid is added. Heating is maintained for 40 min., Then the medium is brought to pH 8-9 by the addition of 19 ml of

triethylamine. The solvent is evaporated under a pressure of 5.2 kPa, at a temperature below 70 ^β C and then the residue is distilled at 61 ° C under a pressure of 13 Pa. 246 g of product are obtained.

[α] ²⁰ _D = + 5.8º (c = 4; methanol).

1.3. (R) -4- (methoxymethyl) -1,3-dioxolan-2-one

245 g (3.31 mol) of (S) -3-methoxypropane-1,2-diol and 560 ml (4.62 mol) are introduced into a flask fitted with an addition funnel and a distillation device. ) of diethylcarbonate. The mixture is heated to 95ºC and then a solution of sodium methylate obtained from 10 ml of methanol and 0.5 g (0.02 mol) of sodium is added. The ethanol formed during the reaction is distilled for 2 hours (temperature of mass: 95 to 112 ° C; column temperature: 82 to 78 ° C.), then the mixture is cooled and distilled under a pressure of 13 Pa to separate the excess diethylcarbonate. 267 g of product are obtained.

[α] ²⁰ _D = + 30.3 ° (c = 1; dichloromethane).

1.4. 2-Hydroxy-4- (phenylmethoxy) benzonitrile

The mixture is heated at 104 ° C. for 8 hours, a mixture of 226 g (1.00 mol) of 2-hydroxy-4- (phenylmethoxy) benzaldehyde in 287 ml (3.83 mol) of nitroethane and 313 g (2, 3 mol) of sodium acetate in 570 ml of acetic acid, then poured into 3 l of a mixture of water and ice. The precipitate is then filtered, rinsed with diisopropyl ether and dried. 118 g of product are obtained.

On the other hand, the filtrate is extracted with ether

diethyl, the organic phase is washed with an aqueous solution of sodium hydrogencarbonate then with water, dried over sodium sulfate, concentrated under reduced pressure, then the residue is triturated in diisopropyl ether. 67 g of additional product are thus obtained, Melting point: 130ºC.

1.5. Ethyl 2-cyano-5- (phenylmethoxy) phenoxyacetate

To a solution of 46 g (0.20 mol) of 2-hydroxy-4- (phenylmethoxy) benzonitrile in a mixture of 450 ml of

tetrahydrofuran and 450 ml of dimethylformamide, 9.7 g (0.20 mol) of 50% sodium hydride are added in small portions. The mixture is stirred for 30 minutes and then 22.4 ml (0.20 mol) of ethyl bromoacetate is added dropwise. The reaction medium is left to react for 30 minutes, then the reaction mixture is poured into ice water and the product is extracted with ethyl acetate. The phase is then washed

organic with water, dried over sodium sulfate and concentrated under reduced pressure. After trituration of the residue in diisopropyl ether, 50 g of product are obtained. Melting point: 84 ° C. 1.6. Ethyl 3-Amino-6- (phenylmethoxy) benzofuran-2-carboxylate

To a sodium ethylate solution obtained from 1.8 g (0.080 mol) of sodium and 400 ml of ethanol, 50 g (0.16 mol) of 2-cyano-5- ( phenylmethoxy) ethyl phenoxyacetate. The mixture is heated for

1 hour at reflux, then it is poured into water and the product is extracted with ethyl acetate. The organic phase is then washed with a saturated aqueous sodium chloride solution, then dried over sodium sulfate and concentrated under reduced pressure. After purification by chromatography on a silica column with

dichloromethane, 40 g of product are obtained.

Melting point: 95 ° C.

1.7. Ethyl 3 - [(Ethoxycarbonyl) amino] -6- (phenylmethoxy) benzofuran-2-carboxylate A mixture of 40 g (0.13 mol) of 3-amino-6- (phenylmethoxy) is refluxed for 18 hours ) ethyl benzofuran-2-carboxylate, 18 ml (0.19 mol) of ethyl chloroformate and 51 g (0.37 mol) of potassium carbonate in 400 ml of benzene, then cooled, filtered and the filtrate is concentrated under reduced pressure. Through

recrystallization of the residue from diisopropyl ether, 41 g of product are obtained.

Melting point: 100 ° C. 1.8. 3 - [(ethoxycarbonyl) amino] -6- (phenylmethoxy) benzofuran-2-carboxylic acid

To a solution of 41 g (0.11 mol) of ethyl 3 - [(ethoxycarbonyl) amino] -6- (phenylmethoxy) benzofuran-2-carboxylate in 400 ml of ethanol, 200 ml of a solution are added. ethanolic 10% potassium hydroxide. The mixture is heated to reflux for 30 minutes and then the solvent is evaporated off under reduced pressure. The residue is taken up with water and the solution is acidified with acid hydrochloric up

pH 2. By filtration of the precipitate formed, 41 g of product are obtained.

Melting point: 198 ° C.

1.9. [6- (Phenylmethoxy) benzofuran-3-yl] ethyl carbamate

We immerse in an oil bath at 185-190ºC for

5 minutes, a reactor containing 38.6 g (0.11 mol) of 3 - [(ethoxycarbonyl) amino] -6- (phenylmethoxy) benzofuran-2-carboxylic acid under nitrogen. The residue is then taken up with ethyl acetate and then the solution is washed with an aqueous solution of potassium hydrogen carbonate and then with a saturated aqueous solution of sodium chloride. The organic phase is then dried over sodium sulfate, the solvent is evaporated off and the residue is purified on a silica column with a mixture of 20% ethyl acetate in cyclohexane. After trituration in diisopropyl ether, 25 g of product are obtained.

Melting point: 140 ° C.

1.10. (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one A mixture of 85 mg (0.6 mmol) is heated to 140 ° C.

dry potassium carbonate in 40 ml of anhydrous dimethylformamide, then 1.6 g (12 mmol) of (S) -4-methoxymethyl-1,3-dioxolane-2-one and a solution of 2.0 g ( 6.4 mmol) of ethyl [6- (phenylmethoxy) benzofuran-3-yl] carbamate in 10 ml of dimethylformamide. The mixture is stirred for 3.5 hours at 140 ° C, then poured into ice water. The product is then extracted with ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by

chromatography on a silica column with a mixture of 30% ethyl acetate in cyclohexane and then with a mixture of 2% ethyl acetate in dichloromethane. After trituration in diisopropyl ether, 1.2 g of product.

Melting point: 112, 6-112, 8 ° C.

[α] ²⁰ _D = - 34 ° (c = 1; dichloromethane). According to the same process, from ethyl [6- (phenylmethoxy) benzofuran-3-yl] carbamate and (R) -4-methoxymethyl-1,3-dioxolane-2-one, the ( S) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one.

Melting point: 111.9 ° C.

[α] ²⁰ _D = + 33.3 ° C (c = 1; dichloromethane).

Example 2: (R) -5- (methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one

To a solution of 1.3 g (3.7 mmol) of (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one in 50 ml of cooled dichloromethane at 0 ° C., 1.4 ml (11 mmol) of dimethylphenylamine and 1.9 g (15 mmol) of aluminum chloride are added. The mixture is stirred for 1 hour until room temperature then it is poured into water and the product is extracted with dichloromethane. The organic phase is then washed with water, dried over sodium sulfate and concentrated under reduced pressure. After trituration of the residue in a mixture of diisopropyl ether and petroleum ether, 0.64 g of product is obtained.

Melting point: 136.0-136.5 ° C.

[α] ²⁰ _D = - 55.3 ° (c = 1; methanol). According to the same process, starting from (S) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one, (S) -5- ( methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one.

Melting point: 141.2 ° C.

[α] ²⁰ _D = + 50.5 ° (c = 1; methanol).

Example 3: (R) -5- (hydroxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one To a solution of 1.5 g (5.7 mol) of (R) -5- (methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one in 100 ml of dichloromethane cooled to 0 ° C, 17 ml of a 1M solution of boron tribromide in dichloromethane are added. The reaction medium is stirred for 2 hours then it is poured into an ammonia solution. The product is then extracted with dichloromethane, then the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. After chromatography of the residue on a silica column with a mixture of 4% methanol in dichloromethane and trituration in diethyl ether, 0.80 g of product is obtained.

Melting point: 172, 1-172, 2 ° C.

[α] ²⁰ _D = - 39.3 ° (c = 1; dimethylsulfoxide).

Example 4: (R) -5- (hydroxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzofuran-3-yl] oxazolidin-2-one

A mixture of 0.30 g (1.2 mol) of (R) -5- (hydroxymethyl) -3- (6-hydroxybenzof uran-3-yl) oxazolidin-2 is stirred at 80 ° C. for 2 hours. -one, 0.30 g (1.6 mol) of 1-bromo-4,4,4- trifluorobutane and 0.33 g (2.4 mol) of potassium carbonate in 10 ml of a 2/8 mixture dimethylformamide and

of acetonitrile, then it is filtered and the solvent is evaporated off under reduced pressure. The residue is then taken up with ethyl acetate, then the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. After recrystallization from isopropyl alcohol, 0.30 g of product is obtained.

Melting point: 194, 0 ° C.

[α] ²⁰ _D = - 26.7 ° (c = 1; dimethylsulfoxide).

Example 5: (R, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one

Stirred at reflux for 2 hours, a mixture of 0.43 g (1.6 mmol) of (R) -5- (methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one, 0 , 63 g (2.1 mmol) of tosylate

(R) -4,4,4-trifluoro-3-hydroxybutyl and 0.45 g (3.6 mmol) of potassium carbonate in 40 ml of acetonitrile, then filtered and the filtrate is concentrated under reduced pressure. The residue is taken up in ethyl acetate, then the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by chromatography on a silica column with a mixture of 50% ethyl acetate in cyclohexane. Through

crystallization from a mixture of diethyl ether and hexane, 0.52 g of product is obtained.

Melting point: 80.5-82.0 ° C.

[α] ²⁰ _D = - 5.3 ° (c = 1; dichloromethane).

According to the same process, starting from (S) -5- (methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one and (R) -4,4,4-trifluoro tosylate -3-hydroxybutyl, we got the

(S, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one.

Melting point: 119, 6-119, 7ºC.

[α] ²⁰ _D = + 50.8 ° (c = 1; dichloromethane).

Example 6: (S, R) -5- (hydroxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one

To a solution of 100 mg (0.26 mmol) of (S, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin -2-one in 8 ml of

dichloromethane cooled to 0 ° C., 0.8 ml of a 1M solution of boron tribromide in dichloromethane is added. The reaction medium is stirred for 2 hours and then it is poured into a solution of ice-cold ammonia. The product is then extracted with dichloromethane, the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. After chromatography of the residue on a silica column with a mixture of 70% ethyl acetate in cyclohexane, 50 mg of product is obtained.

Melting point: 163.9-164.0 ° C.

[α] ²⁰ _D = + 57.9 ° (c = 1; dimethylsulfoxide).

Example 7: (R) -5- (methoxymethyl) -3- [6- (cyclopropylmethoxy) benzofuran-3-yl] oxazolidin-2-one

To a solution of 0.47 g (1.8 mmol) of (R) -5- (methoxymethyl) -3- (6-hydroxybenzofuran-3-yl) oxazolidin-2-one in 40 ml of acetonitrile, the following is added 0.50 g (3.6 mmol) of potassium carbonate and 0.20 ml (2.1 mmol) of bromomethylcyclopropane. The reaction mixture is heated to 50-60 ° C for

24 hours, then it is filtered and the solvent is evaporated off under reduced pressure. We take up the residue with

dichloromethane, then the organic phase is washed with water, dried and the solvent is evaporated. After chromatography of the residue on a silica column with a mixture of 40% ethyl acetate in cyclohexane and two recrystallizations from isopropyl alcohol, 0.39 g of product is obtained.

Melting point: 139, 9-140, 0 ° C.

[α] ²⁰ _D = - 39.2 ° (c = 1; dichloromethane).

Example 8: (R, R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluro-4-hydroxypent-1-enyl) benzofuran-3-yl] oxazolidin-2-one

8.1. (R) -3- [5- (methoxymethyl) -2-oxooxazolidin-3-yl] benzofuran-6-yl trifluoromethanesulfonate

To a solution maintained at -20 ° C of 7.6 g (0.029 mole) of (R) - 3- (6-hydroxybenzofuran-3-yl) -5- (methoxymethyl) oxazolidin-2-one in 60 ml of pyridine 5.8 ml (0.035 mole) of trifluoromethanesulfonic anhydride are slowly added. After returning to room temperature, pour into ice and bring the mixture to a pH of 6 using 2N hydrochloric acid. The product is then extracted with ethyl acetate, the solvent is evaporated off under reduced pressure and the product is purified by chromatography on silica gel with a mixture of cyclohexane and dichloromethane 10/90.

10.2 g of product are recovered. Melting point: 98 ° C

8.2. (R) -3- [5- (methoxymethyl) -2-oxooxazolidin-3-yl] benzofuran-6-carboxylate

To a solution of 15.4 g (0.033 mole) of trifluoromethane (R) -3- [5- (methoxymethyl) -2-oxooxazolidin-3-yl] benzofuran-6-yl sulfonate in 234 ml of dimethyl sulfoxide, 0.26 g (0.001 mol) of palladium acetate is added, 12 ml (0.086 mole) of triethylamine, 86 ml of methanol and 0.48 g (0.001 mole) of bis (diphenylphosphinopropane). The mixture is placed under a carbon monoxide atmosphere and heated for three hours.

Then filtered on celite, the filtrate is taken up with ethyl ether, washed with water, dried over sodium sulfate and the aqueous phase is evaporated under reduced pressure.

The product is purified by chromatography on silica gel with a mixture of dichloromethane and methanol 99/1.

5.3 g of product are recovered. Melting point: 116 ° C

8.3. (R) -3- [6- (hydroxymethyl) benzofuran-3-yl] -5- (methoxymethyl) oxazolidin-2-one To a solution of 3.3 g (0.011 mole) of (R) -3- [5 - (methoxymethyl) -2-oxooxazolidin-3-yl] methyl benzofuran-6-carboxylate in 40 ml of tetrahydrofuran, 22 ml of a 2M solution (0.044 mol) of a borane-dimethylsulfide complex is added in two batches tetrahydrofuran, and heated five hours at 55 ° C. The medium is hydrolyzed with 1N hydrochloric acid. The mixture is poured into water and the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and concentrated under reduced pressure. The product is purified by

chromatography on silica gel with a mixture of

dichloromethane and methanol 99/1. After crystallization from ethyl ether, 2.0 g of product are recovered. Melting point: 112 ° C. 8.4. (R) -3- (6-formylbenzofuran-3-yl) -5- (methoxymethyl) oxazolidin-2-one

To a solution, cooled to -70 ° C, of 0.75 ml (8.6 mmol) of oxalyl chloride in 20 ml of dichloromethane, 1 is added ml (14.4 mmol) of dimethyl sulfoxide in 20 ml of

dichloromethane. The mixture is stirred for 15 min. and a solution of 2.0 g (7.2 mmol) of (R) -3- [6- (hydroxymethyl) benzofuran-3-yl] -5- (methoxy) is added slowly.

methyl) oxazolidin-2-one in 35 ml of dichloromethane. The mixture is stirred for three hours at -70 ° C. and 5.0 ml (36 mmol) of triethylamine are added. After returning to room temperature, the mixture is poured into 50 ml of water, the product is extracted with dichloromethane, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel and an oil is recovered which is crystallized from ethyl ether.

1.1 g of product are obtained. Melting point: 94-95 ° C.

8.5. (R, R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluro-4-hydroxypent-1-enyl) benzofuran-3-yl] oxazolidin-2-one

A mixture comprising 0.23 g (0.8 mmol) of (R) -3- (6-formylbenzofuran-3-yl) -5- (methoxymethyl) oxazolidin-2-one is heated for 24 hours at 80 ° C. 0.50 g (1.0 mmol) of (3-hydroxy-4,4,4,4-trifluorobutyl) triphenyl bromide.

phosphonium, 0.16 g (1.2 mmol) of potassium carbonate in 2.5 ml of dioxane and 0.17 ml of formamide. The mixture is then poured into water, the product is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel with a mixture of dichloromethane and ethyl acetate 95/5. After trituration in diisopropyl ether, 0.10 g of pure trans isomer is recovered. Melting point: 116.5-116.8 ° C. [α] ²⁰ _D = -15.1 ° (c = 1; dichloromethane).

Example 9: (R, R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluoro-4-hydroxypentyl) benzofuran-3-yl] oxazolidin-2-one

To a solution in 8.5 ml of ethanol of 0.26 g (0.67 mmol) of (R, R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluro-4 -hydroxypent- 1-enyl) benzofuran-3-yl] oxazolidin-2-one obtained in Example 8, 0.05 g of palladium on carbon is added. The mixture is placed under a hydrogen atmosphere for 18 hours, the palladium on carbon is removed by filtration and

concentrates the filtrate under reduced pressure. Then, the product is purified by chromatography on silica gel with a mixture of cyclohexane and ethyl acetate 60/40. 0.14 g of product is recovered after crystallization from diisopropyl ether.

Melting point: 85.8-86.2ºC.

[α] ²⁰ _D = -18.0 ° (c = l; dichloromethane).

Example 10: (R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluoropent-1-enyl) benzofuran-3-yl] oxazolidin-2-one

It is heated for six hours, at reflux, a mixture

comprising 0.30 g (1.1 mmol) of (R) -3- (6-formylbenzofuran- 3-yl) -5- (methoxymethyl) oxazolidin-2-one, 0.59 g (1.3 mmol) of (4,4,4-trifluorobutyl) triphenylphosphonium bromide, 0.21 g (1.5 mmol) of potassium carbonate in 3.5 ml of dioxane and 0.22 ml of formamide. The mixture is then poured into water, the product is extracted with ethyl acetate, the organic phase is dried over sodium sulphate and concentrated under reduced pressure. The product is purified by chromatography on silica gel with a mixture of

dichloromethane and ethyl acetate 99.5 / 0.5. We

the product crystallizes from petroleum ether and 0.35 g of it is recovered in the form of a cis / trans mixture of 67/33. Melting point: 57-63 ° C.

[α] ²⁰ _D = -36.3 ° (c = 1; dichloromethane).

Example 11: (R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluoro pentyl) benzofuran-3-yl] oxazolidin-2-one A solution in 5 ml of ethanol 0 , 13 g (0.35 mmol) of the cis / trans mixture of (R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluoropent-1-enyl) benzofuran-3-yl] oxazolidin -2-one obtained in Example 10, 0.03 g of palladium on carbon is added. The mixture is placed under a hydrogen atmosphere for eight hours, then the palladium on carbon is removed by

filtration and the filtrate is concentrated under reduced pressure. The product is then purified by chromatography on silica gel with a mixture of dichloromethane and methanol 99.5 / 0.5. 0.1 g of product is recovered.

Melting point: 65.7-65.9 ° C.

[α] ²⁰ _D = -31.6 ° (c = 1; dichloromethane).

Example 12: (R) -3- (6-ethenylbenzofuran-3-yl) -5- (methoxymethyl) oxazolidin-2-one

A mixture of 3.6 g (9.1 mmol) of trifluoromethanesulfonate of (R) -3- [5- (methoxymethyl) -2-oxo-oxazolidin-3-yl] benzofuran-6-yl is heated to 101 ° C. , 1.1 g (27.3 mmol) of lithium chloride, 2.9 g (9.1 mmol) of tributylvinyltin and 0.18 g (0.15 mmol) of tetrakis (triphenylphosphine) palladium, in 40 ml of dioxane. The solvent is then evaporated off under reduced pressure, the residue is taken up in ethyl acetate, the organic phase is washed with water, dried over sodium sulfate and concentrated under reduced pressure. The residue is purified by

chromatography on silica gel with a mixture of

cyclohexane and ethyl acetate 70/30. 1.9 g of product are recovered.

Melting point: 89.0-89.1 ° C.

[α] ²⁰ _D = -49.4 ° (c = 1; dichloromethane).

Example 13: (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzo_ [b] thien-3-yl] oxazolidin-2-one

13.1. Methyl 3-amino-6-methoxybenzo [b] thiophene-2-carboxylate

To a mixture of 36.3 g (0.204 mole) of 3-nitro-4-cyanoanisole and 26 g (0.245 mole) of methyl thioglycolate in 400 ml of N, N-dimethylformamide, a solution of 20.3 is added g (0.363 mole) of potassium hydroxide in 100 ml of water, maintaining the temperature at 0 ° C. The mixture is left under stirring at 0 ° C for 20 min, then poured into a mixture water and ice. The precipitate is then filtered, rinsed with water and dried. The product is dissolved in a mixture of dichloromethane and tetrahydrofuran, then the organic phase is dried over sodium sulfate, it is concentrated under reduced pressure and the residue is triturated in dichloromethane.

26.2 g of product are thus obtained in the form of a light beige powder.

Melting point: 170 ° C.

13.2. Methyl 3 - [(ethoxycarbonyl) amino] -6-methoxybenzo [b] thiophene-2-carboxylate

A mixture of 27.4 g (0.115 mol) of methyl 3-amino-6-methoxybenzo [b] thiophene-2-carboxylate, 38 g (0.275 mol) of potassium carbonate and 13.2 ml (0.138 mol) of ethyl chloroformate in 330 ml of toluene.

Then 7 ml (0.069 mole) of ethyl chloroformate are added and the mixture is allowed to reflux for a further seven hours, with stirring. The mixture is then diluted with

dichloromethane and washed with water. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. We recrystallize from a mixture

isopropanol and diisopropyl ether.

31.2 g of product are obtained.

Melting point: 137 ° C.

13.3. 3 - [(ethoxycarbonyl) amino] -6-methoxybenzo acid

[b] thiophene-2-carboxylic

To a solution of 31.4 g (0.101 mol) of 3 - [(ethoxycarbonyl) amino] -6-methoxybenzo [b] methyl thiophene-2-carboxylate in 230 ml of ethanol, 92 ml of a solution are added.

ethanolic 10% potassium hydroxide. The mixture is heated at 60 ° C for 10 minutes, then poured over ice water. The mixture is acidified by addition of a 6N hydrochloric acid solution and the precipitate formed is filtered, rinsed with water and dried under reduced pressure. The solid is triturated in ethanol. 22.8 g of product are recovered.

Melting point: 260 ° C. 13.4. (6-methoxybenzo [b] thien-3-yl) ethyl carbamate

11.4 g of 3 - [(ethoxycarbonyl) amino] -6-methoxybenzo [b] thiophene-2-carboxylic acid are heated to 220-225 ° C. A glassy gum is obtained which is taken up with

tetrahydrofuran until dissolved. The solvent is evaporated off under reduced pressure and the residue is purified on a silica column with a mixture of ethyl acetate and cyclohexane 10/90. 19.4 g of product are obtained.

Melting point: 88 ° C.

13.5. (6-hydroxybenzo [b] thien-3-yl) ethyl carbamate

To a solution of 7.7 g (0.031 mol) of ethyl (6-methoxybenzo [b] thien-3-yl) carbamate in 80 ml of

dichloromethane, 46 ml of a 1M solution of boron tribromide (0.046 mole) in dichloromethane, while maintaining the temperature at 0 ° C. The mixture is allowed to return to ambient temperature and 15 ml of a 1M solution of boron tribromide (0.015 mol) in dichloromethane are added. The mixture is stirred for 180 min., Then it is neutralized with a dilute ammonium hydroxide solution and the precipitate obtained is filtered. The latter is washed with water and dried. Purified by chromatography on a column of silica gel with

dichloromethane.

6 g of product are obtained.

Melting point: 159-160 ° C.

13.6. [6- (phenylmethoxy) benzo [b] thien-3-yl] ethyl carbamate A mixture comprising 2 g (8.4 mmol) of (6-hydroxybenzo [b] thien) is refluxed for 11 hours Yl) ethyl carbamate, 2.16 g (12.6 mmol) of benzyl bromide and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile. It is filtered, the solvent is evaporated off under reduced pressure and the residue is triturated in petroleum ether.

2.3 g of product are obtained.

Melting point: 129-130 ° C.

13.7. (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzo [b] thien-3-yl] oxazolidin-2-one

A mixture comprising 1.1 g (3.36 mmol) of ethyl [6- (phenylmethoxy) benzo [b] thien-3-yl] carbamate is brought to 140 ° C.

0.58 g (4.4 mmol) of (S) -4- (methoxymethyl) -1,3-dioxolan-2-one and 46 mg (0.34 mmol) of potassium carbonate, in 16 ml of N , N-dimethylformamide. After 30 min. at 140 ° C., 0.3 g (2 mmol) of (S) -4- (methoxymethyl) -1,3-dioxolan-2-one is added. The mixture is left at this temperature for a further 210 min., It is poured into ice water, then the product is extracted with dichloromethane. The solvent is removed under reduced pressure and purified by chromatography on a column of silica gel with a mixture of cyclohexane and ethyl acetate 80/20.

0.15 g of product is obtained in the form of an oil.

[α] ²⁰ _D = - 18.9 ° (c = 1; dichloromethane).

Example 14: (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzo [b] thien-3-yl] oxazolidin-2-one

14.1. [6- (4,4,4-trifluorobutoxy) benzo [b] thien-3-yl] ethyl carbamate A mixture of 2.0 g is heated at reflux for 90 min.

(8.4 mmol) of ethyl 6-hydroxybenzothiophene-3-carbamate (obtained in step 13.5. Of example 13), 2.4 g (12.6 mmol) of 4.4.4- trifluoro-1-bromobutane and 2.3 g (16.8 mmol) of potassium carbonate in 30 ml of acetonitrile. It is evaporated under reduced pressure and triturated in petroleum ether. 2.65 g of product are obtained.

Melting point: 103 ° C.

14.2. (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzo [b] thien-3-yl] oxazolidin-2-one

The mixture is heated at 140 ° C. for five hours, a mixture

comprising 1.3 g (3.74 mmol) of ethyl [6- (4,4,4,4-trifluorobutoxy) benzo [b] thien-3-yl] carbamate, 0.64 g (4.8 mmol) of (S) -4- (methoxymethyl) -1,3-dioxolan-2-one and 50 mg (0.36 mmol) of potassium carbonate in 16 ml of N, N-dimethylformamide. The solvent is evaporated off under reduced pressure and the oil obtained is purified by chromatography on a column of silica gel with a mixture of cyclohexane and ethyl acetate 80/20. 0.4 g of product is recovered, in the form of an oil.

[α] ²⁰ _D = - 21.8 ° (c = 1; dichloromethane). Example 15: (R, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzo [b] thien-3-yl] oxazolidin-2-one

15.1. (R) -3- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-ethyl trifluorobutanoate

To a solution of 15.2 g (0.082 mol) of (R) -3- (4,4,4-trifluorohydroxy) ethyl butanoate in 75 ml of

N, N-dimethylformamide, 8.36 g (0.123 mole) is added

imidazole, then 13.5 g (0.09 mole) of chloride

t-butyldimethylsilyl. The mixture is poured into 380 ml of water, the product is extracted with dichloromethane and the organic phase is washed with twice 150 ml of water. The product is dried and the solvent is evaporated off under reduced pressure. Purification is carried out by chromatography on a silica gel column with a mixture of cyclohexane and ethyl acetate 95/5.

20.3 g of a colorless oil are obtained.

[α] ²⁰ _D = + 32.4 ° (c = 1; methanol).

15.2. (R) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4- trifluorobutanol

To a solution cooled to -50 ° C of 22.4 g (0.0745 mole) of (R) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-trifluoro butanoate d in 224 ml of dichloromethane, we add 224 ml (0.224 mole) of a 1M hydride solution

diisobutylaluminium. The mixture is allowed to return to ambient temperature and 15 ml of methanol are added at -50 ° C. The mixture is then poured over an acid mixture

1N hydrochloric acid and ice, then the product is extracted with dichloromethane. The organic phase is dried over sodium sulfate and the solvent is evaporated off under reduced pressure. 15.6 g of a pale yellow oil are obtained.

[α] ²⁰ _D = +25.9 (c = 1; methanol).

15.3. (R) -3 - [- ([(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-trifluorobutyl 4-methylbenzenesulfonate

To a solution of 15.1 g (0.058 mol) of (R) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-trifluorobutanol in a mixture of 9.4 ml (0.117 mole) of pyridine and 35 ml of dichloroethane, 11 mg of dimethylaminopyridine are added. Cool to 0 ° C and add a solution of 11.4 g (0.06 mole) of p-methylbenzene sulfonyl chloride in 15 ml of dichloroethane. The mixture is allowed to stir for 48 hours at room temperature. It is poured into ice water, the product is extracted with dichloromethane, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. A yellow oil is recovered which is purified by chromatography on a column of silica gel with a mixture of cyclohexane and dichloromethane 80/20.

14.9 g of a colorless oil are obtained.

[α] ²⁰ _D = + 15.7 ° (c = 1; dichloromethane)

15.4. (R) - [6- [3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-trifluorobutoxy] benzo [b] thien-3-yl] ethyl carbamate

A mixture of 0.3 g (1.26 mmol) of ethyl (6-hydroxybenzo [b] thien-3-yl) carbamate, 0.62 g (1.52) is heated at reflux for four hours. mmol) of (R) -3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4,4,4-trifluorobutyl 4-methylbenzenesulfonate and 0.34 g (2.52 mmol) of potassium carbonate in 5 ml of acetonitrile. We filter the mixture, we the solvent is evaporated off under reduced pressure, the product is taken up in dichloromethane, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The product is purified by chromatography on a column of silica gel with a mixture of cyclohexane and ethyl acetate 90/10. 518 mg of a yellow oil are obtained.

15.5. (R, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzo [b] thien-3-yl] oxazolidin-2-one

Heated at 140 ° C for 10 hours, a mixture of 1.5 g (0.00314 mole) of (R) - [6- [3 - [[(1,1-dimethylethyl) dimethylsilyl] oxy] -4 , 4,4-trifluorobutoxy] benzo [b] thien-3-yl] ethyl carbamate, 0.415 g (0.00314 mol) of (S) -4- (methoxymethyl) -1,3-dioxolan-2- one, 43 mg (0.00031 mole) of potassium carbonate, in 15 ml of N, N-dimethylformamide. Then, the mixture is heated for an additional ten hours at 140 ° C. while adding twice 0.041 g (0.00031 mole) of (S) -4- (methoxymethyl) -1,3-dioxolan-2-one. The solvent is evaporated off under reduced pressure, the product is taken up in dichloromethane, the organic phase is washed with an aqueous solution of

sodium chloride, dried over sodium sulfate and the solvent is evaporated off under reduced pressure.

The product thus obtained is mixed with 297 mg (0.14 mmol) of tetra n-butylammonium fluoride, in 15 ml of

tetrahydrofuran. Stirred at room temperature overnight, the solvent is evaporated off under reduced pressure and the product is purified by chromatography on a column of silica gel with a mixture of cyclohexane and acetate

ethyl 70/30.

150 mg of product are obtained in the form of a yellow oil. [α] ²⁰ _D = - 1.8 ° (c = 1; dichloromethane). Example 16: (R) -5- (hydroxymethyl) -3- [6- (4,4,4- trifluorobutoxy) benzo [b] thien-3-yl] oxazolidin-2-one

Is added to a solution comprising 0.3 g (0.77 mmol) of (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzo [b] thien-3-yl] oxazolidin-2-one in 3 ml of dichloromethane, cooled to 0 ° C, 2.3 ml of a solution of 1M boron tribromide (2.3 mmol) in dichloromethane. After 150 min, the mixture is made alkaline with ammonium hydroxide, while maintaining the temperature at 0 ° C. The mixture is left under stirring for 30 min., The product is extracted with dichloromethane, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. Purification is carried out by chromatography on a silica gel column with a mixture of cyclohexane and

ethyl acetate 40/60.

289 mg of product are obtained.

Melting point: 107.0-107.2 ° C.

[α] ²⁰ _D = - 20.5 ° (c = 1; dichloromethane)

Example 17: {R) -5- (methoxymethyl) -3- [1-methyl-6- (phenylmethoxy) -1H-indol-3-yl] oxazolidin-2-one

17.1. 2-fluoro-4- (phenylmethoxy) benzonitrile

The mixture is brought to reflux temperature for two hours, a mixture of 40.8 g (0.297 mole) of 2-fluoro-4-hydroxybenzonitrile, 61.06 g (0.357 mole) of benzyl bromide and 82 g (0.594 mole) of potassium carbonate in 400 ml of acetonitrile. The mixture is filtered, the solvent is evaporated off under reduced pressure and the evaporation residue is triturated with diisopropyl ether.

65.5 g of product are recovered.

Melting point: 87 ° C.

17.2. 2- (methylamino) -4- (phenylmethoxy) benzonitrile

Heated for 32 hours at 80 ° C, a solution of 32 g (0.14 mol) of 2-fluoro-4- (phenylmethoxy) benzonitrile and 35 ml of methylamine in 150 ml of ethanol.

The reaction mixture is taken up with dichloromethane, the organic phase is washed three times with water and dried over sodium sulfate. The solvent is then evaporated off under reduced pressure and 32.9 g of product are recovered.

Melting point: 120 ° C. 17.3. [[2-cyano-5- (phenylmethoxy) phenyl] methylamino] ethyl acetate

To a solution of 39.3 g (0.285 mol) of potassium carbonate in 393 ml of water is added 64.1 g (0.269 mol) of 2- (methylamino) -4- (phenylmethoxy) benzonitrile in 393 ml of ethanol. Then added 152.8 g (0.914 mole) of

ethyl bromoacetate and the mixture is brought to reflux. After 48 hours, the ethanol is evaporated under reduced pressure, the residue is taken up in dichloromethane, the organic phase is washed with water and dried over sodium sulfate. The solvent is evaporated under reduced pressure and the residue is purified by chromatography on silica gel, eluting with dichloromethane.

19.5 g of product are recovered, which is in the form of an oil.

17.4. Ethyl 3-amino-1-methyl-6- (phenylmethoxy) -1H-indole-2-carboxylate

To a suspension of 9.8 g (0.087 mol) of potassium tert-butoxide in 100 ml of tetrahydrofuran, the following is added

slowly a solution of 28.3 g (0.087 mol) of ethyl [[2-cyano-5- (phenylmethoxy) phenyl] methylamino] acetate in

solution in 80ml of tetrahydrofuran, while keeping the temperature below 30 ° C.

The mixture is left under stirring at room temperature for 25 min., Then it is poured onto a mixture of water and ice. The product is extracted with dichloromethane, the organic phase is washed with water and the solvent is evaporated off under reduced pressure. The residue thus obtained is triturated in ethanol and 22.6 g of product are recovered.

Melting point: 95 ° C. 17.5. Ethyl 3 - [(ethoxycarbonyl) amino] -1-methyl-6- (phenylmethoxy) 1H-indole-2-carboxylate

To a solution of 24 g (0.074 mole) of 3-amino-1-methyl-6- (phenylmethoxy) -1H-indole-2-ethyl carboxylate in 180 ml of a 9/1 mixture of tetrahydrofuran and water, 7.5 g (0.088 mole) of sodium hydrogencarbonate are added, then 8.3 ml (0.076 mole) of ethyl chloroformate, while maintaining the temperature below 25 ° C.

The mixture is left at room temperature for one hour and then the solvent is evaporated off under reduced pressure. The residue is taken up in dichloromethane, washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure.

28.2 g of product are recovered.

Melting point: 124-125 ° C.

17.6. 3 - [(ethoxycarbonyl) amino] -1-methyl-6- (phenylmethoxy) -1H-indole-2-carboxylic acid

A suspension of 28.1 g (0.0708 mol) of ethyl 3 - [(ethoxycarbonyl) amino] -1-methyl-6- (phenylmethoxy) -1H-indole-2-ethyl carboxylate in 170 ml is brought to reflux. ethanol at 96 °. 64 ml of a 10% ethanolic solution of potassium hydroxide and 50 ml of tetrahydrofuran are added to this mixture. The suspension is left to reflux for 150 min., Then it is concentrated under reduced pressure, diluted with a mixture of water and ice and acidified with acid

6N hydrochloric acid. The product is then extracted with a mixture of dichloromethane and tetrahydrofuran, the organic phase is washed with water, dried over sodium sulfate and the solvent is evaporated off under reduced pressure. The residue is triturated in diisopropyl ether and 24.8 g of product are recovered.

Melting point: 180 ° C (decomposition).

17.7. [1-methyl-6- (phenylmethoxy) -1H-indol-3-yl] ethyl carbamate 24.6 g (0.066 mole) of 3 - [(ethoxycarbonyl) amino] -1-methyl-6- acid are heated (phenylmethoxy) -1H-indole-2-carboxylic at a temperature of the order of 180-185 ° C for three

minutes, then the residue is triturated in tetrahydrofuran, filtered and the filtrate is concentrated under pressure scaled down. The product is purified by chromatography on silica gel, eluting with a mixture of cyclohexane and ethyl acetate 80/20.

18.3 g of product are recovered.

Melting point: 140-142 ° C.

17.8. (R) -5- (methoxymethyl) -3- [1-methyl-6- (phenylmethoxy-1H-indol-3-yl] oxazolidin-2-one A mixture comprising 14 hours at 140 ° C.

9.1 g (0.028 mole) of [1-methyl-6- (phenylmethoxy) -1H-indol-3-yl] ethyl carbamate, 6.6 g (0.05 mole) of

(S) -4-methoxymethyl-1,3-dioxolan-2-one and 1.16 g (0.0084 mol) of potassium carbonate in 180 ml of N, N-dimethylformamide. The solvent is evaporated off under reduced pressure and the product is purified by chromatography on silica gel with a mixture of cyclohexane and ethyl acetate 50/50.

6 g of product in the form of a gum are recovered.

[α] ²⁰ _D = -44.1 ° (c = 1; methanol).

According to the same process, starting from (R) - 4-methoxymethyl-1,3-dioxolan-2-one, (S) -5- (methoxymethyl) -3- [1-methyl-6- was prepared (phenylmethoxy) -1H-indol-3-yl] oxazolidin-2-one, which is in the form of an oil.

[α] ²⁰ _D = + 41.5 ° (c = 1; methanol).

Example 18: (S, R) -5- (methoxymethyl) -3- [1-methyl-6- (4,4,4- trifluoro-3-hydroxybutoxy) -1H-indol-3-yl] oxazolidin-2- one

18.1. (S) -5- (methoxymethyl) -3- [1-methyl-6-hydroxy-1H-indol-3-yl] oxazolidin-2-one

The catalytic hydrogenation is carried out of a solution of 1 g (0.0027 mol) of (S) -5- (methoxymethyl) -3- [1-methyl-6- (phenylmethoxy) -1H-indol-3- yl] oxazolidin-2-one, obtained in Example 17, in a mixture of 15 ml of N, N-dimethylformamide and 15 ml of ethanol. The hydrogenation is carried out in 18 hours, under normal hydrogen pressure, in presence of 0.2 g of palladium on carbon.

The reaction medium is filtered to remove the palladium on carbon, the solvent is evaporated off under reduced pressure and 0.53 g of product in the form of a gum is recovered.

18.2. (S, R) -5- (methoxymethyl) -3- [1-methyl-6- (4,4,4-trifluoro- 3-hydroxybutoxy) -1H-indol-3-yl] oxazolidin-2-one Shake at reflux, for 90 min., a mixture of 0.30 g (0.00108 mole) of (S) -5- (methoxymethyl) -3- [1-methyl-6-hydroxy-1H-indol-3-yl ] oxazolidin-2-one, 0.34 g (0.00114 mole)

(R) -4,4,4-trifluoro-3-hydroxybutyl tosylate and 0.3 g (0.00217 mole) of potassium carbonate in 5 ml

of acetonitrile. Then dilute the mixture with

dichloromethane, filtered and the filtrate is concentrated under reduced pressure. The organic phase is washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue is purified by chromatography on a silica column with a mixture of dichloromethane and methanol 95/5. 0.27 g of product is recovered, which is in the form of a gum.

Melting point: 80, 5-82, 0 ° C.

[α] ²⁰ _D = +68.1 ° (c = 1; methanol).

The following table gathers compounds according to the invention, as well as their physical characteristics. These compounds were prepared according to the methods described above.

In the solvent column, the solvent used to measure the rotary power [α] ²⁰ _{D is indicated} (with c = 1, unless otherwise indicated).

The compounds of the invention have been the subject of pharmacological tests making it possible to determine their inhibitory power of monoamine oxidase A and of monoamine oxidase B.

The measurements of MAO-A and MAO-B activities in vitro were carried out using a rat brain homogenate as an enzyme source, according to the method described by C. Fowler and M. Strolin-Benedetti, in J. Neurochem. , 40, 1534-1541 (1983).

The standard assay consists in homogenizing the rat brain in 20 volumes of 0.1 M phosphate buffer (pH = 7.4) and in preincubating 100 μl of homogenate (5 mg of tissue) at 37 ° C. for 20 minutes, the absence or presence of different concentrations of inhibitor studied. The reaction is

started by the addition of [ ¹⁴ C] serotonin ([ ¹⁴ C] 5HT, final concentration 125 μM) for the measurement of the activity of MAO-A or of [ ¹⁴ C] phenylethylamine ([ ¹⁴ C] PEA, concentration final 8 μM) for the measurement of MAO-B activity, in a final volume of 500 μl. After 5 minutes of incubation for [ ¹⁴ C] 5HT and 1 minute of incubation for [ ¹⁴ C] PEA, the reaction is stopped by adding 200 μl of acid

hydrochloric 4N. The radioactive metabolites resulting from oxidative deamination are then separated from the untransformed substrate, by extraction in organic phase, and quantified by counting the radioactivity.

The inhibitory activities with respect to MAO-A and MAO-B are given respectively by the inhibition constants Ki (MAO-A) and Ki (MAO-B).

For the compounds of the invention, the Ki (MAO-A) vary between 1.2 nM and values greater than 1000 nM, while the Ki (MAO-B) vary between 0.3 nM and values

greater than 1000 nM.

Certain compounds of the invention are selective MAO-B inhibitors, the Ki (MAO-A) / Ki (MAO-B) ratio possibly being greater than 10 ³ .

Certain compounds of the invention are selective MAO-A inhibitors, the Ki (MAO-B) / Ki (MAO-A) ratio may be greater than 10 ³ .

Others are mixed inhibitors of MAO-A and MAO-B, the Ki (MAO-A) / Ki (MAO-B) ratio can be between 0.1 and 10.

The results obtained show that the compounds of

the invention can be used for the preparation of drugs which are selective inhibitors of MAO-A or MAO-B or mixed inhibitors of MAO-A and MAO-B, these drugs finding their use in therapeutics in particular in the treatment depressive states of any kind, senile depressive psychoses, hypobulia, social phobias, mood disorders, in improving general brain performance, in preventing and treating neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease and all memory disorders, in anxiety, panic attacks, treatment of dependence and withdrawal related to

consumption of alcohol, tobacco and / or narcotics, and loss of appetite.

The compounds of the invention may be presented, in combination with excipients, in the form of compositions formulated for oral administration,

parenteral or rectal, for example in the form of tablets, dragees, capsules, solutions, suspensions or suppositories.

The dose of active ingredient administered is generally between 0.01 and 50 mg / kg / day, in one or more doses.

Claims

claims

1. Compounds derived from oxazolidin-2-one of general formula (I)

in which:

R ₁ represents a hydrogen atom, an alkyl, hydroxyalkyl, fluoroalkyl, hydroxyfluoroalkyl group,

cyanoalkyl, phenyl substituted or not by an atom

halogen or by an alkoxy, nitrile or nitro, phenylmethyl group substituted or not by a halogen atom or by an alkoxy, nitrile or nitro group, or a group R ₃ A- in which R ₃ is a cycloalkyl or cyclooxyalkyl group , substituted or not substituted by a hydroxy group, and A is a radical -CH ₂ or -CH ₂ -CH ₂ ,

R ₂ represents a hydrogen atom or a methyl group, X represents an oxygen or sulfur atom or a group NR ₄ where R ₄ is an alkyl group or a hydrogen atom, and Z represents an oxygen atom or a group -CH = CH or -CH ₂ -CH ₂

said compounds being in the form of enantiomers or pure diastereoisomers or of a mixture of these different forms, including a racemic mixture.

2. Compounds according to claim 1, characterized in that R ₂ is a methyl group.

3. Compounds according to claim 2, characterized in that X represents an oxygen atom.

4. Compounds according to one of claims 1 to 3 characterized in that when X represents an oxygen atom, the group R ₁ Z represents:

or, i) a group R _a O, where R _a has one of the meanings of R ₁ chosen from a hydrogen atom an alkyl, fluoroalkyl, hydroxyfluoroalkyl, cyanoalkyl, R ₃ A-, phenyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy and phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group, or, ii) a group R _b Z, where Z is a group -CH = Cabbage

-CH ₂ -CH ₂ - and R _b has one of the meanings of R ₁ chosen from a hydrogen atom or an alkyl group,

fluoroalkyl, hydroxyalkyl, hydroxyfluoroalkyl, phenyl substituted or not by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group.

5. Compounds according to claim 4, characterized in that R _a is a hydrogen atom or a phenylmethyl, butyl, 4,4,4-trifluorobutyl, 4,4,4-trifluoro-3-hydroxybutyl group, 3,3 , 3-trifluoro-2-hydroxypropyle,

3-cyanopropyl, p-fluorophenylmethyl, cyclopropylmethyl or 2- (1-hydroxycyclopentyl) ethyl.

6. Compounds according to claim 4, characterized in that R _b Z is chosen from the group ethenyl, 2-phenylethenyl, 2-phenylethyl, 5,5,5-trifluoropentyl, 5,5,5-trifluoropentenyl, 5,5, 5-trifluoro-4-hydroxypentyl and 5,5,5-trifluoro-4-hydroxypentenyl.

7. Compounds according to one of claims 1 to 3,

characterized in that when X represents a sulfur atom, the group R ₀ Z represents a group R _c O, where R _c has one of the meanings of R ₁ chosen from an alkyl, hydroxyalkyl, fluoroalkyl, hydroxyfluoroalkyl, substituted phenyl group or not by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom or by an alkoxy, nitrile or nitro group.

8. Compounds according to one of claims 1 to 3,

characterized in that when X represents a group NR ₄ , R ₄ is a methyl group and the group R ₁ Z represents a group R _d O, where R _d has one of the meanings of R ₁ chosen from a fluoroalkyl or hydroxyfluoroalkyl group , a phenyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group or a phenylmethyl group substituted or not by a halogen atom, a nitro, nitrile or alkoxy group.

9. Compounds according to one of claims 1 to 8

characterized in that when Z represents a group -CH = CH and that R ₁ does not represent a hydrogen atom, said compounds are in the form of cis, trans or of a cis / trans mixture.

10. (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzofuran-3-yl] oxazolidin-2-one and its enantiomer.

11. (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluorobutoxy) benzofuran-3-yl] oxazolidin-2-one and its enantiomer.

12. (R, R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one and its diastereoisomers.

13. (R, R) -5- (hydroxymethyl) -3- [6- (4,4,4-trifluoro-3-hydroxybutoxy) benzofuran-3-yl] oxazolidin-2-one and its diastereoisomers.

14. (R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluoropentyl) benzofuran-3-yl] oxazolidin-2-one and its enantiomer.

15. (R) -5- (methoxymethyl) -3- [6- (5,5,5-trifluro-4-hydroxypent-1-enyl) benzofuran-3-yl] oxazolidin-2-one, its diastereoisomers and their cis and trans isomers.

16. (R) -5- (methoxymethyl) -3- [6- (phenylmethoxy) benzo [b] - thien-3-yl] oxazolidin-2-one and its enantiomer.

17. A compound according to claim 1 characterized in that it is chosen from the group consisting of: * ((R) -5- (methoxymethyl) -3- [6- (cyclopropylmethoxy) benzo. Furan-3- yl] oxazolidin-2-one and its enantiomer,

* la (R) -5- (methoxymethyl) -3- [6- (4,4,4-trifluoro.

butoxy) benzo [b] thien-3-yl] oxazolidin-2-one and its

enantiomer,

* (R) -3- (6-ethenylbenzofuran-3-yl) -5- (methoxymethyl) oxazolidin-2-one and its enantiomer,

* ((R) -5- (methoxymethyl) -3- [6- (tetrahydropyranylmethoxy) benzofuran-3-yl] oxazolidin-2-one and its enantiomer,

* ((R) -5- (methoxymethyl) -3- [6- [4-cyano (propyloxy)] benzofuran-3-yl] oxazolidin-2-one and its enantiomer,

* ((R) -5- (methoxymethyl) -3- [6- [4-methoxy (phenylmethoxy)] benzofuran-3-yl] oxazolidin-2-one and its enantiomer,

* ((R) -5- (methoxymethyl) -3- [6- [3-chloro (phenylmethoxy)] benzofuran-3-yl] oxazolidin-2-one and its enantiomer.

18. Process for preparing the compounds according to one of claims 3 to 9, characterized in that one reacts in the presence of potassium carbonate, an ethyl carbamate derivative of formula (II)

where R ₁ and X have one of the meanings indicated in claim 1, with the exception, as regards R ₁ , of hydrogen, with 4- (methoxymethyl) -1,3-dioxolan-2- one of formula (III)

19. Medicament, characterized in that it consists of a compound according to one of claims 1 to 17.

20. Pharmaceutical composition characterized in that it comprises a compound according to one of claims 1 to 17, in association with at least one pharmaceutically acceptable excipient.

21. Use of a compound according to one of claims 1 to 17 for the preparation of a medicament intended to act as selective MAO-A or MAO-B inhibitors or mixed inhibitors of MAO-A and of MAO-B.