FR2609029A1 - 5-Aminoethylated derivatives of oxazolidin-2-one, process for their preparation and their application in therapeutics - Google Patents

Abstract

Mixture of the 4 stereoisomers of formula I below, each of the corresponding racemic pairs of diastereoisomers and each of the enantiomers corresponding to each pair, that is to say each of the said stereoisomers: in which R1 represents: - a hydrogen atom, - an alkoxy group containing from 1 to 4 carbon atoms, - a trifluoromethyl group, or - one or two halogen atoms; and the pair R2, R3 takes one of the following meanings: (H, H), (H, C1-C4 alkyl), (C1-C4 alkyl, C1-C4 alkyl), and their addition salts with organic and inorganic acids.

Description

5-aminoethyl derivatives of oxazolidinone-2. their process of preparation and their therapeutic application
The present invention relates to novel oxnzolidinones-2, their method of preparation and their therapeutic application.

dans laquelle R1 représente
- un atome d'hydrogène,
- un groupe alkoxy comportant de 1 à 4 atomes de carbone, plus
particulièrement un groupe méthoxy en position méta,
- un groupe trifluorométhyle plus particulièrement en position méta ou
para, ou
- un ou deux atomes d'halogène plus particulièrement en position méta
et/ou para et le couple (R2, R) prend l'une des significations suivantes : (H, H), C1-C4), alkyle en C1-C4, (alkyle en IA(+), alkyle en C1-C). The oxazolidinones-2 according to the invention correspond more precisely to the formula

in which R1 represents
a hydrogen atom,
an alkoxy group containing from 1 to 4 carbon atoms, plus
particularly a methoxy group in the meta position,
a trifluoromethyl group, more particularly in the meta position or
para, or
one or two halogen atoms more particularly in meta position
and / or para and the pair (R2, R) has one of the following meanings: (H, H), C1-C4), C1-C4 alkyl, (C1-C4 alkyl), C1-C4 alkyl ).

 The present invention also extends to the inorganic or organic acid addition salts of these oxazolidinones-2.

Since the above compounds (I) have two asymmetric carbon atoms in their molecule, they each exist in the form of a mixture of 4 stereoisomers, hereinafter symbolized by IB (+), IA), be and IB (-), the symbol A corresponding to the relative configuration erythro and B to the relative configuration threo. This mixture can IA (+), separated into two pairs of racemic diastereoisomers, namely the pair erythro IA (-)
and the threo couple IB (+), IB (-), which can still be symbolized by IA (# and IB (#), each couple being able to be split to isolate the corresponding enantiomers.

 The present invention thus covers each of the mixtures of 4 stereoisomers of formula (I), each of the pairs of corresponding racemic diastereoisomers and each of the enantiomers corresponding to each pair, that is to say each of said steroisomers.

où R. a la même signification que dans la formule (I), respectivement avec le mélange des 4 stèreoisomères de l'époxy-1,2- butanol-3 de formule

cette condensation étant de préférence effectuée & chaud dans un solvant organique, en particulier à reflux dans un solvant organique hydroxylé tel que l'isopropanol.The process according to the invention for the preparation of the compounds of formula (I) is as follows
In a first step, the anilines of formula

where R. has the same meaning as in formula (I), respectively with the mixture of 4 stereoisomers of epoxy-1,2-butanol-3 of formula

this condensation is preferably carried out in an organic solvent, in particular at reflux in a hydroxylated organic solvent such as isopropanol.

The mixture of the 4 stereoisomers of formula (III) is obtained by epoxidation of racemic butene-3,4 ol-2 of formula

 To carry out this epoxidation, an epoxidation agent such as meta-chloroperbenzoic acid is used and the reaction is preferably carried out at room temperature in an organic solvent such as methylene chloride.

où R1 a la même signification que dans la formule < I), à une cyclisation par action du carbonate d'éthyle en présence d'ethylate de sodium, de préférence å chaud dans un solvant organique, en particulier à reflux dans le toluène, ce qui conduit å un mélange de 4 stéréoisomères de formule

où R1 a la mSme signification que dans la formule (I).In a second step, each mixture of 4 stereoisomers of formula (V) obtained from

wherein R 1 has the same meaning as in formula (I), cyclization by the action of ethyl carbonate in the presence of sodium ethoxide, preferably hot in an organic solvent, in particular at reflux in toluene, which leads to a mixture of 4 stereoisomers of formula

where R1 has the same meaning as in formula (I).

 In a third step, each mixture of 4 stereoisomers of formula (VI) is subjected to chromatography on a silica column under medium pressure, which makes it possible to separate said mixture into two pairs of racemic diastereoisomers, namely a pair (the less polar) of relative configuration erythro VI A (+) / VI A (-) òu VI A (#)] and a couple (the most polar) of relative configuration threo VI B (+) / VI B (-) òu VI B (#)].

 In a fourth step, each pair VI A (#) and VI B (t) is split to isolate the corresponding enantiomers.

cette estérification étant suivie d'une séparation par chromatographie sur colonne de silice sous moyenne pression, du couple de diastéréoisomères érythro
VI' A, ce qui conduit d'une part à l'énantiomère ester le moins polaire VI' A(+) et d'autre part à l'énantiomere ester le plus polaire VI' A(-). Les deux énantiomères ester VI' A(+) et VI' A(-) ainsi isolés sont ensuite saponifiés, par exemple à la soude, pour obtenir respectivement l'énantiomère VI A(+) et l'énantiomère VI A(-).The doubling of the erythro VI AA ()) couple may for example be carried out by esterification using 2-phenoxypropionic acid chloride (+) (VII) in pyridine, according to the following scheme

this esterification being followed by separation by chromatography on silica column under medium pressure, the pair of erythro diastereoisomers
VI 'A, which leads on the one hand to the less polar ester enantiomer VI' A (+) and on the other hand to the most polar ester enantiomer VI 'A (-). The two ester enantiomers VI 'A (+) and VI' A (-) thus isolated are then saponified, for example with sodium hydroxide, to obtain respectively the enantiomer VI A (+) and the enantiomer VI A (-).

cette estérification étant suivie d'une séparation par chromatographie sur colonne de silice sous moyenne pression, du couple de diastéréoisoméres thréo
VI" B, ce qui conduit d'une part à l'énantiomère ester le moins polaire VI" B(+) et d'autre part à l'enantiomère ester le plus polaire VI" 3 < -). Les deux énantiomères esters VIh B(+) et VIN B(-) ainsi isolés sont ensuite saponifiés, par exemple à la soude, pour obtenir respectivement l'énantiomère V i B(+) et l'énantiomère VI B(-).As for the doubling of the threo VI B (#) pair, it can be carried out by esterification with the aid of α-methoxy-α-trifluoromethylphenylacetic acid chloride C-) (VIII) in the pyridine according to the scheme.

this esterification being followed by separation by chromatography on silica column under medium pressure, the couple of threo diastereoisomers
VI "B, which leads, on the one hand, to the less polar ester enantiomer VI" B (+) and, on the other hand, to the more polar ester enantiomer VI "3 <-), the two ester enantiomers VIh B (+) and VIN B (-) thus isolated are then saponified, for example with sodium hydroxide, to obtain respectively the enantiomer V i B (+) and the enantiomer VI B (-).

It should also be noted here that the absolute configuration of each of the enantiomers VI A (+), VI A (-), VI B (+) and VI B (-) was determined by the partial kinetic resolution method of the aphenylbutyric anhydride by these enantiomers (Weidmann R., Schoofs AR and Horeau A.,
Accounts Rendus Acad. Sci., Paris, Series II, 1984, page 319 and references cited),
Thus - to the enantiomer VI A (+) may have been assigned the absolute configuration (S, R), - to the enantiomer VI A (-) could be attributed the absolute configuration (R, S), - to the Enantiomer VI B (+) could be assigned the absolute configuration (S, S), and - to the enantiomer VI B (-) could be assigned the absolute configuration (R, R).

[IXA(+), IXA(-), IXB(+) ou IXB(-)] où R1 a la même signification que dans la formule (I) et Ms est le groupe mesyle, cette réaction étant effectuée en présence d'une base organique telle que la triéthylamine, de préférence dans un solvant organique notamment un solvant organique halogéné tel que le chlorure de méthylène.In a fifth step, the mesylate of the VI A (+), VI A (-), VI B (+) and VI B (-) stereoisomers is formed respectively, in particular by reaction of a mesyl halide with these stereoisomers, the resulting mesylates corresponding to the formula

[IXA (+), IXA (-), IXB (+) or IXB (-)] where R1 has the same meaning as in formula (I) and Ms is the mesyl group, this reaction being carried out in the presence of a organic base such as triethylamine, preferably in an organic solvent, in particular a halogenated organic solvent such as methylene chloride.

où le couple (R2, Rs) a la même signification que dans la formule < I), ce qui conduit au stereoisomère correspondant de formule (I). Il est à remarquer que la substitution nucléophile par le composé (X) se produit avec inversion de configuration.Plus précisément
- à partir du stéréoisomère mésylate IX A(+) de configuration absolue
(S, R), on obtient le stéréoisomère thréo < +) El B(+ > ) de configuration
absolue (S, S),
- à partir du stéréoisomère mésylate IX A(-) de configuration absolue
(R, S), on obtient le stéréoisomère thréo < -) (I B(-)] de configuration
absolue (R, R),
- à partir du stéréoisomère mésylate IX B B(+) de configuration absolue
(S, S), on obtient le stérécisomère érythro (+) El A (+) de configuration
absolue (S, R@ et
- à partir du stéréoisomère mésylate IX B(-) de configuration absolue
(R, R), on obtient le stéréoisomère érythro (-) [I A(-)] de configuration
absolue (R, S).In the sixth and last step, each stereoisomeric mesylate obtained from the preceding step is reacted, optionally in the presence of an organic solvent and in particular a hydroxylated organic solvent such as ethanol or isopropanol, with a compound of formula

where the pair (R2, Rs) has the same meaning as in formula (I), which leads to the corresponding stereoisomer of formula (I). It should be noted that the nucleophilic substitution by the compound (X) occurs with inversion of configuration. More precisely
from the IX A (+) mesylate stereoisomer of absolute configuration
(S, R), the threo stereoisomer <+) El B (+>) is obtained
absolute (S, S),
from the stereoisomeric IX A (-) stereoisomer of absolute configuration
(R, S), we obtain the stereoisomer threo <-) (IB (-)] of configuration
absolute (R, R),
from the stereoisomeric IX (+) absolute mesylate stereoisomer
(S, S), the erythroid (+) El A (+) configuration stereoisomer is obtained
absolute (S, R @ and
from the stereoisomeric IX B (-) stereoisomer of absolute configuration
(R, R), one obtains the stereoisomer erythro (-) [IA (-)] of configuration
absolute (R, S).

 The compounds of formula (I) may alternatively be prepared in the following manner.

ou R'@ représente une seule des significations données pour 1 dans la formule (I) > ce qui conduit aux 4 stéréoisoméres de formule

The first four steps defined above are repeated, using as starting material the compound of formula

or R '@ represents only one of the meanings given for 1 in formula (I)> which leads to the 4 stereoisomers of formula

VIaA (+) (S, R)
VIaA (-) (R, S)
VIaB (+) (S, S)
VIaB (-) (R, R) where R'1 has the same meaning as in formula (IIa).

These 4 stereoisomers are then
- respectively treated. as in the fifth and sixth
steps previously described, which leads to the 4 stereoisomers of formula

IaB (+) (S, S)
IaB (-) (R, R)
IaA (+) (S, R)
IaA (-) (R, S)
where R'1. has the unique meaning given for formula (IIa) and the pair (R2, Rs) has the same meanings as in formula (I), - is respectively subjected to debenzylation, which leads to the 4 stereoisomers of formula

XIA (+) (S, R)
XIA (-) (R, S)
XIB (+) (S, S)
XIB (-) (R, R)
This debenzylation may in particular consist of a by-hydrogenolysis in the presence of a hydrogenolysis catalyst such as palladium on carbon, preferably in an organic solvent such as a hydroxylated organic solvent such as ethanol, under a hydrogen atmosphere.

où R". a les mêmes significations que R1 dans la formule (I), à l'exception de la signification de R'1 donnée pour la formule (IIa) et X est un groupe bon partant tel qu'un atome d'halogène. Cette alkylation est de préférence réalisée dans un solvant organique, en particulier un solvant organique polaire tel que l'acétonitrile, le diméthylformamide, le diméthylsulfoxyde ou la butanone-2, en présence d'une base minérale en particulier le carbonate de potassium.This debenzylation is followed by an alkylation of the phenolic function of the stereoisomers XI A (+) (S, R), XI A (-) (R, S), XI B (+) (S, S) and XI B (- ) (R, R), with a compound of formula

where R "has the same meanings as R1 in formula (I), except for the meaning of R'1 given for formula (IIa) and X is a good leaving group such as a halogen atom This alkylation is preferably carried out in an organic solvent, in particular a polar organic solvent such as acetonitrile, dimethylformamide, dimethylsulfoxide or butanone-2, in the presence of a mineral base, in particular potassium carbonate.

This alkylation results respectively the 4 stereoisomers of formula

XIIIA (+) (S, R)
XIIIA (-) (R, S)
XIIIB (+) (S, S)
XIIIB (-) (R, R) where RN 1 has the same meanings as in formula (XII).

These last 4 stereoisomers are then treated respectively as in the fifth and sixth steps described above, which leads to the 4 stereoisomers of formula

IbB (+) (S, S)
IbB (-) (R, R)
IbA (+) (S, R)
IbA (-) (R, S) where R "has the same meanings as in formula (XII) and the pair (Rn,
R3) has the same meanings as in formula (I).

 The following preparations are given by way of example to illustrate the invention.

Example 1 Synthesis of the mixture of the 4 stereoisomers of the 1,2-epoxy-3-butanol
[III] (code number 790255)
To a solution cooled to 0 ° C. of 83.6 g (0.48 mol) of meta-chloroperbenzoic acid in 250 ml of CH 2 Cl 2 is added dropwise a solution of 33.3 g (0.46 mol) of butene- 3,4 ol-2 in 100 ml of CH2Cl2. After stirring for 20 hours at 20 ° C., the partially gelled medium is cooled to -18 ° C. and then filtered. The organic phase is stirred for 30 'in the presence of 10 g of solid Na 2 CO 3. After filtration and evaporation under a very slight vacuum, 36 g of a light yellow oil (yield: 88%) corresponding to the expected mixture and composed of 65% of threo isomer and 35% of erythro isomer are recovered.

Example 2 Synthesis of the mixture of the 4 stereoisomers of [(chloro-3
benzyloxy) -4 phenylamino-1-butanediol-2,3 EV)
(code number 340245)
A solution containing 50 g (0.21 mol) of 4- (chloro-3'-benzyloxy) aniline and 21.6 g (0.24 mol) of the mixture obtained in Example 1 in 850 ml of isopropanol is refluxed for 6 h 30. After evaporation of the isopropanol, the crude mixture is purified by flash chromatography on silica (eluent: CH 2 Cl 2 -CH 3 OH: 97-3). 34 g (yield: 49%) of white solid corresponding to the expected product and having a melting point of 95 ° -96 ° C. are recovered.

EXAMPLE 3 Preparation of the mixture of the 4 stereoisomers of [(chloro-3
benzyloxy) -4-phenyl] -3-hydroxy-1-ethyl-5-oxazolidinone-2 [VI]
From a solution of 600 ml of toluene containing 33.4 g (0.10 mol) of the mixture obtained in Example 2 are distilled 150 ml of solvent under an argon atmosphere. 15 g (15.5 ml, 0.127 mol) of ethyl carbonate and then 3.4 ml of a solution of EtONa in anhydrous EtOH are then successively added ix.

After 4 hours at reflux, the cyclization reaction is complete. The reaction medium is concentrated and then taken up in 300 ml of methyl ethyl ketone. After washing with 2 × HCl and then with a saturated solution of Bacul, 35 g of brown solid corresponding to the expected product are recovered.

Example 4 Separation of the two pairs of racemic diastereoisomers
[VIA (#) and VIB (#)] of [3- (3-chlorobenzyloxy) phenyl] -3 (1-hydroxybenzyloxy)
ethyl) -5 oxazolidinone-2 [VI]
The mixture obtained in Example 3 is subjected to a medium pressure chromatography (eluent: ethyl acetate-heptane: 70-30) and two products with different mobility on SiO 2 plate are thus isolated:
- the most mobile product (the least polar) - 11.4 g of a white solid
having a melting point of 88 ° C - consisting of the diastereoisomer
racemic relative configuration erythro [VIA (#); code number
300868], and
- the least mobile product (the most polar) - 18.7 g of a white solid
having a melting point of 114.5 C - being constituted by the
racemic diastereoisomeric relative configuration threo (VIB (#);
of code 3008693.

EXAMPLE 5 Deduced the racemic threo [VIB (#) diastereoisomer; number
Code: 300869] [3- (3-chlorobenzyloxy) phenyl] -3 (hydroxy-1
ethyl) -5 oxazolidinone-2 [VI].

 In a flask under argon containing 9 g (0.035 mol) of alpha-methoxy-alpha-trifluoromethylphenylacetic acid chloride ([α] D20 = -134.6 (C = 5.2, CCl4)) and 30 ml of pyridine. 11.2 g (0.032 mol) of the VIE couple (t) obtained in Example 4 are added to o C several times. After solubilization with 25 ml of pyridine, 1.2 g (0.014 mol) 4-dimethylaminopyridine are added. After 60 hours of stirring at room temperature, the reaction is complete.

It is poured into 50 ml of water and then extracted 3 times with ether. The organic phase is washed 3 times with 2N HCl and then with a saturated solution of NaHCO 3, dry on
MgSO4 and evaporated.

The crude mixture obtained is chromatographed on a silica column under medium pressure (eluent = ethyl acetate-hexane: 50-50) to give the two separated XOSHER esters VI "B (+) and VI" B (-) in the form oil
- ester enantiomer VI "B (+) (the most mobile on SiO2 plate):
7.9 g; [&alpha;] D20 = + 25.3 @ (C = 1.0; CH2Cl2)
- ester enantiomer VI "B (-) [least mobile on SiO2 plate]
7.6g; [&alpha;] D20 = -73.7 (C = 1.1, CH2Cl2)
To a cooled solution at -10 ° C. of 3.6 g (0.0064 mol) of the ester enantiomer VI "B (+) in 50 ml of CH 3 OH are added 4.8 ml of
2N NaOH The saponification is complete after 8 hours of stirring W 20 'C.

After cold concentration, the reaction medium is extended with 160 ml of methyl ethyl ketone and 50 ml of ice-water mixture. After decantation, the organic phase is washed with a saturated solution of NaCl, dried over XgSO 4 and then evaporated. Flash chromatography (eluent = ethyl acetate-hexane 70-30) yields 2 g (yield = 90%) of a white solid (F = 90 ° C.) which is the threo (+) enantiomer [VIB ( +); code number: 300872] [(3-chlorobenzyloxy) -4-phenyl] -3 (1-hydroxyethyl) -2-oxazolidinone:
[&alpha;] D20 = +39.5 (C = 1.03, CH2Cl2)
absolute configuration: (S, S).

Saponification, under the same conditions as above, of the ester enantiomer VI "B (-), leads to the threo enantiomer (-) [VIB (-), code number: 300873] of the [(chloro) 3 benzyloxy) -4 phenyl] -3 (1-hydroxyethyl) -5 oxazolidinone-2
Melting point: 90 ° C
[&alpha;] D20 = -41. (C = 1.01; CH2Cl2)
Absolute configuration: (R, R).

Example: Duplication of racemic diastereoisomer erythro [VIA (#)
code number: 300868] of [3- (3-chlorobenzyloxy) phenyl] -3
(hydroxy-1-ethyl) -5-oxazolidinone-2 [VI].

To a solution cooled to 0 ° C. of 4.25 g (0.023 mole) of 2-phenoxypropionic acid chloride [[α]] D20 = + 26.3 (C = 1.0, CH2Cl2) and 0, 65 g (0.00053 mol) of 4-dimethylaminopyridine in 50 ml of pyridine are added in 30 '6.15 g of the pair VI (#) obtained in Example 4, dissolved in 30 ml of pyridine. The esterification reaction is complete after stirring for 16 hours at 20 ° C. The reaction medium is treated as in the esterification of Example 5. By means of medium pressure chromatography (eluent = ethyl acetate-hexane: 40.degree. 60), we recover
the ester enantiomer VI'A (+) [the most mobile on SiO 2 plate]
3.51 g; [&alpha;] D20 = +37.6 (C = 1.0, CH2Cl2); and
the ester enantiomer VI'A (-) [the least mobile on SiO 2 plate]
3.66 g; [&alpha;] D20 = - 14.2 (C = 1.0, CH2Cl2).

Saponification with 2N NaOH (1.3 eq) of these ester enantiomers for 2 hours at 20 ° C. under the same operating conditions as in Example 5, followed by a conventional extraction with ethyl acetate allows isolate respectively
- the enantiomer erythro (+) [VIA (+) code number 3401771 of [(chloro-3
benzyloxy) -4-phenyl] -3 (1-hydroxyethyl) -5-oxazolidinone-2
Melting point: 78 ° C
[&alpha;] D20 = + 16.6 (C = 1.0; CH2Cl2)
Absolute configuration: (S, R); and and
the erythro enantiomer (-) [VIA (-); code number: 340176] of [(chloro-3
benzyloxy) -4-phenyl) -3 (1-hydroxyethyl) -5-oxazolidinone-2
Melting point: 78 C
. [&alpha;] D20 = - 16.2 (C = 1.0; CH2Cl2)
Absolute configuration: (R, S).

 Using the methods described in Examples 1 to 6 above, but starting from the appropriate reagents, the other compounds (VI) are obtained.

 Table 1 below collates the physicochemical data of the enantiomers prepared in Examples 5 and 6.

Example 7 Preparation of the stereoisomer threo (-) (R, R) meesylate
3-benzyloxy) -4-phenyl] -3-hydroxy-1-ethyl-5-oxazolidinone-2
[IXB (-) code number 3402703
In a 500 ml flask containing 15 g (43 mmol) of the enantiomer of code number 300873 prepared in Example 5, in solution in 150 ml of CH 2 Cl 2, 7.4 g (5 ml, 65 mmol) of mesyl chloride. After cooling to -10 C., 6.5 g (9 ml, 65 mmol) of triethylamine are added dropwise under an argon atmosphere.

 After stirring for one hour at room temperature, the reaction medium is poured into ice-water and extracted 3 times with CH 2 Cl 2 (150 ml). The organic phases are washed with a saturated solution of NaHCO3 (50 ml) then.

a saturated solution of NaCl (2 x 50 ml).

After drying over XgSO 4, filtration and evaporation under reduced pressure, 18 g of white solid corresponding to the expected stereoisomer are recovered:
Melting point: 117 C
. [&alpha;] D20 = - 45.2 (C = 1; CH2Cl2)
Example 8 Preparation of the Erythro (-) (R, S) stereoisomer [(chloro-3
benzyloxy) -4-phenyl] -3 [(dimethylamino-1-ethyl)] - oxazolidinone-2
LIA (-): code number 200562]
A "bomb" made of stainless steel containing 8.2 g (19.5 mmol) of the mesylate obtained in Example 7 and 30 ml (~ 0.45 mole) of dimethylamine is heated to 100 ° C.

 After stirring for 4 hours under a pressure of 4.10 Pa, the reaction medium is concentrated.

 The precipitate recovered is purified by flash chromatography on a silica column (eluent: CH 2 Cl 2 -CH 3 OH: 96-4).

 4.2 g of a colorless product corresponding to the expected product are thus recovered.

 By carrying out the processes that are the subject of Examples 7 and 8, but starting from the appropriate reagents, the other compounds (I), some of which are listed in Table 2 below, are obtained.

Example 9: Preparation of the threo enantiomer (-) (R, R) of the [4-hydroxy]
phenyl] -3 (hydroxyethyl) -5 oxazolidinone-2 EXIB (-)
code: 340315]
To a 1-liter flask containing 4 g of 10% Pd / C in suspension in 350 ml of 95% ethanol is added 39.3 g (0.125 mol) of the enantiomer of code number 300873 prepared in accordance with the present invention. Example 5 After 2 hours of vigorous stirring under a hydrogen atmosphere, the hydrogenolysis reaction is complete. The catalyst is recovered by filtration and the filtrate is evaporated under reduced pressure to leave a light yellow oil which crystallizes. A stirring of one hour in pentane gives 27 g (yield: 97%) of a white solid corresponding to the expected product.
Melting point: 149 ° C
[&alpha;] D20 = - 73.2 (C = 1.0; CH3OH)
The other enantiomers of [4-hydroxyphenyl] -3 (hydroxyethyl) -5-oxazolidinone-2 are obtained by a similar process from the appropriate reagents and are listed in Table 3 below.

Example 10: Preparation of the threo enantiomer (R, R) (-) [(methoxy-3
benzyloxy) -4-phenyl] -3 (hydroxy-1-ethyl) -5-oxazolidinone [I]
code number: 200436]
In a flask surmounted by a condenser, 1 g (0.0045 mol) of (4-hydroxy-phenyl) -3 (1-hydroxyethyl) -5-oxazolidinone-EXI1 (code number 340315) are introduced successively. ml of acetonitrile, 1.2 g (0.0089 mol) of finely ground K2CO3, 0.1 g of KI and 0.75 ml (0.77 g, 0.005 mol) of 3-methoxy-1-chloromethylbenzene. After stirring for 3 hours under reflux, the minerals are separated by filtration on sintered glass, the filtrate is extended with 150 ml of water. The decanted aqueous phase is extracted with CH 2 Cl 2 (2 × 50 ml). The organic phase is washed with saturated NaCl.sub.2 solution, dried over MgSO.sub.4 and filtered, and then evaporated. The recovered white solid is purified by flash chromatography of silica (eluent: CH 2 Cl 2 -CH 3 OH: 96-4). After evaporation, 0.93 g of the expected product (crystallized, colorless) is recovered.

, Yield: 62%
Melting point: 116 ° C
. [&alpha;] D20 = -41.9 (C = 1; CH2Cl2)
. Elemental analysis for C₁HH₁NNO @: 342.366
Calc (%) C 66.46 H 6.16 I 4.08
Tr. (%) 66.71 6.43 4.30 TABLE 1

Number <SEP> Configura- <SEP>[&alpha;] D20 <SEP> Weight <SEP> Point <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> R1 <SEP><SEP> Formula <SEP> Raw <SEP> Molecule <SEP> Merge
<tb> Code <SEP> absolute <SEP> (C <SEP> = <SEP> 1 <SEP>;<SEP> CH2Cl2) <SEP> lair <SEP> (C) <SEP>% <SEP> C <SEP > H <SEP> N
<tb> 300873 <SEP> 3-Cl <SEP> (R, <SEP> R) <SEP> - <SEP> 41.5 <SEP> C18H18ClNO4 <SEP> 347.789 <SEP> 90 <SEP> Cal. <SEP> 62.16 <SEP> 5.22 <SEP> 4.03
<tb><SEP> Tr. <SEP> 61.99 <SEP> 5.23 <SEP> 3.76
<tb> 300872 <SEP> 3-Cl <SEP> (SE, <SEP> S) <SEP> + <SEP> 39.5 <SEP> C18H18ClNO4 <SEP> 347.789 <SEP> 90 <SEP> Cal. <SEP> 62.16 <SEP> 5.22 <SEP> 4.03
<tb><SEP> Tr. <SEP> 61.99 <SEP> 5.28 <SEP> 3.88
<tb> 340176 <SEP> 3-Cl <SEP> (R <SEP> S) <SEP> - <SEP> 16.2 <SEP> C18H18ClNO4 <SEP> 347.789 <SEQ> 78 <SEP> Cal. <SEP> 62.16 <SEP> 5.22 <SEP> 4.03
<tb><SEP> Tr. <SEP> 61.85 <SEP> 5.41 <SE> 3.78
<tb> 340177 <SEP> 3-CL <SEP> (S, <SEP> R) <SEP> + <SEP> 16.6 <SEP> C18H18ClNO4 <SEP> 347.789 <SEP> 80 <SEP> Cal. <SEP> 62.16 <SEP> 5.22 <SEP> 4.03
<tb><SEP> Tr. <SEP> 62.77 <SEP> 5.48 <SE> 4.09
<tb> TABLE 2

Number <SEP> Config- <SEP> Weight <SEP> Point <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> of <SEP> R1 <SEP> R2 <SEP> R3 <SEP> ration <SEP>[&alpha;] D20 <SEP> Formula <SEP> Raw <SEP> Molecule <SEP> Merge
<tb> Absolute <SEP> code <SEP><SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb> 340271 <SEP> 3-Cl <SEP> CH3 <SEP> H <SEP> (R, S) <SEP> - <SEP> 66 (C = 1 <SEP>;<SEP> H2O) a <SEP > C19H21N2O3Cl <SEP> 360.861a <SEP> 94 <SEP> (basis) <SEP> Cal. <SEP> 57.44 <SEP> 5.58 <SEP> 7.05a
<tb><SEP> 209 <SEP> (salt) <SEP> Tr. <SEP> 56.85 <SEP> 5.32 <SEP> 6.97
<tb> 340179 <SEP>"<SEP> CH3 <SEP>"<SEP> (S, R) <SEP> +31.1 (C = 1 <SEP>;<SEP> CH2Cl2) b <SEP> C19H21ClN2O3 <MS> 360.831b <SEP> 91 <SEP> (base) <SEP> Cal. <SEP> 57.44 <SEP> 5.58 <SEP> 7.05a
<tb><SEP> +59.8 (C = 1 <SEP>;<SEP> CH3OH) a <SEP> 198 <SEP> (salt) <SEP> Tr. <SEP> 57.10 <SEP> 5, 79 <SEP> 7.53
<tb> 340276 <SEP>"<SEP> CH3 <SEP>"<SEP> (R, R) <SEP> -35.4 (C = O,; CH2Cl2) b <SEP> C19H21N2O3Cl <SEP> 360.861b <SEP> 220 <SEP> (salt) <SEP> Cal. <SEP> 57.44 <SEP> 5.58 <SEP> 7.05a
<tb><SEP> Tr. <SEP> 57.20 <SEP> 5.61 <SEP> 7.05
<tb> 340333 <SEP>"<SEP> CH3 <SEP>"<SEP> (S, S) <SEP> +44.4 (C = 1; CH2Cl2) b <SEP> C19H21ClN2O3 <SEP> 360.831b <SEP > 85 <SEP> (base) <SEP> Cal. <SEP> 57.44 <SEP> 5.58 <SEP> 7.05a
<tb><SEP> 225 <SEP> (salt) <SEP> Tr. <SEP> 56.30 <SEP> 5.86 <SEP> 7.18
<tb> TABLE 2 (continued)

Number <SEP> Config- <SEP> Weight <SEP> Point <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> of <SEP> R1 <SEP> R2 <SEP> R3 <SEP> ration <SEP>[&alpha;] D20 <SEP> Formula <SEP> Raw <SEP> Molecule <SEP> Merge
<tb> Absolute <SEP> code <SEP><SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb> 200562 <SEP> 3-Cl <SEP> CH3 <SEP> CH3 <SEP> (R, S) <SEP> -34.7 (C = 1; CH2Cl2) b <SEP> C20H20ClN2O3 <SEP> 374.875b <SEP> 124 <SEP> (base) <SEP> Cal. <SEP> 56.88 <SEP> 6.02 <SEP> 6.63a
<sep>SEP> -29.7 (C = 1; CH2Cl2) a <SEP> C20H24Cl2NO2O3 <SEP> 422.302a <SEP> 117 <SEP> (salt) <SEP> Tr. <SEP> 56.79 <SEP > 5.84 <SEP> 6.53
<tb><SEP> + 2.6% <SEP> H2O
<tb> 340321 <SEP>"<SEP> H <SEP> H <SEP> (R, R) <SEP> -38.3 (C = 1; CH2Cl2) b <SEP> C18H19ClN2O3 <SEP> 346.805b <SEP > 99 <SEP> Cal. <SEP> 55.10 <SEP> 5.39 <SEP> 7.14a
<tb><SEP> Tr. <SEP> 55.11 <SEP> 5.11 <SEP> 7.06
<tb> 340366 <SEP>"<SEP>"<SEP>"<SEP> (S, S) <SEP> +41 (C = 1; CH2Cl2) b <SEP> C18H19ClN2O3 <SEP> 346.805b <SEP> 106 <SEP> (base) <SEP> Cal. <SEP> 56.40 <SEP> 5.26 <SEP> 7.31a
<tb><SEP> 220 <SEP> (salt) <SEP> Tr. <SEP> 56.13 <SEP> 519 <SEP> 7.12
<tb><SEP> Cal.
<Tb>

<SEP> Tr.
<Tb>

a = salt = hydrochloride; b = base TABLE 3

Number <SEP> Configuration <SEP>[&alpha;] D20 <SEP> Weight <SEP> Point <SEP> of <SEP> ANALYSIS <SEP> ELEMENTARY
<tb><SEP> of <SEP> absolute <SEP> Formula <SEP> gross <SEP> molecular- <SEP> merge
<tb><SEP> Code <SEP> (C = 1 <SEP>;<SEP> CH3OH) <SEP><SEP> (C) <SEP>% <SEP> C <SEP> H <SEP> N
<tb> 340315 <SEP> (R, <SEP> R) <SEP> - <SEP> 73.2 <SEP> C11H13NO4 <SEP> 223.222 <SEP> 149 <SEP> Cal. <SEP> 59.18 <SEP> 5.87 <SEP> 6.28
<tb><SEP> Tr. <SEP> 59.42 <SEP> 6.11 <SEP> 6.13
<tb> 200158 <SEP> (S, <SEP> S) <SEP> + <SEP> 71.7 <SEP> C11H13NO4 <SEP> 223.222 <SEP> 154 <SEP> Cal. <SEP> 59.18 <SEP> 5.87 <SEP> 6.28
<tb><SEP> Tr. <SEP> 59.42 <SEP> 6.11 <SEP> 6.13
<tb> 200356 <SEP> (R <SEP> S) <SEP> - <SEP> 28.5 <SEP> C11H13NO4 <SEP> 223.222 <SEP> 163 <SEP> Cal. <SEP> 59.18 <SEP > 5.87 <SEP> 6.28
<tb><SEP> Tr. <SEP> 58.88 <SEP> 5.73 <SEP> 6.12
<tb> 200357 <SEP> (S, <SEP> R) <SEP> + <SEP> 29.8 <SEP> C11H13NO4 <SEP> 223.222 <SEP> 163 <SEP> Cal. <SEP> 59.18 <SEP> 5.87 <SEP> 6.28
<tb><SEP> Tr. <SEP> 59.14 <SEP> 5.85 <SEP> 6.09
<Tb>
The compounds according to the invention have been tested on the laboratory animal and have demonstrated a pharmacological activity and in particular a monoamine oxidase inhibitory activity, in particular monoamine oxidase type B.

 This activity has been demonstrated using the protocol described by DOSTERT P. et al. in J. Pharm. Pharmacol., 1983, 35, 161-165; this protocol is based on enzymatic tests carried out with or without preincubation, in particular for 60 minutes, and it makes it possible to measure in vitro the inhibitory effect with respect to XAO-A and XAO-B of the rat brain.

 Table 4 below summarizes the inhibitory concentrations 50 (IC 50) of forms A and B of XAO obtained for a number of compounds (I) according to the invention by following the above protocol applied to a homogenate of rat brain, 1 g tissue / 16 ml phosphate buffer pH 7.4.

TABLE 4

<tb><SEP> Compound <SEP> Configuration <SEP> CI <SEP> 50 <SEP> (A) <SEP> CI <SEP> 50 <SEP> (B) <SEP> CI <SEP> 50 <SEP> (AT)
<tb><SEP> tested * <SEP> absolute <SEP> in <SEP> n <SEP> M <SEP> in <SEP> nM <SEP> CI <SEP> 50 <SEP> (B
<tb> No. <SEP> of <SEP> code <SEP> (preincubation <SEP> of <SEP> 60 ')
<tb><SEP> 340271 <SEP> (R, S) <SEP> (-) <SEQ> 7430 <SEQ> 78 <SEP> 95
<tb><SEP> 340179 <SEP> (SE, R) <SEP> (+) <SEP> 18300 <SEQ> 1160 <SEP> 16
<tb><SEP> 340276 <SEP> (R, R) <SEP> (-) <SEQ> 148000 <SEQ> 1350 <SEQ> 110
<tb><SEP> 340333 <SEP> (S, S) <SEP> (+) <SEP>> 100000 <SEQ> 1280 <SEP>> 78 <SEP>
<tb><SEP> 200562 <SEP> (R, S) <SEP><SEP> (-) <SEP>> 100000 <SEP> 53 <SEP>> 1887
<tb><SEP> 340321 <SEP> (R, R) <SEP><SEP> (-) <SEQ>> 100000 <SEQ> 5340 <SEP>><SEP> 19
<tb><SEP> 340366 <SEP> (S, S) <SEP> (+) <SEP>> 100000 <SEQ> 1641 <SEP>><SEP> 61
<Tb>
* in hydrochloride form
Substrate concentrations: [@@ C] 5-HT = 480 M [@@ C] SKIN = 12 M for the study of inhibition of forms A and B.

 It emerges from Table 4 that the compounds (I) according to the invention exhibit an XAO inhibitory activity and in particular that the erythro (R, S) (-) configuration compounds are potent and selective inhibitors of the XAO of type B.

 Furthermore, a subacute 15-day toxicological study carried out on the rat revealed the innocuousness of the compounds (1) according to the invention and their pharmaceutically acceptable acid addition salts.

It follows from the foregoing that the compounds (I) and their pharmaceutically acceptable acid addition salts of the invention find application in therapy, especially as monoamine oxidase inhibiting drugs, in part of the monoamine oxidase type B. They may therefore be used for the treatment of depression,
Parkinson's and neurological deficits notably related to senescence.

 The invention extends to pharmaceutical compositions containing, as active ingredient, at least one compound chosen from compounds (I) and their pharmaceutically acceptable acid addition salts according to the invention, in association with a pharmaceutically acceptable vehicle. acceptable. These compositions will be administered orally in the form of tablets, dragees or capsules for example, at doses of active ingredient up to 50 mg / day in one or more doses, rectally in the form of suppositories containing up to 300 mg of active ingredient (1 to 2 per day) or in the form of injectable solutions containing up to 300 mg of active ingredient (1 to 2 injections per day).

Claims (10)

 1. Mixture of the 4 stereoisomers of formula (I) below, each corresponding pair of racemic diastereoisomers and each enantiomer corresponding to each pair, that is to say each of said stereoisomers:

 in which R @ represents  a hydrogen atom,  an alkoxy group comprising from 1 to 4 carbon atoms,  a trifluoromethyl group, or  one or two halogen atoms and the pair (R2, R2) has one of the following meanings: (H, H), <H, C1-C40 alkyl, (C1-C4) alkyl, C1-C4 alkyl C4), as well as their addition salts of organic and inorganic acid.  2. Mixture, couples and enantiomers or stereoisomers according to claim 1, for which R1 represents a chlorine atom in the meta position and the pair (R2, R3) takes one of the following values: (CH3, H), (CH3, CH3) ), (H, H).  3. Enantiomers or stereoisomers according to claim 1 or 2, of relative configuration erythro.  4. Enantiomers or stereoisomers according to claim 3, of absolute configuration (R, S) (->.  5. Pharmaceutical composition, in particular with monoamine oxidase inhibiting activity, in particular of type B, characterized in that it comprises the mixture, a pair or an enantiomer according to one of claims 1 to 4 or a salt thereof. pharmaceutically acceptable acid, in association with a pharmaceutically acceptable carrier.  6. Process for the preparation of enantiomers or stereoisomers erythro (+) [IA (+)], erythro (-) EIA (-)], threo (+) EIB (+)] and threo (-) [IB (-)] , corresponding to the formula (I) according to claim 1, as well as their acid addition salts, characterized in that it consists  - to react a compound of formula

 where the pair (R2, R3) has the same meaning as in the formula (I) defined in claim 1, respectively with stereoisomeric isomers threo (+) [IXB (+)], threo (-) [IXB (-) )], erythro (+) [IXA (+)] and erythro (-) [IXA (-)] corresponding to the formula ::

 to form the acid addition salts of the compounds thus obtained  in the formula (I) defined in claim 1, and optionally  where Xs is the mesyl group and R1 has the same meaning as  7. Process according to claim 6, characterized in that the reaction between the compounds X and IX is carried out in a hydroxylated solvent.  8. Process according to claim 6 or 7, characterized in that the mesylate stereoisomers of formula (IX) are obtained by the action of a mesyl halide respectively on the threo (+) [VIB (+)], threo (-) steroids. ) [VIB (-)], erythro (+) [VIA (+)] and erythro (-) [VIA (-)] corresponding to the formula

  or R1 has the same meaning as in formula (I) defined in claim 1 @  9. Process according to claim 8, characterized in that the reaction is carried out in the presence of an organic base.  10. Stereoisomers threo (+) [IXB (+)], threo (-) [IXB (-)], erythro (+) [IXA (+)] and erythro (-) [IXA (-)] corresponding to formula

 where Xs represents the mesyl group and R @ has the same meaning as in formula (I) defined in claim 1.