HRP920802A2 - Process for obtaining new beta-d-phenyl-thioxylosides - Google Patents

Description

The field of technology

The invention is from the field of synthesis of organic compounds. The designation of the invention according to the International Classification of Patents is C 07 D 335/00; A 61 K 31/38.

Technical problem

The invention solved the technical problem of the procedure for obtaining new derivatives of β-D-phenyl-thioxiloside, new therapeutic agents for the treatment of thrombosis, especially venous thrombosis.

State of the art

In EP-B-051023 benzoyl and alpha-hydroxy-benzoyl-phenyl-oside derivatives have already been proposed as anti-ulcer agents, as anti-platelet aggregation agents, as anti-thrombosis agents and as cerebral oxygenators.

It is also known from EP-A-0133103 that benzyl-phenyl-ozides are useful as such as hypocholesterolemic and hypolidemic agents, and some of these compounds, in particular the product of Example 1, have, among other things, antithrombotic effects.

It has now been found that β-D-phenyl-thioxyloside derivatives according to the invention, which are structurally different from the known products of the prior art, are useful for the treatment and prevention of diseases related to circulation difficulties, especially as agents against venous thrombosis.

Description of the solution to the technical problem

The derivatives of the invention unexpectedly have significantly better anti-thrombotic properties than the known products of the prior art, as shown by the results of the comparative experiments in Table III given below.

The new products according to the invention are characterized by the fact that they are selected from the set consisting of:

(i) β-D-phenyl-thioxylosides of the formula:

[image]

where

R represents a hydrogen atom, a halogen atom, a nitro or a cyano group

A represents a sulfur atom or an oxygen atom,

B represents the group CH2, CHOH or CO,

Y represents a hydrogen atom or an acyl group; and

(ii) their epimers when B is CHOH.

Hydroxyl functions of the ß-D-phenyl-thioxylose residue can be acylated, to some extent they are acetylated. The present invention includes those derivatives of formula I whose hydroxyl functions of the ß-D-phenyl-thioxylose residue are acylated, especially acetylated.

Among the halogen atoms appearing in the definition of group R, fluorine, chlorine and bromine atoms can be cited, whereby the halogen atom is preferably a chlorine atom.

Among acyl groups corresponding to the invention, those having a total of 2 to 5 carbon atoms can be mentioned, the preferred acyl group being CH 3 OH.

Compounds of formula I and the corresponding acylated compounds can be made by a glycosidation reaction characterized by:

(i) the compound of the formula reacts:

[image]

wherein the derivatives A, B and R are as defined above, with a thioxylose derivative selected from the group consisting of haloacylthiooxylosides and acylthiooxylosides of the formula:

[image]

in which Hal represents such a halogen atom as Cl or Br (with the bromine atom being a preferred halogen atom) and Y represents an acyl group, especially an aliphatic acyl group having a total number of carbon atoms of 2 to 5 and preferably an acetyl group;

in some inert solvent, in the ratio of 1 mol of II to about 1.1 to 1.2 mol of thioxylose derivative, in the presence of some acidic acceptor or some Lewis acid and,

(ii) if necessary, the deacetylation reaction is carried out at a temperature between ordinary temperature (15-25°C) and the reflux temperature of the reaction medium, in some C1-C4 lower alcohol (preferably methanol), in the presence of some metal alcoholate (preferably magnesium methylate or sodium methylate).

In this procedure, it is important that in phase (i) compound VIIIa is of the alpha configuration. In turn, compound VIIIb can be of alpha or beta configuration or even a mixture of both configurations.

Acylated or not, compounds of formula I in which B represents either CHOH or CH 2 can also be obtained by reduction according to a known procedure on compounds of formula I (acylated or not) in which B represents CO or CHOH.

Acylated or not, compounds of formula I in which B represents CH can also be obtained by oxidation according to a known process on compounds of formula I (acylated or not) in which B represents CH 2 or CHOH.

Of the known procedures for glycosidation from the prior art, the following have been confirmed:

- KOENIGS-KNORR procedure (described in "The Carbohydrates, Chemistry and Biochemistry", 2nd Edition, New York and London: Academic Press (1972), volume 1A, pages 295-301), by condensation of phenol or thiophenol of formula II with haloacylthiooxylizide VIIIa, in an inert solvent selected from polar and apolar solvents (such as, for example, dimethylformamide, tetrahydrofuran dioxane, acetonitrile, nitromethane, benzene, toluene, siloles and mixtures thereof), in the presence of such a proton acceptor as mercuric cyanide or silver triflate (silver trifluoromethyl sulfonate); and

- HELFERICH procedure (ibidem, pages 292-294) by condensation of acylthioxylizide VIIIb with phenol or thiophenol of formula II in some inert solvent selected from aromatic solvents, chlorinated solvents, ethers and their mixtures, in the presence of some Lewis acid.

According to the preferred way of carrying out the invention, when A represents a sulfur atom in the compound of formula II, in phase (i) of the process, 1 mol of thiol is condensed with 1.2 mol of haloacylthiooxyloside VIIIa in an inert solvent selected from polar and apolar solvents, in the presence of mercury - cyanide.

2,3,4-tri-O-acetyl-1-bromo-α-D-5-thioxylopyranoside will be used conveniently in a mixture of benzene/nitromethane 1/1 (v:v), in the presence of 1.1 to 1.3 moles of mercury cyanide , at a temperature between 0°C and the reflux temperature of the reaction medium, preferably around 40-50°C, for 1 to 4 hours, preferably for around 2 hours.

According to another preferred way of carrying out the invention, when in the compound of formula II A represents an oxygen atom and B represents a methylene group, in phase (i) of the procedure, 1 mol of phenol II is condensed with about 1.1 to 1.2 mol of haloacylthiooxyloside VIIIa, in a non-inert solvent which is selected from aromatic solvents, chlorinated solvents, ethers and their mixtures, in the presence of silver triflate.

2,3,4-tri-O-acetyl-bromo-α-D-5-thioxylopyranoside will be used conveniently in a mixture of anhydrous ntoluene/nitromethane 1/1 (v:v), in the presence of 1.1 to 1.3 moles of silver triflate, whereby the reaction is carried out under protection from light, at a temperature between 0°C and 15°C, preferably at about 3°C, for 5 to 24 hours, preferably for about 12 hours.

According to another preferred method for carrying out the invention, which is also recommended, when A represents a sulfur atom in the compound of formula II, in phase (i) of the process, 1 mol of thiol II is condensed with about 1.1 to 1.3 mol of acylthiooxyloside VIIIb in some inert solvent which is selected from ethers, aromatic solvents, chlorinated solvents and their mixtures, in the presence of SnCl4.

1,2,3,4-tetra-O-acetyl-alpha or beta-D-5-thioxylopyranoside, in methylene chloride, in the presence of 1.1 to 1.2 moles of SnCl4, at a temperature between 0°C and the reflux temperature of the reaction medium will be used. , preferably at about 20°C, for 1 to 5 hours, preferably for about 3 hours.

The glycosidation reaction is performed in all cases on a mixture of alpha and beta isomers in variable quantities.

The beta isomer is isolated according to techniques known in the art, such as, for example, fractional crystallization or chromatography, especially "flash chromatography": chromatography on a column of silica and under pressure according to the technique described in W. C. STILL et al. in J. Org. Chem. (1978), 42, (No. 14) 2923.

The reduction reactions that allow obtaining compounds of formula I, acylated or not, in which B is CHOH, starting from the corresponding compounds in which B is CO, are carried out with classical reagents such as metal hydrides, such as LiAlH4, KBH4 or NaBH4, in such with inert solvents such as ether, tetrahydrofuran or lower alcohols, especially methanol or ethanol, at a temperature between 0°C and ordinary temperature (15-25°C), for 1 to 12 hours, whereby the preferred metal hydride is NaBH4, and the reaction is preferably carried out in methanol at a temperature of 20°C.

The reduction reactions which make it possible to obtain compounds of formula I, acylated or not, in which B is CH2, starting from the corresponding compounds in which B is CO or CHOH, are carried out using such reducing agents as metal hydrides, such as NaBH4 or KBH4, and preferably with NaBH4, in trifluoroacetic acid. Here, the best way to carry out the procedure consists in introducing a reducing agent into the mixture containing the compound to be reduced and trifluoroacetic acid, at a temperature between the solidification temperature of the reaction medium and 0°C, with an excess of the reducing agent compared to the compound to be reduced, and when the addition of the reducing agent is completed, the reaction is allowed to proceed under stirring for 0.5 to 12 hours, at a temperature between 0°C and 20°C. In practice, it is convenient to combine trifluoroacetic acid with some chlorinated solvent, especially with methylene chloride, in order to dissolve the compound being reduced.

Oxidation reactions that enable obtaining compounds of formula I, acylated or not, in which B is CO, starting from the corresponding compounds in which B is CH2, can be carried out with classical oxidizing agents such as CuSO4/K2S2O8 or Cr2O3, in the presence of such an organic base such as pyridine, in some polar or non-polar solvent, such as ethers, aromatic solvents, chlorinated solvents and mixtures thereof and, preferably, a water/acetonitrile 1/1 (v:v) mixture when CuSO4/K2S2O8 is used, and methylene chloride when Cr2O3 is used.

The obtained derivatives are subjected, when necessary, to deacylation, especially deacetylation, which is carried out at a temperature between normal and reflux temperature of the reaction medium in a lower C1-C4 alcohol, in the presence of a suitable metal alcoholate. Methanol will preferably be chosen as the lower alcohol, and sodium methanolate or magnesium methanolate as the metal alcoholate.

Deacylation and reduction reactions (especially the conversion of CO to CHOH) can possibly be carried out successively without isolating the formed intermediate compound.

Intermediate derivatives of formula II in which A represents a sulfur atom are new compounds, with the exception of compounds in which B is CO when R is H or 4-Cl and B is CH 2 when R is H or 4-Cl. Their acquisition is described in our YU P-1036/89, which was separated from the current application.

According to the invention, a therapeutic preparation is proposed which is characterized by comprising, together with a physiologically acceptable ingredient, at least one compound selected from the group consisting of products of formula I and their epimers. The active ingredient in such a preparation is preferably in a therapeutically effective amount.

The compounds of formula I are useful in therapy as antithrombotic agents. They are particularly useful in the treatment of venous circulation problems.

According to the invention, it is proposed to use one substance belonging to the group of compounds of formula I and their epimers to obtain an anti-thrombosis drug intended for therapeutic use for the treatment of venous circulation problems.

Other characteristics and advantages will be best appreciated on the basis of the text that follows with manufacturing examples, by no means limiting, but given for illustrative purposes only, and the results of pharmacological trials. The rotational power angles /alpha/D20 are expressed in degrees and are measured at 20°C.

PREPARATION I

Preparation of 4-(4-nitrobenzoyl)phenyl)-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside

Example 1a

A mixture of 150 ml of anhydrous benzene, 150 ml of nitromethane and 30 g of molecular sieve of 0.4 mm (commercial product of the E. MERCK company) is stirred at room temperature for 15 minutes and then 14.2 g (0.0553 mol) of mercuric cyanide (Hg(CN)) is added. 2). After stirring the reaction mixture for 10 minutes at room temperature, 19.6 g (0.0552 mol) of 2,3,4-tri-O-acetyl-1-bromo-5-thio-alpha-D-xylopyranoside and then 13 g (0.050 mol ) (4-mercaptophenyl)-(4-nitrophenyl)-methanone in small batches. When the addition is complete, the reaction mixture is heated to 40-50°C for four hours and then filtered through Celite-aR (ie, diatomaceous silica for filtration). The residue is washed several times with ethyl acetate. The obtained organic phase is washed successively with saturated sodium chloride solution, with 1N NaOH solution, with sodium chloride solution and then with water until neutral pH. It is dried over magnesium sulfate, filtered and the solvent is evaporated. The obtained yellowish oil is dissolved in 50 ml of ether and kept for 12 hours at 4°C. The product crystallizes. After filtration, 17.2 g of the desired product of beta configuration is obtained. The mother liquors are then evaporated and the products contained in them are separated by "flash chromatography" eluting with a mixture of toluene/ethyl acetate (8:1) v.v. Finally, 18.6 g of the beta isomer (yield: 70%) is obtained, which melts at 166-169°C ([α]20D = +92; C = 0.5 (CHCl2)) and 3.9 g of the alpha isomer (yield: 15%) in the form of foam ([α]20D = +286; C = 0.5 (CHCl3)).

PREPARATION II

Preparation of (4-(4-nitrobenzoyl)phenyl)1,5-dithio-beta-D-xylopyranoside

Example 1

Under a nitrogen atmosphere, 18 g (0.0337 mol) of the desired product obtained in preparation I (example 1a) is dissolved in a mixture of 100 ml of ethyl acetate and 300 ml of methanol, then 8.5 ml of an 8% solution of sodium methylate in methanol is added. After two hours under stirring at room temperature, the formed precipitate is filtered off and washed twice with 50 ml of methanol. The resulting filtrate is neutralized using Amberlite® IR 120 resin (H+) to pH 4-5, then after filtration the solvent is evaporated and the resulting evaporation residue is combined with the previously obtained precipitate.

13.8 g of the desired product (quantitative yield) is obtained, which melts at 183°C. ([α]20D = +60; C = 0.5 (DMSO)).

PREPARATION III

Preparation of (4((nitrophenyl)hydroxymethyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 3

Under a nitrogen atmosphere, 1.2 g (0.0315 mol) of sodium tetraborohydride is added in small amounts in a suspension of 11.2 g (0.0275 mol) of the product obtained in preparation II (example 1). After two hours of mixing at 0°C, a homogeneous solution is obtained. The reaction medium is neutralized using Amberlite® IR 120 resin (H+) to pH 4-5 and after filtration the solvent is evaporated. The resulting evaporation residue is purified on a silica column by eluting with ethyl acetate. 11.2 g (quantitative yield) of the desired product melting at 80°C is obtained. ([α]20D = +8; C = 0.5 (methanol)).

PREPARATION IV

Preparation of (4-((4-nitrophenyl)hydroxymethyl)phenyl)2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside

Example 3a

Under a nitrogen atmosphere, 7 g (0.0131 mol) of (4-(4-nitrobenzoyl)phenyl)-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside obtained in preparation I ( example 1a) is dissolved in 70 ml of methanol and then, at room temperature, 0.5 g (0.0131 mol) of sodium tetraborohydride is added to the reaction mixture. The reaction medium is stirred for 30 minutes and then the reaction medium is acidified by adding Amberlite® IR 120 resin (H+) to pH 4-5. After filtration, the resulting filtrate is evaporated. 6.3 g of the desired product is obtained (yield: 90%) in the form of a yellow foam ([α]20D = +29; C = 0.15 (methanol)).

PREPARATION V

Preparation of (4-(4-nitrobenzyl)phenyl)-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside

Under a nitrogen atmosphere, 3.3 g (0.00616 mol) of (4-((4-nitrophenyl)hydroxymethyl)phenyl)-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside (example 3a) obtained in preparation IV is suspended in 17 ml of methylene chloride. The reaction medium is cooled to 0°C and then 17 ml of trifluoroacetic acid are added all at once and 470 mg (0.0123 mol) of sodium tetraborohydride are added in small batches. Stirring of the medium was continued at 0°C for 1.5 hours. The reaction medium is hydrolyzed on ice and washed with saturated bicarbonate solution and with water until the pH is neutral. The organic phase is dried, filtered and then evaporated. 2.77 g (yield: 87%) of product in the form of foam is obtained.

PREPARATION VI

Preparation of (4-(4-nitrobenzyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 4

2.79 g (0.00537 mol) of (4-(4-nitrobenzyl)phenyl-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside obtained in preparation V is suspended in 40 ml of methanol and then 0.15 ml of an 8% solution of sodium methylate in methanol is added under stirring at room temperature. After 12 hours of stirring at room temperature, sodium methylate is neutralized using Amberlite® IR 120 (H+) resin. The reaction medium is filtered, evaporated and then The resulting residue is purified by "flash chromatography" eluting with a mixture of methylene chloride and methanol (95:5) v/v. 1.3 g of the desired product is obtained (yield: 60%) which melts at 163°C ([α]20D = +10; C = 0.5 (methanol)).

PREPARATION VII

Preparation of (4-(4-nitrobenzyl)phenyl)-2,3,4-tri-O-acetyl-1-5-thio-beta-D-xylopyranoside

Example 2a

Under a nitrogen atmosphere and at 3°C, 4.5 g (0.01965 mol) of 4-4(4-nitrobenzyl)phenol, 3 ml of 2,4,6-trimethylpyridine, 70 ml of a mixture of toluene/nitromethane (1:1) v/ v and 10 g of molecular sieve of 0.4 nm. The reaction medium is stirred vigorously for 20 minutes and then 5.8 g (0.0225 mol) of 1-bromo-2,3,4-tri-O-acetyl-1-5-thio-alpha-D-xylopyranoside are introduced in batches of 2.17 g all in 30 minutes. It is mixed protected from light and at 3°C for 20 hours. The reaction medium is filtered through Celite® and the precipitate is washed three times with 200 ml of ethyl acetate. The resulting filtrate is washed with 1N HCl and then with water until the pH is neutral. After drying over magnesium sulfate, filtration and evaporation, the obtained yellowish oil is purified by "flash chromatography" eluting with a mixture of hexane/ethyl acetate. 3 g (yield: 30%) of the beta isomer melting at 134°C ([α]20D = -25; C = 0.5 (CHCl3)) and 3 g of the alpha isomer ([α]20D = +284° ; C = 0.4 (CHCl3)).

PREPARATION VIII

Preparation of (4-(4-nitrobenzyl)phenyl)-5-thio-beta-D-xylopyranoside

Example 2

Under a nitrogen atmosphere and at 0°C, 2.5 g (0.005 mol) of the product (example 2a) obtained in preparation X is suspended in 150 ml of methanol and then 0.5 ml of an 8% solution of sodium methylate in methanol is added. The reaction medium is stirred for two hours, then Amberlite® IR 120 (H+) resin is added. When a neutral pH is reached, methanol is evaporated under reduced pressure and the thus obtained methanol is lyophilized under reduced pressure and the evaporation residue thus obtained is lyophilized. 1.9 g (quantitative yield) of the desired product melting at 166°C is obtained. ([α]20D = 121; C = 0.5 (methanol)).

PREPARATION IX

Preparation of (4-(-4nitrobenzoyl)phenyl)-2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside

Example 10a

Under a nitrogen atmosphere, 1.1 g (0.0028 mol) of the product (example 2a) obtained in preparation X, 60 ml of anhydrous methylene chloride, 0.66 g (0.043 mol) of chromium oxide (Cr2O8) and 12 ml of pyridine are successively mixed. The resulting mixture is heated to 60°C for 24 hours, then 0.66 g of chromium oxide is added and heated for 24 hours. The organic phase is separated from the undissolved residue by decantation. The undissolved residue was collected using a solution of sodium bicarbonate and isopropyl alcohol and then extracted three times with methylene chloride. The organic phases are combined and washed with sodium bicarbonate solution, with water to neutral pH, with 1N hydrochloric acid and then with water to neutral pH. It is dried over magnesium sulfate, filtered and evaporated. The thus obtained crude residue from evaporation is purified by "flash chromatography" eluting with a mixture of chloroform/ethyl acetate v/v. 0.720 g of the starting product and 0.260 g (yield: 24%) of the desired product, which melts at 152°C, are obtained. ([α]20D = -47; C = 0.3 (CHCl3)).

PREPARATION X

Preparation of (4-(nitrophenyl)hydroxymethyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 3

Under a nitrogen atmosphere, 5.33 g (0.01 mol) of the product (example 1a) obtained in preparation I is dissolved in 50 ml of anhydrous methanol and then 0.5 ml of a solution of 8% sodium methylate in methanol is added. The mixture is stirred for 1 hour while monitoring the disappearance of the starting product by thin layer chromatography. When the disappearance of the starting product is complete, 0.4 mg (0.0105 mol) of sodium tetraborohydride NaBH4 is added in small batches and while controlling the disappearance of the intermediate acetylated derivative formed previously. Finally, Amberlite® IR 120 (H+) resin is added to the obtained mixture in order to neutralize the environment. After filtration, the filtrate is evaporated to dryness. The evaporation residue, which is obtained as a foam, is collected with bidistilled water and then lyophilized. 4 g of the desired product (quantitative yield) is obtained, which melts at 80°C. ([α]20D = +8; C = 0.5 (methanol)).

PREPARATION XI

Preparation of (4-((4-nitrophenyl)hydroxymethyl)phenyl)-5-thio-beta-D-xylopyranoside

Example 8

According to the method described in preparation X starting from (4-(4-nitrobenzoyl)phenyl)-2,3,4-tri-O-acetyl-5-thio-beta-D-xylopyranoside obtained in preparation IX, it is obtained in quantitative yield the desired product melting at 108-118°C. ([α]20D = '7; C = 0.5 (methanol)).

PREPARATION XII

Preparation of (4-(4-cyanobenzoyl)phenyl)-2,3,4-tri-O-acetyl-1,5-dithio-beta-D-xylopyranoside

Example 12a

According to the procedure described in preparation I, starting from 6 g (0.0251 mol) of (4-mercaptophenyl)-(4-cyanophenyl)methanone, 9.8 g (0.0276 mol) of 2,3,4-tri-O-acetyl-1 -bromo-5-thio-alpha-D-xylopyranoside and 7.1 g (0.0276 mol) mercuric cyanide, 7.3 g (yield: 52%) of the beta isomer is obtained, which melts at 172°C. ([α]20D = +50; C = 0.15 (CHCl3)).

PREPARATION XIII

Preparation of (4-(4-cyanobenzoyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 12

According to the procedure described in preparation II, starting from 2 g (0.0356 mol) of the product (example 12a) and 0.75 ml of an 8% sodium methylate solution, 1.38 g (quantitative yield) of the desired product is obtained, which melts at 164 °C. ([α]20D = +53; C = 0.197 (CH3OH)).

PREPARATION XIV

Preparation of (4-(4-cyanophenyl)hydroxymethyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 13

According to the procedure described in preparation III, starting from 3.7 g (0.0095 mol) of the product (example 12) and 0.370 g (0.0097 mol) of sodium tetraborohydride, 3 g ([α]20D = +2.8; C = 0.598 (CH3OH).).

PREPARATION XV

Separation of two epimers (4-((4-nitrophenyl hydroxymethyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

1) Preparation of (+)-(4-((nitrophenyl)-1,5-dithio-beta-D-xylopyranoside)

Example 16

11.2 g of the epimer mixture ([α]20D = +8; C = 0.5 (methanol)) obtained in preparation III was recrystallized from 80 ml of ethyl acetate saturated with water. 7.85 g of crystals (C1) ([α]20D = +4; C = 0.4 (methanol)) and filtrate (F1) are obtained. Crystals (C1) are recrystallized from 150 ml of ethyl acetate containing 1% water (v/v). 3.15 g of crystals (C2) are obtained ([α]20D = +17.6; C = 0.45 (methanol))

Crystals (C2) are recrystallized from 40 ml of ethyl acetate saturated with water. 1.78 g of crystals (C3) ([α]20D = +23.2; C = 0.4 (methanol)) of the (+) isomer are obtained, melting at 141°C.

2) Obtaining .(-)-4(4-nitrophenyl)hydroxymethyl)phenyl)-1,5-dithio-beta-D-xylopyranoside

Example 17

The filtrate (F1) is evaporated in vacuo and taken up in ethyl acetate containing less than 100 ppm water. After crystallization, 3.9 g of crystals (C'2) are obtained ([α]20D = -4.6; C = 0.45 (methanol)).

Crystals (C'2) are recrystallized from 130 ml of ethyl acetate containing less than 100 ppm of water. 1.44 g of crystals (C'3) are obtained ([α]20D = -10.4; C = 0.35 (methanol)).

Crystals (C'3) are recrystallized from 60 ml of ethyl acetate containing less than 100 ppm. 0.96 g of crystals ([α]20D = -15; C = 0.4 (methanol)) of the (-) isomer are obtained, melting at 157 to 163°C.

In a non-limiting way, in the following Table I, a certain number of compounds of formula I according to the invention are collected, and in the following Table II, a certain number of their acetylated derivatives.

Tables I and II summarize the physical characteristics of the compounds according to the invention.

The antithrombotic activity of the product according to the invention was demonstrated according to the operative protocol for venous thrombosis as follows:

- the venous phase is realized under hypercoagulation according to the technique described by WESSLER et al. (J. Applied Physiol. 1959, p. 943-946). The hypercoagulant agent used is, as in the technique described by J. HAUPMAN et al. (Thrombosis and Haemostasis 43 (2) 1980, p. 118), a solution of active factor X provided by the company Flow Laboratories (71 Knat for 12.5 ml of physiological serum).

The study was performed on non-fasted male Wistar rats from 250 to 280 g (groups of 10 animals). The products being tested were administered orally, in suspension in PEG 400. Thrombosis was induced 4 hours after treatment and the formed thrombus was removed and measured. The results obtained with a dose of 12.5 mg/kg p.o. (without contraindications) are shown in Table III. Also in this Table are given the results obtained with known products from the prior art.

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TABLE I

[image]

Notes: (1) residual solvent: 2.3% H2O

(2) residual solvent: 2.5% H2O

(3) lyophilized product

(4) mixture of epimers

(a) DMSO solvent

(b) solvent CH3OH

(c) THF solvent

TABLE II

[image]

[image]

Notes: (1) mixture of diastereomers

(a) CHCl3 solvent

(b) solvent CH3OH

TABLE III

[image]

Notes: A: Comparison product described in example 1

EP-A-0133 103

B: Comparative product described in Example 97

EP-B-0051 023

(1): in a dose of 7.5 mg/kg p.o.

Claims (1)

1. Process for obtaining beta-D-phenyl-thioxyloside compounds of the formula: [image] in which: R hydrogen atom, halogen atom, nitro or cyano group, A is S or O, B is CH 2 , CHOH or CO Y is a hydrogen atom or an acyl group; and their epimers when B is CHOH, indicated by the fact that the compound of the formula reacts: [image] wherein A, B and R are as defined above, with a thioxylose derivative selected from the group consisting of haloacylthiooxylosides and acylthiooxylosides of the formula: [image] in which Hal represents such a halogen atom as Cl or Br (with bromine being the preferred halogen atom) and Y represents an acyl group, especially a C2-C5 aliphatic acyl group and preferably a CH3OH group, in an inert solvent, in the ratio of 1 mol of compound II for about 1.1 to 1.2 moles of thioxylose derivatives of formulas VIIIa and VIIIb, in the presence of an acid acceptor or a Lewis acid, and, if necessary, the deacetylation reaction is carried out at a temperature between ordinary (15-25°C) and the reflux temperature of the reaction medium, in C1- C4 to a lower alcohol (preferably methanol) in the presence of a metal alcoholate (preferably magnesium methylate or sodium methylate).