JPH0753747B2 - β-D-phenylthioxyloside, its preparation method and use as a medicine - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention is a novel industrial product, β-D-phenylthioxyloside (β-D-phenylthion, represented by the following structural formula.
ioxyloside). The invention further relates to the process for its preparation and its therapeutic use as antithrombotic agents, in particular antivenous thrombotic agents.

Benzoylphenyloside and α-hydroxybenzylphenyloside derivatives are used as ulcer therapeutic agents, platelet aggregation inhibitors, antithrombotic agents, or cerebral oxygenation agents (ce
The use as rebral oxygenators) is known from European patent B-0051023. Also, European patent A
-0133103 is a hypocholesterolemic drug (hypocholestero
benzylics) or benzylphenylosides effective as hypolipidemics have been disclosed. Certain of the compounds disclosed herein, particularly the product of Example 1, are also effective as antithrombotic agents.

It was found that the β-D-phenylthioxyloside compound of the present invention, which has a structure different from that of conventional substances, can be used as a drug for treating and preventing diseases of the circulatory system, particularly as an anti-venous thrombosis drug.

It was a surprising fact that the compounds of this invention have a far superior antithrombotic effect compared to conventional compounds (see results of comparative tests in Table I below).

The substance of this invention is selected from the group consisting of the following compounds. That is, (i) a compound represented by the structural formula I below. (In the above structural formula I, R ₁ and R _{2 each} represent a hydrogen atom, a trifluoromethyl group or a cyan group, and they may be the same or different, and A is CHOH group or CO group, Y represents a hydrogen atom or an acyl group), and (ii) an epimer of the above compound when A is CHOH.

β-D-thioxylose res
The hydroxyl group of (idue) can be acylated, especially acetylated. Therefore, among the derivatives of the compound represented by the structural formula I, those in which the hydroxyl group of the β-D-thioxylose residue is acylated, particularly acetylated, are also within the scope of the present invention.

Acyl groups suitable for this invention include aliphatic groups containing a total of 2-5 carbon atoms. As an aliphatic group
CH ₃ CO are preferred.

The compound represented by the above structural formula I and the corresponding acylated compound have a glycosidation reaction.
action). The method of this reaction is: (i) The following structural formula II (Wherein A, R ₁ and R ₂ represent the same as described above) and a compound of the following structural formula II
I, IV, (Wherein Hal represents a halogen atom such as Cl or Br (a preferred halogen atom is a bromine atom), Y is an acyl group, particularly an aliphatic acyl group containing a total of 2 to 5 carbon atoms, and preferably A thioxylose derivative selected from the group consisting of a halogenoacylthioxiroside represented by (representing an acetyl group) and an acylthioxyloside in the presence of an acid acceptor or a Lewis acid in an inert solvent. , A thioxylose derivative is reacted at a ratio of about 1.1-1.2 mol to 1 mol of the compound of structural formula II, and (ii) if necessary, between room temperature (15-20 ° C.) and the reflux temperature of the reaction medium. The deacylation reaction is carried out in the presence of a metal alcoholate (preferably magnesium methylate or sodium methylate) in a C1-C4 lower alcohol (preferably methanol) at a temperature. There, Y to obtain a derivative of formula I is H.

In the case of such a method, it is important that the compound of structural formula III has an α configuration in the step (i). On the other hand, the compound of structural formula IV may be in the α configuration, the β configuration, or a mixture of the two.

The acylated or non-acylated compound represented by the structural formula I in which A is CHOH can also be obtained by reducing the compound of the structural formula I (acylated or non-acylated compound) in which A is CO by a known method. To be

Further, the acylated or non-acylated compound represented by the structural formula I in which A is CHOH can be obtained by oxidizing a compound of the structural formula I in which A is CO (a non-acylated compound during acylation) by a known method. Can also be obtained.

Although there are several glycosidation methods known to those skilled in the art, it is preferable to use the following method.

・ KOENIGS-KNORR method (The Carbohydrates, Chemistry and Biochemis published in New York and London)
try ”, Second Edition, Academic Press (1972), Volume IA, 295-
HELFERICH method (described on pages 292 to 294 of the above-mentioned document) In the present invention, the glycosidation reaction is carried out by using either of the above methods, and the phenol is replaced with thiophenol.

The best way to carry out the invention is about 1.1-
1.2 moles of halogenoacylthiooxiroside III and 1 mole of thiophenyl II are combined with an inert polar and non-polar solvent (eg dimethylformamide, tetrahydrofuran,
Dioxane, acetonitrile, nitromethane, benzene, toluene, xylene, and mixtures of the above)
It is desirable to condense in the presence of mercuric cyanide in a more selected inert solvent.

In addition, 2,3,4-tri-O-acetyl-1-bromo-α-
D-5-thioxylopyranoside was added in the presence of 1.1-1.3 mol of mercuric cyanide at a temperature between 0 ° C. and the reflux temperature of the reaction medium, preferably at about 40 ° -50 ° C. A temperature in the range is preferably used for 1 to 4 hours, preferably about 2 hours.

In all cases, the glycosidation reaction resulted in a mixture of isomers of varying α and β configurations.

Isomers of the β configuration are known to those skilled in the art, such as fractional crystallization and chromatography, especially flash chromatography (ie, WCSTILL et al., J. Org. Chem.
8), 42 (no. 14) 2923, chromatography on a silica column under pressure).

The reduction reaction for preparing an acylated or non-acylated compound represented by the structural formula I in which A is CHOH from a corresponding compound in which A is CO is ether, tetrahydrofuran, a lower alcohol (especially methanol or ethanol). A conventional reagent dissolved in an inert solvent such as, for example, a metal hydride such as LiAlH ₄ , KBH ₄ or NaBH ₄ is used.
1-12 at temperatures ranging from ℃ to room temperature (15 ° -25 ° C)
Do on time. NaBH ₄ is preferred as the metal hydride. Also, this reaction is preferably carried out in methanol at a temperature of 20 ° C.

The derivative thus obtained is subjected to deacylation, especially deacetylation, if necessary. Such a treatment is carried out in a C1-C4 lower alcohol in the presence of the corresponding metal alcoholate at a temperature between room temperature and the reflux temperature of the reaction medium. Methanol is preferably used as the lower alcohol, and sodium methanolate or magnesium methanolate is preferably used as the metal alcoholate.

The deacylation and reduction reactions (especially when CO is converted to CHOH) may be continuously performed without separating the intermediate compound generated in the middle.

To prepare the thiophenol represented by Structural Formula II, (a) Dimethylaminothiocarbamoyl chloride represented by
The following structural formula VI (However, in this formula, the meanings of A, R ₁ and R ₂ are the same as above.) Condensed with a phenol in a strongly basic medium to give the following structural formula VII: (In the formula, the meanings of A, R ₁ and R ₂ are the same as above), (b) the obtained compound represented by the structural formula VII is heated by Newmann rearrangement (J.Org.Chem). . (1966) 31, p. 3980)
The following structural formula VIII (In the formula, the meanings of A, R ₁ and R ₂ are the same as above), and (c) the obtained compound represented by the structural formula VIII is converted into C1-C
Treatment with a metal alcoholate, preferably sodium methanolate or magnesium methanolate, in a lower alcohol of 4, provides the thiophenol of structural formula II.

The compounds represented by Structural Formula II are all novel compounds except that R ₁ and R ₂ are both hydrogen atoms.

The compounds represented by Structural Formula VI are all novel compounds except those in which R ₁ is a hydrogen atom and R ₂ is a hydrogen atom or a cyano group.

The compounds represented by Structural Formulas VII and VIII are all novel compounds.

The therapeutic composition of the present invention contains at least one compound selected from the group consisting of the product represented by structural formula I and its epimer together with a physiologically harmless excipient. It goes without saying that the amount of the active ingredient contained in this type of composition is such that a therapeutic effect can be expected.

The compound represented by Structural Formula I can be used therapeutically as an antithrombotic agent, and is particularly effective for the prevention and treatment of venous circulation disorders.

The compounds of structural formula I according to the invention and their epimers are preferably used for the preparation of antithrombotic agents for the treatment of venous circulatory disorders.

Other features and advantages of the present invention will be apparent from the following description of preparation examples and the results of pharmacological tests. These preparation examples do not limit the scope of the present invention, but are merely shown as specific examples.

Preparation Example I Preparation of (2-benzoyl-4-cyanophenyl) -1,5-dithio-β-D-xylopyranoside I a) Preparation of O- (2-benzoyl-4-cyanophenyl) dimethylthiocarbamate 24 g (0.107) Mol) 3-benzoyl-4-hydroxybenzonitrile in 240 cm ³ of acetone, then 240 cm ³
Water and 7.2 g (0.121 mol) of potassium hydroxide pellets were sequentially added. After stirring the mixture thus obtained for 15 minutes, 16.5 g (0.121 mol) of dimethylthiocarbamoyl chloride solution in 40 cm ³ of acetone as a solvent were added. The emulsion thus obtained was stirred at room temperature for 3 hours.
The resulting mixture was decanted. 200 cm ^{3 to} this
After adding water, the aqueous phase was extracted with ethyl acetate.
The organic phase thus obtained was combined with saturated sodium chloride solution, then washed with the same solution, dried over magnesium sulphate and evaporated under reduced pressure. Part of the resulting product (23 g) crystallized spontaneously. It was evaporated to dryness and then washed with ether to give 8 g of product.

31 g of the desired product was finally obtained (yield: 90%).

Melting point = 92 ° C. I b) Preparation of S- (2-benzoyl-4-cyanophenyl) dimethyl-thiocarbamate O- (2-benzoyl-4-cyanophenyl) dimethylthiocarbamate 10 g (obtained in the above Preparation Example Ia) 0.032 mol) was heated at 200 ° C. for 30 minutes in an argon atmosphere with stirring.

10 g of the oily desired product were obtained (yield: 100%) n _D ^{28.5 ° C.} = 1.6122 I c) Preparation of 3-benzoyl-4-mercaptobenzonitrile S- (2-benzoyl-4) thus obtained -Cyanophenyl) dimethylthiocarbamate 10 g (0.032 mol)
It was dissolved in 100 cm ³ of methanol. After cooling the resulting green solution to 0 ° C., 19.3 cm ³ of sodium methylate (ratio of sodium in methanol 8% w /
v) was dropped (color changed to red). The reaction medium was stirred at room temperature for 3 hours and then hydrolyzed with a 1N aqueous hydrochloric acid solution. The desired product was extracted with ethyl acetate. Sodium hydroxide solution was added to the organic phase thus obtained, the aqueous phase was acidified and extracted with ethyl acetate. The resulting organic phase was washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated under vacuum. The crystals thus obtained were washed with hexane and ether to obtain 6 g (yield: 80%) of the desired product as white crystals.

Melting point = 84 ° C. I d) (2-benzoyl-4-cyanophenyl)-
Preparation of 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 1a) 8.16 g (0.024 mol) of 2,3,4-tri-O-acetyl-1
-Bromo-5-thio-α-D-xylopyranoside, 5 g (0.0205 mol) of 3-benzoyl-4-mercaptobenzonitrile obtained in Preparation Example 1c, and 5.8 g (0.023 mol) of mercuric cyanide. 20 g of 0.4 nm molecular sieve (E.ME
RCK) and 125 cm ³ of benzene and 125 cm ³ of nitromethane were sequentially added to the mixture. After the thus obtained reaction medium was stirred for 4 hours at room temperature and filtered Celite ^R (i.e. diatomaceous silica for filtration). The residue was washed several times with ethyl acetate. The organic phase thus obtained was washed successively with 1N hydrochloric acid solution, 1N sodium hydroxide solution and saturated sodium chloride solution, then dried over magnesium sulphate and evaporated under reduced pressure. The oil thus obtained was purified by flash chromatography using a toluene / ethyl acetate mixture (8/2, v / v) as eluent.

9 g of the oily desired product was obtained (yield: 75%). The product crystallized when ethanol was added. The crystals obtained were recrystallized from ether.

In this way, 5.38 g (yield: 46%) of the desired product was obtained.

Melting point = 173 ° C. [α] _D ^{20 ° C.} = + 34.9 ° (c = 0.53; CHCl ₃ ) I e) (2-benzoyl-4-cyanophenyl) 1,
Preparation of 5-dithio-β-D-xylopyranoside (Example 1) (2-benzoyl-4-cyanophenyl) -2,3,4-tri-O-acetyl-1,5-dithio obtained in Preparation Example Id. -Β
The -D- xylopyranoside 4g (0.0078 mol) was dissolved in methanol 80 cm ³ in an argon atmosphere. After cooling this solution to 0 ° C, 0.2 cm ³ of sodium methylate (sodium in methanol 10% w / v solution)
Was added. After the thus obtained mixture was stirred for 1 hour at room temperature and neutralized with Amberlite ^R IR120H ₊ resin. After filtration, the solvent of this solution was evaporated under reduced pressure to obtain 2.9 g of the desired product (yield: 70%).

Melting point = 100 ° C. [α] _D ^{22 ° C.} = + 72 ° C. (c = 0.52; CH ₃ OH) Preparation Example II (4-cyano-2-phenylhydroxymethylphenyl) -1,5-dithio-β-D-xylopyranoside ( Preparation of Example 2) 1 g of (2-benzoyl-4-cyanophenyl) -1,5-dithio-β-D-xylopyranoside obtained in Preparation Example Ie
A mixture of (0.026 mol) and 10 cm ³ of methanol at 0 ° C.
It was cooled to and 0.11 g (0.00284 mol) of NaBH ₄ was added. After the resulting reaction mixture was stirred for 45 min at 0 ° C., it was neutralized with Amberlite ^R IR120 ₊ resin. After filtration, the solvent was evaporated under reduced pressure. It is then purified by flash chromatography using a chloroform / methanol mixture as eluent to give 1 g of the expected product.
(Quantitative yield) was obtained.

Melting point = 98 ° to 100 ° C. [α] _D ^{22 ° C.} = + 30.3 ° C. (c = 0.52; CH ₃ OH) Preparation Example III (2-benzoylphenyl) -1,5-dithio-β-D-
Preparation of xylopyranoside III a) Preparation of O- (2-benzoylphenyl) dimethylthiocarbamate Starting from 9.5 g (0.048 mol) of 2-hydroxyphenylmethanone and 10.3 g (0.083 mol) of dimethylthiocarbamoyl chloride, The desired product was obtained in the same manner as in Preparation Example Ia.
11.2 g was obtained (yield: 82%).

Melting point = 98 ° C. III b) Preparation of S- (2-benzoylphenyl) dimethylthiocarbamate The O- (2 obtained in Preparation IIIa was prepared in the same manner as in Preparation Ib.
-Benzoylphenyl) dimethylthiocarbamate 9g
After purification by flash chromatography starting from (0.031 mol) with a toluene / ethyl acetate mixture as eluent, 1.8 g of the expected product is obtained as an oil.

n _D ^{32 ° C.} = 1.6142 III c) Preparation of 2-mercaptophenyl phenylmethanone Using 1.8 g of S- (2-benzoylphenyl) dimethylthiocarbamate, the desired product (1 g, yield) was obtained in the same manner as in Preparation Example Ic. Rate: 74%).

III d) Preparation of (2-benzoylphenyl) -2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 3a) 1.03 g (0.0048 mol) 2-mercaptophenyl Phenylmethanone and 1.29 g (0.0034 mol) of 2,3,4-tri-
Starting from O-acetyl-1-bromo-5-dithio-α-D-xylopyranoside and 1.28 g (0.0051 mol) mercuric cyanide, the methyl acetate / toluene mixture was prepared in the same manner as in Preparation Id. (1/9, v / v) was used as the eluent,
Purification by flash chromatography gave 0.16 g (yield: 6%) of the desired product.

Melting point = 188 ° C. [α] _D ^{23 ° C.} = + 34 ° C. (c = 0.2; CH ₃ OH) III e) Preparation of (2-benzoylphenyl) -1,5-dithio-β-D-xylopyranoside (Example 3) Preparation (2-benzoylphenyl) -2, obtained in Example IIIa,
0.150 g (3.06 × 10 ⁻⁴ mol) of 3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside and 2 ml of sodium methylate (the proportion of sodium in methanol is 8% w / v)) and purified by flash chromatography using a methanol / chloroform mixture (5/96, v / v) as eluent to give the desired product.
0.090 g (yield: 85%) was obtained.

Melting point = 82 ° to 84 ° C. [α] _D ^{20 ° C.} = + 47.5 ° (c = 0.225; CH ₃ OH) Preparation Example IV (2- (4-cyanobenzoyl) phenyl) -1,5-dithio-β- Preparation of D-xylopyranoside IV a) Preparation of 4- (2-methoxybenzoyl) benzonitrile 6.15 ml (0.049 mol) 2-bromoanisole in 1.8 g (0.0074 mol) magnesium in 3 ml anhydrous tetrahydrofuran. It was added dropwise. After stirring for 20 minutes, the mixture solidified. After dilution (adding 20 ml of tetrahydrofuran), the reaction medium obtained was added dropwise to a mixture of 8.18 g (0.0496 mol) of 4-cyanobenzoyl chloride in 30 ml of anhydrous tetrahydrofuran kept at -25 ° C. The reaction medium is then heated to room temperature and then hydrolyzed with a mixture of concentrated hydrochloric acid and ice and the desired product is extracted with an ethyl acetate / ether mixture. Petroleum ether was added to the precipitate to precipitate it.
(Yield: 82%) was obtained.

Melting point = 92 ° to 94 ° C. IV b) Preparation of 4- (2-hydroxybenzoyl) benzonitrile 4- (2-methoxybenzoyl) obtained in Preparation Example IVa
Benzonitrile 6g (0.0253mol) and pyridinium chloride
A mixture with 17.53 g (0.151 mol) was heated at 220 ° C. for 12 hours. After hydrolysis of the reaction medium, the desired product was extracted with ethyl acetate. The organic phase was washed with a 1N aqueous hydrochloric acid solution and a concentrated solution of NaCl and then dried over magnesium sulphate, then ethyl acetate was evaporated under reduced pressure.
An ethyl acetate / ether mixture was added to the oily product thus obtained. The precipitate was removed and the filtrate was concentrated.
The filtrate was precipitated with ether to obtain 2.65 g of the desired product (yield: 47%).

Melting point = 116 ° C. IV c) Preparation of 0-2- (4-cyanobenzoyl) phenyl dimethylthiocarbamate The 4- (2-hydroxybenzoyl) benzonitrile obtained in Preparation IVb was treated with 150 cm ³ of water and 100 cm ³ of Suspend in a mixture of acetone, add 4.15 g (0.0735 mol) of potassium hydroxide to it, and add 50 parts of the resulting reaction medium.
Heated and stirred for 20 minutes at 0 ° C (red color appeared when completely dissolved). The solution thus obtained was cooled to 0 ° C. and then 9.14 g (0.074 mol) of a solution of dimethylthiocarbamoyl chloride in 80 ml of acetone as a solvent was added thereto, and the resulting mixture was stirred at room temperature for 3 hours. . The reaction medium is hydrolyzed. The precipitate thus formed is filtered,
Ground in ether. 17.4 g (yield: 84%) of the desired product (beige solid) was obtained.

Melting point = 156 ° -157 ° C. IV d) Preparation of S-2- (4-cyanobenzoyl) phenyl dimethylthiocarbamate 2-2 g (0.0064) of 0-2- (4-cyanobenzoyl) phenyl dimethylthiocarbamate obtained in Preparation Example IVc Mol) in the same manner as in Preparation Ib, toluene /
Purification by flash chromatography using a mixture of ethyl acetate (99/1, v / v) as eluent gave 1.35 g (yield: 45%) of the desired product.

IV e) Preparation of 4- (2-mercaptobenzoyl) benzonitrile Starting from 2.25 g (0.00725 mol) O-2- (4-cyanobenzoyl) phenyl dimethylthiocarbamate, acetic acid was prepared in the same manner as in Preparation Ic. Purification by flash chromatography using ethyl / hexane mixture (1/6, v / v) as eluent gave the desired product.

Melting point = 98 ° to 100 ° C IV f) (2- (4-cyanobenzoyl) phenyl)
-2,3,4-tri-O-acetyl-1,5-dithio-β-D-
Preparation of xylopyranoside (Example 4a) 1.54 g (0.00643 mol) 4- (2-mercaptobenzoyl) benzonitrile and 3.7 g (0.010 mol) 2,3,4-tri-O-acetyl-1-bromo-5. Starting from -thio-α-D-xylopyranoside and 2.526 g (0.010 mol) mercuric cyanide Hg (CN) ₂ , the ethyl acetate / toluene mixture (1/12 , V / v) as the eluent, followed by precipitation in methanol to give 0.4 g (yield: 12%) of the desired product.

Melting point = 160 ° C. [α] _D ^{22 ° C.} = − 2.4 ° (c = 0.5; CHCl ₃ ) IV g) (2- (4-cyanobenzoyl) phenyl)
Preparation of -1,5-dithio-β-D-xylopyranoside (Example 4) Obtained in Preparation Example IVf (2- (4-cyanobenzoyl)
Phenyl) -2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside starting from 0.36 g (0.00070 mol) in the same manner as in Preparation Ie, methanol / chloroform mixture ( 0.15 g of the expected product by purification by flash chromatography using 1/25, v / v) as eluent and then precipitation in methanol.
(Yield: 63%) was obtained.

Melting point: 154 ° to 155 ° C. [α] _D ^{20 ° C.} = + 33.4 ° (c = 0.1; CH ₃ OH) Preparation Example V (2- (4-cyanophenylhydroxymethyl) phenyl) -1,5-dithio- Preparation of β-D-xylopyranoside (Example 5) 450 mg (0.00087 mol) of (2- (4-cyanobenzoyl) phenyl) -2,3,4-using 5 ml of methanol as solvent.
To the tri-O-acetyl-1,5-dithio-β-D-xylopyranoside solution was added 0.2 ml sodium methylate (8% w / v sodium in methanol solution). After deacetylation, chromatography was carried out using a chloroform / ethanol mixture (9/1, v / v) as eluent. After the completion of deacetylation, 0.050 g (0.0013 mol) of sodium borohydride (NaBH ₄ ) was added to the reaction medium kept at 0 ° C. The resulting mixture is A
It was neutralized with mberlite ^R IR120H ⁺ resin. It is filtered and the solvent evaporated under reduced pressure to give the desired product 0.06
Got 5g.

Melting point = 85 ° to 95 ° C. [α] _D ^{20 ° C.} = + 12.5 ° (c = 0.12; CHCl ₃ ) Preparation Example VI (2- (3-cyanobenzoyl) phenyl) -1,5-dithio-β-D -Preparation of xylopyranoside VI a) 3- (2-Methoxybenzoyl) benzonitrile 30 g (0.16 mol) 2-bromoanisole, 3.85 g (0.16 mol) magnesium containing iodine crystals 0.7 g.
Drop into 5 ml anhydrous tetrahydrofuran. The reaction mixture is refluxed for 1 hour. The resulting solution was added dropwise to a solution of 26.48 g (0.16 mol) of 3-cyanobenzoyl chloride in anhydrous tetrahydrofuran,
Cool to 75 ° C. The temperature is raised to 20 ° C. and the reaction medium is hydrolyzed with a 1N aqueous solution of hydrochloric acid. Then the desired product is extracted with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulphate and then evaporated under reduced pressure. 30 g (yield: 80
%) Obtained.

Melting point = 180 ° C. VI b) Preparation of 3- (2-hydroxybenzoyl) benzonitrile 16 g (0.0675 mol) 3- (2-methoxybenzoyl)
A mixture of benzonitrile and 50 g (0.43 mol) of pyridinium chloride is heated at 180 ° C. for 12 hours, the reaction mixture is cooled to 140 ° C. and hydrolyzed with an ice / concentrated hydrochloric acid mixture. After stirring for 15 hours, the desired product is extracted with ethyl acetate. The organic phase obtained is washed with water and then with brine (NaCl
Saturated aqueous solution) until the pH is neutral, dried over magnesium sulphate and evaporated under reduced pressure. The oil formed is purified on silica using a toluene / ethyl acetate mixture as eluent. After evaporating the solvent from the eluate, 8.5 g of a yellow solid was obtained (yield 60
%).

Melting point = 100 ° C. VI c) Preparation of 0-2- (3-cyanobenzoyl) phenyl dimethylthiocarbamate According to the procedure described in Preparation Ia 3 obtained in Preparation VIb
-(2-Hydroxybenzoyl) benzonitrile 8.5g
Starting from (0.038 mol), 2.56 g (0.0046 mol) potassium hydroxide and 5.65 g (0.046 mol) dimethylthiocarbamoyl chloride, 11 g of the desired product was obtained (94% yield).

Melting point = 90 ° C. VI d) Preparation of S-2- (3-cyanobenzoyl) phenyl dimethylthiocarbamate Starting from 7 g (0.0226 mol) of O-2- (3-cyanobenzoyl) phenyl dimethylthiocarbamate according to Preparation Example Ib. After purification by flash chromatography using a toluene / ethyl acetate mixture (90/2, v / v) as eluent, 4.2 g (60% yield) of the desired product are obtained.
%)Obtained.

Melting point = 86 ° C. VI e) Preparation of 3- (2-mercaptobenzoyl) benzonitrile Following the procedure described in Preparation Ic, the S-obtained in Preparation VId
Chromatography on a silica column starting with 3.3 g (0.0106 mol) of 2- (3-cyanobenzoyl) phenyl dimethylthiocarbamate and using a toluene / ethyl acetate mixture (85/15, v / v) as eluent. After purification, 1.29 g (yield 51%) of the desired product was obtained in total. It had NMR characteristics.

VI f) (2- (3-cyanobenzoyl) phenyl)-
Preparation of 2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 6a) According to the procedure described in Preparation Id, 3 obtained in Preparation VIe
-(2-Mercaptobenzoyl) benzonitrile 0.300g
After starting from (0.0012 mol), a total of 0.200 g was obtained after purification by flash chromatography using a toluene / ethyl acetate mixture (8/2, v / v) as eluent, followed by crystallization from ethyl ether. The desired product was obtained (yield 35%).

Melting point = 140 ° C. [α] _D ^{20 ° C.} = + 21 ° C. (c = 0.24; CH ₃ OH) VI g) (2- (3-cyanobenzoyl) phenyl)
Preparation of -1,5-dithio-β-D-xylopyranoside (Example 6) According to the procedure described in Preparation Example Ie, the compound was obtained in Preparation Example VIf (2-
(3-Cyanobenzoyl) phenyl) -2,3,4-tri-
Starting from 0.200 g (0.00039 mol) of O-acetyl-1,5-dithio-β-D-xylopyranoside, a total of 0.105 g of the desired product (yield 70%) is used as the eluent in a chloroform / methanol mixture (95 / 5, v / v) was obtained after purification by flash chromatography.

Melting point = 70 ° to 83 ° C. [α] _D ^{20 ° C.} = + 25.16 ° C. (c = 0.15; CH ₃ OH) Preparation Example VII (2- (3-cyanophenylhydroxymethyl) phenyl) -1,5-dithio- β-D-xylopyranoside (Example 7)
Preparation of the compound obtained in Preparation Example VIg according to the procedure described in Preparation Example II (2-
(3-Cyanobenzoyl) phenyl) -1,5-dithio-
After purification by flash chromatography starting from 0.170 g (0.00033 mol) of β-D-xylopyranoside using a chloroform / methanol mixture as eluent, 0.070 g (60% yield) of the desired product is obtained.

Melting point = 57 ° -80 ° C. [α] _D ^{20 ° C.} = + 38.3 ° (c = 0.1; CH ₃ OH) Preparation Example VIII (2 (2-cyanobenzoyl) phenyl) -1,5-dithio-β-D -Preparation of xylopyranoside VIII a) Preparation of 2-bromophenyl 2-methoxyphenylmethanone Following the procedure described in Preparation VIa, 9.4 g (0.050 mol) of 2
Starting from -bromoanisole, 1.7 g (0.069 mol) magnesium and 11 g (0.050 mol) 2-bromobenzoyl chloride, after crystallization from ether, 9.6 g of the desired product (yield 66 %)Obtained.

Melting point = 68 ° C. VIII b) Preparation of 2-bromophenyl 2-hydroxyphenylmethanone 21 g (0.072 mol) of 2-bromophenyl 2-methoxyphenylmethanone obtained in Preparation Example VIIIa and 30 parts of hydrobromic acid
A mixture of 50 ml of a 50% strength aqueous solution and 50 ml of acetic acid is refluxed for 4 hours. The reaction mixture is hydrolyzed with ice and then extracted with ethyl acetate. The organic phase is washed with water until the pH is aqueous and then evaporated in vacuo. After crystallization from diisopropyl ether, the desired product was 6.4 g.
(Yield 85%) was obtained.

Melting point = 78 ° C. VIII c) Preparation of 2- (2-hydroxybenzoyl) benzonitrile 10.1 g (0.036 mol) of 2-bromophenyl 2-hydroxyphenylmethanone and 6.6 g (0.074 mol) of cuprous cyanide (CuCN) ) Is heated at 180 ° C. for 2 hours. The reaction medium formed was treated with 1N hydrochloric acid / ice mixture (50/10
0, v / v) and then extracted with ethyl acetate. The organic phase is washed with a 1N aqueous solution of hydrochloric acid and then with a saturated aqueous solution of NaCl, then with water until the pH is neutral, and then evaporated under reduced pressure. After purification by flash chromatography using a hexane / ethyl acetate mixture (5/1, v / v) as eluent, a total of 5.8 g of the desired product (yield 59
%) Obtained.

Melting point = 100 ° C. VIII d) O-2- (2-Cyanobenzoyl) phenyl dimethylthiocarbamate preparation In 200 ml of tetrahydrofuran, the 2-
(2-Hydroxybenzoyl) benzonitrile 6.7 g (0.
030) mol is added to the solution, 1 g (0.041 mol) of sodium hydride is added in small portions. The resulting mixture is stirred for 1 hour at 50 ° C. The reaction medium is cooled to room temperature and to this is added a solution of 4.6 g (0.037 mol) of dimethylthiocarbamoyl chloride in 50 ml of tetrahydrofuran. The resulting mixture was stirred for 3 hours at room temperature, then
Hydrolyze with an ice / water mixture. The extraction is carried out with ethyl acetate. The organic phase obtained is washed with water, dried over magnesium sulphate and evaporated under reduced pressure. After crystallization from ether, 6 g (yield 64.5%) of the desired product was obtained.

Melting point = 140 ° C. VIII e) Preparation of S-2- (2-cyanobenzoyl) phenyl dimethylthiocarbamate Following the procedure described in Preparation Ib, the O obtained in Preparation VIIId
2- (2-Cyanobenzoyl) phenyl dimethylthiocarbamate Starting from 6.5 g (0.021 mol), a toluene / ethyl acetate mixture (6/1, v
After purification by flash chromatography with (v / v) and crystallization from an ethyl acetate / ether mixture, 4.65 g (yield 68.5%) of the desired product was obtained in total.

Melting point = 130 ° C. VIII f) Preparation of 2- (2-mercaptobenzoyl) benzonitrile S following the procedure described in Preparation Ic and obtained in Preparation VIIIe.
After starting from 1 g (0.0032 mol) of 2- (2-cyanobenzoyl) phenyl dimethylthiocarbamate, 1.2 g (54.5% yield) of the desired product were obtained after purification by flash chromatography.

Melting point = 94 ° C. VIII g) (2- (2-cyanobenzoyl) phenyl) -2,3,4-tri-O-acetyl-1,5-dithio-β-
Preparation of D-xylopyranoside (Example 8a) Following the procedure described in Preparation Example Id, 1.2 g (0.0050 mol) of 2-
(2-mercaptobenzoyl) benzonitrile, 2.14
g (0.0060 mol) of 2,3,4-tri-O-acetyl-1-bromo-5-thio-α-D-xylopyranoside, 1.27 g
After crystallization from ether, starting with (0.0050 mol) mercuric cyanide (Hg (CN) ₂ ), the expected product is
1.4 g (yield 54.5%) was obtained.

Melting point = 210 ° C. [α] _D ^{20 ° C.} = + 51.4 ° C. (c = 0.3; CH ₃ OH) VIII h) (2- (2-cyanobenzoyl) phenyl) -1,5-dithio-β-D-xylopyranoside Preparation of (Example 8) According to the procedure described in Preparation Example Ie and obtained in Preparation Example VIIIg, (2- (2-cyanobenzoyl) phenyl) -2,3,4.
Starting from 0.500 g (0.00097 mol) of tri-O-acetyl-1,5-dithio-β-D-xylopyranoside, the desired product was obtained after crystallization from ether in a total of 0.250 g (yield 70%).

Melting point = 107 ° to 112 ° C. [α] _D ^{20 ° C.} = + 32.5 ° (c = 0.36; CH ₃ OH) Preparation Example IX (2- (4-cyanobenzoyl) -4-trifluoromethylphenyl) -1, Preparation of 5-dithio-β-D-xylopyranoside IX a) Preparation of 4- (2-methoxy-5-trifluoromethylbenzoyl) benzonitrile Following the procedure described in Preparation IVa, 1.85 g (0.076 mol)
2-bromo-4-trifluoromethylanisole,
1.86g (0.00765mol) magnesium and 8.45g (0.051mol)
Mol) 4-cyanobenzoyl chloride,
Toluene / ethyl acetate mixture (8/1, v / v) as eluent
After purification by flash chromatography using, a total of 12 g of the desired product was obtained (yield 77.5%).

Melting point = 88 ° C. IX b) Preparation of 4- (2-hydroxy-5-trifluoromethylbenzoyl) benzonitrile Following the procedure described in Preparation IVb, and 13.5 g (0.049 mol) of 4- (2-methoxy-). After purification by flash chromatography starting with 5-trifluoromethylbenzoyl) benzonitrile and 31 g (0.27 mol) of pyridinium chloride using a hexane / ethyl acetate mixture as eluent, 8.4 g of the expected product ( Yield 65%).

Melting point = 118 ° C. IX c) Preparation of O-2- (4-cyanobenzoyl-4-trifluoromethylphenyl dimethylthiocarbamate) According to the procedure described in Preparation IVc, 8 g (0.0274 mol) of 4
Hexane / ethyl acetate mixture starting from-(2-hydroxy-5-trifluoromethylbenzoyl) benzonitrile, 1.97 g (0.035 mol) potassium hydroxide and 4.1 g (0.033 mol) dimethylthiocarbamoyl chloride. After purification by flash chromatography using (5/1, v / v) as eluent, a total of 8.1 g of the desired product was obtained (yield 77.9%).

Melting point = 142 ° C. IX d) Preparation of S-2- (4-cyanobenzoyl) -4-trifluoromethylphenyl dimethylthiocarbimate According to the procedure described in Preparation Example IVd, 7.9 g (0.0185 mol) O-2. After starting from-(4-cyanobenzoyl) 4-trifluoromethylphenyl dimethylthiocarbamate and crystallizing from diisopropyl ether, 6.7 g (85% yield) of the desired product are obtained.

Melting point = 159 ° C. IX e) Preparation of 4- (2-mercapto-5-trifluoromethylbenzoyl) benzonitrile S-2- (4-obtained according to the procedure described in Preparation IVe and also in Preparation IX d Starting from cyanobenzoyl) -4-trifluoromethylphenyl dimethyl thiocarbamate, toluene / ethyl acetate mixture (9/1, v / v)
After purification by flash chromatography using as the eluent, 3.3 g of the expected product having NMR characteristics was obtained (yield 67%).

IX f) Preparation of (2- (4-cyanobenzoyl) -4-trifluoromethylphenyl-2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 9a) Following the procedure described for Example Id, 4-
3 g (0.0097 mol) of (2-mercapto-5-trifluoromethylbenzoyl) benzonitrile and 4.2 g (0.012) of 2,3,4-tri-O-acetyl-1-bromo-5-thio-α-D-xylopyranoside. Mol) and 2.5 g (0.0099 mol) of mercuric cyanide (Hg (CN) ₂ ) and crystallized from ether, 1.3 g of the expected product (yield: 22
%) Obtained.

Melting point = 210 ° C. [α] _D ^{20 ° C.} = + 6 ° C. (c = 0.25; CHCl ₃ ) IX g) (2- (4-cyanobenzoyl) -4-trifluoromethylphenyl) -1,5-dithio-β- Preparation of D-xylopytinoside (Example 9)) According to the procedure described in Preparation Ie, it was obtained in Preparation IXf (2-
(4-Cyanobenzoyl) -4-trifluoromethylphenyl-2,3,4-tri-O-acetyl-1,5-dithio-β
Starting from -D-xylopyranoside, methylene chloride /
After purification by flash chromatography using an acetic acid acetate mixture (8/2, v / v) as eluent, a total of 0.45 g of the desired product was obtained (yield 56%).

Melting point = 106 ° to 111 ° C. [α] _D ^{20 ° C.} = + 39.8 ° C. (c = 0.63; CH ₃ OH) Preparation Example X (2- (4-cyanophenylhydroxymethyl) -4-
Trifluoromethylphenyl) -1,5-dithio-β-D
-Preparation of xylopyranoside (Example 10) Following the procedure described in Preparation Example II and also prepared in Preparation Example IXg (2- (4-cyanobenzoyl) -4-trifluoromethylphenyl-1,5-dithio-β). -D-xylopyranoside 0.24 g (0.000527 mol) and 0.022 g (0.000579 mol)
After purification with flash chromatography starting from NaBH ₄ with chloroform / methanol mixture (95/5, v / v) as eluent, a total of 0.2 g of the desired product was obtained (yield 83 %).

Melting point = 76 ° -87 ° C. [α] _D ^{20 ° C.} = + 42.8 ° C. (c = 0.25; CH ₃ OH) The antithrombotic activity of the substances according to the invention was verified by the following experimental protocol for venous thrombosis.

Technique by WESSLER and others (J. Applied Physiol. 1959, p.
943-946), hypercoagulation
Make venous congestion underneath. Techniques by J.HAUPMAN and others (T
As in the case of hrombosis and Heamostasis 43 (2), 1980, p.118), as a hypercoagulant,
A solution of active factor X (Xa) supplied by Flow Laboratories is used (71 Knat physiological serum per 12.5 ml).

The test was performed using unfasted male Wistar rats. Rats weighed 250-280 g and were divided into groups of 10 animals. The test substance was administered orally as a suspension in PEG400. After this, thrombosis was induced for 4 hours, the resulting thrombus was removed, and the weight was measured.

The results are shown in Table I when the oral dose was 12.5 mg / kg. In addition, Table I also shows the results when the above-mentioned known substances were used.

The anti-venous thrombotic activity of the substances according to the invention is significantly better than that of the known substances.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Francois Bellamy France 21910 Thoron La Chapel Thoron Lallier Le Bassedex 11

Claims (1)

[Claims] (I) β-D-phenylthioxyloside having the following structural formula (wherein R ₁ and R ₂ may be the same or different, and each is a hydrogen atom or a trifluoromethyl group): Or represents a cyano group, A is a CHOH group or
Represents a CO group, Y represents a hydrogen atom or a C ₂ -C ₅ aliphatic acyl group), (Ii) an oside compound selected from the group consisting of an epimer of the above compound when A is CHOH;