FR2652353A1 - New benzopyran-2-one-ss-D-thioxylosides, process for preparing them and their therapeutic use - Google Patents

Abstract

The present invention relates, as new industrial products, to the benzopyran-2-one-ss-D-thioxylosides of formula: in which: - X represents a sulphur atom or an oxygen atom, - R1 and R2, which are identical or different, each represent a hydrogen atom, a C1-C4-alkyl group, a halogen atom, a trifluoromethyl group, a phenyl group, it being possible for R1 and R2, taken together, to form with the benzopyran-2-one group to which they are attached, a dibenzo[b,d]pyran-6-one group; and, - Y represents a hydrogen atom or an aliphatic acyl group. These compounds are useful in therapy especially as venous antithrombotic agents.

Description

The present invention relates, as new industrial products, to the compounds benzopyran-2-one-B-
D-thioxylosides of formula I below. It also relates to their method of preparation and their therapeutic use as antithrombotic agents, especially venous antithrombotics.

It has already been proposed in EP-B-0051023 derivatives of benzoyl-phenyl-osides and α-hydroxybenzyl-phenylosides as anti-ulcer agents, platelet anti-aggregators, antithrombotics and cerebral oxygenators.

Also known from EP-A-0133103 are benzyl-phenylosides useful as hypocholesterolemic and hypolipidemic agents, some of these compounds, in particular the product of Example 1, further having antithrombotic effects.

It has now been found that the benzopyran-2-one-ss-D-thioxyloside compounds according to the invention, which are structurally different from the products known from the prior art, are useful in the treatment and prevention of diseases related to circulatory disorders. , especially as venous antithrombotic agents.

The compounds according to the invention have, unexpectedly, antithrombotic properties much higher than those known products of the prior art, see for this purpose the results of the comparative tests recorded in Table I below.

dans laquelle
- X représente un atome de soufre ou un atome d' oxyène,
- R1 et Rz, identiques ou différents, représentent
chacun un atome d'hydrogène, un groupe alkyle en
C1-C4, un atome d'halogène, un groupe
trifluorométhyle, un groupe phényle, R1 et R2,
considérés ensemble, pouvant former avec le groupe
benzopyran-2-one auquel ils sont liés, un groupe
dibenzotb,d]pyran-6-one,
- les positions 5, 6, 7 et 8 représentent les
possibilités de liaison de l'atome X au cycle
benzopyran-2-one ; et,
- Y représente l'atome d'hydrogène ou un groupe
acyle aliphatique.The new products according to the invention are characterized in that they are chosen from the group consisting of benzopyran-2-one-BD-thioxylosides of formula

in which
X represents a sulfur atom or an oxygen atom,
- R1 and Rz, identical or different, represent
each a hydrogen atom, an alkyl group
C1-C4, a halogen atom, a group
trifluoromethyl, phenyl, R1 and R2,
considered together, able to form with the group
benzopyran-2-one to which they are linked, a group
dibenzotb, d] pyran-6-one,
positions 5, 6, 7 and 8 represent the
Possibilities of linking the atom X to the cycle
benzopyran-2-one; and,
Y represents the hydrogen atom or a group
aliphatic acyl.

Among the aliphatic acyl groups which are suitable according to the invention, there may be mentioned those which contain in total 2 to 5 carbon atoms, the preferred aliphatic acyl group being CH3CO.

By C1-C4 alkyl group is meant here a hydrocarbon radical, branched or linear, containing 1 to 4 carbon atoms, the preferred alkyl group being methyl.

By halogen atom is meant here the chlorine, fluorine and bromine atoms, the preferred halogen atom being the chlorine atom.

où X, Ri et R2 sont définis comme ci-dessus, avec un dérivé du thioxylose choisi parmi l'ensemble comprenant
(i) les halogénures d'acylthioxylosyle de formule

(ii) les thioxyloses peracylés de formule

et, (iii) les trichloracétimidates d'acylthioxylosyle de formule

dans lesquelles Hal représente un atome d'halogène tel que Cl ou Br (l'atome de brome étant ici l'atome d'halogène préféré) et Y représente un groupe acyle, notamment un groupe acyle aliphatique comprenant un nombre total d'atomes de carbone de 2 à 5 et de préférence le groupe acétyle, dans un solvant inerte, à raison de 1 mole de Il pour environ 0,6 à 1,2 moles de composé III, IV ou V > notamment en présence d'un accepteur d'acide et/ou d'un acide de Lewis, et, (ii) si nécessaire, on soumet le composé de formule I ainsi obtenu où Y est un groupe acyle en C2-C5 à une réaction de désacylation à une température comprise entre OgC et la température de reflux du milieu réactionnel, dans un alcool inférieur en Cl-C4 (de préférence le méthanol), en présence d'un alcoolate métallique (de préférence le méthylate de magnésium ou le méthylate de sodium, pour obtenir un composé de formule I où Y est H.The compounds of formula I and the corresponding acyl compounds can be prepared according to a glycosylation reaction characterized in that (i) a compound of formula

where X, R 1 and R 2 are defined as above, with a thioxylose derivative selected from the group consisting of
(i) acylthioxylosyl halides of the formula

(ii) peracyl thioxyloses of the formula

and, (iii) acylthioxylosyl trichloroacetimidates of the formula

in which Hal represents a halogen atom such as Cl or Br (the bromine atom being here the preferred halogen atom) and Y represents an acyl group, in particular an aliphatic acyl group comprising a total number of carbon of 2 to 5 and preferably the acetyl group, in an inert solvent, at a rate of 1 mole of II for about 0.6 to 1.2 moles of compound III, IV or V> especially in the presence of an acceptor d acid and / or a Lewis acid, and (ii) if necessary, subjecting the compound of formula I thus obtained wherein Y is a C 2 -C 5 acyl group to a deacylation reaction at a temperature between OgC and the reflux temperature of the reaction medium, in a C1-C4 lower alcohol (preferably methanol), in the presence of a metal alkoxide (preferably magnesium methoxide or sodium methoxide, to obtain a compound of formula Where Y is H.

Compounds III, IV and V may be of the α or β configuration or an anomeric mixture of the two configurations.

The glycosylation reactions of the compounds of formula II were conducted, either starting from compound III in the presence of a catalyst such as salts or oxides of silver, mercury or zinc, or starting from compound V in the presence of a Lewis acid, especially boron trifluoride etherate or zinc chloride, is also starting from compound IV in the presence of a Lewis acid.

According to a preferred embodiment of the invention, it is recommended to condense 1 mole of the compound of formula II with about 1.1 to 1.2 moles of acylthioxylosyl halide III in an inert solvent selected from polar solvents. or apolar (such as dimethylformamide, tetrahydrofuran, dioxane, acetonitrile, nitromethane, benzene, toluene, xylenes and mixtures thereof) in the presence of mercuric cyanide.

2,3,4-Tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide will advantageously be used in a benzene / nitromethane (1/1) v: v mixture, in the presence of 1.1 to 1.3 moles of mercuric cyanide, at a temperature between 0 G and the reflux temperature of the reaction medium, preferably at about 40-50 ° C, for 1 to 4 hours, preferably for about 2 hours.

According to a second preferred embodiment of the invention, it is recommended to condense 1 mole of the compound of formula II with about 1.1 to 1.2 moles of acylthioxylosyl halide III in an inert solvent (for example dichloromethane or acetonitrile) in the presence of silver imidazolate and zinc chloride.

2,3,4-Tri-O-acetyl-5-thio-D-xylopyranosyl bromide is advantageously used in dichloromethane or a dichloromethane / acetonitrile mixture in the presence of 1.5 to 1.7 moles of silver imidazolate and from 2 to 2.2 moles of zinc chloride, at a temperature between 0 ° C and the reflux temperature of the reaction medium, preferably at about 40-60 ° C, for 24 to 48 hours.

According to a third preferred embodiment of the invention, it is recommended to condense 1 mole of the compound of formula II with about 0.6 to 1 mole of acylthioxylosyl halide III in an inert solvent (such as toluene, for example). and / or acetonitrile) in the presence of zinc oxide.

2,3,4-Tri-O-acetyl-5-thio-D-xylopyranosyl bromide will advantageously be used in a toluene / acetonitrile mixture in the presence of 0.5 to 1.2 moles of zinc oxide. a temperature between room temperature and the reflux temperature of the reaction medium, preferably at about 40-60 ° C, for 18 to 48 hours.

According to a fourth preferred embodiment of the invention, it is recommended to condense 1 mole of the compound of formula II with about 1.1 to 1.3 moles of acylthioxylosyl trichloroacetimidate in an inert solvent (such as dichloromethane or acetonitrile) in the presence of boron trifluoride etherate or zinc chloride.

2,3,4-Tri-O-acetyl-5-thio-α-D-xylopyranosyl trichloroacetimidate in dichloromethane is advantageously used in the presence of 0.1 to 0.4 moles of boron trifluoride etherate. in solution in dichloromethane or acetonitrile, or in the presence of zinc chloride, at a temperature between 40 ° C and room temperature (15-253 ° C), preferably at about -20 ° C to 0 ° C, for 1 to 5 hours.

In all cases, the glycosylation reaction leads to a mixture of the isomers of configuration a and ss in variable proportions.

The configuration isomer ss is isolated according to methods known to those skilled in the art, such as fractional crystallization or chromatography, especially flash chromatography [i.e.

chromatography on a silica column and under pressure according to the technique described by WC STILL et al. in
J. Org. Chem. (li78), to (N14) 29231.

The derivatives obtained are subjected, where appropriate, to deacylation, more particularly to deacetylation, which is carried out at a temperature of between 0 ° C. and the reflux temperature of the reaction medium in a lower C 1 -C 4 alcohol, in the presence the corresponding metal alkoxide. Preferably, methanol is selected as lower alcohol and sodium or magnesium methanolate as metal alcoholate.

The deacylation reaction may optionally be conducted after glycosylation without isolating the intermediate acyl compound form.

The enzymatic deacylation reaction can also be carried out, for example by the action of porcine liver esterase.

sur un composé de formule

où R1 et Rz ont les significations indiquées ci-dessus, pour obtenir un composé de formule

où Rl et R2 ont les significations indiquées ci-dessus, (ii) soumettre le composé de formule VII ainsi obtenu à un réarrangement de Newmann (J. Org.Chem. (1966) l1, p 3980), par chauffage, pour obtenir un composé de formule

ou Ri et R2 ont les significations indiquées ci-dessus, (iii) traiter le composé de formule VIII ainsi obtenu par un alcoolate métallique, de préférence le méthanolate de sodium ou de magnésium, dans un alcool inférieur en Cl-C4, de préférence le méthanol, le diméthylformamide ou le dioxanne pour obtenir un composé de formule II où X = S.To access the intermediate compounds of formula II where X = S it is recommended (i) to condense, in a strong basic medium, dimethylamino-thiocarbamoyl chloride, of formula

on a compound of formula

where R1 and Rz have the meanings indicated above, to obtain a compound of formula

wherein R 1 and R 2 have the meanings indicated above, (ii) subjecting the compound of formula VII thus obtained to a rearrangement of Newmann (J.Org.Chem. (1966) 11, p 3980), by heating, to obtain a compound of formula

or R 1 and R 2 have the meanings indicated above, (iii) treating the compound of formula VIII thus obtained with a metal alkoxide, preferably sodium or magnesium methanolate, in a C 1 -C 4 lower alcohol, preferably methanol, dimethylformamide or dioxane to obtain a compound of formula II where X = S.

The intermediate compounds of formula II where X = S can also be obtained by nucleophilic substitution of an appropriate halobenzopyran-2-one compound according to the method described by L. TESTAFERRI in Tetrahedron
Letters Vol. 21 p. 3099-3100 (1980).

Intermediate compounds of formula II where X = S are novel compounds except 7-mercapto-3-phenyl-2H-1-benzopyran-2-one described in GB-A-1154272.

dans laquelle
- RI et RZ, identiques ou différents, représentent
chacun un atome d'hydrogène, un groupe alkyle en
Cl-C4, un atome d'halogène, un groupe
trifluorométhyle, un groupe phényle, à l'exception
du groupe 3-phényle quand R1 = H et le groupe SH
est lié en position 7, Ri et R2 considérés
ensemble, pouvant former avec le groupe
benzopyran-2-one auquel ils sont liés un groupe dibenzo(b,d]pyran-6-one,
- les positions 5, 6, 7 et 8 représentent les
possibilités de liaison de l'atome de soufre au
cycle benzopyran-2-one, constituent donc un des objets de l'invention.Compounds of formula

in which
- RI and RZ, identical or different, represent
each a hydrogen atom, an alkyl group
Cl-C4, a halogen atom, a group
trifluoromethyl, a phenyl group, with the exception
of the 3-phenyl group when R1 = H and the SH group
is bound in position 7, Ri and R2 considered
together, able to form with the group
benzopyran-2-one to which they are attached a dibenzo (b, d] pyran-6-one group,
positions 5, 6, 7 and 8 represent the
possibilities of bonding the sulfur atom to
benzopyran-2-one cycle, therefore constitute one of the objects of the invention.

The intermediate compounds of formula VIII are novel compounds.

dans laquelle
- R1 et R2, identiques ou différents, représentent
chacun un atome d'hydrogène, un groupe alkyle en
Ci-C4 , un atome d'halogène, un groupe
trifluorométhyle, un groupe phényle, R1 et R2
considérés ensemble, pouvant former avec le groupe
benzopyran-2-one auquel ils sont liés un groupe dibenzo[b,dlpyran-6-one,
- les positions 5, 6, 7 et 8 représentent les
possibilités de liaison de l'atome de soufre au
cycle benzopyran-2-one, constituent donc un des objets de l'invention.Compounds of formula

in which
- R1 and R2, identical or different, represent
each a hydrogen atom, an alkyl group
Ci-C4, a halogen atom, a group
trifluoromethyl, a phenyl group, R1 and R2
considered together, able to form with the group
benzopyran-2-one to which they are bonded a dibenzo [b, dlpyran-6-one group,
positions 5, 6, 7 and 8 represent the
possibilities of bonding the sulfur atom to
benzopyran-2-one cycle, therefore constitute one of the objects of the invention.

According to the invention, there is provided a therapeutic composition characterized in that it contains, in association with a physiologically acceptable excipient, at least one compound chosen from the group consisting of the products of formula I. Of course, in such a composition the active ingredient is involved in a therapeutically effective amount.

The compounds of formula I are therapeutically useful as antithrombotic agents. They are particularly useful in the prevention and treatment of disorders of the venous circulation.

According to the invention, it is recommended the use of a substance belonging to all the compounds of formula I for obtaining an antithrombotic drug for therapeutic use vis-à-vis disorders of the venous circulation.

Other characteristics and advantages of the invention will be better understood on reading which follows, examples of preparation, in no way limiting, given by way of illustration, and results of pharmacological tests.

In the following preparation examples, the compounds were named specifying the configuration a or ss when said configuration was determined.

When the configuration is not indicated, it means that the corresponding product is an anomeric mixture of the configurations a and ss in proportions which have not been determined.

PREPARATION I
Obtaining 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4tri-O-acethyl-5-thio-ss-D-xylopyranoside (Example la)
A suspension of 2.28 g (12.10 -3 mol) of 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one, 4.7 g (13.2.10-mol) of bromide of 2,3 , 4-tri-O-acetyl-5-thio-Dxylopyranosyl and 0.4 nm molecular sieve, in 125 ml of toluene and 120 ml of acetonitrile, is stirred, in the presence of 3.28 g (24.10- 3 mol) of zinc chloride and 4.2 g (14.10-3 mol) of silver imidazolate, protected from light, under an inert atmosphere. After heating at 55 ° C. for 24 hours, the reaction mixture on celite (ie diatomaceous silica for filtration) in ethyl acetate The filtrate is washed with 1N hydrochloric acid solution, 1N sodium hydroxide solution and then with a saturated solution of chloride of sodium, dried over magnesium sulfate and the solvents are evaporated under reduced pressure. After purification by chromatography on silica gel, eluting with a 1/6 (v / v) ethyl acetate / toluene mixture and precipitation in ether, 0.93 g (yield: 17%) of expected product.

Mp = 189 ° C [α] D 20 C = = 73.8 (c = 0.25, CHCl 3)
PREPARATION II
Obtaining 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 5-thio ss-D-xylopyranoside (Example 1)
To a solution of 0.45 g (0.97 mole) of 4-ethyl-2oxo-2H-1-benzopyran-7-yl 2,3,4-tir-O-acetyl-5-thio-ss-Dxylopyranoside in 5 ml of methanol, 60 μl of sodium methoxide (8% Na (w / v) in methanol) are added. After stirring for 24 h at room temperature, the reaction medium is neutralized by addition of AmberliteR IR 120H + resin, solubilized with tetrahydrofuran, filtered, treated with animal black.
The solvents are evaporated under reduced pressure and after lyophilization, 0.285 g (yield 87 x) of the expected product are obtained.

F = 192 C [α] D20 C = = -69 (c = 0.21 dimethylsulfoxide)
PREPARATION III
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-6-yl 2,3,4tri-O-acethyl-5-thio-ss-D-xylopyranoside (Example 2a)
According to the procedure described in Preparation I, starting from 7.93 g (45 × 10 -3 mol) of 6-hydroxy-4-methyl-2H-1-benzopyran-2-one, 10.65 g (30 × 10 -3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 8.30 g (60.10 -3 mol) of zinc chloride and 5.42 g (30.10-3 mol) of silver imidazolate in 250 ml of toluene and 250 ml of acetonitrile is obtained, after purification by chromatography on silica gel, eluting with a mixture of ethyl acetate / toluene 3/17 (v / v) and precipitation in ether 2.6 g (yield: 13%) of the expected product.

Mp = 179-184 C [+]; D20 C = -47.9 (c = 0.33, CHCl3)
PREPARATION IV
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-6-ylthiol-5 S-D-xylopyranoside (Example 2)
According to the procedure described in Preparation II, starting from 0.9 g (2.10 mole) of 4-methyl-2-oxo-2H-benzopyran-6-yl 2,3,4-tri-O-acetyl- 5-thio-BD-xylopyranoside and 150 μl of sodium methoxide (8%
Na (w / v) in methanol), in 10 ml of methanol for 30 minutes, after lyophilization, 550 mg (yield: 85%) of the expected product are obtained.

Mp = 109-113 ° C [α D C = -63.3 (c = 0.24 dimethylsulfoxide)
PREPARATION V
Obtaining 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5-thio-ss-D-xylopyranoside Example 3a)
According to the procedure described in Preparation I, starting from 1.3 g (5.6 × 10 -3 moles) of 7-hydroxy-4-trifluoromethyl-2H-1-benzopyran-2-one, 2.5 g (6 g. > 9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 1.55 g (11.2 · 10 -3 mol) of zinc chloride and 0.98 g (5.6 × 10 -3 moles) of silver imidazolate in 10 ml of toluene and 10 ml of acetonitrile give, after crystallization in ethanol, 560 mg (yield: 20%) of the expected product.

Mp 184
[α] D20 C = +29.2 (c = 0.5D, CHCl3
PREPARATION VI
Obtaining 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-ss-D-xylopyranoside (Example 3)
According to the procedure described in Preparation II, starting from 520 mg (1.10-3 mol) of 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O-acetyl-5 thio-ss
D-xylopyranoside and 60 μl of sodium methoxide (8% Na (w / w) in methanol) in 5 ml of methanol for 12 h, 150 mg (yield: 40%) are obtained after crystallization from methanol. the expected product.

Mp 210-213 ° C
[a] D2OC = + 34.1 (c = 0.5, CH3OH)
PREPARATION VII
Obetnion of 4-methyl-2-oxo-2H-1-benzopyran-8-yl 2,3,4tri-O-acetyl-5-thio-ss-D-xylopyranoside (Example 4a)
According to the procedure described in Preparation I, starting from 0.8 g (4.5 × 10 -3 mol) of 8-hydroxy-4-methyl-2H-1-benzopyran-2-one, 1.93 g (8, 2.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 24 g (9.1 × 10 -3 mol) of zinc chloride and 0.88 g ( 5.0 × 10 -mole) of silver imidazolate in 50 ml of toluene and 50 ml of acetonitrile are obtained after purification by chromatography on silica gel, eluting with a mixture of ethyl acetate / toluene. 7 (v / v), 500 mg (yield: 28%) of the expected product.

Mp = 220-223aC [α] D23 C = - 121.9 (c = 0.21, CHCl3)
PREPARATION VIII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-8-yl-5thio-ss-D-xylopyranoside (Example 4)
According to the procedure described in Preparation II, starting from 400 mg (0.89 × 10 -3 mole) of 4-methyl-2-oxo-2H-1-benzopyran-8-yl 2,3,4-tri-O 5-thio-ss-Dxylopyranoside and 60 μl of sodium methoxide (8%
Na (w / v) in methanol) in 12 ml of methanol for 4 h, 212 mg (yield: 74%) of the expected product are obtained after lyophilization.

F = 120-125 ° C [α] D 20 C = -16 (c = 0.12 dimethylsulfoxide)
PREPARATION Ix
Obtaining 2-oxo-4-propyl-2H-1-benzopyran-7-yl 2,3,4tri-O-acetyl-5-thio-ss-D-xylopyranoside
(example 5a)
According to the procedure described in Preparation I, starting from 410 mg (2.10 -3 moles) of 7-hydroxy-4-propyl-2H-1-benzopyran-2-one, 780 mg (2.2.10-mole) of 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 550 mg (4.10-3 mol) of zinc chloride and 350 mg (2.10-3 mol) of imidazolate of 50 ml of toluene and 50 ml of acetonitrile are obtained after purification by chromatography on silica gel, eluting with a 1/3 (v / v) ethyl acetate / hexane mixture and crystallization in a mixture. ethyl acetate / ether, 85 mg (yield: 9%) of the expected product.

Mp = 165-1674C [α] D20 C = - 71.2 (c = 0.11, CHCl3)
PREPARATION X
Obtaining 2-oxo-4-propyl-2H-1 thio-ss-D-xylopyranoside (Example 5)
According to the procedure described in Preparation II, starting from 1.5 g (3.1 × 10 -3 mol) of 2-oxo-4-propyl2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5-thio-ss-Dxylopyranoside and 270 μl of sodium methoxide (8%
Na (w / v) in methanol) in 15 ml of methanol, after lyophilization, 800 mg (yield 73%) of the expected product are obtained.

Mp = 192 C [α] D24 C = - 61.3 (c = 0.15 dimethylsulfoxide)
PREPARATION XI
Obtaining 2-oxo-2H-1-benzopyran-5-yl 2,3,4thio-O-acetyl-5-thio-ss-D-xylopyranoside (Example 6a)
According to the procedure described in Preparation I, starting from 740 mg (4.2 × 10 -3 mole) of 5-hydroxy-4-methyl-2H-1-benzopyran-2-one, 1.74 g (4.9 × 10 -3) mole) 2,3,4-tri-O -acetyl-5-thio-D-xylopyranosyl bromide, 1.16 g (8.5 × 10 -3 mole) zinc chloride and 800 mg (4.6 × 10 -3) mole) of silver imidazolate in 50 ml of toluene and 50 ml of acetonitrile, is obtained after purification by chromatography on silica gel, eluting with a 1/7 mixture of ethyl acetate / toluene (v / v). v) and precipitation in ether 150 mg (yield: 8%) of the expected product.

Mp = 167 C [α] D22 C = -81 (c = 0.15, CHCl3)
PREPARATION XII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-5-yl-5thio-ss-D-xylopyranoside (Example 6)
According to the procedure described in Preparation II, starting from 250 mg (0.55 × 10 -3 mole) of 4-methyl-2-oxo-2H-1-benzopyran-5-yl 2,3,4-tri-O- acetyl-5-thio-BD-xylopyranoside and 100 μl of sodium methoxide (8%
Na (w / v) in methanol) in 15 ml of methanol for 1 hour, 135 mg is obtained after freeze-drying.
(yield: 75%) of the expected product.

M.p. 184-188 ° C .;
[?] D23 C = -85.2 (c = 0.11 dimethylsulfoxide)
PREPARATION XIII
Obtaining 0- (4-methyl-2-dimethylthiocarbamate
To a suspension of 1 g (5.7 × 10 -3 moles) of 5-hydroxy-4-methyl-2H-1-benzopyran-2-one in 10 ml of water and 10 ml of acetone is added under an inert atmosphere. mg
(7.3.10-3 mol) of potassium hydroxide. After 10 minutes to
room temperature, added to 0 C, 770 mg
(6.2 × 10 -3 moles) dimethylthiocarbamoyl chloride in 10 ml acetone. Stirring is maintained for 2 hours at room temperature and after evaporation of acetone, the expected derivative is precipitated in water. 1.35 g is obtained (yield
90%) of the expected product.

Mp = 166-168 ° C .;
PREPARATION XIV
Obtaining S- (4-methyl-2oxo-2H-1-benzopyran-5-yl) dimethylthiocarbamate
A solution of 3.7 g (14.10 mol) of O- (4-methyl-2-oxo-2H-1-benzopyran-5-yl) dimethylthiocarbamate in 50 ml of 1,2,3,4-tetrahydronaphthalene is 220 = C for 14 hours. After cooling, the expected product is precipitated in ether. The crystals obtained are rinsed with cyclohexane and 2.95 g (80% yield) of the expected product are obtained.

F = 129 ° C
PREPARATION XV
Obtaining the methyl ester of 3- (2hydroxy-6- (dimethylamino-carbonylthio) phenyl) -2-butenoic acid
To a solution of 2 g (7.6 moles) of S- (4-methyl-2-oxo-2H-1-benzopyran-5-yl) dimethylthiocarbamate in 20 ml of methanol is added under an inert atmosphere. 4 ml of sodium methoxide (8%
Na (w / v) in methanol). After 4 hours at room temperature, the reaction medium is hydrolysed on an ice / hydrochloric acid mixture and the precipitate formed is filtered. 1.7 g (yield: 76%) of the expected product are obtained.

Mp = 152 ° C
PREPARATION XVI
Obtaining 7-mercapto-4-methyl-2H-1-benzopyran-2-one
To a solution of 1 g (3.4 × 10 -3 moles) of methyl ester of 3- (2-hydroxy-6- (dimethylamino-carbonylthio) phenyl) -2-butenoic acid in 10 ml of anhydrous dimethylformamide 4 ml of sodium methoxide (8% Na (w / v) in methanol) is added at 60 ° C.

After 6 hours at 60 ° C., the reaction medium is hydrolysed on a hydrochloric acid / ice mixture. 0.550 g (yield: 85%) of the expected product is obtained.

F = 136 C
PREPARATION XYII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-5-yl 2,3,4tri-O-acethyl-1,5-dithio-ss-D-xylopyranoside (Example 7a)
A suspension of 420 mg (2.2.10 -3 mole) of 5-mercapto-4-methyl-2H-1-benzopyran-2-one, 970 mg (2.7.10-mole) of 2,3,4-bromide tri-O-acetyl-5thio-D-xylopyranosyl, 550 mg (2.2.10 -3 mol) of mercuric cyanide and 0.4-nm molecular sieve in 50 ml of nitromethane and 50 ml of benzene is stirred with 45oC under inert atmosphere for 24 h. The reaction mixture is then filtered through
CeliteR in ethyl acetate. The filtrate is washed with 1N hydrochloric acid solution, 1N sodium hydroxide solution and then with a saturated solution of sodium chloride, dried over magnesium sulfate and evaporated under reduced pressure. After purification by chromatography on silica gel, elution is carried out using a 1/5 ethyl acetate / toluene (vZv) mixture and then precipitation in ether 250 mg (yield: 25%) of the expected product.

F = 187C [+ alpha] D22 C = + 34.5 (c = 0.11, CHCl3)
PREPARATION XVIII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-5-yl 1,5-dithio-s-D-xylopyranoside (Example 7)
According to the procedure described in Preparation II, starting from 210 mg (0.45 × 10 -3 mole) of 4-methyl-2-oxo-2-1-benzopyran-5-yl 2,3,4-tri-O-acethyl -1,5-dithio-ss-Dxylopyranoside and 100 l of sodium methoxide (8%
Na (w / v) in methanol), in 5 ml of methanol for 1 h, is obtained after crystallization from an ethanol / water mixture and then purification by chromatography on silica gel, eluting with a methanol / chloroform 1/12 (v / v) and lyophilization, 50 mg (yield: 33%) of the expected product.

Mp = 203 ° C [+ alpha] D = +28.3 (c = 0.12, CH3OH)
PREPARATION XIX
Obtaining O- (4-methyl-2oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate
To a suspension of 30 g (0.170 mol) of 7-hydroxy-4-methyl-2H-1-benzopyran-2-one in 400 ml of acetone / water 1/1 (v / v) is added 10, 5 g (0.187 mol) of potash in pellet and stirred for 30 minutes at room temperature. The reaction mixture is then brought back to ODC and a solution of 23.15 g (0.187 mol) of dimethylthiocarbamoyl chloride in 200 ml of acetone is added dropwise. The addition is complete, the reaction mixture is stirred for 2 hours at room temperature, then the acetone is evaporated under reduced pressure. After addition of water, the precipitate is filtered off and dried over
PzOs at 60 ° C. under reduced pressure. 42.1 g (yield: 94%) of the expected product are obtained.

Mp = 216 ° C
PREPARATION XX
Obtaining S- (4-methyl-2oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate
While stirring, 40 g (0.150 mole) of O- (4-methyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate are heated at 250 ° C. for 6 hours. The disappearance of the starting material is controlled by thin layer chromatography, eluting with a 4/1 (v / v) ethyl acetate / toluene mixture. After cooling, ethyl ether is added and the precipitate obtained is filtered off. 36.1 g (yield: 90%) of the expected product are obtained in the form of a yellow powder.

F = 154 C EBEPARATIOn XXI
Obtaining 7-mercapto-4-methyl-2H-1-benzopyran-2-one
Under a nitrogen atmosphere, 26.3 g (0.1 mol) of S- (4-methyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate are suspended in 300 ml of methanol. 0.2 mole of sodium methoxide (8% Na (w / v) solution in methanol) is added at ambient temperature and heated at 45 ° C. for 4 hours. The thin layer chromatography is monitored by eluting with a mixture of ethyl acetate / toluene 1/4 (v / v) the disappearance of the starting material. After cooling, the reaction medium is hydrolysed on an ice / concentrated hydrochloric acid mixture and after stirring for 30 minutes, the precipitate obtained is filtered and then washed with water. After drying on P 2 O 5, 19.2 g (yield t 100 is obtained. %) of the expected product.

Mp = 132 ° C
PREPARATION XXII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4tri-O-acethyl-1,5-dithio-ss-D-xylopyranoside (Example 8a)
A mixture of 8 g (41.6 × 10 -3 mole) of 7-mercapto-4-methyl-2H-1-benzopyran-2-one, 17.7 g (50 × 10 -3 mole) of 2,3,4-bromide, tri-O-acetyl-5-thio-α-D-xylopyranosyl and 3.4 g (42.10 -3 mole) of zinc oxide in 180 ml of toluene and 180 ml of acetonitrile is heated for 12 hours at 45 ° C. After filtration through CeliteR and washing the residue obtained with ethyl acetate, the organic phase is washed with a 1N hydrochloric acid solution, then with a 1N sodium hydroxide solution and finally with a saturated solution. sodium chloride. The organic phase obtained is dried over magnesium sulphate and evaporated under reduced pressure. 14.2 g (73% yield) of a yellow powder are obtained after precipitation by addition of ethyl ether.

F = 168 C [α] D22 C = + 46.4 (c = 0.7, CHCl3)
PREPARATION XXIII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-7-yl 1,5dithio-ss-D-xylopyranoside (Example 8)
According to the procedure described in Preparation II, starting from 7 g (15 × 10 -3 mol) of 4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O-acetyl-1 , 5-dithio-ss-Dxylopyranoside and 2.6 ml of sodium methylate (8% solution of Na (w / v) in methanol), 2 g of the expected product are obtained after recrystallization from methanol.

Mp = 216 ° C
[?] D23oc = + 19.4 (c = 0.3; dimethylsulfoxide)
PREPARATION XXIV
Obtaining O- (4-methyl-2oxo-2H-1-benzopyran-8-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 1.86 g (10.5 mmol) of 8-hydroxy-4-methyl-2H-1-benzopyran-2-one, of 0.76 g (11.5.10-mole) of potassium hydroxide. and 1.44 g (11.6 × 10 -3 mol) of dimethylthiocarbamoyl chloride give 2.5 g (yield: 90%) of the expected product.

F = 194 C
PREPARATION XXV
Obtaining S- (4-methyl-2oxo-2H-1-benzopyran-8-yl) dimethylthiocarbamate
According to the procedure described in Preparation XX, starting from 2.4 g (9.1 × 10 -3 mol) of 0- (4-methyl-2-oxo-2H-1-benzopyran-8-yl) dimethylthiocarbamate, 1.77 g (yield: 74%) of the expected product.

F = 154C
PREPARATION XXVI
Obtaining 8-mercapto-4-methyl-2H-1-benzopyran-2-one
According to the procedure described in the preparation
XXI, starting from 1.7 g (6.46 × 10 -3 mole) of S- (4-methyl-2-oxo-2H-1-benzopyran-8-yl) dimethylthiocarbamate and 0.013 mole of sodium methoxide ( 8% Na (w / v) solution in methanol) gives 1.13 g (yield: 91%) of the expected product.

F = 114-115 ° C
PREPARATION XXVII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-8-yl 2,3,4tri-O-acethyl-1,5-dithio-s-D-xylopyranoside (Example 9a)
A mixture of 1 g (5.2 × 10 -3 moles) of 8-mercapto-4-methyl-2H-1-benzopyran-2-one, 2.3 g
(6.5.10 moles) 2,3,4-tri-O-acetyl-5-diol-α-D-xylopyranosyl bromide and 1.3 g (5.2 × 10 -3 moles) mercuric cyanide in 16 ml of 1/1 (v / v) benzene / acetonitrile mixture is heated at 45 ° C. for 12 hours. The reaction medium obtained is then filtered through CeliteR (ie diatomaceous silica for filtration). The residue is washed several times with ethyl acetate. The organic phase collected is washed successively with an aqueous hydrochloric acid solution 1H, an aqueous solution of 1N sodium hydroxide, a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and then evaporated under reduced pressure. The product obtained is purified by "flash chromatography" eluting with a mixture of ethyl acetate / toluene (1/8) v / v, and then recrystallized from ethyl ether. 0.650 g (yield 27%) of the expected product is obtained.

F = 205 C [α] D23 C = 86.25 (c = 0.3, CHCl3) 4-methyl-2-oxo-2H-1-benzopyran-8-yl 1,6-dithio-s-D- xylopyranoside (Example 9)
According to the procedure described in Preparation II, starting from 0.466 g (0.9 × 10 -3 mole) of 4-methyl-2-oxo-2H-1-benzopyran-8-yl 2,3,4-tri-O -acetyl-1,5-dithio-ss-Dxylopyranoside and 60 μl of sodium methoxide (8% Na (w / v) solution in methanol). After lyophilization, 0.260 g (yield: 76%) of the expected product are obtained.

Mp = 178 ° C [α] D 23 ° C = - 61.5 (c = 0.2, dimethyl sulfoxide) PREPARATION XXIX
Obtaining O- (4-methyl-2-oxo-2H-1-benzopyran-6-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 30 g (0.170 mol) of 6-hydroxy-4-methyl-2H-1-benzopyran-2-one, 10.5 g (0.187 mol) of potassium hydroxide and 23.15 g (0.187 mol) of dimethylthiocarbamoyl chloride gives 41.7 g (93% yield) of the expected product.

Mp = 164 ° C
PREPARATION XXX
Obtaining S- (4-methyl-2oxo-2H-1-benzopyran-6-yl) dimethylthiocarbamate
According to the procedure described in Preparation XX, starting from 25 g (0.095 mole) of O- (4-methyl-2-oxo-2H-1-benzopyran-6-yl) dimethylthiocarbamate, 10.2 g are obtained. (yield: 41%) of the expected product.

F = 137C
PREPARATION XXXI
Obtaining 6-mercapto-4-methyl-2H-1-benzopyran-2-one
According to the procedure described in Preparation XXI, starting from 4.7 g (0.018 mol) of S- (4-methyl-2-oxo-2H-1-benzopyran-6-yl) dimethylthiocarbamate, 2 was obtained, 62 g (yield: 76%) of the expected product.

M.p. 138-140 ° C .;
PREPARATION XXXII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-6-yl 2,3,4tri-O-acethyl-1,5-dithio-ss-D-xylopyranoside (Example 10a)
According to the procedure described in the preparation
XXVII. from 2 g (10.4 × 10 -3 moles) of 6-mercapto-4-methyl-2H-1-benzopyran-2-one, 2.75 g (10.8.10-moles) of mercuric cyanide (Hg (CN)) 2) and 4.6 g (12.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, after crystallization from ethyl ether 0, 78 g (yield: 16%) of the expected product.

F = 139-140 ° C [α] D23 C = -66.13 (c = 0.3; CHCl3)
PREPARATION XXXIII
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-6-yl 1,5
According to the procedure described in Preparation II, starting from 0.466 g (0.001 mole) of 4-methyl-2-oxo-2H-benzopyran-6-yl 2,3,4-tri-O-1,5-acethyl -dithio-ss-Dxylopyranoside, 0.27 g (yield: 79%) of the expected product is obtained.

F = 182 C [α] D20 C = + 6.9 (c = 0.6, tetrahydrofuran)
PREPARATION XXXIV
Obtaining 0- (4trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 6 g (0.027 mol) of 7-hydroxy-4-trifluoromethyl-2H-1-benzopyran-2-one, 1.6 g (0.0285 mol) of potassium hydroxide and 3.54 g (0, 0286 mol) of dimethylthiocarbamoyl chloride, 7.0 g (yield: 85%) of the expected product are obtained.

F = 160 C
PREPARATION XXXV
Obtaining S- (4trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl) Dimethylthiocarbamate
A mixture of 7 g (0.022 mole) of O- (4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate and 10 ml of 1,2,3,4-tetrahydronaphthalene is heated to room temperature. 230 C for three hours. After cooling the reaction medium, ethyl ether is added.

The expected product crystallizes. After filtration, 5.2 g (yield: 75%) of the expected product are obtained.

F = 138 C
PREPARATION XXXVI
Obtaining 4-trifluoromethyl-7-mercapto-2H-1bezopyran-3-one
According to the procedure described in the preparation
XXI, starting from 4.7 g (14.8.10 mol) of S- (4-trifluoromethyl-2-oxo-2H-benzopyran-7-yl) dimethylthiocarbamate, 2.8 g (yield: 77%) is obtained. ) of the expected product.

F = 115bC
PREPARATION XXXVII
Obtaining 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O-acetyl-1,5-dithio-s-D-xylopyranoside (Example 11a)
According to the procedure described in the preparation
XXII, starting from 2.6 g (10.5 × 10 -3 mole) of 4-trifluoromethyl-7-mercapto-2H-1-benzopyran-2-one, 0.86 g (10.5 × 10 -3 mole) of zinc and 4.7 g (12.6 × 10 -3 moles) of 2,3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl bromide, 2.8 g (51% yield) of expected product.

Mp = 184C [+ alpha] D23 C = + 80.25 "(c = 0.5; CHCl3)
PREPARATION XXXVIII
Obtaining 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 1,5-dithio-ss-D-xylopyranoside (Example 11)
According to the procedure described in Preparation II, starting from 2 g (3.8.10 mole) of 4-trifluoromethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O-acetyl- 1.5dithio-s-D-xylopyranoside is obtained after purification by "flash chromatography" eluting with a methanol / chloroform (1/19) v / v then lyophilization 0.380 g (yield: 27%) of the expected product.

Mp: 178-180 ° C [α] D 25 ° C = + 40.8 (c = 0.26, CH 3 OH)
PREPARATION XXXIX
Obtaining 0- (3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 15 g (71.2 × 10 -3 mol) of 3-chloro-7-hydroxy-4-methyl-2H-1-benzopyran-2-one, 4.41 g (76.8 × 10 -3 mol) of potash and 9.8 g (79.3.10-3 mol) of dimethylthiocarbamoyl chloride, 20.8 g (yield: 98.1%) of the expected product are obtained.

Mp 184.5 ° C
XL PREPARATION
Obtaining S- (3-chloro-4-methyl-2-oxo-2H-1-benzonran-7-yl) dimethylthiocarbamate
According to the procedure described in Preparation XXXV, starting from 5 g (16.8 × 10 -3 moles) of O- (3-chloro-4-methyl-2-oxo-2H-benzopyran-7-yl) dimethylthiocarbamate, in 80 ml of 1,2,3,4-tetrahydronaphthalene, 4.3 g (86% yield) of the expected product are obtained.

Mp = 229 CpREPARATIONL1 benzopyran-2-one
Slon the procedure described in the preparation
XXI, starting from 14.1 g (47.3.10 -3 mol) of S- (3-chloro-4-methyl-2-oxo-2H-benzopyran-7-yl) dimethylthiocarbamate, is obtained after recrystallization from toluene 4.6 g (yield: 43%) of the expected product.

F = 153 ° C
XLII PREPARATION
Obtaining 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-1,5-dithio-s-D-xylopyranoside (Example 12a)
According to the procedure described in the preparation
XXII, starting from 5 g (22.10 mol) of 3-chloro-7-mercapto-4-methyl-2H-1-benzopyran-2-one, 9.4 g (26.5 × 10 -3 mol) of bromide of 2 , 3,4-tri-O-acethyl-6-thio-α-D-xylopyranosyl and 1.8 g (22.1.10 -3 mole) of zinc oxide, after recrystallization from ethyl ether 7.4 g (yield 67%) of the expected product.

F = 180-182 ° C [+]; D23 C = + 70.2 (c = 0.5; CHCl3)
PREPARATION XLIII
Obtaining 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 1,5-dithio-s-D-xylopyranoside (Example 12)
According to the procedure described in Preparation II, starting from 5 g (9.9.10 -3 mol) of 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4 tri-O-acetyl-1,5-dithio-s-D-xylopyranoside, 3.00 g (yield: 80%) of the expected product are obtained.

F = 230C [+ alpha] D22 C = +32.7 (c = 0.3; dimethylsulfoxide)
Obtaining 0- (4-ethyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 25 g (0.131 mol) of 4-ethyl-7-hydroxy-2H-1-benzopyran-2-one, 8.11 g (0.144 mol) of potassium hydroxide and 17.9 g (0.144 mol) of dimethylthiocarbamoyl chloride, 33.9 g (93% yield) of the expected product are obtained.

Mp = 168-160 ° C .;
XLV PREPARATION
Obtaining S- (42H-1-benzopyran-7-yl) dimethylthiocarbamate
According to the procedure described in Preparation XXXV, starting from 30 g (0.108 moles) of O- (4-ethyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate in 50 ml of 1,2 , 3,4-Tetrahydronaphthalene, 21.4 g (71% yield) of the expected product are obtained.

F = 124C
XLVI PREPARATION
Obtaining 4-ethyl-7-mercapto-2H-1-benzopyran-2-one
According to the procedure described in the preparation
XXI, starting from 20 g (61.5.10-mole) of S- (4-ethyl-2-oxo-2H-1-benzopyran-7-yl) dimethylthiocarbamate, 10.6 g are obtained after recrystallization from acetone. (yield: 68%) of the expected product.

Mp = 132 ° C
PREPARATION XLVII
Obtaining 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4tri-O-acethyl-1,5-dithio-ss-D-xylpyranoside (Example 13a)
According to the procedure described in the preparation
XXII, starting from 6 g (29.1.10-3 mol) of 4-ethyl-7-mercapto-2H-1-benzopyran-2-one, 12.4 g
(34.9.10-3 mol) of 2,3,4-tri-O-acetyl-5-diol-α-D-xylopyranosyl bromide and 2.4 g (29.1 × 10 -3 mol) of zinc oxide were obtained. after recrystallization from ethyl ether 10.0 g (yield: 72%) of the expected product.

F = 153 ° C
[α] D23 C = + 28.11 (c = 0.5; CHCl3)
PREPARATION XLVIII
Obtaining 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 1,5dithio-ss-D-xylopyranoside (Example 13)
According to the procedure described in Preparation II, starting from 8 g (16.6 × 10 -3 mol) of 4-ethyl-2-oxo-2H-benzopyran-7-yl 2,3,4-tri-O-acetyl -1,5-dithio-ss-Dxylopyranoside, 4.98 g (85% yield) of the expected product are obtained.

Mp: 184 C [a] D 25 C = + 0.6 (c = 0.3, tetrahydrofuran)
XLIX PREPARATION
Obtaining 0- (2-oxo-4-propyl-2H-1-benzopyran-7-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 25 g (122.4.10 -3 mol) of 7-hydroxy-4-propyl-2H-1-benzopyran-2-one, 7.6 g (135.10-mol) of potassium hydroxide and 16.64 (135.10-3 mol) dimethylthiocarbamoyl chloride gives 33.5 g.
(yield: 94%) of the expected product.

F = 118-120G
PREPARATION L
Obtaining S- (2-oxo-4) dimethylthiocarbamate
According to the procedure described in the preparation
XXXV, starting from 25 g (85.8 × 10 -3 mol) of O- (2-oxo-4-propyl-2H-1-benzopyran-7-yl) dimethylthiocarbamate in 100 ml of 1,2,3,4-tetrahydronaphthalene. 22.2 g (89% yield) of the expected product are obtained.

Mp = 99-100 ° C
PREPARATION LI
Obtaining 7-mercapto-4-propyl-2H-1-benzopyran-2-one
According to the procedure described in the preparation
XXI, starting from 20 g (68.6 × 10 -3 mol) of S- (2-oxo-4-propyl-2H-1-benzopyran-7-yl) dimethylthiocarbamate, 14.3 g are obtained (yield: 95%). the expected product.

Mp 88-89 ° C
LII PREPARATION
Obtaining 2-oxo-4-propyl-2H-1-benzopyran-7-yl 2,3,4tri-O-acetyl-1,5-dithio-ss-D-xylopyranoside (Example 14a)
According to the procedure described in the preparation
XXII, starting from 12 g (54.5.10 mol) of 7-mercapto-4-propyl-2H-1-benzopyran-2-one, 23.2 g (65.4 × 10 -3 mol) of bromide of 2 , 3,4-tri-O-acetyl-5-thio-α-D-xylopyranosyl and 4.4 g (54.5 × 10 -3 mole) of zinc oxide, after precipitation in ethyl ether 20.1 are obtained. g (yield: 75%) of the expected product.

Mp = 137 ° C [α] D 23 C = + 31.174 (c = 0.5; CHCl 3)
PREPARATION LIII Obtaining 2-oxo-4-propyl-2H-1-benzopyran-7-yl 1,5-dithio-s-D-xylopyranoside (Example 14)
According to the procedure described in Preparation II, starting from 15 g (30.3 × 10 -3 mol) of 2-oxo-4-propyl2H-1-benzopyran-7-yl 2,3,4-tri-O-acethyl -1,5-dithio-ss-Dxylopyranoside, 9.7 g (yield: 87%) of the expected product are obtained.

Mp = 176-178 ° C [α] D25 C = + 3.04 (c = 0.3, tetrahydrofuran)
LIV PREPARATION
Obtaining 0- (7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, dlpyran-3-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XIX, starting from 25 g (0.116 mole) of 7,8,9,10-tetrahydro-3-hydroxy-6H-dibenzo [b, d] pyran-6-one, 8.3 g (0.148 mole) and 15 g. 7 g (0.127 mol) of dimethylthiocarbamoyl chloride gives 33.33 g (95% yield) of the expected product.

Mp 159-160 ° C .;
LV PREPARATION
Obtaining S- (7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, d] pyran-3-yl) dimethylthiocarbamate
According to the procedure described in the preparation
XXXV, starting from 25 g (82.10 -3 mol) of 0- (7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, dlpyran-3-yl) dimethylthiocarbamate in 40 ml of 1 , 2,3,4-tetrahydronaphthalene, 18.66 g (yield: 72%) of the expected product are obtained after precipitation with ether.

F = 132eC
LVI PREPARATION
Obtaining 7,8,9,10-tetrahydro-3-mercapto-6H-dibenzo [b, d] pyran-6-one
According to the procedure described in the preparation
XXI, starting from 8 g (26.4.10 -3 mol) of S- (7,8,9,10-tetrahydro-6-oxo-6-dibenzo [d, d] pyran-3-yl) dimethylthiocarbamate, 6.1 g
(yield: 99%) of the expected product.

F = 139; C
PREPARATION LVII
Obtaining 7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, d] pyran-3-yl 2,3,4, -tri-O-acetyl-1,5-ditbio-ss
D-xylopyranoside (Example 15a)
According to the procedure described in the preparation
XXVII, starting with 4.6 g (0.198 moles) of 7.8,9,10
tetrahydro-3-mercapto-6H-dibenzo [d, d] pyran-6-one,
5.1 g (0.198 moles) of mercuric cyanide (Hg (CN) 2),
8.9 g (0.0250 mol) of 2,3,4-tri-O-acetyl-5 bromide
thio-α-xylopyranosyl, one obtains after
recrystallization from ether 3.7 g (yield: 37%)
the expected product.

F = 191 C
[aiD23C = +14.5 (c = 0.3, CHCl3)
PREPARATION LVIII
Obtaining 7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, d] pyran-3-yl 1,5-dithio-s-D-xylopyranoside (Example 15)
According to the procedure described in Preparation II, starting from 3.5 g (69.1 × 10 -3 mol) of 7,8,9,10-tetrahydro-6-oxo-6H-dibenzo [b, d] pyran-3- 2,3,4,6-tri-O-acetyl-1,5-dithio-s-D-xylopyranoside, after lyophilization, 2.55 g (yield: 97%) of the expected product are obtained.

Mp = 182-183 ° C [α] D 2 Zoc = + 20.6 (c = 0.3; dimethyl sulfoxide)
LIX PREPARATION
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4tri-O-acethyl-5-thio-ss-D-xylopyranoside (Example 16a)
A suspension of 2 g (11.3.10 mol) of 7-hydroxy-4-methyl-2H-1-benzopyran-2-one, 4.44 g (12.4 × 10 -3 mol) of bromide of 2,3,4 tri-O-acetyl-5-thio-α-Dxylopyranosyl and 0.4 nm molecular sieve, in 50 ml of dichloromethane and 50 ml of acetonitrile, is stirred with 3.1 g (22.7 × 10.7 -3 moles) of zinc chloride and 2 g (11.4 × 10 -3 moles) of silver imidazolate, protected from light, under an inert atmosphere. After heating at 45-50 ° C. for 36 hours, the reaction mixture is filtered through Celite® in dichloromethane. The filtrate is washed with 1N HCl solution, 1N sodium hydroxide solution and then with water. dried over magnesium sulphate and evaporated to dryness. After precipitation in an ether / methanol mixture, 1.55 g (yield 30%) of the expected product are obtained.

F = 193 C [α]; D20 C = -72 (c = 0.5; CHCl3)
PREPARATION LX
Obtaining 4-methyl-2-oxo-2H-1-benzopyran-7-yl-5thio-ss-D-xylopyranoside (Example 16)
According to the procedure described in Preparation II, starting from 8.5 g (18.9 × 10 -3 moles) of 4-methyl-2-oxo-2H-1-benzopyran-2,3,4-tri-triol 0-acetyl-5-thio-ss-Dxylopyranoside and 0.6 ml of sodium methoxide (8% Na (w / v) in methanol), after crystallization from methanol and washing with ether, 4.73 g (yield: 77.5%) of the expected product.

Mp 190-206 ° C
[α] D20 C = - 72 (c = 0.5; dimethylsulfoxide)
LXI PREPARATION
Obtaining 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5-thio-ss-D-xylopyranoside (Example 17a)
According to the procedure described in Preparation I, starting from 5.26 g (25 × 10 -3 moles) of 3-chloro-7-hydroxy-4-methyl-2H-1-benzopyran-2-one, 9.77 g ( 27.5 × 10 -3 moles) of 2,3,4-tri-O-acetyl-5-yl-D-xylopyranosyl bromide, 6.83 g (50 × 10 -3 mole) of zinc chloride and 4.37 g (25 × 10 3 moles) of silver imidazolate, after purification by chromatography on silica gel, eluting with a 1/7 (v / v) ethyl acetate / toluene mixture and precipitation in ether. 2.5 g (yield: 21%) of the expected product.

F = 227 C [α] D 20 C = -50.7 (c = 0.27, CHCl 3)
PREPARATION LXII
Obtaining 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-ss-D-xylopyranoside (Example 17)
According to the procedure described in Preparation II, starting from 1 g (2 × 10 -3 moles) of 3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri -0-acetyl-5-thio-RD-xylopyranoside and 120 l of sodium methoxide (8% Na (w / v) in methanol), after lyophilization, 560 mg (yield: 76%) of expected product.

Mp: 208-2104C [a] D 20 C = = - 22.9 (c = 0.24 dimethylsulfoxide)
PREPARATION LXIII
Obtaining 4-methyl-2-oxo-3-phenyl-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5-thio-ss-D-xylopyranoside
(example 18a)
According to the procedure described in Preparation I, starting from 2.52 g (10 × 10 -3 mol) of 7-hydroxy-4-methyl-3-phenyl-2H-1-benzopyran-2-one, of 4.26 g. g
(12.10-3 moles) 2,3,4-tri-O-acetyl-5-thio bromide
D-xylopyranosyl, 2.72 g (20 × 10 -3 mol), zinc chloride and 1.75 g (10 × 10 -3 mol) of silver imidazolate, is obtained after purification by chromatography on silica gel. eluent with a mixture of ethyl acetate / dichloromethane 1/24
(v / v) and crystallization from ether, 1.24 g
(yield: 24%) of the expected product.

F = 210 C
[α] D27.5 C = -56.5 (c = 0.1; CHCl3)
PREPARATION LXIV
Obtaining 4-methyl-2-oxo-3-phenyl-2H-1-benzopyran-7-yl-5-thio-ss-D-xylopyranoside (Example 18)
According to the procedure described in Preparation II, starting from 200 mg (1.5 × 10 -3 mol) of 4-methyl-2-oxo
3-phenyl-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5thio-ss-D-xylopyranoside and 130 μl of sodium methoxide (8% Na (w / v) in methanol), after lyophilization, 316 mg (yield: 52%) of the expected product are obtained.

F = 188-200 ° C [α] D 22 C = -59.2 (c = 0.12, CH 3 OH)
LXV PREPARATION
Obtaining 4- (1-methylethyl) -2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-O -acetyl-5-thio-ss-D-xylopyranoside (Example 19a)
According to the procedure described in Preparation I, starting from 2.04 g (10 × 10 -3 moles) of 7-hydroxy-4- (i-methylethyl) -2H-1-benzopyran-2-one, A, 26 g. (12.10-mole) 2,3,4-tri-O-acetyl-5-thio-D-xylopyranosyl bromide, 2.72 g (20.10 -3 mole) zinc chloride and 1.75 g (10.10- 3 moles) of silver imidazolate in 60 ml of toluene and 60 ml of acetonitrile are obtained, after chromatography on silica gel, eluting with a 6/194 ethyl acetate / dichloromethane mixture (v / v). v) and precipitation in ether, 1 g (yield = 21%) of the expected product
F = 144-145 ° C [α] D30 C = -26.4 (c = 0.1; CH3OH)
PREPARATIOn LXVI
Obtaining 4- (1-methylethyl) -2-oxo-2H-1-benzopyran-7-yl-5-thio-s-D-xylopyranoside (Example 19)
According to the procedure described in Preparation II, starting from 650 mg (1.36 × 10 -3 mole) of 4- (1-methylethyl) -2-oxo-2H-1-benzopyran-7-yl 2,3,4 tri-α-acetyl-5-thio-ss-D-xylopyranoside in 10 ml of methanol and 120 l of sodium methylate (8% Na (w / v) in methanol) for 30 minutes, after lyophilization 266 mg (yield: 61%) of the expected product.

Mp = 186-1903c [+ alpha] D22 C = -74.3 (c = 0.14, CH3OH)
In a nonlimiting manner, the compounds according to the invention are recorded in Table I given below.

The anti-thrombotic activity of the products according to the invention has been demonstrated according to the following venous thrombosis operating procedure.
Venous stasis under hypercoagulation is performed 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), an activated factor X solution (Xa) provided by the so-called
Flow Laboratories (71 Knat for 12.5 ml saline).

The study is carried out on Wistar male rats, not fasted, of 250 to 280 g distributed in batches of 10 animals each. The products to be tested are administered orally, in suspension in PEG 400. Thrombosis is induced 4 hours after this treatment and the thrombus formed is removed and weighed.

The results obtained at the dose of 3 mg / kg p.o. were recorded in Table I. This table also shows the results obtained with the known products of the aforementioned prior art.

The products according to the invention exhibit a venous antithrombotic activity which is clearly greater than the activity of the products known from the prior art. TABLE I

#
<Tb>

Example <SEP> X <SEP> MS Position <SEP> R1 <SEP> R2 <SEP> Y <SEP>% <SEP>
<tb><SEP> to <SEP> 3 <SEP> mg / kg
<tb> 1a <SEP> O <SEP> 7 <SEP> -CH2-CH3 <SEP> -H <SEP> -COCH3 <SEP> 65
<tb> 1 <SEP> O <SEP> 7 <SEP> -CH2-CH3 <SEP> -H <SEP> -H <SEP> 87
<tb> 2a <SEP> O <SEP> 6 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 53
<tb> 2 <SEP> O <SEP> 6 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 81
<tb> 3a <SEP> O <SEP> 7 <SEP> -CF3 <SEP> -H <SEP> -COCH3 <SEP> 47
<tb> 3 <SEP> O <SEP> 7 <SEP> -CF3 <SEP> -H <SEP> -H <SEP> 80
<tb> 4a <SEP> O <SEP> 8 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 51
<tb> 4 <SEP> O <SEP> 8 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 52
<tb> 5a <SEP> O <SEP> 7 <SEP> - (CH2) 2-CH3 <SEP> -H <SEP> -COCH3 <SEP> 46
<tb> 5 <SEP> O <SEP> 7 <SEP> - (CH2) 2-CH3 <SEP> -H <SEP> -H <SEP> 26
####

Example <SEP> X <SEP> MS Position <SEP> R1 <SEP> R2 <SEP> Y <SEP>% <SEP>
<tb><SEP> to <SEP> 3 <SEP> mg / kg
<tb> 6 <SEP> O <SEP> 6 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 42
<tb> 7a <SEP> S <SEP> 5 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 7 <SEP> S <SEP> 5 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 38
<tb> 8a <SEP> S <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 65
<tb> 8 <SEP> S <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 46
<tb> 9a <SEP> S <SEP> 8 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 9 <SEP> S <SEP> 8 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 31
<tb> 10a <SEP> S <SEP> 6 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 32
<tb> 10 <SEP> S <SEP> 6 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 37
<tb> 11a <SEP> S <SEP> 7 <SEP> -CF3 <SEP> -H <SEP> -COCH3 <SEP> 11 <SEP> S <SEP> 7 <SEP> -CF3 <SEP> -H <SEP> -H <SEP> 36
<tb> 12a <SEP> S <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 32
<tb> 12 <SEP> S <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 65
<tb> 13a <SEP> S <SEP> 7 <SEP> -CH2-CH3 <SEP> -H <SEP> -COCH3 <SEP> 58
<tb> 13 <SEP> S <SEP> 7 <SEP> -CH2-CH3 <SEP> -H <SEP> -H <SEP> 54
<tb> TABLE I (continued)

Example <SEP> X <SEP> MS Position <SEP> R1 <SEP> R2 <SEP> Y <SEP>% <SEP>
<tb><SEP> to <SEP> 3 <SEP> mg / kg
<tb> 14a <SEP> S <SEP> 7 <SEP> - (CH2) 2 -CH3 <SEP> -H <SEP> -COCH3 <SEP> 25
<tb> 14 <SEP> S <SEP> 7 <SEP> - (CH2) 2-CH3 <SEP> -H <SEP> -H <SEP> 43
<tb> 15a <SEP> S <SEP> 7 <SEP> -CH2-CH2-CH2-CH2- <SEP> -COCH3 <SEP> 23
<tb> 15 <SEP> S <SEP> 7 <SEP> -CH2-CH2-CH2-CH2- <SEP> -H <SEP> 31
<tb> 16a <SEP> O <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -COCH3 <SEP> 63
<tb> 16 <SEP> O <SEP> 7 <SEP> -CH3 <SEP> -H <SEP> -H <SEP> 63
<tb> 17a <SEP> O <SEP> 7 <SEP> -CH3 <SEP> -Cl <SEP> -COCH3 <SEP> 67
<tb> 17 <SEP> O <SEP> 7 <SEP> -CH3 <SEP> -Cl <SEP> -H <SEP> 64
<tb> 18a <SEP> O <SEP> 7 <SEP> -CH3 <SEP>#<SEP> -COCH3 <SEP> 20
<tb> 18 <SEP> O <SEP> 7 <SEP> -CH3 <SEP>#<SEP> -H <SEP> 43
<tb> TABLE I (end)

Example <SEP> X <SEP> MS Position <SEP> R1 <SEP> R2 <SEP> Y <SEP>% <SEP>
<tb><SEP> to <SEP> 3 <SEP> mg / kg
<tb> 19a <SEP> O <SEP> 7 <SEP> -CH (CH3) 2 <SEP> -H <SEP> -COCH3 <SEP> 19 <SEP> O <SEP> 7 <SEP> -CH (CH3 ) 2 <SEP> -H <SEP> -H <SEP> 36
<tb> A <SEP> Product <SEP> of <SEP> Comparison <SEP> Describes <SEP> to <SEP> Example <SEP> 1 <SEP> 14 <SEP> (1)
<tb><SEP> of <SEP> EP-A-0133103
<tb> B <SEP> Product <SEP> of <SEP> Comparison <SEP> Describes <SEP> to <SEP> Example <SEP> 1 <SEP> 5.5 <SEP> (1)
<tb><SEP> from <SEP> EP-B-0051023
<tb> Note: (1) products tested at 12.5 mg / kg po

Claims (14)

1) Oside compound characterized in that it is chosen from 1 group comprising benzopyran-2-one-ss-D-thioxylosides of formula

 in which  X represents a sulfur atom or an atom  oxygen,  - R1 and R2, z identical or different, represent  each a hydrogen atom, an alkyl group  C1-C4, a halogen atom, a group  trifluoromethyl, phenyl, R1 and R2,  considered together, able to form with the group  benzopyran-2-one to which they are linked, a group  dibenzo [b, d] pyran-6-one; and,  Y represents the hydrogen atom or a group  aliphatic acyl. 2) oside compound according to claim 1, characterized in that the aliphatic acyl group Y contains from 2 to 5 carbon atoms and represents in particular the group CH 3 CO. 3) 4-methyl-2-oxo-2H-1-benzopyran-6-yl 5-thio-ss-Dxylopyranoside. 4) 4-ethyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-ss-D xylopyranos ide. 5) 3-Chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio ss-D-xylopyranoside. 6) 4-methyl-2-oxo-2H-1-benzopyran-7-yl 5-thio-ss-Dxylopyranoside. 7) 3-Chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl 1,5-dithio-β-D-xylopyranoside. 8) 4-Ethyl-2-oxo-2H-1-benzopyran-7-yl 2,3,4-tri-0-ethyl-1,5-dithio-ss-D-xylopyranoside. 9) therapeutic composition characterized in that it contains, in combination with a physiologically acceptable excipient, at least one oside compound according to any one of claims 1 to 8. 10) Use of a substance according to any one of claims I to 8 for obtaining an antithrombotic drug for therapeutic use vis-à-vis disorders of the venous circulation. 11) Process for the preparation of a benzopyran-2-one-ss-D-thioxyloside of formula I according to claim 1, characterized in that (i) a compound of formula

  where X, R1 and R2 are defined as above, with a thioxylose drift selected from the group consisting of  (i) acylthioxylosyl halides of the formula

 (ii) peracyl thioxyloses of the formula

 and, (iii) acylthioxylosyl trichloroacetimidates of the formula

 in which Hal represents a halogen atom such as C1 or Br (the bromine atom being here the preferred halogen atom) and Y represents an acyl group, in particular an aliphatic acyl group comprising a total number of carbon of 2 to 5 and preferably being the acetyl group, in an inert solvent, at a rate of 1 mole of II for about 0.6 to 1.2 moles of compound III, IV or V, in the presence of an acceptor d acid and / or an acid Lewis and (ii) if necessary, subjecting the compound of formula I thus obtained wherein Y is a C 1 -C 6 aliphatic acyl group to a deacylation reaction at a temperature between 0 ° C. and the reflux temperature of the reaction medium, in a C1-C4 lower alcohol (preferably methanol) in the presence of a metal alkoxide (preferably magnesium methoxide or sodium methoxide), to obtain a compound of formula I wherein Y is H. 12) Process according to claim 11, further characterized in that the compound of formula II in which X represents the sulfur atom in step (i) is prepared according to the following steps  a) condensation, in a strong basic medium of the  dimethylaminothiocarbamoyl chloride  formula

  with a compound of formula

 where R1 and R2 have the meanings indicated above, to obtain a compound of formula

 where R 1 and R 2 are defined as above b) rearrangement of the compound of formula VII thus obtained by heating, to obtain a compound of formula

 where R 1 and R 2 are defined as indicated above and,  c) treatment of the compound of formula VIII as well  obtained by a metal alkoxide, preferably  sodium or magnesium methanolate, in a  C1-C4 lower alcohol, dimethylformamide or  dioxane, to obtain a compound of formula II  where X = S. 13) New intermediate product involved in the synthesis of benzopyran-2-one-BD-thioxylosides of formula I wherein X represents the sulfur atom according to claim 1, characterized in that it is chosen from the group consisting of compounds of formula

 in which  - R1 and R2, identical or different, represent  each a hydrogen atom, an alkyl group  C1-C4, a halogen atom, a group  trifluoromethyl, a phenyl group, with the exception  of the 3-phenyl group when R1 = H and the SH group  is bound in position 7, R1 and R2 considered  together, able to form with the group  benzopyran-2-one to which they are linked a group  dibenzo [b, d] pyran-6-one. 14) New intermediate product involved in the synthesis of benzopyran-2-one-ss-D-thioxylosides of formula I wherein X represents the sulfur atom according to res-endication 1, characterized in that it is chosen from together constituted by the compounds of formula

 in which  - R1 and Rz, identical or different, represent  each a hydrogen atom, an alkyl group  Ci-C4, a halogen atom, a group  trifluoromethyl, a phenyl group, R1 and R2  considered together, able to form with the group  benzopyran-2-one to which they are linked a group  dibenzo [b, d] pyran-6-one.