CZ463890A3 - Benzopyranone-beta-D-thioxyloside compounds, process of their preparation, pharmaceutical preparation containing those compounds and their use - Google Patents

Abstract

Beta-benzopyranone-D-thioxylosides of formula (I) are new. One of R and R1 = =O and the other = R.. The dotted line = double bond conjugated to the R or R1 group that forms a CO moiety. X = S or O. R. and R2 = independently H, 1-4C alkyl, halogen, CF3 or phenyl. R. and R2 together may also form a 7,8,9,10-tetrahydrodibenzo-(b.d) pyran-6-one group or a 1,2,3,4-tetra hydro -9H-xanthene-9-one group. Y = H or aliphatic 2-5C acyl. 3 compounds are specifically claimed, including 4-methyl-2-oxo-2H-1-benzopyran-7-yl . 1,5-dithio-beat-D-xylopranoside. Preparation of (I) and their use as antithrombotics are also claimed. Further claimed are novel intermediates in the prepartion of (I), e.g. 2-ethyl-7-hydroxy-4H-1- benzoepyran-4-one.

Description

Technical field

The invention relates to benzopyranone-β-D-thioxyloside compounds, to a process for the preparation of these compounds, to a pharmaceutical composition comprising the compounds and to the use of these compounds as venous antithrombotic preparations.

BACKGROUND OF THE INVENTION

EP-B-0 051 023 discloses benzoylphenyloside and alpha-hydroxybenzylphenyloside derivatives as anti-inflammatory, anti-ulcer, antiplatelet, antithrombotic and cerebrally oxidizing active compounds.

Also known from EP-A-0 133 103 are benzylphenylosides which can be used as hypocholesterolemically and hypolipidemically active substances, and some of the benzylphenyloside derivatives described, in particular the product of Example 1, also exhibit antithrombotic effects.

Finally, EP-A-0 290 321 discloses benzoylphenylthioxyloside, alpha-hydroxybenzylphenylthioxyloside and benzylphenylthioxyloside derivatives which have been proposed as antithrombotically active substances.

SUMMARY OF THE INVENTION

We have now found benzopyranone-β-D-thioxyloside compounds which are structurally different from known compounds and are useful for the treatment and prevention of diseases associated with circulatory disorders, particularly useful as venous antithrombotics.

The present invention provides benzopyranone-p-D-thioxyloside compounds of the formula

I:

in which :

- one of R or R 'represents an oxygen atom attached by a double bond to the corresponding cyclic carbon atom and the other of R or R' represents a group R 6, the symbol - - - means a double bond conjugated to a CO group formed by one of R or R substituents ',

X represents a sulfur atom or an oxygen atom,

R 1 and R 2 are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 1 and R 2 together with the benzopyran group to which they are attached may form 7 , 8,9,10-tetrahydro3

-dibenzo [b, d] pyran-6-one or 1,2,3,4-tetrahydro-9H-xanthen-9-one, and

Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms.

Preferred according to the invention are thioxyloside compounds of the formula Ia:

in which :

X is sulfur or oxygen,

R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R1 and R2 together with the benzopyran-2-one group to which they are attached, create

7,8,9,10-tetrahydrodibenzo [b, d] pyran-6-one, a

Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms.

Also preferred according to the invention are thioxyloside compounds of formula 1b:

cr (lb) in which:

X is sulfur or oxygen,

R 1 and R 2 are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 1 and R ₂ together with the benzopyran-4-one group to which are bound to form a 1,2,3,4-tetrahydro-9H-xanthen-9-one group, and

Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms.

In these compounds, X is preferably attached to the 7-position of the benzopyranone ring and R 1 and R ₂ , which are the same or different, each independently represent a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom or a phenyl group.

Preference is also given to the thioxylosides of the above formulas in which Y is CH 2 CO.

Particularly preferred thioxyloside compounds of the invention include: 4-methyl-2-oxo-2H-1-bezopyran-7-yl-1,5-dithio-β-D-xylopyranoside;

3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl-1,5-dithio-β-D-xylopyranoside, and 4-ethyl-2-oxo-2H-1-benzopyran-7 -yl-5-thio-β-D-

-xylopyranoside.

The present invention also provides a pharmaceutical composition comprising as active ingredient at least one compound of formula I, Ia or 1b in combination with a physiologically acceptable excipient.

The present invention also relates to the use of the aforementioned thioxyloside compounds of formula Ia or Ib in combating venous circulation disorders.

The present invention also relates to a process for the preparation of the benzopyranone-β-D-thioxylosides of formula (I), wherein (i) the compound of formula (II) is:

(II) wherein X, R, R 'and R2 are as defined above, reacts with a thioxylose derivative selected from the group consisting of:

- acylthioxylosyl halides of the general formula III

Sludge (III)

peracylated thioxylose compounds of the general formula

IV:

- and acylthioxylosyltrichloroacetimidates of the general formula V:

in which :

Hal represents a halogen atom such as a chlorine or bromine atom, preferably a bromine atom, and

Y represents an aliphatic acyl group having 2 to 5 carbon atoms, in an inert solvent and in the presence of an acid acceptor and / or Lewis acid, using 0.6 to 1.2 mol of the compound of the formula III, IV per mole of the compound of the formula II or V, (ii) where appropriate, the compound of formula (I) in which Y is an acyl group having 2 to 5 carbon atoms is optionally deacylated at 0 ° C to the reflux temperature of the reaction medium, which is a C 1 -C 4 alcohol, preferably methanol, in the presence of a metal alcoholate,

Preferably in the presence of magnesium methylate or sodium methylate.

According to an alternative process for the preparation of the benzopyran-2-one-p-D-thioxylosides of formula la:

(la)

YO in which:

X represents a sulfur atom or an oxygen atom,

R1 and R2 are the same or different and each represents a hydrogen atom, a C1-C4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R1 and R2 together with the benzopyran-2-one group to which they are attached, create

7,8,9,10-tetrahydrodibenzo [b, d] pyran-6-one, a

Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms, starting from a compound of formula II:

HX

(II) '2 in which:

R 'means R- ^,

R is an oxygen atom, and

X and R6 have the same meaning as previously described.

According to another alternative process for the preparation of benzopyran-4-on-β-D-thioxylosides of the general formula Ib:

in which :

X represents a sulfur atom or an oxygen atom,

R 1 and R 2 are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group and a phenyl group, or R 1 and R 2 together with the benzopyran-4-one group to which they are bound, make up

1,2,3,4-tetrahydro-9H-xanthen-9-one, a

Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms, starting from a compound of formula II:

'2 in which:

R is R 6,

R znamená means an oxygen atom, and

X and R 2 have the same meaning as previously described.

Among the preferred aliphatic acyl groups according to the invention, mention may be made of groups having a total of 2 to 5 carbon atoms, with the preferred aliphatic acyl group being CH 3 CO.

C 1 -C 4 alkyl means here a linear or branched C 1 -C 4 hydrocarbon radical, the preferred C 1 -C 4 alkyl being methyl.

The term halogen atom refers to chlorine, fluorine and bromine atoms, with a preferred halogen atom being a chlorine atom.

The compounds of formula (I) and the corresponding acylated compounds may be prepared by a glycosylation reaction comprising: (a) reacting a compound of the above formula (II) wherein X, R, R 'and R2 are as defined above; with a thioxylose derivative selected from the group consisting of:

(1) acylthioxylosyl halides of the above formula

(2) peracylated thioxylose of the above formula

IV, and (3) acylthioxylosyltrichloroacetimidates of formula V wherein Hal is a halogen atom such as chlorine or bromine, wherein the preferred halogen atom is a bromine atom, and Y is an acyl group, especially an aliphatic acyl group containing a total of 2 to 5 carbon atoms, preferably acetyl, in an inert solvent in an amount of 1 mole of the compound of formula II to about 0.6 to 1.2 mole of the compound of formula III, IV or V, especially in the presence of an acid acceptor and / or Lewis acid, ), whereupon the compound of the formula I in which Y is an acyl group having 2 to 5 carbon atoms is optionally subjected to a deacylation reaction at a temperature in the range of 0 ° C and the reflux temperature of the reaction mixture in a lower alcohol C 1 -C 4 (preferably in methanol) in the presence of a metal alcoholate (preferably in the presence of methylate) magnesium or sodium methylate) to form a compound of formula I wherein Y is hydrogen.

Compounds of formulas III, IV and V may either have an alpha or beta configuration or may be in the form of an anomeric mixture of both.

The glycosylation reaction of compounds of formula II is carried out either by reaction with a compound of formula III in the presence of a catalyst such as a salt or a silver, mercury or zinc oxide, or by reaction with a compound of formula V in the presence of a Lewis acid, especially in the presence of boron trifluoride etherate; zinc chloride, or by reaction with a compound of formula IV in the presence of a Lewis acid.

In a preferred embodiment of the process, 1 mole of a compound of formula II is condensed with about 1.1 to 1.2 moles of an acylthioxylosyl halide of formula III in an inert solvent selected from the group consisting of polar or apolar solvents such as dimethylformamide, dioxane, acetonitrile, nitromethane , benzene, toluene, xylenes and mixtures of these particular solvents in the presence of mercuric cyanide.

Preferably, 2,3,4-tri-O-acetyl-5-thio-Dxylopyranosyl bromide is used in a 1: 1 by volume mixture of benzene and nitromethane or in dichloroethane in the presence of 1.1 to 1.3 moles of mercuric cyanide at z temperature. a temperature range defined by 0 ° C and the reflux temperature of the reaction mixture, preferably at 40 to 50 ° C, for one hour to 4 days.

According to another preferred embodiment of the process of the invention, 1 mole of the compound of formula II is condensed with about 1.1 to 1.2 moles of an acylthioxylosyl halide of formula III in an inert solvent such as dichloromethane or acetonitrile in the presence of silver imidazolate and zinc chloride.

Preferably, 2,3,4-tri-O-acetyl-5-thio-Dxylopyranosyl bromide is used in dichloromethane or in a mixture of dichloromethane and acetonitrile in the presence of 1.5 to 1.7 moles of silver imidazolate and 2 to 2.2 moles of zinc chloride at a temperature in the range of 0 ° C and the reflux temperature of the reaction mixture, preferably at about 40 and 60 ° C, for 18 to 48 hours.

According to another preferred embodiment of the process of the invention, 1 mole of the compound of formula II is condensed with about 0.6 to 1 mole of an acylthioxylosyl halide of formula III in an inert solvent such as toluene and / or acetonitrile in the presence of zinc oxide.

Preferably, 2,3,4-tri-O-acetyl-5-thio-Dxylopyranosyl bromide is used in a mixture of toluene and acetonitrile in the presence of 0.5 to 1.2 moles of zinc oxide at a temperature ranging from ambient temperature and boiling point. of the reaction mixture under reflux, preferably at a temperature of about 40 to 60 ° C, for 18 to 48 hours.

According to another preferred embodiment of the process of the invention, 1 mole of the compound of formula (II) is condensed with about 1.1 to 1.3 moles of acylthioxylosyltrichloroacetimidate in an inert solvent such as dichloromethane or acetonitrile in the presence of boron trifluoride etherate or zinc chloride.

Preferably, 2,3,4-tri-O-acetyl-5-thio-Dxylopyranosyltrichloroacetimidate in dichloromethane is 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 z temperature. a temperature range defined by -40 ° C and ambient temperature (15-25 ° C), preferably at a temperature in the range of about -20 ° C to 0 ° C, for 1 to 5 hours.

This glycosylation reaction leads in all cases to a mixture of alpha and beta isomers in different ratios.

The beta configuration isomer may be isolated by known methods such as fractional crystallization or chromatography, in particular flash chromatography (i.e.

silica gel column chromatography under pressure as described in W.C. Still et al. J, Org.

Chem. (1978), 42 (No. 14) 2923).

Optionally, the derivatives obtained are subjected to deacylation, in particular deacetylation, which is carried out at a temperature in the range of 0 DEG C. and the reflux temperature of the reaction mixture in a lower C1 -C4 alcohol in the presence of the corresponding metal alkoxide. Preferably, methanol is used as the lower alcohol and sodium metallate or magnesium methoxide is preferably used as the metal alcoholate.

Preferably, said deacylation reaction can be carried out immediately after glycosylation without isolating the formed intermediate acyl compound.

The deacylation reaction may also be carried out by an enzymatic route, for example by treatment with a pig liver esterase.

In order to obtain the compounds of formula (II) which form intermediates in the process of the invention and in which X represents a sulfur atom,

(1) condenses in strongly basic medium dimethylaminothiocarbamoyl chloride of formula VI:

CH.

Cl (5)

with a compound of formula IIIa

wherein R, R ', and R2 are as defined above to form a compound of formula VII

wherein R, R * and R2 are as defined above, (2) whereupon the compound of formula (VII) thus obtained is subjected to a Newman rearrangement (J. Org. Chem. (1966) 31, p. 3980) to give a compound of formula VIII

Wherein R, R 'and R2 are as defined above, (3) and then the compound of formula (VIII) thus obtained is treated with a metal alcoholate, preferably sodium methoxide or magnesium methoxide, in a lower alcohol having 1 to 4 carbon atoms, preferably in methanol, dimethylformamide or dioxane, to form a compound of formula II wherein X is sulfur.

Intermediates of formula (II) in which X is a sulfur atom, R is an oxygen atom attached by a double bond to a cyclic carbon atom, R 'is a group R 1 and - - - is a double bond conjugated to a CO group formed by R can also be obtained by nucleophilic substitution of the appropriate halobenzopyran-2-one compound according to the procedure of L. Testaferri in Tetrahedron Letters, Vol. 21, pp. 3099-3100 (1980).

The 2-ethyl-7-hydroxy-4H-1-benzopyran-4-one intermediate is a novel compound which is also within the scope of the invention.

The intermediates of formula (II) in which X represents a sulfur atom are also novel compounds with the exception of 7-mercapto-3-phenyl-2H-1-benzopyran-2-one which has already been described in GB-A-1154272.

The compounds of the present invention can be used for the preparation of antithrombotically active drugs and pharmaceutical compositions for therapeutic use in the treatment of venous circulation disorders.

16-21

DETAILED DESCRIPTION OF THE INVENTION

The preparation of the compounds of the present invention will be illustrated in more detail by means of specific examples, which are, however, only illustrative and not limiting. In particular, these examples relate to the preparation of compounds of formula I and confirmation of their therapeutic efficacy by pharmacological tests.

In the following examples, the configuration of the compounds to be prepared is indicated by their α or β configuration, which applies where this configuration has been determined. In the absence of this configuration, the product is an anomeric mixture of α and β configurations in ratios not determined.

Preparation

Obtaining 4-ethyl-2-oxo-2H-1-benzopyrrolidin-7-yl-2,3,4-tri-O-Bcetyl-> thio- [beta] -D-xylopyranosideA (Example 1a)

A suspension of 2.28 g (12.IO ^"3 mol) of 4-ethyl-7-L-hyúroxy2H benzopran-2-one (4.7 g 13,2.1Q ~ ³ mol) of 2,3,4-tri- Oacetyl-5-thio-D-xylopyrenosyl bromide and molecular sieves (0.4 na) in 129 ml of toluene and 120 ml of acetonitrile are stirred under an inert atmosphere 6 in the presence of light in the presence of 3.28 g (24.1Ο ^- * ³ mol) chloride zinc and 4.2 g (14.1ο * ³ tables) of silver imidazolate. After heating at 55 ° C for 24 hours, the reaction mixture was filtered through celite (i.e. diatomaceous earth for filtration) in ethyl acetate. The filtrate was washed with 1N hydrochloric acid solution, 1N sodium hydroxide solution and then with saturated sodium chloride solution, dried over sodium sulfate and freed from the solvents under reduced pressure.

Purification by chromatography on silica gel, eluting with a mixture of ethyl acetate

Toluene / toluene (1: 6, v / v) and precipitated in ether gave the desired product.

..

*

XXiX ·· ': ··

Yield: 0.93 (17%) j '• 7: ^r>

/ 3 AK - :, G .... ; ,. ·.

, ‘J: · .7 ··? '· .-' 3. <· -?

J ·. · '

XA / rl ::

23 melting point: 1S9 ° C;

From ^"e ° L7Í ° - 73.8 ° c = 0.25; CKCip.

In the same procedure, the following compounds were prepared:

4-Methyl-2-oxo-N-1-benzopyridin-6-yl-2,3,4-tri-O-acetyl-5-thio-3-D-xylopyronoside (Example 2a) Mp 179-184 ° C

Zc <7d ° * 47.9 ° ^(c * θ »33ϊ CHCl ₃ );

4-Trifluoromethyl-2-oxo-2H-1-henzopyran-7-yl-2,3,4-tri-O-acetyl-5-thio-β-D-xylopyranoeide (Example 3a) Melting point &lt; 184 ° C;

ZX7 | ♦ * ° ° 29.2 ° ^{with tc} »55J CHC1 _3);

4-Methyl-2-oxo-2K-1-benzopyrr-8-yl-2,3,4-tri-O-acetyl-5'-thio-β-D-xylopyranoside Example 4 ») Melting point» Mp 220-223 ° C

- 121.9 ° (c »0.21; CSC1 ₃ )}

24-2-oxo-4-propyl-2H-1-benzopyridin-7-yl-2,3,4-tri-3-acetyl-5-thio-f-D-xylopyranoside (Example 5a)

M, _m.p. = 1651 * 167 ° C;

ZX7d ° ^s “71.2 ° φ = 0.11; CHCKlj);

4-Methyl-2-oxo-2H-1-benzopyran-5-yl-2,3,4-tri-O-ethyl-5-thio- [3-D-xylopyrrolidide (Example 6a) m.p. 167 [deg.] C. = -S1 [deg.] (C = 0.15; CSCl3);

4-methyl-2-oxo-2H-1-benzopyran-7-yl-2,3,4-tri-C-methyl-5-thio-β-D-xylopyrosnoside (Example 16a) mp &gt; 193 ° C;

Z ⁼ -7 ° (-72 °) (c = 0.5; CHCl 3);

3-chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl-2,3,4-trioacetyl-5-thio-f-D-xy lepyranoside (Example 17a) m.p. 227 ^° C;

50.7 ° (e = 0.27, CHCl 3)

-254-ethyl-2-oxo-3-phenyl-2H-1-benzopyrr-7-yl-2,3,4-oxo-6-acetyl-5-thio- 3 -N-xylopyranoside (Example 18e) melting point - 210 ° C;

ZX7b 7.5si ^· 5M ° * 0.1 J CKCl ₃ ) j

4- (1-diethylethyl) -2-oxo-2H-1-benzopyridin-7-yl-2,3,4-tri-C-ethyl-5-thio- [3-O-xylopyranoalde (Example 19) Mp 144-145 ° C; .

Z = -7.4 ° -26.4 ° (e χ 0.1; CH 3 OH);

2-methyl-4-oxo-4K-1-benzopyran-7-yl-2,3,4-tri-O-ethyl-5-thio-3-D-xylopyrrolidine (Example 20a) m.p. &gt; 188 ° C ;

“77.4 ° χ 0.47; díCl- ^)

2-ethyl-4-oxo-4H-1-benzopyren-7-yl-2,3,4-tri-C-methyl-5-thio-4-D-xylopyranoside ses

(Example 21a) Melting point < 150-151 ° C;

Z ^ Zp ^{1 e} “ ⁶ * ° <* 0.54; CHCl 3);

χτ.

in,

2,3-Dimethyl-4-oxo-4H-1-benzopyrr-7-yl-2,3,4-tri-O-acetyl-5-thlo-4-D-4-pyrrolidinide (Example 22a) S melting point &gt; 203 + 205 ° C;

^ ΠΧζ / ^ ^{1 s} “65 ° c» 0.6} CHG1-j)

2-ethyl-4-oxo-4K-1-benzopyran-6-yl-2,3-4-tri-Q-acetyl-5-thiol-4-D-xylopyranoside (Example 24a) S ^; m.p. 168-180 ° C;

/ oC_7 ²⁵ = “θ1» 9 ° f - 0.3} CHCI.);

4-oxo-2-phenyl-4H-1-benzopyrr-Y-yl-2,3,4-tri-O-ethyl-p-thio- [beta] -D-xylopyronoeid (Example 25a) m.p. * 215 [deg.] C ;

Ζ ^ Τρ ⁴ * - ⁶² ° ± 0.5 *; CHC1 ₃ )

3-bromo-2-methyl-4-oxo-4H-1-isopropyl-7-yl-2,3,4-tri-O-acetyl-5-thio-4-D-xylopyranoaid (Example 28a) c / 6tx temperature »192 + 194 Cj 7¾ ^ * * 54® (c« 0.54; CHeip.

IT Preparation

Obtaining 4-methyl-2-oxo-2H-1-benzopyridin-5-yl-2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyranoside (Example 7a)

A suspension of 420 mg (2,2.10 ^J ynol) 5-merkrpto-4-methyl-2H-benzopyrsn-2-one, 970 mg (2.7 · 10 ^ ~ mol) of 2,3,4-tri-O- of ethyl ethyl 5-ihio-D-xylopyrenosyl bromide, 550 mg (2.2 * 10 &lt; -4 &gt; mol) of copper cyanide and molecular sieves (0.4 nm) in 50 ml of nitromethene and 50 ml of benzene are stirred at 45 [deg.] C. under inert atmosphere. for 24 hours. The reaction mixture was then filtered through celite in ethyl acetate. The filtrate was then washed with 1N hydrochloric acid, 1N sodium hydroxide solution and finally with saturated sodium chloride solution. The filtrate is dried over magnesium sulphate and then evaporated under reduced pressure.

SJ ·> -ί>

Purification by silica gel column chromatography eluting with ethyl acetate / toluene (1: 5, v / v) gave the desired product.

Product yield: 250 mg (25%) mp 187 ° C;

- 28 ° C ° 2d ^{2 =} * 34.5 ° (c = 0.11; CFCip.

Following an analogous procedure, the following compounds are not prepared ϊ

4-Methyl-2-oxo-2K-1-benzopyran-8-yl-2,3,4-tri-O-acetyl-1,5-dithio-4-D-xylopyranoaid (Example 8) m.p. 205 ° C;

+ 86.25 ° (c = 0.3-0HCl ₃ ) j

4-Methyl-2-oxo-2H-1-benzopyran-6-yl-2,1,4-tri-O-acetyl-1,5-dithio-4-D-xylopyrenoside (Example 10®) Melting point » 1394140 ^e C - 66.13 ° (c »0.3, CHC1 _3);

7,8,9,10-tetrahydro-6-oxo-6K-aiberizo [b, d] pyrimidin-3-yl-2,3,4-tri-O-ethyl-1,5-dithi-4-yl- xylopyranoside (Example 15a) mp pl = 191 ° C,

From “Ky | ³ »♦ 14,5® (about 0,3j = CHC1 ₃₎ j

- 29 2- £ Otiiyl 4-OAO-4H-ben2opyran-7-yl 2,3,4-tri-O-butyl sce ~ l _{t-dithio-5/3-D-xylopyran0sid} (Example 23a) mp &gt; 171 ° C;

/ TV * ¹ “ ⁺ ? ⁴ 3 ° ^(en ° ¹⁴ ; CKCl ₃ );

2,3-Dimethyl-4-oxo-4H-1-benzopyrr-7-yl-2,3,4-tri-O-ethoxy-1,5-diethio-D-xylopyranoside (Example 26a)

Mp &lt; XX &gt; t mp &lt; 169 + 173 ° C;

Ζ “θθ ^ ⁰ « 55.5 ° (c * 0.38; CHCl · *);

2-ethyl-4-oxo-4H-1-benzopyran-7-yl-2,3,4-tri-O-acetyl-1,5-chloro-β-D-xylopyrrose (Example 27®) mp »65f" 90 - $ G / ¾¾ ⁰ «♦ 53 ° (c = °, 5; CHC1 ₃₎

Attraction of 4-ethyl-2-oxo-2B-1-benzopyran-7-yl-2,3,4-tri-o-acetyl-1,5 * di-thio- [beta] -D-xylopyrenoside. 4 <ΓΛ4 žSSeeíi

- 30 A mixture of 8 g (41,6.10 "^ mole), 7-4-H'erkspto ffiethyl-2K" benzopyrsn-l l-2-one (17.7 g, 50.10 * ^"J mol) of 2,3,4 Three-O-acetyl-5-thio-β-D-xylopyrenosyl bromide and 3.4 g (42.10%) of zinc oxide in 160 ml of toluene and 160 ml of acetonitrile and heated for 12 hours at 45 ° C. . After filtration through celite and washing the residue with ethyl acetate, the organic phase is washed with 1N hydrochloric acid solution, then with 1N sodium hydroxide solution and finally with saturated sodium chloride solution. The resulting organic phase is dried over magnesium sulphate and evaporated under reduced pressure. In this way, after precipitation by addition of ethyl ether, the desired product is obtained in the form of a yellow powder.

Product yield: 14.2 g (73%)

mp 168 ° C

From “° £ 7d ² ” to 46.4 ° (c «0.7; I want ₃ ).

Using an analogous procedure, the following compounds are prepared:

4-trifluoromethyl-2-oxo-2H-benzopyrene-7-yl _{2,3,4-tri-0-acetyl-5-yl-dithio-β-D-xylopyrenoeid} (Example IIa) m.p. ^ 1 4 ° C;

r-vj? = + 80.25 ° C. + -. 0.5; CHCl 3);

3-chloro-4-acetyl-2-oxo-2H-1-benzopyran-7-yl-2,3,4-tri-O-acetyl-1,5-dithio-β-D-xylopyrrolidine (Example 12 a ) / f _rt mp iso-j-162 ° C;

[Α] ⁷ P ³ = * 70.2 ° c = 0.5; CHC1 _3);

4-ethyl-2-oxo-2H-1-benzopyran-7-yl-2,3,4-tri-O-methyl-1,5-di-thio-4'-xylopyranoside (Example 13a) m.p. ° C;

[.alpha.] D @ 20 = ⁺ 28.11 DEG (c 0.5, CTTC11);

2-Oxo-4-propyl-2H-1-benzopyren-7-yl-2,3,4-tri-O-acetyl-1,5-di-thio-D-xylopyranoeide (Example 14a) Melting point: 137 ° C;

[.Alpha.] D @ 17, 17 DEG (e .alpha. 0.5; CHCl3;

; · £ <- -! · * £? · ’. <, *: Λ: C-. . · -:

S «i Í / J, Λ - / ñ-Y -i, S $ * 0? '‘' By J‘ ‘V '

ΑΐΛ * '' J, *

In * · * ‘T Λ

5 * (v ⁾ (i * · «

Xáýíí & eVA '- ^' ‘ν» »í

- 32 Preparation IV

Obtaining A-ethyl-S-oxo-1H-1-benzopyrr-V-yl-4-thio- [3-Z-xylopyrnoside (Example 1)

To a solution of 0.45 g (0.97 · 10 -3 aiol) of 4-ethyl-2-oxo-2R-1-benzopyrr-7-yl-2,3,4-tri-O-methyl-3-thio- N-D-xylopyrenoeide in 3 mL of methanol was added with 60 µL of sodium methylene (8% Ke (w / v) in methanol). After stirring for 24 hours at ambient temperature, ^T the reacting mixture was neutralized by addition of Amberlite 120H IFT + te trahydrof solubilise uranium filtered with charcoal treated. The solvents are then removed from the reduced printing, after which a poisonous product is obtained after lyophilization.

Yield of product: 0.263 Burmese (87%); Melting point: 192 ° C ^{36 to} 69 ° (c ^0.21 j Dimethyl sulphoxide).

/ · A: h

.. f, i

-and·

Using an analogous procedure, the following compounds were prepared:

4-Methyl-6-oxo-2H-1-benzopyran-6-yl-p-thio-6-methylpyrrolidine (Example 2) m.p.

/ "Οθ / ^s ρ ° - 63.3 ° (c = ^, 24; dimethylsulfoxide);

4-trifluoromethyl-2-o-o-2H-2-ol; _{k. benzopvr9r-i} -7 - '. 5-yl-β-tbio- Σ> - py lo xy morning SID (example 3) / cC7p DEG = + 34.1 DEG (c = 0.3; CH.OH) ;

4-methyl-2-oxo-2H-1-benzopyran-6-yl-5-thio-β-D-xylopyrsnoside (Example 4) melting point »1202125« - 16 ° (c = 0,12; dimethylsulfoxide)

2-oxo-4-propyl-2H-1-benzopyran-7-yl-5-thio-3-D-xylopyrrolidine;

(Example 5) Mp &gt; 192 ° C;

Α; - _: Α-β ·.

. [.alpha.] D @ 20 = + 61.3 DEG (c = 0.15; dimethylsulfoxide);

\, \

4-Methyl-2-oxo-2H-1-benzopyridin-5-yl-5-thio- [eta] &lt; 3 &gt; -Xylopyrrolidine (Example 6) mp & lt ^; -1 &gt; 11 (dimethylsulfoxide);

4-n: ethyl-2-oxo-2H-1-benzopyran-5-yl-1,5-dithio-.beta.-xylopyrrolidine (Example 7) ' T, m.p. &lt; 203 ° C;

/ ^- ^ ² * ¾ ^{+ 2i} .3 ° te = 0.12, CH ₃ OH);

4-Ethyl-2-oxo-2H-1-methyl-7-yll | b-dithio-β-S-xylopyrenoside (Example 8) melts at &lt; 216 ° C;

[Deg.] - 19.4 [deg.] (E &lt;0.3;diaethylephloxide);

4-Isopropyl-2-oxo-2H-1-benzopyran-8-yl-l, 5-di-thio-β-1H-oxy-lopyranodeide (Example 9) mp &lt; 178 ° C;

⁸⁵ - 61.5 ° (c «0.2 $ dimethyl sulfoxide);

AND

4-Methyl-2-oxo-2H-1-benzopyran-6-yl-1,5-dithio- [beta] -D-xylopyranoside (Example 10) m.p. = 182 [deg.] C .;

[.Alpha.] D @ 25 = -6.9 DEG (c = 0.6; tetrahydrofuran);

4-trifluoromethyl-2-oxo-1. ^KL ~ benzopyrtm-7-1-1,5-di-thio · 'β-D-xylopyrproeÍd (Example 11) mp live _Λ »1784180 C;

[Α] D = + 40.8 ° C = 0.26; CE (OE);

3- chloro-4-Kethyl-2-oxo-2H-7-behhopyTeň ^,, 'yl ~ l »5-dithio. - β-D-xylopyrenoeid (Example 12) melting point - 230 ° C;

[.Alpha.] D @ 25 = + 32.7 DEG (c ^88, 0.3>dimethylsulfoxide);

4-ethyl-2-oxo-2H: -1-benzopyren-7-yl-1,5-diethio [3-E-xylopyrenoid (Example 13), m.p. &lt; 184 ° C;

/ oC7J ^? + 0.6 ° (c = 0.3; tetrahydrofurene);

36-2-oxo-4-propyl-2H-1-benzopyran-7-yl-1,5-dithio- [S-D-xylopyrenoid] (Example 14) o

mp ³⁵ 176-178 ° C;

* 3 * 0 ° (<s "0.3.> Tetrahydrofuran);

7,3,9,10-tetrahydro-6-oxo-6H-dibenzo [b] b] p-pyrazol-1-yl-1,5-dithio [3-O-xylopyranoside (Example 15);

'. - '' Jj. · Λ'— ί ·. ·. _Γ . C> F thaw - 182 ° -183 ° C; >

~ ^{+ 2σ} > 6 ° φ = 0.3; dimethylsulfoxide);

4-methyl-2-oxo-2H-1-benzopyridin-7-yl-5-thio-β-D-xylopyranoside (Example 16);

o melting point ^with 190/206 G;

³ * 72 ° (δ ³ 0.5; dimethyl sulf oxide);

, ϊ> **

........

W ·. '/

3-Chloro-4-methyl-2-oxo-2H-1-benzopyrr-7-yl-thio-β-D-xylopyranoside (Example 7) melting point > 208-110 ° C;

[.alpha.] D @ 20 = -22.9 DEG (c = 0.24; dimethylsulfoxide);

37 4-Methyl-2-oxo-3-phenyl-23-1-benzopyrn-7-yl-5-thio-β-S-xylopyranoside (Example 18) o

melting point = 16.6200 ° C;

Ζ "ζ7β ² ° = - ^» ² ° ^C = ^{ΰ »12>} CK-OK);

4- (1-methylethyl) -2-oxo-2H-1-benzopyrrolidin-7-yl-5-thio-β-D-xylopyranoside (Example 19) m.p. = 136-190 ° C;

Z7 í7j °) = ² - ^{74> IC 3} ° 7 ° »^ i ¹⁴ OH);

2-methyl-4-oxo-4H-1-benzopyren-7'-yl-5-thio-4-D-xylopyranoeide (Example 20) mp * 193 + 195 ° C;

”92 ° (c 0,5 0.5, methanol);

2-ethyl-4-oxo-4H-1-benzopyrr-7-yl-3-thio-4-D-xylopyrenoid

7- »« 7-.

v'ť'f · '

Λ * «A>. V ⁴

A, V 14 J ^r

More >> Wl *. *, even fy.

(Example 21) ^'V teploteténí * 1304137 C;

[.Alpha.] D @ 20 = -84 DEG (e = 0.54; methanol);

- 3ε 2,3-diethyl-4'-oxo-dH-1-benzopyrr-T-yl-γ-thio-β-γ-yl-pyrrolidine (Example 22) m.p. = 177-194 ° C;

/ ~ CC / p - - 66, δ π »0.45; tetrahydrofuran);

2-methyl-4-oxo-4H-1-benzopyrrole, di-thio- [beta] -D-sylopyrosnoside (Example 23) m.p. = 1S4 -190C;

[.Alpha.] D @ ²⁵ = ⁺ 3.9.1 DEG (c = 0.2; diyl thyl oulphide oxide);

2-Methyl-4-oxo-4K-1-benzopyrr-6-yl-5-thio-β-D-xylopyrrose (Example 24), m.p. &gt; 108 ° C (decomposition: 200-240 ° C) );

[.alpha.] D @ ²⁵ = -107.7 DEG (c = 0.3; methanol);

4-ozo-2-phenyl-4H-1-benzopyran-7-yl-1H-thi-β-D-xylopyranooid; d (example melting point - 222 ° C;

¾ ^ ⁰ -90 ° (c c0.5, tetrahydrofuran);

· * ££>> ´ ν / '´' Šy ** γ pi.

'' In '*' * ££ ** '·'

-3,2,3-Dimethyl-4-exo-4H-1-benzopyren-7-yl-1,1'-dithioxy-3-xylopyrenoid (Example 26) x4 ° C t 4 ° + 200 ° C;

[.Alpha.] D @ 25 ⁼ 0.33 (0.33, methanol);

2-ethyl-4-oxo-4H-1-benzopyridin-7-yl-1,3-dithio-4-D-xylopyranoeide (Example 27) m.p.

[.Alpha.] D @ 25 = + 26.2 DEG (c = 0.53; methanol);

3-Bromo-2-methyl-4-oxo-4'-1-benzopyrr-7-yl-3-thio-β-b-xylopyrenoid (Example 28) mp - 135 ° C (° C) / οΟ / β ¹ ® - 43 ° (c »0.5 · diethyl sulfoxide) ·

Prípreve V

Obtaining O- (4-Ethyl-2-oxo-2R-1-benzopyran-5-yl-di-ethylcarbemate)

'' in _vl - * / AA

-, · «.

 and

- 40 -3

To a suspension of 5-hydroxy-4-α: ethyl-2H-1-benzopyren-2-one (1 g, 5.7.10 ^J c.ol) in 10 ml of water (10 ml) of acetone and (3) under an atmosphere of inert gas is added 410 cg. ^(J 7,3.10 mole) of potassium hydroxide. After 10 minutes at ambient temperature at 0 ^C was added 770 mg of C <6,2.10 "^ mole) in 10 ml dimethy1thiokerbaaoylchloridu ecetonu. The addition mixture is kept from stirring at ambient temperature for two hours, after which the desired derivative is precipitated after evaporation of acetone. in the water.

Product yield: 1.35 g ($ 0 &lt; + &gt;).

Using the analogous procedure, the compounds listed in Tables III and I below were prepared

Preparations © VI

Recovery of S- (4-methyl-2-oxo-2K-1-benzopyran-3-yl) dimethylthiocarbamate * · 14 · ß

-ta, F4G i ^r * », ^A +" * ΪΖ "V. * A solution of 3.7 g (14.1 *" 3 mol) of 0- (4-methyl-2-oxo-2H-benzopyrene-5- yl) dimethyl thiokerbemate in 50 ml 1,2,3,4-tetrehydronephthalene is maintained at 220 ° C for

14 hours. After cooling, the desired product precipitated in ether. The crystals thus obtained are washed with cyclohexene.

Product yield; 2.95 grams (? 0%);

mp 129 ° C.

2a Using the analogous procedure, the compounds listed in Tables V and VI above are prepared.

Preparation VII

Obtaining methyl 3- (2-hydroxy-b-thioxylmethylcarbonylthio) phenyl) -2-butenoic acid methyl ester

To a solution of 2- (4-methyl-2-oxo-2H-1-benzopyrr-5-yl) diethylthiokerbosphate (2 g, 7.6 g) in 20 ml of methanol was added 4.4 ml of sodium methylate under an inert atmosphere. (8% Na (w / v) in methanol). After 4 hours at ambient temperature, the reaction mixture is hydrolyzed with ice / hydrochloric acid and the precipitate formed is filtered off.

to obtain the desired product ·

Product yield; 1.7 g (76%); melting point; 152 [deg.] C.

«! (.

Preparation VIII

Obtaining 7-aryl-pto-4-methyl-2H-1-benzopyren-2-one

To a solution of 1 g <3,4.10 "mole) of methyl 3- (2-hydroxy-6- (dimethylaminocarbonylthio) phenyl) -2-butenoic acid in 10 roles of anhydrous dimethylforaiRinide is added 4 ml at 60 ° C. sodium methylate (8% Ne (w / v) in methanol). After 6 hours at 60 ° C, it is hydrolyzed with a mixture of hydrochloric acid and ice to give the desired product.

Yield of product: 0.550 g (85%); m.p .: 136 ° C.

Preparation IX

Obtaining 7-mercapto-4-methyl-2H-1-benzopyran-2-one

3 g (0.1 mol) of S- (4-methyl-2-oxo-2H-1-benzopyron-7-yl) dimethylthiokerbamate were suspended in 300 ml of methanol under a nitrogen atmosphere. To the resulting suspension was added 0.2 moles of sodium methylate at ambient temperature (8% solution of Na (w / v) in methanol and the mixture was heated

temperature

% of the starting product which is continuously monitored by chromatography on a thin layer using a 1: 4 ethylene acetate / toluene eluent system. After cooling, the reaction mixture is hydrolyzed with a mixture of ice and concentrated hydrochloric acid, after which the precipitate formed is filtered off and washed with water. After drying over phosphorus pentoxide, the desired product is obtained.

Product yield: 15.2 graizu. íténař 100;

melting point; 132 [deg.] C.

Using the illogical procedure, the compounds shown in Table VIIe VIIIII are prepared.

Preparation X

Obtaining 2-ethyl-7-yl-oxopropoxy) -3- (1-oxopropyl) -4H-1,4-benzopyrrole-4-one

A solution of 5 g (32.2, 10 -3 moles) of 1- (2,4-dihydro-2-phenylphenyl);

¹ ; ♦ c - -Vt ;, under an inert mercury of n? The test mixture is then hydrolyzed in the presence of sodium bicarbonate and the product is extracted with ethyl acetate, and washed with water. The organic phase thus obtained is dried over magnesium sulphate. The solvent is removed from the reduced print. After addition of toluene, the remaining solvent was evaporated again from the reduced press. Purification by silica gel eluting with hexane / ethyl acetate (6: 1, v / v) gave the desired product.

Yield of product: 2 g (20%);

mp 84 ° C.

Příprsva XI

Obtaining 2-ethyl-7-hydroxy-4H-1-benzopyren-4-one

A suspension of 6.5 g (21.5 * 10 * mol) of 2-ethyl-7- (1-oxopropoxy) -3- (1-oxopropyl) -4H-1-benzopyrr-4-one and 5 g (47%). # Ά abiii) sodium carbonate in 65 l of water and kept at 150 ° C for 9 hours. The reaction mixture is then hydrolyzed with 1N hydrochloric acid solution. The product ee was extracted with ethyl acetate. After chromatographic purification

Silica gel, eluting with 1: 2 ether / dichloromethane, affords the desired product.

Product yield: 2.45 grams (61%);

melting point: mp # ° C.

Right XII

Obtaining 7-ethyl-3-bromo-2-methyl-4H-1-benzopyren-4-one.

To a solution of 8.8 g (40.10 ^- ^ mole) of 7-acetyl-2-methyl-4H-L benzopyrftn-4-one in 80 sl acetic acid are added at 60 DEG C. under an inert atmosphere 77, The reaction mixture was then maintained at 60 ° C for two hours and then left to stand for 12 hours. Pot022 is concentrated by evaporation under reduced pressure and the residue is neutralized with saturated sodium bicarbonate solution. The mixture was extracted with ethyl acetate. The organic phase is washed with water until neutral, then dried over magnesium sulphate and concentrated to dryness.

Chromatographic purification on silica gel, eluting with a dichloromethane / methaphenol (12: 1) mixture, gave the desired product.

- 46 Yield of product: temp

2.3 yr (1 $

V ♦

^{3-Bromo-7-hydroxy-2-methyl-4H-benzopyi>} dioxolan-4-one

X suspension of 2.3 g (7.7 ^»J ~ 1O mole) of 7-ficetyl-3-bromo-2-methyl-4H-benzopyrsn-4-one in 40 mL methanol was added 2.2 ml of sodium methoxide 18 & solution of No (w / v) in methanol) under an inert atmosphere. After 30 minutes, the reaction mixture was hydrolyzed with an ice-cold hydrochloric acid solution. The precipitate formed is filtered off and then washed until neutral to give the desired product.

Product yield: 1.9 g ($ 6 $);

Mn Melting point: 30> f310 C (with decomposition).

Some of the compounds of the present invention are listed in Tables I and II below, and the compounds are merely illustrative and not limiting.

Antithrombotic activity of compounds of the general formula

I was the following procedure;

The venous stoma was performed by the action of perugulum hypertension by the technique invoked by U / essler et al. x in f. / poiied Physiol. etr. 94j-94u). The bleaching agent used was (as was the case with the technique described above by H. &apos; * r ' et al., Thromboois ar.d ex-ostasis).

S i K ~) 19 1 Sul ´ · ile) X Oz-f CX. ti. C. > Lo X‘U λ. . n) commercially available from flow hoboratories (71 Knot for 12 ml mL of physiological sera?).

fest was performed with male rats of the species M / iot? r, with a body weight of 250 to 220 gx-am. The experimental animals were not fasted. The animals were divided into groups of ten individuals, the test products were administered orally in a foxia suspension at pH 400. 4 hours after the administration of the test product, thrombosis was induced and the thrombue formed was isolated and weighed.

The results of this test obtained for a dose of 3 Eg / ktf are also shown in the following Tables

- 48 Table

® O > Ό • H * 4 4 # * S ft Φ tí clay • rt X> • H •WITH and β W

and \ ε— να ω ra

- 49 About what

H tfs

CM SO Ό cf \ CM

I »r

CO i m

r-l as m ffi r-l ffi F* * T * · ** 8 O O O O O O O ffi O ffi O ffi O 1 1 1 1 1 t t

r-t

O

O

O t

ffi í

Table 1 (continued) ao t

ffi i

ffi

I ffi

I ffi t

ffi

AND

Í * S m

η »o

& * o

I m

«

ffi

About »

s0 i> t * 0

CO ooo ffi o

and

CM ffi

ÍM o

ÍM

CM ffi

O * W *

R-k ffi r-1 ffi r-1 ffi

About «

{«~ I— W \ &

LTS if • ifs

O O ffi ffi c-cis

SO s ©

- 50 ιΛ £ s £) 'V

N «Μ trn m m ι

£ ίη £ Μ ¢ 0 πΙ Ό ίί \

m ΡΠ <* 3 35 35 35 8 Ο Ο 8 ο 1 ** 5 Τ ϋ 1 ο 1

f * 3 «• Ί 35 35 Ο Ο Ο Ο Ο Ο ο 35 ο 3! ο 1 1 AND 1 1

>8>

Ο χ>

Μ ο

ο.

W es

JQ «

Η

Τ *?

I »3!

AND

I r-4 r-t 35 Ο Ο ι ι

AND

Ο

AND

η m ί * 3 <* 3 η η <* » <η AND*" ο, 3 $ 25 35 35 35 Si » and" 35 35 ο Ο Ο Ο Ο ϋ ο ο ο Ο Ο ♦ 1 1 1 1 « AND AND 1 1 1

C— * * 03 <0

ΚΟ κθ

C— ρ- Ρ ~

Ct'W 05 03

03 /

03 «

«« Ο £ 3 \ ΟΚ »-Ι α

r4 a α ο »η mJ» »

- 51 x m m! A CM <a ra xt· cy κ <a ra ¢ra co m>

xr what about

CM <a

X o

I ra x

o o

o ♦

sa cs

I o

o o

t • a

X o

o o

I «a

X

Table I (continued)

I t

CM is about

«<M * ÍM se o

»»

ÍM rH

O

AND

ra δ

AND

I <a w

O

AND

CM ra w

o t

ra «

O (

I x-x.

ÍM «

and

AND

AND

CM is about

I AM O

AND

I o

t <M

X

O t

ca x

O

I ra <a ra ra x x x o o o

I cn <Λ «0 co es xr ffi

Lf \ iPi ®

what about ~ 2.

«R

* · * «. r-t #"to r-l ÍM «$ · 0 * O r-i CM

Table I (continued)

7 /

X t

irt

O rt m

rt

O

I · * ¢ 5 «

• rt

C.

<8

O

AND

Ό ►

ss ©

♦ »n

CM o

rt! Λ

O o

tí

Ό «

F*"

X o

AND

CM «—I. <* »

S3

About rt%

Qt>

f = 1

Š • rt

O.

o o

A g

+ »«

and, tCh

JS

R «1 rt

Λ!

rt

HIM

O, -S

CM n

o σ »

ÍM o

I i

j4 a

cs • rt

and.

®

Yippee

S o

+ »C

©

4 »©

E.

on

Ό ©

rt

J4 rt * »

O.

& v

O « « t « « ra O. and. 0. O n O and. and p 4 » + » 3 •with Ό O Ό O «4 O, 1, fc and. ί- rt rt rt O O O « at ® ► ► > MB β MB £ XB £ Ο £ and £ «0 £ ra

1) product tested at an oral dose of 12.5 mg / kg

2) product tested at an oral dose of 3 mg / kg

O\

Table II

XS and _6/31 \ l λ '/

j \ í i 'and YO / and AND 1 OY 0 Example X Position Y «1 «2 Inhibition at 3 mg / kg dose / * / 20a 0 7 -COCH2 -ch ₃ —H 20 May 20 May 0 '7 -TO -CH _? -H 53 2la 0 7 -CXH ₃ ~ ° 2 ^Η 5 -H 42 21 0 7 -H ^ 2 ^B 5 -H 70 22a 0 7 -coch ₃ -CH ₃ -ch ₃ 66 22nd 0 7 -H -CH ₃ -ch ₃ 36

- 54 Table II / continued /

23a WITH 7 -CXH _} -ch ₃ -H 23 with 7 -H -cb ₃ -H 26 24a 0 6 -COCB-j -CH- -and «·» 24 0 6 -E -CHj -H 36 25a 0 7 -COCH ₃ -C ^ M 25 0 7 -Π - ° 6 «5 -H 28 26a with 7 -CXH, 3 -CH ^ w » 26 with 7 -H -ch ₃ -ch ₃ 27 Mar: 27 a with 7 -CXH, 3 ^ * 2 ^ 5 -H 23 27 Mar: with 7 -fí -CjHg -H 26 28a 0 7 -CXH4 -ch ₃ -Br 49 28 0 7 -H -ch ₃ -3r 49 AND Comparative product described in the case of 14/1 /

1 of EP-A-0133 103

B the comparative product described in Example 5 of SP-B091023

- 55 Table II / continued /

C Comparative product described in Example 20 (2) of Example 3 of U.S. Pat. No. 290,321

1 / product tested at 12.5 mg / kg ρ · ο · 2 / product tested at 3 mg / kg p.o.

Table III

Position * 2 Melting point 5 -CB ₃ -H 166-168 7 -H 216 8 -ch ₃ -H 154 6 -H 164 7 -C? ₃ 163 7 -CBL j -Cl 184.5 7 • ~ _CH2 ~ CB ₃ -B 158-160

il

Table III / continued /

-C 8 -CH 3 -CH 3 -H 118-120

7 (1) -CHg-CBg-C1-4-CHg-155-160 [1- (718,9,13-tetrahydro-6-oxo-6B-dibenzo) -d7-pyran-3-yl] dimethylthiocarbamethyl-4-oxo-6B

- 53 Table IV

N — CH. J 3 /

/

CH.

Position ^E , ^S 2 Melting point / ° C / 7 -CH ₃ -fi 13? 7 -ch ₃ -cb ₃ lóQ 7 ~ Cl ₂ -CH ₃ -H 140

Position

CHR «

-ch ₃

-ch ₃

-CH ₃

-ch ₃

-CP ₃

Table V

CHH

JS ‘

R.

m Melting point / ° C / «&

-CH ₂ -CH ₃

-H

-H

-H

-H

-H

-Cl

-H

129

154

154

137

138

229

124

Table V / continued /

7 (1) • CH ₂ -CH ₂ -CH ₃ -H 99-100

-CH ₂ -CK ₂ -CK ₂ -CH ₂ - 132 / 7,8,9,1 O-tetrahydro-6-oxo-6H-azoquinone (f) b, d-7-pyranyl) dimethylthiocarbamic acid

1 /

- 61 Table VI

β.

rs ⁿ í

N CK,

B / ch ₃

Position ^S 1 e ₂ Melting point / ° C / 7 -cu ₃ -H 164 7 -CH ₃ -ch ₃ 1 38 7 -CH ₂ -CH ₃ -and 116

VIT table

⁶

Position * 1 k ₂ Melting point / ° C / 7 -Cfi ₃ — Knows 136 7 -CH- ₃ -H 132 8 -ch ₃ -H 114-115 6 -ch ₃ -TO 138-140 7 -CF ₃ -H 115 7 -CBj -Cl 153 7 -C ^C -C -H 152

-63-.

iabulka VII / continued /

-H 38-89

7/1 / -CIL-CSk-CIL-CS * - 139 e ~ <t ί. ύ.

(7,8,9,1-3-trahydro-3-mercapto-6H-d-lber.zo / b, d-7-pyren-6-one)

VITI table

O

Position ^K , r ₂ Melting point / ° C 7 -CItj -H »20 7 -CS ₃ - ° ^Η 3 122 7 -CH ₂ -CH ₃ -H 74

Claims (21)

PATENT CLAIMS A benzopyranone-p-D-thioxyloside of the formula I wherein: - one of R or R 'represents an oxygen atom attached by a double bond to the corresponding cyclic carbon atom and the other of R or R' represents a group R 6, the symbol - - - means a double bond conjugated to a CO group formed by one of R or R substituents ', X represents a sulfur atom or an oxygen atom, R 1 and R ₂ are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 1 and R ₂ together with the benzopyran group to which they are attached may form 7 , 8,9,10-tetrahydro-dibenzo [b, d] pyran-6-one or 1,2,3,4-tetrahydro-9H-xanthen-9-one, and Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms. A thioxyloside according to claim 1 of the general formula (Ia) in which: X is sulfur or oxygen, R 8 and R 8 are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 1 and R 2 together with a benzopyran-2-one group may that are bound, create 7,8,9,10-tetrahydrodibenzo [b, d] pyran-6-one, a Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms. 3. A compound according to claim 1, wherein: X is sulfur or oxygen, R 1 and R 2 are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 1 and R 2 together with the benzopyran-4-one group to which they are linked to form a 1,2,3,4-tetrahydro-9H-xanthen-9-one group; and Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms. A compound according to claim 1, wherein X is bonded to the 7-position of the benzopyranone ring and R 1 and R 2 are the same or different, each independently hydrogen, C 1 -C 4 alkyl, halogen or phenyl group. 5. A compound according to claim 2 wherein X is attached to the 7-position of the benzopyranone ring and R1 and R2 are the same or different, each independently hydrogen, C1-C4alkyl, halogen or phenyl group. A compound according to claim 3, wherein X is bonded to the 7-position of the benzopyranone ring and R 1 and R 2 are the same or different, each independently hydrogen, C 1 -C 4 alkyl, halogen or phenyl. A compound according to claim 1, wherein Y is CH 2 CO. 8. A compound according to claim 2, wherein Y is CH3CO. A compound according to claim 3 or 6, wherein Y is CH 2 CO. 10. The compound of claim 2, wherein the compound is 4-Methyl-2-oxo-2H-1-bezopyran-7-yl-1,5-dithio-β-D-xylopyranoside. 11. The compound of claim 2, wherein the compound is 3-Chloro-4-methyl-2-oxo-2H-1-benzopyran-7-yl-1,5-dithio-β-D-xylopyranoside. A compound according to claim 2, wherein the compound is 4-Ethyl-2-oxo-2H-1-benzopyran-7-yl-5-thio-β-D-xylopyranoside. 13. A pharmaceutical composition comprising as active ingredient one thioxyloside according to claim 1 of the general formula Also in combination with a physiologically acceptable excipient. 14. A pharmaceutical composition comprising, as active ingredient, a thioxyloside of the formula Ia according to claims 2 and 10 &lt; 2 &gt; in combination with a physiologically acceptable excipient. 15. A pharmaceutical composition characterized in that it contains as active substance one thioxylosid _of formula Ib according to claim 3 in combination with a physiologically acceptable excipient. 16. Thioxyloside according to its use in combating disorders The thioxyloside according to Ia for use in combating claim 1 of formula I for venous circulation. of claims 2 and 10/12 of the general formula of venous circulation disorders. The thioxyloside of claim 3 of formula Ib for use in combating disorders of venous circulation. A process for the preparation of the benzopyranone-β-D-thioxylosides of the formula I according to claim 1, characterized in that (i) the compound of the formula II (II) in which X, R, R 'and R2 are as defined above is reacted with a thioxylose derivative selected from the group consisting of - acylthioxylosyl halides of the general formula III OY - peracylated thioxylose compounds of formula IV: (IV) - and acylthioxylosyltrichloroacetimidates of the general formula V: OY NH II C-CCX ₃ (V) in which: Hal represents a halogen atom such as a chlorine or bromine atom, preferably a bromine atom, and Y represents an aliphatic acyl group having 2 to 5 carbon atoms, in an inert solvent and in the presence of an acid acceptor and / or a Lewis acid, using 0.6 to 1.2 mol of the compound of the formula III, IV per mole or V, (ii) where appropriate, the compound of formula (I) in which Y is an acyl group having 2 to 5 carbon atoms is optionally deacylated at 0 ° C to the reflux temperature of the reaction medium, which is a C1-C4 alcohol, preferably methanol, in the presence of a metal alcoholate, preferably in the presence of magnesium methylate or sodium methylate. A process according to claim 19 for the preparation of benzopyran-2-one-β-D-thioxylosides of the formula Ia wherein: X represents a sulfur atom or an oxygen atom, R 1 and R ₂ are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group or a phenyl group, or R 5 and R ₂ together with a benzopyran-2-one group may that are bound, create 7,8,9,10-tetrahydrodibenzo [b, d] pyran-6-one, a Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms, characterized in that a compound of the formula II is used as the starting product: in which : R 'means R ^, R is an oxygen atom, and X and R ₂ have the same meaning as above. A process according to claim 19 for the preparation of benzopyran-4-one-δ-D-thioxylosides of the general formula Ib (Ib) in which: X represents a sulfur atom or an oxygen atom, R 1 and R ₂ are the same or different and each represents a hydrogen atom, a C 1 -C 4 alkyl group, a halogen atom, a trifluoromethyl group and a phenyl group, or R 1 and R 2 together with the benzopyran-4-one group to which they are attached , make up 1,2,3,4-tetrahydro-9H-xanthen-9-one, a Y represents a hydrogen atom or an aliphatic acyl group having 2 to 5 carbon atoms, characterized in that a compound of the formula 11½ is used as the starting product in which: R means R znamená means an oxygen atom, and X and R2 have the same meaning as previously described Represented by: