CZ414998A3 - Novel glycosides exhibiting anticoagulative activity and pharmaceutical compositions prepared therefrom - Google Patents

Abstract

This invention relates to novel 1,5-dithio-pyranosides of formula (I) wherein R1 represents hydrogen, hydroxy or an azido group, R2 represents hydroxy, azido, amino or an acetamido group, R3 represents hydroxy or an azido group, R4 represents hydrogen, methyl or a hydroxymethyl group, R5 represents hydrogen, R4 and R5 together represent a methylene group, R6 represents a nitro, cyano, amidino, aminothiocarbonyl, -C(=NH)-OCH3, -C(=NH)-NH-NH2 or -C(=NH)-SCH3 group, with the proviso that R6 represents only a group other than a nitro or cyano group if R1-R3 each represents hydroxy groups, and R4 as well as R5 represent hydrogen, furthermore that R6 represents only a group other than a nitro group if R1-R3 each represents hydroxy groups, R4 represents a hydroxymethyl group and R5 represents hydrogen, and the acid addition salts thereof formed with organic or inorganic acids, if possible and pharmaceutical compositions containing the same. The compounds of the invention possess valuable therapeutic, particularly anticoagulant properties.

Description

Technical field

The present invention relates to novel 1,5-dithiopyranosides of formula (I)

K where:

Rj represents hydrogen, hydroxyl or azido group, R ₂ represents hydroxy, azido, amino or acetamido group,

K ₃ represents a hydroxy group or an azide group,

R 1 represents hydrogen, methyl or hydroxymethyl,

R ₅ represents hydrogen,

R ₄ and R 8 together represent a methylene group

R 6 represents a nitro-, cyano-, amidino-, aminothiocarbonyl, -C (= NH) -OCH _{3 group} ,

-C (= NH) -NH-NH ₂ or -C (= NH) -SCH ₃ with the proviso that R ₆ represents exclusively a group other than nitro- or cyano when R _x -R ₃ represent hydroxy groups and R ₄ as well as R 4 R ₆ is furthermore that R ₆ is exclusively a non-nitro group when - R ₃ is hydroxy, R ₄ is hydroxymethyl and R ₃ is hydrogen and, where possible, acid addition salts thereof formed with organic and inorganic acids.

· · · ♦

BACKGROUND OF THE INVENTION

The compounds of the invention have valuable pharmaceutical properties, particularly anticoagulant activity even when administered orally.

Particularly valuable representatives of Formula (I) according to the invention are:

/ 1 __ f ττίίι T ~ k / - \ * 1 (tyi nhb r. Vi f) mril ^- bi 1 1 r ·, mr 1. '1 \ 1.U r, t. a.. ·, νγ - _Lu Ulij XiVliy j J.

R-z-J 4 4-to 4 -, _ Ρ_ΓΎ _ »uxlíixv | _ / a_ '

XV

2. opy i? o. ncoi

4- (aminothiocarbonyl) phenyl-1,5-dithio-β-D-xylopyranoside

4- (imino) (methylthio) methylphenyl-1,5-dithio-p-Dxylopyranoside

4-amidinophenyl-1,5-dithio-β-D-xylopyranoside

4- (hydrazino) (imino) methylphenyl-1,5-dithio-β-D-xylopyranoside 4-cyanophenyl-4-azido-4-deoxy-1,5-dithio-β-D-xylopyranoside

4-Cyanophenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside

4-cyanophenyl-2-deoxy-1,5-dlthio, β-D-threo-pentopyranoside 4-cyanophenyl-2-azido-2-deoxy-1,5-dithio-β-D-xylopyranoside 4- (imino) (methoxy) methylphenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside

4-cyanophenyl-1,5-dithio-β-D-glucopyranoside

4-Cyanophenyl-6-deoxy-1,5-dithio-β-D-glucopyranoside

4- (imino) (methoxy) methylphenyl-1,5-dithio-β-D-glucopyranoside 4-nitrophenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside 4- (aminothiocarbonyl) phenyl-6-deoxy -1,5-dithio-β-D-glucopyranoside

4- (aminothiocarbonyl) phenyl-2-deoxy-1,5-dithio-β-D-threopentopyranoside

4- (aminothiocarbonyl) phenyl-1,5-dithio-β-D-glucopyranoside 4- (imino) (methylthio) methylphenyl 4-aminophenyl-2-deoxy-1,5-dihydro-β-D-threo-pentopyranoside -1,5-dithio-β-D-glucopyranoside

4-Nitrophenyl-2-deoxy-1,5-dithio-β-D-threo-pentopyranoside Some derivatives of formula (I) wherein R ₃ -R ₃ are hydroxy, R ₄ and R ₅ are hydrogen (i.e., 1,5-dithioxylopyranosides) and R ₆ represents a chloro, nitro, cyano, methyl or methoxy group are known in the literature (E. Bellamy et al., Eur. J. Med. Chem., vol. 30, supra). Advantageous anticoagulant activity in oral administration of such, vn v-. - ,, τ ,, - ι i π, ir, 1 v-, ~ l 1 _L 1 C l \ £, OL CUC L.CN UJC IJ1L1U UCL »U Rý Q 1J UJ ΛUU 2 IIU \ I_iL O.

365.397). Also, the 1,5-dithioglucopyranoside of formula (I) wherein R 1 -R 1 are hydroxy, R ₄ hydroxymethyl, R ₅ hydrogen and R ₆ nitro is known in the literature (B. Joseph and P. Rollin, J. Carbohydr. Chem. 12, 1993, p. 719), but the biological activity of this compound has not been described in detail.

SUMMARY OF THE INVENTION

It was an object of the present invention to provide such novel carbohydrate derivatives that are potent inhibitors of coagulation processes than known compounds and are also active when administered orally.

Surprisingly, it has been found that it is possible to substantially increase the antithrombotic activity of saccharide derivatives by replacing the hydroxyl groups of the saccharide structural component (R 1 -R ₃ ) with hydrogen or an azide group. Similarly, increased activity was found in thioglycosides in which the carbohydrate member was thiohexose (R ₄ represents hydroxymethyl group) instead of thiopentose, as well as other derivatives in which the cyano gubstituent on the C-4 aglycone was transformed into a carboxyl group derivative.

The compounds of the invention can be synthesized by various known methods.

a) A compound of formula (1) in which F 1 - R ₃ are hydroxy, R ₄ and R ₅ are hydrogen and R _e is _C (= NH) -OCH 3 can be prepared, for example, by treatment with sodium methoxide (sodium methylate) in methanol to a compound of formula (I) wherein R ₃ -R ₅ is as defined above and R ₆ is cyano, or for example by heating a methanol solution of a compound of formula (T) wherein R ₃ -R ₅ is as defined above, and R ₆ is -C (= NH) -SCH ₃ .

b) Compound of formula (I) in which R _T - R ₃ represent hydroxy, R ₄ and R $ are hydrogen and _R6 represents an aminothiocarbonyl group, can be prepared for example by treatment with hydrogen sulfide to the compound of formula (I) wherein the meaning of Ri - _R is as defined above and R ₆ is cyano, an organic base as solvent.

This reaction is preferably carried out at room temperature using a 1: 1 mixture of triethylamine and pyridine as solvent.

c) A compound of formula (T) wherein R ₃ -R ₃ are hydroxyl groups, R _a and R _b are hydrogen and R ₆ is -C (= NH) -SCH ₃ can be prepared by treating the compound of formula with methylating agent (I) wherein R 1 -R ₅ is as defined above and R ₆ is an aminothiocarbonyl group.

This reaction is preferably carried out using acetone as the solvent and methyl iodide as the methylating agent at reflux (heating at reflux).

d) A compound of formula (I) wherein R ₁ - R ₃ are hydroxyl groups, R ₄ and R ₅ are hydrogen and R ₆ represents an amidino group can be prepared by treatment of a compound of formula (T) with ammonium acetate or ammonia in which: expressions • · · c ·· «· · ·

About «·» ··· ·

R 1 -R 5 are as defined above and R ₆ is -C (= NH) SCH ₃ , in a lower aliphatic alcohol solvent.

This reaction can be advantageously performed using methanol or ethanol as solvent at reflux temperature.

e) A compound of formula (I) wherein R 1 -R ₃ are hydroxyl groups, R ₄ and R ₅ are hydrogen and R ₆ is -C (= NH) -NH-NH 2 can be prepared by treatment of a compound of formula (hydrazine) with ( I), wherein the terms R 1 -R ₅ are as defined above and R ₆ is -C (-NH / 5 CH 3) in a lower alcohol solvent.

This reaction can be advantageously carried out using 98% hydrazine hydrate as the reagent and ethanol as the solvent.

f) A compound of formula (I) wherein R 1 and R ₂ are hydroxy, R 1 is an azide group, R 1 and R ₅ are hydrogen and R 1 is cyano can be prepared, for example, by separation of the β-anomer from the anomeric mixture of formula ( I1)

wherein R represents a cyano group, followed by removal of the acetyl groups by the action of the base in the lower aliphatic and 1-carbonate,

This reaction is preferably carried out by resolving the anomeric mixture of formula (II) in which R represents a cyano group, by column chromatography and removing the acetyl groups from the separated β-anomer using sodium methoxide in methanol solution.

The glycosides of formula (II) in which R is cyano are novel compounds and can be prepared, for example, from a compound of formula (VII),

CH 1 OR (Vlf) wherein R 1 and R ₂ are hydrogen, by applying a protecting group to the primary hydroxyl group and mesylating the secondary hydroxyl group. The obtained compound of formula (VII) wherein R 1 represents a mesyl (melhansuifonyl) group and R ₂ represents a self protecting group is transformed by reaction with a suitable azide to a compound of formula (VI)

SEt wherein R represents a hydroxy group protected with a suitable protecting group. This protecting group is then removed, and the free hydroxyl group is preferably sequentially removed by mesylation. Reaction with a thioacid salt yields the corresponding thioester from which the ethyl mercapto groups are cleaved. From the obtained aldehyde of formula (V)

CHO

Ο /

benzovlová group was removed and then the isopropylidene group, and the resulting thiosacharid ¹ is converted either directly or tra metiivl AD vkosi d V7nrce / Tyl

i - J - i - - - - - - -

wherein R is methoxy, to the tri acetate of formula (IV), wherein R is acetoxy. Condensation of this compound with 4-cyanothiophenol of formula (III)

SH

CN produces an anomeric mixture of glycosides of formula (II) wherein R is cyano.

In an alternative method of preparation, the same mixture of glycosides can be obtained by converting a triacetate of formula (IV) wherein R is acetoxy to a diacetate of formula (IV) wherein

R is hydroxy followed by the trichloroacetimidate of formula (IV) in which R is *

-O-C (NH) -CCl ₃ . Its condensation with compound (III) provides an anomeric mixture of glycosides of formula (II) in which R represents a cyano group.

This reaction sequence can be advantageously carried out by subjecting the mercaptal of formula (VII), wherein a R ₂ represents hydrogen, preferably in an organic base most preferably pyridine, to the treatment first

A) 1.1 equivalents of benzoyl chloride followed by mesylchloririn to give compounds of formula (VII) in which R 1 represents a mesyl group and R _{2 a} benzoyl group, or by treatment first

B) 1.1 equivalents of tert-butyldimethylsilyl chloride (TBDMSCl) followed by mesyl chloride to give compounds of formula (VII) wherein R 1 is a mesyl group and R _{2 is} a TBDMS group. The obtained compound was reacted at 100'150 ^e C, preferably at 120 ° C, with a suitable salt of nitrous acid KOVOD Premium (.izoimidem), preferably sodium azide, in a nonpolar solvent, preferably N, N-dimethylformamide or dimethylsulfoxide. Then, the benzoyl group is removed from the obtained intermediate of formula (VII) wherein R 1 represents a mesyl group and R ₂ represents a benzoyl group with sodium methoxide in methanol, while the TBDMS protecting group of the intermediate of formula (VII) wherein R _x represents a mesyl group and R? is a TBDMS group, cleaved with tetrabutylammonium fluoride (tetrabutylammonium fluoride) in tetrahydrofuran. The obtained compound of formula (VI), wherein R is hydroxy, is converted to the mesylate of formula (VI), wherein R is mesyloxy, with mesyichloride in pyridine solution. This is reacted with a thiocarboxylic acid salt, preferably potassium thiobenzoate in an aprotic solvent, preferably in N, N-dimethylformamide, to an ester of formula (VI) wherein R is benzoylthio.

The ethyl mercapto groups of this intermediate, preferably mercuric chloride in aqueous acetone in the presence of cadmium carbonate, are cleaved to give the aldehyde of formula (V). The aldehyde ester group of formula (V) is removed with sodium methoxide in methanol, followed by cleavage of the isopropylidene group by acidifying the solution with hydrochloric acid. Neutralization of this solution and reaction of the evaporation residue with anhydride. in pyridine gave a mixture of a- £ θ "3 CTD iri I ^- Λ formula (TV) wherein R represents an acetoxy group. When the acidified solution in methanol is allowed to stand for a longer period of time, or when heated before neutralization and acetylation, a mixture of acetylated α- and β-methylglycosides of formula (IV) is obtained, wherein R is methoxy. This latter compound can be transformed with sulfuric acid in acetic anhydride to give the triacetates of formula (IV) above, wherein R is acetoxy. When a solution of this mixture of triacetates in an aprotic solvent, preferably dichloromethane, is reacted with the 4-cyanothiophenol of formula (III) in the presence of a promoter, more preferably trimethylsilyl triflate, a mixture of glycosides of formula (II) is obtained, wherein R is cyano.

Alternatively, the same mixture is formed when the triacetate of formula (IV) in which R is acetoxy is reacted with hydrazine acetate in N, N-dimethylformamide and the resulting compound of formula (IV) in which R is hydroxy is reacted with trichloroacetonitrile in dichloromethane in the presence potassium carbonate and provides an imidate of formula (IV) wherein R is -O-C (NH) -CCl ₃ . Reaction of this compound with 4-cyanothiophenol of formula (III) in the presence of boron trifluoride etherate in dichloromethane or 1,2-dichloroethane at low temperature, preferably at -15 ° C, affords the same glycoside mixture of formula (II) described above, wherein R is cyano.

«· V v v v v v v v« «

g) A compound of formula (I) wherein R 1 and R ₃ are hydroxy, R ₂ is azido, R ₄ and R ₅ are hydrogen and R ₆ is cyano can be prepared, for example, by reaction of xylopyranose of formula (VIII),

J (VIII) wherein R is acetoxy or OC (NH) -CCl ₃ , with 4-cyanothiophenol of formula (III) in the presence of a promoter and removal of acetyl groups from the resulting glycoside of formula (X), wherein R is cyano , by the action of a base in a lower aliphatic alcohol environment.

This reaction can be advantageously carried out by reacting A) an acetate of formula (VIII) in which R is an acetoxy group with a 4-cyanothiophenol of formula (III) in dichloromethane at low temperature, preferably at -10 ° C in the presence of trimethylsilyl. filament as a promoter, or alternatively

B) an imidate of formula (VIII) wherein R represents O-C (NH) CCl 3 with 4-cyanothiophenol of formula (III) in dichloromethane; or

1,2-dichloroethane in the presence of boron trifluoride etherate as a promoter at low temperature, preferably at -15 ° C. In both ► «· · · ·« ft «» <

In some cases, a mixture of glycosides is formed, from which the β-anomer of formula (X) in which R is cyano is separated by column chromatography. The deacetylation of a compound of formula (X) wherein R is cyano can be accomplished with sodium methoxide in methanol to give a compound of formula (I) wherein R 1 and R ₃ are hydroxy, R ₂ is an azide group, R ₄ and R ₅ are hydrogen and R ₆ is a cyano group.

ΓΊ, -, v-4, TÁ4-γγι r 1 p v- v A i -. *. ,. - π / JIT XT \ * i / Cx. jvavc * v xvpy r uivivý vv í. t; ; in J. ± ±) _f VII from: May,. r \ represents an acetoxy group, is also a novel compound and may be prepared for example by converting the known (RI. Ohrui daisic Agric. Biol. Chem., Vol. 34, 1970, p. 375) 3-azido-3-deoxy-1,2-isopropylidene-5-O-tosyl-D-xylofuranose with potassium thiobenzoate per ester of formula (ΓΧ),

'11 O

From which is debenzoylated first, the isopropylidene group is cleaved off and the resulting 5-thioxylopyranose derivative is transformed into its peracetate.

This reaction sequence can advantageously be quenched by reacting 3azido-3-deoxy-1,2-O-isopropylidene-5-O-tosyl-D-xylofuranose with potassium thiobenzoate in N, N-dimethylformamide at 100 ° C. The resulting ester of formula (IX) is debenzoylated with sodium methoxide in methanol, then the solution is acidified with aqueous hydrochloric acid, boiled and the trihydroxy derivative obtained is converted with acetic anhydride in pyridine to its peracetate of formula (VIII) in which R is acetoxy.

h) A compound of formula (I) wherein R _1, R ₄ and R ₅ are hydrogen, R 6, and R ₃ is hydroxy and R ₆ is cyano, can be prepared, for example, by adding hydrogen bromide in an aprotic solvent to the pentose derivative of formula (XI),

OR wherein R represents benzoyl groups, and reacting the resulting bromide of formula (XII), (XH) i

O 2 Z in which R represents a bromine atom with a 4-cyanothiophenol salt of formula (III). The ester groups of the resulting glycoside of formula (XTT), wherein the R concept is 4-cyanophenyl-1hio, are removed by treatment with a base in a lower aliphatic alcohol and the desired above-mentioned β-anomer of formula (I) is separated by crystallization from the resulting mixture of anomeric glycosides.

Alternatively, the same mixture of glycosides of formula (XII) in which R is 4-cyanophenylthio can be obtained by first substituting the bromine atom of the bromide of formula (XII) in which R is bromo with acetoxy and reacting the resulting acetate with structure (XII) in wherein R is an acetoxy group, with the 4-cyanothiophenol of structure (III) in the presence of a promoter.

This reaction sequence can preferably be done by saturating the double bond of the pentose derivative of formula (XI) wherein R represents a benzoyl group, with hydrogen bromide in benzene solution and reacting the obtained reactive intermediate of formula (XII) wherein _R

R is bromo, without isolation with sodium cyanothiophenol sodium prepared in situ from compound (III) and sodium hydride. The resulting mixture of anomers of structure (XII) wherein R is 4-cyanophenylthio is separated from the undesired component of formula (XI) in which R is benzoyl by column chromatography.

Alternatively, the same mixture of glycosides of structure (XII) wherein R is 4-cyanophenylthio is obtained when the thickened intermediate of formula (XII) wherein R is bromo is reacted without isolation with silver acetate in acetonitrile and the resulting acetate of formula (XII), wherein R is acetoxy, is reacted with 4-cyanothiophenol of formula (III) in dichloromethane in the presence of trimethylsilyltrilate. Eíenzoylové groups of the obtained mixture of glycosides of the structure (XII), wherein R represents 4kyanofenylthioskupinu may be removed methoxide with sodium in methanol to form a mixture of the anomeric glycosides from which the desired β-anoruor formula (I) wherein R _HR R _4, and _R j .sou hydrogen R ₂ and R ₃ represent hydroxy, and R represents a cyano group _Fe, separated by crystallization.

i) A compound of formula (I) wherein Ry is an azide group, R ₂ and R ₃ are hydroxy, R ₄ and R ₅ are hydrogen and R _e is cyano can be prepared, for example, by azidonitration in an aprotic solvent of the pentose derivative of formula (XI) , wherein R is benzoyl, replacing the O-nitro group of the obtained intermediate of formula (XIII), (XIII) wherein R is O-nitro, acetoxy, and condensing the formed triester of formula (XIII), wherein R is acetoxy, with 4-cyanothiophenol structure (III) in the presence of a promoter. The two anomers of the glycoside mixture of structure (XIII) in which R is 4-cyanophenylthio are separated and the ester groups of the βanomer are removed by treatment with a base in a lower aliphatic alcohol.

This reaction sequence is preferably carried out using acetonitrile as solvent and sodium azide and cerium ammonium nitrate as reagents and azidonitration of the pentose derivative of formula (XI) in which R represents a benzoyl group. The resulting intermediate of formula (XIII), wherein R is O-nitro, is reacted in acetic acid at elevated temperature (preferably 100 ° C) with potassium acetate to give the triester of formula (XIII), wherein R is acetoxy, and this is reacted with 4-cyanothiophenol of formula (III) using tetramethylsilyl triflate as a promoter. The resulting mixture of glycosides of structure (XII) in which R represents

The 4-cyanophenylthio group is separated by column chromatography and the benzoyl groups are removed from the β-anomer by treatment with sodium methoxide in methanol to give the desired glycosides of formula (I) wherein R 1 is azido, R ₂ and R ₃ are hydroxy, R 4 and R ₅ R ₆ is hydrogen and R ₆ is cyano,

j) A compound of formula (I) wherein R ₄ and R ₃ are hydroxy, R _z is amino, R ₄ and R 5 are hydrogen and R ₆ is cyano can be prepared, for example, by reducing the 3-azido group of the compound of formula (I) wherein R ₁ and R ₃ are hydroxy, R ₂ is azido, R ₄ and R 8 are hydrogen and R ₆ is cyano in a lower aliphatic alcohol solvent.

This reaction can be advantageously carried out using ethanol as solvent and sodium borohydride nickel chloride as reagent.

k) A compound of formula (I) wherein R 1 and R ₃ are hydroxy, R ₂ is acetamido, R _q and R ₅ are hydrogen and R ₆ is cyano can be prepared, for example, by reacting a compound of formula (I) wherein R 1 and R 2 are R ₃ is hydroxy. R 1 is amino, R ₅ and R ₅ are hydrogen and R ₆ is cyano, with acetic anhydride in the presence of a base and subsequent removal of the ester groups formed.

This reaction can be conveniently performed using pyridine as the base and sodium methoxide in methanol to remove the ester groups.

l) A compound of formula (I) wherein R 1 and R ₃ are hydroxy, R ₂ is azido, R 4 and R _{5 are} preferably hydrogen and R ₅ . is -C (= NH) -OCH-, so can be prepared, for example, by reacting a compound of formula (I) wherein R 1 -R ₅ is as defined above and R ₆ is cyano with sodium methoxide in methanol.

m) A compound of formula (I) wherein R 1 -R 3 are hydroxy, R ₄ is hydroxymethyl, R ₅ is hydrogen and R ₆ is cyano can be prepared, for example, by separation of two anomers of formula (XIV),

OAc in which R is acetoxy and X is cyano, and removal of the acetyl groups from the β-anomer by reaction with a base in a lower aliphatic alcohol.

Column chromatography is preferably used to isolate both anomers and deacetylation of the isolated β-anomer is performed with sodium methoxide in methanol.

The glycosides of formula (XIV), wherein R is acetoxy and X is cyano, are novel compounds and can be prepared, for example, by the reaction of the already known compounds of formula (XIV). ......- “··· *» / \ ”· 'J

1ΠΟ

1982), p. 293) Acetobromo-5-thio-D-glucose with 4Ln nrc, tbxAnriA 1 r / TTT 1 n i U, i i i, i v oli, they ϊ o vi . OO + - / -. r ·. λά n f i A - Λ '. t r

1. _L. L-Ulit 1 1 i_) k- _L kXO Δ. t In an aprotic solvent.

This reaction can preferably be carried out under reflux using acetone as the solvent and potassium carbonate as the base.

n) A compound of formula (I) wherein Γ <1 - R ₃ is hydroxy, R ₄ is methyl, R _f) is hydrogen and R ₆ is cyano can be prepared, for example, by eliminating the acetyl groups of the β-anomer of the compound of formula (XIV), wherein R is hydrogen and X is cyano, by reaction with a base in a lower aliphatic alcohol.

The β-glycoside of formula (XIV) wherein R is hydrogen and X is cyano is a novel compound and can be prepared, for example,

A) converting the primary hydroxyl group of the glycoside of formula (I) wherein R 1 -R ₃ are hydroxyl groups, R ₄ is hydroxymethyl, R ₅ is hydrogen and R ₆ is cyano to the active ester which reacts with the iodide in the protecting the remaining hydroxyl groups and the iodinated substituent is removed by a reductive route from the formed intermediate of formula (XIV) in which R represents □ of iodine and X represents a cyano group, or

B) a known compound (E. Bozo et al., Carbohydr. Res., Vol. 290, (1996), p. 159) 1,2,3,4-tetra-O-acetyl-6-deoxy-5-thioD- glucopyranose is converted to an acetobromo derivative, the condensation of which with 4-cyanothiophenol of formula (III) is carried out in an aprotic solvent in the presence of a base. Then, the βanomer is isolated from the obtained anomeric mixture of formula (XIV) wherein R is hydrogen and X is a cyano group.

The sequence of operations referred to in method A) can preferably be carried out as follows: The primary hydroxy group of glycoside of formula (I) wherein R ~ R ₃ represent hydroxy, R ₄ is hydroxymethyl, _R is hydrogen, and R _E is cyano with mesylation prepared for cleavage and the remaining hydroxy groups are protected by acetylation. The obtained mesylate of formula (XIV), wherein R is mesyloxy and X is cyano, is reacted with sodium iodide in diethyl ketone at reflux temperature and from the iodinated derivative of the resulting compound of formula (XIV) wherein R is 1 is iodine and X is cyano group, the iodine substituent is removed by the reduction route using sodium borohydride-nickel chloride reagent.

The sequence of reactions shown in Method B) can preferably be carried out as follows: acetobromo-6-deoxy-5-thio-D-glucose is converted by the action of 4-cyanothiophenol of formula (III) in boiling acetone and in the presence of potassium carbonate to a mixture of anomeric glycosides of formula (XIV) ), wherein R is hydrogen and X is a cyano group, and the β-anomer of structure (I) in which R 1 -R 3 are hydroxy, R ₄ is methyl, R ₅ is hydrogen and R _e is cyano is separated by crystallization 2 of this mixture.

o) A compound of formula (I) wherein R 1 -R 3 are hydroxy, R ₄ and R 2 together represent a methylene group and R _e represents a cyano group, may be prepared by flflflflflf Flflfl, for example by removing acetyl groups from the β-anomer of formula (XV)

OAc (XV) by the base in a lower aliphatic alcohol environment.

This reaction can advantageously be carried out with sodium methoxide in methanol.

The β-glycoside of formula (XV) is a novel compound and can be prepared, for example, by cleavage of hydrogen iodide from the iodide of a compound of formula (XIV), wherein R represents an iodine atom and X represents a cyano group.

This elimination reaction can advantageously be carried out in pyridine using silver trifluoride as reagent.

p) A compound of formula (I) wherein - R ₃ is hydroxy, R ₄ is hydroxymethyl, R 8 is hydrogen and R ₆ is -C (= NH) -OCH ₃ , can be prepared, for example, by reaction of a derivative of formula (I) I), wherein R ₃ R ₃ are hydroxy, R ₄ is hydroxymethyl, R ₅ is hydrogen and R ₆ is a cyano group, by reaction with sodium methoxide in methanol.

q) A compound of formula (I) wherein R ₃ and R ₃ are hydroxy, R ₂ is azido, R ₄ and R ₅ are hydrogen and R ₆ is nitro can be prepared, for example, by reacting a xylopyranose derivative of formula (VITI) wherein: R is acetoxy, with 4-nitrothiophenol in the presence of a promoter and removal of acetyl groups from the obtained glycoside of formula (X) in which R is nitro, with a base in a lower aliphatic alcohol.

This reaction sequence may conveniently be carried out by reacting a xylopranose derivative of formula (VIII) in which R is acetoxy with 4-nitrothiophenol in dichloromethane at low temperature, preferably at -10 ° C using trimethylsilyl triflate as promoter, or in 1,2-dichloroethane at 20 ° C using boron trifluoride etherate as promoter. From the anomeric mixture obtained, the β-glycoside of formula (X) wherein R is nitro is separated by column chromatography and then deacetylated with sodium methoxide in methanol to give a compound of formula (I) wherein R _x and R ₃ are hydroxy groups, R ₂ is azido, R ₄ and R 6 are hydrogen and R ₆ is nitro.

r) The compound of formula (I) in which R - _R is hydroxy, R ₄ represents a methyl group, _R5 represents hydrogen and R represents an amino not.hi okarbonylovou group can be prepared by reacting a compound of formula (I) wherein the meaning of _{R f} - R 5 are as defined above, and R _E is a cyano group, with hydrogen sulfide using an organic base as solvent.

This reaction is preferably carried out at room temperature using a 1: 1 mixture of triethylamine-pyridine as solvent.

s) The compound of formula (I) in which Ri, R ₄ and R ₅ are hydrogen, R ₂ and R ₃ represent hydroxy, and R _E represents an aminothiocarbonyl group, can be prepared for example by reacting a compound of formula (I) wherein the terms R - R > are as defined above, and R _E is a cyano group, with hydrogen sulfide using an organic base as solvent.

This reaction is preferably carried out at room temperature using a 1: 1 mixture of triethylamine-pyridine as solvent.

t) A compound of formula (I) wherein R 1, R 2, and R ₅ are hydrogen, R ₂ and R ₃ are hydroxy and R 6 is an amidino group can be prepared, for example, by reacting a compound of formula (I) wherein R 1 - R ₅ is as defined above and R ₆ is an aminothiocarbonyl group with a methylating agent to give an intermediate compound of formula (I) wherein R 1 -R ₅ are as defined above and R _e is -C (= NH) -SCH ₃ . Its reaction with ammonium acetate or ammonia using a lower aliphatic alcohol as solvent provides the desired product of formula (I) wherein R _1, R ₄ and R ₅ are hydrogen, R ₂ and R ₃ are hydroxy and R ₆ is an amidine group.

These reactions can advantageously be carried out using methyl iodide as the reagent and acetone as the solvent in methylation and replacing the resulting methylthio group with ammonium acetate in methanol or ethanol as the solvent at reflux.

u) A compound of formula (I) wherein R _x -R ₃ are hydroxy, R ₄ is hydroxymethyl, R 5 is hydrogen and R ₆ is aminothiocarbonyl can be prepared, for example, by reacting a compound of formula (I) wherein R _x R _{5 is} as defined above and R ₆ is a cyano group, with hydrogen sulfide using an organic base as solvent.

This reaction is preferably carried out at room temperature using a 1: 1 mixture of triethylamine-pyridine as solvent.

v) A compound of formula (I) wherein R 1, R ₃ is hydroxy, R ₄ is hydroxymethyl, R 5 is hydrogen and R ₆ is -C (NH) -SCH ₃ , can be prepared, for example, by reacting a compound of formula (Γ), wherein the terms Fh-R ₅ are as defined above and R ₆ is an aminothiocarbonyl group, with a methylating agent.

This reaction can preferably be carried out at reflux temperature using acetone as the solvent and methyl iodide as the reagent,

w) A compound of formula (I) wherein R ₁ -R ₃ are hydroxy, R ₄ is methyl, R ₅ is hydrogen and R ₆ is nitro can be prepared, for example, by removing acetyl groups from the β-anomer of formula (X.IV), wherein R is hydrogen and X is nitro by the action of bases using a lower aliphatic alcohol as solvent.

The β-anomer of formula (XIV), wherein R is hydrogen and X is nitro, is also a novel compound and can be prepared, for example, by conversion of the known compound 1,2,3,4-tetraO-acetyl-S-alkoxy-S-thio- Dq ¹ . By reacting with 4-nitrothiophenol, we obtain a mixture of α, β-anomers of formula (XIV) wherein R is hydrogen and X is a nitro group from which the β-anomer is isolated.

This reaction sequence can be advantageously carried out using acetone as solvent in the reaction of acetobromo-6-deoxy-5-thio-D-glucopyranose with 4-nitrothiophenol and in the presence of potassium carbonate at reflux temperature. The β-anomer is preferably isolated from the mixture of α, β-anomers by crystallization.

x) The compound of formula (I) in which R _{L R} R _<5 and R are hydrogen, _R and R ₃ represent hydroxy and R _e is nitro, can be prepared, for example, by saturating the double bond of the pentenose derivative of formula (XI), wherein P. is benzoyl, with hydrogen bromide in an aprotic solvent. The bromide group of the obtained intermediate of formula (XII) in which R is bromo is replaced by acetoxy and the resulting ester of formula (XII) in which R is acetoxy is reacted with 4-nitrothiophenol in the presence of a promoter. From the obtained anomeric mixture of glycosides of formula (XII) in which R represents a 4-nitrophenylthio, the benzoyl groups are removed base in a lower aliphatic alcohol and the β-anomer of formula (I) wherein R _{L R} R ₄ and R _s are hydrogen, R ₂ and R ₃ is hydroxy and R ₆ is nitro, crystallization is isolated.

Said reaction sequence is preferably carried out using benzene as the hydrogen bromide saturation solvent of the double bond of the pentenose derivative of formula (XI), wherein R represents a benzoyl group. The reactive 1-brominated compound of formula (XII) in which R is bromo is reacted without isolation with silver acetate in acetonitrile and the resulting ester of formula (XTI) in which R is acetoxy is reacted with 4-nitrothiophenol in dichloromethane using the promoter of Lrimothylsilyl triflate (trlmethyisilyl trifluoromethanesulfonates). The benzoyl groups are removed with sodium methoxide in methanol from the resulting mixture of glycosides of formula (XII) in which R is 4-nitrophenylthio and the β-anomer is then isolated by crystallization.

y) A compound of formula (I) wherein R x and R ₂ are hydroxy, R ₃ is azido, R ₍ and R ₅ are hydrogen and R ₆ is nitro) can be prepared, for example, by resolution of an anomeric mixture of glycosides of formula (II), wherein R is nitro, and by cleavage of the acetyl groups from the β-anomer with a base using a lower aliphatic alcohol as solvent.

These reactions can advantageously be carried out using column chromatography to separate the anomers and remove the acetyl groups from the β-anomer with sodium methoxide in methanol.

• · ··

The glycosides of formula (II) wherein R is nitro are novel compounds and can be prepared, for example, by reacting the triacetate of formula (IV), wherein R is acetoxy, with 4-nitrothiophenol.

This reaction may advantageously be carried out in an aprotic solvent, preferably dichloromethane or 1, 6 dichloroethane in the presence of a promoter, most preferably boron trifluoride etherate.

z) A compound of formula (I) wherein R 1 is azido, R ₂ and R ₃ are hydroxy, R ₄ and R ₅ are hydrogen and R ₆ is nitro can be prepared, for example, by synthesis of acetate (XIII) in which R is acetoxy , according to method i) and its condensation with 4-nitrothiophenol in the presence of a promoter. The resulting two anomers of formula (XII), wherein R is 4-nitrophenylthio, are separated and the β-anomer is cleaved off the base ester groups in the lower aliphatic alcohol.

This condensation reaction can advantageously be carried out in the presence of boron trifluoride etherate promoter and the benzoyl group is removed from the isolated β-anomer by sodium methoxide in methanol.

As stated in the introduction, the compounds of formula (I) of the invention have valuable anticoagulant activities.

This anticoagulant activity of the compounds of formula (I) of the invention was determined in male SPRD rats using the Pescador model of venous thrombosis (D. Bagdy et al., Thromb. Haemost., Vol. 68, (1992), p. 125). In this test, 12.5 mg of each individual compound was dissolved in 300 μΐ DMSO and this solution was diluted to 1 ml with physiological saline. 12.5 mg of this solution per kg animal weight were administered orally 3 hours prior to thrombus induction.

Table 1 shows the antithrombotic activity of several ft ftftftftft ftftft ftftft ftftft ftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftftft ftftft percent induced inhibition at the same dose and compared to Beciparcil used as reference (4-cyanophenyl 1,5-dithio-β-D-xylopyranoside _f European patent 365,397).

Table 1

Antithrombotic activity of the compounds of formula (I) on rats at oral administration at a dose of 12.5 mg / kg

Ex. Ri r ₂ R3 R « Rs Rg Inhib % 1 OH OH OH H H -C (= NH) -OCH ₃ 54 2 OH OH OH H H -CS _(NH2) 66 3 OH OH OH H H -C (= NH) -SCH ₃ 71 4 OH OH OH H H -C (= NH) -NH ₂ 70 5 OH OH OH H H -C (= NH) -NH-NH ₂ 7’3 6 OH OH h ₃ H H ”CN ' 64 7 OH n ₃ OH H H -CN 54 8 H OH OH H H -CN 72 9 n ₃ OH OH H H -CN 65 10 OH NH ₂ OH H H -CN 48 12 OH n ₃ OH H H -C (-NH) -OCH ₃ 70 13 OH OH OH ch ₂ oh H -CN 64 14 OH OH OH ch ₃ H -CN 51 15 Dec OH OH OH = ch ₂ -CN 45 16 OH OH OH ch ₂ oh H -C (= NH) -OCH ₃ 52 17 OH n ₃ OH H H -no ₂ 77 18 OH OH OH CH ₃ H -CS _(NH2) 50 19 Dec H OH OH H H -CS _(NH2) 65 20 May H OH OH H H -C (= NH) -NH ₂ 68 21 OH OH OH ch ₂ oh H -CS _(NH2) 76

·· «* ··

22nd OH OH OH ch ₂ oh H -C (= NH) -SOH 3 71 24 H OH OH H H -no ₂ 51 Ref. OH OH OH H H -CN 44

As can be seen from Table 1, the antithrombotic activity of some representatives of the compounds of formula (I) of the invention outweighs the activity of the reference compound, in some cases to a great extent.

For therapeutic purposes, the compounds of the invention as well as their pharmaceutically acceptable salts can be used as such or in the form of suitable pharmaceutical compositions. These compositions are also within the scope of this invention.

These pharmaceutical compositions contain such amount of a compound of formula (I) or pharmaceutically acceptable salts thereof that is required to achieve a therapeutic effect, with the addition of well known carriers, vehicles, diluents and / or other additives commonly used in pharmaceutical practice.

For oral administration, the antithrombotic compound is formulated in capsules or tablets, which may contain vehicles such as binding agents, lubricants, disintegrating agents and the like. For parenteral administration, the antithrombotic compound is formulated in a pharmaceutically acceptable diluent, for example, physiological saline (0.9%), 5% dextrose, Ringer's solution and the like.

The dosages required to achieve the desired therapeutic effect of the compounds of the invention may vary according to the individual condition and age of the patients to be treated and are ultimately determined by the attending physician. However, for the prevention and / or treatment of diseases requiring administration of anticoagulants, daily doses of these compounds in the range of about 0.01 mg / kg body weight and about 0.1 mg / kg of body weight are used. 100 mg / kg of body weight and preferably in the range of about 0.1 mg / kg of body weight and about 10 mg / kg of body weight for both oral and parenteral e.g.

intravenous route.

The compounds of the present invention and their preparation are illustrated in detail by the following non-limiting examples.

R _f values in the experimental part were determined by TLC using silica gel plates coated with Silica Gel 60 F 254, E. Merck and the following solvents:

(A) benzene (B) benzene-ethanol (100: 1) (C) benzene-methanol (9: 1) (D) benzene-methanol (4: 1) (E) hexane-ethyl acetate (1: 1) (F) ) hexane-ethyl acetate (2: 1) (G) hexane-ethyl acetate (3: 1) (H) hexane-ethyl acetate (4: 1) (I) hexane-ethyl acetate (5: 1) (J) hexane-ethyl acetate (9) (1) (K) Ethyl acetate-pyridine-water-acetic acid (60: 20: 11: 6)

Spots were detected by spraying the plates with 0.02 M iodine solution and 0.3 M potassium iodide solution in 10% sulfuric acid solution, followed by heating to about 200 ° C.

For column chromatography, Kieselgel 60 was used. Melting points were not corrected. Optical rotations were determined at 20 ° C. Nuclear magnetic resonance (NMR) spectra were obtained on a Varian XL-400 spectrometer at 400 MHz ( ⁷ H) and 100 MHz ( ¹³ C) or on a Bruker AC 250 spectrometer at 250 MHz (7) and 62.9 MHz ( ¹³ C). (Me ₄ Si was used as internal standard). Multiplicities (cleavage of signals) of the ¹³ C NMR spectra were determined by DEPT assays. Proton specification was based on interference spin-spin interaction (homonuclear) and DNOE experiments. Connectivity of identified protons and protonated carbons was determined by HETCOR experiments. Mass spectra were recorded on an Einnigan MAT 8430 mass spectrometer. For FAB spectra, samples were dissolved in 3-nitrobenzaldehyde or glycerin.

A common procedure for carrying out acylation reactions in pyridine means that if the product did not crystallize when the reaction mixture was poured into ice water, it was extracted with dichloromethane and the organic solution was washed with 1M sulfuric acid until pH ~ 3, then water, 5% aqueous sodium bicarbonate and finally water. The organic solution was dried over sodium sulfate, followed by concentration under reduced pressure.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

4- (Imino) (methoxy) methylphenyl-1,5-dithio-f-D-xylopyranoside (I, R 1 = R ₂ - = OH, R _t = H, Re = -C (HJH) -OCH ₃ )

Method A)

To a solution of 0.45 g of 4-cyanophenyl-1,5-dithio-β-Dxylopyranoside (European patent 365.397) was added 0.1 ml of a 1M solution of sodium methoxide in methanol in 10 ml of methanol.

After standing at room temperature for 24 hours, the mixture was neutralized with carbon dioxide and concentrated. The residue was subjected to column chromatography (solvent C) to give after concentration of the first fraction _(Rf = 0.4) unchanged starting material (350 mg). Concentration of the second fraction _(Rf = 0.3) yielded>

• *

V 4 • * ··

100 mg (90% of the starting material) of the title compound. Melting point: 174-177 ^D C; [a] D + 28 ° (c = 0.5, methanol) NMR (DMSO-d6) ^X H: 4.52 (H), 3.34 (H-2), 3.12 (H-3 ), 3.48 (H-4), 2.62 (H-5a), 2.50 (H-5b), 5.07, 5.10 and 5.50 (OH), 7.50 and 7, 75 (aromatic?), 9.00 (NH), 3.80 ppm (OMe); Jjř2 10.1, ^, 38.6, _{34 of} 8.6 J J _{4, and} 10.9, J _4, 5b, 4,3, _{JS (5b}

13.3 Hz; ¹³ C: 51.6 (Cl), 73.0, 75, 8 and 78.9 (C-2.3.4), 33.6 (C-5), 164.9 (C = NH), 138 0, 132.5, 129.5, 127.5 (aromatic C), 53.2 ppm (OMe), TS: 315 (M) ⁺ .

Method B)

To a solution of 100 mg of 4- (imino) (methylthio) methylphenyl-1,5-dithio-β-D-xylopyranoside (Example 3) in 10 ml of methanol was added 0.1 ml of a 3M solution of sodium methoxide in methanol and refluxed for 1 hour. . After cooling, the mixture was neutralized with carbon dioxide and then treated as described in Method A) to give 20 mg (21%) of the title compound, identical to the product of Method A).

Example 2

4- (Aminothiocarbonyl) phenyl-1,5-dithio-β-D-xylopyranoside (I _f R 1 = R ₂ = R ₃ = OH, R 1 = ph = H, = CS (NH ₂ ))

A solution of 0.5 g of 4-cyanophenyl-1,5-dithio-β-D-xylopyranoside (European patent 365.397) in 10 ml of pyridine and 10 ml of triethylamine was saturated with a slow stream of anhydrous hydrogen sulfide for 5 hours. The mixture was allowed to stand overnight at room temperature and then concentrated. The residue was recrystallized from methanol to give 0.46 g (82%) of the title compound. Melting point: 174 to 179 ⁱⁿ C, Rf (D) = - 0.3, [?] _D = t38 ° (c - 0.5, methanol), NMR (DMSO-d ^T H: 4.30 ( H1), 3.28

«« · V v v v v v v v

4 * (H-2), 3.06 (H-3), 3.44 (H-4), 2.64 (H-5a), 2.48 (H-5b), 7.48 and 7.85 (aromatic H), 5.08, 5.12 and 5.53 (OH), 9.48 and

9.85 ppm (NH); Jj., 2 10.1, Jj, 3 8.6, J3, ₄ 8.6, J _{4, and} 10.6, J _4, SB 4.6, full, 5b 13.3 Hz.

Example 3

4- (imino) (methylthio) methylphenyl 1,5-dithio-.beta.-xylopyranoside (I, R _R = R ₂ = R ₃ = OH, L ₄ = R ₅ = Η, _R6 = -C (= NH) ~ SCH ₃ )

To a solution of 350 mg of 4- (aminothiocarbonyl) phenyl-1,5-D-dithioβ xyiopyranosidu (I, R = R ₂ - R ₃ = OH, R ₄ = R ₅ = H, R _e = -CS _(NH2) (Example 2) in 35 ml of acetone was added 0.2 ml of methyl iodide and the reaction mixture was heated under reflux for 2 1/2 hours. After cooling, the precipitated product was filtered and washed with acetone to yield 400 mg (79%) of the title compound as the hydroiodide. Melting point: 191-194 ° C, Rf _(D) - 0,4, [a] _D - (70 DEG (c = 0.4, 503 aqueous solution of acetic acid); NMR (DMSO-d _e), 4 54 (Η-1)

3, 36 (H-2), 3.12 (H -3), 3.48 (H-4 ), 2.72 (H-5a) , 2.52 (H- 5b), 4.5-5.5 (OH), 11,0- -12.0 (NH), , 7.65 and 7.80 (aromatic H), 2.85 ppm (SMe); Jl, 2 11,1, d ₂ , 3 9, 5, J3, ₄ 9, 5 J4,5a 11,0, J4,5b 4.1, 0 & a, 5b 13.0 Hz.

Example 4

4-Amidinophenyl-1,5-dithio-β-D-xylopyranoside (I, R ₃ = R ₂ = R ₃ -OH, R ₄ = J ₅ = H, R ₆ = C (= NH) -NH ₂ )

To a solution of 0.65 g of 4- (imino) (methylthio) methylphenyl 1,5dithio-.beta.-D-xylopyranoside (I, R = P ₂ = R ₃ = OH, R ₄ = R _s = H,

R ₆ - -C (= NH) -SCH 3 (Example 3) in 30 ml of anhydrous ethanol was added with stirring 0.2 g of ammonium acetate and stirring.

.........

was continued for 5 hours at 60 ^e C, then added 0.2 g of ammonium acetate and stirring continued for 3 hours. The reaction mixture was cooled and the precipitated product was filtered to yield 0.4 g (78%) of the title compound as an acetate. M.p .: 195-199 ° C, R _f (K) = 0.6, [α] _D - + 30 ° (c - 0.5, 50% aqueous acetic acid), NMR (DMSO-d 6), * H: 4.42 (H-1), 3.35 (H-2), 3.12 (H-3), 3.45 (H-4), 2.65 (H-5a), 2.50 (H) -5b), 7.5-7.8 (aromatic H); Jt.? 9.9, 8.6, J _{3rd 4} 8,6,

84.5 and 9.8, J _{4 (5b} 4.2, J _5a , _5b 13.2 Hz; ¹³ C: 51.0 (Cl), 73.0, 75.8 and 79.0 (C-2, 3.4), 33.6 (C-5), 165.6 (C (NH ₂ ) ₂ ⁺ ), 141.7, 128.8,

128.1 and 126.6 ppm (aromatic C).

Example 5

4- (Hydrazino) (imino) methylphenyl-1,5-dihydro-β-D-xylopyranoside (I, R 1 - R ₂ = R> = OH, R ₄ = R 5 = 1 /, Re = ~ (= MV - _NH-NH2)

Method A)

To a solution of 320 mg of 4- (aminothiocarbonyl) ienyl-1,5-dithioβ-D-xylopyranoside (I, R _x = R ₂ = R ₃ = OH, R ₄ = R ₅ -H, R ₆ = -CS (NH ₂₎ (Example 2) in 50 ml. of ethanol, 1 ml of 98% hydrazine hydrate was added and the reaction mixture was stirred at room temperature for 18 hours. The precipitated product was filtered and washed with ether to yield 380 mg (99%) of the title compound contaminated with hydrazine acid sulfide. To remove it, the crude product was dissolved in 30 ml of 10% aqueous acetic acid and the evaporation residue was purified by column chromatography using a 60:38:10 mixture of chloroform-methanol-water as eluent. Evaporation of the appropriate fractions gave 125 mg (33%) of the title compound as an acetate. Melting point: 225-230 ° C, _E (K) ~ 0.5, [α] _D = + 12 ° (c = 0.5, pyridine), NMR (DMSO-d 6), H: 4.15 (H1), 3.24 (H-2), 3.05 (H-3), 3.40 (H • 4 * 4)

4), 2.58 (H-5a), 2.46 (H-5t), 5.4-6.2 (OH, NH), 7.45-7.65 ppm (aromatic H); J _b2 10.1, J ₂ , ₃ 8.6, J _{3 ( 4.8} , J _4fSa 10.7,

J _4, 5b 4.6, J _5a, 5b 13.2 Hz; ¹³ C: 52.4 (C-1), 73.0, 75.8, and 79.0 (C-2.3.4), 33.7 (C-5), 133.8 (C (= NH 2)) ⁺ ) (NH-NH2) 146.4,133.8

130.8 and 126.0 ppm (aromatic C),

Method B)

To a solution of 100 mg of 4- (imino) (methylthio) methylphenyl-1, 5-dithio-.beta.-xylopyranoside (I, R = R ₂ = R ₃ = OH, R ₄ = R ₅ = H, R ₆ = C ( = NH) -SCH ₃ ) (Example 3) in 10 ml of ethanol was added 0.35 ml of 98% hydrazine hydrate and the reaction mixture was stirred at room temperature for 5 hours. The precipitated product was filtered, washed with ethanol and dried to yield 60 mg (88%) of the title compound. Mp 193-196 ° C.

Example 6

4-Cyanophenes 1-4 and zido-4-deoxy-1,5-dithio-β-D-xylopyranoside (I, R 1 = R ₂ = OH, R ₃ -R ₄ = R ₅ -b, R ₆ = CN)

To a solution of 130 mg of 4-cyanophenyl-2,3-di-O-acetyl-4-azido-4-deoxy-1,5-dithio-β-D-xylopyranoside (II, R = CN) in 10 mL of methanol was added 0.1 mL A 1M solution of sodium methoxide in methanol and the reaction mixture was stirred for 1 hour at room temperature. Then, the solution was neutralized using Dowex 50 WX resin and concentrated to yield 72 mg (70%) of the title compound. Melting point 105-110 ° C. R _f (C) = 0.2, [Otjo = (139 ° (c = 0.5, methanol) NMR _(DMSO-d6)? H: 4.54 (H1), 3.44 (H 2), 3.34 (H-3), 3.64 (H-4), 2.80 (H-5a), 2.66 (H-5b), 5.80 and 6.00 (OH), 7.60 and 7.80 (aromatic H);

9/0, J ₂ , 3 8.5 / J ₃ , 4 9.0, J ₄ , 5a 11.0, J ₄ , 5b 4.4, J5a, 5b

13.4 Hz;

The starting material (II, R = CN) can be prepared as follows:

Method A)

Step a)

5-O-tert-Butyldimethylsilyl-2,3-O-isopropylidene-4-O-methanesulfonyl-L-arabinose diethyldithioacetal (Vil, R 1 = Ms,

_R2 = TBDMS)

To a solution of 7 g of 2,3-O-isopropylidene-L-arabinose diethyldithioacetal (H. Zinner et al., Ber., Vol. 90, (1957), p. 1).

2688) 3.75 g of tert-butyldimethylsilyl chloride were added at 25 ° C in 25 ml of pyridine and after 2 hours, 2 ml of mesyl chloride was added. The mixture was allowed to stand at room temperature for 24 hours and after usual work-up and isolation by column chromatography gave 10 g (87%) of the title compound as syrup using solvent F. Rf (J) 0.5, [α] _D - -57 ° (c = 1, chloroform), NMR (CDCl ₃ ), ¹ H: 3.98 (H 1), 4.50 (H-2), 4 , 30 (H-3), 4.64 (H-4), 3.85 (H-5a), 4.00 (H-5b), 2.65-2.80 (SCH ₂ CH ₃ ), 1 25 (SCH ₂ CH ₃ ), 1.40 and 1.46 (= CMe ₂ ), 3.12 (Ms), 0.12 (SiMe ₂ ), 0.92 ppm (SiCMe ₃ ); J _{1 (2} 3.1, 2.3 ^ 7.2, J _3, 4 7.2, J, 5 6.8, J4, AC 3.2, J5a, 5b 11.8 Hz; ¹³ C: 52 9 (C-1), 83.8 (C-2), 82.3 (C-3), 76.5 (C-4), 63.1 (C-5), 25.3 and 25, 4 (SCH ₂ CH ₃ ), 14.3 (SCH ₂ CH ₃ ), 110.5 (= CMe ₂ ), 26.9 and 27.0 (= CMe ₂ ), 38.8 (Ms), -5, 5, 18.3 and 25.8 ppm (SiCMe ₃ ).

Step b)

4-Azido-deoxy-2,3-O-isopropylidene-Dxylose diethyldithioacetal (VI, R = OH)

Solution 10 g diethyldithioacetal 5-033 «· · ·

tert-butyldimethylsilyl-2,3-O-isopropylidene-4-methanesulfonyl-L-arabinose (VII, R ₃ = Ms, R ₂ = TBDMS) and 2 g of sodium azide were stirred in 100 ml of N, N-dimethylformamide at 110 ° C for 15 hours. C. The residue after concentration was dissolved in chloroform, washed with water and concentrated. The resulting mixture - a mixture of derivative (R _f (J) = 0.8), 5-O-TBDMS (VI, R = OTBDMS) and derivative (R _f (J) = 0.1) - was dissolved in 100 mL tetrahydrofuran and 4 g of tetrabutylammonium fluoride trihydrate were added with stirring. The reaction mixture was concentrated after 2 hours, the residue was dissolved in chloroform, washed with water, dried, evaporated and the residue was subjected to column chromatography (I) to yield 5.8 g (88%) of the title compound. R _f (I) = 0.3, [a] _D = -97 ° (c = 1, chloroform) NMR (CDC1 ₃₎ 'Η: 3.90 (H), 4.37 (H-2) 4.23 (H-3), 3.67 (H-4), 3.90 (H-5a), 3.90 (H-5b), 2.65-2.80 (SCH ₂ CH ₃ ) 1.28 (SCH ₂ CH ₃ ), 1.46 and 1.48 ppm (= CMe ₂ ); J _lf2 5.8,

J _2/3/4 , υ _{3 (} 4 2.6, J 2 ₍ 5a 4.9), J 4 ₍ 5b 7.5 Hz; ¹³ c: 52.5 (C -1)) / 9.6 (C-2) ), 9.5 (C-3) 62.4 (C-4), 63.0 (C-5), 24.9 and 25.3 (SCH ₂ CH ₃ ), 14.1 and 14.2 (SCH ₂ CH _3), 110.2 (= _CME), 26.7 and 26.9 ppm (= _CME).

Step c)

4-Azido-4-deoxy-2,3-O-isopropylidene-5-O-methanesulfonyl-D-xylose diethyldithioacetal (VI, R = OMc)

To a solution of 5.6 g of 4-azido-4-deoxy-2,3-O-isopropylidene-D-xylose (VI, R = OH) diethyldithioacetal in 50 ml of pyridine was added dropwise with stirring at a temperature below 10 ° C. ml of mesyl chloride. The mixture was allowed to stand at room temperature for 1 hour and after usual work-up gave 6.3 g (90%) of the title compound as syrup. Rf (B) = 0.45, [a] _D = -52 DEG (c = 1, chloroform) NMR (CDC1 _3), ^1H: 3.94 (H) »♦« · · · ·

4.36 (H-2), 4.15 (H-3), 3.98 (H-4), 4.48 (H-5a), 4.48 (H5b), 2.65-2, 85 (SCH ₂ CH ₃ ), 1.28 (SCH ₂ CH ₃ ), 1.43 and 1.47 (= CMe ₂ ), 3.10 ppm (Ms); Ji, ₂ 6.4, J _2f3 7.4, J _{3 | 4} 2.1, J _4f3a 6.6, J ₄ , sb 6.6

Hz; ¹³ C: 52.4 (Cl), 79.3 (C-2), 78.2 (C-3) 60.0 (C-4), 68.6 (C-5), 25.0 and 25 , 5 (SCH ₂ CH ₃ ), 14.1 and 14.3 (SCH ₂ CH ₃ ), 110.5 (CM CMe ₂ ), 26.6 and 26.9 (= CMe ₂ ) 37.5 ppm (Ms) ).

Step d) diethyldithioactal 4azido 5 d-benzoyl-4-deoxy-2,3-isopropylidene-D-xylose (VI, R = SBz)

A solution of 3.5 g of 4-azido-4-deoxy-2,30-1sopropylidene-5-O-methanesulfonyl-D-xylose diethyldithioacetal (VI, R = OMs) and

2.2 g of potassium thiobenzoate was boiled in 40 ml of acetone for 1 hour. The resulting thick suspension was cooled, filtered and the salts washed with 20 mL acetone. The filtrate was boiled for 4 hours, cooled and concentrated. The resulting residue was partitioned between chloroform and water and concentrated to give 3.6 g (93%) of the title compound. R _f (B) = 0.85, [a] _D = -3 ° (c - 1, chloroform) NMR (CDCl₃, ^3H: 3.90 (H), 4.36 (H-2), 4 21 (H-3), 3.72 (H-4), 3.46 (H-5a), 3.46 (H5b), 2.60-2.80 (SCH ₂ CH ₃ ), 1.25 (SCH _from CH ₃ ), 1.44 and 1.46 (= CMe ₂ ), 7, 45-7.98 ppm (aromatic H); J 1 _{R 2} 5.9, J _{2 (3} 6.5, J ₃ F ₄ 2) 2, J ₄ , _Sa 8.2, J _4r5b 6.5, J _5a , _5b 11.8 Hz ¹³ C: 53.0 (Cl), 80.7 (C-2),

79.9 (C-3), 61.0 (C-4), 30.4 (C-5), 25.0 and 25.4 (SCH ₂ CH ₃ ),

14.2 and 14.3 (SCH ₂ CH ₃ ), 110.4 (= CMe ₂ ), 27.0 and 27.2 (= CMe ₂ ), 127.3 - 190.7 ppm (aromatic C).

Step e)

4-Azido-5-S-benzoyl-4-deoxy-2,3-O-isopropylidene-5-thio-xylose (V)

J b *** · · · * * * * * *

Κ A solution of 5.7 g of 4-azido-5-Sbenzoyl-4-deoxy-2,3-O-isopropylidene-D-xylose (VI, R = SBz) diethyldithioacetal in 140 ml of acetone was added with 35 ml of water, 23 g of carbonate cadmium followed by a solution of 26 g of mercuric chloride in 70 ml of acetone. The suspension was stirred for 20 hours, filtered and concentrated in the presence of sodium carbonate (2 g). The residue was partitioned between chloroform and water, the precipitated salts were filtered and washed with chloroform. The organic solution was washed with 10% aqueous potassium iodide solution and water and concentrated to give 4.5 g (~ 100%) of the title compound containing some hydrate of the title compound by NMR spectroscopy. R _f (F) = 0.3, (a] _D = + 59 DEG (c = 1, chloroform) NMR (CDC1 ₃₎ 'll 9.85 (H), 4.52 (H-2) , 4.30 (H-3), and 1.40] 46 ppm (= CMe _2), it ₍₂ 1.2, J _2j3 6.5, J _3, 4 4.2 Hz, ^N C 201 4 (Cl aldehyde) and 96.0 ppm (C-1 aldehyde hydrate).

Step f)

Methyl-2,3-di-O-acetyl-4-a from Ido-4-deoxy-5-thio-D-xylopyranoside (IV, R = OMe)

Under a nitrogen atmosphere, 0.5 ml of 4M was added to a solution of 4.5 g of 4-azido-5-Sbenzoyl-4-deoxy-2,3-O-isopropylidene-5-thio-D-xylose (V) in 45 ml of methanol. solution of sodium methoxide in methanol. After deacylation was complete (TLC, Rf 0.3 -> 0.4, solvent G), the pH of the solution was adjusted to 1 by addition of 20%

HCl in methanol and the mixture was boiled for 1 hour. The cooled solution was concentrated and benzene was evaporated from the residue. Then 15 ml of pyridine and 10 ml of acetic anhydride were added and after 20 hours at room temperature the mixture was concentrated. The residue afforded 2.5 g (67%) of the title compound by column chromatography (solvent G). Mp 85-86 ° C, [α] _D t 226 ° (c - 1, chloroform), NMR (CDCl ₃ ), ^J H: 4.60 (H 1),

6

5.12 (H-2), 5.36 (H-3), 3.78 (H-4), 2.82 (H-5a), 2.56 (H5b), 3.40 (OMe), 2.05 and 2.09 ppm (OAc); J _lj2 2.8, _2F3 J 10.0, 3.4 ^ 10.0, J4.5a 11.8, J4, SB 4.4, full, 5bl3,5 Hz; ¹³ C: 81.2 (Cl), 74.7 (C-2), 71.0 (C-3), 63.4 (C-4), 25.1 (C-5), 20.5 and 20.6 (OCOCH ₃ ), 169.4 and 170.1 (OCOCH ₃ ), 56.3 ppm (OMe).

Step g)

1,2,3-Tri-O-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranose (IV, R = OAc)

To a solution of 5, 8 g of methyl 2, 3-di-0-acetyl-4-azido-4-deoxy-5-thio-D-xylopyranose (IV, R = OMe) in 15 ml of acetic anhydride at 0 ^D C was added 1 ml concentrated sulfuric acid. The mixture was kept at 0 ° C for 30 minutes and at room temperature for 2 hours and then poured into a mixture of 200 ml of chloroform, 35 g of ice and 20 g of sodium bicarbonate. The organic solution was separated, the aqueous solution was extracted with chloroform (2 x 100 mL), and the combined chloroform solutions were washed with 5% sodium bicarbonate solution and water. The residue was purified by column chromatography (solvent G) to yield 4.9 g (77%) of the title compound as syrup. R £ = 0.45, [?] D = + 214 DEG (c = 1, chloroform) NMR (CDC13) ^X H: 6.06 (H), 5.18 (H-2), 5.34 (H-3), 3.86 (H-4), 2.98 (H-5a), 2.72 (H-5b), 2.00, 2.10, and 2.16 ppm (OAc); Jlr2 3.0 82.3 10.0 J 10.0 _3F4, 04,53 11.9, J4,5b 4.4, _JS, 5b 13.7 Hz;

¹³ C: 73.0 (Cl), 71.0 (C-2), 70.8 (C-3), 63.0 (C-4), 26.7 (C5), 20.4 and 20, 5 and 20.8 (OCOCH ₃ ), 169, 0, 169, 5 and 169.6 ppm (OCOCH ₃ ).

Step h)

4-Cyanophenyl-2,3-di-O-acetyl-4-azido-4-deoxy-1,5-dihio-p-Dxylopyranoside (II, R = CN)

Κ of solution 1.0 g of 1,2,3-tri-O-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranose (IV, R = OAc) were added under argon at -10 ° C 0.63 ml of trimethylsilyl triflate and 0.8 g of 4-cyanothiophenol in 40 ml of dichloromethane, then the reaction mixture was stirred for one hour at room temperature. After neutralization with triethylamine, the mixture was concentrated and the residue was subjected to column chromatography (solvent H) to yield 260 mq (21%) of the title compound. 115-120 ° C, [α] _D = + 78 ° (c = 0.5, chloroform), NMR (CDCl ₃ ), ¹ H: 4.20 (H 1), 5.16 (H-2) 4.96 (H-3), 3.86 (H-4), 2.66-2.86 (H5a, 5b), 2.02 and 2.10 (OAc), 7.45-7.60 ppm (aromatic H); Ji, 2 10.6, J23 9.5, J _3, 9.5 mu, mu 5 9.5 dj Sb 5.6 Hz; C: 50.6 (C-1), 73.3 and 75.1 (C-2.3), 62.8 (C-4), 31.9 (C-5), 169.5 (OCOCH ₃₎ ), 20.5 _(OCOCH3), 118.2 (CN), 147 6, 132.5, 131.2 and

111.2 ppm (aromatic C).

Method B)

Step a)

5-O-benzoyl-4-O-methanesulfonyl-2,3-isopropylidene-L-arabinose diethyldithioacetal (VII, R 1 = Ms, = Bz)

To a solution of 1.2 g of 2,3-isopropylidene-L-arabinose diethyldithioacetal (VII, R 1 = R ₂ = () (H. Zinner et al., Ber., Vol. 90, (1957), p. 2688) in 10 ml. of pyridine was added over 0.5 hour at -10 ° C 0.5 ml benzoyl chloride and then 0.5 ml mesyl chloride at 0 ° C. The reaction mixture was stirred at room temperature for 2 hours, poured into ice water and worked up in a conventional manner to give, after concentration and column chromatography (solvent F), 1.4 g (73%) of the title compound as syrup. R _c (F) = 0.6, (a] _D = -59 DEG (c = 1, chloroform) NMR (CDC1 _3), Bi: 3.95 (H) • ·

4.46 (H-2), 4.46 (H-3), 5.15 (H-4), 4.48 (H-5a), 4.82 (H5b), 2.65-2.80 (SCH ₂ CH ₃ ), 1.25 (SCH ₂ CH ₃ ), 1.46 and 1.48 (= CMe ₂ ), 3.10 (Ms), 7.45 - 8.05 ppm (aromatic H); J _{x, 2,} 3.7, about _4, 5 7.0, J _{4, 5b} 2.5, J _5a, 5b 12.7 Hz; ¹³ C: 53.0 (Cl), 82.2 (C-2),

79.5 (C-3), 77.4 (C-4), 63.4 (C-5), 25.1 and 25.3 (SCH ₂ CH ₃ ),

14.3 (SCH ₂ CH _3), 111.0 (= CMe _2), 27.0 and 27.1 (= _CME), 39.0 (Ms)

128.5-166.0 ppm (aromatic C).

Step b)

4-Azido-5-O-benzoyl-4-deoxy-2,3-isopropylidene-D-xylose diethyldithioacetal (VI, R = OBz)

To a solution of 19.2 g of 5-O-benzoyl-4-methanesulfonyl-2,3-O-isopropylidene-L-arabinose diethyldithioacetal (VII, R _x =

Ms, _R2 = Bz) in 300 ml of N, N-dimethylformamide was added 4 g of sodium azide and stirring is continued for 20 hours at 100 ° C. The residue obtained after concentration of the mixture was partitioned between dichloromethane and water. The organic solution was washed with water and the residue was purified by column chromatography (solvent A) to yield 13.6 (80%) of the title compound. [α] _D = -36 ° (c = 1, chloroform), NMR (CDCl ₃ ), ¹ H: 3.94 (H 1), 4.40 (H-2), 4.25 (H-3), 4.00 (H-4), 4.62 (H-5a),

4, 65 (H-5b), 2.60 - 2,80 (SCH ₂ CH ₃ ), 1,26 (SCH ₂ CH ₃ ), 1, 44 and 1.47 (= CMe ₂ ), 7.45 - 8.06 ppm (aromatic H) ,; Ji, ₂ 6.2, J2.3 7.4, J3.4 2.2, J _4, 5 8.1, J _4, 5b 4.9, J5a, 5bHf7 Hz; C: 52, 6 (C-

1), 79.6 (C-2), 78.8 (C-3), 60.3 (C-4), 64.8 (C-5), 25.1 and

25.4 (SCH ₂ CH ₃ ), 14.2 and 14.3 (SCH ₂ CH ₃ ), 110.4 (= CMe ₂ ), 26.8 and 27.0 (= CMe ₂ ), 128.4 - 166.2 ppm (aromatic C).

Step c)

4-Azido-4-deoxy-2,3-O-isopropylidene-Dxylose diethyldithioacetal (VI, R = OH)

To a solution of 8.5 g of 4-azido-5-benzoyl-4-deoxy-2,3-O-isopropylidene-D-xylose (VI, R = OBz) diethyldithioacetal in 40 ml of methanol was added 3 ml of 4M sodium methoxide solution in of methanol and the mixture was refluxed for 30 minutes. After neutralization with carbon dioxide, the mixture was concentrated, the residue was dissolved in chloroform, washed with water, dried and concentrated. The obtained syrupy substance was purified by column chromatography (solvent I) to give 5.9 g (92%) of the title compound, identical to the compound of step c) of process A).

Steps d) - h) of process B are identical to steps c) - g) of process A).

Step i)

2,3-Di-O-acetyl-4-azido-4-deo-5-thio-D-xylopyranose (IV, R-OH)

To a solution of 1.0 g of 1,2,3-tri-O-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranose (IV, R = OAc) in 30 ml of N, N-dimethylformamide was stirred at room temperature with stirring under argon atmosphere, 0.43 g of hydrazine acetate was added. After 1 hour 50 ml of ethyl acetate and 50 ml of di-chloromethane were added, the organic layer was washed with brine, concentrated and the residue was subjected to column chromatography (solvent F) to yield 0.65 g (75%) of the title compound (α: β ratio 9: 1). R _f (F) = 0.4, NMR (CDCl), ⁴ Η: a-anomer 5.13 (HI), 5.15 (H-2), 5.45 (H-3), 3.82 ( H-4), 3.14 (H-5a), 2.70 (H-5b), 2.13 and 2.10 ppm (OAc); _LF2 J 2.8, J _{2, 3} 9.7, J _3, <

9.7, ₄ J _(5a 11.8, J 4.3 _{4j5b, JS,} 5bl3,5 Hz; β-anomer 4.83 ppm (H1); _LRZ J 9.8 Hz.

• * »v

Step j)

O- (2,3-di-O-acetyl-4-azido-4-deoxy-5-thio α-Dxylopyranosyl) trlchloroacetimidate (IV, R = O-C (NH) -CCl ₃ )

To a solution of 0.5 g of 2,3-di-O-acetyl-4-azido-4-deoxy-5-thio-d-xyopyranose (IV, R = OH) in 10 ml of dichloromethane was added under stirring and under argon atmosphere. 8 ml of trichloroacetonitrile and 2.5 g of potassium carbonate. After 24 hours, the mixture was diluted with ether, filtered through celite, concentrated and the residue was subjected to column chromatography (solvent H) to yield 0.65 g (85%) of the title compound; mp 68-72 ° C, R _f (H) = 0.6, [α] _D = + 195 ° (c = 0.5, chloroform), NMR (CDCl ₃ ), * H: 6.18 (Η) -1), 5.18 (H2), 5.39 (H-3), 3.85 (H-4), 3.00 (H-5a), 2.69 (H-5b), 8.60 (NH), 2.05 and 1.95 ppm (OAc); J _b2 3.0, J _2r3 10.1, 10.0,

81, δ 13.6, J4, st · 4.3, Jsa, sb 13.6 Hz; ¹ 6 ,: 76.0, 73, 5 / 0.9 (ΟΙ, 2, 3), 63.0 (C-4), 26.9 (C-5), 1 69, 8, 169, 4 (CO), 160.7 (ONH), 90.6 (CCl ₃ ), 20.6 and 20.5 ppm (COCH ₃ ).

Step k)

4-Cyanophenyl-2,3-di-O-acetyl-4-azido-4-deoxy-1,5-di-thio-1'-Dxylopyranoside (II, R = CN)

In argon, a solution of 210 mg of O- (2,3-di-O-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranosyl) trichloroacetimidate (IV, R = O-C (NH) -CCl 3) and 160 mL of 4-cyanothiophenol in 10 mL of dichloromethane was cooled to -15 ° C with stirring, then 0.5 mL of a 0.1 M solution of boron trifluoride etherate in dichloromethane was added and stirring was continued for a further 15 minutes at

5 ° C. After the addition of 0.5 ml of triethylamine, the mixture was concentrated and concentrated.

The residue was subjected to column chromatography (solvent H) to yield 63 g (32%) of the title compound, identical to the compound of step h) of process A).

Example 7

4-Cyanophenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (1, R f = R ₃ = OH, = N ₃ , R ₄ = K ₅ = H, R ₆ = CN)

Method A)

At -10 ° C under argon to a solution of 1.0 g], 2,4-tri-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc) and 0.8 g of 4-cyanothiophenol in 30 ml of dichloromethane was added with 0.63 ml of trimethylsilyl triflate, then the reaction mixture was stirred at room temperature for 2 hours. After neutralization with 0.8 ml of triethylamine, the mixture was concentrated and the residue was subjected to column chromatography (solvent F) to yield 0.47 g (38%) of 4-cyano-phenyl 2,4-di-O-acetyl-3-azido-3-deoxy -1,5-dithio-β-D-xylopyranoside (1, R 1 - R ₃ = OAc, R ₂ = N ₃ , R 1 = R ₅ = H, R ₆ = CN.) This was dissolved in 30 ml of methanol and 0 was added. 1 ml of a 3M solution of sodium methoxide in methanol. After standing at room temperature for 2 hours, the solution was neutralized with Dowex 50 WX resin, filtered and evaporated to yield 0.34 g (92%) of the title compound. The melting point was 192-194 C ^e, R _f (C) = 0.3, [?] _D = + 81 ° (c - 0.5, methanol), NMR (DMSO-d ^_6): H: 4 85 (H1),

3.35 (H-2), 3.20 (H-3), 3.52 (H-4), 2.75 (H-5a), 2.58 (H5b), 5.45 and 5.92 (OH), 7.5-7.7 (aromatic H); J _{i (2} 10.0,

J ₃ , 8.5, J ₃ , 4 8.5, J 4.5 _and 10.8, J ₁ , 5b 4.5, J 5a, 5b 13.2 Hz.

The starting material (VIII, R = OAc) can be prepared as follows:

Step a)

3-Azido-5-S-benzoyl-3-deoxy-1,2-isopropylidene-5-thio42

D-xylofuranose (IX)

To a solution of 5.2 g of 3-azido-3-deoxy-1,2-O-isopropylidene-5O-tosyl-D-xylofuranose (H. Ohrui et al., Agr. Biol. Chem., Vol. 34, (1970)) 375) in 35 ml of N, N-dimethylformamide was added 2.7 g of potassium thiobenzoate and the mixture was stirred at 110 ° for 30 minutes. After concentration, the residue was dissolved in chloroform, washed with water, dried and concentrated. The residue was subjected to column chromatography (solvent H) to yield 2 g (42%) of the title compound. Mp 71-74 ^e C. Rf (H) = 0.6, [?] D = - 118 ° (c = 0.5, chloroform) NMR (CDC13) ^X H: 5.92 (H) 4.70 (H-2), 4.02 (H-3), 4.38 (H-4), 3.32 (H-5a), 3.42 (H-5b), 1.30 and 1 .45 (= CMe2), 7, 45, 7.55 and 7.97 ppm (aromatic H); _LR2 J 3.7, J ~ _2.3 0 J _{3> 4} 3.2, J _4r5a 7.0, J _{4, 5b} 7.0, J _Sa, 5b 13.6 Hz; ¹³ C: 104.7 (C1), 78.4 and 83.4 (C-2.4), 66.8 (C-3), 27.3 (C-5), 127.3,

127.6, 136.5 and 136.5 (aromatic C); 190.7 (CO), 26.2 and 26.5 (= CMe ₂ ), 112.3 (= CMe ₂ ).

Step b)

1,2,4-Tri-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc)

To a solution of 2.9 g of 3-azido-5-S-benzoyl-3-deoxy-1,2-isopropylidene-5-thio-D-xylofuranose (IX) in 40 mL of methanol was added with stirring 4.4 mL of a 3M solution sodium methoxide in methanol. After standing at room temperature for 1 hour, the mixture was acidified with 20 ml of a 4% aqueous HCl solution and refluxed for 2 hours. After cooling, it was neutralized with triethylamine and concentrated. The residue was dissolved in 20 mL of pyridine and 10 mL of acetic anhydride and kept at room temperature overnight. After routine work-up, the residue was subjected to column chromatography (solvent H) to yield 2 g (73%) of the title compound. Ratio α: β = 85: 15; Rf (H) = 0.4, NMR (CDCl3), α-anomer ^] H: 6.04 (H1), 5.02 (H2), 3.86 (H-3), 4.95 (H-4) 1.90 (H-5a), 2.78 (H-5b), 2.15 2.11 and 2.05 ppm (OAc); _B2 J 3.0, J _{2, 3} 10.5, J _{3, 4} 10.2, J _{4, 5} 11.1, J _{4, 5b} 4.7, J _{5a, 5b} 13.2 Hz; ⁿ C: 73.9, 73.7, 70.2 (ΟΙ, 2.4), 62.3 (C-3), 26.0 (C-5), 169, 5, 169, 3, and 168, 8 fr \ aa A ar \ A - a A r ί, -κ-άοττ in - - * ... _ .. Itt r- aa _f bu _t o _f Of from · ppm · p-dnunitsi n; at ppm (H1); J _b2 9.1 Hz.

Column chromatography gave 0.2 g (8%) methyl-2,4-di-O-acetyl-3-azido-3-deoxy-5-thio-Dxylopyranoside (VIII, R = OCH ₃ ) as a by-product. (mp 64-67 ° C; R f (H) = 0.5), which can be transformed to the title compound in 90% yield according to step g) of Example 6.

Method B)

Step a) _f 4-Di-O-acetyl-3-azido-3-deoxy-5-thlo-D-xylopyranose (VIII, R = OH)

To a solution of 1.0 g of 1,2,4-tri-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc) in 30 ml of N, N-dimethylformamide was added with stirring 43 g of hydrazine acetate and stirring continued for 1 hour at room temperature. The reaction mixture was treated according to step i) of Example 6 to yield 0.68 g (78%) of the title compound (Rf (F) = 0.6).

Step b)

O- (2,4-Di-O-acetyl-3-azido-3-deoxy-5-thio-α-Dxylopyranosyl) trichloroacetimidate (VIII, R = OC (NH) -CCl ₃ ) • 4

To a solution of 1.35 g of 2,4-di-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OH) in 20 mL of dichloromethane was added 6.75 g of potassium carbonate with stirring. and 4.8 ml of trichloroacetonitrile and stirring was continued for 24 hours at room temperature. After dilution with ether, the reaction mixture was filtered through celite, concentrated and the residue was subjected to column chromatography (solvent H) to yield 1.5 g (73%) of the title compound. _T R (H) = 0.8, [?] _D = + 223 ° (c = 0.5, chloroform) NMR (CDC1 ₃₎ * Η, 6.22 (H), 5.10 (H 2), 4.00 (H-3), 5.00 (H-4), 2.95 (H-5a), 2.80 (H-5b),

8.70 (NH), 2.13 and 2.08 ppm (OAc); Ji, 2, 2.8, J _{2, 3} 10.4 J _3i4 10.3, J _{4, 5} 11.2, J _{4, 5b} 4.6, J _{Sa, Sb} 13.2 Hz; ¹³ C: 75.4, 74.2 and 73.0 (C-1.2.4), 62.3 (C-3), 26.00 (C-5), 169.6, 169.5 ( CO), 160.4 (C = NII), 90.7 (CCl ₃ ), 20.8 and 20.6 ppm (COCH ₃ ).

Step c)

4-Cyanophenyl-2,4 dl O-acetyl-3-azido-3 deoxy-1,5-dithio-β-D-xylopyranoside (I, R ₁ = R ₃ = OAc, R ₂ = V ₃ , R ₄ = = H, R _& =

CN)

To a solution of 0.52 g of O - (2,4-di-O-acetyl-3-azido-3-deoxy-5-thio-α-D-xylopyranosyl) trichloroacetimidate (VIII, R = OC (NH) -CCl ₃ ) and O, 42 g of 4-cyanothiophenol (III) in 30 ml of 1,2-dichloroethane was added at -15 ° C with 1 ml of 0.1M boron trifluoride etherate in 1,2-dichloroethane and stirring was continued for 15 minutes. The reaction was then quenched by the addition of triethylamine to the reaction mixture, followed by concentration, and the residue was subjected to column chromatography (solvent H) to yield 210 mg (43%) of the title compound. M.p. 163-166 ° C. _Rf (H) = 0.6, [?] _D = + 44 DEG (c = 0.5, chloroform) NMR (CDC1 ₃₎ ^X H: 4.11 (H), 5.08 (H 2), 4.54? (? -3), 4.94 (? -4), 2.70 (H-Sa), 2.87 ppm (H-5b); _LF2 J 10.6, 2.3 ^ 9.9, J3 _{/ 4} 9.9, J _4, 5 10.8, J _4, 5b 4.6, J5a, 5b 13.5 Hz; ¹³ C: 50.9 (Cl), 73.0 (C-2), 67.2 (C-3), 73.6 (C-4), 31.8 ppm (C-5).

The compound thus obtained was deacetylated in a solution of sodium methoxide in methanol to give the final product of method A).

Example 8

4-Cyanophenyl-2-deoxy-1,5-dihydro-β-D-threo-pentopyranoside (I, R 1 = R 1 = R 6 -H, R 2 -R 3 -OH, R ₆ -CN)

To a solution of 0.5 g of 4-cyanophenyl-3,4-di-O-benzoyl-2-deoxy-1,5-dithio-α, β-D-threo-pentopyranoside (XII, R = 4-cyanophenylthio) in 20 ml of methanol 0.1 ml of a 3M solution of sodium methoxide in methanol was added. After standing at room temperature for 1 hour, the reaction mixture was neutralized with Bowex 50 WX resin and concentrated. The residue was crystallized from ether to yield 0.16 g (57%) of the title compound. Melting point 169-172 ° C, R _f (D) = 0.4, [α] D = -15 ° (c = 0.5, methanol), NMR (DMSO-d 6), H: 4.58 ( H1), 1.78 (H2a), 2.45 (H-2b), 3.30-3.50 (H-3.4), 2.55-2.85 (H-5a, b),

7.60 and 7.80 ppm (aromatic H); Ji _(2a 11.7, Ji, _2b 3.6, J _2a , _2b 13.1, J _2a , ₃ 11.6, J _2b , 3.5 Hz; ¹³ C: 44.2 (Cl), 33 .8 (C-2), 72.7, 73.2 (C-3.4), 42.7 (C-5), 142.0, 132.7, 128.6 and 108.5 ppm (aromatic) C, 119.0 (CN).

The starting material (XII, R = 4-cyanophenylthio) can be prepared as follows:

Method A)

Step a)

3,4-Di-O-acetyl 2,5-anhydro-5-thio-2-deoxy-D-threo-pent-246 cnitol (XI, R = Ac)

To a solution of 11.2 g of acetobromothioxylose (RLWhistler and TVEs, J. Org. Chem., Vol. 28 (1963), p. 2303) in 110 ml of anhydrous benzene was added, with vigorous stirring, 3.2 ml of 4-picoline and 13 g. zinc powder and stirring was continued for 1 hour at 80 ° C. After cooling, the mixture was filtered, washed with benzene, the filtrate was concentrated and the residue was subjected to column chromatography (solvent F) to yield 5.8 g (85%) of the title compound. R _f (E) = 0.7, [a] _D =

- 324 ° (c = 0.5, chloroform) NMR _(CDCl3) ³ Η: 6.36 (H)

5.75 (H-2), 5.28 (H-3), 5.16 (H-4), 3.00-3.10 (H-5a, b), 2.08 and 2.04 ppm (OAc); Ji, _2, 10.0, J _{2 (3} 4,4, J _{3, 4} 4.6, J _4, 5 ~ 5

J ₄ , sb ~ 5Hz; ¹³ C: 125.8 (Cl), 117.2 (C-2), 66.7, 66.4 (C3.4), 26.3 (C-5), 169.8, 169.9 (COCH) ₃ ), 21.0 and 20.9 ppm (COCH ₃ ).

Step b)

1,5-Anhydro-3,4-di-O-benzoyl-5-thio-2-deoxy-D-threo-pent-2-enitol. (X, R = Bz)

A solution of 4.2 g of 3,4-di-O-acetyl-1,5-anhydro-5-thio-2-deoxy-D-threo-pent-2-enitol (XI, R = Ac) in 50 ml of methanol stirring added 0.1 ml of a 3M solution of sodium methoxide in methanol and stirring was continued for an additional 1 hour. The reaction mixture was neutralized with carbon dioxide and concentrated. A solution of 7 ml of benzoyl chloride in 35 ml of dichloromethane was added dropwise to the residue dissolved in 15 ml of pyridine and 60 ml of dichloromethane. The reaction mixture was allowed to stand overnight at room temperature and then poured into ice water, extracted with dichloromethane and worked up in the usual manner. The residue after concentration was recrystallized from ethanol in a yield of · · ”

4.95 g (75%) of the title compound. Mp 119-122 ° C, R _f (J) = 0.6, [α] _D = -468 ° (c = 0.5, chloroform), NMR (CDCl ₃ ), H: 6.50 (H1) ), 5.95 (H-2), 5.75 (H-3), 5.58 (H4), 3.25-3.35 (H-5a, b), 8.02, 7.55 and 7.40 ppm (aromatic 11); Ji, 2 10.2, J ₂ , ₃ 4.2, J _{3 | 4} 4.2, J ₄ , _5a -5.5, 8 < _(5b -5.5 Hz; ¹³ C:

126.1 (C-1), 117.4 (C-2), 67.3, 67.0 (C-3.4), 26.8 (C-5),

165, 5, 165, 4, 133, 3, 133.2, 129, 8, 129, 7, 128, 4, and 128.4 ppm

Step c)

4-Cyanophenyl-3,4-di-O-benzoyl 2-deoxy-1,5-diethio-α, β-D-threo-pentopyranoside (XII, R = 4-cyanophenylthio)

A solution of 1.7 g of 1,5-anhydro-3,4-di-O-benzoyl-5-thio-2-deoxy-D-threo-pent-2-enitol (XT, R = Bz) in 20 ml of anhydrous benzene was The mixture was saturated with anhydrous hydrogen bromide for 20 minutes at 10 ° C, then nitrogen was bubbled through the solution to remove excess hydrogen bromide. The resulting solution was added dropwise to a mixture of 0.6 g of 4-cyanothiophenol (III) and 0.2 g of sodium hydride (50% in oil) in 10 ml of N, N-dimethylformamide. The reaction mixture was stirred at room temperature overnight, then poured into ice water and extracted with benzene. The organic layer was washed with 5% sodium bicarbonate solution in water, dried and concentrated. The residue was purified by column chromatography (solvent 8 then H). Concentration of the first fraction (Rf (J) - 0.6) gave 0.73 g (43%) of the starting material. Concentration of the second fraction (Rf (H) = 0.4) gave 0.56 g (41% conversion) of the title compound as a, β-anomeric mixture (3: 7 ratio). NMR (CDCl ₃ ), α-anomer: ³ H: 4.68 (H1), 2.60 (H-2a), 2.72 (H-2b), 5.70 (H-3), 5.40 (H-4), 3.34 (H-5a), 3.14 (H-5b), 7.3-8.0 ppm (aromatic H); J _b2a 4.4, J1 _(2b 4.4, J _2a , _2b 13.8, J _2a , ₃ 9.6) • »·

J2b, 3 4.5, J _3, 4 9.2, J4,5 _9.3, 4.1 84,5b, being a,; @ 43.7 Hz; βanomer: li: 4.45 (H1), 2.35 (H-2a), 2.90 (H-2b), 5.40 (H3), 5.40 (H-4), 2.98 ( H-5a), 3.20 (H-5b), 7.3-8 ppm (aromatic H); Ji, 2 _and 11.1 / Ji, 2b 2.9, Jia, 2b 13.2, J _2a , 3 11.1,

820.3 3.1, J4, 9.4, 3.5 84,5b, _JS, 5b 13.7 Hz; ¹³ C: 46.0 (CI),

31.1 (C-2), 71.8, 72.0 (C-3.4), 39.5 (C-5), 110.7, 128-134 and 148.0 (aromatic C), 118 3 (CN, 165.5 (CO)).

Method B)

Process steps (a) and (b) are identical to process steps (a) and (b).

Step c)

4-Cyanophenyl-3,4-di-o-benzoyl-2-decxy-1,5-dithio-a, (R) -pentopyranoside (XII, R = 4-cyanophenylthio); to 1.7 g of 1,5-anhydro-3,4-di-benzoyl-5-thio-2-deoxy-f-threo-pent-2-enitol (XI, R-Bz) in 20 ml of anhydrous benzene The mixture was saturated with anhydrous hydrogen bromide for 20 minutes at 10 ° C, then nitrogen was bubbled through the solution to remove excess hydrogen bromide. The resulting solution was added dropwise to a suspension of 4.0 g of silver acetate in 35 ml of acetonitrile. After two hours, the salts were filtered off, the filtrate was concentrated and subjected to column chromatography (solvent H). The compound obtained by concentrating the fractions with Rf = 0.4 (1.5 g) was dissolved in 40 ml of dichloromethane, cooled to -10 ° C, then 1.0 g of 4-cyanothiophenol and 0.8 ml of trimethylsilyl triflate were added. The reaction mixture was stirred at room temperature for 1 hour, quenched with trimethylamine, followed by concentration and treatment of the residue by column chromatography (solvent F) in yield.

1.6 g (67%) of the title compound as a, β-anomeric mixture (15:85 ratio).

Example 9

4-Kynophenyl-2-azido-2-deoxy-1,5-dithio-β-Dxylopyranoside (I, R f = N ₃ , R ₂ = R ₃ = OH, R ₄ = R ₅ = H, R ₆ -CN)

To a solution of 1,3 g of 1-O-acetyl-2-azido-2-deoxy-3,4-di-benzoyl-5-thio-xyl opvranose (RTTT, R = OAc) and 0.8 g of 4-cyanothiophenol ( III) in 35 ml of dichloromethane at -10 ° C, under argon and with stirring, was added 0.6 ml of trimethylsilyl phthalate. The reaction mixture was stirred at room temperature for 1 hour, quenched with triethylamine, followed by concentration and column chromatography (solvent H) to yield 0.35 g (23%) of 4-cyanophenyl-2-azido-3,4-di-O- benzoyl-2-deoxy-1,5-dithio-β-D-xylopyranoside (T, R 1 = N ₃ , R ₂ -R ₃ -OH, R <= R ₅ -H, R ₆ = CN), R _f = 0 , 5.

This compound was deacetylated in 15 mL of methanol in the presence of 0.1 mL of a 3M solution of sodium methoxide in methanol. After 1 hour, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 160 mg (77%) of the title compound as an oil; Rf (C) = 0.3, [ _.alpha. ] _D = + 91 DEG (c = 0.5, methanol), NMR (DMSO-d6, 4.62 (H1), 3.20-3, 60 (H) -2, 3, 4), 2.75 (H-5a), 2.52 (H-Sb), 7.65 and 7.80 (aromatic H), 5.40 and 5.75 ppm (OH); jf _j2 10.9, J _{4 (5a} 10.9, J _4, 5b 4.4, _JS, 5b 13.3 Hz.

The starting material (XIII, R = OAc) can be prepared as follows:

Step a)

2-Azido-3,4-di-O-benzoyl-2-deoxy-5-thio-α-Dxylopyranosyl nitrate (XIII, R = 0NO ₂ ) • »

To a suspension of 2.4 g of 1,5-anhydro-3,4-di-O-benzoyl-5-thio-2-deoxy-D-threo-pent-2-enitol (XI, R = Bz) and 0.7 g of azide of sodium in 40 ml acetonitrile with stirring and under argon, was added ceric ammonium nitrate at ⁴ -20 C and stirring was continued for two hours at -20 ° C. Then the reaction mixture was poured into 170 ml of ice-cold dichloromethane, washed with water, 6% aqueous sodium bicarbonate solution, dried, concentrated and the residue was subjected to column chromatography (solvent J) to yield 1.1 g (35%) of the title compound. _Rf (J) = 0.3, [tx] _D = + 140 ° (c = 0.5, chloroform) NMR (CDC1 ₃₎ 6.22 HK (H), 4.25 (H-2) 5.80 (H-3), 5.46 (H-4), 3.20 (H5a), 3.04 (H-5b), 7.3 - 8.0 ppm (aromatic H); _LR2 J 3.4, J _{2 (3} 10.0 J _{3 liters,} 10.0 J _{4, 5} 11.1, J _{4, 5b} 4.5, J _{5a, 5b} 13.4 Hz; ¹³ C: 81, 0 (C-1), 64.9 (C-2), 71.0, 72.8 (C-3.4), 26.4 (C-5), 128.4 128, 6, 129.8 , 133, 6, 164, 9 and 165.1 ppm (aromatic C),

Step b)

1-O-Acetyl-2-azido-3,4-dl O-benzoyl-2-deoxy-5-thio-α, β-Dxylopyranose (XIII, R = OAc)

To a solution of 1.34 g of 2-azido-3,4-di-O-benzoyl-2-deoxy-5-thio-α-D-xylopyranosyl nitrate (XIII, R = 0NO ₂ ) in 10 ml of acetic acid was added 0.5 g of sodium acetate and the reaction mixture was stirred at 100 ° C for 1 hour. After cooling to room temperature, it was diluted with 40 mL of dichloromethane, washed with water, 6% aqueous sodium bicarbonate, dried and concentrated. The residue was subjected to column chromatography (solvent H) to yield 0.87 g (65%) of the title compound as a 1: 1 mixture of α, β-anomers. Rf (H) = 0.6;

NMR (CDCl ₃ ), α-anomer: ³ H: 6.16 (H 1), 4.05 ( h-2) 5, 40 (H- 3), 5.40 (H-4), 3.15 (H-5a), 3.02 (H-5b), 7, 3-8.0 ppm (aromatic H); J _b2 3.1, J ₂ , ₃ 10.5, J ₄ , _{5 and} 11.0, 0i, 5b 4, 6, Jsa, 5b

13.2 Hz; β-anomer: 5.88 (H-1), 4.16 (H-2), 5.88 (H-3),

5.48 (H-4), 3.15 (H-5a), 2.90 (H-5b), 7.3 - 8.0 ppm (aromatic H); J _1f2 9.4, J ₂ , ₃ 9.8, J ₃ , ₄ 10.1, J ₄ , _5a 11.1, J ₄ , _5b

4.7, J ₅ and SB 13.3 Hz; α, β-anomer: ¹³ C: 72.9 and 73.2 (C-1), 65.3 and 66.9 (C-2), 72, 6, 72, 5, 72, 3 and 71.1 (C-3,4), 26.4 and 27.9 (C-5), 128, 4, 128, 8, 129.7, 133, 5 165.2 and 165.5 (aromatic C), 20, 6 and 21.0 (OCOCH ₃ ), 168, 5 168, 8 ppm (OCOCH ₃ ).

Example 10

Cyanophenyl-3-annuo-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R 1 - R ₃ = OH, R ₂ = NH ₂ , R t = R ₅ = H, R ₆ = CN)

To a solution of 230 mg of 4-cyanophenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R 1 = R ₃ = OH, R ₂ = N ₃ , R ₄ = R ₅ = H, R ₆ = CN) (Example 7) in 25 ml of ethanol was added with stirring 80 mg of sodium borohydride and 10 mg of nickel (II) iodide hexahydrate. After 30 minutes, the reaction mixture was neutralized with 4% aqueous HCl, filtered, concentrated, and the residue was purified by column chromatography (methanol solvent) to yield 200 mg (95%) of the title compound. R _f (K) = 0.9, Mp: 195-200 ° C, [a] _D = + 45 DEG (c = 0.5, methanol) NMR (DMSO-d _e), H: 4 55 (H1), 3.46 (H-2), 2.78 (H-3), 3.62 (H-4), 2.73 (H-5a), 2.58 (H-5b), 7.65 and 7.80 (aromatic Η), 4.8-6.5 ppm (OH, NH ₂ ); Ji, 2, 10.1, J _2, 3 9.4, J _{3) 4} 9.5, J _4, 9.5, J _4, 5b, 4.0, 13.6 Hz Jsa.sb.

Example 11

4-cyanophenyl-3-acetamido-3-deoxy-l, 5-dithio-.beta.-xylopyranoside (I, R = R ₃ = OH, _R2 = AcNH, K ₄ = H, R = _€

CN)

To a solution of 200 mg of 4-cyanophenyl-3-amino-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R _x = R ₃ = OH, R ₂ = NH ₂ , R ₄ = R ₅ = -H, R (CN) (Example 10) in 5 ml of pyridine was added 2.5 ml of acetic anhydride and the mixture was allowed to stand overnight at room temperature. The residue obtained after the usual work-up was deacetylated in 10 ml of methanol in the presence of 0.1 ml of a 3M solution of sodium methoxide in methanol. After 1 hour, the mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was recrystallized from methanol to yield 180 mg (78%) of the title compound. _T R (D) = 0.4, Mp: 245-248 DEG C. [CXJ _D = + 50 DEG (c = 0.5, methanol) NMR {DMSO-d ₆₎ 4.48 (H) , 3, 38-3,65 (H-2, 3, 4), 2.74 (H-5a), 2.55 (H-5b), 7.60 and 7.75 (aromatic H), 5, 10 and 5.50 (OH), 7.75 (NH), 1.86 ppm (NAc); Ji, ₂ 9.5, J _{4 (5a} 10.4, J ₄ , 5b

3.7, Jsa, 5b 13.2 Hz.

Example 12

4- (I / nino) (methoxy) methyl phenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R _x = R 3 = OH, R ₂ = N ₃ , R ₃ = R @ ₅ = H, R @ ₆ =

- C (MJH) -OCH ₃ )

To a solution of 0.5 g of 4-cyanophenyl-3-azido-3-deoxy-1,5-dithio-β-xylopyranoside (I, R _x = R ₃ = OH, R ₂ = N ₃ , R 4 = R 5 H, R _e) = CN) (Example 7) in 20 ml of methanol was added 0.1 ml of a 3M solution of sodium methoxide in methanol and the reaction mixture was allowed to stand at room temperature overnight. After neutralization with carbon dioxide, it was concentrated and the residue was subjected to column chromatography (solvent C).

Concentration of the first fraction (Rf = 0.3) gave 270 mg of the (recovered) starting material. Concentration of the second fraction gave 130 mg (51% conversion) of the title compound.

9 999

9

9 * 9 9 * 9

R _f (C) 0.2 Melting point: 126-130 ° C, [a] _D = +52 '(c - 0.3, methanol), NMR _(DMS0-d6)? H: 4.38 (H1), 3.34 (H-2), 3.25 (H-3), 3.44 (H-4), 2.75 (H-5a), 2.55 (H-5b), 7 55 and 7.80 (aromatic), 5.80 and 6.30 (OH), 9.00 (NH), 3.80 ppm (OMe); Ji, from 9.9, J ₂ , 3 9.3, J 3 ₍₄ 9.3, J 4.5 _and 10.8, J 4, & b 4.5, J _a , 5b 13.3 Hz; Ms: 340 [M + H] ⁺ .

Example 13

4-Cyano-phenyl _r 1 ± 5 Dith O-0-D-glucopyranoside (I, R = R ₂ = R ₃ =

OH, = CH ₂ OH, R ₅ = H, Re = CM)

To a solution of 0.9 g of 4-cyanophenyl-2,3,4,6-tetra-O-acetyl-1,5-dithio-β-D-glucopyranoside (XIV, R = OAc, X = CN) in 20 mL of methanol was added 1 ml of a 3M solution of sodium methoxide in methanol. After 1 hour, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 0.55 g (93%) of the title compound. R _f (D) = 0.25, mp 206-209 ° C, (a] _D = -14 ° (c = 0.5, methanol) NMR (PMSO-d, H: 4.46 ( H1), 3.32, (H-2), 3.15 (H-3), 3.34 (H-4), 2.95 (H-5), 3.50 (H-6a), 3 76 (H-6b), 7.60 and 7.76 (aromatic Η), 4, 68, 5.00, 5, 10, and 5.56 ppm (OH); _LF2 J 10.2,

OI, 3 8.6, J3 _r 4 8.6, J4,5 8.9, Js, 6 6.6, JS, eb 3.3, Jea, 6b 11.4 Hz.

The starting material (XIV, R = OAc, X = CN) can be prepared as follows:

To a solution of 2.8 g of acetobromothioglucose (W. Korytnyk et al., Carbohydrate Res., Vol. 108 (1982), p. 293) in 160 ml of acetone was added with stirring 1.0 g of 4-cyanothiophenol (III) and 1. 65 g of potassium carbonate and the reaction mixture was refluxed for 1 hour. After cooling, the salts were filtered off, washed with acetone, the filtrate was concentrated and the residue was subjected to column chromatography (solvent E) to yield 2.15 g (68%) of the title compound as a 15: 85 mixture of alpha and beta anomers. from ether gave 1.63 g (52%) of the β-anomer (XIV, R = OAc, X = CN). R _t (E) = 0.7, temperature táníl25-127 'H NMR (CDC1 ₃₎ ^l H: 4.27 4) 3.32 (H-5), 4.10 \ ΟΙ ΌΊΙΐυθ £ L i jf Pf \ J \ ff

[Α] _D = + 38 ° (c = 0.5, chloroform), (H1), 5.24 (H-2), 5.1.0 (H-3), 5.28 (H (H-) 6a), 4.26 (H-6b), 7.59 and 7.61

O

£.

π Γ *. / '- ____ ir \ T \' \. IOR bfVo τ u z. f HH ^1U uu ii '^ 1.2 IU of _R

J2.3 9.4, J _{3) 4} 9.4, ₄ J _(10.6 5, Js, 6 _and 3,3, $ J _(6b 5.3, 12.0 Hz;

¹³ C: 50.1 (Cl), 71.4, 73.3 and 74.3 (C-2.3.4), 44.6 (C-5),

60.9 (C-6), 111.5, 131.5, 132.5 and 138.8 (aromatic C), 118.1 (CN), 20, 3-20, 5 (OCOCH ₃ ), 169, 2 - 170.4 (OCOCH ₃ ).

Example 14

4-cyanophenyl 6-deoxy-l, 5-dithio-ss-D- <jlukopyranosid (I, R = R = R ₃ = OH, R¹ = CH _3, R ₅ = H, _R = CN)

To a solution of 180 mg of 4-cyanophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-β-D-glucopyranoside (XIV, R = Η, X = CN) in 8 mL of methanol was added 0, 1 ml of a 3M solution of sodium methoxide in methanol. After 1 hour, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 100 mg (78%) of the title compound, R _f (C) = 0.3, mp 207-212 ° C. [α] _D = -28 '(c - 0.5, methanol), NMR (DMSO-d ₆ ): _δ : 4.52 (H1), 3.32 (H-2), 3.00-3 , 20 (H-3,4), 2.85 (H-5), 1.12 (H-6), 7.60 and 7.78 (aromatic), 5.10, 5.12 and 5, 60 ppm (OH); Ji, _2, 10.2, J _{2, 3} 8.4, J ₅ Hz _e 6.9;

The starting material (XIV, R - Η, X = CN) can be prepared as follows:

«·

Method A)

Step a)

4-Cyanophenyl-2,3,4-tri-O-acetyl-1,5-dithio-6-methanesulfonyl-β-D-glucopyranoside (XIV, R = OMs, X = CN)

To 1.3 g of 4-cyanophenyl-1,5-dithio-β-D-glucopyranoside (I, R 1 = R ₂ = R ₃ = OH, R <= CH ₂ OH, R ₅ = H, R _e -CN) (Example 13) in 18 ml of pyridine, a solution of 0.6 ml of mesyl chloride in 6 ml of chloroform was added dropwise with stirring at 0 ° C, over 15 minutes. The reaction mixture was stirred at room temperature for 3 hours, then 8 mL of acetic anhydride was added and the mixture was allowed to stand overnight at room temperature. After routine work-up, the residue was subjected to column chromatography (solvent E) to yield 1.15 g (54%) of the title compound. R ((E) = 0.3, Mp: 119-122 C. ^e [a] D = + 28 DEG (c = 0.5, chloroform) NMR (CDCl), ^1H: 4.28 (H ), 5.23 (H-2), 5.12 (H-3), 5.24 (H-4), 3.38 (H-5), 4.24 (H-6a), 4.30 (H-6b), 7.08 and 7.12 (aromatic Η), 3.05 (Ms), 2.00, 2.05 and 2.06 ppm (OAc); JB2 10.3, J _{2, 3} 9.5, J ₃ , ₄ 9.5, J ₄ , ₅ 10.3, J ₅ , _6a

3.7, J _5, 5.2 _{eb, ea} J, _6b 10.9 Hz; ¹³ C: 50.2 (Cl), 71.2, 73.1 and 74.0 (C-2.3.4), 44.4 (C-5), 64.9 (C-6), 111 , 7, 131.6, 132.6 and 138.5 (aromatic C), 118.1 (CN), 37.6 (Ms), 20, 3, 20, 4, and

20.5 (OCOCH ₃ ), 169, 2, 169, 4, and 169.5 ppm (OCOCH ₃ ).

Step b)

4-Cyanophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dlthio-6-iodo-β-D-glucopyranoside (XIV, R = I, X-CN)

To a solution of 1.15 g of 4-cyanophenyl-2,3,4-tri-O-acetyl-1,5-dithio-6-O-methanesulfonyl-β-D-glucopyranoside (XIV, R = OMs,

X = CN) 0.6 g of sodium iodide was added in 55 ml of diethyl ketone and the reaction mixture was refluxed for 4 hours. After cooling, the salts were filtered and washed with dichloromethane. The filtrate was concentrated and the residue was subjected to column chromatography (solvent F) to yield 1.2 g (98%) of the title compound. _Rf (F) = 0.6, [?] _D = 0 ° (c = 0.5, chloroform) NMR (CDC1J, H: 4.32 (H) 5.05 to 5.30 (H -2.3.4), 3.36 (H-5), 3.04-3.20 (H-6), 7.58 and 7.60 (aromatic H), 2.00, 2.05, and 2.07 ppm (OAc); J ₂ 10.4 Hz;

¹³ r · tn n rc-n ία a va q =. v / ι o tr-? and di, 6 n 9 ^{in T in} f ⁱⁿ \ · - · -L. ; _r . · - · _ø - _r '· - f'.-I '* r *. t, * - _r f -, _r * - - f · - - rrf (C-6), 111.8, 131.5, 132.5 and 138.8 (aromatic C), 118.1 (CN) ), 20, 3, 20, 4 and 20.5 (OCOCH ₃ ), 169, 1, 169, 2 and 169.5 ppm (OCOCH ₃ ).

Step c)

4-Cyanophenyl -2,3,4-triethyl acetyl 6-deoxy-1,5-dihalo-f-D-glucopyranoside (XIV, R Η, X = CN)

To a solution of 1.2 g of 4-cyanophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-6-iodo-β-D-glucopyranoside (XIV, R = I, X = CN) in 45 ml of ethanol were added with stirring 0.22 g of sodium borohydride and 20 mg of nickel chloride hexahydrate and stirring was continued for another 30 minutes. The reaction mixture was neutralized with 4% HCl in water, filtered and concentrated. The residue was subjected to column chromatography (solvent F) to yield 0.4 g (43%) of the title compound. R _f (F) = 0.4, Mp: 134-136 ° C, [a] _D = + 57 DEG (c = 0.5, chloroform) NMR (CDC1 ₃₎ H: 4.24 ( H1), 5.00 5.30 (H-2.3.4), 3.08 (H-5), 1.15 (H-6), 7.59, 7.61 (aromatic H), 2 .00, 2.05 and 2.06 ppm (OAc); Ji ₍₂ 10.7, J _{4, 5} 9.9, J _{5 (6} 6.6 Hz; ¹³ C 50.0 (C-1), 73, 6, 74, 3, and 75.7 (C2, 3.4), 40.1 (C-5), 15.3 (C-6), 110.7, 131.3, 132.5 and 138.8 (aromatic C), 118.0 (CN), 20.5 (OCOCH 3), 169, 4, 169.5 and 169.6 ppm (OCOCH 3).

• φφφ

Method Β)

A solution of 1.3 g of 1,2,3,4-tetra-O-acetyl-6-deoxy-5-thio-D-glucopyranose (E. Bozó et al., Carbohydrate Res., Vol.

290 (1996), p. 159) in 20 ml of dichloromethane were added with stirring 4 ml of a 33% solution of hydrogen bromide in acetic acid. After standing at room temperature for 1 hour, the reaction mixture was poured into ice water, extracted with dichloromethane, washed with 6% sodium bicarbonate solution in water, water, dried and concentrated. The residue was dissolved in 110 ml of acetone, 0.54 g of 4-cyanothiophenol and 1.1 g of potassium carbonate were added, and the mixture was refluxed for 3 hours. After cooling, the salts were filtered and washed with acetone. The filtrate was concentrated and the residue was subjected to column chromatography (solvent F) to yield 0.97 g (61%) of glycosides in the form of a, β-anomeric mixture 1: 8, which after recrystallization from ether gave 0.6 g (38%). %) of the β-anomer, identical to the compound prepared in step c) of process A).

Example 15

4-cyanophenyl-6-deoxy-l, 5-dithio-.beta.-D-xylo-hex 5 enopyranosíd (I R _R - R _Z = R ₃ = OH, R ₄ + R ₅ = CH _2, R ₆ - CN )

To a solution of 4-cyanophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-β-D-xylo-hex-5-enopyranoside (XV) in 10 mL of methanol was added 3M sodium methoxide solution with stirring in methanol. After 1 hour, the solution was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 140 mg (91%) of the title compound. _Rf (D) = 0.4, Mp: 152-156 DEG C., [<x] _D = -99 ° (c = 0.3, methanol) NMR (DMSO-DJ, H: 4.44 ( H1), 3.48 (H-2), 3.10 (Η-3), 3.92 (H-4), 5.33 (H-6a), 5.60 (H-6b), 7, 60 and 7.78 (aromatic), 5.36, 5.58

44 and 5.75 ppm (OH); J 12,1, J ₂ , ₃ 8,5, J ₃ , ₄ 8,8, J _6a , 6b ~ _1,0 Hz.

The starting material (XV) can be prepared as follows:

To a solution of 4 g of 4-cyanophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-6-iodo-β-D-glucopyranoside (XIV, R = J, X =

CN) in 12 ml of pyridine were added 0.4 g of silver fluoride with stirring and after 2 hours 50 ml of chloroform. The reaction mixture was filtered, the filtrate was concentrated and the residue was subjected to column chromatography (solvent F) to yield 0.27 g (70%) of the title compound. R _f = 0.4, m.p. 150-153 ° C, [a] _D = -36 ° (c = 0.5, chloroform) NMR (CDC1. _3)> H: 4.28 (H) 5.37 (H-2), 5.08 (H-3), 5.60 (H-4), 5.47 (H-6a), 5.58 (H-6b), 7.55, 7.62 (aromatic), 2.02, 2.04 and 2.14 ppm (OAc); _B2 J 10.6, J _{2, 3} 9.4, J _{3, 4} 9.4, J _6a, 6b ~ l, 0 Hz;

¹³ C: 50.8 (C-1), 73.6, 73.2, and 73.1 (C-2.3.4), 134.0 (C-5),

118.3 (C-6), 111.4, 131.3, 132.5 and 138.9 (aromatic C),

118.2 (CN), 20.5 (OCOCH ₃ ), 168, 9, 169, 2 and 169.4 ppm (OCOCH ₃ ).

Example 16

4- (imino) (methoxy) methylphenyl 1,5-dithio -β-D-glucopyranoside (I, R = R _Z = R ₃ = OH, R <CfyOH = R ₅ = H, R ₆ = -C ( = NH) -OCH ₃ )

To a solution of 210 mg of 4-cyanophenyl-1,5-dithio-β-D-glucopyranoside (I, R 1 = R ₂ = R ₃ = OH, R ₄ = CH ₂ OH, R ₅ = H, Re = CN) (Example 13) in 10 mL of methanol was added 0.1 mL of a 3M solution of sodium methoxide in methanol. After standing at room temperature for 24 hours, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was subjected to column chromatography (solvent D). Concentration of the first fraction (Rf ₌ 0.25) gave 100 mg of the (recovered) starting material. Concentration of the second fraction _(Rf = 0.2) yielded 80 mg (66% conversion) of the title compound. Melting point: 181-184 ° C. [α] _D = -10 ° (c ~ 0.5,

methanol), NMR (DMS0-d ₆₎ , 4.30 ( H-1), 3.30 (H- 2), 3.12 (H-3), 3.30 (H-4), 2.98 (H-5), 3.48 (H-6a) 3 75 (H-6b) 6, 64, 4, 95, 5.08 and 5.48 (OH) 9.00 (NH), 3.80 ppm _(OCH3); Ji, 2 10.2, J ₂ , 3 8.5, J33 8 , 5, J ₄ , 5 9.7, J5,6a 6,6, Js, 6b 3 y 11 Jfia, 6b

11.5 Hz.

Example 17

4-Nitrophenyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R ₃ -R ₃ -OH, R ₂ = N ₃ , R ₄ = R ₅ -H, phi ₆ - NO ₂ )

Method A)

To a solution of 0.8 g of 1,2,4-tri-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc) and 0.8 g of 4-nitrothiophenol in 20 ml of dichloromethane 0.45 ml of trimethylsilyl triflate was added under argon at -10 ° C. The reaction mixture was stirred at room temperature for 5 hours, then quenched with triethylamine, followed by washing with 5% sodium bicarbonate solution and water. The residue obtained after concentration of the organic layer was subjected to column chromatography (solvent F). The residue obtained on concentration of fraction having _Rf = 0.6 was dissolved in 10 ml of methanol and 0.1 ml of a 3M solution of sodium methoxide in methanol. After standing at room temperature for 1 hour, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 90 mg (11%) of the title compound. Melting point: 145-150 ° C, R _E (D) = 0.4, [α] _D = -88 ® (c = 0.1, methanol), NMR (DMSO-d ₆ ), 1 H: 4, 62 (H1), 3.35 (H2), 3.28 (H-3), 3.48 (H-4), 2.83 (H-5a), 2.60 (H-5b), 5, 78 and 6.35 (OH), 7.68 and 8.15 ppm (aromatic H); Ji, ₂ 9.8, J _{2 (3} 9.1, • · fc

Fcfc fcfc

J _3, <9.1, J _{4, 5} 10.8, J _{4, 5b} 4.4, J _{5a, 5b} 13.3 Hz; ¹³ C: 50.6 (Cl),

74.8, 73.2 (C-2.4), 72.0 (C-3), 34.0 (C-5), 124.0, 128.5,

144.9 and 145.3 ppm (aromatic C).

Method B)

To a solution of 1.54 g of 1,2,4-tri-O-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc) and 0.82 g of 4-nitrothiophenol in 24 ml of 1 Of 2-dichloroethane was added 0.6 ml of boron trifluoride etherate under argon. The reaction mixture was stirred at room temperature for 24 hours, then washed with 5% aqueous sodium bicarbonate and water. The residue obtained after concentration of the organic layer was subjected to column chromatography (solvent F) to yield 0.76 g (38%) of 4-nitrophenyl-2,4-di-O-acetyl-3-azido-3-deoxy-1,5-dithio- pD-xylopyranoside (I, R 1 - R ₃ = OAc, R ₂ = N ₃ , R ₄ = R ₅ - H, R ₆ = NC ₆ ). The obtained material was deacetylated with a solution of sodium methoxide in methanol to give a compound identical to the final product of Method A).

Example 18

- (Aminothiocarbonyl) phenyl-6-deoxy-1,5-dihydro-β-β) glucopyranoside (I, R ₃ = R ₃ = OH, R 4 CH ₃ , R 8 = H, Re -CS (HH ₂₎ ))

Solution containing 0,3 g of 4-cyanophenyl-6-deoxy-1,5-dithio-β-D-glucopyranoside (I, R ₃ - R ₂ = R ₃ = OH, R ₄ = CH ₃ , R ₅

H, R _b = CN) (example 14) in 6 ml of pyridine and 6 ml of triethylamine was fed the anhydrous sulfide 5 hours at room temperature. After standing overnight at room temperature, the reaction mixture was concentrated and the residue was recrystallized from ether to yield 310 mg (93%) of the title compound. Melting point 92-96 ° C, R _f (D) = 0.3, [α] _D = + 5 ° (c = 0.5, methanol),

NMR _(DMS0-d) , ‘H: 4.38 (H-1), 3.28 (H-2) 1, 3.08 (H-3), 3.02 (H-4 ), 2.80 (H-5) 1.12 (H-6) 7.45 a 7, 85 (aromatic Η), 5, 05 , 5.10 and 5, 55 (OH), 9.45 and 9.85 ppm (NH); _B2 J 10.2, J _2: 8/3, 83.4 8/5, 84.5 8.8, ₅ J, _e 6.8 Hz.

EXAMPLE 19 (Aminothiocarbonyl) phenyl-2-deoxy-1,5-di-thio-β-D-threo-pentopyranoside (I, R 1 = R ₄ = T 1 = H, R ₂ = R ₃ = OH, R _e =

- CS (NH ₂ )

The solution containing 0, 3 g of 4-cyanophenyl 2-deoxy-l-.beta. 5dithio-threo-pentopyranoside (I, R = R ₄ = R $ - H, R ₂ = R ₃

OH, R ₆ = CN) (Example 8) in 6 ml of pyridine and 6 ml of triethylamine was saturated with anhydrous hydrogen sulfide at room temperature for 5 hours. After standing overnight at room temperature, the reaction mixture was concentrated and the residue was recrystallized from ether to yield 300 mg (89%) of the title compound. Melting point 169-173 ° C, R _f (D) = 0.3, (α) _D = -25 ° (c - 0.5, pyridine), NMR (DMSO-D ₆ ), 4.62 (H ₁ ). ), 1.72 (H-2a), 2.42 (H-2b), 3.25, 3.40 (H-3, 4), 2.55-2.64 (H-5a, b), 7.48 and 7.90 (aromatic Η), 4.95 and 5.12 (OH), 9.50 and 9.94 ppm (NH); Ji, ₂

11.9, Ji, ₂ b 2.5, J _2a, 2b 12.8, J _2, 3 -10.5, _J2 b, 3 ~ 2.5 Hz.

Example 20

-Amldinofenyl -2-deoxy-5 - dithio-.beta.-D-threo-pentopyranoside (I, R = R = R ₄ = H, R ₂ = R ₃ = OH, R = CS (NH) -NH ₂ )

To a solution of 150 mg of 4- (aminothiocarbonyl) phenyl-2-deoxy-1,5-dithio-β-D-threo-pentopyranoside (I, R _x = R ₄ = R ₅ = H, R ₂₎

- R ₃ = OH, Re - -CS (NH ₂ )) (Example 19) in 35 ml acetone was added 0.2 ml methyl iodide, the reaction mixture was refluxed for 5 hours and concentrated. The residue was dissolved in 10 ml of ethanol, 120 mg of ammonium acetate were added, and the mixture was stirred at 60 ° C for 6 hours and then concentrated. The residue was dissolved in 10 mL of 10% aqueous acetic acid and purified on Varion AD resin (10 mL) to yield a cryoprotect solution of 70 mg (41%) of the title compound as an acetate. Melting point 183-188. R _f (K) = 0.7, [a] _D = -18 DEG (c. = 0.5, methanol), NMR (DMSO-D ₆₎ ^r H 4.62 (H), 1.74 (H-2a), 2.42 (H-2b), 3.28, 4.42 (H-3.4), 2.56-2.66 (H-5a, 5b), 7.60 and 7, respectively. 72 (aromatic H), 4.6 and 5.6 ppm (NH, OH); J1, 2a 11.7, Ol, 2b 2.5, J2a, 2b 13.0, J2a, 3-10, J2b, 3.2 Hz; ¹³ C: 44.5 (Cl), 42.9 (C-2), 72.7, 73.4 (C-3.4), 33.9 (C-5), 165.7 (C (= NH) -NH2), 141.0, 128, 6, 128, 3 and 127.0 ppm (aromatic C).

Example 21

- (Aminothiocarbonyl) phenyl-1,5-dihydro-β-D-glucopyranoside (I, R 1 - R ₂ = R ₃ = OH, R <= CH ₂ OH, - H, R 8 - -CS (NH ₂₎ ))

A solution of 0.9 g of 4-cyanophenyl-1,5-dithio-β-D-glucopyranoside (I, R 1 = R ₂ = R ₃ = OH, R ₄ = CH ₂ OH, R ₅ = H, = CN) (Example 13 in 20 ml of pyridine and 20 ml of triethylamine was saturated with anhydrous hydrogen sulfide at room temperature for 5 hours. After standing overnight at room temperature, the reaction mixture was concentrated and the residue was recrystallized from methanol to yield 0.68 g (68%) of the title compound. Mp 165-168 ° C, R _t (D) - 0.2, NMR (DMSO-DJ, δ H; 4.33 (H)), 3.32 (H-2), 3.16 (H-3) ), 3.34 (H-4), 2.93 (H-5), 3.56 (H-6a), 3.79 (H-6b), 7.50 and 7.88 (aromatic H), 5.48, 5, 08, 4, 98 and 4,64 (OH), 9.45 and 9.85 ppm (NH); _b2 J 10.2, J _{2, 3} 8.6, J _{3 (4} 8 6, J ₄ , ₅ ~ 10, Js, 6a 6.6, 85.6b 3.1, J6a, 6b 11.2 Hz.

Example 22

4- (imino) (methylthio) methylphenyl 1,5-dithio-.beta.-Dglukopyranosid ((I, R ₂ = R ₂ = R <= OH, R, ₌ CH ₂ OH, R _b = H, R $ = -C (= HH) -SO 2)

A solution of 80 mg of 4- (aminothiocarbonyl) phenyl 1,5-dithioP-D-glucopyranoside (I, R _x = R ₂ = R ₃ = OH, R ₄ = CH ₂ OH, R ₅ = H, R ₆ = - CS (NH ₂ )} in 20 ml of acetone was added 0.1 ml of methyl iodides and the reaction mixture was refluxed for 4 hours.The precipitated product was filtered and washed with acetone to give 110 mg (98%) of the title compound. melting point 207-209 ^mp C.

R _f (D) = 0.4, NMR ^(DMSO-de): H 4.52 (H), 3.32 (H-2)

3.15, (H-3), 3.32 (H-4), 2.95 (H-5), 3.50 (H-6a), 3.76 (H6b), 7.80 and 7, 65 (aromatic H), 4.0-3.0 (NH, OH), 2.75 ppm (SMe); Ji ₍₂ 10.1, J _2f3 8.7, 8.7, J ₄ , ₅ ~ 10, J _{5 (6 and} 6.6,

Js, 6b 3.1 (Ota,) b 11.3 Hz.

Example 23

4-Nitrophenyl-6-deoxy-1,5-dithio-f-D-glucopyranoside (I, R 1 = R ₂ = R 1 = OH, R 1 = CH ₃ , R ₅ = II, R _e = NO ₂ )

To a solution of 320 mg of 4-nitrophenyl-2,3,4-tri-O-acetyl-6-deoxy-1,5-dithio-β-D-glucopyranoside (XIV, R = Η, X = NO ₂ ) in 20 mL of methanol was added 0 1 ml of a 3E solution of sodium methoxide in methanol. After 2 hours at room temperature, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was recrystallized from ether to yield 130 mg (57%) of the title compound. Melting point 157-159 ° C. R _f (D) = 0.4, [α] _D = + 9 '(c = 0.5, methanol), NMR (DMSO-D 6), T: 4.58 (H 1), 3.35 (H- 2), 3.13, fl flfl (H-3), 3.06 (H-4), 2.86 (H-5), 1.10 (H-6), 8.15 and 7.65 ( aromatic Η), 5.64 and 5.12 (OH)); J _{X (2} 10.3, J _2f3 8.2, J _3f4 8/8, Ja, s _0/8 / J 6, δ 7.2 Hz).

The starting material (XIV, R = Η, X = NO ₂ ) was prepared according to method B) of Example 14, but instead of 4-cyanothiophenol, 4-nitrothiophenol was used as the aglycone. This gave the pure β-anomer in a yield of 31%. The melting point was 138-141 ° C.

R _f (F) = 0.6, [?] _D = + 55 DEG (c = 0.5, chloroform) NMR (CDC1 ₃₎ HI 4.30 (H), 5.26 (H-2 ), 5.25-5.00 (H-3.4), 3.08 (H-5),

1.16 (H-6), 8.16 and 7.60 (aromatic H), 2.03, 2.02 and 1.96 (OAc); J 1 _{R 2} 10.6, J ₂ , 3 10.0, J ₄ , ₅ 10.0, J ₅ , ₆ 6.4 Hz; ¹³ C: 49.8 (Cl), 75.7, 74.2, 73.4 (C-2.3.4), 40.1 (C-5), 15.2 (C-6), 169 , 7, 169, 6, 169, 3 (CO), 124.0, 130, 6, 141.7 and 148.8 (aromatic C), 20.5 and 20.4 ppm (COCH ₃ ).

Example 24

-Nitrophenyl-2-deoxy-1,5-dithio-β-D-threo-pentopyranoside (I, R _x = R ₄ = = H, R ₂ -R ₃ = OH, R ₆ = NO ₂ )

To a solution containing 0,57 ga, β-mixtures (1: 9 ratio) 4-nitrophenyl-3,4-di-O-benzoyl-2-deoxy-1,5-dithio-D-threopentopyranoside (XII, R = 4-nitrophenylthio ) in 20 ml of methanol and 10 ml of dichloromethane was added 0.1 ml of a 3M solution of sodium methoxide in methanol. After 24 hours, the reaction mixture was neutralized at room temperature with Dowex 50 WX resin, filtered and concentrated. The residue was recrystallized from ether to yield 235 mg (71%) of the title compound. Mp 150-152 ° C, _Rf (C) = 0.3, [a] _D = -26 ° (c = 0.5, methanol) NMR (DMSO-D ₆₎ ³ Η:

4.78 (H-1), 1.78 (H-2a), 2.43 (H-2b), 3.32-3.44 (H-3.4),

2, 60-2.78 (H-5a, 5b), 7.64 and 8.16 (aromatic), 5.15 and 5.04

I * I * I * I * ppm (OH); 81.2 $} Α, Ί, Ji, jb 2.6, J _2a , 2b 12.7, J _2a , 3 ~ 10, 82b, 3 2.9 Hz.

The starting material (XII, R = 4-nitrophenylthio) was prepared according to step c) of method B) of Example 8, but instead of 4-cyanothiophenol, 4-nitrothiophenol was used as the aglycone. This gave the α, β-anomeric mixture in a ratio of 1: 9 in a yield of 92%. R _f (H) = 0.5, NMR (CDC1 ₃₎ 7 4.52 (H), 2.38 (H2a), 2.94 (H-2b), 5.34 to 5.50 (H-3.4), 3.02 (H-5a), 3.22 (H-5b),

7, 30-8.20 ppm (aromatic); 8 _{1) 23} 11.0, Ji, _2b 2.9, J _2a , 2b

12.9, J 2a, 3 10.8, 82b, 3.2, 84.5 and 9.4, 84.5b 3.7, 853.5b 13.8 Hz; ^I3 C: 45.8 (Cl), 39.3 (C-2), 71.8, 71.6 (C-3.4), 31.0 (C-5), 165, 6, 165, 5 (CO), 124.0, 128.4, 129, 2, 129, 3, 129.6, 129.7, 133.3, 143.1 and 146.4 (aromatic C).

Example 25

4-Nitrophenyl 4 AXID-4-deoxy-1,5-dithio-.beta.-D-xy1opyranos disulfide (I, R = R ₂ - OH, R ₃ --- N _{3, t} = 10 R = H, = NO ₂ )

To a solution of 2.0 g of 1,2,3-tri-O-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranoside (IV, R = OAc) (step g) of method A) of Example 6) and 1 1 g of 4-nitrothiophenol in 50 ml of anhydrous 1,2-dichloroethane was added with stirring 0.78 ml of boron trifluoride etherate. After standing at room temperature for 24 hours, the reaction mixture was washed with 5% aqueous sodium bicarbonate solution and water. The residue obtained after concentration of the organic layer was subjected to column chromatography (solvent H) to yield 0.65 g (25%) of 4-nitrophenyl-2,3-di-O-acetyl-4-azido-4-deoxy-1,5-dithio- p-Dxylopyranoside (IT, R = NO ₂ ). The compound thus obtained was dissolved in 20 ml of methanol and 0.1 ml of a 1M solution of sodium methoxide in methanol was added. After standing at room temperature for 1 hour, the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue obtained after concentration was recrystallized from ether to yield 0.38 g (73%) of the title compound. Melting point 126-129 ° C,

R _f (C) = 0.4, (a] _D = + 104 ° (c = 0.5, methanol) NMR (DMSO-D ₆₎

4.60 (H1), 3.40 (H-2), 3.30 (H-3), 3.62 (H-4), 2.76 (H5a), 2.66 (H-5b), 5.80 and 5.95 (OH), 7.62 and 8.15 ppm (aromatic H); Ji _r2 10.0, J _{2, 3} 9.8, J _{3 (4} 9.3, J _{4, 5} 11.3, J _{4, 5b,} 4.5, 13.4 Hz Jsa.Sb.

Example 26

4-Ni-trophenyl-2-azido-2-deoxy-1,5-dithio-β-D-xylopyranoside (ΐ, R 1 = N ₃ , R ₂ -R ₃ -OH, R ₄ = H, R _b = NO ₂ )

To a solution of 0.85 g-O-acetyl-2-azido-2-deoxy-3,4-di-Obenzoyl-5-thio-D-xylopyranose (XIII, R = OAc) (step b) of Example 9) at 15 ml of anhydrous 1,2-dichloroethane was added 0.33 g of 4-nitro-thiophenol and 0.26 ml of boron trifluoride etherate under an argon atmosphere. After standing at room temperature for 24 hours, the reaction mixture was washed with 5% aqueous bicarbonate and water. The residue obtained by concentrating the organic layer was subjected to column chromatography (solvent H) to yield 0.3 g (30%) of 4-nitrophenyl-3,4-di-0-benzoyl-2-azido-2-deoxy-1,5-dithio- pD-xylopyranoside (XIII, R = 4-nitrophenylthio). The compound thus obtained was dissolved in 20 ml of methanol and 10 ml of dichloromethane, then 0.1 ml of a 1M solution of sodium methoxide in methanol was added. After 1 hour at room temperature, the reaction mixture was neutralized with solid carbon dioxide, concentrated and subjected to column chromatography (solvent C) to yield 80 mg (44%) of the title compound. Rf (C) = 0.3, [?] _D = + 120 ° (c = 0.5, methanol), NMR (DMSO-DJ ^T H: 4.70

(H1), 3.55 (H-2), 3.26 (H-3), 3.55 (H-4), 2.76 ( H-5a), 2.54 (H-5b), 8.20 and 7.66 (aromatic), 5.44 and 5.78 ppm (OH);

Ol, 2 10.9, J ₁ , 3.9, J ₃₎ 4.9, J4.5a 10.8, J4.5fc 4.4, J5a, 5b 13.3 Hz.

• · · · · * * * •

Claims (4)

PATENT CLAIMS 1,5-Dithiopyranosides of formula (I) characterized in that: Ri represents hydrogen, hydroxy or an azido group, R ₂ represents hydroxy, azido, amino or acetamido group, R ₃ is hydroxy or an azido group, represents hydrogen, methyl or hydroxymethyl, R ₅ represents hydrogen, RFL FL and together represent a methylene group represents R _€ nitro, cyano, amidino, aminothiocarbonyl, -C (= NH) -OCH _3, -C (= NH) -NH-NH ₂ or -C (= NH) -SCH ₃ with the proviso that R 8 represents exclusively a group other than nitro or cyano when R ₃ -R ₃ are hydroxy and R 8 is the same as R ₅ is hydrogen, then the FL represents * exclusively group other than nitro when R ₃ - R ₃ represent hydroxy, R <is hydroxymethyl * group and _R is hydrogen and, if possible, of them formed the acid addition salts with organic and inorganic acids. 2. 4- (Hydrazino) (imino) methylphenyl-1,5-dithio-p-Dxylopyranoside. Fefe * fefe * 3. 4- (imino) (methylthio) methylphenyl-1,5-dithio - [.beta.-piperidinyl] id. 4. 4-Cyano-phenyl-2-deoxy-1,5-dithio-3-D-threopentopyranoside. 5. 4- (Imino) methoxy) methyl phenyl-3-azido-3-deoxy-1,3-thiophene-β-D-xylopyranoside d. 6. 4-Ni triphenyls 1-3- and from i-3-deoxy-1,5-di-β-β-Γ.xylopyranoside. /. 4- (Aminothiocarbonyl) phenyl- Copyranoside. B-dithio-p-b- I. Farmacent ical composition u n u c u j i i ; s o i Γ / 7 n O b b -d h 1; b ? jacket active at ; n idll S 1 QUCHUU 1 U H general pattern · :: e! I), in which R _: - R, have the same \ ýzuam o in claim 1, or if possible their farmacoul : i cky liver salts, solvents, thinner, wear no ? and fillers yki.e used in pharmaceuticals. r 1 -n,, λ: 4- I 0. i 0 u b, b b ± compounds of formula { 1), but not from P _; to D. i '' f ¹ H / i R ,. have standing As in claim 1, as described in claim 1 or height p 1 and v 11. 10. Use compounds of the formula (11, in which lb, R, in R, R ·· and Ρ ,; have s the same meaning as in claim 1, for preparation anti-cocaine drugs.