WO1997049716A1

WO1997049716A1 - Novel anticoagulant glycosides and pharmaceutical compositions thereof

Info

Publication number: WO1997049716A1
Application number: PCT/HU1997/000031
Authority: WO
Inventors: Éva KOVÁCSNÉ BOZÓ; János KUSZMANN; Gabriella Szabó; Sándor BOROS; Imre Moravcsik
Original assignee: Richter Gedeon Vegyészeti Gyár Rt.
Priority date: 1996-06-25
Filing date: 1997-06-23
Publication date: 1997-12-31
Also published as: CA2256504A1; SK175798A3; JP2000512989A; PL330727A1; EP0907656A1; HUP9601756A3; HUP9601756A2; CZ414998A3; HU9601756D0; AU3354797A

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

NOVEL ANTICOAGULANT GLYCOSIDES AND PHARMACEUTICAL

COMPOSITIONS THEREOF

This invention relates to novel 1 ,5-dithio-pyranosides of the formula (I),

wherein

R-, 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 represent hydroxy groups, and R₄ as well as R₅ represent hydrogen, furthermore that R₆ represents only a group other than a nitro group if R_rR₃ each represent 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.

The compounds of the invention possess valuable pharmaceutical properties, especially anticoagulant activity, even when administered by the oral route. Particularly valuable representatives of formula (I) according to the invention are the following ones:

4-(imino)(methoxy)methylphenyl 1 ,5-dithιo-β-D-xylopyranoside 4-(aminothiocarbonyl)phenyl 1 ,5-dithio-β-D-xylopyranoside

4-(imino)(methylthio)methylphenyl 1 ,5-dithio-β-D-xylopyranoside 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-dithio-β-D-fr7reo-pentopyranoside 4-cyanophenyl 2-azido-2-deoxy-1 ,5-dithio-β-D-xylopyranoside 4-(imiπo)(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-(imiπo)(methoxy)methylphenyl 1 ,5-dithio-β-D-glucopyranoside 4-πitrophenyl 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-r7/reo-pentopyranoside 4-amidinopheny! 2-deoxy-1 ,5-dithio-β-D-r77reo-pentopyranoside 4-(aminothiocarbonyl)phenyl 1 ,5-dithιo-β-D-glucopyranoside 4-(imino)(methylthio)methylphenyl 1 ,5-dithio-β-D-glucopyranoside 4-nitrophenyl 2-deoxy-1 ,5-dithio-β-D-fr7reo-pentopyranoside

Some derivatives of the formula (I), in which R1-R3 each represent hydroxy groups, R₄ and R₅ are hydrogen (i.e 1 ,5-dithio-xylopyranosides), and R₅ represents a chloro, nitro, cyano, methyl or methoxy group, are known from the literature [F. Bellamy et al.. Eur. J. Med. Chem. 30 (1995) 101]. From among these derivatives those, in which R₆ represents a nitro or a cyano group, possess advantageous anticoagulant activity even when administered orally (EP 365.397). Furthermore the 1 ,5-dithio-glucopyranoside of formula (I), in which R1-R3 each represent hydroxy groups, R₄ represents a hydroxymethyl group, R5 represents a hydrogen and R₆ represents a nitro group, is also known from the literature [B. Joseph and P. Rollin, J. Carbohydr. Chem. 12 (1993) 719], but the biological activity of this compound has not been described so far.

The aim of the invention was to synthesize such new carbohydrate derivatives which are stronger inhibitors of the coagulation process than the known ones and are orally active too.

Surprisingly it was found, that the antithrombotic activity of carbohydrate derivatives can be substantially increased, by exchanging the hydroxy groups of the carbohydrate moiety (R1-R3) with hydrogen or with azido groups. A similarly increased activity was found for thioglycosides, in which the carbohydrate part was a thiohexose (R₄ represents a hydroxymethyl group) instead of a thiopentose, as well as in further derivatives, in which the cyano substituent at C-4 of the aglycon was transformed into a carboxylic acid derivative. The compounds of the invention can be synthesized by different known methods. a) The compound of formula (I), in which R1-FR3 each represent hydroxy groups, R₄ and R₅ are hydrogens and Rc represents a -C(=NH)-OCH₃ group, can be prepared e.g. by treatment of a compound of formula (I), wherein the meaning of R₁-R5 is as defined above and R₆ is a cyano group, with sodium methoxide in methanol, or e.g. by heating of a compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is a -C(=NH)-SCH₃ group, in methanolic solution. b) The compound of formula (I), in which R_rR₃ each represent hydroxy groups, R₄ and R5 are hydrogens and R₆ represents an aminothiocarbonyl group, can be prepared e.g. by treatment of a compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is a cyano group, with hydrogen sulfide using an organic base as solvent.

The above reaction can preferably be carried out at room temperature, using a 1 :1 mixture of triethylamine-pyridine as solvent. c) The compound of formula (I), in which R-1-R3 each represent hydroxy groups, R₄ and R₅ are hydrogens and R₆ represents a -C(=NH)-SCH₃ group, can be prepared e.g. by treatment of a compound of formula (I), wherein the meaning of R₁-R5 is ^as defined above and R₆ is a aminothiocarbonyl group, with a methylating agent.

The above reaction can preferably be carried out, using acetone as solvent and methyl iodide as reagent at reflux temperature. d) The compound of formula (I), in which R^-R₃ each represent hydroxy groups, R₄ and R₅ are hydrogens and R₆ represents an amidino group, can be prepared e.g. by treatment of a compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is a -C(=NH)-SCH₃ group, with ammonium acetate or with ammonia using a lower aliphatic alcohol as solvent. The above reaction can preferably be carried out, using methanol or ethanol as solvent at reflux temperature. e) The compound of formula (I), in which R-1-R3 each represent hydroxy groups, R₄ and R₅ are hydrogens and RQ represents a -C(=NH)-NH-NH₂ group, can be prepared e.g. by treatment of a compound of formula (I), wherein the meaning of R1-R5 is as defined above and Re is a -C(=NH)-SCH₃ group, with hydrazine, using a lower aliphatic alcohol as solvent.

The above reaction can preferably be carried out, using 98% hydrazin hydrate as reagent and ethanol as solvent. f) The compound of formula (I), in which R₁ and R₂ each represent hydroxy groups, R₃ represents an azido group, R₄ and R₅ are hydrogens and R₆ represents a cyano group, can be prepared e.g. by separating the β-anomer of an anomenc mixture of formula (II),

γ

wherein R represents a cyano group, and removing subsequently the acetyl groups in a lower aliphatic alcohol by treatment with base. The above reaction can preferably be carried out by separating the anomenc mixture of formula (II) in which R represents a cyano group, by column chromatography and removing the acetyl groups from the separated β-anomer by using sodium methoxide in methanolic solution.

The glycosides of formula (II), wherein R represents a cyano group are new compounds and can be prepared e.g. from compounds of formula (VII),

wherein R-_| and R₂ represent hydrogen, by introducing a protecting group at the primary hydroxy group and mesylating the secondary one. The obtained compound of formula (VII), in which R-| represents a mesyl group and R₂ represents a proper protecting group, is converted by treatment with an appropriate azide into the compound of formula (VI),

wherein R represents a hydroxy group carrying a suitable protecting group. This protecting group is then removed and the free hydroxy group is converted preferably by mesylation into a leaving group. The latter gives on treatment with the salt of a thioacid the corresponding thioester from which the ethylmercapto groups are split off. From the obtained aldehyde of formula (V)

the benzoyl group and thereafter the isopropylidene group is removed and the resulting thiosugar is converted either directly, or via the methyl glycoside of formula (IV),

wherein R represents a methoxy group, into the triacetate of formula (IV), in which R represents an acetoxy group. Condensation of the latter compound with 4-cyanothiophenol of formula (III)

affords an anomeric mixture of the glycosides of formula (II), in which R represents a cyano group.

According to an alternative procedure the same mixture of glycosides can be obtained by converting the triacetate of formula (IV), in which R represents an acetoxy group, into the diacetate of formula (IV), in which R represents a hydroxy group, and subsequently into a trichloroacetimidate of formula (IV), in which R represents an -0-C(NH)-CCI₃ group. Condensation of the latter with (III) affords the anomeric mixture of the glycosides of formula (II), in which R represents a cyano group. The above reaction sequence can preferably be carried out by treating the mercaptal of formula (VII), wherein R^ and R₂ represent hydrogen, in the presence of an organic base, preferably in pyridine first with

A) 1.1 equiv. of benzoyl chloride and subsequently with mesyl chloride affording compounds of formula (VII) , in which R-| represents a mesyl group and R₂ represents a benzoyl group, or first with

B) 1.1 equiv. of t-butyldimethylsilyl chloride (TBDMS-CI) and subsequently with mesyl chloride affording compounds of formula (VII), in which R-_] represents a mesyl group and R₂ represents a TBDMS group. The obtained derivative is treated with an appropriate salt of hydrazoic acid, preferably with sodium azide in an apolar solvent, preferably in N.N-dimethylformamide or dimethylsulfoxide at 100-150 °C, preferably at 120 °C. Thereafter the benzoyl group is removed from the obtained intermediate of formula (VII), in which R-i represents a mesyl group and R₂ represents a benzoyl group, in methanol with sodium methoxide, while the TBDMS protecting group of the intermediate of formula (VII), in which R₁ represents a mesyl group and R₂ represents a TBDMS group, is split off with tetrabutyiammonium fluoride in tetrahydrofuran. The obtained compound of formula (VI), wherein R represents a hydroxy group, is converted with mesyl chloride in pyridine solution into mesylate of formula (VI), wherein R represents a mesyloxy group. The latter gives on treatment with a salt of a thiocarboπic acid, preferably with potassium thiobenzoate in an aprotic solvent, preferably irr N₍N-dimethylformamide the ester of formula (VI), wherein R represents a benzoylthio group. The ethylmercapto groups of this intermediate are split off, preferably in aqueous acetone with mercury(ll) chloride in the presence of cadmium carbonate when aldehyde of formula (V) is obtained. The ester group of the aldehyde of formula (V) is removed with sodium methoxide in methanol and subsequently the isopropylidene group is split off by acidifying the solution with hydrochloric acid. A mixture of the α- and β-triacetates of formula (IV), wherein R represents an acetoxy group is obtained, when the above solution is neutralized and the residue obtained after evaporation is treated with acetic anhydride in pyridine. When the acidified methanolic solution is kept for a longer time, or when it is heated before neutralization and acetylation, a mixture of the acetylated α- and β-methylglycosides of formula (IV), wherein R represents a methoxy group, is obtained. This latter compound can be converted with sulfuric acid in acetic anhydride into the former triacetates of formula (IV), wherein R represents an acetoxy group. When a solution of this mixture of triacetates in an aprotic solvent, preferably in dichloromethane is treated with 4-cyanothiophenol of formula (III) in the presence of a promoter, preferably trimethylsilyl triflate a mixture of the glycosides of formula (II), wherein R represents a cyano group, is obtained.

Alternatively the same mixture is formed, when the triacetate of formula (IV), wherein R represents an acetoxy group, is treated with hydrazine acetate in N,N-dimethylformamide and the resulting compound of formula (IV), wherein R represents a hydroxy group, is treated with trichloroacetonitrile in dichloromethane in the presence of potassium carbonate, affording the imidate of formula (IV), wherein R represents a -0-C(NH)-CCI₃ group. Treatment 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 yields the same mixture of glycosides of formula (II) described above, wherein R represents a cyano group, g) The compound of formula (I), in which R^ and R₃ each represent hydroxy groups, R₂ represents an azido group, R₄ and R₅ are hydrogens and R₆ represents a cyano group, can be prepared e.g. by treating the xylopyranose of formula (VIII),

^V wherein R represents an acetoxy group or a -0-C(NH)-CCI₃ group, with 4- cyanothiophenol of formula (III) in the presence of a promoter and removing the acetyl groups of the resulting glycoside of formula (X),

wherein R represents a cyano group, by treatment with base in a lower aliphatic alcohol. The above reaction can preferably be carried out by reacting

A) the acetate of formula (VIII) wherein R represents an acetoxy group, with 4- cyanothiophenol of formula (III) in dichloromethane at low temperature, preferably at -10 °C in the presence of trimethylsilyl triflate as promoter, or alternatively

B) the imidate of formula (VIII), wherein R represents a -0-C(NH)-CCI₃ group, with 4-cyanothiophenol of formula (III) in dichloromethane or 1 ,2-dichloroethane in the presence of boron trifluoride etherate as promoter at low temperature, preferably at -15 °C. In both cases a mixture of glycosides is formed from which the β-anomer of formula (X), wherein R represents a cyano group, is separated by column chromatography. Deacetylation of the compound of formula (X), wherein R represents a cyano group, can be carried out with sodium methoxide in methanol affording the compound of formula (I), in which R^ and R₃ each represent hydroxy groups, R₂ represents an azido group, R₄ and R₅ are hydrogens and RQ represents a cyano group

The xylopyranose derivative of formula (VIII) wherein R represents an acetoxy group, is also a new compound and can be prepared e.g. by converting the known [H. Ohrui et al.: Agric. Biol. Chem. 34 (1970) 375] 3-azido-3-deoxy-

1 ,2-0-isopropylidene-5-0-tosyl-D-xylofuranose with potassium thiobenzoate into the ester of formula (IX)

which is first debenzoylated, then the isopropylidene group is split off and the resulting 5-thio-xylopyranose derivative is converted into its peracetate. The above reaction sequence can preferably be carried out by treating 3-azido- 3-deoxy-1 ,2-0-isopropylidene-5-0-tosyl-D-xylofuranose with potassium thiobenzoate in N,N-dimethylformamide at 100 °C. The formed ester of formula (IX) is debenzoylated with sodium methoxide in methanol, the solution is then acidified with aqueous hydrochloric acid, boiled and the obtained trihydroxy derivative is converted with acetic anhydride in pyridine into its peracetate of formula (VIII), in which R represents an acetoxy group, h) The compound of formula (I), in which R_{1 t} R₄ and R₅ are hydrogens, R₂ and R₃ represent hydroxy groups, and RQ represents a cyano group, can be prepared e.g. by the addition of hydrogen bromide in an aprotic solvent to the pentose derivative of formula (XI),

V

wherein R represent benzoyl groups, and treating the resulting bromide of formula (XII),

V wherein R represents a bromo atom with a salt of 4-cyanothiophenol of formula (III). The ester groups of the resulting glycoside of formula (XII), wherein R represents a 4-cyanophenylthio group, are removed by treatment with base in a lower aliphatic alcohol and the needed β-anomer of formula (I), mentioned above, is separated by crystallization from the resulting mixture of the anomeric glycosides.

Alternatively the same mixture of glycosides of formula (XII), wherein R represents a 4-cyanophenylthio group, can be obtained by exchanging first the bromo atom of the bromide of structure (XII), wherein R represents a bromo atom with an acetoxy group, and reacting the resulting acetate of structure (XII), wherein R represents an acetoxy group, with 4-cyanothiophenol of structure (III) in the presence of a promoter. The above reaction sequence can preferably be carried out 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 treating the obtained reactive intermediate of formula (XII), wherein R represents a bromo atom, without isolation with the sodium salt of 4-cyanothiophenol, prepared in situ from compound (III) and sodium hydride. The formed mixture of anomers of structure (XII), wherein R represents a 4-cyanophenylthio group, is separated from the formed elimination product of formula (XI), wherein R represents a benzoyl group, by column chromatography.

Alternatively the same mixture of glycosides of structure (XII), wherein R represents a 4-cyanophenylthio group, is obtained, when the bromo intermediate of formula (XII), wherein R represents a bromo atom, is treated without isolation with silver acetate in acetonitrile, and the formed acetate of formula (XII), wherein R represents an acetoxy group, is treated with 4- cyanothiophenol of formula (III), in dichloromethane in the presence of trimethylsilyl triflate. The benzoyl groups of the obtained mixture of glycosides of structure (XII), wherein R represents a 4-cyanophenylthio group, can be removed with sodium methoxide in methanol affording a mixture of the anomeric glycosides from which the needed β-anomer of formula (I), in which R-, , R₄ and R5 are hydrogens, R₂ and R₃ represent hydroxy groups, and R_Q represents a cyano group, is separated by crystallization. i) The compound of formula (I), in which R-j represents an azido group, R₂ and R₃ represent hydroxy groups, R₄ and R₅ are hydrogens and R₆ represents a cyano group, can be prepared e.g. by the azidonitration of the pentose derivative of formula (XI), wherein R represents a benzoyl group, in an aprotic solvent, exchange of the O-nitro group of the obtained intermediate of formula

wherein R represents a O-nitro group, by an acetoxy group, and coupling of the formed triester of formula (XIII), wherein R represents an acetoxy group, with 4- cyanothiophenol of structure (III) in the presence of a promoter. The two anomers of the obtained mixture of glycosides of structure (XIII), wherein R represents a 4-cyanophenylthιo group, are separated, and the ester groups of the β-anomer are removed by treatment with base in a lower aliphatic alcohol. The above reaction sequence can preferably be carried out by using acetonitrile as solvent and sodium azide and ceπc ammonium nitrate as reagents for the azidonitration of the pentose derivative of formula (XI), wherein R represents a benzoyl group. The formed intermediate of formula (XIII), wherein R represents a O-nitro group, is treated with potassium acetate in acetic acid at elevated temperature, preferable at 100 °C to yield the tnester of formula (XIII), wherein R represents an acetoxy group, and this is treated with 4-cyanothιophenol of formula (III) using trimethylsilyl triflate as promoter. The formed mixture of glycosides of structure (XIII), wherein R represents a 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 affording the needed glycoside of formula (I), in which R-) represents an azido group, R₂ and R₃ represent hydroxy groups, R₄ and R₅ represent hydrogens and R₆ represents a cyano group. j) The compound of formula (I), in which R₁ and R₃ represent hydroxy groups, R₂ represents an ammo group, R₄ and R5 represent hydrogens and R₆ represents a cyano group, can be prepared e.g. by reducing the 3-azιdo group of the compound of formula (I), in which R-| and R₃ represent hydroxy groups, R₂ represents an azido group, R₄ and R₅ represent hydrogens and R₆ represents a cyano group, using a lower aliphatic alcohol as solvent The above reduction can preferably be carried out by using ethanol as solvent and sodium borohydπde - nιckel(ll) chloride as reagents k) The compound of formula (I), in which R₁ and R₃ represent hydroxy groups, R₂ represents an acetamido group, R₄ and R₅ represent hydrogens and R₆ represents a cyano group, can be prepared e.g. by treating the compound of formula (I), in which R-_| and R₃ represent hydroxy groups, R₂ represents an amino group, R₄ and R₅ represent hydrogens and R₆ represents a cyano group, with acetic anhydride in the presence of a base, and removing subsequently the formed ester groups.

The above reaction can preferably be carried out by using pyridine as a base and sodium methoxide in methanol for removing the ester groups.

I) The compound of formula (I), in which R-| and R₃ represent hydroxy groups, R₂ represents an azido group, R₄ and R₅ represent hydrogens and R₆ represents a -C(=NH)-OCH₃ group, can be prepared e.g. by treating the compound of formula (I), in which the meaning of R1-R5 is as defined above and R₆ represents a cyano group, with sodium methoxide in methanol. m) The compound of formula (I), in which R-pR₃ each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a cyano group, can be prepared e.g. by separating the two anomers of formula (XIV),

wherein R represents an acetoxy group and X represents a cyano group, and removing the acetyl groups from the β-anomer by treatment with base in a lower aliphatic alcohol. For the separation of the two anomers preferably column chromatography is applied and deacetylation of the separated β-anomer is carried out with sodium methoxide in methanol.

The glycosides of formula (XIV), wherein R represents an acetoxy group and X represents a cyano group, are new compounds and can be prepared e.g. by reacting the known [W. Korytnyk et al.: Carbohydrate res., 108 (1982) 293] acetobromo 5-thio-D-glucose with 4-cyanothiophenol of formula (III) in the presence of a base in an aprotic solvent.

The above reaction can preferably be carried out under reflux, using acetone as solvent and potassium carbonate as base. n) The compound of formula (I), in which R-|-R₃ each represent hydroxy groups, R₄ represents a methyl group, R₅ represents hydrogen and R₆ represents a cyano group, can be prepared e.g. by removing the acetyl groups of the β- anomer of formula (XIV), in which R represents hydrogen and X represents a cyano group in a lower aliphatic alcohol by treatment with base. The β-glycoside of formula (XIV), in which R represents hydrogen and X represents a cyano group, is a new compound and can be prepared e.g.

A) by converting the primary hydroxy group of glycoside of formula (I), in which R_rR₃ each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a cyano group into an active ester, which is treated with an iodide salt after protection of the remaining hydroxy groups, and the iodo substituent is reductively eliminated from the formed intermediate of formula (XIV), in which R represents an iodo atom and X represents a cyano group, or

B) the known [E. Bozό et al.: Carbohydr. Res. 290 (1996) 159] 1 ,2,3,4-tetra-O- acetyl-6-deoxy-5-thio-D-glucopyranose is converted into its 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. Thereafter the β- anomer is separated from the obtained anomeric mixture of formula (XIV), in which R represents hydrogen and X represents a cyano group. The reaction sequence mentioned in method A) can preferably be carried out the following way. The primary hydroxy group of the glycoside of formula (I), in which R_rR₃ each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a cyano group, is converted by mesylation into a leaving group and the remaining hydroxy groups are protected by acetylation. The obtained mesylate of formula (XIV), in which R represents a mesyloxy group and X represents a cyano group, is treated with sodium iodide in diethylketone at reflux temperature and from the iodo derivative of the resulting compound of formula (XIV), in which R represents an iodo atom and X represents a cyano group, the iodo substituent is reductivefy removed by using sodium borohydride - nickel(ll) chloride as reagents. The reaction sequence mentioned in method B) can preferably be carried out the following way. Acetobromo-6-deoxy-5-thio-D-glucose is converted with 4- cyanothiophenol of formula (III) in boiling acetone in the presence of potassium carbonate into a mixture of the anomeric glycosides of formula (XIV), wherein R represents hydrogen and X represents a cyano group, and the β-anomer of structure (I), in which R1-R3 each represent hydroxy groups, R₄ represents a methyl group, R5 represents hydrogen and R₆ represents a cyano group, is separated from this mixture by crystallization. o) The compound of formula (I), in which R_rR₃ each represent hydroxy groups, R₄ and R₅ together represent a methylene group and R₆ represents a cyano group, can be prepared e.g. by removing the acetyl groups from the β-anomer of formula (XV)

in a lower aliphatic alcohol by treatment with base.

The above reaction can preferably be carried out with sodium methoxide in methanol. The β-glycoside of formula (XV) is a new compound and can be prepared e.g. by elimination of hydrogen iodide from the iodide of formula (XIV), wherein R represents an iodo atom and X represents a cyano group. The above mentioned elimination reaction can preferably be carried out in pyridine, using silver fluoride as reagent. p) The compound of formula (I), in which R-1-R3 each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a -C(=NH)-OCH₃ group, can be prepared e.g. by treating the derivative of formula (I), wherein R-]-R₃ each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a cyano group, with sodium methoxide in methanol. q) The compound of formula (I), in which R^ and R₃ each represent hydroxy groups, R₂ represents an azido group, R₄ and R5 are hydrogens and R_Q represents a nitro group, can be prepared e.g. by treating the xylopyranose derivative of formula (VIII), wherein R represents an acetoxy group, with 4- nitrothiophenol in the presence of a promoter and removing the acetyl groups from the obtained glycoside of formula (X), wherein R represents a nitro group, with base in a lower aliphatic alcohol. The above reaction sequence can preferably be carried out by treating the xylopyranose derivative of formula (VIII), wherein R represents an acetoxy group, 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 obtained anomeric mixture the β-glycoside of formula (X), wherein R represents a nitro group, is separated by column chromatography and is subsequently deacetylated with sodium methoxide in methanol to afford the compound of formula (I), in which R_i and R₃ each represent hydroxy groups, R₂ represents an azido group, R₄ and R₅ are hydrogens and R₆ represents a nitro group. r) The compound of formula (I), in which R-1-R3 each represent hydroxy groups, R₄ represents a methyl group, R₅ represents hydrogen and R₆ represents an aminothiocarbonyl group, can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is a cyano group, with hydrogen sulfide using an organic base as solvent.

The above reaction can preferably be carried out at room temperature, using a 1:1 mixture of triethylamine-pyridine as solvent. s) The compound of formula (I), in which R., , R₄ and R₅ are hydrogens, R₂ and R₃ represent hydroxy groups, and R₆ represents an aminothiocarbonyl group, can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is a cyano group, with hydrogen sulfide using an organic base as solvent.

The above reaction can preferably be carried out at room temperature, using a 1 :1 mixture of triethylamine-pyridine as solvent. t) The compound of formula (I), in which R-|, R₄ and R₅ are hydrogens, R₂ and

R₃ represent hydroxy groups, and R₆ represents an amidino group, can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R_rR₅ is as defined above and R₆ represents an aminothiocarbonyl group, with a methylating agent when an intermediate of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ represents a -C(=NH)-SCH₃ group is obtained. Reaction of the latter with ammonium acetate or with ammonia using a lower aliphatic alcohol as solvent yields the desired product of formula (I), in which R_{1 t} R₄ and R5 are hydrogens, R₂ and R₃ represent hydroxy groups, and R₆ represents an amidino group. The above reactions can preferably be carried out, by using methyl iodide as reagent and acetone as solvent for the methylation, and exchanging the formed methylthio group with ammonium acetate in methanol or ethanol as solvent at reflux temperature. u) The compound of formula (I), in which R1-R3 each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents an aminothiocarbonyl group, can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R-1-R5 is as defined above and R₆ is a cyano group, with hydrogen sulfide using an organic base as solvent.

The above reaction can preferably be carried out at room temperature, using a 1 :1 mixture of triethylamine-pyridine as solvent, v) The compound of formula (I), in which R-1-R3 each represent hydroxy groups, R₄ represents a hydroxymethyl group, R₅ represents hydrogen and R₆ represents a -C(=NH)-SCH₃ group, can be prepared e.g. by treating the compound of formula (I), wherein the meaning of R1-R5 is as defined above and R₆ is an aminothiocarbonyl group, with a methylating agent. The above reaction can preferably be carried out at reflux temperature, using acetone as solvent and methyl iodide as reagent. w) The compound of formula (I), in which R-|-R₃ each represent hydroxy groups, R₄ represents a methyl group, R₅ represents hydrogen and R₆ represents a nitro group, can be prepared e.g. by removing the acetyl groups from the β-anomer of formula (XIV), wherein R represents hydrogen and X represents a nitro group, with base using a lower aliphatic alcohol as solvent.

The β-anomer of formula (XIV), wherein R represents hydrogen and X represents a nitro group, is also a new compound and can be prepared e.g. by converting the known 1 ,2,3,4-tetra-O-acetyl-6-deoxy-5-thio-D-glucopyranose into its acetobromo derivative the reaction of which with 4-nitrothiophenol yields a mixture of the α,β-anomers of formula (XIV), wherein R represents hydrogen and X represents a nitro group, from which the β-anomer is separated. The above reaction sequence can preferably be carried out by using for the reaction of acetobromo-6-deoxy-5-thio-D-glucopyranose with 4-nitrothiophenol acetone as solvent, and carrying out the reaction in the presence of potassium carbonate at reflux temperature. The β-anomer is preferably separated from the mixture of the α,β-anomers by crystallization. x) The compound of formula (I), in which R-| , R₄ and R₅ are hydrogens, R₂ and R₃ represent hydroxy groups, and R₆ represents a nitro group, can be prepared e.g. by saturating the double bond of the pentenose derivative of formula (XI), wherein R represents a benzoyl group, with hydrogen bromide in an aprotic solvent. The bromide of the obtained intermediate of formula (XII), wherein R represents a bromo atom, is exchanged with an acetoxy group and the formed ester of formula (XII), wherein R represents an acetoxy group, is treated with 4- nitrothiophenol in the presence of a promoter. From the obtained anomeric mixture of glycosides of formula (XII), wherein R represents a 4-nitrophenylthio group, the benzoyl groups are removed with base in a lower aliphatic alcohol and the β-anomer of formula (I), in which R-i , R₄ and R5 are hydrogens, R₂ and R₃ represent hydroxy groups, and R₆ represents a nitro group, is separated by crystallization.

The above reaction sequence can preferably be carried out by using benzene as solvent for the saturation of the double bond of the pentenose derivative of formula (XI), wherein R represents a benzoyl group, with hydrogen bromide. The reactive 1 -bromo compound of formula (XII), wherein R represents a bromo atom, is treated without isolation with silver acetate in acetonitrile and the formed ester of formula (XII), wherein R represents an acetoxy group, is reacted with 4-nitrothiophenol in dichloromethane, using trimethylsilyl triflate as promoter. The benzoyl groups are removed with sodium methoxide in methanol from the formed mixture of glycosides of formula (XII), wherein R represents a 4-nitrophenylthio group, and the β-anomer is then separated by crystallization, y) The compound of formula (I), in which R-) and R₂ each represent hydroxy groups, R₃ represents an azido group, R₄ and R₅ are hydrogens and R₆ 97/49716 PO7HU97/00031

represents a nitro group, can be prepared e.g. by separating the anomeric mixture of the glycosides of formula (II), wherein R represents a nitro group, and removing the acetyl groups from the β-anomer with base using a lower aliphatic alcohol as solvent. The above reactions can preferably be carried out by using column chromatography for the separation of the anomers and removing the acetyl groups from the β-anomer with sodium methoxide in methanol.

The glycosides of formula (II), wherein R represents a nitro group, are new compounds and can be prepared e.g. by reacting triacetate (IV), wherein R represents an acetoxy group, with 4-nitrothiophenol.

The above reaction can preferably be carried out in an aprotic solvent, preferably in dichloromethane or 1 ,2-dichloroethane in the presence of a promoter, preferably boron trifluoride etherate. z) The compound of formula (I), in which R-_] represents an azido group, R₂ and R₃ represent hydroxy groups, R₄ and R₅ are hydrogens and R₆ represents a nitro group, can be prepared e.g. synthesizing the acetate (XIII), wherein R represents an acetoxy group, according to method i) and coupling it with 4- nitrothiophenol in the presence of a promoter. The two formed anomers of formula (XIII), wherein R represents a 4-nitrophenylthio group, are separated and the ester groups are removed from the β-anomer using a base in a lower aliphatic alcohol.

The condensation reaction mentioned above can preferably be carried out in the presence of boron trifluoride etherate as a promoter, and the benzoyl groups are removed from the separated β-anomer with sodium methoxide in methanol.

As mentioned in the introduction, the compounds of formula (I) of the invention possess valuable anticoagulant activity. This anticoagulant activity of the compounds of formula (I) of the invention was determined on male SPRD rats, using the Pescador's venous thrombosis model [D. Bagdy et al.: Thromb. Haemost. 68 (1992) 125]. Accordingly 12.5 mg of the individual compounds was dissolved in 300 μl DMSO and this solution was diluted to 1 ml with physiological saline. From this solution a dose of 12.5 mg/kg was administered orally to the animals 3h prior to provoking the thrombus.

In Table 1 the antithrombotic activity of several representatives of the compounds of the invention is given in percentage of the inhibition caused at the same dose level by Beciparcil (4-cyanophenyl 1 ,5-dithio-β-D- xylopyranoside, EP 365.397) which was used as reference compound. Table 1.

The oral antithrombotic activity of compounds of formula (I) in rats at a dose of 12.5 mg/kg

As can be seen from Table 1. the antithrombotic activity of several representatives of the compounds of formula (I) of the present invention exceeds that of the reference, in certain cases to a significant degree.

For therapeutical purposes, the compounds of the present invention as well as their pharmaceutically acceptable salts can be used as such or suitably in the form of pharmaceutical compositions. These compositions also fall within the scope of the present invention.

These pharmaceutical compositions contain an amount required to excert the therapeutical effect of a compound of formula (I) or its pharmaceutically acceptable salt, in admixture with known carriers, excipients, diluents and/or other additives commonly used in the pharmaceutical practice. For oral administration the antithrombotic compound is formulated in capsules or tablets which may contain excipients such as binders, lubricants, disintegration agents and the like. For parenteral administration the antithrombotic compound is formulated in a pharmaceutically acceptable diluent, e.g. physiological saline (0.9 %), 5% dextrose, Ringer's solution and the like.

The doses required to excert the therapeutical effect of the compounds according to the invention may be varied depending on the individual condition and age of the patient to be treated an finally these doses are determined by the attending physician. However, for the prevention and/or treatment of diseases, where the application of an anticoagulant is desirable, daily doses of these compounds falling between about 0.01 mg/kg of body weight and about

100 mg/kg of body weight and preferably between about 0.1 mg/kg of body weight and about 10 mg/kg of body weight are used by the oral or parenteral, e.g. intravenous, route.

The compounds according to the invention and the process for the preparation thereof are illustrated in detail by the following not limiting

Examples. The Rf values given in the experimental part were determined by TLC, using E. Merck precoated Silica Gel 60 F₂₅₄ plates, with the following solvents:

(A) benzene

(β) benzene - ethanol (100:1) (C) benzene - methanol (9:1)

(D) benzene - methanol (4:1) (£F) 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 a 0.02 M solution of iodine and a 0.30 M solution of potassium iodide in 10% aq sulfuric acid solution followed by heating at ca. 200 °C. For column chromatography, Kieselgel 60 was used.

Mp's are uncorrected. Optical rotations were determined at 20 °C. NMR spectra were recorded with a Varian XL-400 spectrometer at 400 MHz (¹H) and 100 MHz (¹³C) or with a Bruker AC 250 spectrometer at 250 MHz (¹H) and 62.9

MHz (¹³C) (Me₄Si was used as internal standard). Multiplicities of the ¹³C NMR spectra were obtained from DEPT experiments. The assignment of the protons were based on homonuclear decoupling and DNOE experiments.

Connectivities between identified protons and protonated carbons were determined by HETCOR experiments. MS spectra were recorded with a

Finnigan MAT 8430 mass spectrometer. In the case of FAB spectra samples were dissolved in 3-nitrobenzaldehyde or in glycerin.

The "usual processing" during the work-up of acylation reactions, carried out in pyridine means, that if the product did not crystallize on pouring the reaction mixture on ice-water, it was extracted with dichloromethane and the organic solution was washed with 1 M sulfuric acid until a pH of -3 was reached, then with water, with 5% aq sodium hydrocarbonate and finally with water The organic solution were dried over sodium sulfate pπor to concentration which was carried out under diminished pressure.

Example 1 4-(lmιno)(methoxy)methylphenyl 1 ,5-dιthιo-β-D-xylopyranosιde (I, R-, = R₂ = R3 = OH, R₄ = R₅ = H, R₆ = -C(=NH)-OCH3)

Method A)

To a solution of 0.45 g of 4-cyanophenyl 1 ,5-dithio-β-D-xylopyranoside (EP 365.397) in 10 ml of methanol 0 1 ml of 1 M methanolic sodium methoxide was added. After 24 h at room temperature, the mixture was neutralized with carbon dioxide and concentrated. The residue was submitted to column chromatography (solvent C) to give, on concentration of the first fraction (Rf = 0.4), the unchanged starting material (350 mg) Concentration of the second fraction (Rf = 0.3) yielded 100 mg (90 % counted on the recovered starting material) of the title compound. Mp: 174-177°C, [α]_D + 28° (c = 0.5, methanol) NMR (DMSO-d₆), ¹ H: 4.52 (H-1 ), 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 H), 9.00 (NH), 3 80 ppm (OMe); J_{1 r2} 10.1 , J_{2 3} 8.6, J_{3 4} 8.6, J_{4 5a} 10.9, J_{4 5b} 4.3, J_{5a 5b} 13.3 Hz; ¹3C: 51.6 (C-1), 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-(ιmιno)(methylthιo)methylphenyl 1 ,5-dιthιo-β -D-xylopyranoside (example 3) in 10 ml of methanol 0 1 ml of 3 M methanolic sodium methoxide was added and the mixture was refluxed under nitrogen for 1 h The solution was neutralized with carbon dioxide after cooling and was worked up as described in method A) to yield 20 mg (21 %) of the title compound, which was identical to the one prepared according to method A).

Example 2 4-(Aminothiocarbonyl)phenyl 1 ,5-dithio-β-D-xylopyranoside (I, R₁ = R₂ = R₃ - OH, R₄ = R₅ = H, R₆ = -CS(NH^)

A solution of 0.5 g of 4-cyanophenyl 1 ,5-dithio-β-D-xylopyranoside (EP 365.397) in 10 ml of pyridine and 10 ml of triethylamine was saturated with a slow stream of dry hydrogen sulfide for 5 h. The mixture was kept at room temperature overnight and was then concentrated. The residue was recrystallized from methanol to yield 0.46 g (82%) of the title compound. Mp: 174-179 °C, Rf (D) = 0.3, [α]_D = +38° (c = 0.5, methanol). NMR (DMSO-d₆): ¹H, 4.30 (H-1), 3.28 (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); J_{1 2} 10.1 , J_2ι3 8.6, J_{3 4} 8.6, J_4ι5a 10.6, J_4>5b 4.6, J_5a<5b 13.3 Hz.

Example 3

4-(lmino)(methylthio)methylphenyl 1 ,5-dithio-β-D-xylopyranoside (I, R₇ = R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = -C^NHj-SCHJ

To a solution of 350 mg of 4-(aminothiocarbonyl)phenyl 1 ,5-dithio-β-D- xylopyranoside (I, R-, = R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = -CS(NH₂)) (example 2) in 35 ml of acetone 0.2 ml of methyl iodide was added and the reaction mixture was refluxed for 2.5 h. The precipitated product was filtered after cooling and was washed with acetone to yield 400 mg (79%) of the title compound as its hydroiodide. Mp: 191-194 °C, R_f (D) = 0.4, [α]_D = +70° (c = 0.4, 50 % aq acetic acid). NMR (DMSO-d₆), ¹ H: 4.54 (H-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); J, ₂ 1 1.1 , J_{2 3} 9.5, J_{3 4} 9.5 J_{4 5a} 11.0, J_{4 5b} 4.1 , J_5a,5b 13.0 Hz.

Example 4

4-Amidinophenyl 1 ,5-dithio-β-D-xylopyranoside (I, R-j = R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = -C(=NH)-NH2)

To a stirred solution of 0.65 g of 4-(imino)(methylthio)methylphenyl 1,5- dithio-β-D-xylopyranoside (I, R^ = R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = -C(=NH)-

SCH₃) (example 3) in 30 ml of dry ethanol 0.2 g of ammonium acetate was added and stirring was continued at 60 °C for 5 h, then 0.2 g of ammonium acetate was added and stirring was continued for an other 3 h. The reaction mixture was cooled and the precipitated product was filtered off to yield 0.4 g (78%) of the title compound as its acetate. Mp: 195-199 °C, Rf (K) = 0.6, [α]_D =

+30° (c = 0.5, 50% aq acetic acid). NMR (DMSO-d₆), ¹H: 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 ppm (aromatic H); J_{λ 2}

9.9, J_2ι3 8.6, J_3ι4 8.6, J_4|5a 9.8, J_4ι5b 4.2, J_5a,5b 13.2 Hz; ¹³C: 51.0 (C-1 ), 73.0,

75.8 and 79.0 (C-2,3,4), 33.6 (C-5), 165.6 (C(NH₂)₂ ⁺), 141.7, 128.8, 128.1 and 126.6 ppm (aromatic C).

Example 5

4-(Hydrazino)(imino)methylphenyl 1 ,5-dithio-β-D-xylopyranoside (I, R-, = R₂ =

R₃ = OH, R₄ = R₅ = H, R₆ = -C(=NH)-NH-NH2)

Method A)

To a solution of 320 mg of 4-(aminothiocarbonyl)phenyl 1 ,5-dithio-β-D- xylopyranoside (I, R^ = R₂ = R3 = OH, R₄ = R₅ = H, R₆ = -CS(NH₂)) (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 h. The precipitated product was filtered off and was washed with ether to yield 380 mg (99%) of the title compound contaminated with hydrazine hydrosulfide. In order to remove the latter the crude product was dissolved in 30 ml off 10% aq acetic acid and the residue obtained after evaporation was purified by column chromatography using chloroform-methanol-water 60:38:10 for elution. Evaporation of the proper fractions afforded 125 mg (33%) of the title , compound as its acetate. Mp: 225- 230 °C, Rf (K) = 0.5, [α]_D = +12° (c = 0.5, pyridine). NMR (DMSO-d₆), ¹H: 4.15 (H-1), 3.24 (H-2), 3.05 (H-3), 3.40 (H-4), 2.58 (H-5a), 2.46 (H-5b), 5.4-6.2 (OH,

NH), 7.45 and 7.65 ppm (aromatic H); J_{1 2} 10.1 , J_{2 3} 8.6, J_{3 4} 8.6, J_{4 5a} 10.7, J_{4 5b} 4.6, J_5aj5b 13.2 Hz; ™C: 52.4 (C-1 ), 73.0, 75.8 and 79.0(C-2,3,4), 33.7 (C- 5), 133.8 (C(=NH₂ ⁺)(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-β

-D-xylopyranoside (I, R-, = R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = -C(=NH)-SCH₃) hydroiodide (example 3) in 10 ml of ethanol 0.35 ml of 98% hydrazine hydrate was added and the reaction mixture was stirred for 5 h at room temperature.

The precipitated product was filtered off, washed with ethanol and dried to yield

60 mg (88%) of the title compound. Mp: 193-196°C.

Example 6 4-Cyanophenyl 4-azido-4-deoxy-1,5-dithlo-β-D-xylopyranoside (I, R-, = R₂ = OH, R₃ = N₃, R₄ = R₅ = H, R₆ = CN) To a solution of 130 mg of 4-cyanophenyl 2,3-di-0-acetyl-4-azido-4- deoxy-1 ,5-dithio-β-D-xylopyranoside (II, R = CN) in 10 ml of methanol 0.1 ml of 1 M methanolic sod ium methoxide was added and the reaction mixture was stirred at room temperature for 1 h. Thereafter the solution was neutralized with Dowex 50 WX resin and concentrated to yield 72 mg (70%) of the title compound. Mp: 105-110 °C, Rf (C) = 0.2, [α]_D = +139° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.54 (H-1), 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 ppm (aromatic H); J, ₂ 9.9, J_{2 3} 8.5, J_{3 4} 9.0, J_4ι5a 11.0, J_4>5b 4.4, J_{5a 5b} 13.4 Hz.

The starting material (II, R = CN) can be prepared the following way:

Method A) Step a) 5-0-tert-Butyldimethylsilyl-2, 3-0-isopropylidene-4-0-methanesulfonyl-L- arabinose diethyl dithioacetal (VII, R₁ = Ms, R₂ = TBDMS)

To a solution of 7 g of 2,3-O-isopropylidene-L-arabinose diethyl dithioacetal [H. Zinner et al, Ber. 90 (1957) 2688] in 25 ml of pyridine 3.75 g of te/τ-butyldimethylsilyl chloride, and after 1.5 h 2 ml of mesyl chloride was added at 20 °C. The mixture was kept at room temperature for 24 h to give after usual processing and column chromatography (solvent F) 10 g (87%) of the title compound as a syrup; Rf (J) = 0.5, [α]_D = -57° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 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 (SCH₂CH₃), 1.25 (SCH₂CH₃), 1.40 and 1.46 (=CMe₂), 3.12

(Ms), 0.12 (SiMe₂), 0.92 ppm (SiCMe₃); J_{1 ι2} 3.1 , J_{2 3} 7.2, J_{3 4} 7.2, J_{4 5a} 6.8, J_4ι5b 3.2, J_5a>5b 11.8 Hz; ¹³C: 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 (SCH₂CH₃), 14.3 (SCH₂CH₃), 110.5 (=CMe₂), 26.9 and 27.0 (=CMe₂), 38.8 (Ms), -5.5, 18.3 and 25.8 ppm (SiCMe₃).

Step b) 4-Azido-4-deoxy-2,3-0-isopropylidene-D-xylose diethyl dithioacetal (VI, R = OH)

A solution of 10 g of 5-0-tert-butyldimethylsilyl-2,3-0-isopropyiidene-4-O- methanesulfonyl-L-arabinose diethyl dithioacetal (VII, R-_] = Ms, R₂ = TBDMS) and 2 g of sodium azide in 100 ml of N,N-dimethylformamide was stirred at 110 °C for 15 h. The residue obtained on concentration was dissolved in chloroform washed with water and concentrated. The resulting mixture - which is a mixture of the 5-O-TBDMS (VI, R = OTBDMS) derivative (Rf (J) = 0.8) and the 5-OH (VI, R = OH) derivative (Rf (J) = 0.1 ) - was dissolved in 100 ml of tetrahydrofuran and 4 g of tetrabutylammonium fluoride trihydrate was added to the stirred solution. The reaction mixture was concentrated after 2 h, the residue was dissolved in chloroform, washed with water, dried, evaporated and the residue submitted to column chromatography (/) to yield 5.8 g (88%) of the title compound. Rf (I) = 0.3, [α]_D = -97° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 3.90 (H-1), 4.37 (H-2), 4.23 (H-3), 3.67 (H-4) 3.90 (H-5a), 3.90 (H-5b), 2.65- 2.80 (SCH₂CH₃), 1.28 (SCH₂CH₃), 1.46 and 1.48 ppm (=CMe₂); J_1>2 5.8, J_2ι3 7.4, J_{3 4} 2.6, J_4ι5a 4.9, J_{4 5b} 7.5, Hz; 1³C: 52.5 (C-1 ), 79.6 (C-2), 79.5 (C-3), 62.4 (C-4), 63.0 (C-5), 24.9 and 25.3 (SCH₂CH₃), 14.1 and 14.2 (SCH₂CH₃), 110.2 (=CMe₂), 26.7 and 26.9 ppm (=CMe₂).

Step c)

4-Azido-4-deoxy-2,3-0-isopropylidene~5-0-methanesulfonyl-D-xylose diethyl dithioacetal (VI, R = OMs) To a stirred solution of 5.6 g of 4-azido-4-deoxy-2,3-0-isopropylidene-D- xylose diethyl dithioacetal (VI, R = OH) in 50 ml of pyridine 2.7 ml of mesyl chloride was added dropwise below 10 °C. The mixture was kept at room temperature for 1 h to give, after usual processing, 6.3 g (90%) of the title compound as a syrup. Rf (B) = 0.45, [α]_D = -52° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 3.94 (H-1), 4.36 (H-2), 4.15 (H-3), 3.98 (H-4) 4.48 (H-5a), 4.48 (H- 5b), 2.65-2.85 (SCH₂CH₃), 1.28 (SCH₂CH₃), 1.43 and 1.47 (=CMe₂), 3.10 ppm (Ms); J_{1 ι2} 6.4, J_2ι3 7.4, J_3>4 2.1 , J_4ι5a 6.6, J_4>5b 6.6 Hz; 1³C: 52.4 (C-1), 79.3 (C- 2), 78.2 (C-3), 60.0 (C-4), 68.6 (C-5), 25.0 and 25.5 (SCH₂CH₃), 14.1 and 14.3 (SCH₂CH₃), 110.5 (=CMe₂), 26.6 and 26.9 (=CMe₂), 37.5 ppm (Ms).

Step d)

4-Azido-5-S-benzoyl-4-deoxy-2, 3-O-isopropylidene-D-xylose diethyl dithio¬ acetal (VI, R = SBz) A solution of 3.5 g of 4-azido-4-deoxy-2,3-0-isopropylidene-5-0- methanesulfonyl-D-xylose diethyl dithioacetal (VI, R = OMs) and 2.2 g of potassium thiobenzoate in 40 ml of acetone was boiled for 1 h. The resulting thick slurry was cooled, filtered and the salts were washed with 20 ml of acetone. The filtrate was boiled for 4 h, cooled and concentrated. The obtained residue was partitioned between chloroform and water to give, after concentration of the organic solution, 3.6 g (93%) of the title compound. Rf (B) = 0.85, [α]_D = -3° (c = 1 , chloroform). NMR (CDCI₃), ^""H: 3.90 (H-1), 4.36 (H-2), 4.21 (H-3), 3.72 (H-4) 3.46 (H-5a), 3.46 (H-5b), 2.60-2.80 (SCH₂CH₃), 1.25 (SCH₂CH₃), 1.44 and 1.46 (=CMe₂), 7.45-7.98 ppm (aromatic H); J_{1 2} 5.9, J_{2 3} 6.5, J_3,4 2.2, J_4,5a 8.2, J_4>5b 6.5, J_5aι5b 11.8 Hz; 1³C: 53.0 (C-1 ), 80.7 (C-2), 79.9 (C-3), 61.0 (C-4), 30.4 (C-5), 25.0 and 25.4 (SCH₂CH₃), 14.2 and 14.3 (SCH₂CH₃), 110.4 (=CMe₂), 27.0 and 27.2 (=CMe₂), 127.3-190.7 ppm (aromatic C). Step e) 4-Azido-5-S-benzoyl-4-deoxy-2,3-0-isopropylidene-5-thio-D-xylose (V)

To a stirred solution of 5.7 g of 4-azido-5-S-benzoy)-4-deoxy-2,3-O- isopropylidene-D-xylose diethyl dithio-acetal (VI, R = SBz) in 140 ml of acetone 35 ml of water, 23 g of cadmium carbonate and subsequently a solution of 26 g of mercury(ll) chloride in 70 ml of acetone were added. The slurry was stirred for 20 h, filtered and concentrated in the presence of sodium carbonate (2 g). The residue was partitioned between chloroform and water, the precipitated salts were filtered off and washed with chloroform The organic solution was washed with 10% aq potassium iodide solution and water to give on concentration 4.5 g (-100%) of the title compound containing according to NMR spectroscopy some of its hydrate. Rf (F) = 0.3, [α]p = +59° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 9.85 (H-1), 4.52 (H-2), 4.30 (H-3), 1.40 and 1.46 ppm (=CMe₂); J_{1 t2} 1.2, J_2>3 6.5, J_{3 4} 4.2 Hz; ¹³C: 201.4 (C-1 aldehyde) and 96.0 ppm (C-1 aldehyde hydrate).

Step f) Methyl 2,3-di-0-acetyl-4-azido-4-deoxy-5-thio-D-xylopyranoside (IV, R = OMe)

Under nitrogen to a solution of 4.5 g of 4-azido-5-S-benzoyl-4-deoxy-2,3- O-isopropylidene-5-thio-D-xylose (V) in 45 ml of methanol, 0.5 ml of 4 M methanolic sodium methoxide was added. When the deacylation was complete (TLC, Rf 0.3 → 0.4, solvent G), the pH of the solution was adjusted to 1 by adding 20% HCI in methanol and the mixture was boiled for 1 h. 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 h at room temperature the mixture was concentrated. The residue gave after column chromatography (solvent G) 2.5 g (67%) of the title compound. Mp: 85- 86 °C, [α]_D = +226° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 4.60 (H-1), 5.12 (H- 2), 5.36 (H-3), 3.78 (H-4) 2.82 (H-5a), 2.56 (H-5b), 3.40 (OMe), 2.05 and 2.09 ppm (OAc); J_{1 >2} 2.8, J_{2 3} 10.0, J_{3 4} 10.0, J_{4 5a} 11.8, J_{4 5b} 4.4, J_{5a 5b} 13.5 Hz; 1SC: 81.2 (C-1), 74.7 (C-2), 71.0 (C-3), 63.4 (C-4), 25.1 (C-5), 20.5 and 20.6 (OCOCH₃), 169.4 and 170.1 (OCOCH₃), 56.3 ppm (OMe).

Step g) 1,2,3-Tή-0-acetyl-4-azido-4-deoxy-5-thio-a-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-α- D-xylopyranoside (IV, R = OMe) in 15 ml of acetic anhydride, 1 ml of concentrated sulfuric acid was added at 0 °C. The mixture was kept at 0 °C for 30 min and at room temperature for 2 h and was thereafter poured into a mixture of chloroform (200 ml), ice (35 g) and sodium hydrocarbonate (20 g) The organic solution was separated, the aq solution was extracted with chloroform (2 x 100 ml) and the combined chloroform solutions were washed with 5% aq sodium hydrocarbonate and water. The residue obtained on concentration was purified by column chromatography (solvent G) to give 4.9 g (77%) of the title compound, as a syrup. Rf = 0.45, [α]_D = +214° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 6.06 (H-1), 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); J_{1 2} 3.0, J_{2 3} 10.0, J_{3 4} 10.0, J_{4 5a} 11.9, J_{4 5b} 4.4, J_{5a 5b} 13.7 Hz; ™C: 73.0 (C-1 ), 71.0 (C-2), 70.8 (C-3), 63.0 (C-4), 26.7 (C-5), 20.4, 20.5 and 20.8 (OCOCH₃), 169.0, 169.5 and 169.6 ppm (OCOCH₃).

Step h) 4-Cyanophenyl 2, 3-di-0-acetyl-4-azido-4-deoxy-1, 5-dithio-β-D-xylopyranoside (II, R = CN)

Under argon, 0.63 ml of trimethylsilyl triflate was added at -10 °C to a solution of 1.0 g of 1 ,2,3-tri-0-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranose (IV, R = OAc) and 0.8 g of 4-cyanothiophenol in 40 ml of dichloromethane, then the reaction mixture was stirred for 1 h at room temperature. After neutralizing with triethylamine the mixture was concentrated and the residue submitted to column chromatography (solvent H) to yield 260 mg (21 %) of the title compound. Mp: 115-120 °C, [α]_D = +78° (c = 0.5, chloroform); NMR (CDCI₃), 1H: 4.20 (H-1 ), 5.16 (H-2), 4.96 (H-3), 3.86 (H-4) 2.66-2.86 (H-5a,5b), 2.02 and 2.10 (OAc), 7.45-7.60 ppm (aromatic H); J_{1 <2} 10.6, J_{2 3} 9.5, J_{3 4} 9.5, J_{4 5a} 9.5, J_4j5b 5.6 Hz; 13C: 50.6 (C-1), 73.3 and 75.1 (C-2,3), 62.8 (C-4), 31.9 (C- 5), 169.5, (OCOCH₃), 20.5 (OCOCH₃), 118.2 (CN), 147.6, 132.5, 131.2 and 111.2 ppm (aromatic C).

Method B) Step a)

5-0-Benzoyl-4-0-methanesulfonyl-2,3-0-isopropylidene-L-arabinose diethyl dithioacetal (VII, R₇ = Ms, R₂ = Bz)

To a solution of 1.2 g of 2,3-O-isopropylidene-L-arabinose diethyl dithioacetal (VII, R^ = R₂ = H) [H. Zinner et. al, Ber. 90 (1957) 2688] in 10 ml of pyridine 0.5 ml of benzoyl chloride was added during 15 min at -10 °C and then 0.5 ml of mesyl chloride at 0 °C. The reaction mixture was stirred at room temperature for 2 h, poured into ice-water and processed as usual to give after concentration and column chromatography (solvent F) 1.4 g (73%) of the title compound as a syrup. Rf (F) = 0.6, [α]_D = -59° (c = 1 , chloroform). NMR (CDCI₃), 1H: 3.95 (H-1), 4.46 (H-2), 4.46 (H-3), 5.15 (H-4) 4.48 (H-5a), 4.82 (H- 5b), 2.65-2.80 (SCH₂CH₃), 1.25 (SCH₂CH₃), 1.46 and 1.48 (=CMe₂), 3.10 (Ms), 7.45-8.05 ppm (aromatic H); J_{1 2} 3.7, J_{4 5a} 7.0, J_{4 5h} 2.5, J_{5a 5b} 12.7 Hz; ¹³C: 53.0 (C-1 ), 82.2 (C-2), 79.5 (C-3), 77.4 (C-4), 63.4 (C-5), 25.1 and 25.3 (SCH₂CH₃), 14.3 (SCH₂CH₃), 111.0 (=CMe₂), 27.0 and 27.1 (=CMe₂), 39.0

(Ms), 128.5-166.0 ppm (aromatic C).

Step b)

4-Azido-5-0-benzoyl-4-deoxy-2, 3-O-isopropylidene-D-xylose diethyl dithio- acetal (VI, R = OBz)

To a stirred solution of 19.2 g of 5-0-benzoyl-4-0-methanesulfonyl-2,3- O-isopropylidene-L-arabinose diethyl dithioacetal (VII, R₁ = Ms, R₂ = Bz) in 300 ml of N,N-dimethylformamide 4 g of sodium azide was added and stirring was continued at 100 °C for 20 h. The residue obtained on concentration of the mixture was partitioned between dichloromethane and water. The organic solution was washed with water and the residue obtained on concentration was purified by column chromatography (solvent A) to give 13.6 g (80%) of the title compound; [α]_D = -36° (c = 1 , chloroform). NMR (CDCI₃), ¹H: 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 (SCH₂CH₃),

1.26 (SCH₂CH₃), 1.44 and 1.47 (=CMe₂), 7.45-8,06 ppm (aromatic-H); J_{1 >2} 6.2, J_2ι3 7.4, J_{3 4} 2.2, J_4,5a 8.1 , J_4ι5b 4.9, J_5a,5b 11.7 Hz; 1³C: 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 (SCH₂CH₃), 14.2 and 14.3 (SCH₂CH₃), 110.4 (=CMe₂), 26.8 and 27.0 (=CMe₂), 128.4-166.2 ppm (aromatic-C).

Step c) 4-Azido-4-deoxy-2,3-0-isopropylidene-D-xylose diethyl dithioacetal (VI, R = OH)

To a solution of 8.5 g 4-azido-5-0-benzoyl-4-deoxy-2,3-0- isopropylidene-D-xylose diethyl dithioacetal (VI, R = OBz) in 40 ml of methanol 3 ml of 4 M methanolic sodium methoxide was added and the reaction mixture was refluxed for 30 min. After neutralizing with carbon dioxide the mixture was concentrated, the residue was dissolved in chloroform, washed with water, dried and concentrated. The obtained syrupy material was purified by column chromatography (solvent I) to yield 5.9 g (92%) of the title compound, which was identical to the compound of step c) of method A).

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

Step i)

2,3-Di-0-acetyl-4-azido-4-deoxy-5-thio-D-xylopyranose (IV, R = OH)

Under argon, 0.43 g of hydrazine acetate was added to a stirred solution of 1.0 g of 1 ,2,3-tri-0-acetyl-4-azido-4-deoxy-5-thio-α-D-xylopyranose (IV, R = OAc) in 30 ml of N,N-dimethylformamide at room temperature. After 1 h 50 ml of ethyl acetate and 50 ml of dichloromethane were added, the organic layer was washed with brine, concentrated and the residue submitted to column chromatography (solvent F) to yield 0.65 g (75%) of the title compound (α:β ratio 9:1); Rf (F) = 0.4, NMR (CDCI₃), ¹H: oc-anomer 5.13 (H-1), 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); J_{1 (2} 2.8,

^2_,3 9-⁷- ^JZ_,4 ⁹-⁷- ^J4_,5a ^{1 1} -⁸- ^J4,5b 4.3, J_5a,_5b 13.5 Hz; β-anomer 4.83 ppm (H- 1); ^ ₂ 9.8 Hz. Step j)

0-(2,3-Di-0-acetyl-4-azido-4-deoxy-5-thio-a-D-xylopyranosyl) trichloroacet¬ imidate (IV, R = 0-C(NH)-CCl3)

To a stirred solution of 0.5 g of 2,3-di-0-acetyl-4-azido-4-deoxy-5-thio-D- xylopyranose (IV, R = OH) in 10 ml of dichloromethane 1.8 ml of trichloroacetonitrile and 2.5 g of potassium carbonate were added under argon. After 24 h the mixture was diluted with ether, filtered through celite, concentrated and the residue submitted to column chromatography (solvent H) to yield 0.65 g (85%) of the title compound; Mp: 68-72 °C, Rf (H) = 0.6, [α]_D = +195° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 6.18 (H-1 ), 5.18 (H-2), 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); 4_,2 3-0, J_2>3 10.1 , J_{3 4} 10.0, J_4,5a 13.6, J_4,5b 4.3, J_{5a 5b} 13.6 Hz; ¹³C: 76.0, 73.5, 70.9 (C-1 ,2,3), 63.0 (C-4), 26.9 (C-5), 169.8, 169.4 (CO), 160.7 (C=NH), 90.6 (CCI₃), 20.6 and 20.5 ppm (COCH₃).

Step k)

4-Cyanophenyl 2, 3-di-0-acetyl-4-azido-4-deoxy- 1 , 5-dithio-β-D-xylopyranoside

(II, R = CN)

Under argon, a stirred solution of 210 mg of 0-(2,3-di-0-acetyi-4-azido- 4-deoxy-5-thio-α-D-xylopyranosyl) trichloroacetimidate (IV, R = 0-C(NH)-CCI₃) and 160 mg of 4-cyanothiophenol in 10 ml of dichloromethane was cooled to -15 °C, then 0.5 ml of 0.1 M boron trifluoride etherate in dichloromethane was added and stirring was continued at -15 °C for 15 min. After addition of 0.5 ml of triethylamine, the mixture was concentrated and the residue submitted to column chromatography (solvent H) to give 63 mg (32%) of the title compound, which was identical to the compound of step h) of method A). Example 7

4-Cyanophenyl 3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R₁ = R₃ = OH, R₂ = N₃, R₄ = R₅ = H, R₆ = CN)

Method A)

Under argon to a solution of 1.0 g of 1 ,2,4-tri-0-acetyl-3-azido-3-deoxy- 5-thio-D-xylopyranose (VIII, R = OAc) and 0.8 g of 4-cyanothiophenol in 30 ml of dichloromethane 0.63 ml of trimethylsilyl triflate was added at -10 °C, then the reaction mixture was stirred for 2h at room temperature. After neutralizing with 0.8 ml of triethylamine the mixture was concentrated and the residue submitted to column chromatography (solvent F) to yield 0.47 g (38%) of 4- cyanophenyl 2,4-di-0-acetyl-3-azido-3-deoxy-1 ,5-dithio-β-D-xylopyranoside (I, R-, = R₃ = OAc, R₂ = N₃, R₄ = R₅ = H, R₆ = CN). This was dissolved in 30 ml of methanol and 0.1 ml of 3 M methanolic sodium methoxide was added. After 2 h at room temperature the solution was neutralized with Dowex 50 WX resin, filtered and evaporated to yield 0.34 g (92%) of the title compound, Mp: 192- 194 °C, R_f (C) = 0.3, [α]_D = +81° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.85 (H-1), 3.35 (H-2), 3.20 (H-3), 3.52 (H-4), 2.75 (H-5a), 2.58 (H-5b), 5.45 and 5.92 (OH), 7.5 - 7.7 ppm (aromatic H); J_{1 >2} 10.0, J_{2 3} 8.5, J_{3 4} 8.5, J_{4 5a}

10.8, J_4ι5b 4.5, J_5a,5b 13.2 Hz.

The starting material (VIII, R = OAc) can be prepared the following way:

Step a)

3-Azido-5-S-benzoyl-3-deoxy- 1 , 2-0-isopropylidene-5-thio-D-xylofuranose (IX) To a solution of 5.2 g of 3-azido-3-deoxy-1 ,2-0-isopropylidene-5-0-tosyl- D-xylofuranose [H. Ohrui et al., Agr. Biol. Chem. 34 (1970) 375] in 35 ml of N,N- dimethylformamide 2.7 g of potassium thiobenzoate was added and the mixture was stirred at 110 °C for 30 min. After concentration the residue was dissolved in chloroform, washed with water, dried and concentrated. The residue was submitted to column chromatography (solvent H) to yield 2 g (42%) of the title compound. Mp: 71-74 °C, R_f (H) = 0.6, [α]_D = -118° (c = 0.5, chloroform). NMR (CDCI₃), 1H: 5.92 (H-1 ), 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), J, ₂ 3-7, J_{2 3} ~0, J_{3 4} 3.2, J_4t5a 7.0, J_{4 5b} 7.0, J_5aι5b 13.6 Hz. ¹³C: 104.7 (C-1 ), 78.4, and 83.4 (C-2,4), 66.8 (C-3), 27.3 (C-5), 127.3, 128.6, 136.5, 136.5 (aromatic-C), 190.7 (CO), 26.2 and 26.5 (=CMe₂), 112.3 ppm (=CMe₂).

Step b) 1,2,4-Tri-0-acetyl-3-azido-3-deoxy-5-thio-D-xylopyranose (VIII, R = OAc)

To a stirred solution of 2.9 g of 3-azido-5-S-benzoyl-3-deoxy-1 ,2-0- isopropylidene-5-thio-D-xylofuranose (IX) in 40 ml of methanol 4.4 ml of 3 M methanolic sodium methoxide was added. After 1h at room temperature the mixture was acidified with 20 ml of 4% aq HCI and was refluxed for 2 h. 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 was kept overnight at room temperature. After usual processing the obtained residue was submitted to column chromatography (solvent H) to yield 2 g (73%) of the title compound; α:β ratio 85:15; Rf (H)= 0.4. NMR (CDCI₃), α-anomer ¹H: 6.04 (H- 1), 5.02 (H-2), 3.86 (H-3), 4.95 (H-4), 2.90 (H-5a), 2.78 (H-5b), 2.15, 2.11 and 2.05 ppm (OAc), J_{1 >2} 3.0, J_2ι3 10.5, J_3A 10.2, J_{4 5a} 11.1 , J_{4 5b} 4.7, J_{5a 5b} 13.2 Hz. ¹³C: 73.9, 73.1 , 70.2 (C-1 , 2,4), 62.3 (C-3), 26.0 (C-5), 169.5, 169.3 and 168.8 (OCOCH₃), 20.8, 20.8 and 20.5 ppm (OCOCH₃). β-anomer ¹H: 5.80 ppm (H-1); J_{1 ι2} 9.1 Hz.

During column chromatography 0.2 g (8%) of methyl 2,4-di-0-acetyl-3-azido-3- deoxy-5-thio-D-xylopyranoside (Vlll, R = OCH3) was obtained as by-product (Mp: 64-67 °C; Rf (H) = 0.5), which can be transformed into the title compound in 90% yield according to step g) of example 6.

Method B) Step a) 2,4-Di-0-acety!-3-azido-3-deoxy-5-thio-D-xylopyranose (Vlll, R = OH)

To a stirred solution of 1.0 g of 1 ,2,4-tri-0-acetyl-3-azido-3-deoxy-5-thio-

D-xyiopyranose (Vlll, R = OAc) in 30 ml of N,N-dimethylformamide 0.43 g of hydrazine acetate was added and stirring was continued for 1 h at room temperature. The reaction mixture was worked up according to step i) of example 6 to yield 0.68 g (78%) of the title compound. Rf(F) = 0.6.

Step b)

0-(2,4-Di-0-acetyl-3-azido-3-deoxy-5-thio-α-D-xylopyranosyl) trichloroacet¬ imidate (Vlll, R = O-CfNH^CCI^

To a stirred solution of 1.35 g of 2,4-di-0-acetyl-3-azido-3-deoxy-5-thio- D-xylopyranose (Vlll, R = OH) in 20 ml of dichloromethane 6.75 g of potassium carbonate and 4.8 ml of trichloroacetonitrile were added and stirring was continued for 24 h at room temperature. After diluting with ether the reaction mixture was filtered through celite, concentrated and the residue submitted to column chromatography (solvent H) to yield 1.5 g (73%) of the title compound. Rf (H) = 0.8, [α]_D = +223° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 6.22 (H-1), 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); J_{1 ι2} 2.8, J_2ι3 10.4, J_{3 4} 10.3, J_{4 5a} 11.2, J_{4 5b} 4.6, J_5a,5b 13.2 Hz; ¹³C: 75.4, 74.2, 73.0 (C-1 ,2,4), 62.3 (C-3), 26.0 (C-5), 169.6, 169.5 (CO), 160.4 (C=NH), 90.7 (CCI₃), 20.8 and 20.6 ppm (COCH₃).

Step c)

4-Cyanophenyl 2, 4-di-0-acetyl-3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside

(I, R₁ = R₃ = OAc, R₂ = N₃, R₄ = R₅ = H, R₆ = CN)

Under argon, to a stirred solution of 0.52 g of 0-(2,4-di-0-acetyl-3-azido-

3-deoxy-5-thio-α-D-xylopyranosyl) trichloroacetimidate (Vlll, R = 0-C(NH)-CCI₃) and 0.42 g of 4-cyanothiophenol (III) in 30 ml of 1 ,2-dichloroethane 1 ml of 0.1 M boron trifluoride etherate in 1 ,2-dichloroethane was added at -15 °C and stirring was continued for 15 min. Then the reaction mixture was quenched with triethylamine, concentrated and the residue submitted to column chromatography (solvent H) to yield 210 mg (43%) of the title compound. Mp: 163-166 °C, Rf (H) = 0.6, [α]_D = +44° (c = 0.5, chloroform). NMR (CDCI₃), ¹H:

4.11 (H-1 ), 5.08 (H-2), 4.54 (H-3), 4.94 (H-4), 2.70 (H-5a), 2.87 ppm (H-5b); J, ₂ 10.6, J_2>3 9.9, J_3ι4 9.9, J_4,5a 10.8, J_4>5b 4.6, J_5a<5b 13.5 Hz. 1³C: 50.9 (C-1 ), 73.0 (C-2), 67.2 (C-3), 73.6 (C-4), 31.8 ppm (C-5).

The so obtained compound was deacetylated in methanolic sodium methoxide to yield the final product of method A).

Example 8 4-Cyanophenyl 2-deoxy-1,5-dithio-β-D-threo-pentopyranoside (I, R-, = R₄ - R5 = H, R₂ = R₃ = OH, R₆ = CN) To a solution of 0.5 g of 4-cyanophenyl 3,4-di-0-benzoyl-2-deoxy-1 ,5- dithio-α,β-D-threo-pentopyranoside (XII, R = 4-cyanophenylthio) in 20 ml of methanol 0.1 ml 3 M methanolic sodium methoxide was added. After 1 h at room temperature the reaction mixture was neutralized with Dowex 50 WX resin and concentrated. The residue was crystallized from ether to yield 0.16 g (57%) of the title compound. Mp: 169-172 °C, R_f (D) = 0.4, [α]_D = -15° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.58 (H-1), 1.78 (H-2a), 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) J, _2a 11.7, 4_,2b 3.6, J_2a,2b 13.1 , J_2a,3 11 -6, J_2b,₃ 3.5 Hz. 1³C: 44.2 (C-1), 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 the following way:

Method A)

Step a)

3,4-Di-0-acetyl-1,5-anhydro-5-thio-2-deoxy-D-threo-pent-2-enitol (XI, R = Ac)

To a vigorously stirred solution of 11.2 g of acetobromo thioxylose [R. L.

Whistler and T. V. Es, J. Org. Chem. 28 (1963) 2303] in 110 ml of dry benzene 3.2 ml of 4-picoline and 13 g of zinc powder were added and stirring was continued for 1 h at 80 °C. The mixture was filtered after cooling, washed with benzene, the filtrate was concentrated and the residue submitted to column chromatography (solvent F) to yield 5.8 g (85%) of the title compound. Rf (F) = 0.7, [α]_D = -324° (c = 0.5, chloroform). NMR (CDCI₃), ¹ H: 6.36 (H-1), 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); J_{1 2} 10.0, ^2_,3 4-4, J_3ι4 4.6, J_4ι5a -5, J_4ι5b -5 Hz. 1³C: 125.8 (C-1 ), 117.2 (C-2), 66.7, 66.4 (C-3,4), 26.3 (C-5), 169.8, 169.9 (COCH₃), 21.0 and 20.9 ppm (COCH₃).

Step b) 1,5-Anhydro-3,4-di-0-benzoyl-5-thio-2-deoxy-D-threo-pent-2-enitol (XI, R = Bz)

To a stirred solution of 4.2 g of 3,4-di-0-acetyl-1 ,5-anhydro-5-thio-2- deoxy-D-threo-pent-2-enitol (XI, R = Ac) in 50 ml methanol 0.1 ml of 3 M methanolic sodium methoxide was added and stirring was continued for 1 h. The reaction mixture was neutralized with carbon dioxide and concentrated. To the residue dissolved in 15 ml of pyridine and 60 ml of dichloromethane a solution of 7 ml of benzoyl chloride in 35 ml of dichloromethane was added dropwise. The reaction mixture was kept overnight at room temperature and was then poured into ice-water, extracted with dichloromethane and processed the usual way. The residue obtained on concentration was recrystallized from ethanol to yield 4.95 g (75%) of the title compound. Mp: 119-122 °C, Rf (J) - 0.6, [α]_D = -468° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 6.50 (H-1 ), 5.95 (H-2), 5.75 (H-3), 5.58 (H-4), 3.25-3.35 (H-5a,b), 8.02, 7.55 and 7.40 ppm (aromatic H); J_{1 >2} 10.2, J_Z3 4.2, J_{3 4} 4.2, J_4ι5a -5.5, J_{4 5b} -5.5 Hz. ¹³C: 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 (aromatic C).

Step c)

4-Cyanophenyl 3, 4-di-0-benzoyl-2-deoxy-1,5-dithio-α,β-D-threo-pentopyrano- side (XII, R = 4-cyanophenylthio)

A stirred solution of 1.7 g of 1 ,5-anhydro-3,4-di-0-benzoyl-5-thio-2- deoxy-D-threo-pent-2-enitol (XI, R = Bz) in 20 ml of dry benzene was saturated with anhydrous hydrogen bromide during 20 min at 10 °C, then nitrogen was bubbled through the solution to remove the excess of hydrogen bromide. The so obtained solution was added dropwise to a mixture of 0.6 g 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 overnight at room temperature, then poured into ice-water and extracted with benzene. The organic layer was washed with 5% aq sodium hydrocarbonate, water, dried and concentrated. The residue was purified by column chromatography (solvent J then H). Concentration of the first fraction (Rf (J) = 0.6) gave 0.73 g (43%) of starting material. Concentration of the second fraction (Rf (H) = 0.4) yielded 0.56 g (41% based on the conversion) of the title compound as α,β = 3:7 anomeric mixture. NMR (CDCI₃) α-anomer: ¹H, 4.68 (H-1), 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 (aromatic H); 4_,2a 4-4, J_{1 2b} 4.4, J_23t2b 13.8, J_{2a 3} 9.6, J_{2b 3} 4.5, J_{3 4} 9.2, J_{4 5a} 9.3, J_{4 5b} 4.1 , ^J5a_,5b ¹3-7 Hz. β-anomer: ¹H, 4.45 (H-1), 2.35 (H-2a), 2.90 (H-2b), 5.40 (H-3), 5.40 (H-4), 2.98 (H-5a), 3.20 (H-5b), 7.3-8.0 ppm (aromatic H); J_{1 2a} 11.1 , J_{1 2b} 2.9, J_{2a 2b} 13.2, J_2a,₃ 11.1 , J_2b>3 3.1 , J_4,5a 9.4, J₄,_5b 3.5, J_{5a 5b} 13.7 Hz; 1³C: 46.0 (C-1 ), 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 ppm (CO).

Method B)

Steps a) and b) of method B) are identical to steps a) and b) of method A).

Step c) 4-Cyanophenyl 3,4-di-0-benzoyl-2-deoxy-1,5-dithio-α,β-D-threo-pentopyrano- side (XII, R = 4-cyanophenylthio) A stirred solution of 1.7 g of 1 ,5-anhydro-3,4-di-0-benzoyi-5-thio-2- deoxy-D-threo-pent-2-enitol (XI, R = Bz) in 20 ml of dry benzene was saturated with anhydrous hydrogen bromide during 20 min at 10 °C, then nitrogen was bubbled through the solution to remove the excess hydrogen bromide. The so obtained solution was added dropwise to a suspension of 4.0 g silver acetate in 35 ml of acetonitrile. After 2 h the salts were filtered off, the filtrate was concentrated and submitted to column chromatography (solvent H). The compound obtained upon concentration of fractions having Rf = 0.4 (1.5 g) was dissolved in 40 ml of dichloromethane, the solution was 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 h, then quenched with triethylamine, concentrated and the residue submitted to column chromatography (solvent F) to yield 1.6 g (67%) of the title compound as α,β = 15:85 anomeric mixture.

Example 9

4-Cyanophenyl 2-azido-2-deoxy-1,5-dithio-β-D-xylopyranoside (I, Rη = N₃, R₂ =

R₃ = OH, R₄ = R₅ = H, R₆ = CN)

Under argon, to a stirred solution of 1.3 g of 1-0-acetyl-2-azido-2-deoxy-

3,4-di-0-benzoyl-5-thio-D-xylopyranose (XIII, R = OAc) and 0.8 g of 4- cyanothiophenol (III) in 35 ml of dichloromethane 0.6 ml of trimethylsilyl triflate was added at -10 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with triethylamine, concentrated and submitted to column chromatography (solvent H) to yield 0.35 g (23%) of 4-cyanophenyl 2-azido-3,4- di-0-benzoyl-2-deoxy-1 ,5-dithio-β-D-xylopyranoside (I, R-| = N₃, R₂ = R₃ = OH, R₄ = R₅ = H, R₆ = CN), Rf = 0.5. This compound was deacylated in 15 ml of methanol in the presence of 0.1 ml 3 M methanolic sodium methoxide. After 1 h 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, [α]_D = +91° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.62 (H-1), 3.20-3.60 (H-2,3,4), 2.75 (H-5a), 2.52 (H-5b), 7.65 and 7.80 (aromatic H), 5.40 and 5,75 ppm (OH); J_{Λ >2} 10.9, J_{4 5a} 10.9, J_4|5b 4.4, J_5a>5b 13.3 Hz.

The starting material (XIII, R = OAc) can be prepared the following way:

Step a) 2-Azido-3,4-di-0-benzoyl-2-deoxy-5-thio-α-D-xylopyranosyl nitrate (XIII, R = ON0₂)

Under argon, to a stirred suspension of 2.4 g of 1,5-anhydro-3,4-di-0- benzoyl-5-thio-2-deoxy-D-threo-pent-2-enitol (XI, R = Bz) and 0.7 g of sodium azide in 40 ml of acetonitrile 11.6 g of eerie ammonium nitrate was added at -20 °C and stirring was continued for 2 h at -20 °C. Then the reaction mixture was poured into 170 ml of ice-cold dichloromethane, washed with water, 6% aq sodium hydrocarbonate, dried, concentrated and the residue submitted to column chromatography (solvent J) to yield 1.1 g (35%) of the title compound. R_f (J) = 0.3, [α]_D = +140° (c = 0.5, chloroform), NMR (CDCI₃), ^">H: 6.22 (H-1),

4.25 (H-2), 5.80 (H-3), 5.46 (H-4) 3.20 (H-5a), 3.04 (H-5b), 7.3-8,0 ppm (aromatic H); J_{1 >2} 3.4, J_2ι3 10.0, J_{3 4} 10.0, J_{4 5a} 11.1 , J_{4 5b} 4.5, J_5aι5b 13.4 Hz; ¹³C: 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)

1-0-Acetyl-2-azido-3, 4-di-0-benzoyl-2-deoxy-5-thio-α, β-D-xylopyranose (XIII, R

= OAc) To a solution of 1.34 g of 2-azido-3,4-di-0-benzoyl-2-deoxy-5-thio-α-D- xylopyranosyl nitrate (XIII, R = 0N0₂) in 10 ml acetic acid 0.5 g of sodium acetate was added and the reaction mixture was stirred at 100 °C for 1 h. After cooling to room temperature it was diluted with 40 ml of dichloromethane, washed with water, 6% aq sodium hydrocarbonate, water, dried and concentrated. The residue was submitted to column chromatography (solvent H) to yield 0.87 g (65%) of the title compound, as a 1 :1 mixture of the α,β anomers. Rf (H) = 0.6. NMR (CDCI₃), α-anomer ¹H: 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_{1 2} 3.1 ,

J_{2 3} 10.5, J_4ι5a 11.0, J_{4 5b} 4.6, J_5aι5b 13.2 Hz; β-anomer 1H: 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); 4,2 9-4, 4i,3 ⁹-8, 4.4 10.1 , 4,5a U L 4,5b 4.7, J_{5a 5b} 13.3 Hz. α,β-anomer 1³C: 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 (OCOCH₃), 168.5 and 168.8 ppm (OCOCH₃).

Example 10

4-Cyanophenyl 3-amino-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R-j = R₃ = OH, R₂ = NH₂, R₄ = R₅ = H, R₆ = CN)

To a stirred solution of 230 mg of 4-cyanophenyl 3-azido-3-deoxy-1 ,5- dithio-β-D-xylopyranoside (I, R₁ = R₃ = OH, R₂ = N_3> R₄ = R₅ = H, R₆ = CN) (example 7) in 25 ml of ethanol 80 mg of sodium borohydride and 10 mg of nickel(ll) chloride hexahydrate were added. After 30 min the reaction mixture was neutralized with 4% aq HCI, filtered, concentrated and the residue purified by column chromatography (methanol) to yield 200 mg (95%) of the title compound, Rf (K) = 0.9, Mp: 195-200 °C, [α]_D = +45° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.55 (H-1), 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 H), 4.8-6.5 ppm (OH, NH₂); 4_>2 10.1 , J_2ι3 9.4, 4_,4 9-5- 4_,5a 9-5, J_4,5b 4.0, J_{5a 5b} 13.6 Hz.

Example 11

4-Cyanophenyl 3-acetamido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R-_j = R₃ = OH, R₂ = AcNH, R₄ = R₅ = H, R₆ = CN)

To a solution of 200 mg of 4-cyanophenyl 3-amino-3-deoxy-1,5-dithio-β- D-xytopyranoside (I, R^ - R₃ = OH, R₂ = NH₂, R₄ = R₅ = H, R₆ = CN) (example

10) in 5 ml of pyridine 2.5 ml of acetic anhydride was added and the mixture was kept overnight at room temperature. The residue obtained after usual processing, was deacetylated in 10 ml of methanol in the presence of 0.1 ml 3

M methanolic sodium methoxide. After 1 h the reaction 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, Rf (D)

= 0.4, Mp: 245-248 °C, [α]_D = +50° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H:

4.48 (H-1 ), 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); J_{1 2} 9.5, J_4ι5a 10.4, J_{4 5b} 3.7, J_5a;5b 13.2 Hz.

Example 12

4-(lmino)(methoxy)methylphenyl 3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside

(I R_j = R₃ = OH, R₂ = N₃, R₄ = R₅ = H, R₆ = -C(=NH)-OCH₃)

To a solution of 0,5 g of 4-cyanophenyl 3-azido-3-deoxy-1 ,5-dithio-β-D- xylopyranoside (I, R^ = R₃ = OH, R₂ = N₃, R₄ = R₅ = H, R₆ = CN) (example 7) in 20 mi of methanol 0.1 ml of 3 M methanolic sodium methoxide was added and the reaction mixture was kept overnight at room temperature. After neutralizing with carbon dixide, it was concentrated and the residue was submitted to column chromatography (solvent C). Concentration of the first fraction (Rf - 0.3) gave 270 mg of recovered starting material. Concentration of the second fraction yielded 130 mg (51 % based on the conversion) of the title compound, R_f (C) = 0.2, Mp: 126-130 °C, [α]_D = +52° (c = 0.3, methanol). NMR (DMSO-d₆), ¹H: 4.38 (H-1), 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 H), 5.80 and 6.30 (OH), 9.00 (NH), 3.80 ppm (OMe); J_{1 >2} 9.9, J_2>3 9.3, J_3A 9.3, J_{4 5a} 10.8, J_{4 5b} 4.5, J_{5a 5b} 13.3 Hz; MS: 340 [M+H]⁺.

Example 13

4-Cyanophenyl 1 ,5-dithio-β-D-glucopyranoside (I, R-j = R₂ = R₃ = OH, R₄ =

CH₂OH, R₅ = H, R₆ = CN).

To a solution of 0.9 g of 4-cyanophenyl 2,3,4, 6-tetra-0-acetyl-1 ,5-dithio-β -D-glucopyranoside (XIV, R = OAc, X = CN) in 20 ml of methanol 0.1 ml of 3 M methanolic sodium methoxide was added. After 1 h 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, [α]_D = -14° (c = 0.5, methanol). NMR (DMSO-d₆): ¹H, 4.46 (H-1), 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 H), 4.68, 5.00, 5.10 and 5.56 ppm (OH); J_{1 2} 10.2, J_2>3 8.6, J_{3 4} 8.6, J_{4 5} 8.9, J_{5 6a} 6.6, J_5>6b 3.3, J_6a>6b 11.4 Hz.

The starting material (XIV, R = OAc, X = CN) can be prepared the following way: To a stirred solution of 2.8 g of acetobromo thioglucose [W. Korytnyk et al. Carbohydrate Res. 108 (1982) 293] in 160 ml of acetone 1.0 g of 4- cyanothiophenol (III) and 1.65 g of potassium carbonate were added and the reaction mixture was refluxed for 1 h. After cooling, the salts were filtered off, washed with acetone, the filtrate was concentrated and the residue submitted to column chromatography (solvent E) to yield 2.15 g (68%) of the title compound, as a 15:85 α,β anomeric mixture. This was recrystallized from ether to give 1.63 g (52%) of the β anomer (XIV, R = OAc, X = CN). R_f (E) - 0.7, Mp: 125-127 °C, [α]_D = +38° (c = 0.5, chloroform). NMR (CDCI₃), ^""H: 4.27 (H-1), 5.24 (H-2), 5.10 (H-3), 5.28 (H-4), 3.32 (H-5), 4.10 (H-6a), 4.26 (H-6b), 7.59 and 7.61 (aromatic H), 2.00, 2.03, 2.06 and 2.08 ppm (OAc); J_{1 2} 10.6, J_{2 3} 9.4, 4_,4 9.4, J_4|5 10.6, J_5ι6a 3.3, J_5ι6b 5.3, J_6a<6b 12.0 Hz; 1³C: 50.1 (C-1), 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 (OCOCH₃), 169.2-170.4 ppm (OCOCH₃)

Example 14

4-Cyanophenyl 6-deoxy-1,5-dithio-β-D-glucopyranoside (I, R-_j = R₂ = R₃ = OH,

R₄ = CH₃, R₅ = H, R₆ = CN)

To a solution of 180 mg of 4-cyanophenyl 2,3,4-tri-0-acetyl-6-deoxy-1 ,5- dithio-β-D-glucopyranoside (XIV, R = H, X = CN) in 8 ml of methanol 0.1 ml of 3 M methanolic sodium methoxide was added. After 1 h 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-d₆), ¹H: 4.52 (H-1), 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 H), 5.10, 5.12 and 5.60 ppm (OH); J_r2 10.2, 4_,3 8.4, J_{5 6} 6.9 Hz. The starting material (XIV, R = H, X = CN) can be prepared the following way:

Method A) Step a)

4-Cyanophenyl 2,3,4-tri-0-acetyl-1,5-dithio-6-0-methanesulfonyl-β-D-gluco- pyranoside (XIV, R = OMs, X = CN)

To a stirred solution of 1.3 g of 4-cyanophenyl 1 ,5-dithio-β-D-gluco- pyranoside (I, R-| = R₂ = R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = 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 at 0 °C during 15 min. The reaction mixture was stirred at room temperature for 3 h, then 8 ml of acetic anhydride was added and the mixture was kept overnight at room temperature. After the usual processing, the residue was submitted to column chromatography (solvent E) to yield 1.15 g (54%) of the title compound, R_f (E) = 0.3, Mp: 119-122 °C, [α]_D =

+28° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 4.28 (H-1 ), 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 H),

3.05 (Ms), 2.00, 2.05 and 2.06 ppm (OAc); J_{1 2} 10.3, J_{2 3} 9.5, J_{3 4} 9.5, J_{4 5} 10.3, J_5j6a 3.7, J_5ι6b 5.2, J_6a,6b 10.9 Hz; 1³C: 50.2 (C-1), 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 (OCOCH₃), 169.2, 169.4 and 169.5 ppm (OCOCH₃).

Step b)

4-Cyanophenyl 2, 3, 4-tri-0-acetyl-6-deoxy- 1 , 5-dithio-6-iodo-β-D-glucopyrano- side (XIV, R = I, X = CN) To a stirred solution of 1.15 g of 4-cyanophenyl 2,3,4-tri-0-acetyl-1 ,5- dithio-6-O-methanesulfonyl-β-D-glucopyranoside (XIV, R = OMs, X = CN) in 55 ml of diethylketone 0.6 g of sodium iodide was added and the reaction mixture was refluxed for 4 h. The salts were filtered off after cooling and were washed with dichlorometane. The filtrate was concentrated and the residue submitted to column chromatography (solvent F) to yield 1.2 g (98%) of the title compound, R_f (F) = 0.6, [α]_D = 0° (c = 0.5, chloroform). NMR (CDCI₃), ^"Η: 4.32 (H-1), 5.05- 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_{1 2} 10.4, Hz; ¹³C: 50.0 (C-1), 73.3, 73.9, 74.2 (C- 2,3,4), 46.6 (C-5), 0.2 (C-6), 111.8, 131.5, 132.5 and 138.8 (aromatic C), 118.1 (CN), 20.3, 20.4 and 20.5 (OCOCH₃), 169.1 , 169.2 and 169.5 ppm (OCOCH₃).

Step c)

4-Cyanophenyl 2,3,4-tri-0-acetyl-6-deoxy-1,5-dithio-β-D-glucopyranoside (XIV, R = H, X = CN)

To a stirred solution of 1.2 g of 4-cyanophenyl 2,3,4-tri-0-acetyi-6-deoxy- 1 ,5-dithio-6-iodo-β-D-glucopyranoside (XIV, R = I, X = CN) in 45 ml of ethanol 0.22 g of sodium borohydride and 20 mg of nickel(ll) chloride hexahydrate were added and stirring was continued for 30 min. The reaction mixture was neutralized with 4% aq HCI, filtered and concentrated. The residue was submitted to column chromatography (solvent F) to yield 0.4 g (43%) of the title compound, R_f (F) = 0.4, Mp: 134-136 °C, [α]_D = +57° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 4.24 (H-1), 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); J-, ₂ 10.7, J_{4 5} 9.9, J_{5 6} 6.6 Hz; 1³C: 50.0 (C-1 ), 73.6, 74.3 and 75.7 (C-2,3,4), 40.1 (C-5), 15.3 (C-6), 110.7, 131.3, 132.5 and 138.8 (aromatic C), 118.0 (CN), 20.5 (OCOCH₃), 169.4, 169.5 and 169.6 ppm (OCOCH₃). Method B)

To a stirred solution of 1.3 g of 1 ,2,3,4-tetra-0-acetyl-6-deoxy-5-thio-D- glucopyranose [E. Bozό et al. Carbohydrate Res. 290 (1996) 159] in 20 ml of dichloromethane 4 ml of 33% hydrogen bromide in acetic acid was added. After 1 h at room temperature the mixture was poured into ice-water, extracted with dichloromethane, washed with 6% aq sodium hydrocarbonate, 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 h. The salts were filtered after cooling and were washed with acetone. The filtrate was concentrated and the residue was submitted to column chromatography (solvent F) to yield 0.97 g (61 %) of the glycosides as an α,β = 1 :8 anomeric mixture, which on recrystallization from ether gave 0.6 g (38%) of the β-anomer, identical to the compound prepared in step c) of method A).

Example 15

4-Cyanophenyl 6-deoxy-1,5-dithio-β-D-xylo-hex-5-enopyranoside (I, R-_j = R₂ =

R₃ = OH, R₄ + R₅ = CH₂, R₆ = CN)

To a stirred solution of 200 mg of 4-cyanophenyl 2,3,4-tri-0-acetyl-6- deoxy-1 ,5-dithio-β-D-xylo-hex-5-enopyranoside (XV) in 10 ml of methanol 0.1 ml of 3 M methanolic sodium methoxide was added. After 1 h the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 140 mg (91%) of the title compound, R_f (D) = 0.4, Mp: 152-156 °C, [α]_D = -99° (c = 0.3, methanol). NMR (DMSO-d₆), ¹H: 4.44 (H-1 ), 3.48 (H-2), 3.10 (H- 3), 3.92 (H-4), 5.33 (H-6a), 5.60 (H-6b), 7.60 and 7.78 (aromatic H), 5.36, 5.58 and 5.75 ppm (OH); J_{1 2} 10.1 , J_2>3 8.5, J_3ι4 8.8, J_{6a 6b} -1.0 Hz. The starting material (XV) can be prepared the following way:

To a stirred solution of 0.5 g of 4-cyanophenyl 2,3,4-tri-0-acetyl-6-deoxy- 1 ,5-dithio-6-iodo-β-D-glucopyranoside (XIV, R = I, X = CN) in 12 ml of pyridine 0.4 g of silver fluoride and after 2 h 50 ml of chloroform were added. The reaction mixture was filtered, the filtrate was concentrated and the residue submitted to column chromatography (solvent F) to yield 0.27 g (70 %) of the title compound, R_f = 0.4, Mp: 150-153 °C, [α]_D = -36° (c = 0.5, chloroform). NMR (CDCI₃), ¹H: 4.28 (H-1), 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 H), 2.02, 2.04 and 2.14 ppm (OAc); J_{1 2} 10.6, 4_,3 9.4, J_3,4 9.4, J_{6a 6b} -1.0 Hz; ¹³C: 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 (OCOCH₃), 168.9, 169.2 and 169.4 ppm (OCOCH₃).

Example 16

4-(lmino)(methoxy)methylphenyl 1 ,5-dithio-β-D-glucopyranoside (I, Rf = R₂ =

R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = -C^NHyOCH^.

To a solution of 210 mg of 4-cyanophenyl 1 ,5-dithio-β-D-glucopyranoside

(I, R₁ = R₂ = R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = CN) (example 13) in 10 ml of methanol 0.1 ml of 3 M methanolic sodium methoxide was added. After 24 h at room temperature the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was submitted to column chromatography (solvent D). Concentration of the first fraction (R_f = 0.25) gave 100 mg of recovered starting material. Concentration of the second fraction (Rf = 0.2) yielded 80 mg (66% based on the conversion) of the title compound, Mp: 181-184 °C, [α]_D = -10° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 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), 4.64, 4.95, 5.08 and 5.48 (OH), 9.00 (NH), 3.80 ppm (OCH₃); J, ₂ 10.2, J₂3 8.5, J_{3 4} 8.5, J_4?5 9.7, J_5f6a 6.6, J₅._6b 3.1 , J_6a,6b 11.5 Hz.

Example 17

4-Nitrophenyl 3-azido-3-deoxy-1,5-dithio-β-D-xylopyranoside (I, R-, = R₃ = OH, R₂ = N₃, R₄ = R₅ = H, R₆ = Nθ2)

Method A) Under argon, to a solution of 0.8 g of 1 ,2,4-tri-0-acetyl-3-azido-3-deoxy-

5-thio-D-xylopyranose (Vlll, R = OAc) and 0.8 g of 4-nitrothiophenol in 20 ml of dichloromethane 0.45 ml of trimethylsilyl triflate was added at -10 °C. The reaction mixture was stirred at room temperature for 5 h, then quenched with triethylamine, washed with 5% aq sodium hydrogen carbonate and water. The residue obtained upon concentration of the organic layer was submitted to column chromatography (solvent F). The residue obtained on concentration of fraction having R_f = 0.6 was dissolved in 10 ml of methanol and 0.1 ml of 3 M methanolic sodium methoxide was added. After 1 h at room temperature the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated to yield 90 mg (11%) of the title compound, Mp: 145-150 °C, Rf (D) = 0.4, [α]_D = +88° (c = 0.1 , methanol). NMR (DMSO-d₆), ^"Η: 4.62 (H-1), 3.35 (H-2), 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); J_{1 2} 9.8, J_2ι3 9.1 , J_{3 4} 9.1 , J_4ι5a 10.8, J_4ιs_b 4.4, 4a_,5b 13-3 Hz. 1³C: 50.6 (C-1), 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) Under argon, to a solution of 1.54 g of 1 ,2,4-tri-0-acetyl-3-azido-3- deoxy-5-thio-D-xylopyranose (Vlll, R = OAc) and 0.82 g 4-nitrothiophenol in 24 ml of 1 ,2-dichloroethane 0.6 ml of boron trifluoride etherate was added. The reaction mixture was stirred at room temperature for 24 h, then washed with 5% aq sodium hydrogen carbonate and water. The residue obtained upon concentration of the organic layer was submitted to column chromatography (solvent F) to yield 0.76 g (38%) of 4-nitrophenyl 2,4-di-0-acetyl-3-azido-3- deoxy-1 ,5-dithio-β-D-xylopyranoside (I, R^ = R₃ = OAc, R₂ = N₃, R₄ = R₅ = H, R₆ = N0₂). The so obtained material was deacetylated with methanolic sodium methoxide to yield a compound identical to the final product of method A).

Example 18

4-(Aminothiocarbonyl)phenyl 6-deoxy-1,5-dithio-β-D-glucopyranoside (I, R-j =

R₂ = R₃ = OH, R₄ = CH₃, R₅ = H, R₆ = -CSfNH^

A solution containing 0.3 g of 4-cyanophenyl 6-deoxy-1 ,5-dithio-β-D- glucopyranoside (I, R-| = R₂ = R₃ = OH, R₄ = CH₃, R₅ = H, R₆ = CN) (example 14) in 6 ml of pyridine and 6 ml of triethylamine was saturated with dry hydrogen sulfide at room temperature for 5 h. After standing at room temperature overnight the reaction mixture was concentrated and the residue crystallized with ether to yield 310 mg (93%) of the title compound, Mp: 92-96 °C, R_f (D) = 0.3, [α]_D = +5° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.38 (H- 1), 3.28 (H-2), 3.08 (H-3), 3.02 (H-4), 2.80 (H-5), 1.12 (H-6), 7.45 and 7.85 (aromatic H), 5.05, 5.10 and 5.55 (OH), 9.45 and 9.85 ppm (NH); J_{1 >2} 10.2, J_{2 3} 8.3, J_{3 4} 8.5, J_{4 5} 8.8, J_5,6 6.8 Hz.

Example 19 4-(Aminothiocarbonyl)phenyl 2-deoxy-1,5-dithio-β-D-threo-pentopyranoside (I, R₁ = R₄ = R₅ = H, R₂ = R₃ = OH, R₆ = -CS(NH₂))

A solution containing 0.3 g of 4-cyanophenyl 2-deoxy-1 ,5-dithio-β-D- threo-pentopyranoside (I, R-j = R₄ = R5 = H, R₂ = R₃ = OH, R₆ = CN) (example 8) in 6 ml of pyridine and 6 ml of triethylamine was saturated with dry hydrogen sulfide at room temperature for 5 h. After standing at room temperature overnight the reaction mixture was concentrated and the residue crystallized with ether to yield 300 mg (89%) of the title compound, Mp: 169-173 °C, R_f (D) = 0.3, [α]_D = -25° (c = 0.5, pyridine). NMR (DMSO-d₆), 1H: 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,5b), 7.48 and 7.90 (aromatic H), 4.95 and 5.12 (OH), 9.50 and 9.94 ppm (NH); J_{1 <2a} 11.9, J_{1 >2b} 2.5, J_2aι2b 12.8, J_2at3 -10.5, J_2b,3 ~2.5 Hz.

Example 20

4-Amidinophenyl 2-deoxy-1,5-dithio-β-D-threo-pentopyranoside (I, R-_j = R₄ = R₅ = H, R₂ = R₃ = OH, R₆ = -C(=NH)-NH2)

To a solution of 150 mg of 4-(aminothiocarbonyl)phenyl 2-deoxy-1 ,5- dithio-β-D-threo-pentopyranoside (I, R., = R₄ = R₅ = H, R₂ = R₃ = OH, R₆ = - CS(NH₂)) (example 19) in 35 ml of acetone 0.2 ml of methyl iodide was added, the reaction mixture was refluxed for 5 h, then concentrated. The residue was dissolved in 10 ml of ethanol 120 mg of ammonium acetate was added and the mixture was stirred at 60 °C for 6 h, then concentrated. The residue was dissolved in 10 ml of 10% aq acetic acid and purified on Varion AD resin (10 ml) to yield after freezdrying of the solution 70 mg (41 %) of the title compound, as its acetate, Mp: 183-188 °C, R_f (K) = 0.7, [α]_D = -18° (c = 0.5, methanol). NMR (DMSO-d₆), 1H: 4.62 (H-1), 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 7.72 (aromatic H), 4.6-5.6 ppm (NH, OH); J_{1 2a} 11.7, 4_,2_b 2.5, J₂a_,2b 13-0, J_2a,3 -10, J_2b,3 3.2 Hz; ¹³C: 44.5 (C-1 ), 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

4-(Aminothiocarbonyl)phenyl 1 ,5-dithio-β-D-glucopyranoside (I, R-_j = R₂ = R₃ =

OH, R₄ = CH₂OH, R₅ = H, R₆ = -CSfNH∑))

A solution of 0.9 g of 4-cyanophenyl 1 ,5-dithio-β-D-glucopyranoside (I,

R₁ = R₂ = R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = CN) (example 13) in 20 ml of pyridine and 20 ml of triethylamine was saturated with dry hydrogen sulfide at room temperature for 5 h. After standing overnight at room temperature the reaction mixture was concentrated and the residue crystallized with methanol to yield 0.68 g (68%) of the title compound, Mp: 165-168 °C, R_f (D) = 0.2, NMR (DMSO-d₆), ¹H: 4.33 (H-1), 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); J_{1 2} 10.2, J_2,3 ⁸-⁶- 4_,4 8.6, J_4>5 -10, J_{5 6a} 6.6, J_5βb 3.1 , J_6a,6b 11.2 Hz.

Example 22

4-(lmino)(methylthio)methylphenyl 1 ,5-dithio-β-D-glucopyranoside (I, R-j - R₂ =

R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = -C(=NH)-SCH3)

To a solution of 80 mg of 4-(aminothiocarbonyl)phenyl 1 ,5-dithio-β-D- glucopyranoside (I, R₁ = R₂ = R₃ = OH, R₄ = CH₂OH, R₅ = H, R₆ = -CS(NH₂)) in 20 ml of acetone 0.1 ml of methyl iodide was added and the reaction mixture was refluxed for 4 h. The precipitated product was filtered after cooling and was washed with acetone to yield 110 mg (98%) of the title compound, as its hydroiodide, Mp: 207-209 °C, R_f (D) = 0.4. NMR (DMSO-d₆), ¹H: 4.52 (H-1), 3.32 (H-2), 3.15 (H-3), 3.32 (H-4), 2.95 (H-5), 3.50 (H-6a), 3.76 (H-6b), 7.80 and 7.65 (aromatic H), 4.0-3.0 (NH, OH), 2.75 ppm (SMe); J, ₂ 10.1 , J_{2 3} 8.7, J_{3 4} 8.7, J₄5 -10, J5_6a 6.6, Jζ _6b 3.1 , Jβa.δb H -3 Hz.

Example 23

4-Nitrophenyl 6-deoxy-1,5-dithio-β-D-glucopyranoside (I, R-j = R₂ = R₃ = OH,

R₄ = CH₃, R₅ = H, R₆ = NO2)

To a solution of 320 mg of 4-nitrophenyl 2,3,4-tri-0-acetyl-6-deoxy-1 ,5- dithio-β-D-glucopyranoside (XIV, R = H, X = N0₂) in 20 ml of methanol 0.1 ml of 3 M methanolic sodium methoxide was added. After 2 h at room temperature the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was crystallized with ether to yield 130 mg (57%) of the title compound, Mp; 157-159 °C, R_f (D) = 0.4. [α]_D = +9° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.58 (H-1), 3.35 (H-2), 3.13 (H-3), 3.06 (H^t), 2.86 (H-5), 1.10 (H-6), 8.15 and 7.65 (aromatic H), 5.64 and 5.12 (OH); J_{1 ?2} 10.3, J_{2 3} 8.2, J_{3 4} 8.8, J₄₎₅ 8.8, J_5ι6 7.2 Hz.

The starting material (XIV, R = H, X= N0₂) was prepared according to method B) of example 14, but instead of 4-cyanothiophenol 4-nitrothiophenol was used as aglycon. This way the pure β-anomer was obtained in 37% yield, Mp: 138-141 °C, R_f (F) = 0.6. [α]_D = +55° (c = 0.5, chloroform). NMR (CDCI₃), 1H: 4.30 (H-1), 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 2} 10.6, J_{2 3} 10.0, J_4>5 10.0, J_{5 6} 6.4 Hz. ^"<³C: 49.8 (C-1 ), 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 (COCH₃).

Example 24 4-Nitrophenyl 2-deoxy-1,5-dithio-β-D-threo-pentαpyranoside (I, R_ή = R₄ - R₅ = H, R₂ = R₃ = OH, R₆ = NOz)

To a solution containing 0.57 g of an α,β = 1 :9 mixture of 4-nitrophenyl 3,4-di-0-benzoyl-2-deoxy-1 ,5-dithio-D-threo-pentopyranoside (XII, R = 4-nitro- phenylthio) in 20 ml of methanol and 10 ml of dichloromethane 0.1 ml of 3 M methanolic sodium methoxide was added. After 24 h at room temperature the reaction mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was crystallized with ether to yield 235 mg (71%) of the title compound. Mp: 150-152 °C, R_f (C) = 0.3, [α]_D = -26° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 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 H), 5.15 and 5.04 ppm (OH); 4_,2a H -⁷- 4,2b ²-6. 4a,2b 12-7, 4a,3 ~10, 4b,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 aglycon. This way the α,β = 1 :9 anomeric mixture was obtained in 92% yield, R_f (H) = 0.5. NMR (CDCI3), ¹H: 4.52 (H-1), 2.38 (H- 2a), 2.94 (H-2b), 5.34-5.50 (H-3,4), 3.02 (H-5a), 3.22 (H-5b), 7.30-8.20 ppm (aromatic H); J_{1 <2a} 11.0, J_{1 >2b} 2.9, J_2a,2b 12.9, J_{2a 3} 10.8, J_2bι3 3.2, J_4,5a 9.4, J_{4 5b} 3.7, J_{5a 5b} 13.8 Hz; ¹³C: 45.8 (C-1), 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 ppm (aromatic C). Example 25

4-Nitrophenyl 4-azido-4-deoxy-1,5-dithio-β-D-xylopyranoside (I, R₁ - R₂ = OH,

R₃ = N₃, R₄ = R₅ = H, R₆ = Nθ2)

To a stirred solution of 2.0 g of 1 ,2,3-tri-0-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 dry 1 ,2-dichloroethane 0.78 ml of boron trifluoride etherate was added. After 24 h at room temperature the reaction mixture was washed with 5% aq sodium hydrogen carbonate and water. The residue obtained upon concentration of the organic layer was submitted to column chromatography (solvent H) yielding 0.65 g (25%) of 4-nitrophenyl 2,3- di-0-acetyl-4-azido-4-deoxy-1 ,5-dithio-β-D-xylopyranoside (II, R = N0₂). The so obtained compound was dissolved in 20 ml of methanol and 0.1 ml of 1 M methanolic sodium methoxide was added. After 1 h at room temperature the recation mixture was neutralized with Dowex 50 WX resin, filtered and concentrated. The residue was crystallized with ether yielding 0.38 g (73%) of the title compound, Mp: 126-129 °C, R_f (C) = 0.4, [α]_D = +104° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.60 (H-1 ), 3.40 (H-2), 3.30 (H-3), 3.62 (H-4) 2.76 (H-5a), 2.66 (H-5b), 5.80 and 5.95 (OH), 7.62 and 8.15 ppm (aromatic H); J_{1 ι2} 10.0, J_{2 3} 9.8, J_3ι4 9.3, J_4,5a 11.3, J_4<5b 4.5, J_{5a 5b} 13.4 Hz.

Example 26

4-Nitrophenyl 2-azido-2-deoxy-1,5-dithio-β-D-xylopyranoside (I, R-j = N₃, R₂ =

R₃ = OH, R₄ = R₅ = H, R₆ = N02)

Under argon, to a solution of 0.85 g of 1 -0-acetyl-2-azido-2-deoxy-3,4- di-O-benzoyl-5-thio-D-xylopyranose (XIII, R = OAc) (step b) of example 9) in 15 ml of dry 1 ,2-dichioroethane 0.33 g of 4-nitrothιophenol and 0.26 ml of boron trifluoride etherate were added. After 24 h at room temperature the reaction mixture was washed with 5% aq sodium hydrogen carbonate and water. The residue obtained upon concentration of the organic layer was submitted 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-β-D-xylopyranoside (XIII, R = 4-nitro- phenylthio). The so obtained compound was dissolved in 20 ml of methanol and 10 ml of dichloromethane, then 0.1 ml of 1 M methanolic sodium methoxide was added. The recation mixture was neutralized after 1 h at room temperature with solid carbon dioxide, concentrated and submitted to column chromatography (solvent C) to yield 80 mg (44%) of the title compound, R_f (C) = 0.3, [α]_D = +120° (c = 0.5, methanol). NMR (DMSO-d₆), ¹H: 4.70 (H-1), 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 H), 5.44 and 5.78 ppm (OH); J, ₂ 10.9, J_{2 3} 8.9, J_{3 4} 8.9, J_{4 5a} 10.8, J_{4 5b} 4.4,

Claims

What we claim is:

1. 1 ,5-Dithio-pyranosides of formula (I),

Y

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 or

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 provisio that R₆ represents only a group other than a nitro or cyano group if Rι-R₃ each represent 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 represent hydroxy groups, R₄ represents a hydroxymethyl group and R₅ represents hydrogen and if possible, the acid addition salts thereof formed with organic or inorganic acids.

2. 4-(Hydrazino)(imino)methylphenyl 1 ,5-ditio-β-D-xylopyranoside.

3. 4-(lmino)(methylthio)methyiphenyl 1 ,5-dithio-β-D-xylopyranoside. 4. 4-Cyanophenyl 2-deoxy-1 ,5-dithio-β-D-fr^;reo-pentopyranoside. 5.

4-(lmino)(methoxy)methylphenyl 3-azido-3-deoxy-1 ,

5-dithio-β-D- -xylopyranoside.

6. 4-Nitrophenyl 3-azido-3-deoxy-1 ,5-dithio-β-D-xylopyranoside.

7. 4-(Amino-thiocarbonyl)phenyl 1 ,5-dithio-β-D-glucopyranoside

8. Pharmaceutical composition comprising as active ingredient a compound of general formula (I), wherein R^-R_Q have the same meaning as in claim 1 , or, if possible, a pharmaceutically acceptable salt thereof and solvents, diluents, carriers and filling materials usually applied in pharmaceuticals.

9. Use of compounds of formula (I), wherein R^-R_Q have the same meaning as in claim 1 , as pharmaceuticals.

10. Use of compounds of formula (I), wherein R-pR₆ have the same meaning as in claim 1 , for the preparation of anticoagulant drugs.