UA64697C2 - Platelet aggregation inhibitors - Google Patents

Abstract

Compounds of formula (I), wherein é is O or CH2; X is selected from NR1R2, SR1, and C1-C7 alkyl; Y is selected from SR1 NR1R2, and C1-C7 alkyl; R1 and R2 are each and independently selected from H, or C1-C7 alkyl optionally substituted upon or within the alkyl chain by one or more of O, S, N or halogen; R3 and R4 are both H, or R3 and R4 together form a bond; A is COOH, C(O)NH(CH2)pCOOH, C(O)N[(CH2)qCOOH]2; C(0)NHCH(COOH)(CH2)rCOOH, or 5-tetrazolyl, wherein p, q and r are each and independently 1, 2, or 3; as well as pharmaceutically acceptable salts and prodrugs thereof, pharmaceutical compositions comprising the novel compounds and use of the compounds in therapy. Also within the scope of the invention are novel intermediates to the novel compounds. The novel compounds are in particular useful in the prevention of platelet aggregation. , (I)

Description

This invention relates to novel compounds, their preparation, their use, and pharmaceutical compositions containing the novel compounds. The new compounds are useful for therapy, and in particular, for preventing platelet aggregation.

A number of interconnected processes lead to the aggregation of platelets. Whatever the initial stimulus, the final overall result is the cross-linking of platelets by the binding of fibrinogen to the binding site of the membrane - the glycoprotein PIr/Pa cRIB/LINa). The high antiplatelet efficacy of antibodies or antagonists of SILIB/LNP can be explained by their effect on the final overall outcome. However, this efficacy may also explain the bleeding problems observed with this class of agent.

Thrombin can aggregate platelets largely independently of other processes, but significant amounts of thrombin are unlikely to be present without prior platelet activation by other mechanisms. Thrombin inhibitors such as hirudin are highly effective antithrombotic agents, but again may lead to excessive bleeding because they act as antiplatelets as well as anticoagulants. (Ipmesiidasog5 TIMI 9a (1994), Sigsshayop 90, 1624-1630; Tne Sioba! Ove oi bigagediev

Orep Ossitsdei Sogopagu Apegiyev (5050) Pa Ipueziidayugv (50570) Sigsshayop 90, 1631-1637; Meipatsv, her a!. (1994) Sigsshayop 90, 1638-1642).

Aspirin, which is known to have a beneficial effect on platelet aggregation (see, for example,

Apiriateiiei Tgiaiiviv" SoParogaynop (1994), Vg. Mea. 9). 308, pp. 81-106; Apiiriaiteiiei Tpaiiviv" SoParogaiop (1994),

VI. May 9. 308, pp. 159-168), does not affect aggregation created by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow. The cardinal role of ADP is confirmed by the fact that other agents, such as epinephrine and 5-hydroxytryptamine (5-HT, serotonin), carry out aggregation only in the presence of ADP.

In this invention, it was assumed that an antagonist of the action of ADP on its platelet membrane receptor, the Roth-purinoceptor, would provide a more effective antithrombotic agent than aspirin, but with a less severe bleeding effect than that of fibrinogen receptor antagonists.

US Patent 4,543,255 discloses carbocyclic analogs of 2-amino-6-substituted-purine-2'-deoxyribofuranosides and 2-amino-6-substituted-8-azapurine-2'-deoxyribofuranosides. The compounds described in this patent are shown to have an inhibitory effect against the herpes virus.

MO patent 90/06671 discloses the use of carbocyclic analogues of various nucleosides for the treatment of diseases caused by the Hepatitis B virus.

The task underlying the present invention is the search for new compounds that have improved antagonistic activity against the Rheot receptor and significant advantages compared to known antiplatelet agents, such as improved efficacy, reduced side effects, lack of toxicity, and better selectivity for the Rheot receptor .

The above-mentioned task was solved by obtaining new compounds, which are 5,7-disubstituted 1,2,3-triazolo!|4,5-4|-pyrimidin-3-yl derivatives, which are described below.

The new compounds of the present invention are described by the general formula (I) x

A er vi M mu 3 v () (I! but he in which

B is O or CH;

X represents МРЕ'В2, 58! and Ci-C7-alkyl;

M represents 5, МВ!B2 and C-C7-alkyl;

IN! and 22 each independently represents H or C1-C7-alkyl, optionally substituted on or in the alkyl chain by one or more atoms of 0, 5, M or halogen;

ВЗ and Р" - both represent H or РЗ and РЕ" together form a bond;

A is COOH, C(IOMH(CHgHCOOH, COM(CHgzCOOnNIg, CHOOMNON(COOH)CHg)COOH or 5-tetrazolyl, where p, 4 and g are each independently equal to 1, 2 or 3;

The term "alkyl" includes straight branched and cyclic alkyl chains, as well as saturated and unsaturated alkyl chains.

Substituents 0, 5 and M may be substituents on or in the alkyl chain, meaning C1-C7-alkyl, in which one methylene in the chain may be replaced by O, 5, or MH, and in which the alkyl chain may be substituted by one or more groups OH, 5H, MH" or halogen.

Halogen includes chlorine and fluorine.

The scope of the invention also includes pharmaceutically acceptable salts of compounds of formula (I), as well as prodrugs, such as esters and amides of compounds.

The scope of the invention also includes compounds of formula (I) in tautomeric, enantiomeric and diastereomeric forms.

More acceptable compounds of the invention are compounds of formula (I), in which

X represents ME 'B2;

M is 58;

A is SIOUMNHSN(COOHCHCHnISOOH; and in which VE", B2 and r are defined above.

Especially acceptable compounds of the invention are compounds of formula (I), in which

X represents MEN, where B! is hydrogen and B? defined above;

M represents 5, where B! represents a Ci-Cv-alkyl, optionally substituted by one or more halogens; and

A is SIOUMNSN(СООН)ИСНСООН.

The most acceptable compounds of the invention are (E)-M-(/1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo!|4,5-4|-pyrimidine-3- il|-1,5,6-trideoxy-p-YO-ribo-hept-5-enofuranuronoyl)-I -aspartic acid; 1 A-To028,Zr,4001-Ich-I3-I4-(7-"Butylamino )-5-(propylthio)-3H-1,2,3-triazolo(4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|propanoyl)-I -aspartic acid;

HT A-To(E),2p,30,4091-M-(3-I4-(7-«(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-ypyrimidine -3-yl|-2,3-dihydroxycyclopentyl)-2-propenoyl|-1-aspartic acid; and

PT A-To(E),28,30,401-M-(3-I4-I5-(3,3,3-trifluoropropyl)thio|-7-(2-(methylthio)-ethylamino|-ZH-1,2 ,3-triazoloi|4,5-4|pyrimidin-3-yl/-2,3-dihydroxycyclopentyl/-2-propanoyl/-I -aspartic acid, monoammonium salt.

The new compounds of the present invention are useful for therapy, in particular, for preventing platelet aggregation.

The compounds of the present invention are therefore useful as antithrombotic agents and are therefore useful in the treatment or prevention of unstable angina pectoris, coronary artery bypass graft surgery and myocardial infarction.

The compounds of the present invention are also useful for the treatment or prevention of primary arterial thrombotic complications of atherosclerosis, such as thrombotic stroke, peripheral vascular disease, myocardial infarction (ie, without thrombolysis).

Further indications, when the compounds of the invention are useful, are the treatment or prevention of arterial thrombotic complications caused by intervention in atherosclerotic diseases, such as plastic surgery on vessels, endarterectomy, stenting, graft surgery of coronary and other vessels.

Further indications where the compounds of the invention are useful are the treatment or prevention of thrombotic complications of surgical or mechanical injury such as tissue salvage after surgical or accident trauma, plastic surgery including skin grafts, and "reconstructive" surgery such as breast reconstruction.

The compounds of the invention are also useful for preventing mechanically induced activation of platelets of the migo, such as artificial blood circulation (aversion of microthromboembolism), aversion of mechanically induced activation of platelets of the migo, such as the use of compounds for the preservation of blood products, such as platelet concentrates, prevention of shunt occlusion, such as hemodialysis and plasmapheresis, thrombosis secondary to vascular damage/inflammation such as vasculitis, arteritis, glomerulonephritis and organ transplant rejection.

Further indications for the use of the compounds of the invention are the component of diffuse thrombotic/platelet loss, such as disseminated intravascular coagulation, thrombotic purpura, hemolytic uremic syndrome, thrombotic embolism, adult respiratory distress syndrome, antiphospholipid syndrome, heparin-induced thrombocytopenia, and preeclampsia/eclampsia. .

Further indications for the use of the compound of the invention are the treatment or prevention of venous thrombosis such as thrombophlebitis, veno-occlusive diseases, hematological conditions such as thrombocythemia and polycythemia and migraine.

In a particularly acceptable variant of the present invention, the compounds are used for the treatment of unstable angina, plastic surgery on coronary vessels and for the treatment of myocardial infarction.

In another particularly acceptable variant of the invention, the compounds of the present invention are useful as an adjunctive therapy in the prevention of coronary arterial thrombosis during the treatment of unstable angina, in plastic surgery on coronary vessels and acute myocardial infarction, i.e., perithrombolysis. You can use agents that are usually used as adjunctive therapy in the treatment of thrombotic diseases, for example, heparin and/or aspirin, to name only a few.

The compounds of the present invention can be obtained in the following ways.

A) () The starting material, 4,5-diamino-2,6-dimercaptopyrimidine, is alkylated with subsequent diazotization, obtaining the compound of formula (II)

ZV! and cha

M I KO

Shchy ay what M V in which E! determined as in formula (I). (i) The product of formula (Ii) of stage (i) reacts with a compound of formula (PI)

Ra,

In z (I) t z o OR, in which Rg is a protective group; and I. is a departing group; in an inert solvent and in the presence of a base. Solvents that can be used include

DMF, and bases that may be used include sodium amide. The reaction is carried out at temperatures from -20 to 50°C. More preferably, the reaction is carried out at ambient temperature, the solvent is acetonitrile and the base is sodium hydride. A suitable protecting group includes an acyl group such as benzoyl, and a suitable leaving group includes a halogen such as bromine.

The reagent of formula (II), which is used at this stage, is obtained by halogenation of an appropriately protected ribose.

Thus, the group X-ME'VZ, in which B! and 2 defined in formula (I) above, can be introduced by reaction with a compound of the formula NMPE'B2, in which B' and 22 are defined in formula (I) above, in an inert solvent at a temperature from 0 to 150"C. A more acceptable solvent is 1,4-dioxane and the temperature is 1007C.

Protecting groups Po can be removed by treatment with a nucleophile, for example, an alkoxide in an alcohol solvent, more preferably sodium methoxide in methanol at 607С.

The product obtained at this stage is a compound of the formula (IM) re u - o else, (m no on in which X represents ME'B2; Y represents 5; and where ВЕ! and Р? are defined in the formula (I ) above, (its) The product of formula (IM) of step (iii) reacts with the corresponding carbonyl compound or orthoester in an inert solvent and in the presence of an inorganic or organic acid as an acid catalyst at a temperature between -15 and 10072 to give a compound of formula (M) x - M

M is not yet I in which X represents MV'B2; M is 58; B is 0, and Ri is a protecting group, more preferably R/R together form a ring.

More preferably, Ri/Ri is ethoxymethylidene introduced using triethylorthoformate in 1, 4-dioxane at 50"C and in the presence of trichloroacetic acid.

B) () 4,6-dihydroxy-2-mercaptopyrimidine is alkylated, then nitrated, thus converting two alcohols into leaving groups, obtaining compounds of the formula (MI)

NK Frishn

M M "in which E! defined in formula (I); and M is a leaving group.

Examples of leaving groups that may be used are halogens.

The compound of formula (MI) reacts with an appropriately protected 5,6-dihydroxy-2-azabicyclo|2,2,1|heptane-

Z-one, more acceptable (Zaz-(2ax,4p,7p,7ar|-tetrahydro-2,2-dimethyl-4,7-methane-1,3-dioxolo|4,5-c|pyridine-6b (ZanH)-one, in the presence of a base, such as butyllithium, in an inert solvent, such as tetrahydrofuran, at temperatures of 10-1007C to give a compound of the formula (MII)

Obama will also have an IF; rya " M. E

And (U) v.o ov, in which M represents 58; IN! defined in formula (I); M is a leaving group; and Ri is a protective group.

More preferably R1/R1 together form a ring such as isopropylidene and more preferably the leaving group is chlorine.

More preferably, the base is sodium hydride, the solvent is DMF, and the reaction is carried out at room temperature. (i) The nitro group and the lactam in the product of formula (MI) of stage () are reduced with further cyclization, obtaining a triazole.

Methods of reduction of the nitro group that can be mentioned include hydrogenation using transition metal catalysts, such as palladium on carbon in a hydrogen atmosphere at a pressure of 1-5 atm in a suitable solvent, for example, ethanol. It is more appropriate to use iron in an acidic solvent, such as acetic acid, at temperatures between 20 and 150°C, most preferably at a temperature of 10076.

Reduction methods that may be named include the use of complex metal hydrides such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran at temperatures between 0 and

100"C. It is more acceptable to use sodium borohydride in methanol at a temperature of 0-30".

The diamino alcohol obtained in this way is cyclized by a diazotization reaction, using metal nitrites or alkyl nitrites in a suitable solvent, for example, using sodium nitrite in diluted aqueous HCl at a temperature from -20 to 1007C. It is more acceptable to use isoamyl nitrite in acetonitrile at 8076.

The group ХАМЕВ'В: is introduced by reaction with the compound of the formula НМВ'В: in an inert solvent at a temperature from 0 to 150"С, obtaining a compound of the formula (M), in which X represents ME 'В2; M represents 5; В! and 2 is defined in formula (I), B is SnHe, and Ri is a protecting group.

It is more acceptable to use 1,4-dioxane as a solvent, and the reaction is carried out at a temperature of 100"C. It is more acceptable that R/R" together form a ring, and the most acceptable R/R" is isopropylidene. c) () The product of stages A) and B), i.e., the compound of the formula (M), obtained in stages A) and B), respectively, are oxidized and subjected to an olefination reaction, obtaining the compound of the formula (MI!) kovy; and

Kh liv av , V a3

B - and washed in Ov, in which B is O or Sn", X, U and Ri are defined in formula (M) at stages A) and B), respectively; A is a SOOV" in which B"! is lower (ar)alkyl; and RZ and B" together form a connection.

Oxidation methods that may be mentioned include the Swern (meth) reaction and the use of a reagent

Dess Martin (Oez55 Mapip) in appropriate solvents at a temperature between -78 and 120"C. It is more acceptable to use the Pfitzner-Moffatt oxidation (Riigpeg-Moyayu in DMSO as a solvent at ambient temperature, and the protective groups R/R; together they form a ring, the most the case where R/R" is isopropylidene is acceptable. Examples of olefination methods that may be mentioned include the Peterson reaction (Regegzop) and the Horner-Emmons reaction (Nogpeg-Ettopv5). The Wytig reaction with a phosphorus ylide, such as ( carboxymethylene) triphenylphosphorane, particularly acceptable is (tert-butoxycarbonylmethylene)triphenylphosphorane. (i) 2" is removed by de-esterification using acidic or alkaline hydrogenolysis conditions and finally deprotection to give a compound of formula (I) in which X is MB'B2 ; M represents 58"; B represents O or SnHe, B' and P? are defined in formula (I); C and P" together form a bond; and A is COOH.

EB" groups that may be mentioned include methyl, ethyl, isopropyl, tert-butyl and benzyl. B!!! groups can be removed by hydrolysis under acidic or basic conditions. Basic hydrolysis can be carried out using metal hydroxides or quaternary ammonium hydroxides , such as sodium hydroxide in a solvent such as aqueous ethanol, at a temperature between 10 and 100"7C. More preferably, lithium hydroxide in aqueous tetrahydrofuran at ambient temperature. Acid hydrolysis can be carried out using an inorganic acid such as HCl or a strong organic acid such as trifluoroacetic acid in a suitable solvent such as aqueous 1,4-dioxane. Benzyl groups can be removed by hydrogenolysis using transition metal catalysts, for example, palladium on carbon, in a hydrogen atmosphere at a pressure of 1-5 atm in a suitable solvent, such as acetic acid. More acceptable B!!! is tert-butyl and hydrolysis is carried out using trifluoroacetic acid in dichloromethane.

Protecting groups in the case of acyl and benzyl can be eliminated as described for B! above, silyl protecting groups can be eliminated using, for example, fluoride ion. Lower alkyl groups can be eliminated using, for example, boron tribromide. Methylidene and ethoxymethylidene can be eliminated using, for example, an inorganic or organic acid. All these methods can be carried out at a temperature between -80 and 1502C. More preferably, BV"! represents tert-butyl and Ri/Ri represents isopropylidene, and both groups are removed at the same time using trifluoroacetic acid in dichloromethane at ambient temperature. p)

A compound of formula (I), in which X is 5B!, MA'B2 or Ci-C7-alkyl; M represents 5B!, MVV, Si-

C-alkyl; IS! and 22 are defined in formula (I); B is O or CH", BZ and EE" represent hydrogen or together form a bond; 5 A is COOH; react with a compound of the structure

MnHg(СНаРСООВв", MNI((СНгаСООВ g or MNESN(СООВ")СНg) СО, where p, 4 and g are equal to 1, 2 or З and

IN! is lower (ar)alkyl; using methods used in peptide synthesis, for example, using a coupling agent. Coupling agents that may be used include 1,1-carbonylimidazole and M-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

At this stage, a compound of the formula (I) is obtained, in which X is 5E", MBA'B? or C1-C7-alkyl; Y is 5, MB'B2 or Ci-C7-alkyl; B is O or CH "e; VZ and P" represent hydrogen or together form a bond; ota A is C(OMN(CHgSOOV", 0 C(OM(CHgSOOV r 0 or

C(OMNHN(SOOVA)(CHg) CO", in which p, d and g are equal to 71, 2 or C and KE"! is lower (ar)alkyl;

"BE" groups that may be used include methyl, ethyl, isopropyl, tert-butyl and benzyl.

The coupling reaction is carried out in a suitable solvent at a temperature between -15 and 120°C. It is more acceptable to use dicyclohexylcarbodiimide or bromotrispirolidinophosphonium hexafluorophosphate in M,M-dimethylformamide (DMF) at a temperature between 0°C and room temperature.

(i) The product of formula (I) of stage (i) is de-esterified to obtain a compound of formula (I) in which

B is O or CH"; X represents ME'B2, 5B! or C1-C7-alkyl; M represents ME'B2, 5B! or

Ci-C-alkyl; IN! and 22 each independently represents H or C-C7-alkyl, optionally substituted on or in the alkyl chain by one or more O, 5, M or halogen; RES and P" both represent hydrogen or

VAZ and B' form a bond; and A is C(OMN(SNaPSOOnH, C(OM(CHgSOOHnI; or

C(OMNHN(COOH)CHg) SON, where p, 4 and r are equal to 1, 2 or 3.

"BE" groups that may be used include methyl, ethyl, isopropyl, tert-butyl and benzyl.

The B" groups can be removed by hydrolysis under acidic or basic conditions. Basic hydrolysis can be carried out using metal hydroxides or quaternary ammonium hydroxides such as sodium hydroxide in a solvent such as aqueous ethanol at a temperature between 10 and 100°C. Lithium hydroxide is more suitable. in aqueous tetrahydrofuran at ambient temperature. Acid hydrolysis can be carried out using an inorganic acid such as HCl or a strong organic acid such as trifluoroacetic acid in a suitable solvent such as aqueous 1,4-diocene. Benzyl groups can be removed by hydrogenolysis using transition metal catalysts, such as palladium on carbon, under a hydrogen atmosphere at 1-5 atm pressure in a suitable solvent such as acetic acid. More preferably B!!! is tert-butyl and hydrolysis using trifluoroacetic acid in dichloromethane .

IS)

The product obtained in stage C (iii) is reduced, obtaining a compound of formula (I), where B, X, M, B! and B? determined at stage C (her) above; A is the COOH; and R and E" both represent hydrogen.

Reduction methods that can be used include hydrogenolysis using transition metal catalysts, for example, palladium on carbon, in a hydrogen atmosphere in a suitable solvent, such as acetic acid, at a pressure of 1-5 atm. It is more appropriate to use a diimide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonylhydrazide, at a temperature between 60 and 1007C in a tetrahydrofuran (THF) solvent.

E) () Appropriately protected 5-amino-1-(8-Y-ribo-furanosyl)-1,2,3-triazole-4-carboxamide, more preferably 5-amino-1-(2,3-0-( 1-methylethylidene)-8-Y-ribo-furanosyl|-1,2,3-triazole-4-carboxamide, treated with a base, followed by treatment with an ester of the formula ВЕSORB?, where ВЕ! is defined in formula (I) and E? is a lower alkyl Then protection is carried out and the compound of formula (IX) is obtained

I) "Oh

МY and mesh, EK, where U represents Cx-Su-alkyl; Ri is a protecting group and more preferably Ri/Ri together form a ring; Rho is a protective group; and M is OH.

Protecting groups P'' that may be used include lower alkyl or acyl. More preferably, Po is acetyl, introduced by treatment with acetyl chloride and triethylamine in a suitable solvent, for example, dichloromethane, at ambient temperature. The most acceptable P/P: is isopropylidene and Po is acetyl. (i) The compound of formula (IX), where M is OH, is halogenated and the group X-MV'B is introduced? administered by treatment with a compound of the formula ME'B? in an inert solvent at a temperature from 0 to 15020. Then the protective group Po is removed and a compound of the formula M is obtained, in which X is ME'B?, B'y is defined in formula (I); X is C1-C7-alkyl; B is 0; and Ri is a protecting group and more preferably R/R: together they form a ring. The most acceptable R/R: represents isopropylidene.

Halogenating reagents that can be used include P(II) or P(M) or 5(II) or 5(IM) halides, such as phosphorus trichloride, at a temperature of 0 to 150°C. The reaction can be carried out in a halogenating reagent used as a solvent or in an inert solvent such as methylene chloride. More acceptable is thionyl chloride in DMF/chloroform under reflux.

A more acceptable solvent used for the introduction of the X-MV'VZ2 group is 1,4-dioxane at a temperature of 100"C. The protective group Pg can be removed under the same conditions. Alternatively, it can be removed using acid or basic hydrolysis.

It is more acceptable to use ammonia in methanol at room temperature. (ii) The product of formula (M) of stage (ii) is subjected to the same reactions as described in stage Si) and (i), obtaining a compound of formula (I) in which X is MVV; IN! and 2 are defined in formula (I); B is 0; U is C-C7-alkyl; A is the COOH; and BZ and P" together form a bond. c) () A suitable protecting group Pz is introduced into the protected 5-amino-1-(2d-O-ribo-furanosyl)-1,2,3-triazole-4-carboxamide, more acceptable is 5-amino-1-(2,3-0-(1-methylethylidene)-8-Y-ribo-furanosyl-1,2,3-triazole-4-carboxamide. The resulting intermediate product is treated with a base, more acceptable with sodium hydride , with further treatment with a reagent of the formula i, where I represents a leaving group, more preferably imidazolyl, obtaining a compound of the formula (X)

M

M man more, so

Po OR, in which Ri is a protecting group, more acceptable when Ri/Ri together form a ring; and Pz is a protecting group, more preferably a silyl group. The most acceptable case is when R1/R1 is isopropylidene and R3 is tert-butyldimethylsilyl. (i) The product of formula (X) of step () was treated with a base such as butyllithium in an inert solvent such as THF at a temperature between -20 and 502C, followed by treatment with an alkylating reagent B'C, where b is a group that departs, such as halogen, and where B! defined in formula (1).

It is more acceptable to use sodium hydride in DMF at room temperature as a base, and C is iodine.

P3 is then removed from the compound above and replaced by a new protecting group P". More preferably, P" represents an acyl.

More acceptable, Pz is a silyl group, which is removed by treatment with a fluoride ion and replaced by an acyl group. Most preferably, Pz is tert-butyldimethylsilyl, which is removed by reaction with tetra-n-butylammonium fluoride in THF, followed by the introduction of the protecting group Po by reaction with acetyl chloride in dichloromethane at ambient temperature.

At the end, halogenation is carried out and compounds of the formula (IX) are obtained, in which M is a leaving group, for example, halogen and, more preferably, chlorine; Ri represents a protective group, more appropriately

Ru/Ri together form a ring; and Po is a protecting group, more preferably acetyl; and M is a

ZV.

Halogenating reagents that can be used include P(II) or P(M) or 5(I) or 5(IM) halides, such as phosphorus trichloride, at temperatures from 0 to 150°C. The reaction can be carried out in a halogenating reagent, used as a solvent or in an inert solvent such as methylene chloride. More conveniently, thionyl chloride in DMF/chloroform under reflux is used. (ii) The product of step (ii) was reacted with a nucleophilic alkyl such as Grignard reagent in in an inert solvent such as THF at a temperature between -20 and 15070. A more suitable nucleophilic alkyl is an alkyltin compound used in the presence of a Ra(II) catalyst. Then the protecting group

Pg was removed and a compound of formula (M) was obtained, in which X is C1-C7-alkyl; M represents 5; IN! defined in formula (I); B is 0; and Ri is a protecting group, more preferably P/P: together they form a ring, which is most preferably isopropylidene.

The protective group P" can be removed by acid or basic hydrolysis. More preferably, Po is acetyl, which is removed by reaction with ammonia in methanol at room temperature.

H) () Compound of formula (I), in which

X represents ME!'B2, Y represents 5; IN! and B2 are defined in formula (I); B is 0; B3 and B" both represent hydrogen; and A is C(IO)MNON(COOB )(CHg)Sov" in which r is 1, 2, or C and B"! are defined above; treated with an oxidizing agent such as magnesium monoperoxyphthalate, in an inert solvent such as THF at a temperature between -20 and 1009C, followed by treatment with a compound of the formula HME'B: in an inert solvent at a temperature of 0 to 1502C to give a compound of the formula (I) wherein X is MEM; represents MEM; B represents 0; C and B" both represent hydrogen; and A is a

C(OMNHN(COOV)(CHg)COOV", in which r is 1, 2 or C and E!! is determined at stage 0) above.

It is more acceptable to use M-chloroperoxybenzoic acid in the solvent ethanol at room temperature as an oxidizing agent, and the substitution is carried out in 1,4-dioxane at 1007C.

AND)

A compound of formula (I), in which X is 5E!; M represents 5E!, B represents 0, B7 and P8 both represent hydrogen; A is the COOH; can be obtained by the reaction of the compound of the formula (II), in which B' is defined in the formula (I), with the compound of the formula (XI) 0 o - she ov g in which K!? is lower (ar)alkyl and Pa is a protecting group such as acetyl.

The reaction can be carried out by heating the compounds together in the presence of an acid, such as trichloroacetic acid, under reduced pressure and at a temperature between 50 and 1752C. Is it more acceptable? is ethyl, R. is acetyl, and the reaction is carried out at 140"C in the presence of p-toluenesulfonic acid in the vacuum of a water jet pump.

The protecting groups and group B" can then be removed by hydrolysis under acidic or basic conditions to give a compound of formula (I) wherein X is 58; M is 58; B' is as defined in formula (1);

B is 0; Ez and P" both represent hydrogen; A represents COOH;

Examples of reagents and conditions that can be used for hydrolysis are metal alkoxides in alcohol at a temperature between 0 and 100°C, or, alternatively, trifluoroacetic acid in dichloromethane can be used. HB/?-ethyl and R.-acetyl are more acceptable and lithium hydroxide in aqueous tetrahydrofuran at ambient temperature.

The compound of formula (XI), which is one of the starting materials in this reaction stage, is first obtained from ethyl ether (E)-methyl-5,6-dideoxy-2,3-0-(1-methylethylidene)-8-ХО- ribo-hept-5-enofuranosiduronic acid by hydrolysis with an aqueous acid such as aqueous acetic acid and reaction with an acetylating reagent such as acetyl chloride in the presence of a base such as pyridine and a suitable solvent such as methylene chloride followed by reduction, e.g. by hydrogenation using transition metal catalysts, such as palladium on carbon, in a hydrogen atmosphere in a suitable solvent, for example, ethanol, at a pressure between 1 and Ztm.

IN)

Compounds of formula (I), in which

X represents ME'B2, Y represents 5E"; B! and B? are defined in formula (I); B represents O or CH";

VZ and 27 both represent hydrogen; and A is 5-tetrazolyl; received in this way.

A product of stage A (iii) or a product of stage B (iii), for example, a compound of formula (M) in which B is OO or Sn" and X and M are defined in formula (M) above and Ri is a protecting group, more acceptable Ri/Ri together form a ring, oxidized with subsequent olefination reaction and with subsequent reduction.

Oxidation methods that can be used include the Swern reaction (BZuegp) and the use of Dess Martin's reagent (Oez5 Magip) in appropriate solvents at temperatures between -78 and 120°C. More acceptable is the Pfitzner-Moffatt oxidation (Riipeg-Moitash! in DMSO as solvent at ambient temperature using a compound of formula (M) in which P/R" is isopropylidene. Olefination methods that can be used include the Peterson reaction (Regeg5op) and the Horner-Emmons reaction (Nogpeg-Ettop5). The Wittig reaction is more acceptable with phosphorus ylide-(triphenylphosphoranylidene) acetonitrile Reduction methods that can be used include hydrogenation using transition metal catalysts such as platinum under a hydrogen atmosphere in a suitable solvent such as acetic acid at temperatures between 0 and 10070. More it is acceptable to use palladium on carbon at a pressure of 4 atm in ethanol at ambient temperature.

The product obtained in this way is a compound of formula (XIII) may? in

Mo m. then BA (XI)

В.О ов, in which В represents О or СН"; Ri is a protecting group, more preferably Ri/Ri together form a ring and most preferably R/Ri is isopropylidene; and RE! and R? defined in formula (1).

This compound of formula (CP) reacts with an azide such as sodium azide in an inert solvent, e.g.

DMF, at a temperature between 0 and 175"C. Isopropylidene is a more acceptable protecting group. Tributyltin azide in toluene at a temperature of 11070 is more acceptable.

The protecting groups are then removed by treatment with an inorganic or organic acid in an inert solvent at a temperature between 0 and 100°C. Trifluoroacetic acid in dichloromethane at room temperature is more acceptable.

In this way, the product of formula (I) is obtained, in which X is ME'B2; M represents 58"; B' and 2 are defined in formula (I), B represents O or CH»e: BZ and B" both represent hydrogen; and A is 5-tetrazolyl.

K)

The compound of formula (I), in which

X represents 5, MVV: or Ci-C7-alkyl; M represents 5, MA'B2 or C-C7-alkyl; B' and b2 are defined in formula (I); B is СНе or О; BZ and B" together form a connection; and A represents itself

SOOV", in which B"! defined in formula (I) above; reduced to give a compound of formula (MI) in which EZ and EE" represent hydrogen; X, M, B, A, B!! and Ri are defined above.

Reduction methods that can be used include hydrogenation using transition metal catalysts, for example, palladium on carbon in a hydrogen atmosphere in a suitable solvent, such as acetic acid, at a pressure of 1-5 atm. It is more appropriate to use a diamide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonylhydrazide, at a temperature between 60 and 100°C in a tetrahydrofuran solvent. (i) The product of step (i) is introduced into the same reaction as described for stage Y (i), obtaining a compound of formula (I), in which

X represents 5E!, MB!B2 or C-C7-alkyl; M represents 5", MAV? or Ci-C7-alkyl; B! and B? are defined in formula (I), B represents CH?" or O; and A is COOH.

Compounds of formula (I), as well as their salts and prodrugs, such as esters or amides, can be isolated from reaction mixtures by conventional methods.

Salts of the compound of formula (I) can be obtained by the reaction of a free acid or its salt or a free base or its salt or derivative with one or more equivalents of the corresponding base or acid. The reaction can be carried out in a solvent or medium in which the salt is not soluble, or in a solvent in which the salt is soluble, for example, water, ethanol, tetrahydrofuran or diethyl ether, which can be removed in vacuo or by freeze drying. The reaction can also be an exchange process or it can be carried out on an ion exchange resin. Non-toxic, physiologically acceptable salts are preferred, although other salts may be useful, for example, for isolation or purification of the product.

Pharmaceutically acceptable esters of compounds of formula I can be obtained by conventional methods, for example, esterification and transesterification.

Pharmaceutically acceptable esters of compounds of formula 1 can be obtained by conventional methods, for example, by reaction of the ester of the corresponding acid with ammonia or the corresponding amine.

The invention is further described in more detail by way of examples, which should not be construed as limiting the scope of the invention. The temperature is given in the Examples in degrees Celsius, unless otherwise specified. Abbreviations: MS-mass spectrometry, E1-EU (electron impact), АРС1-FI (photo-ionization), E5I-Pi (surface ionization), RAV-BSHA (fast atom bombardment).

EXAMPLES

Example 1

Sodium salt (A-(To(E), 28, ZD, 4001-3-I4--7-«(butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5- a |pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid

A) 2-(Propylthio)-4,6(1H,5H)-pyrimidinedione

Propyliodide (13bml) was added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200g) in water (8O0Oml) containing sodium hydroxide (55.6g). The reaction mixture was stirred for 2 weeks, then concentrated to half the volume, 2M hydrochloric acid was added, and the product was isolated by filtration (167g).

MS (EU): 186 (Mk, 10095). p) 6-Hydroxy-5-nitro-2-(propylthio)-4,6 (1H)-pyrimidinone

The product of step a) (70g) was slowly added to ice-cooled fuming nitric acid (323ml).

The reaction mixture was stirred for 1 hour, then poured onto ice, and the product was isolated by filtration (65 g).

MS (EU): 231 (Mk, 41 (10095).

C) 4,6-Dichloro-6-nitro-2-(propylthio)pyrimidine

M,M-diethylaniline (150ml) was added dropwise to a stirred suspension of the product of stage B) (134g) in phosphoryl chloride (500ml) and the resulting solution was heated at reflux for 1 hour. The cooled reaction mixture was poured onto ice, then extracted with diethyl ether (3x500ml). The combined extracts were dried and concentrated. Chromatography (510", isohexane:diethyl ether 19:1 as eluent) afforded the title compound (128Hg).

MS (EU): 271, 269, 267 (M), 41 (100965). a) IZa5-(Zae, 4p, 7p, 7ao)|-5-|b-chloro-5-nitro-2-(propylthio)pyrimidin-4-yl| Tetrahydro-2, 2-dimethyl-4, 7- methano-1, 3-dioxolo (4,5-s| pyridine-b (Zan)-one

Sodium hydride (6095, 4.00 g) was added in portions to IZa5-(Zae, 4p, 7p, 7asu| tetrahydro-2, 2-dimethyl-4, 7-methane-1, 3-dioxolo (|4.5-s| of pyridine-b(Zan)-one (18.3g) in THF (500ml). While stirring for 1 hour, the solution was added dropwise to the product of step c) (54.0g) in THF (500ml). The reaction mixture was stirred at room temperature for 45 minutes, then concentrated and purified by chromatography (5iO, dichloromethane:isohexane 3:2 as eluent) to give the title compound (79.2g).

MS (FI): 417, 415 (KHAN), 415 (10095). f) IZa5-(Zae, 4r, 7r. 7ao)|-5-(5-Amino-b-chloro-2-(propylthio)pyrimidin-4-yl| tetrahydro-2, 2-dimethyl-4, 7-methane -1, Z-dioxolo-I|4,5-s|pyridin-6b (zan)-one

The recovered iron powder (50 g) was added to a solution of the product of stage a) (50.0 g) in glacial acetic acid (1.1 ml) and the reaction mixture was heated at reflux for 15 minutes.

The cooled reaction mixture was concentrated and the residue was extracted with ether (2L), then washed with sodium bicarbonate solution (2x1L). The organic phase was dried and concentrated to give the title compound (42.6g).

MS (FI): 387, 385 (MAN), 385 (10095).

In IZaB-(Zas, 4o., bo, baso|-6-(5-amino-6-chloro-2-(propylthio)pyrimidin-4-ylamino)|tetrahydro-2, 2-dimethyl-4H-cyclopenta-1 , Zdioxol-4-methanol.

Sodium borohydride (8.37g) was added to an ice-cooled solution of the product of stage 1) (42.6g) in methanol (1.3L). After stirring for 1 hour, the solution was poured into water (2 L) and extracted with diethyl ether (2 x 1 L). The combined extracts were dried and concentrated. Purification (5iO2, dichloromethane: ethyl acetate 1:1 as eluent) afforded the title compound (36.1g).

MS (FI): 419, 417 (MaNya), 417 (10095).33H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl| tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol

Isoamyl nitrite (24.9ml) was added to a solution of the product of stage E) (36.0g) in acetonitrile (80ml) and the solution was heated for 1 hour at 70°C. The cooled reaction mixture was concentrated and purified (5105, dichloromethane:ethyl acetate 4:1 as eluent) to give the title compound (33.6Hg).

MS (EU): 401, 399 (MaN.k), 43 (10095).

IzaB-(Zaye, 40, bo, basd|-6-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4 pyrimidine-Z-yl tetrahydro-2 , 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-methanol

The product of stage 9) (16.75g) and butylamine (30ml) in 1,4-dioxane (500ml) were heated at reflux for 1 hour. The reaction mixture was concentrated and the residue was purified (5105, dichloromethane:ethyl acetate 4:1 as eluent) to give the title compound (17.8 g).

MS (FI): 437 (MAN, 100965).

In IZaB-(Zae, 4a(E), bo, bao)|-3-(6-(7-"Butylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4 |pyrimidin-3Z-yl tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl|-g--propenoic acid, 1,1-dimethylethyl ether

A stirred solution of the product of stage n) (0.5 g), pyridine (0.093 ml) and trifluoroacetic acid (0.04 d8 ml) in DMSO (25 ml) was treated with 1,3-dicyclohexylcarbodiimide (0.72 g) and the mixture was stirred at room temperature for 24 hours . Tert-butoxycarbonylmethylenetriphenylphosphorane (0.69g) was added and the reaction was stirred for another 18 hours. The reaction mixture was cooled to 0°C, diluted with ethyl acetate (100ml) and oxalic acid (0.51g) was added. The mixture was filtered through a 300ml cover and the filtrate was washed with a saturated solution of sodium bicarbonate (100ml), dried and concentrated. Chromatography (5%, hexane: ethyl acetate) 5:1 as eluent) afforded the title compounds (0.55 g).

MS (USA): 533 (MaeNk, 10090).

I) PpA-Lo(e), 2p, ZB, 40d1-3-(4--7-(Butylamino)-5-(propylthio)-ZH-1,2,3-triazoloi|4,5-4|pyrimidine -Z-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid, sodium salt

A solution of the product of stage o) (0.9 g) in 5095 aqueous trifluoroacetic acid (100 ml) was stirred at room temperature for 5 hours. The reaction mixture was concentrated and the product was recrystallized from ethyl acetate (3 mL). The free acid was dissolved in a mixture of methanol: water (2:3, 30 ml) and passed through an ion-exchange resin Juoueh 50x100 (sodium form), eluting with water. Lyophilization gives the salt of the target compound as a colorless solid (0.43 g).

5H NMR (d6-DMSO): 6.59 (1H, dd), 5.89 (1H, d), 4.94 (1H, m), 4.45 (1H, t), 4.12 (1H, t), 3.45 (2Н, m), 2.83 (ЗН, m), 2.47 (IN, m), 2.00 (1Н, m), 1.5 (4Н, m), 1, 20 (2H, m), 0.82 (ZH, t), 0.71 (ZH, t).

Example 2 (1A-To(e), 2p, ZB, 4o9|-Ich-I3-I4-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5- 4|pyrimidin-Z-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|)-I -aspartic acid, bis (1; 1-dimethylethyl) ether a) PAK-To(e), 2p, Zr, 40 )1-3-I4-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-ylI|-2,3-dihydroxycyclo-pentyl |-2-propenoyl)|)-I -aspartic acid, bis (1,1-dimethylethyl) ether

I-aspartic acid di-tert-butyl ether hydrochloride (0.46g) and triethylamine (0.23ml) were added to a solution of the compound of Example 1 (0.6g) in DMF (25ml). 1-Hydroxybenzotriazole (0.22g) was added and the solution was cooled in an ice bath before adding 1,3-dicyclohexylcarbodiimide (0.34g). The reaction mixture was stirred for 30 minutes at 0°C, then at room temperature for 3 days. After removal of the solvent, chromatography (5 µgO2, chloroform:methanol 40:1 as eluent) afforded the title compound (0.63 g).

MS (USA): 664 (MaeN i), 57 (100905).

B) PA-To(E), 2p, Zr, 40)1-3-I4-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4| pyrimidine-3-yl-2,3-dihydroxycyclopentyl-2-propenoyl)-I-aspartic acid, disodium salt

A solution of the product of stage a) (0.60g) in dichloromethane (30ml) containing trifluoroacetic acid (30ml) was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified (HPLC, Moma-RakisC18 column, 0.195 aqueous ammonium acetate:methanol 50:50 to 0:100 over 15 min as eluent) to give the title salt as a colorless solid (0.19G).

5H NMR (y6-DMSO): 6.74 (1H, dd), 6.12 (IN, d), 5.07 (1H, m), 4.38 (1H, m), 4.05 (1H, t), 3.95 (2Н, m), 3.12 (2Н, t), 2.85 (IN, m), 2.49 (1Н, m), 2.30-2.45 (2Н, m ), 2.0 (IN, m), 1.75 (2Н, m), 1.52 (2Н, m), 1.47 (2Н, m), 1.0 (ЗН, т), 0.98 (ZN, t).

Example C

I15-o, 28, Zr, 40)1-4-(7--"Butylamso)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3-ylI| -2,3-dihydroxycyclopentanepropanoic acid, sodium salt a) (15-(1o, 28, ZD, 4001-3-I4--7-"Butylamino)-5-(propylthio)-3H-1,2,3-triazolo |4,5-4|Ipyrimidin-Z-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid, ethyl ether

A stirred solution of the product of Example 1 PP) (0.6g) of pyridine (0.112ml) and trifluoroacetic acid (0.05d8ml) in DMSO (25ml) was treated with 1,3-dicyclohexylcarbodiimide (0.87g) and the mixture was stirred at room temperature within 24 hours. Carboethoxymethylenetriphenylphosphorane (0.90 g) was added and the reaction was stirred for another 18 hours. The reaction mixture was cooled to 0°C, diluted with ethyl acetate (100 ml) and oxalic acid (0.51 g) was added. (50ml) and stirred overnight.The solvent was removed and the residue was purified by chromatography (5102, dichloromethane:ethyl acetate 1:1 as eluent) to afford the title compound (0.36g).

MS (USA): 465 (MaANk, 10090).

B) 0115-10, 28, ZD, 40) 1-4--7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-Z-yl |-2,3-dihydroxycyclopentanepropanoic acid, 2,4,6-tripisopropylbenzenesulfonohydrazide ethyl ether (0.50g) was added to a solution of the product of stage a) (0.35g) in dry THF (175ml) and the resulting solution was heated for 3 hours at 70 "C. The cooled reaction mixture was purified by chromatography (5%, dichloromethane: ethyl acetate 1:1 as eluent) to give the title compound (0.16 g).

MS (EU): 466 (M)), 43 (10095) s) (15-75, 28, ZB, 40d|-4-(7-"Butylamilio)-5-(propylthio)-3H-1,2 ,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentanepropanoic acid, sodium salt

Lithium hydroxide monohydrate (14mg) was added to a solution of the product of stage p) (0.16g) in THF (10ml)/water (10ml). The solution was stirred at room temperature for 18 hours, then the solvent was removed under vacuum. Purification (HPLC, Moma-RakisC18 column, 0.195 aqueous ammonium acetate:methanol from 50:50 to 0:100 over 15 min as eluent) gave the acid, which was dissolved in methanol (2ml) and 1N sodium hydroxide solution (0.28ml) was added. The solution was concentrated to give the title salt (0.13 g).

MS (PI): 439 (M-Ma--N.-, 10095).

NMR 5 H (020): 5.07 (1H, m), 4.65 (1H, T), 4.08 (1H, t), 3.49 (2H, t), 3.05 (2H, m ), 2.62 (1Н, m), 2.36 (2Н, m), 2.17 (IN, m), 2.00 (1Н, m), 1.70 (2Н, m), 1.65 (2Н, m), 1.61 (2Н, m), 1.40 (2Н, m), 1.00 (ЗН, t), 0.97 (ЗН, t).

Example 4

PA-To(E),. 28, ZB, 40d|-3-(4-(7-(Butylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-Z-yl|-2, 3-

dihydroxycyclopentyl|-2-propenoic acid, sodium salt a) 2-(Phenylthio)-4,6 (1H, 5H)-pyrimidinedione

To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (14.4g) in 2N sodium hydroxide solution: (100ml) was added pentyliodide (15.bml) in ethanol (25ml) and the resulting reaction mixture was stirred at room temperature for 4 days. Ethanol was removed under reduced pressure, M,M-dimethylformamide (dOml) and pentyliodide (1.6bml) were added, and the reaction mixture was stirred for another 16 hours. The solution was acidified by adding 2N HCl solution and the aqueous layer was decanted. The remaining resin was dissolved in methanol and evaporated to dryness, followed by azeotropic distillation with toluene (x2). The solid was triturated with ether, filtered, dried to afford the title compound as a white solid (11.9 g).

MS (EU): 214 (M, 144 (10090). p) 6-Hydroxy-5-nitro-2-(phenylthio)-4 (1H)-pyrimidinone

Obtained by the method of Example 1 B) using the product of stage a).

MS (EU): 259 (Mk, 43 (10095). c) 4,6-Dichloro-5-nitro-2-(phenylthio)pyrimidine

Obtained by the method of Example 1 c) using the product of stage B).

MS (US): 295, 297, 299 (MN): 41 (10095). a) IZa5-(Zas, 48, 78, 7ao)d|-5-(6-Chloro-5-nitro-2-(pentylthio)pyrimidin-4-yl|hetrahydro-2, 2-dimethyl-4, 7- methano-1, 3-dioxolo-|4, 5-c| pyridine-b (Zan)-one

Obtained by the method of Example 1 4) using the product of stage c).

MS (US): 445, 443 (MAN k), 443 (10095). f) IZaz-(Zayu, 4p, 7p, 7ao)|-5-(5-Amino-b-chloro-2-(pentylthio)pyrimidin-4-yl|Hytetrahydro-2, 2-dimethyl-4, 7-methane -1, Z-dioxolo-|4,5-s|pyridine-b (zan)-one

Obtained by the method of Example 1c) using the product of stage a).

MS (EU): 414, 412 (Mk), 412 (10095).

In IZaB-(Zayu, 4p, br, basod|-6-(5-Amino-b-chloro-2-(pentylthio)pyrimidin-4-ylamino|hetrahydro-2, 2-dimethyl-4H-cyclopenta-1, C -dioxol-4-methanol.

Obtained according to the method of Example 11) using the product of stage 1).

MS (EI): 418, 416 (M), 327 (10095). 9) IZaB-(Zase, 4r, br, bas |-6-(7-Chloro-5-(pentylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|tetrahydro -2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol

Obtained by the method of Example 19) using the product of stage 0.

MS (FI): 430, 428 (MAN .k), 338 (10096). n) IzaB-(Zaye, 40, bo, bao)|-6-(7-"Butylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-6|pyrimidine-3- il|Itetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-methanol

Obtained by the method of Example 1P) using the product of stage 9).

MS (USA): 465 (MaeNk, 10090). 8) IZanv-(Zaye, 40, bo, bao)|-3-(6-(7-"Butylamino)-5-(pentylthio)-3H-1,2,3-triazoloi(4,5-4|pyrimidine -Z-yl tetrahydro-2, 2-dimethyl-4H-cyclopenta-1, Z-dioxol-4-yl|-2-propenoic acid, 1,1-dimethyl ethyl ether

Obtained by the method of Example 15) using the product of stage n).

MS (USA): 561 (MAN q), 505 (100965).

I) PA-o(e), 2r, Zr, 40d|-3-I4-(7-(Butylamino)-5-(pentylthio)-3H-1,2,3-triazoloi|4,5-4| pyrimidine -Z-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid, sodium salt

Obtained by the method of Example 1)) using the product of stage i).

IS (BSHA): 487 (MaiMachN.), 465 (10095).

NMR 5 N (y6-DMSO): 9.00 (1N, t), 6.43 (1N, dd), 5.70 (1N, d), 4.97 (1N, q), 4.32 (1N , t), 3.87 (1H, t), 3.50-3.47 (2H, xX), 3.12-3.04 (2H, m), 2.68 (1H, m), 2, 38-2.34 (1Н, m), 1.93-1.89 (1Н, m), 1.64 (2Н, m), 1.62 (2Н, m), 1.37- 1.30 ( 6Н, m), 0.91 (ЗН, t), 0.87 (ЗН, t).

Example 5

The named compounds were obtained according to the method of Example 4:

PA-That(is). 28, ZD, /40)|-3-I4--7-"Ethylamino)-5-(pentylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-Z-yl|-2 ,3-dihydroxycyclopentyl)-2-propenoic acid, sodium salt a) IZaB-(Zae, 40, bo, bas)d|-6--7--"Eethylamino)-5-(pentylthio)-3H-1,2 ,3-triazolo|4,5-4|pyrimidin-3-yl|Itetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-methanol

MS (USA): 437 (MN, 10095).

B) IZaB-(Zae, 4o(E): bo, bao)|-3-I6|Y-7-«"Ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5 -4|pyrimidin-3-yl|Ittetrahydro-2, 2-dimethyl-4H-cyclopenta-!, 3-dioxol-4-yl|-2--propenoic acid, 1,1-dimethylethyl ether

MS (USA): 533 (MaN kyu), 477 (10090). c) PA-To(e), 28, ZD, 404-3-(4-(7-(Ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine -3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid, sodium salt

MS (US): 459 (M-Makhnya), 437 (10090).

NMR 5 N (y6-DMSO): 8.99 (1N, t), 6.55 (1N, dd), 5.76 (1N, d), 4.98 (1N, q), 4.32 (1N , t), 3.90 (1Н, t), 3.81-3.50 (2Н, m), 3.16-3.08 (2Н, m), 2.74-2.70 (1Н, m ), 2.46-2.37 (1Н, m), 1.98-1.89 (1Н, m), 1.71-1.67 (2Н, m), 1.62 (2Н, m), 1.37-1.24 (AN, m), 1.19 (ZN, t), 0.86 (ZN, t).

Example 6

I15-o, 2b, Zr, 40)|-4-(7-(Butylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|- 2,3-dihydroxycyclopentapropanoic acid, sodium salt

Obtained by the method of Example ZB) using the product of Example 4.

MS (FI): 467 (MaAN.yu), 295 (100905).

5H NMR (y6-DMSO): 8.95 (1H, t), 4.93-4.86 (1H, m), 4.32 (1H, t), 3.88 (1H, t), 3, 49-3.45 (2H, m), 3.07-3.05 (2H, m), 2.74-2.70 (1H, m), 2.28-2.08 (1H, m), 2.01-1.92 (ЗН, m), 1.74-1.55 (7Н, m), 1.37-1.33 (6Н, m), 0.90 (ЗН, t),

0.86 (ZN, t).

Example 7 (15-(1o., 2c, Zr, 40)1-4-(7--"Ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo(4,5-4|pyrimidine -Z-yl|-2,3-dihydroxycyclopentanepropanoic acid, sodium salt

Obtained by the method of Example ZB) using the product of Example 5.

MS (US): 461 (Ma-MahN.), 154 (100905).

5H NMR (y6-DMSO): 8.96 (1H, t), 4.91 (1H, kw), 4.33 (Tn, t), 3.75 (1H, t), 3.51 (2H, m), 3.08-3.06 (2Н, m), 2.30-2.24 (1Н, m), 2.06-1.93 (ЗН, m), 1.75-1.55 ( 5H, m), 1.37-1.09 (AN, m), 1.15 (ZH, t), 0.87 (ZH, t).

Example 8 (15-(1u, ho, ZB, 58)1-3-(7-(Butylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-Z -yl|-5-I2-(1H- tetrazol-5-yl)ethyl|-1,2-cyclopentanediol a) |(ZaB-(Zae, 49(E), bo, bas) |-3-(6- (7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|- 2,2-dimethyltetrahydro-4H-cyclopenta-1,3- dioxol-4-yl|-2-propenonitrile

Obtained by the method of Example 1) using the product of Example 1) and (triphenylphosphoranylene) acetonitrile.

MS (EU): 457 (Mk, 414 (10090).

BYU) IzaB-(Zas, 4c, bo, bao))-3-(6-(7-"Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine -3-ylI|-2,2-dimethyltetrahydro-4H-cyclopenta-1,3-dioxol-4-yl|-2-propanonitrile

The product of stage a) (0.75 g) in ethanol (ZOO ml) containing 1095 palladium on carbon (0.37 g) was stirred for 48 hours at 4 atm of hydrogen. The catalyst was removed by filtration and the filtrate was concentrated to give the title compound (0.34g).

MS (USA): 460 (MaANk, 10090). c) IZav-(Zaech, 40, bo, bas)|-M-butyl-5-(propylthio)-3-(6-(2-(1H-tetrazol-5-yl)-ethyl|tetrahydro-2, - 2- dimethyl-4H-cyclopenta-1,3-dioxol-4-yl|-3IN-1,2,3-triazolo 4,5-4Hygrimidin-7-amine

The product of stage B) (0.40g) and tributyltin azide (0.70g) in toluene were heated at reflux for 48 hours, then concentrated. Purification by chromatography (5102, dichloromethane:methanol 95:5 as eluent) gave the title compound (0.19Hg).

MS (USA): 503 (MaeNk, 10090). 9) PA-oe, 2, ZR, 508)1-3-(7-"Butylamino)-5-(propylthio)-3H-1,2,3-triazoloi|4,5-4|pyrimidin-3-yl1 |-5-I(2-(1H-tetrazol-5-yl)ethyl)-1,2-cyclopentanediol

Obtained by the method of Example 1) using the product of stage c).

MS (USA): 463 (MAN, 100965).

NMR 5H (d6-DMSO): 8.64 (1H, t), 5.11 (1H, m), 4.96 (1H, m), 4.85 (1H, m), 4.38 (1H, m), 3.38 (1Н, m), 3.50 (2Н, m), 3.07 (2Н, m), 2.97 (2Н, m), 2.41 (1Н, m), 2, 00 (2H, m), 1.80 (2H, m), 1.69 (2H, m), 1.61 (2H, m), 1.35 (2H, m), 0.97 (ЗН, m ), 0.91 (ZH, t).

Example 9

PA- To, 28, ZR, 4c91-M-I3-I(4-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-Z3 -ylI|-2,3-dihydroxycyclopentyl|-2-propanoyl|)-I-aspartic acid

A) (1K-( To, 28, ZD, 4001-3-I4-(7-("Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5|pyrimidine-Z- yl|-2,3-dihydroxycyclopentyl!-2-propanoyl|-I-aspartic acid, bis (1,1-dimethylethyl) ether

M,M-dixopropylethylamine ethyl amine (0.35 ml) was added to a solution of I-aspartic acid di-tert-butyl ether hydrochloride (0.28 g), bromotris (pyrrolidino) phosphonium hexafluorophosphate (0.44 g) and the product of Example C (0. 44 g) in DMF (20 ml). The reaction mixture was stirred for 1 hour at room temperature, then concentrated. Chromatography (5i0, ethyl acetate as eluent) afforded the title compound (0.49G).

MS (FI): 666 (MAN, 100965).

B) HPA-To, 28, ZB, /4с001-3-I4-(7-"Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5|pyrimidin-3-yl |-2,3-dihydroxycyclopentyl|-2-propanoyl|)-I -aspartic acid

Obtained by the method of example 20) using the product of stage a).

NMR 5 N (doe-DMSO): 9.03 (1N. 1Nb), 7.79 (1N, d), 4.92 (1N, m), 4.35 (1N, m), 4.19 (1N , t), 3.75 (2Н, m), 3.49 (2Н, t), 3.08 (2Н, m), 2.43 (1Н, m), 2.32 (1Н, m), 2 ,18 (ЗН, m), 1.91 (1Н, m), 1.73 (ЗН, m), 1.58 (2Н, m), 1.34 (2Н, m), 1.0 (ЗН, t), 0.98 (ZH, t).

Example 10 (1 A-To(E), 2p, Zp, 4od|-M-(3-(4-(-7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo| 4,5-4|pyrimidin-Z-yl|2,3-dihydroxycyclopentyl|-2-propenoyl|)-I -aspartic acid 7 IzaB-(Zae, 40, bo, 0 bo)|-6-(7-« (Hexylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-a|pyrimidin-3-yl|Itetrahydro-2, 2-dimethyl-4H-cyclopenta-1, Z-dioxol- 4-methanol

Sodium borohydride (1.16 g) was added to an ice-cooled solution of the product of stage Te) (5.90 g) in methanol (200 ml). After stirring for 1 hour, the solution was concentrated and the residue was purified by chromatography (5102, diethyl ether as eluent). The obtained intermediate was dissolved in acetonitrile (300 ml) and isoamyl nitrite (2.9 ml) was added. The reaction mixture was stirred for 30 minutes at 60°C, concentrated, and the residue was dissolved in 1,4-dioxane (300 mL). Hexylamine (20 mL) was added and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and the residue was purified (5102 , diethyl ether as eluent) and gave the title compound (4.69 g).

MS (FI): 465 (MAN, 100965).

B) H1A-( To (E), 2p, Zr, 40)1-3-I4-17-(Hexylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4| pyrimidine-3-yl|-2,3-dihydroxy-cyclopentyl|-2-propenoic acid

Obtained by the method of example 15) and the following method using the product of stage a).

NMR OH (020): 9.03 (1H, t), 6.96 (1H, dd), 5.89 (1H, d), 5.31 (1H, s), 5.10 (1H, s) , 5.00 (1Н, m), 4.29 (1Н, t), 4.02 (1Н, t), 3.49 (2Н, m), 3.01 (2Н, m), 2.83 ( 2Н, m), 2.49 (1Н, m), 2.01 (1Н, m), 1.72 (2Н, m), 1.65 (2Н, m), 1.29 (6Н, m), 0.98 (ZH, t), 0.86 (ZH, t).

c) 1 A-To(eE), 2p, ZB, 4031-M-(3-(4-(7-(Hexylamino)-5-(propylthio)-ZH-1,2,3-triazoloi|4,5 -4|pyrimidin-Z-yl|- 2,Z-dihydroxy-cyclopentyl)i 2-propenoyl)-I -aspartic acid, bis (1,1-dimethylethyl) ether

Obtained by the method of example 2) using the product of stage b).

MS (FI): 692 (MAN, 100965). a) (18-(To(E), 2p, 3P, 40)|-h-(3-(4-(7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo| 4,5-4|pyrimidin-Z-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|)-I -aspartic acid

Obtained by the method of example 20) using the product of stage c).

NMR OH (d6-DMSO): 7.94 (1H, d), 7.23-7.11 (1H, s), 6.75 (IN, dd), 6.17 (1H, d), 5, 19 (1H, s), 5.08 (1H, s), 5.00 (1H, m), 4.91 (2H, m), 3.96 (1H, m), 3.62 (2H, m ), 3.07 (2Н, m), 2.81 (1Н, m), 2.49-2.31 (ЗН, m), 2.01 (1Н, m), 1.67 (2Н, m) , 1.61 (2Н, m), 1.91 (6Н, m), 0.96 (ЗН, t), 0.85 (ЗН, t).

Example 11

The following compounds were obtained according to the method of example 1. a) PA-Lo(e) 28, ZB, 40))-3-I4-(7-(3,3-Dimethylbutylamino)-5-(propylthio)-3H-1,2 ,3-triazolo|4,5-a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid y) (Zak-(Zas., 4s., bo, vas) |-6-I7 -(3,3-dimethylbutylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-

3-yl|Hytetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

MS (FI): 465 (MAN, 100965). i) (Zak-(Zae, 49(H), bo, bvao)|-3-I6-I(I7-(3,3-Dimethylbutylamino)-5-(propylthio)-ZIN-1,2,3-triazoloi4 ...

MS (FI): 561 (MAN, 100965). i) (P1f-Lo(e) 28, ZB, 40)|-3-I4--7-(3,3-dimethylbutylamino)-5-(propylthio)-3H-1,2,3-triazolo4,5- a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid

5H NMR (d6-DMSO): 8.59 (1H, t), 6.84 (1H, dd), 5.84 (1H, d), 5.03-4.96 (1H, m), 3, 98 (1H, m), 3.52 (2H, m), 3.07 (2H, i), 2.81 (1H, m), 2.43 (1H, m), 1.97 (1H, m ), 1.75 (2Н, m), 1.55 (2Н, m), 0.99 (ЗН, t), 0.95 (9Н, s).

B) PA-(To(E), 28, ZD, 40)1-3-I4-(7-(2-methoxyethylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5 -4|pyrimidine-

3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid i) I(Zac-(Zca, 4, bo, bao)1|-6-(7-(2-methoxyethylamino)-5-(propylthio) -ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|Itetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-methanol

MS (USA): 439 (MAN, 100965). iii) (Zac-(Zaech, 4o(E), bo, bao)|-3-I6-(7-(2-methoxyethylamino)-5-(propylthio)-3H-1,2,3-triazoloi|4, 5- 4|pyrimidin-3-yl|Hytetrahydro-2, 2-dimethyl-4H-cyclopenta-!, 3-dioxol-4-yl|-2-propenoic acid, 1,1- dimethylethyl ether

MS (US): 535 (IN, 10095). iii) (1f-Co(E) 28, ZB, 40))|-3-I(4--7-(3,3-dimethylbutylamino)-5-(propylthio)-3H-1,2,3-triazolo |4,5- a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid

MS (USA): 439 (MAN, 100965).

Example 12

PA-To, 2p, ZD, 40)|-M-I3-(4-(7-«"Hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-a|Ipyrimidine -3-ylI|-2,3-dihydroxycyclopentyl|-propanoyl|)-I-aspartic acid

A) 18-10, 28, ЗР, 400|-4-(7-(Hexylamino)-5-(propylthio)-3H-1,2,3-triazoloi4,5-4|pyrimidin-3-yl|-2 ,3-dihydroxycyclopentanepropanoic acid

Obtained by the method of example Zb) using the product of stage 106b).

MS (FI): 467 (MAN, 100965). c) HA To, 2p, ZD, 40d1-M-I3-(4-(7-(Hexylamino)-5-(propylthio)-Z3H-1,2,3-triazoloi|4,5-4|pyrimidine-Z3 -yl|-2,3-dihydroxycyclopentyl|-propanoyl)-I-aspartic acid, bis (1,1-dimethylethyl) ether

Obtained by the method of example 9 a) using the product of stage a).

MS (FI): 694 (MAN, 100965).

C) Pp Ak-(To, 28, Zr, 40)1-6-I3-I4-(7-(Hexylamino)-5-(propylthio)-Z3H-1,2,3-triazolo|4,5-4 |pyrimidine-3-yl1-2,3-dihydroxycyclopentyl|-propanoyl|)-I-aspartic acid

Obtained by the method of example 20) using the product of stage B).

5H NMR (a6-DMSO): 8.90 (1H, 1He), 7.61 (1H, d), 4.97 (1H, m), 4.36 (1H, t), 4.21 (1H , m), 3.77 (1H, m), 3.47 (2H, m), 3.07 (2H, t), 2.51 (2H, i), 2.28 (1H, m), 2 ,20 (2Н, m), 1.93 (1Н, m), 1.77 (1Н, m), 1.62 (ЗН, m), 1.59 (ЗН, m), 1.33 (6Н, m), 1.00 (ZN, t), 0.88 (ZN, t).

Example 13 (1 A-To(E), 2c, Zr, 40) 1-M-(3-(4-(5-(3,3,3-trifluoropropylthio)-7-(2-(methylthio)ethylamino| -ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|-I -aspartic acid, monoammonium salt a) 2-I(3 ,3,3-trifluoropropyl)/thio|-4,6 (1H, 5H)-pyrimidinedione

Obtained by the method of example 14).

MS (FI, negative ionization): 239 (M-N.yu), 143 (10090). p) 2-((3,3,3-trifluoropropyl)/thio|-6-hydroxy-5-nitro-4(1H)-pyrimidinone.

Obtained by the method of example 16b) using the product of stage a).

MS (FI, negative ionization): 284 (M-Nyu, 10090). c) 4,6-Dichloro-2-I|(3,3,3-trifluoropropyl)thio|-5-nitropyrimidine

Obtained by the method of example 1c) using the product of stage b).

H NMR (SOCI3): 3.30 (2Н, m), 2.60 (2Н, m). a) IZa5-(Zae, 48, 70, 7ao)|-5-(b-Chloro-5-nitro-2-(3,3,3-trifluoropropyl)/thio|-pyrimidin-4-yl tetrahydro-2, 2- dimethyl-4, 7-methano-1,3-dioxolo I4,5-c|Ipyrimidin-6b (Zan)-one

Obtained by the method of example 1c) using the product of stage b).

5 N NMR (SOSI»v): 4.77 (1Н, s), 4.73 (1Н, d), 4.56 (1Н, d), 3.33 (2Н, m), 3.05 (1Н , c), 2.58 (2Н, m), 2.33 (1Н,

d), 2.20 (1Н, т), 1.53 (ЗН, с), 1.36 (ЗН, с). f) IZa5 (Zas, 40, 7, 7ao)d|-5-(5-amino-b-chloro-2-(3,3,3-trifluoropropyl)thio|-pyrimidin-4-yltetrahydro-2, 2 - dimethyl-4, 7-methano-1,3-dioxolo I4,5-c|Ipyrimidin-6b (Zan)-one

Obtained by the method of example 1e) using the product of stage 4).

MS (FI): 439 (MAN, 100965). 7 Van-(Zaekh, 40, bo, /basd|-6-(5-amino-6b-chloro-2-I((3,3,3-trifluoropropyl)-thio|-4-pyrimidinylamino tetrahydro-2, 2 -dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

It was obtained according to the method of example 17) using the product of stage e).

MS (FI): 443 (MAN, 100965). 9) IZan-(Zaye, 40, bo, bah|-6-(5-(3,3,3-trifluoropropyl)thio|-7-(2-(methylthio)ethylamino|-Z3H-1,2,3- triazolo

I4,5-4|Ipyrimidin-3-yl|-tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol

Obtained by the method of example 1) using the product of stage I).

MS (FI): 509 (MN, 100965).

P") IZaB-(Zae, 4o(E), bo, bao)|-3-(6-15-((3,3,3-trifluoropropyl)thio|-7-(2-(methylthio)ethylamino|- ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-tetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-yl|---propenoic acid , 1,1-dimethylethyl ether

Obtained according to the method of example 1 and) using the product of stage 9).

MS (FI): 605 (MaAN.yu), 549 (10095). n) OO PA-To(e) 28, 0038, 0 4c91|-3-I4-I5-((3,3,3-Trifluoropropyl)thio|-7-(2-methylthio)ethylamino|-ZH-1, 2,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid

Obtained according to the method of example 1)) using the product of stage PP).

MS (FI): 509 (MAN, 100965).

I) PA-Lo) 28, 098, 409|-M-I3-I4-I5-((3,3,3-trifluoropropyl)thio)-7-((2-(methylthio)ethylamino|-ZH-1, 2,3-triazolo|4,5-4|pyrimidin-3Z-yl|2,3-dihydroxycyclopentyl|-2-propenoyl)|-I -aspartic acid, bis (1,1-dimethylethyl) ether

Obtained according to the method of example 3) using the product of stage i).

MS (FI): 736 (Ma-N.yu), 624 (10095).

KU GIA-To(ye), 28, ZD, 4001-M-(3-(4-(5-(3,3,3-trifluoropropyl)-thio|-7-(2-methylthio)ethylamino|-ZH- 1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|-I-aspartic acid, monoammonium salt

Obtained by the method of example 20) using the product of stage |).

NMR 5 H (a6-DMSO): 7.90 (1H, d), 6.76-6.68 (1H, dd), 6.15 (1H, d), 4.99 (1H, m), 4 , 30 (2Н, m), 3.71 (2Н, t), 3.30 (2Н, m), 2.74 (5Н, m), 2.50 (1Н, m), 2.42 (2Н, m), 2.11 (ZH, s), 1.98 (1H, m).

Example 14 (E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|-trymidin-3-yl|-1,5,6 -trideoxy-p-O-ribohept-5-enofuranuronic acid a) 2,6-bis(propylthio)-4,5-pyrimidinediamine

Propyliodide (2.52ml) was added to a stirred solution of 4,5-diamino-2,6-dimercaptopyrimidine (2.0g) in 1N potassium hydroxide solution (26.4ml). After stirring for 24 hours, the solid was collected by filtration to afford the title compound as a pink solid (2.2g).

MS (EU): 258 (Mk, 10095).

B) 5,7-bis(propylthio)-1H-1,2,3-triazolo|4,5-4| pyrimidine

A solution of sodium nitrite (0.6g) in water (/ml) was added to the suspension of the product of stage a) (2.0g), which was stirred, in a mixture of acetic acid: water (1: 1.90ml) at 50°C. The reaction mixture stirred for 1 hour at 50°C, the solid was collected by filtration to give the title compound.

MS (EU): 269 (Mk, 43 (10095). c) 5,7-bis(propylthio)-3-(2,3,5-tri-O-benzoyl-D-B-ribofuranosyl)-ZH-1 ,2,3-triazolo|4,5-a|pyrimidine

Gaseous hydrogen bromide was bubbled into an ice-cooled solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-ZD-Y-ribofuranose (2.02 g) in dichloromethane (15 ml) for 15 min. The reaction was stirred for 1 hour at 0"C, then for 15 minutes at room temperature. The solution was concentrated, and the residue was subjected to azeotropic distillation with dichloromethane (3x5Oml). Sodium hydride (6095, 0.19g) was added to the suspension of the product of stage B) (1, 08g), which was stirred, in acetonitrile (29ml). After stirring for 15 minutes at room temperature, the bromosugar described above in acetonitrile (10ml) was added and stirring was continued for 24 hours. The reaction mixture was partitioned between ethyl acetate and water, and the organic layer was dried Chromatography (5iO, dichloromethane:diethyl ether 39:1 as eluent) afforded a mixture of 5,7-bis(propylthio)-3-(2,3,5-tri-O-benzoyl-D-XO-ribofuranosyl) -3H-1,2,3-triazolo4,5-a|Ipyrimidine (MS (USA): 714 (MaeNyayu, 105 (10095)))| and 5,7-bis(propylthio)-2-(2,3,5 -tri-O-benzoyl-p-O-ribofuranosyl)-Z3H-1,2,3-triazolo|4,5-4|pyrimidine (MS (USA): 714 (MAN), 105 (10095)) (1, 9d). Further elution gave 5,7-bis(propylthio)-1-(2,3,5-tri-O-be nzoyl-D-YOO-ribofuranosyl)-ZH-1,2,3-triazolo4,5-a|pyrimidine in the form of a colorless foam (0.46 g). (MS (US): 714 (MaAN.k), 105 (10095)|. a) M-Butyl-5-(propylthio)-3-(3-B-ribofuranosyl)-ZN-1,2,3-triazolo |4,5-4|pyrimidine-7-amine n-Butylamine (7.37g) was added to a solution of the mixture of isomers from stage c) (9.0g) in 1,4-dioxane (100ml) and water (30ml). The solution was heated for 40 hours at 100"C, then concentrated. The residue was dissolved in a 0.1 M solution of sodium methoxide in methanol (250 ml) and the reaction mixture was heated at reflux for 30 minutes. After cooling to room temperature, acetic acid was added to pH 7 and the solution was concentrated.

MS (Electrospraying): 399 (Ma-Nya, 10090). is). M-Butyl-5-(propylthio)-3-(2,3-ethoxymethylene-D-O-ribofuranosyl)-ZH-1,2,3-triazolo-|4,5-4|pyrimidine-7-amine

A solution of the product of stage a) (0.40g) in 1,4-diocane (Xml) was treated with trichloroacetic acid (0.44g) and triethyl orthoformate (0.44g). The resulting solution was heated for 9 minutes at 50°C. The cooled solution was diluted with dichloromethane (100 ml), washed with a saturated solution of sodium bicarbonate (50 ml) and water (50 ml), then dried and concentrated. Chromatography (5%, hexane:ethyl acetate 2:1 as eluent ) afforded the title compound as a colorless solid (0.32 g).

MS (USA): 455 (MAN .k), 267 (100905).

In (E)-1-(7-(Butylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|Ipyrimidin-3-yl)|-1,5,6- trideoxy-8D-O-ribohept-5-enofuranoronic acid, ethyl ether

A stirred solution of the product of step i) (3.25g) of pyridine (0.57g) and trifluoroacetic acid (0.41g) in DMSO (30ml) was treated with 1,3-dicyclohexylcarbodiimide (4.42g) and the mixture was stirred at room temperature within 24 hours. Carboethoxymethylenetriphenylphosphorane (3.98 g) was added and the reaction was stirred for another 18 hours. The reaction mixture was cooled to 0°C, diluted with ethyl acetate (400 ml) and oxalic acid (3.51 g) was added. After 30 minutes, the mixture was filtered and the filtrate was washed with a saturated solution of sodium bicarbonate (200 ml), dried and concentrated. Chromatography (5%, hexane: ethyl acetate) 5: 1 as eluent) gave the intermediate product, which was dissolved in 8095 acetic acid (aqueous) (25 ml) and heated for 2 days at 36"C. The solution was concentrated and the residue was purified by chromatography (500, hexane:ethyl acetate 2:1 as eluent) to give the title compound as a colorless solid (1.84g).

MS (USA): 467 (MaAN kyu), 267 (100905). 9) (E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-Z-yl|-1,5,6- Dtideoxy-p-O-ribohept-5-enofuranuronic acid

Obtained by the method of Example Cc) using the product of stage b).

NMR 5 H (d6-DMSO): 9.10 (1H, t), 6.82 (1H, dd), 6.15 (1H, d), 5.89 (1H, d), 4.76 (1H , t), 4.60 (1Н, t), 4.39 (TN, t), 3.50 (2Н, m), 3.08 (2Н, m), 1.69 (2Н, m), 1 .61 (2Н, m), 1.34 (2Н, m), 0.98 (ЗН, t), 0.91 (ЗН, t).

MS (USA): 439 (MAN), 267 (100965).

Example 15 (E)A-M-11-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5 ,6-trideoxy-p-O-ribohept-5-enofuranuronoyl)-I -aspartic acid a) (E)-M-P1-(7-(Butylamino)-5-(propylthio)-3H-1,2, 3-triazolo-I(4,5-4|pyrimidin-Z3-yl|-1,5,6-trideoxy-pD-O-ribohept-5-enofuranuronoyl|)-I -aspartic acid, bis (1,1- dimethyl ethyl) ether

Obtained by the method of Example 2a) using the product of Example 14.

MS (Electrospraying): 666 (MN, 10090).

B) ОСОС(Е)-М-11-(7-(Butylamino)-5-(propylthio)-З3Н-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5 ,6-trideoxy-B-O-ribohept-5-enofuranuronoyl)-I -aspartic acid

Obtained by the method of Example 20) using the product of stage a).

NMR 6 N (pre-DMSO): 12.57 (2N, shob), 9.09 (1N, t), 8.42 (1N, d), 6.70 (1N, dd), 6.13 (2N , m), 5.78 (1H, d), 5.60 (1H, d), 4.71 (1H, m), 4.56 (2H, m), 4.40 (1H, sq), 3 .07 (2Н, m), 2.63 (2Н, m), 1.68 (2Н, m), 1.60 (2Н, m), 1.35 (2Н, m), 0.98 (ЗН, t), 0.91 (ZH, t).

Example 16

The following compound was obtained according to the method of Examples 14 and 15: (B)-M-(11-(7-Amino-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3 -yl)-1,5,6-trideoxy-D-O-ribohept-5-enofuranuronoyl)-I -aspartic acid, monoammonium salt a) 5-(Propylthio)-3-(8-B-ribofuranosyl)-Z3H- 1,2,3-triazolo|4,5-4|pyrimidine-7-amine

A solution of the mixture of isomers from Example 14c) (12.0 g) in methanol (tlu was cooled to 0"C and saturated with gaseous ammonia. The solution was stirred at room temperature for 72 hours, then concentrated. Chromatography (5102, dichloromethane: methanol 14: 1 as eluent ) afforded the title compound as a colorless solid (4.94 g).

MS (Electrospray): 343 (MN, 10090).

B) 5-(Propylthio)-3-I(2,3-O-(ethoxymethylene)-D-YUO-ribofuranosyl|-ZH-1,2,3-triazolo|4,5-4|pyrimidin-7-amine

MS (Electrospray): 399 (MAN, 10095). c) (E)-1-(7-amino-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- D-YUO-ribohept-5-enofuranuronic acid, ethyl ether

MS (Electrospraying): 411 (Ma-Nya, 10090). a) (E)-1-(7-amino-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- D-YUO-ribohept-5-enofuranuronic acid, ethyl ether

MS (Electrospraying): 383 (MN, 10090).

E) (E)-h-P1-(7-amino-5-(propylthio)-3H-1,2,3-triazolo4,5-hy|-pyrimidin-3-ylI-1,5,6-trideoxy- 0-O-ribohept-5-enofuranuroyl)-I -aspartic acid, bis (1,1-dimethylethyl) ether Mo (Electrospray): 610 (MH, 10095).

In (E)-M-(11-(7-amino-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|-pyrimidin-Z-yl|-1,5,6 -trideoxy-I -O-ribohepta-

B-enofuranuronoyl|)-I -aspartic acid, monoammonium salt

H NMR (a6-DMSO): 8.53 (1H, seh), 8.18 (1H, ss), 6.66 (1H, dd), 6.62 (1H, d), 6.15 (1H, d), 5.78 (1Н, t), 4.54 (1Н, t), 4.39 (1Н, t), 4.25 (1Н, m), 3.05 (2Н, m), 2 .53-2.25 (2H, m), 1.68 (2H, m), 0.97 (ZH, t).

Example 17 (E)-M-11-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5, 6-trideoxy-p-O-ribohept-5-enofuranuronoyl)-I -aspartic acid, monoammonium salt a) (E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2, 3-triazolo|4,5-4|pyrimidin-Z-yl|-1,5,6-trideoxy-rD-O-ribohept-5-enofuranuronic acid, ethyl ether

Obtained by the method of Example ZB) using the product of stage 145.

MS (Electrospraying): 469 (MN, 10090).

B) (E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-Z-yl|-1,5,6- trideoxy-pD-O-ribohept-6b-enofuranronic acid

Obtained by the method of Example Cc) using the product of stage a).

MS (Electrospray, negative ionization): 439 (М-Н-- 100965). c) (E)-M-P11-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo-I(4,5-4|pyrimidin-Z-yl|-1, 5,6-trideoxy-pD-O-ribohept-5-enofuranuronoyl)-I -aspartic acid, bis (1,1-dimethylethyl) ether

Obtained by the method of Example 2a) using the product of stage B).

MS (Electrospraying): 668 (MN, 10090). a) (E)-M-11-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo-|4,5-4|pyrimidine-Z-ylI-1,5, 6-trideoxy-0-O-ribohept-5-enofuranuronoyl)-I-aspartic acid, monoammonium salt

Obtained by the method of Example 2a) using the product of stage c).

NMR 5 H (a6-DMSO): 9.07 (1H, t), 7.69 (1H, d), 6.04 (1H, d), 5.50 (2H, sho), 4.76 (1H , t), 4.18 (2H, m), 3.91 (IN, m), 3.49 (2H, sq), 3.08 (2H, t), 2.46-2.23 (2H, m), 2.13 (2Н, m), 1.93 (1Н, m), 1.70 (ЗН, m), 1.60 (2Н, m), 1.34 (2Н, m), 0, 99 (ZN, t), 0.91 (ZN, t).

Example 18 (E)А-М-11,5,6-trideoxy-1-(7-(hexylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine- Z-yl|-B-O-ribohept-5-enofuranuronoyl|)-I-aspartic acid, monoammonium salt

A) 3-(5-O-benzoyl-;D-Y-ribofuranosyl)-M-hexyl-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-7-amine

Obtained by the method of Example 144) using n-hexylamine.

MS (USA): 531 (MaAN kyu), 295 (100905). p) 3-I5-O-benzoyl-2,3-0-(1-methylethylidene)-2-YO-ribofuranosyl|-M-hexyl-5-(propylthio)-ZH-1,2,3-triazolo|4 ,5-si|pyrimidine-7-amine

The product of stage a) (4.93g) in acetone (120ml) containing 2,2-dimethoxypropane (11.4ml) was treated with p-toluenesulfonic acid (4.47). The resulting solution was stirred for 2 hours at room temperature, basified with triethylamine (3.25 ml) and concentrated. Chromatography (510, cyclohexane:ethanol 95:5 as eluent) afforded the title compound (5.03 g).

MS (Electrospraying): 571 (Ma-Nya, 10090). c) M-Hexyl-3-I2,3-0-(1-methylethylidene)-VD-Y-ribofuranosyl)-5-(propylthio)-ZH-1,2,3-triazolo|4,5- d|Ipyrimidine -7-amine

A solution of the product of stage B) (5.02g) in a 0.1M solution of sodium methoxide in methanol (38ml) was heated under reflux for 30 minutes. Acetic acid (ml) was added and the reaction was concentrated.

Chromatography (5102, dichloromethane:acetonitrile 95:5 as eluent) afforded the title compound (3.6 g). MS (Electrospraying): 467 (Ma-N.k, 100965). a) (E)-1,5,6-Trideoxy-1-|7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|-pyrimidine-3- yl)-2,3-0-(1-methylethylidene)-D-Y-ribohept-5-enofuranuronic acid, 1,1-dimethyl-ethyl ether

Obtained by the method of Example Id) using the product of stage c).

MS (USA): 563 (MAN, 100965).

E) (E)-1,5,6-trideoxy-1-(7-«(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3- il|-D-O-ribohept-5-enofuranuronic acid

Obtained by the method of Example 1)) using the product of stage a).

MS (USA): 467 (MAN .k), 295 (100905). 7УОС(Е)-М-11,5,6-trideoxy-1-(7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|-pyrimidine-Z -yl|-B-O-ribohept-5-enofuranuronoyl|)-I -aspartic acid, bis (1,1-dimethylethyl) ether

Obtained by the method of Example 3) using the product of stage 1).

MS (USA): 694 (MAN), 295 (100965). 9) (E)-M-I11,5,6-Trideoxy-1-|7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3 -ylI|-B-O-ribohept-5-enofuranuronoyl|)-I -aspartic acid, monoammonium salt

Obtained by the method of Example 2B) using the product of stage i).

MS (USA): 582 (MAN .k), 295 (100905).

NMR 5 H (d6-DMSO): 8.74 (1H, t.), 8.00 (1H, m), 6.66 (1H, dd), 6.23 (IN, d), 6.15 ( 1H, m), 4.76 (1H, m), 4.55 (IN, t), 4.40 (IN, t), 4.27 (1H, t), 3.50 (2H, m), 3.07 (2Н, m), 2.51 (2Н, m), 1.68 (4Н, m), 1.30 (6Н, m), 0.98 (ЗН, m), 0.87 (ЗН , m).

Example 19 (E)-1-(7-(M-Butyl-M-methylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|1 ,5,6-trideoxy-

B-O-ribohept-5-enofuranuronic acid a) M-Butyl-M-methyl-5-(propylthio)-3-(8-Y-ribofuranosyl)-ZH-1,2,3-triazolo|4,5- 4|pyrimidine-7-amine

Obtained by the method of Example 144) using M-methyl-M-butylamine.

MS (USA): 413 (MAN), 281 (100965). p) M-Butyl-M-methyl-5-(propylthio)-3-(2,3-0-(1-methylethylidene)-D-ХО-ribofuranosyl|-ЗН-1,2,3- triazolo|4, 5-in|Ipyrimidine-7-amine

Obtained by the method of Example 186) using the product of stage a).

MS (USA): 453 (MAN .k), 281 (100965). c) (E)-1-(7-(M-Butyl-M-methylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl)- 1,5,6-trideoxy-2,3-0-(1-methylethylidene)-D-B-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether

Obtained by the method of Example 11) using the product of stage B).

MS (US): 549 (MaeAN.k, 10090). a) (E)-1-(7-(M-Butyl-M-methylamino)-5-(propylthio)-3H-1,2,3-triazolo4,5-4|pyrimidin-3-yl|-1, 5,6- trideoxy-D-YUO-ribohepta-5-enofuranuronic acid

Obtained by the method of Example 1)) using the product of stage c).

MS (USA): 453 (MaeANk, 10090).

NMR 5 H (a6-DMSO): 6.51 (1H, dd), 6.12 (1H, d), 5.83 (1H, d), 4.71 (1H, t), 4.51 (1H , t), 4.31 (1Н, m), 3.76 (2Н, m), 3.71 (ЗН, с), 3.08 (2Н, m), 1.69 (4Н, m), 1 .61 (2Н, m), 1.34 (2Н, m), 0.94 (6Н, m).

Example 20 (E)-M-11-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5, 6-trideoxy-p-O-

ribohept-5-enofuranuronoyl)-I -aspartic acid a). 3-(2,3,5-Tri-O-benzoyl-;D-Y-ribofuranosyl)-5,7-bis(methylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine and 2-(2,3,5-tri-O-benzoyl-D-Y-ribofuranosyl)-5,7-bis(methylthio)-ZH-1,2,3-triazole4,5-4|Ipyrimidine

Obtained by the method of Example 14c) using 5,7-bis(methylthio)-1H-triazolo4,5-4|-pyrimidine (obtained by the method described by - A. Mopidotegu, A.T. Zpopapsu, B. Agpei, M .N. Zpappop, U. Med. Spec., 1977, 20, 401). Chromatography (50%, dichloromethane:ethyl acetate 99:1 as eluent) afforded the title compound (13.3 g).

MS (Electrospraying): 467 (MAN, 10095). r) M-Butyl-3-I2,3-0-(1-methylethylidene)-D-YUO-ribofuranosyl|-5-(methylthio)-ZH-1,2,3-triazolo|4,5- 4|pyrimidine -7-amine n-Butylamine (13.5 ml) was added to a solution of the mixture of isomers from stage a) (22.5 g) in a mixture of dioxane (17 ml)/water (25 ml). The solution was stirred at room temperature for 24 hours, then concentrated.

The residue was dissolved in a 0.1 M solution of sodium methoxide in methanol (500 ml) and heated under reflux for 30 minutes. After cooling to room temperature, the solution was concentrated and the residue was dissolved in DMF (80 mL). p-toluenesulfonic acid (5.91g) and 2,2-dimethoxypropane (50ml) were added and the reaction mixture was stirred at room temperature for 24 hours. The solution was concentrated and the residue was partitioned between ethyl acetate (500 ml) and saturated sodium bicarbonate solution (50 ml), the organic phase was dried and concentrated. Chromatography (51O", hexane:ethyl acetate 7:Z as eluent) afforded the title compound as a colorless solid (3.67).

MS (Electrospray): 411 (MaeH, 100905) c) (E)-1-(7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine- 3-yl|-1,5,6-trideoxy-2,3-0-(1-methylethylidene)-8-YOO-ribohept-5-enofuranuronic acid, ethyl ether

Obtained according to the method of Example li) using the product of stage b) and carbetoxymethylenetriphenylphosphorane.

MS (US): 479 (MaeN.k, 10090). a) (E)-1-(7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3-ylI-1,5,6-trideoxy -0-O-ribohept-5-enofuranuronic acid, ethyl ether

The product of stage c) (1.4g) was dissolved in a 2M solution of HCl in methanol (75ml) and the reaction mixture was stirred for 15 minutes at room temperature, then concentrated. The residue was dissolved in ethyl acetate (300ml), washed with saturated sodium bicarbonate solution (3x100ml), dried and concentrated.

Chromatography (5g, dichloromethane:methanol 97:Z as eluent) afforded the title compound as a colorless solid (1.10 g).

MS (USA): 439 (MAN .k), 239 (100905). g) (E)-1-(7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3-ylI-1,5,6-trideoxy -0-O- ribohept-5-enofuranuronic acid

Obtained by the method of Example Cc) using the product of stage a).

MS (USA): 411 (MaeN kyu), 154 (100965).

U (E)-H-(4-(7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-Z-ylI-1,5,6 -trideoxy-0-O-ribohept-5-enofuranuronoyl)-I -aspartic acid, bis (1,1-dimethylethyl) ether

Obtained by the method of Example 2a) using the product of stage e).

MS (US): 638 (M.--N.-»), 239 (10095). 9) (E)-m-P1-(7-(Butylamino)-5-(methylthio)-3H-1,2,3-triazolo-I4,5-4|grimidin-3Z-ylI-1,5,6 -trideoxy-0-O-ribohept-5-enofuranuronoyl)-I -aspartic acid

Obtained by the method of Example 25) using the product of stage b).

MS (USA): 526 (MAN), 239 (1003).

Example 21 (E)-1-(5-butyl-7-(butylamino)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-ylI-1,5,6-trideoxy-D -ХО-ribohept-5-enofuranuric acid a) 5-butyl-3,4-dihydro-3-(2,3-0-(1-methylethylidene)-Д-ХО-ribofuranosyl|-7 H-1,2, 3-triazolo4,5-4|pyrimidin-7-one

Sodium (4.6g) was dissolved in ethanol (200ml), then 5-amino-1-I(2,3-0-(1-methylethylidene)-8-O-ribofuranosyl-1H-1,2,3- triazole-4-carboxamide (obtained as described by O. Viadi et al., Ragtaso, 1992, 47, 525) (6.0 g) and the mixture was heated under reflux. Methyl valerate (10.5 ml) was added and refluxed refrigerator for 17 hours. The mixture was neutralized using Juolech 50x8-200 (H'-form), filtered, the filtrate was concentrated. The residue was dissolved in ethanol, acetic acid was added, and the solution was concentrated. Chromatography (5i0", hexane: ethyl acetate 7: Z as eluent ) afforded the title compound as a colorless oil (3.08 g).

MS (USA): 366 (MAN q). p) 5-butyl-3,4-dihydro-3-(5-O-acetyl-2,3-0-(1-methylethylidene)-D-ХО-ribofuranosyl|-7H-1,2,3-triazolo |4,5-4|Ipyrimidin-7-one

Triethylamine (0.42g) and acetyl chloride (0.3g) were added sequentially to an ice-cooled solution of the product from step a) (1.41g) in dichloromethane (30ml). The mixture was stirred for 30 minutes at 5-7C, then washed with saturated sodium chloride solution, dried and concentrated. Chromatography (510, dichloromethane:methanol 95:5 as eluent) gave the title compound (1,2).

MS (EU): 408 (MAN). c) 5-Butyl-7-chloro-3-I5-O-acetyl-2,3-0-(1-methylethylidene)-Wob-Y-ribofuranosyl|-ZH-1,2,3-triazolo|4,5 - 4|pyrimidine

The product of stage B) (1.197 g) and DMF (299 mg) in chloroform was heated under reflux, thionyl chloride (3.47 g) was added and refluxed for 45 min. After cooling in an ice bath, the mixture was slowly added to a saturated solution of sodium bicarbonate, which was stirred. The mixture was extracted with dichloromethane (3x200ml), the combined extracts were dried, filtered and concentrated. Chromatography (5i0, hexane:ethyl acetate 5:1 as eluent) afforded the title compound (1.14g).

MS (EU): 427, 425 (MAN.Yu). a) M, 5-Dibutyl-3-(2,3-0-(1-methylethylidene)-Y-Y-ribofuranosyl|-ZH-1,2,3-triazolo|4,5-a|pyrimidine-7- amine

Obtained by the method of Example 1!) using the product of stage c).

MS (EU): 420 (Ma). g) (E)-1-(5-Butyl-7-(butylamino)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- 2,3-0-(1-methylethylidene)-8-Y-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether

Obtained by the method of Example 11) using the product of stage a).

MS (USA): 517 (MAN, 10095).

In (E)-1-I5-Butyl-7-(butylamino)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-D- ХО-ribohept-5-enofuranuronic acid

Obtained by the method of Example 1)) using the product of the stage is).

NMR 5 H (a6-DMSO): 8.87 (1H, t), 6.71 (1H, dd), 6.20 (1H, m), 5.89 (1H, d), 4.75 (1H , m), 4.56 (1H, t), 4.37 (IN, t), 3.54 (2H, sq), 2.73 (2H, t), 1.74 (2H, m), 1 .62 (2Н, m), 1.35 (4Нр m), 0.91 (6Н, t).

Example 22 (E)-1-(7-Butyl-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- D-ХО-ribohept-5-enofuranuronic acid

ІІ 5-Amino-1-І5-0-(1,1-dimethylethyl)dimethylsilyl|-2,3-0-(1-methylethylidene)-Д-ХО-ribofuranosyl-1 H- 1,2,3-triazol- 4-carboxamide

A solution of 5-amino-1-12,3-0-(1-methylethylidene)-2y-Y-ribofuranosyl|-1H-1,2,3-triazole-4-carboxamide (obtained as described by Viadi et al. ,, Raptaso, 1992, 47, 525) (10.0g), imidazole (2.20g) and tert-butyldimethylsilyl chloride (4.99g) in DMF (200ml) were stirred for 16 hours at room temperature. The solution was concentrated and the residue was purified (5iO2, dichloromethane:ethyl acetate 1:1 as eluent) to give the title compound.

MS (EU): 398 (M-CH3-), 73 (100925). p) 3,6-Dihydro-3-(5-0O-(1,1-dimethylethyl)dimethylsilyl|-2,3-0-(1-methylethylidene)-D-ХО-ribofuranosyl|-5- mercapto-7Н- 1,2,3-triazoles4,5-4|pyrimidin-7-one

The product of stage a) (26.0g) in DMF (100ml) was added over 1 hour to a stirred suspension of sodium hydride (6095, 2.52g) in DMF (200ml). 1,1-thiocarbonyldiimidazole (11.2 g) was added and the reaction mixture was refluxed for 1 hour, then concentrated. The residue was dissolved in water (1 L), acidified with glacial acetic acid, and the title compound was isolated by filtration (14.1 g).

MS (USA): 456 (MAN .k), 69 (100905). c) 3-I5-0-(1,1-Dimethylethyl)dimethylsilyl|-2,3-0-(1-methylethylidene)-VD-Y-ribofuranosyl|-3,4-dihydro-5-(propylthio)-7 H-1,2,3-triazolo|4,5-4|pyrimidin-7-one

The product of stage B) (19.3g) was added to a stirred suspension of sodium hydride (60905, 1.41g) in DMF (200ml). After 15 minutes, iodopropane (3.55 g) was added, the mixture was stirred for 1 hour, then concentrated. The residue was partitioned between water (Il) and dichloromethane (Tl). The organic layer was dried, concentrated to give the title compound (18Hg).

MS (US): 498 (MN .k), 73 (100905). a) 3-(2,3-0-(1-Methylethylidene)-D-ХО-ribofuranosyl|-3,4-dihydro-5-(propylthio)-7 H-1,2,3-triazoloi4,5-4 |pyrimidin-7-one

Tributylammonium fluoride (1M in THHF, 40.bml) was added to a stirred solution of the product of step c) (20.2g) in THF (300ml) and the reaction mixture was stirred for 12 hours at room temperature. The solution was concentrated and the residue was partitioned between water (1 L) and ethyl acetate (T). The organic phase was dried, concentrated and the title compound was obtained (14.1 g).

MS (electrospray): 382 (M-N.yu, 10090). f) 3-I5-O-Acetyl-2,3-O-(1-methylethylidene)-Y-Y-ribofuranosyl|-3,4-dihydro-5-(propylthio)-7H-1,2,3- triazolo|4,5-4|Ipyrimidin-7-one

Obtained by the method of Example 216) using the product of stage a).

MS (Electrospraying): 443 (MN, 10090).

IY 3-I5-O-Acetyl-2,3-0-(1-methylethylidene)-2-Y-ribofuranosyl|-7-chloro-5-(propylthio)-ZH-1,2,3-triazolo!|4 ,5-4|pyrimidine

Obtained according to the method of Example 21c) using the product of stage e).

MS (US): 444, 446 (MAN .yu). 9). 3-I5-O-Acetyl-2,3-0-(1-methylethylidene)-D-YOO-ribofuranosyl|-7-butyl-5-(propylthio)-3H-1,2,3-triazolo (4,5 -4|Ipyrimidine

Obtained according to the method of Example 21c) using the product of stage e).

Bis(triphenylphosphine)palladium (11) chloride (40mg) and tetrabutyltin (0.81ml) were added to a solution of the product of stage B (500mg) in 1-methyl-2-pyrrolidinone (Xml) and the mixture was stirred for 2 hours at 100°C. then at room temperature for 72 hours. The mixture was partitioned between water (100ml) and ethyl acetate (200ml), the organic layer was washed with saturated sodium chloride solution (50ml), dried and concentrated. Chromatography (5iO»2, hexane:ethyl acetate 85:15 as eluent ) gave the title compound (230 mgHg).

MS (USA): 466 (MAN q).

P) 7-Butyl-3-I(2,3-0-(1-methylethylidene)-D-YUO-ribofuranosyl|-5-(propylthio)-ZH-1,2,3-triazoloi4,5-4|pyrimidine

Obtained by the method of Example 1ba) using the product of stage 4).

MS (USA): 424 (MAN q).

Y) | (EB)-1-(7-Butyl-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-Z- U-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether

Obtained by the method of Example 1) using the product of stage n).

MS (USA): 520 (MAN q).

With 0 (B)-1-(7-Butyl-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- D-ХО-ribohept-5-enofuranuronic acid

Obtained by the method of Example 1) using the product of stage n).

NMR 5 N (a6-DMSO): 7.00 (1N, d), 6.52 (1N, s), 6.01 (1N, d), 5.30 (2N, ss), 4.94 (1N , c), 4.56 (1H, t), 4.76- 4.81 (2H, d), 3.12 (4H, sho), 1.80 (2H, sq), 1.70 (2H, sq), 1.37 (2Н, sq), 0.99 (ЗН, t), 0.89 (ЗН, t).

Example 23 (E)-M-(1-(5,7-Di(butylamino)-3H-1,2,3-triazolo|4,5-a|pyrimidin-3-yl|-1,5,6- trideoxy-8-O-riboheptofuranoyl|-D-aspartic acid, monoammonium salt a).(E)-M-11-(7-Butylamino-5-(methylsulfonyl)-3H-1,2,3-triazolo|4, 5-4|-pyrimidin-3-yl|-1,5,6-trideoxy-

B-O-riboheptofuranoyl)-I -aspartic acid, 1,1-dimethylethyl ether

C-Chloroperoxybenzoic acid (5095, 0.12g) in ethanol (ml) was added 1 hour before the product solution

Example 17c) (0.1 g) in ethanol, which was stirred. After stirring for 16 hours at room temperature, the solution was diluted with dichloromethane (50ml), then washed with an aqueous solution of sodium metabisulfite (30ml) and an aqueous solution of sodium carbonate (2x20ml). The organic layer was dried, concentrated to give the title compound (9OmgHg).

MS (USA): 700 (MaeNk), 299 (100965). p) (E)-M-(11-(5,7-Di(butylamino)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-ylI|-1,5,6- trideoxy-D-O-riboheptofuranoyl|/-I -aspartic acid, 1,1-dimethylethyl ether

Obtained by the method of Example 1P) using the product of stage a).

MS (USA): 665 (MaeNk, 10090). c) (B)-M-(11-(5,7-Di(butylamino)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-ylI|-1,5,6- trideoxy-D-O-riboheptofuranoyl|/-I -aspartic acid, monoammonium salt

Obtained by the method of Example 20) using the product of stage B).

MS (Electrospraying): 553 (MN, 10090).

Example 24 (2)-1-(7-(Butylamino)-5-(propylthio)-ZH-1,2,3-triazolo4,5-a|-pyrimidin-3-yl|-1,5,6-trideoxy -B-O-ribohept-5-enofuranuric acid a) M-Butyl-5-(propylthio)-3-(2,3-0-(1-methylethylidene)-VD-Y-ribofuranosyl|-ZH-1,2 ,3-triazolo|4,5- 4|pyrimidine-7-amine

Obtained by the method of Example 186) using the product of stage 14e).

MS (USA): 443 (MAN .k), 267 (100905).

B). (2)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- 2,3-0-(1-methylethylidene)-8-Y-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether

Obtained according to the method of Example 1) using the product of stage a), and the compound specified in the title was isolated as a product obtained in a small amount.

MS (USA): 535 (MaeNk, 10090). c) (2D-1-(7-(Butylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidin-Z-yl|-1,5,6-trideoxy -рД-О- ribohept-5-enofuranuronic acid

Obtained by the method of Example 1)) using the product of stage b).

MS (USA): 439 (MAN .k), 267 (100905).

Example 25

M-Butyl-5-(propylthio)-3-(5,6-dideoxy-6-(1H-tetrazol-5-yl)-D-Y-ribohexofuranosyl|-3H-1,2,3- triazolo (4 ,5-4|pyrimidine-7-amine a).(E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine 3-yl|-1,5,6-trideoxy-2,3-0-(1- methylethylidene)-8-YOO-ribohept-5-enofuranurononitrile

Obtained by the method of Example 1) using the product of stage 24a) and (triphenylphosphonarylidene) acetonitrile.

MS (USA): 460 (MaANk, 10090).

B). (E)-1-(7-(Butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5.6-trideoxy-2, 3-O-(1-methylethylidene)-B-Y-riboheptofuranurononitrile

Obtained by the method of Example 860) using the product of stage a).

MS (FI): 462 (MAN, 100965). c) M-Butyl-5-(propylthio)-3-|5,6-dideoxy-2,3-0-(1-methylethylidene)-6-(1H-tetrazol-5-yl)-D-O- ribohexafuranosyl-ZH-1,2,3-triazolo|4,5-4|pyrimidine-7-amine

Azidotrimethylsilane (0.30g) and dibutyltin oxide (32mg) were added to a solution of the product of stage B) (0.60g) in toluene (bml) and the resulting solution was refluxed for 72 hours. After cooling to room temperature, the solvent was removed and the residue was purified by chromatography (51O, ethyl acetate:isohexane:acetic acid 100:100:1 as eluent) to give the title compound (0.26g).

MS (USA): 505 (MaN kyu), 267 (100905). a) M-Butyl-5-(propylthio)-3-|15,6-dideoxy-6-(1H-tetrazol-5-yl)-D-Y-ribohexofuranosyl)-3H-1,2,3-triazol |4,5-4|Ipyrimidine-7-amine

Obtained by the method of Example 1)) using the product of stage c).

MS (USA): 465 (MAN .k), 267 (100905).

5H NMR (d6-DMSO): 9.08 (1H, t), 6.08 (1H, d), 5.65 (1H, d), 5.35 (1H, m), 4.76 (1H, t), 4.30 (1H, t), 3.98 (IN,

M), 3.50 (2Н, m), 3.06 (2Н, m), 2.92 (2Н, m), 2.05 (2Н, m), 1.63 (4Н, m), 1, 34 (2Н, m), 0.97 (ЗН, т), 0.91 (ЗН, т).

Example 26 1,5,6-Tridesoxy-1-I(5,7-bis(propylthio)-3H-1,2,3-triazolo-I4,5-4|Ipyrimidin-3-yl|-B-O- riboheptofuranuronic acid, sodium salt a) (E)-1,2,3-tri-O-acetyl-5,6-dideoxy-D-ХО-ribohept-5-enofuranuronic acid, ethyl ether

Ethyl ester of (E)-methyl-5,6-dideoxy-2,3-0-(1-methylethylidene)-8-Y-ribohept-5-enofuranosiduronic acid (obtained as described by A.). Sooreg, K.O. Zzaiotop, Teigapedgop Geyi, 1990, 31, 3813) (88.0g) was heated at 80"C in a mixture of acetic acid (25bml) and water (b4ml) for 16 hours at room temperature.

Evaporation gave a residue, which was dissolved in pyridine (1 mL) and treated with acetic anhydride (19.8 mL). After 24 hours, the reaction mixture was diluted with ethyl acetate (500 mL) and washed with diluted

NOSE Drying and evaporation gave an oil which was purified by chromatography (5i0, isohexane:ethyl acetate 5:1 as eluent) to give the title compound (5.34g).

MS (BSHAchkKrI): 431, 429 (Mark), 285 (100965).

B) 1,2, 3-Tri-O-acetyl-5,6-dideoxy-3-SO-riboheptofuranuronic acid, ethyl ether

Obtained by the method of Example 860) using the product of stage a).

MS (BSHAchkKrI): 433, 431 (Mark), 185 (10095). with). 2,3-Di-O-acetyl-1,5,6-trideoxy-1-|5,7-bis(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidine-3- yl|-8-O-riboheptofuranuronic acid, ethyl ether, and 2,3-di-O-acetyl-1,5,6-trideoxy-1-(5,7-bis(propylthio)-

ZH-1,2,3-triazolo|4,5-4|pyrimidin-2-yl|--Y-riboheptofuranuronic acid, ethyl ether

The product of stage B) (1.00g) and the product of stage 145) (0.78g) were mixed with p-toluenesulfonic acid (12mg) and thoroughly mixed under the vacuum of a water jet pump. The mixture was immersed in an oil bath heated to 140°C. Heating was continued for 1 min, then the flask was cooled and the reaction mixture was treated with chloroform. Washing with saturated sodium bicarbonate solution, drying, evaporation and chromatography (5uOg, dichloromethane-ethyl acetate 15:1 as eluent) gave compounds indicated in the title (5.34g) in the form of an indivisible mixture. a) 1,5,6-trideoxy-1-I|5,7-bis(propylthio)-3H-1,2,3-triazolo-I4, 5-4|pyrimidin-3-ylI|-D-O-riboheptofuranuronic acid, sodium salt

Obtained by the method of Example Cc) using the product of stage c).

MS (BSHAchKII): 433, 431 (Mak).

Pharmaceutical compositions

The new compounds of the present invention can be administered parenterally, intravenously, by inhalation or orally. A more acceptable route of administration is intravenous infusion.

The dose of administration depends on the method of administration, the complexity of the disease, the age and weight of the patient, as well as on other factors that are usually taken into account by the hospital doctor when determining the individual regimen and level of doses that are most acceptable for a particular patient.

Examples of pharmaceutical compositions that can be used and suitable excipients, diluents or carriers are as follows: for intravenous administration or infusion - purified water or saline; for inhalation compositions - unprocessed lactose; for tablets, capsules and dragees - microcrystalline cellulose, calcium phosphate, diatomaceous earth, sugar such as lactose, dextrose or mannitol, talc, stearic acid, starch, sodium bicarbonate and/or gelatin; for suppositories - natural or hardened oils or waxes.

If the compound of the present invention is intended for use in an aqueous solution, for example, for infusion, it may be necessary to include other fillers. In particular, chelating agents or passivators, antioxidants, tone-regulating agents, pH-regulating agents, and buffering agents may be used. Solutions containing compounds of formula (I) can, if desired, be evaporated, for example by freeze drying or spray drying, to obtain a solid composition which can be reconstituted before use. The compositions may also contain suitable preservatives, stabilizers and wetting agents, solubilizing agents, for example, a water-soluble cellulose polymer such as hydroxypropylmethylcellulose or a water-soluble glycol such as propylene glycol, sweetening and coloring agents, and fragrances. If necessary, the compounds may be formulated in a sustained-release form.

According to another aspect, the invention relates to the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the production of a medicament for the treatment of disorders associated with platelet aggregation.

According to yet another aspect, the invention relates to a method of treating any disorder involving platelet aggregation, comprising administering an effective amount of a compound of formula (1) to a patient suffering from such a disorder.

Pharmaceutically acceptable salts of compounds of formula (I) include alkali metal salts, for example, sodium and potassium salts; salts of alkaline earth metals, for example, calcium and magnesium salts; salts of elements of group I, for example, aluminum salts; and ammonium salts. Salts with suitable organic bases, for example, salts with hydroxylamine; lower alkylamines, for example, methylamine or ethylamine; with substituted lower alkylamines, for example, hydroxy-substituted alkylamines; or with monocyclic heterocyclic compounds containing nitrogen, for example, piperidine or morpholine; and salts with amino acids, for example, arginine, lysine, etc. or their M-alkyl derivatives; or with amino sugars, for example, M-methyl-O-glucamine or glucosamine. The above salts are only examples of salts that may be used in accordance with the present invention and should not be considered exhaustive.

More acceptable pharmaceutically acceptable salts of the compounds of formula (I) are alkali metal salts and ammonium salts, even more acceptable are sodium salts and monoammonium salts.

Biological test

The effectiveness of the compounds of the present invention as platelet aggregation inhibitors was determined by their ability to act as Roth receptor antagonists, as shown in the text below.

Quantification of agonist/antagonist activity against the Roth receptor of washed human platelets.

Preparation.

Venous human blood (100ml) was divided equally between 3 tubes, each containing 3.290 trisodium citrate (4ml) as an anticoagulant. Tubes were centrifuged for 15 minutes at 24,005 to obtain platelet-rich plasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize the platelets during the washing operation. RBCs free of red cells were obtained by centrifugation for 100 min at 12555 and further centrifugation for 15 min at 6400. The supernatant was discarded, and the platelet pellet was resuspended in calcium-free modified Thugodet's solution (NTC) (1 Oml), which consisted of: mass 137 mm,

MansSoz 11.9mM, MangRO"x 0.4mM, KSI 2.7mM, Masig2 1.1mM, dextrose 5.6mM, saturated with a gaseous mixture of 950 O2/595 CO" and kept at 37"C. After adding another ZOOng/ml of PG I», the combined suspension was centrifuged again for 15 min at 6400. The supernatant was discarded, and the platelets were resuspended first in 1 Oml of NKT, then more NKT was added to bring the final platelet content to 2x105/ml. This final suspension was stored in a 60-ml syringes at 3"C without air access. To suggest recovery of normal function after PG I inhibition, platelets were used for aggregation studies no earlier than 2 hours after final resuspension.

In all studies, 3-ml aliquots of platelet suspension were added to test tubes containing Sasig solution (boOmcl 50 mM solution, final concentration 1 mM). Human fibrinogen (Zidta, P 4883) and 8-sulfophenyltheophylline (8-SFT) were added to block any antagonistic activity of the compounds against

Pi) with obtaining final concentrations of 0.2 mg/ml (bOml of a solution of protein capable of coagulation in a physiological solution with a concentration of 1Omg/ml) and ZO0nNM (10 μl of a 15mM solution in 69o glucose), respectively.

Platelets or buffer, respectively, were added in a volume of 150 μl to individual cells of a tablet with 96 cells. All measurements were made three times with platelets from each donor.

Test protocol a) Evaluation of agonistic/antagonistic activity

Aggregate reactions in a 96-well plate using a change in absorbance recorded by a plate recorder at bbm.

The absorbance of each cell in the plate was recorded at bbonm to establish a baseline figure. Physiological solution or a suitable solution of the compound to be tested was added to each cell in a volume of 10 μl to obtain a final concentration of 0.001, 0.1, 1, 10 or 100mM. The tablet was then shaken for 5 minutes on a rotary shaker at position 10 and the absorbance was recorded at 6boOhm. Aggregation at this point is indicative of the agonistic activity of the compound being tested. Then, physiological solution or ADP (30mM; 10μl of 450mM solution) was added to each cell and the tablet was shaken for another 5 minutes until the absorbance was fixed again at bbonm.

Agonistic activity was evaluated as 95 inhibition of the control response to ADP. The compounds of the present invention showed antiaggregation activity when tested by the above method.

Claims (38)

1. ZN-1,2,3-triazolo-I4,5-4|pyrimidine derivatives of general formula (I) B is O or CH"; X is ME!'B2, 58! and C-C7-alkyl; M is 58, MW! B2 and C-C7-alkyl; B! and 2 are each independently H or C1-C7-alkyl, optionally substituted on or in the alkyl chain by one or more 0, 5, M or halogen; BZ and P? both represent hydrogen, or VAZ and B" together form a bond; A represents SON, C(O)MH(CHgOxCOOHn, C(OM(CHg)zCOOnNiI, C(OMNOCH(COOHuCHgCOOH) or 5-tetrazolyl, where p, 4 and g are each independently equal to 1, 2 or 3; as well as their pharmaceutical acceptable salts and prodrugs. 2. The compound of formula (I) according to item 1, where X represents ME'B2; M represents 5В8!; A is C(OMNHN(COOHuCHgCOOH; and where B", B? and d are defined in clause 1. 3. The compound according to item 2, where X represents MEN, where KE! represents hydrogen and 2 is defined in clause 1; M represents 5, where B! - Ci-Cv-alkyl, optionally substituted by one or more halogens; A is a somnenesooOnusngsoon. 4. The compound according to item 1, which is PA-I (E),2 r 5349 )1-3-I4-I(7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo |4,5-a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid sodium salt; PA-I (E),2 r Z BA A 31-AM-(3-(4- (7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|-I - disodium salt of aspartic acid; 5-2 r Z r «A 95 3)-4-(7-(butylamino)-5-propylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-Z -yl|-2,3- dihydroxycyclopentalpropanoic acid sodium salt; PV (2 В З В «А 92 3)-3-(4-І7-(butylamino)-5-(pentylthio)-ЗН-1,2,3- sodium salt of triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid; PA-I (E),2 r Z r «A 31-3-(4-( 7-(ethylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid sodium salt; PO - 2 B Z B A 3)-4-(7-(butylamino)-5-(pentylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-Z-yl|-2,3 - dihydroxycyclopentanepropanoic acid nat sea salt; 5-2 r Z r «A 95 3)-4-(7-(ethylamino)-5-(pentylthio)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-Z-ylI-2 ,3-dihydroxycyclopentanepropanoic acid sodium salt; PA-eZ B Ko; B 31-3-I7-"butylamino)-5-(propylthio)-3IN-1,2,3-triazolo(4,5-4|pyrimidine-3 -ylI|-5-(2-(1H-tetrazol-5-yl)ethyl-1,2-cyclopentanediol; I A- 2 B Z B 49 3I-AM-I3-(4-(7-(butylamino)- 5-(propylthio)-Z3H-1,2,3-triazolo|4,5-4|pyrimidine-Z-yl|- 2,dihydrooxycyclopentylpropanoyl 1--aspartic acid; PA-I (E),2 B 5349 31- AM-I3-I4-(7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3- dihydroxycyclopentyl|-2 -propenoyl|-I -aspartic acid; PV (2 r З r «А 92 3)-3-(4-I(7-(3,3-dimethylbutylamino)-5-(propylthio)-ZH-1,2, 3-triazolo|4,5-4|pyrimidin-Z-yl|- 2,3-dihydroxycyclopentyl|-2-propenoic acid; IA-I (E)2 B Z B a 9 31-3-(4-(7 -(2-methoxyethylamino)-5-(propylthio)-ZH-1,2,3-triazolo|4,5-4d|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoic acid; PA 2 r Z r 4 95 31-M-3-I4-(7-(hexylamino)-5-(propylthio)-Z3H -1,2,3-triazolo|4,5-4|pyrimidine-Z-yl|-2,3-dihydroxycyclopentylpropanoyl|-I-aspartic acid; PA (2 r Z BA 92 3-AM-(83-I4-I(5-(3,3,3-trifluoropropyl)thio|-7-(2-(methylthio)ethylamino|-ZH-1,2, 3-triazolo|4,5-a|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl|-I-aspartic acid monoammonium salt; (E)-1-(7-(butylamino)-5 -(propylthio)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-p-Y-ribohept-5-enofuranuronic acid; (E) -M-P1-(7-(butylamino)-5-(propylthio)-3IN-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-B -Y-ribohept-5-enofuranuronoyl|-I -aspartic acid; (E)-IR-(D-(7-amino-5-(propylthio)-ZN-I,2,3-triazolo|4,5-4|pyrimidin-3-ylI|-1,5,6-trideoxy - p -YOO-ribohept-5-enofuranuronyl|-I-aspartic acid monoammonium salt; (E)-M-P1-(7-(butylamino)-5-(propylthio)-3IN-1,2,3-triazolo| 4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-p-p-riboheptofuranoyl|-I-aspartic acid monoammonium salt; (E)-Ch-11,5,6-trideoxy-1 -|7-(hexylamino)-5-(propylthio)-3H-1,2,3-triazolo4,5-4|pyrimidin-3-yl|- B -Y-ribohept-5-enofuranuronoyl|-I -aspartic acid monoammonium salt; -1,5,6-trideoxy-p-p-ribohept-5-enofuranuronic acid; (E)-M-P1-(7-(butylamino)-5-(methylthio)-3H-1,2,3-triazolo |4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-B-Y-ribohept-5-enofuranuronoyl|-I-aspartic acid; (E)-1-I5-butyl-7- (butylamino)-ZH-1,2,3-triazolo|4,5-4|pyrimidine-Z3-yl|-1,5,6-trideoxy-p-Y-ribohept-5-enofuranuric acid; (E)- 1-(7-butyl-5-(propylthio)-3H-1,2,3-triazolo|4 ,5-4|pyrimidin-3-yl|-1,5,6-trideoxy-B-YOO-ribohept-5-enofuranuronic acid; (E)-M-P1-(5,7-di(butylamino)-3H-1,2,3-triazolo|4,5-4|pyrimidin-3-yl|-1,5,6-trideoxy- p -Y-ribohept-5-enofuranuronoyl-I-aspartic acid monoammonium salt; (2)-1-(7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-4 |-pyrimidin-3-yl|-1,5,6-trideoxy-B-Y-ribohept-5-enofuranuronic acid; M-butyl-5-(propylthio)-3-15,b-dideoxy-6-(1 N-tetrazol-5-yl)-p-Y-ribohexofuranosyl|-Z3H-1,2,3-triazolo|4,5-4|pyrimidin-7-amine or 1,5,6-trideoxy-1-I| 5,7-bis(propylthio)-3IN-1,2,3-triazoloi|4,5-4|pyrimidine-Z-ily|- B.p- riboheptofuranuronic acid sodium salt. 5. The compound according to item 4, which is (E)-M-|1-(7-(butylamino)-5-(propylthio)-3H-1,2,3-triazolo|4,5-a|pyrimidine- C-yl|-1,5,6-trideoxy-B-Y-ribohept-5-enofuranuronyl|-I-aspartic acid. 6. The compound according to point 4, which is CIV-(I 2 2B ЗР 4 3-M-I3-4-(7-(butylamino)-5-(propylthio)-ZH-1,2,3-triazol!| 4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|propanoyl)-I -aspartic acid. 7. The compound according to point 4, which is |IV-(19 (E),2 В Z r A 9 3-M-I3-I4-(7-hexylamino)-5-(propylthio)-ZH-1,2 ,3-triazolo|4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl)-I -aspartic acid. 8. The compound according to point 4, which is (IV-((E),2 В З В А 95 31-М-(3-И4-И5-((3,3,3-trifluoropropyl)thio|7-( 2- (methylthio)ethylamino|-3H-1,2,3-triazolo(4,5-4|pyrimidin-3-yl|-2,3-dihydroxycyclopentyl|-2-propenoyl)|-I - aspartic acid monoammonium salt . 9. The compound of formula (I) according to item 1 in the form of a salt. 10. The compound according to item 9, which is an alkali metal salt or ammonium salt of the compound of formula (I) according to item 1. 11. The compound according to item 10, which is the sodium salt of the compound of formula (I) according to item 1. 12. The compound according to item 10, which is a monoammonium salt of the compound of formula (I) according to item 1. 13. The compound of formula (I) according to item 1, which is in any one of its tautomeric, enantiomeric or diastereomeric forms. 14. The compound of formula (I) according to item 1 for use in therapy. 15. The compound according to claim 14, the therapeutic indication of which is the prevention of platelet aggregation. 16. The compound according to claim 14, the therapeutic indication for which is unstable angina pectoris. 17. The compound according to item 14, the therapeutic indication for which is plastic surgery on coronary vessels. 18. The compound according to item 14, the therapeutic indication for which is myocardial infarction. 19. The compound according to any one of clauses 16-18, for which the therapy is additional therapeutic measures. 20. The compound of formula (I) according to item 1, for the production of a medicament for use in the treatment of disorders associated with platelet aggregation. 21. The compound of formula (I) according to item 1, for the production of a medicament for use in the treatment of unstable angina pectoris. 22. The compound of formula (I) according to item 1, for the production of a medicament for use in the treatment of plastic surgery on coronary vessels. 23. The compound of formula (I) according to item 1, for the production of a medicament for use in the treatment of myocardial infarction. 24. The compound of formula (I) according to point 1, as an additional therapeutic agent. 25. The compound of formula (I) according to item 1, where B, X, M, B", B2, VZ and ER" are defined in item 1 and A is SOOV'!, C(OMN(СНа Сов", СИОМ(СНг )аСООВ|g or СООМНСН(СООВ "СНИ СООВ», where p, 4 and g are equal to 1, 2 or C and B"! is a lower (ar)alkyl. 26. A pharmaceutical composition containing a compound of formula (I) according to item 1 as an active ingredient together with a pharmaceutically acceptable carrier. 27. The method of obtaining the compound of formula (I) according to item 1, in which the following stages are carried out: () alkylation of 4,5-diamino-2,6-dimercaptopyrimidine with subsequent diazotization to obtain the compound of formula (II) VI M r, y: M mmM , M NOM! , (1) where V! defined in the formula (Her); (i) the reaction of the product of formula (II) from stage (i) with the compound of formula (II) Ro from (c); (11) where Rg is a protecting group; and I. is a departing group; in an inert solvent and in the presence of a base, at a temperature from -20 to 50"C, with subsequent introduction of the X-MV'B:2 group by reaction with a compound of the formula HME'B:2 in an inert solvent at a temperature from 0 to 1502C, where EE ! and 2 are defined in the formula (I) above, and then the removal of protective groups P by treatment with a nucleophile, with the preparation of the compound of the formula (IM) Y represents 5; and where E! and B? are defined in formula (I) above; (iii) reaction of the product of formula (IM) from step (ii) with the appropriate carbonyl compound or orthoester in an inert solvent and in the presence as a catalyst of an inorganic or organic acid at a temperature from -15 to 100"C to obtain the compound of the formula (M) x M; M m Ж MM y also, M where X represents ME'B2; M is 58; B is 0, and Ri is a protecting group; (m) oxidation of the compound of the formula (M) and the olefination reaction to obtain the compound of the formula (MI) x Y Z M mad AK - Mom u v Z RIO OR, « (MY) in which V is O or СНе, X, X and Rii are defined in formula (M); A represents SOOV'", where B!! represents lower (ar)alkyl; and B3 and B7 together form a bond; (y) elimination of B"! de-esterification using acidic or alkaline hydrogenolysis conditions and, finally, removal of the protective group to obtain a compound of formula (I), where X is ME!B2; M represents 5V!; V Her 22 is defined in formula (1); B is O or CH", BZ and B" together form a bond; and A is COOH. 28. The method according to claim 27, where the product of stage (ii) is oxidized with a subsequent olefination reaction and further reduction, with the preparation of a compound of formula (XIII) maya? Y che M. m MK M M and A in RO ОР 1 1 z (ХИ)) where В represents О or СН"; Ri is a protecting group, and B and 22 are defined in formula (1); then the resulting compound reacts with azide in an inert solvent at a temperature from 0 to 175"C, with subsequent removal of protective groups by treatment with an inorganic or organic acid in an inert solvent at a temperature from 0 to 1007C to obtain a product of the formula (I), where X is ME !B2; M is 5; B! and B? are as defined in formula (I), B is O or CH"; BZ and 2? are both hydrogen; and A is 5-tetrazolyl. 29. The method according to item 27, in which the compound of formula (I) is additionally reduced, where X represents ME!B2; M represents 5; В Its 22 are defined in formula (I), В represents О or CH"; B3 and B" together form a bond; and A is COOH, to give a compound of formula (I) where B, X, M, B! and E2 are defined above; A is COOH and B3 and 27 are both hydrogen . 30. The method of obtaining the compound of the formula (I) according to point 1, in which the following stages are carried out: (I) alkylation of 4,6-dihydroxy-2-mercaptopyrimidine with subsequent nitration and conversion of alcohol groups to leaving groups, with the preparation of the compound of the formula ( MI) "Zhk z (MI) de VE! defined in formula (1); and M is a leaving group; then the reaction of the compound of the formula (MI) with an appropriately protected 5,6-dihydroxy-2-azabicyclo(2,2,1|heptan-3-one, in the presence of a base in an inert solvent at a temperature from 10 to 100"C, with the result compounds of the formula (MII) M Ge) , Ж M u Ro ОР 1 (MI) where M is 58; B! is defined in formula (I); M is a leaving group and Ri is a protecting group; (and ) reduction of the nitro group and lactam in the product of stage (i) with subsequent cyclization into a triazole; cyclization of the obtained diamino alcohol reduction by diazotization reaction, using metal nitrites or alkyl nitrites in a suitable solvent at a temperature from -20 to 1002C, then introduction of the X-:ME'B2 group by reaction with a compound of the formula HMV'B: in an inert solvent at a temperature from 0 to 15022 to obtain a compound of the formula (M), where X is ME'B2; M is 58; B is CH"; and Ri is a protecting group; (ii) oxidation of the compound of the formula (M) and olefination reaction to obtain the compound of the formula (MI!) - Mom y in З РО ОР, « (MY) in which В is O or СНе, X, M and Ri are defined in formula (M); A is SOORV!, where E!! is lower (ar)alkyl; and VZ and B7 together form a connection; (m) removal of B"! by de-esterification, using acidic or alkaline hydrogenolysis conditions and, finally, removal of the protective group to obtain a compound of formula (I), where X represents ME'B2; M represents 5; V Her 22 is defined in formula (1); B is O or CH", BZ and B" together form a bond; and A is COOH. 31. The method according to claim 30, where the product of stage (i) is oxidized with a subsequent olefination reaction and further reduction, with the preparation of the compound of formula (XII) may? Y che M m mn M M y A in РО ОР 1 1 z (ХИЙ) where В represents О or СН"; Ri is a protective group, and EE! and 22 are defined in formula (1); then the obtained compound reacts with azide in an inert solvent at a temperature from 0 to 175"C, followed by removal of the protective groups by treatment with an inorganic or organic acid in an inert solvent at a temperature from 0 to 100"C to obtain a product of formula (I), where X represents itself ME'B2; M is 58; IN! and B? defined in formula (I), B is О or СНо: ВЗ и 2? both are hydrogen; and A is 5-tetrazolyl. 32. The method according to item 30, in which the compound of formula (I) is additionally reduced, where X represents ME!B2; M represents 5; IN! and B? defined in formula (1); B is O or CH", B3 and B" together form a bond; and A is COOH, giving a compound of formula (I) where B, X, M, B! and E2 are defined above; A is COOH and BZ and B? both represent hydrogen. 33. The method of obtaining the compound of formula (I) according to point 1, in which the following stages are carried out: () the reaction of the compound of formula (I), where X is 5", MWV: or C-C7-alkyl; M is 58, MW "B2, Ci-C7-alkyl; B Her 22 are defined in formula (1); B is O or CH", B3 and 27 are hydrogen or together form a bond; and A is COOH; with a compound of the structure MNa (CHgСООВ!, МН((СНg)зяСООв1" or МНаCH(СООВ"))(CHg Сов", where p, 4 and r are equal to 1, 2 or З and BV"! is a lower (ar)alkyl; using the methods peptide synthesis to obtain a compound of the formula (I), where X represents 5", MVV: or Ci-C7-alkyl; M represents 5! MVA!B2 or Ci-C7-alkyl; B! and ВЕ? are defined in the formula ( 1); B is O or CH"; BZ and 27 are hydrogen or together form a bond; and A is C(IOMN(SNIIrSOOV!!, COM(CHg)zSOOV |" or C(IOMNSN(SOOV" )CHgUSOOV", where p, d and g are equal to 1, 2 or C; and B" represents a lower (ar)alkyl; (i) de-esterification of the product of formula (I) of stage (i) to obtain a compound of the form ly (I), where B is O or CH"; X represents ME!B2, 5B! or Ci-C7-alkyl; M is 5! MVA!B2 or Ci-C7-alkyl; B and 2, each independently, represent H or C1-C;-alkyl, optionally substituted on or in the alkyl chain by one or more 0.5, M or halogen; VZ ii 2? both are hydrogen; or EZ and B" together form a bond; and A is C(O)MH(CHgCOOH, C(O)M((CHg)COOHN" or C(IOMNHCH(COOH)(CH2g)COOH, where p, a and d are equal to 1, 2 or 3. 34. The method of obtaining the compound of formula (I) according to item 1, in which the following stages are carried out: () treatment of appropriately protected 5-amino-1-P-O-ribofuranosyl-1 2,3-triazole-4-carboxamide with a base, with further treatment with a complex ether of the formula B'SOOBV", where B! defined in the formula (I) and 25 is a lower alkyl, then protection to obtain a compound of the formula (IX) "М She: М М || i le eh RO OR, ,; (X) where U represents C-C7-alkyl; Ri is a protective group; P" represents a protective group; and M is OH; (i) halogenation of the compound of formula (IX) obtained at the previous stage and the introduction of the X-ME'B2 group? by treatment with a compound of the formula HME'B: in an inert solvent at a temperature from 0 to 150"C, then removal of the protective group Pg to obtain a compound of the formula (M), where X is MEN, Y is C1-C7-alkyl; B is 0; and Ri is a protective group; (ii) oxidation of a compound of the formula (M) and an olefination reaction to obtain a compound of the formula (MI!) is O or CH", X, M and Ri are defined in formula (M); A is SOOV'", where B!! is lower (ar)alkyl; and VZ and E? together form a bond; (m) removal of BC!!! de-esterification using acidic or alkaline hydrogenolysis conditions and, finally, removal of the protective group to obtain a compound of formula (I), where X is ME!B2; B is 0; U represents C1-C7-alkyl; A is COOH and VZ and B7 together form a bond. 35. The method of obtaining the compound of formula (I) according to item 1, in which the following stages are carried out: () introduction of a suitable protective group Pz into the protected 5-amino-1-Y-Y-ribofuranosyl-1,2,3-triazole-4- carboxamide, treatment of the obtained intermediate compound with a base, followed by treatment with a reagent of the formula I, Her, where I is a leaving group, with the formation of a compound of the formula (X) o) K, iy nn Mi MM vn o de Ri and Rz, each independently, represents a protective group; (ii) treatment of the product of the formula (X) of stage (i) with a base in an inert solvent at a temperature from -20 to 507C, followed by treatment with an alkylating reagent B'C, where C is a leaving group, and where E' is defined in the formula (I), then, removal of P" and replacement with a new protecting group P" and, finally, halogenation to obtain a compound of formula (IX), where M is a leaving group, Ri is a protecting group, Pg" is a protecting group group, M represents 58; and B! defined in formula (1); (ii) reaction of the product of formula (IX) of stage (iii) with an alkyl nucleophile at a temperature from -20 to 150"C, then removal of the protecting group Ra to obtain a compound of formula (M), where X is C1-C7-alkyl; M is 5, B! is defined in formula (1), B is 0, and Ri is a protecting group. 36. The method of obtaining the compound of formula (I) according to item 1, in which the following stages are carried out: () processing of the compound of formula (Y), where X represents MEN, M represents 58; V Her 22 is defined in formula (1); B is 0; VZ and R? both are hydrogen; and A is C(IOMNHSN(COOV")(CHg) CO, where r is equal to 1, 2 or C and B"! is defined above; by an oxidizing agent in an inert solvent at a temperature from -20 to 100"C, followed by treatment with a compound of the formula NMV'B: in an inert solvent at a temperature from 0 to 1502C to give a compound of formula (I) where X is ME!B2, M is ME!B2, B is 0, BZ and P? are both hydrogen; and A is C(IOMNHSN(SOOV")(CHg)CO, where r is 1, 2 or C and B" is defined above. 37. The method of obtaining the compound of formula (I) according to item 1, in which the following stages are carried out: the reaction of the compound of formula (II), where B! defined in the formula (I), with the compound of the formula (XI) / 0 ОР ne) 4 (ho where B" is a lower (ar)alkyl and Ra. is a protecting group, by heating the compounds together in the presence of an acid under reduced pressure and temperature from 50 to 1752C, then removal of protective groups and group B" by hydrolysis in acidic or basic conditions to obtain a compound of formula (I), where X represents 5B!; M represents 58; B! is defined in formula (1); B represents 0; B3 and B" both represent hydrogen; A represents COOH; where the compound of formula (XI) is first obtained from ethyl ether (E)-methyl-5,6-dideoxy-2,3-0-(1 - methylethylidene)- " -O-ribohepta-5-enofuranosiduronic acid by hydrolysis with aqueous acid and reaction with an acylating reagent in the presence of a base and a suitable solvent, followed by reduction. 38. The method of obtaining the compound of formula (I) according to item 1, which includes the following stages: () reduction of the compound of formula (I), where X represents 5E!, MVA!B2 or Ci-C7-alkyl; M is 5! MVA!B2 or Ci-C7-alkyl; IN! and VE? defined in formula (1); B is SNeo; BZ and B" together form a bond; and A is SOOV!, where B!!! is defined above; to give a compound of formula (MI) where C and P" are hydrogen; X, Y, B, A and Ri are defined above; (i) de-esterification of the product of stage (i) to obtain a compound of formula (I), where X represents 5E!, MVA!B2 or C-C7-alkyl; M is 5! MVA!B2 or Ci-C7-alkyl; B is CH»e or O; and A is COOH.