RU2174518C2 - Derivatives of 3-h-1,2,3-triazolo-[4,5-d]-pyrimidine, pharmaceutical composition and method of their synthesis - Google Patents

Abstract

FIELD: organic chemistry, pharmacy. SUBSTANCE: invention relates to derivatives of 3-H-1,2,3-triazolo-[4,5-d] -pyrimidine of the general formula (I)

where B means O or CH₂; X is taken among NR¹R²,SR¹ and C₁-C₇-alkyl; Y is taken among SR¹,NR¹R² and C₁-C₇-alkyl; R¹ and R² each means independently H or C₁-C₇-alkyl; or R¹ means C₁-C₇-alkyl optionally substituted in alkyl chain with O or S or one or more halogen atoms and R² means hydrogen atom; R³ and R⁴ both mean hydrogen atom or in common they form bons; A means COOH, C(O)NH-(CH)_p-COOH, C(O)N[(CH₂)_q-COOH]₂, C(O)NHCH-(COOH)-(CH₂)_r-COOH or 5-tetrazolyl where p, q and r each = 1, 2 or 3 independently and also their pharmaceutically acceptable salts or esters. Invention describes also method of synthesis of these compounds and pharmaceutical composition containing thereof. Claimed compounds prevent platelet aggregation. EFFECT: improved method of synthesis, valuable medicinal properties. 17 cl, 26 ex

Description

Field of Invention
The invention relates to new compounds, to a method for their preparation, their use and pharmaceutical compositions containing new compounds. The new compounds are useful for therapy, and, in particular, to prevent platelet aggregation.

BACKGROUND OF THE INVENTION AND BACKGROUND
A number of interconnected processes lead to platelet aggregation. Whatever the initial stimulus, the final overall result is platelet cross-linking by binding of fibrinogen to the membrane binding site, glycoprotein (11b / 111a GP11b / 111a). The high antiplatelet efficiency of antibodies or antagonists of GP11b / 111a can be explained by their influence on the final overall result. However, this effectiveness can also explain the bleeding problems that were observed when using an agent of this class.

 Thrombin can produce platelet aggregation to a large extent independent of other processes, but significant amounts of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors, such as hirudin, are highly effective antithrombotic agents, but again can lead to excessive bleeding because they act as antiplatelet agents as well as anticoagulants (Investigators TIMI 9a (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators (GUSTO) Circulation 90, pp. 1631-1637; Neuhaus, et al. (1994) Circulation 90, pp. 1638-1642).

 Aspirin, which is known to have a beneficial effect on platelet aggregation (see, for example, Antiplatelet Trialists 'Collaboration (1994), Br. Med. J. 308, pp. 81-106; Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 159-168) does not affect the aggregation produced by other ADP sources, such as damaged cells or ADP released under turbulent blood flow conditions. The cardinal role of ADP is confirmed by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5-HT, serotonin), aggregate only in the presence of ADP.

In the present invention, it was assumed that the antagonist of the action of ADP on its platelet membrane receptor, a P _2T purineceptor, would provide a more effective antithrombotic agent than aspirin, but with a lesser effect on bleeding than fibrinogen receptor antagonists.

 US Pat. No. 4,543,255 discloses carbocyclic analogues of 2-amino-6-substituted-purine-2′-deoxyribofuranosides and 2-amino-6-substituted-8-azapurin-2′-deoxyribofuranosides. The compounds described in this patent are shown to have an inhibitory effect against the herpes virus.

 WO 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 to find new compounds with improved antagonistic activity against the P _2T receptor and significant advantages compared with known antiplatelet agents, such as improved efficiency, reduced side effects, lack of toxicity and better selectivity for P _2T to the receptor.

 The problem indicated above is solved by the preparation of new compounds which are 5,7-disubstituted 1,2,3-triazolo [4,5-d] pyrimidin-3-yl derivatives described below.

,
в которой В представляет собой О или CH₂;
X представляет NR¹R², SR¹ и С₁-С₇-алкил;
Y представляет SR¹, NR¹R² и C₁-С₇-алкил;
R¹ и R² каждый независимо представляет H или С₁-C₇-алкил, необязательно замещенный на или в алкильной цепи одним или более атомами О, S, N или галогена;
R³ и R⁴ оба представляют H или R³ и R⁴ вместе образуют связь;
А представляет COOH, C(O)NH(CH₂)_pCOOH, С(O)N[(CH₂)_qCOOH]₂, C(O)NHCH(COOH) (CH₂)_rCOOH или 5-тетразолил, где p, q и r каждый независимо равен 1, 2 или 3.DETAILED DESCRIPTION OF THE INVENTION
The new compounds of the present invention are described by the general formula (1)

,
in which represents O or CH ₂ ;
X represents NR ¹ R ² , SR ¹ and C ₁ -C ₇ alkyl;
Y represents SR ¹ , NR ¹ R ² and C ₁ -C ₇ alkyl;
R ¹ and R ² each independently represents H or C ₁ -C ₇ alkyl optionally substituted on or in the alkyl chain by one or more O, S, N or halogen atoms;
R ³ and R ⁴ both represent H or R ³ and R ⁴ together form a bond;
A represents COOH, C (O) NH (CH ₂ ) _p COOH, C (O) N [(CH ₂ ) _q COOH] ₂ , C (O) NHCH (COOH) (CH ₂ ) _r COOH or 5-tetrazolyl, where p, q, and r are each independently 1, 2, or 3.

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

The substituents O, S and N can be substituents on or in the alkyl chain, which means C ₁ -C ₇ -alkyl in which one methylene in the chain can be replaced by O, S or NH, and in which the alkyl chain can be substituted by one or more by OH, SH, NH ₂ or halogen.

 Halogen includes chlorine and fluorine.

 Also included within the scope of the invention are pharmaceutically acceptable salts of the compounds of formula (1), as well as prodrugs such as esters and amides of the compounds.

 Also included in the scope of the invention are compounds of formula (1) in tautomeric, enantiomeric and diastereomeric forms.

Preferred compounds of the invention are compounds of formula (1) in which
X represents NR ¹ R ² ;
Y represents SR ¹ ;
A represents C (O) NHCH (COOH) (CH ₂ ) _r COOH;
and in which R ¹ , R ² and r are defined above.

Particularly preferred compounds of the invention are compounds of formula (1) in which
X represents NR ¹ R ² where R ¹ represents hydrogen and R ^{2 as} defined above;
Y is SR ¹ , where R ¹ is C ₁ -C ₅ alkyl optionally substituted with one or more halogens; and
A represents C (O) NHCH (COOH) CH ₂ COOH.

The most preferred compounds of the invention are (E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid;
[1R- (1 α, 2 β, 3 β, 4 α)] - N- [3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4 , 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] -L-aspartic acid;
[1R- (1 α, (E), 2 β, 3 β, 4 α)] - N- [3- [4- [7- (hexylamino) -5- (propylthio) -3H- 1,2,3 triazolo [4,5-d-pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid; and
[1R- (1 α (E), 2 β, 3 β, 4 α)] - N- [3- [4- [5 - [(3,3,3-Trifluoropropyl) thio] - 7- [2- (methylthio) ethylamino] -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl / -2,3-dihydroxycyclopentyl / -2-propanoyl / -L-aspartic acid, monoammonium salt.

 The novel 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, therefore, are useful for the treatment or prophylaxis of unstable angina, plastic surgery on coronary vessels 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 (i.e., without thrombolysis).

 Further indications when the compounds of the invention are useful are the treatment or prophylaxis of arterial thrombotic complications due to interference with atherosclerotic diseases such as vascular plastic surgery, endarterectomy, stent insertion, coronary and other vascular graft surgery.

 Further indications when the compounds of the invention are useful are the treatment or prophylaxis of thrombotic complications in surgical or mechanical injuries, such as rescuing tissue from trauma due to surgery or an accident, plastic surgery, including skin grafts, and reconstructive surgery, such as breast repair.

 The compounds of the invention are also useful for preventing mechanically induced platelet activation in vivo, such as cardiopulmonary bypass (preventing microthromboembolism), preventing mechanically induced platelet activation in vitro, such as using compounds for preserving blood products, for example platelet concentrates, and preventing clogging of a shunt, such as hemodialysis and plasmapheresis, thrombosis secondary to vascular damage / inflammation, such as vasculitis, arteritis, glomerulonephritis and otto transplant organ neighing.

 Further indications for the use of the compounds of the invention are a component of diffuse thrombotic / platelet flow, such as disseminated intravascular coagulation, thrombotic purpura, hemolytic uremic syndrome, thrombotic complications, adult respiratory distress syndrome, antiphospholipid syndrome, thrombocytopenia, and pre-thrombocytopenia, and hepreclampiasis.

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

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

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

Production methods
Compounds of the present invention can be obtained by the following methods.

,
в которой R¹ определяют как в формуле (1).A)
(i) The starting material, 4,5-diamino-2,6-dimercaptopyrimidine, is alkylated, followed by diazotization, to give a compound of formula (II)

,
in which R ¹ is determined as in formula (1).

,
в которой P₂ представляет защитную группу; и L представляет уходящую группу;
в инертном растворителе и в присутствии основания. Растворители, которые могут быть использованы, включают ДМФ, а основания, которые могут быть использованы, включают амид натрия. Реакцию проводят при температурах от -20 до 50^oC. Предпочтительно реакцию проводят при температуре окружающей среды, растворителем является ацетонитрил и основание представляет собой гидрид натрия. Подходящая защитная группа включает ацильную группу, такую как бензоил, а подходящая уходящая группа включает галоген, такой как бром.(ii) The product of formula (II) of step (i) is reacted with a compound of formula (III)

,
in which P ₂ represents a protective group; and L represents a leaving group;
in an inert solvent and in the presence of a base. Solvents that can be used include DMF, and bases that can be used include sodium amide. The reaction is carried out at temperatures from -20 to 50 ^° C. 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 (III) used in this step is prepared by halogenation of a suitably protected ribose.

Thus, the group X = NR ¹ R ² in which R ¹ and R ^{2 are} defined in formula (1) above can be introduced by reaction with a compound of the formula HNR ¹ R ² in which R ¹ and R ^{2 are} defined in formula (1 ) above, in an inert solvent at a temperature of from 0 to 150 ^o C. Preferably, the solvent is 1,4-dioxane and a temperature of 100 ^o C.

The protecting groups P ₂ can be removed by treatment with a nucleophile, for example, alkoxide in an alcohol solvent, preferably sodium methoxide in methanol at 60 ^° C.

,
в которой X представляет NR¹R²; Y представляет SR¹; и где R¹ и R² определены в формуле (1) выше.The product obtained in this step is a compound of formula (IV)

,
in which X represents NR ¹ R ² ; Y represents SR ¹ ; and where R ¹ and R ^{2 are} defined in formula (1) above.

,
в которой X представляет NR¹R²; Y представляет SR¹; B представляет O и P₁ представляет защитную группу, предпочтительно P₁/P₁ вместе образуют кольцо.(iii) The product of formula (IV) of step (ii) is reacted with an appropriate carbonyl compound or orthoester and an inert solvent and in the presence of an inorganic or organic acid as an acid catalyst at a temperature between -15 and 100 ^° C. to give a compound of formula (V)

,
in which X represents NR ¹ R ² ; Y represents SR ¹ ; B represents O and P ₁ represents a protecting group, preferably P ₁ / P ₁ together form a ring.

Preferably, P ₁ / P ₁ is ethoxymethylidene, introduced using triethyl orthoformate in 1,4-dioxane at 50 ^° C. and in the presence of trichloroacetic acid.

,
в которой R¹ определен в формуле (1); и М представляет уходящую группу.IN)
(i) 4,6-dihydroxy-2-mercaptopropyrimidine is alkylated, then nitrated, so that two alcohols are converted to leaving groups to give a compound of formula (VI)

,
in which R ^{1 is} defined in formula (1); and M represents a leaving group.

 Examples of leaving groups that can be used are halogens.

,
в которой Y представляет SR¹; R¹ определен в формуле (1); М представляет уходящую группу; и P₁ представляет защитную группу.The compound of formula (VI) is reacted with suitably protected 5,6-dihydroxy-2-azabicyclo [2.2.1] heptan-3-one, preferably [3aS- (2aα, 4β, 7β, 7α-tetrahydro-2, 2 -dimethyl-4,7-methano-1,3-dioxolo [4,5-c] pyridin-6 (3aH) -one, in the presence of a base such as butyllithium, in an inert solvent such as tetrahydrofuran, at temperatures of 10- 100 ^o C to obtain the compounds of formula (VII)

,
in which Y represents SR ¹ ; R ^{1 is} defined in formula (1); M represents a leaving group; and P ₁ represents a protecting group.

Preferably, P ₁ / P ₁ together form a ring, such as isopropylidene, and preferably the leaving group is chlorine.

 Preferably, the base is sodium hydride, the solvent is DMF, and the reaction is carried out at ambient temperature.

 (ii) The nitro group and lactam in the product of formula (VII) of step (i) are reduced, followed by cyclization to give triazole.

Methods for reducing the nitro group that may be mentioned include hydrogenation using transition metals as catalysts, such as palladium on carbon in a hydrogen atmosphere at a pressure of 1-5 atmospheres in a suitable solvent, for example ethanol. Iron is preferably used in an acidic solvent such as acetic acid at temperatures between 20 and 150 ^° C, most preferably at a temperature of 100 ^° C.

Reduction methods that may be mentioned include the use of complex metal hydrides, such as lithium aluminum hydride in an inert solvent such as tetrahydrofuran, at temperatures from 0 to 100 ^° C. Sodium borohydride in methanol is preferably used at a temperature of 0-30 ^° C.

The diamino alcohol thus obtained is cyclized by a diazotization reaction using metal nitrites or alkyl nitrites in a suitable solvent, for example, sodium nitrite is used in dilute aqueous HCl at a temperature of from -20 to 100 ^° C. Isoamyl nitrite in acetonitrile is preferably used at 80 ^° C.

The group X = NR ¹ R ² is introduced by reaction with a compound of formula HNR ¹ R ² in an inert solvent at a temperature of from 0 to 150 ^° C. to give a compound of formula (V) in which X is NR ¹ R ² ; Y represents SR ¹ ; R ¹ and R ^{2 are} defined in formula (1); B represents CH ₂ ; and P ₁ is a protecting group.

Preferably, 1,4-dioxane is used as the solvent and the reaction is carried out at a temperature of 100 ^° C. Preferably P ₁ / P ₂ together form a ring, most preferably P ₁ / P ₂ is isopropylidene.

,
в которой В представляет О или CH₂; X, Y и P₁ определены в формуле (V) на стадиях А) и В) соответственно; А представляет COOR¹¹, в которой R¹¹ представляет низший (ар)алкил; и R³ и R⁴ вместе образуют связь.FROM)
(i) The product of steps A) and B), that is, the compound of formula (V) obtained in steps A) and B), respectively, is oxidized and subjected to an olefination reaction to give a compound of formula (VIII)

,
in which represents O or CH ₂ ; X, Y and P _{1 are} defined in formula (V) in steps A) and B), respectively; A represents COOR ¹¹ , in which R ¹¹ represents lower (ar) alkyl; and R ³ and R ⁴ together form a bond.

Oxidation methods that may be mentioned include the Swern reaction and the use of Dess Martin reagent in appropriate solvents at temperatures between -78 and 120 ^° C. Pfitzner-Mofatt oxidation in DMSO is preferably used. as a solvent at ambient temperature and the protective groups P ₁ / P ₁ together form a ring, the case where P ₁ / P ₂ is isopropylidene is most preferred. Methods of olefination that may be mentioned include the Peterson reaction and the Horner-Emmons reaction. Preferably, a Wittig reaction with a phosphorus ylide such as (carboxymethylene) triphenylphosphorane is used, particularly (tert-butoxycarbonylmethylene) triphenylphosphorane is particularly preferred.

(ii) R ^{11 is} removed by deesterification using acidic or alkaline hydrogenolysis conditions and, finally, deprotected to give a compound of formula (1) in which X is NR ¹ R ² ; Y represents SR ¹ ; B represents O or CH ₂ ; R ¹ and R ^{2 are} defined in formula (1); R ³ and R ⁴ together form a bond; and A represents COOH.

R ¹¹ groups that may be mentioned include methyl, ethyl, isopropyl, tert-butyl, and benzyl. R ¹¹ 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. 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, for example, in aqueous 1,4-dioxane. Benzyl groups can be removed by hydrogenolysis using transition metals as catalysts, for example palladium-on-charcoal, in a hydrogen atmosphere at a pressure of 1-5 atmospheres in a suitable solvent, such as acetic acid. Preferably, R ¹¹ is tert-butyl and hydrolysis is carried out using trifluoroacetic acid in dichloromethane.

The protective groups in the case of acyl and benzyl can be removed as described for R ¹¹ above, silyl protective groups can be removed using, for example, fluoride ion. Lower alkyl groups can be removed using, for example, boron tribromide. Methylidene and ethoxymethylidene can be removed using, for example, an inorganic or organic acid. All of these methods can be carried out at a temperature between -80 and 150 ^° C. Preferably R ¹¹ is tert-butyl and P ₁ / P ₁ is isopropylidene, both groups being removed simultaneously using trifluoroacetic acid in dichloromethane at ambient temperature.

D)
A compound of formula (1) wherein X is SR ¹ , NR ¹ R ^2, or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² , C ₁ -C ₇ alkyl; R ¹ and R ^{2 are} defined in formula (1); B represents O or CH ₂ ; R ³ and R ⁴ represent hydrogen or together form a bond; and A represents COOH; react with a compound of structure NH ₂ (CH ₂ ) _p COOR ¹¹ , NH [(CH ₂ ) _q COOR ¹¹ ] ₂ or NH ₂ CH (COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ , where p, q and r are equal 1, 2 or 3 and R ¹¹ represents lower (ar) alkyl;
using methods used in peptide synthesis, for example, using a combination agent. Combination agents that may be used include 1,1'-carbonyldiimidazole and N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline.

In this step, a compound of formula (1) is prepared in which X is SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; B represents O or CH ₂ ; R ³ and R ⁴ represent hydrogen or together form a bond; and A represents C (O) NH (CH ₂ ) _p COOR ¹¹ , C (O) N [(CH ₂ ) _q COOR ¹¹ ] ₂ or C (O) NHCH (COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ , of which p, q and r are 1, 2 or 3 and R ¹¹ represents lower (ar) alkyl;
R ¹¹ 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. Dicyclohexylcarbodiimide or bromotrispyrrolidinophosphonium hexafluorophosphate in N, N-dimethylformamide (DMF) is preferably used at a temperature between 0 ^° C. and room temperature.

(ii) The product of formula (1) of step (i) is deesterified to give a compound of formula (1) in which
B represents O or CH ₂ ; X represents NR ¹ R ² , SR ¹ or C ₁ -C ₇ alkyl; Y represents NR ¹ R ² , SR ¹ or C ₁ -C ₇ alkyl; R ¹ and R ² each independently represents H or C ₁ -C ₇ alkyl optionally substituted on or in the alkyl chain by one or more O, S, N or halogen; R ³ and R ⁴ both represent hydrogen or R ³ and R ⁴ together form a bond; and A represents C (O) NH (CH ₂ ) _p COOH, C (O) N [(CH ₂ ) _q COOH] ₂ or C (O) NHCH (COOH) (CH ₂ ) _r COOH, where p, q and r are equal to 1.2 or 3.

R ¹¹ groups that may be used include methyl, ethyl, isopropyl, tert-butyl, and benzyl. R ¹¹ 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. 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, for example, in aqueous 1,4-dioxane. Benzyl groups can be removed by hydrogenolysis using, as catalysts, transition metals, for example palladium-on-charcoal, in a hydrogen atmosphere at a pressure of 1-5 atmospheres in a suitable solvent, such as acetic acid. Preferably R ¹¹ is tert-butyl and hydrolysis using trifluoroacetic acid in dichloromethane.

E)
The product obtained in step C (ii) is reduced to give a compound of formula (1), wherein B, X, Y, R ¹ and R ^{2 are} defined in step C (ii) above; A represents COOH; and R ³ and R ⁴ both represent hydrogen.

Reduction methods that can be used include hydrogenolysis using transition metals as catalysts, for example palladium-on-carbon, in a hydrogen atmosphere in a suitable solvent, such as acetic acid, at a pressure of 1-5 atmospheres. Preferably, diimide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonyl hydrazide, is used at a temperature between 60 and 100 ^° C. in a tetrahydrofuran (THF) solvent.

,
где Y представляет C₁-С₇-алкил; P₁ представляет защитную группу и предпочтительно P₁/P₁ вместе образуют кольцо; P₂ представляет защитную группу; и М представляет ОН.F)
(i) suitably protected
5-amino-1- (β-D-ribofuranosyl) -1,2,3-triazole-4-carboxamide, preferably 5-amino-1- [2,3-O- (1-methylethylidene) -β-D- ribo-furanosyl] -1,2,3-triazole-4-carboxamide, treated with a base, followed by treatment with an ester of the formula R ¹ COOR ⁵ , where R ^{1 is} defined in formula (1) and R ⁵ is lower alkyl. Then carry out the protection and get the compound of formula (IX)

,
where Y is C ₁ -C ₇ alkyl; P ₁ represents a protective group and preferably P ₁ / P ₁ together form a ring; P ₂ represents a protecting group; and M represents OH.

Protecting groups P ₂ that may be used include lower alkyl or acyl. Preferably, P ₂ is acetyl, which is introduced by treatment with acetyl chloride and triethylamine in a suitable solvent, for example dichloromethane, at ambient temperature. Most preferably, P ₁ / P ₁ is isopropylidene and P ₂ is acetyl.

(ii) The compound of formula (IX), where M is OH, is halogenated and a group X = NR ¹ R ² is introduced, introduced by treatment with a compound of the formula HNR ¹ R ² in an inert solvent at a temperature of from 0 to 150 ^° C. Then, the protecting group P is removed. ₂ and obtain a compound of formula Y in which X is NR ¹ R ² ; R ¹ and R ^{2 are} defined in formula (1); Y represents C ₁ -C ₇ alkyl; B represents O; and P ₁ represents a protecting group, and preferably P ₁ / P ₁ together form a ring. Most preferably, P ₁ / P ₁ are isopropylidene.

Halogenating reagents that can be used include halides of P (III), or P (V), or S (II), or S (IV), such as phosphorus trichloride, at a temperature of from 0 to 150 ^o C. The reaction can be carried out in a halogenating reagent used as a solvent or in an inert solvent such as methylene chloride. Preferably, thionyl chloride in DMF / chloroform is refluxed.

The preferred solvent used to introduce the group X = NR ¹ R ² is 1,4-dioxane at a temperature of 100 ^° C. The protecting group P ₂ can be removed under the same conditions. Alternatively, it can be removed using acidic or basic hydrolysis.

 Ammonia in methanol is preferably used at ambient temperature.

(iii) The product of formula (V) of step (ii) is introduced into the same reactions as described in steps C (i) and (ii) to give a compound of formula (1) in which X is NR ¹ R ² ; R ¹ and R ^{2 are} defined in formula (1); B represents O; Y represents C ₁ -C ₇ alkyl; A represents COOH; and R ³ and R ⁴ together form a bond.

,
где L представляет уходящую группу, предпочтительно имидазолил, с получением соединения формулы (X)

,
в которой P₁ представляет защитную группу, предпочтительно когда P₁/P₁ вместе образуют кольцо; и P₃ представляет защитную группу, предпочтительно силильную группу. Наиболее предпочтителен случай, когда P₁/P₁ представляет изопропилиден и P₃ представляет трет-бутилдиметилсилил.G)
(i) A suitable protecting group P ₃ is introduced into the protected 5-amino-1- (β-D-ribofuranosyl) -1,2,3-triazole-4-carboxamide, preferably 5-amino-1- [2,3-O - (1-methylethylidene) -β-D-ribofuranosyl] -1,2,3-triazole-4-carboxamide. The resulting intermediate is treated with a base, preferably sodium hydride, followed by treatment with a reagent of the formula

,
where L represents a leaving group, preferably imidazolyl, to give a compound of formula (X)

,
in which P ₁ represents a protective group, preferably when P ₁ / P ₁ together form a ring; and P ₃ represents a protecting group, preferably a silyl group. Most preferred is when P ₁ / P ₁ is isopropylidene and P ₃ is tert-butyldimethylsilyl.

(ii) The product of formula (X) of step (i) was treated with a base, such as butyllithium, in an inert solvent, such as THF, at a temperature between -20 and 50 ^° C, followed by treatment with an alkylating agent R ¹ G, where G is a leaving a group such as halogen, and where R ^{1 is} defined in formula (1).

 Preferably, sodium hydride in DMF is used as the base at ambient temperature, and G is iodine.

Then P _{3 is} removed from the compound above and substituted with a new protecting group P ₂ . Preferably P ₂ is acyl.

Preferably, P ₃ is a silyl group that is removed by treatment with fluoridione and is replaced by acyl. Most preferably, P ₃ is tert-butyldimethylsilyl, which is removed by reaction with tetra-n-butylammonium fluoride in THF, followed by the introduction of a protective group P ₂ by reaction with acetyl chloride in dichloromethane at ambient temperature.

At the end, halogenation is carried out and a compound of formula (IX) is obtained in which M represents a leaving group, for example, halogen and preferably chlorine; P ₁ represents a protecting group, preferably P ₁ / P ₁ together form a ring; and P ₂ represents a protecting group, preferably acetyl; and Y represents SR ¹ .

Halogenating reagents that can be used include P (III), or P (II), or S (II), or S (IV) 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. Thionyl chloride in DMF / chloroform is preferably used under reflux.

(iii) The product of step (ii) was reacted with nucleophilic alkyl, for example, Grignard reagent, in an inert solvent such as THF, at a temperature between -20 and 150 ^° C. Preferably, the nucleophilic alkyl is an alkyltin compound used in the presence of Pd ( Ii) a catalyst. Then, the protecting group P ₂ was removed and a compound of formula (V) was obtained in which X is C ₁ -C ₇ alkyl; Y represents SR ¹ ; R ^{1 is} defined in formula (1); B represents O; and P ₁ represents a protecting group, preferably P ₁ / P ₁ together form a ring, which is most preferably isopropylidene.

The protecting group P ₂ can be removed by acid or basic hydrolysis. Preferably, P ₂ is acetyl, which is removed by reaction with ammonia in methanol at ambient temperature.

H)
(i) The compound of formula (1) in which
X represents NR ¹ R ² ; Y represents SR ¹ ; R ¹ and R ^{2 are} defined in formula (1); B represents O; R ³ and R ⁴ both represent hydrogen; and A represents C (O) NHCH (COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ in which r is 1, 2 or 3 and R ^{11 is as} defined above;
treated with an oxidizing agent, such as magnesium monoperoxyphthalate, in an inert solvent, such as THF, at a temperature between -20 and 100 ^° C, followed by treatment with a compound of the formula HNR ¹ R ² in an inert solvent at a temperature of 0 to 150 ^° C to obtain a compound of the formula (1) in which
X represents NR ¹ R ² ; Y represents NR ¹ R ² ; B represents O;
R ³ and R ⁴ both represent hydrogen; and A represents C (O) NHCH (COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ in which r is 1, 2 or 3 and R ^{11 is} determined in step D) above.

Preferably, m-chloroperoxybenzoic acid in an ethanol solvent is used as the oxidizing agent at ambient temperature, and the substitution is carried out in 1,4-dioxane at 100 ^° C.

,
в которой R¹² представляет низший (ар)алкил и P₄ представляет защитную группу, такую как ацетил.I)
A compound of formula (1) in which X is SR ¹ ; Y represents SR ¹ ; B represents O; R ³ and R ⁴ both represent hydrogen; A represents COOH;
can be obtained by reacting a compound of formula (II) in which R ^{1 is} defined in formula (1) with a compound of formula (XI)

,
in which R ¹² represents lower (ar) alkyl and P ₄ represents a protective 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 a temperature between 50 and 175 ^o C. Preferably R ¹² is ethyl, P ₄ is acetyl and the reaction is carried out at 140 ^o C in the presence of p-toluenesulfonic acid in a vacuum water-jet pump.

The protecting groups and the R ¹² group can then be removed by hydrolysis under acidic or basic conditions to give a compound of formula (1) in which X is SR ¹ ; Y represents SR ¹ ; R ^{1 is} defined in formula (1); B represents O; R ³ and R ⁴ 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 ^o C, or, alternatively, trifluoroacetic acid in dichloromethane can be used. Preferably, R ¹² is ethyl and P ₄ is acetyl and lithium hydroxide in aqueous tetrahydrofuran at ambient temperature.

 The compound of formula (XI), which is one of the starting materials in this reaction step, is first prepared from (E) -methyl-5,6-dideoxy-2,3-O- (1-methylethylidene) -β-D- ethyl ester ribohept-5-enofuranosiduronic acid by hydrolysis with aqueous acid, for example aqueous acetic acid, and reaction with an acylating reagent such as acetyl chloride, in the presence of a base, for example pyridine, and a suitable solvent, for example methylene chloride, followed by reduction, for example, by hydrogenation using as catalysts base metals, such as palladium-on-carbon, in a hydrogen atmosphere in a suitable solvent, for example ethanol, at a pressure between 1 and 3 atm.

J)
The compound of formula (1) in which
X represents NR ¹ R ² ; Y represents SR ¹ ; R ¹ and R ^{2 are} defined in formula (1); B represents O or CH ₂ ; R ³ and R ⁴ both represent hydrogen; and A is 5-tetrazolyl;
received as follows.

The product of stage A (iii) or the product of stage B (ii), for example a compound of formula (V) in which B is O or CH ₂ and X and Y are as defined in formula (Y) above and P ₁ is a protecting group, preferably P ₁ / P ₁ together form a ring, oxidized, followed by an olefination reaction and subsequent reduction.

Oxidation methods that can be used include the Swern reaction and the use of Dess Martin reagent in appropriate solvents at temperatures between -78 and 120 ^° C. Pfitzner-Mofatt oxidation in DMSO is preferably used. as a solvent at ambient temperature, using a compound of formula (Y) in which P ₁ / P ₂ is isopropylidene. Methods of olefination that may be used include the Peterson reaction and the Horner-Emmons reaction. Preferably, the Wittig reaction with phosphorus- (triphenylphosphoranilidene) acetonitrile ylide. Reduction methods that can be used include hydrogenation using transition metals as catalysts, such as platinum, in a hydrogen atmosphere, in a suitable solvent, for example acetic acid, at temperatures between 0 and 100 ^o C. It is preferable to use palladium-on coal at a pressure of 4 atm in ethanol at ambient temperature.

,
в которой B представляет О или CH₂; P₁ представляет защитную группу, предпочтительно P₁/P₁ вместе образуют кольцо и наиболее предпочтительно P₁/P₁ представляет изопропилиден; и R¹ и R² определены в формуле (1).The product obtained in this way is a compound of formula (XII)

,
in which B represents O or CH ₂ ; P ₁ represents a protecting group, preferably P ₁ / P ₁ together form a ring and most preferably P ₁ / P ₁ represents isopropylidene; and R ¹ and R ^{2 are} defined in formula (1).

This compound of formula (XII) is reacted with an azide, such as sodium azide, in an inert solvent, for example DMF, at a temperature between 0 and 175 ^° C. Isopropylidene is a preferred protecting group. Tributyltin azide in toluene is preferably used at a temperature of 110 ^° C.

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 is preferably used at ambient temperature.

Thus, a product of formula (1) is obtained in which X is NR ¹ R ² ; Y represents SR ¹ ; R ¹ and R ^{2 are} defined in formula (1), B is O or CH ₂ ; R ³ and R ⁴ are both hydrogen; and A is 5-tetrazolyl.

TO)
The compound of formula (1) in which
X represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; R ¹ and R ^{2 are} defined in formula (1); B represents CH ₂ or O; R ³ and R ⁴ together form a bond; and A represents COOR ¹¹ in which R ^{11 is} defined in formula (1) above;
restore to obtain the compounds of formula (VIII) in which R ³ and R ⁴ represent hydrogen; X, Y, B, A, R ¹¹ and P _{1 are} defined above.

Reduction methods that can be used include hydrogenation using transition metals as catalysts, for example, palladium-on-carbon, in a hydrogen atmosphere in a suitable solvent, such as acetic acid, at a pressure of 1-5 atmospheres. Preferably, diimide obtained from a suitable precursor, such as 2,4,6-triisopropylbenzenesulfonyl hydrazide, is used at a temperature between 60 and 100 ^° C. in a tetrahydrofuran solvent.

(ii) The product of step (i) is introduced into the same reaction as described for step D (ii) to give a compound of formula (1) in which
X represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; R ¹ and R ^{2 are} defined in formula (1), B is CH ₂ or O; and A represents COOH.

 The compounds of formula (1), as well as their salts and prodrugs, such as esters or amides, can be isolated from the reaction mixtures by conventional methods.

 Salts of the compounds of formula (1) can be prepared by reacting the free acid or its salt, or the free base or its salt, or a 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 insoluble, 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 may also be an exchange process or may be carried out on an ion exchange resin. Non-toxic physiologically acceptable salts are preferred, although other salts may be useful, for example, to isolate or purify a product.

 Pharmaceutically acceptable esters of compounds of formula 1 can be prepared by conventional methods, for example, esterification and transesterification.

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

DETAILED DESCRIPTION OF THE INVENTION
The invention is hereinafter described in more detail using examples that should not be construed as limiting the scope of the invention. The temperature is given in Examples in degrees Celsius, unless specifically indicated. Abbreviations: MS - mass spectrometry, E1 - EU (electron impact), APCI - FI (photoionization), ESI - PI (surface ionization), FAB - BBA (fast atom bombardment).

EXAMPLES
Example
The sodium salt of [1R- (1α (E), 2 β, 3β, 4α)] - 3- [4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid
a) 2- (Propylthio) -4.6 (1H, 5H) -pyrimidinedione
Propyl iodide (136 ml) was added to a suspension of 4,6-dihydroxy-2-mercaptopopyrimidine (200 g) in water (800 ml) containing sodium hydroxide (55.6 g). The reaction mixture was stirred for 2 weeks, then concentrated to half volume, 2 N hydrochloric acid was added and the product was isolated by filtration (167 g).

MS (EU): 186 (M ⁺ , 100%).

b) 6-Hydroxy-5-nitro-2- (propylthio) -4 (1H) -pyrimidinone
The product of step a) (70 g) was slowly added to ice-cooled fuming nitric acid (323 ml). The reaction mixture was stirred for 1 hour, then poured onto ice and the product was isolated by filtration (65 g).

MS (EU): 231 (M ⁺ ), 41 (100%).

c) 4,6-Dichloro-5-nitro-2- (propylthio) pyrimidine
N, N-Diethylaniline (150 ml) was added dropwise to a stirred suspension of the product of stage b) (134 g) in phosphoryl chloride (500 ml), and the resulting solution was heated under reflux for 1 hour. The cooled reaction mixture was poured onto ice, then extracted with diethyl ether (3 x 500 ml). The combined extracts were dried and concentrated. Chromatography (SiO ₂ , isohexane: 19: 1 diethyl ether as eluent) gave the title compound (128 g).

MS (EU): 271, 269, 267 (M ⁺ ), 41 (100%).

d) [3aS- (3aα, 4β, 7β, 7aα)] -5- [6-Chloro-5-nitro-2- (propylthio) pyrimidin-4-yl] tetrahydro-2,2-dimethyl-4,7- methano-1, 3-dioxolo [4,5-c] pyridin-6 (3aH) -one
Sodium hydride (60%, 4.00 g) was added portionwise to [3aS- (3aα, 4β, 7β, 7aα)] tetrahydro-2, 2-dimethyl-4,7-methano-1,3-dioxolo [4,5 -c] pyridin-6 (3aH) -one (18.3 g) in THF (500 ml). With stirring for 1 hour, the solution was added dropwise to the product of step c) (54.0 g) in THF (500 ml). The reaction mixture was stirred at room temperature for 45 minutes, then concentrated and purified by chromatography (SiO ₂ , dichloromethane: isohexane 3: 2 as eluent) to obtain the title compound (79.2 g).

MS (FI): 417, 415 (M + H ⁺ ), 415 (100%).

e) [3aS- (3aα, 4β, 7β, 7aα)] -5- [5-amino-6-chloro-2- (propylthio) pyrimidin-4-yl] tetrahydro-2,2-dimethyl-4,7- methano-1, 3-dioxolo- [4,5-c] pyridin-6 (3aH) -one
Reduced iron powder (50 g) was added to a solution of the product of stage d) (50.0 g) in glacial acetic acid (1.8 L) and the reaction mixture was heated under reflux for 15 minutes. The cooled reaction mixture was concentrated and the residue was extracted with ether (2 L), then washed with sodium bicarbonate solution (2 x 1 L). The organic phase was dried and concentrated to give the title compound (42.6 g).

MS (FI): 387, 385 (M + H ⁺ ), 385 (100%).

 f) [3aR- (3aα, 4α, 6α, 6aα)] -6- [5-amino-6-chloro-2- (propylthio) pyrimidin-4-ylamino] tetrahydro-2,2-dimethyl-4H-cyclopenta- 1,3-dioxol-4-methanol.

Sodium borohydride (8.37 g) was added to an ice-cooled solution of the product of step e) (42.6 g) in methanol (1.3 L). 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 (SiO ₂ dichloromethane: ethyl acetate 1: 1 as eluent) gave the title compound (36.1 g).

MS (FI): 419, 417 (M + H ⁺ ), 417 (100%).

g) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7-Chloro-2- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
Isoamyl nitrite (24.9 ml) was added to a solution of the product of stage f) (36.0 g) in acetonitrile (80 ml) and the solution was heated for 1 hour at 70 ^° C. The cooled reaction mixture was concentrated and purified (SiO ₂ , dichloromethane: ethyl acetate 4: 1 as eluent) to give the title compound (33.6 g).

MS (EU): 401, 399 (M + H ⁺ ), 43 (100%).

h) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
The product of step g) (16.75 g) and butylamine (30 ml) in 1,4-dioxane (500 ml) were heated under reflux for 1 hour. The reaction mixture was concentrated and the residue was purified (SiO ₂ , dichloromethane: ethyl acetate 4: 1 as eluent) to obtain the title compound (17.8 g).

MS (FI): 437 (M + H ⁺ , 100%).

f) [3aR- (3aα, 4α (E), 6α, 6aα)] -3- [6- [7- (Butylamino) - 5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic acid, 1,1-dimethylethyl ether
A stirred solution of the product of step h) (0.5 g), pyridine (0.093 ml) and trifluoroacetic acid (0.048 ml) in DMSO (25 ml) was treated with 1,3-dicyclohexylcarbodiimide (0.72 g) and the mixture was stirred at room temperature in within 24 hours. Tert-butoxycarbonylmethylene triphenylphosphorane (0.69 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. After 30 minutes, the mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution (100 ml), dried and concentrated. Chromatography (SiO ₂ , hexane: 5: 1 ethyl acetate as eluent) afforded the title compound (0.55 g).

MS (FAB): 533 (M + H ⁺ , 100%).

j) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt
A solution of the product of step i) (0.8 g) in 50% 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 (30 ml). Free acid was dissolved in methanol: water (2: 3, 30 ml) and passed through a Dowex 50 x 100 ion exchange resin (sodium form), eluting with water. Lyophilization gives the salt of the target compound as a colorless solid (0.43 g).

NMR δ H (d ₆ -DMSO): 6.59 (1H, dd), 5.89 (1H, d), 4.94 (1H, m), 4.45 (1H, t), 4.12 ( 1H, t), 3.45 (2H, m), 2.83 (3H, m), 2.47 (1H, m), 2.00 (1H, m), 1.5 (4H, m), 1.20 (2H, m), 0.82 (3H, t), 0.71 (3H, t).

Example 2
[lR- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7- (Butylamino) - 5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid, bis (1; 1-dimethylethyl) ether
a) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-acparaginic acid, bis (1,1-dimethylethyl) ether
L-aspartic acid di-tert-butyl ester hydrochloride (0.46 g) and triethylamine (0.23 ml) were added to a solution of the compound of Example 1 (0.6 g) in DMF (25 ml). 1-Hydroxybenzotriazole (0.22 g) was added and the solution was cooled in an ice bath before adding 1,3-dicyclohexylcarbodiimide (0.34 g). The reaction mixture was stirred for 30 minutes at 0 ^° C., then at room temperature for 3 days. After removal of the solvent, chromatography (SiO ₂ , chloroform: methanol 40: 1 as eluent) gave the title compound (0.63 g).

MS (FAB): 664 (M + H ⁺ ), 57 (100%).

b) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3,3-dihydroxycyclopentyl] -2-propenoyl] - L-aspartic acid, disodium salt
A solution of the product of step a) (0.60 g) in dichloromethane (30 ml) containing trifluoroacetic acid (30 ml) was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified (HPLC, Nova-Pak ^R C18 column, 0.1% aqueous ammonium acetate: methanol from 50:50 to 0: 100 in 15 minutes as an eluent) gave the title salt as a colorless solid substances (0.19 g).

NMR δ H (d ₆ -DMSO): 6.74 (1H, dd), 6.12 (1H, d), 5.07 (1H, m), 4.38 (1H, m), 4.05 ( 1H, t), 3.95 (2H, m), 3.12 (2H, t), 2.85 (1H, m), 2.49 (1H, m), 2.30-2.45 (2H , m), 2.0 (1H, m), 1.75 (2H, m), 1.52 (2H, m), 1.47 (2H, m), 1.0 (3H, t), 0 98 (3H, t).

Example 3
[1S- (1α, 2β, 3β, 4α)] -4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] -2,3- dihydroxycyclopentane propanoic acid, sodium salt
a) [1S- (1α, 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, ethyl ether
A stirred solution of the product of Example 1 h) (0.6 g), pyridine (0.112 ml) and trifluoroacetic acid (0.058 ml) in DMSO (25 ml) was treated with 1,3-dicyclohexylcarbodiimide (0.87 g) and the mixture was stirred at room temperature in 24 hours. Carboethoxymethylene triphenylphosphorane (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. After 30 minutes, the mixture was filtered and the filtrate was washed with saturated sodium bicarbonate solution (100 ml), dried and concentrated. The residue was dissolved in dichloromethane (50 ml) / trifluoroacetic acid (50 ml) and stirred overnight. The solvent was removed and the residue was purified by chromatography (SiO ₂ , dichloromethane: ethyl acetate 1: 1 as eluent) to give the title compound (0.36 g).

MS (FAB): 465 (M + H ⁺ , 100%).

b) [1S- (1α, 2β, 3β, 4α)] -4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] -2,3-dihydroxycyclopentane propanoic acid, ethyl ether
2,4,6-Triisopropylbenzenesulfonohydrazide (0.50 g) was added to a solution of the product of step a) (0.35 g) in dry THF (175 ml) and the resulting solution was heated for 3 hours at 70 ° C. The cooled reaction mixture was purified by chromatography (SiO ₂ , dichloromethane: ethyl acetate 1: 1 as eluent) to give the title compound (0.16 g).

MS (EU): 466 (M ⁺ ), 43 (100%).

c) [1S- (1α, 2β, 3β, 4α)] -4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] -2,3-dihydroxycyclopentane propanoic acid, sodium salt
Lithium hydroxide monohydrate (14 mg) was added to a solution of the product of step b) (0.16 g) in THF (10 ml) / water (10 ml). The solution was stirred at room temperature for 18 hours, then the solvent was removed in vacuo. Purification (HPLC, Nova-Pak ^R C18 column, 0.1% aqueous ammonium acetate: methanol 50: 50 to 0: 100 in 15 minutes as an eluent) gave an acid, which was dissolved in methanol (2 ml) and 1 N was added sodium hydroxide solution (0.28 ml). The solution was concentrated to give the title salt (0.13 g).

MS (PI): 439 (M-Na + H ⁺ , 100%).

NMR δ H (D ₂ O): 5.07 (1H, m), 4.65 (1H, t), 4.08 (1H, t), 3.49 (2H, t), 3.05 (2H , m), 2.62 (1H, m), 2.36 (2H, m), 2.17 (1H, m), 2.00 (1H, m), 1.70 (2H, m), 1 65 (2H, m), 1.61 (2H, m), 1.40 (2H, m), 1.00 (3H, t), 0.97 (3H, t).

Example 4
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5-d ] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt
a) 2- (pentylthio) -4.6 (1H, 5H) -pyrimidinedione
To a solution of 4,6-dihydroxy-2-mercaptopyrimidine (14.4 g) in a 2H sodium hydroxide solution (100 ml) was added pentyl iodide (15.6 ml) in ethanol (25 ml) and the resulting reaction mixture was stirred at room temperature for 4 days. Ethanol was removed under reduced pressure, N, N-dimethylformamide (80 ml) and pentyl iodide (1.56 ml) were added, and the reaction mixture was stirred for another 16 hours. The solution was acidified by adding 2 N solution, HCl and the aqueous layer was decanted. The remaining resin was dissolved in methanol and evaporated to dryness, then azeotropic distillation was performed with toluene (x 2). The solid was triturated with ether, filtered, dried and the title compound was obtained as a white solid (11.9 g).

MS (EU): 214 (M ⁺ ), 144 (100%).

b) 6-Hydroxy-5-nitro-2- (pentylthio) -4 (1H) -pyrimidinone
Obtained by the method of Example 1 b) using the product of stage a).

MS (EU): 259 (M ⁺ ), 43 (100%).

c) 4,6-Dichloro-5-nitro-2-pentylthio) pyrimidine
Obtained by the method of Example 1 c) using the product of stage b).

MS (FAB): 295, 297, 299 (M + H ⁺ ): 41 (100%).

d) [3aS- (3aα, 4β, 7β, 7aα) -5- [6-Chloro-5-nitro-2- (pentylthio) pyrimidin-4-yl] tetrahydro-2,2-dimethyl-4,7-methano -1, 3-dioxolo- [4,5-s] pyridin-6 (3aH) -one
Obtained by the method of Example 1 d) using the product of stage c).

MS (FAB): 445, 443 (M + H ⁺ ), 443 (100%).

e) [3aS- (3aα, 4β, 7β, 7aα)] - 5- [5-amino-6-chloro-2- (pentylthio) pyrimidin-4-yl] tetrahydro-2,2-dimethyl-4,7- methano-1,3-dioxolo- [4,5-s] pyridin-6 (3aH) -one
Obtained by the method of Example 1 c) using the product of stage d).

MS (EU): 414, 412 (M ⁺ ), 412 (100%).

 f) [3aR- (3aα, 4β, 6β, 6aα)] - 6- [5-amino-6-chloro-2- (pentylthio) pyrimidin-4-ylamino] tetrahydro-2,2-dimethyl-4H-cyclopenta- 1,3-dioxol-4-methanol.

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

MS (EI): 418, 416 (M ⁺ ), 327 (100%).

q) [3aR- (3aα, 4β, 6β, 6aα)] -6- [7-Chloro-5- (pentylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol
Obtained by the method of Example 1 d) using the product of stage f).

MS (FI): 430, 428 (M + H ⁺ ), 338 (100%).

h) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (Butylamino) -5- (pentylthio) -3H- 1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
Obtained by the method of Example 1 h) using the product of stage g).

MS (FAB): 465 (M + H ⁺ , 100%).

i) [3aR- (3aα, 4α, 6α, 6aα)] -3- [6- [7- (Butylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1 i) using the product of stage h).

MS (FAB): 561 (M + H ⁺ ), 505 (100%).

j) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (pentylthio) -3H-1,2, 3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt
Obtained by the method of Example 1 j) using the product of stage i).

MS (FAB): 487 (M + Na + H ⁺ ), 465 (100%).

NMR δ H (d ₆ -DMCO): 9.00 (1H, d), 6.43 (1H, dd), 5.70 (1H, d), 4.97 (1H, q), 4.32 ( 1H, t), 3.87 (1H, t), 3.50-3.47 (2H, m), 3.12-3.04 (2H, m), 2.68 (1H, m), 2 , 38-2.34 (1H, m), 1.93-1.89 (1H, m), 1.64 (2H, m), 1.62 (2H, m), 1.37-1.30 (6H, m), 0.91 (3H, t), 0.87 (3H, t).

Example 5
The following compound was prepared according to the procedure for Example 4: [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Ethylamino) -5- (pentylthio) -3H-1,2,3 triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt
a) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (Ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
MS (FAB): 437 (M + H ⁺ , 100%).

b) [3aR- (3aα, 4α (E): 6α, 6aα)] -3- [6 [-7- (Ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic acid, 1,1-dimethylethyl ether
MS (FAB): 533 (M + H ⁺ ), 477 (100%).

c) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt
MS (FAB): 459 (M + Na + H ⁺ ), 437 (100%).

NMR δ H (d ₆ -DMSO): 8.99 (1H, d), 6.55 (1H, dd), 5.76 (1H, d), 4.98 (1H, KB), 4.32 ( 1H, t), 3.90 (1H, t), 3.81-3.50 (2H, m), 3.16-3.08 (2H, m), 2.74-2.70 (1H, m), 2.46-2.37 (1H, m), 1.98-1.89 (1H, m), 1.71-1.67 (2H, m), 1.62 (2H, m) 1.37-1.24 (4H, m); 1.19 (3H, t); 0.86 (3H, t).

Example 6
[1S- (1α, 2β, 3β, 4α)] -4- [7- (Butylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] -2,3-dihydroxycyclopentapropanoic acid, sodium salt
Obtained by the method of Example 3 b) using the product of Example 4.

MS (FI): 467 (M + H ⁺ ), 295 (100%).

NMR δ H (d ₆ -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 (3H, m), 1.74-1.55 (7H, m), 1.37-1.33 (6H, m), 0.90 (3H, t), 0.86 (3H, t).

Example 7
[1S- (1α, 2β, 3β, 4α)] -4- [7- (Ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] -2,3- dihydroxycyclopentane propanoic acid, sodium salt
Obtained by the method of Example 3 b) using the product of Example 5.

MS (FAB): 461 (M + Na + H ⁺ ), 154 (100%).

NMR δ H (d ₆ -DMSO): 8.96 (1H, t), 4.91 (1H, KB), 4.33 (1H, t), 3.75 (1H, t), 3.51 ( 2H, m), 3.08-3.06 (2H, m), 2.30-2.24 (1H, m), 2.06-1.93 (3H, m), 1.75-1, 55 (5H, m), 1.37-1.09 (4H, m), 1.15 (3H, t), 0.87 (3H, t).

Example 8
[1S- (1α, 2α, 3β, 5β)] -3- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] -5- [2- (1H-tetrazol-5-yl) ethyl] -1,2-cyclopentanediol
a) [3aR- (3aα, 4α (E), 6α, 6aα)] -3- [6- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenonitrile
Obtained by the method of Example 1 i) using the product of Example 1 h) and (triphenylphosphoranilylene) acetonitrile.

MS (EU): 457 (M ⁺ ), 414 (100%).

b) [3aR- (3aα, 4α, 6α, 6aα)] -3- [6- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl] -2-propanonitrile
The product of step a) (0.75 g) in ethanol (300 ml) containing 10% palladium-on-charcoal (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 obtain the title compound (0.34 g).

MS (FAB): 460 (M + H ⁺ , 100%).

c) [3aR- (3aα, 4α, 6α, 6aα)] -N-Butyl-5- (propylthio) -3- [6- [2- (1H-tetrazol-5-yl) ethyl] tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -3H-1,2,3-triazolo [4, 5-d] pyrimidin-7-amine
The product of step b) (0.40 g) and tributyltin azide (0.70 g) in toluene were heated at reflux for 48 hours, then concentrated. Purification by chromatography (SiO ₂ , dichloromethane: methanol 95: 5 as eluent) gave the title compound (0.19 g).

MS (FAB): 503 (M + H ⁺ , 100%).

d) [1R- (1α, 2α, 3β, 5β)] -3- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] -5- [2- (1H-tetrazol-5-yl) ethyl] -1,2-cyclopentanediol
Obtained by the method of Example 1 j) using the product of stage c).

MS (FAB): 463 (M + H ⁺ , 100%).

NMR δ H (d ₆ -DMSO): 8.64 (1H, m), 5.11 (1H, m), 4.96 (1H, m), 4.85 (1H, m), 4.38 ( IH, m), 3.38 (1H, m), 3.50 (2H, m), 3.07 (2H, m), 2.97 (2H, m), 2.41 (1H, m), 2.00 (2H, m), 1.80 (2H, m), 1.69 (2H, m), 1.61 (2H, m), 1.35 (2H, m), 0.97 (3H m) 0.91 (3H, t).

Example 9
[lR- (1α, 2β, 3β, 4α)] -N- [3- [4- [7- (Butylamino) - 5- (propylthio) -3H-1,2,3-triazolo [4,5-d ] pyrimidin-3-yl] -2, 3-dihydroxycyclopentyl] -2-propanoyl] -L-aspartic acid
a) [1R- (1α, 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propanoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
N, N-Diisopropylethylamine (0.35 ml) was added to a solution of L-aspartic acid di-tert-butyl ester hydrochloride (0.28 g), bromtris (pyrrolidino) phosphonium hexafluorophosphate (0.44 g) and the product of Example 3 (0 , 44 g) in DMF (20 ml). The reaction mixture was stirred for 1 hour at room temperature, then concentrated. Chromatography (SiO ₂ , ethyl acetate as eluent) gave the title compound (0.49 g).

MS (FI): 666 (M + H ⁺ , 100%).

b) [1R- (1α, 2β, 3β, 4α)] -3- [4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5] pyrimidine- 3-yl] -2,3-dihydroxycyclopentyl] -2-propanoyl] -L-aspartic acid
Obtained by the method of example 2 b) using the product of stage a).

NMR δ H (d ₆ -DMSO): 9.03 (1H, br), 7.79 (1H, d), 4.92 (1H, m), 4.35 (1H, m), 4.19 ( 1H, t), 3.75 (2H, m), 3.49 (2H, t), 3.08 (2H, m), 2.43 (1H, m), 2.32 (1H, m), 2.18 (3H, m), 1.91 (IH, m), 1.73 (3H, m), 1.58 (2H, m), 1.34 (2H, m), 1.0 (3H , t), 0.98 (3H, t).

Example 10
[1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4 [-7- (Hexylamino) - 5- (propylthio) -3H-1,2,3-triazolo [4, 5- (1] pyrimidin-3-yl] 2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid
a) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
Sodium borohydride (1.16 g) was added to an ice-cooled solution of the product of stage 1 e) (5.90 g) in methanol (200 ml). After stirring for 1 hour, the solution was concentrated and the residue was purified by chromatography (SiO ₂ , diethyl ether as eluent). The resulting intermediate was dissolved in acetonitrile (300 ml) and isoamyl nitrite (2.8 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, the residue was purified (SiO ₂ , diethyl ether as eluent), and the title compound (4.69 g) was obtained.

MS (FI): 465 (M + H ⁺ , 100%).

b) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentyl] -2-propenoic acid
Obtained by the method of example 1 i) and the subsequent method 1 j) using the product of stage a).

NMR δ H (D ₂ O): 9.03 (1H, d), 6.96 (1H, dd), 5.89 (1H, d), 5.31 (1H, s), 5.10 (1H , s), 5.00 (1H, m), 4.29 (1H, t), 4.02 (1H, t), 3.49 (2H, m), 3.01 (2H, m), 2 83 (2H, m), 2.49 (1H, m), 2.01 (1H, m), 1.72 (2H, m), 1.65 (2H, m), 1.29 (6H, m), 0.98 (3H, t), 0.86 (3H, t).

c) [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [ 4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] 2-propenoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of example 2 b) using the product of stage b).

MS (FI): 692 (M + H ⁺ , 100%).

d) [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [ 4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid
Obtained by the method of example 2 b) using the product of stage c).

NMR δ H (d ₆ -DMSO): 7.94 (1H, d), 7.23-7.11 (1H, s), 6.75 (1H, dd), 6.17 (1H, d), 5.19 (1H, s), 5.08 (1H, s), 5.00 (1H, m), 4.31 (2H, m), 3.96 (1H, m), 3.62 (2H , m), 3.07 (2H, m), 2.81 (1H, m), 2.49-2.31 (3H, m), 2.01 (1H, m), 1.67 (2H, m), 1.61 (2H, m), 1.31 (6H, m), 0.96 (3H, t), 0.85 (3H, t).

Example 11
The following compounds were obtained according to the method of example 1.

a) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (3,3-Dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid
i) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (3,3-Dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d ] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
MS (FI): 465 (M + H ⁺ , 100%).

ii) [3aR- (3aα, 4α (H), 6α, 6aα)] -3- [6- [7- (3,3-Dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic acid, 1,1-dimethylethyl ether
MS (FI): 561 (M + H ⁺ , 100%).

iii) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (3,3-Dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid
NMR δ (d ₆ -DMSO): 8.59 (1H, d), 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, m), 2.81 (1H, m), 2.43 (IH, m), 1.97 (1H, m), 1.75 (2H, m), 1.55 (2H, m), 0.99 (3H, t), 0.95 (9H, s).

b) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (2-Methoxyethylamino) -5- (propylthio) -3H-1,2,3-triazolo [4 , 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid
i) [3aR- (3aα, 4α, 6α, 6aα)] -6- [7- (2-Methoxyethylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine -3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
MS (FAB): 439 (M + H ⁺ , 100%).

ii) [3aR- (3aα, 4α (E), 6α, 6aα)] - 3- [6- [7- (2-Methoxyethylamino) -5- (propylthio) -3H-1,2,3-triazolo [4 , 5-d] pyrimidin-3-yl] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic acid, 1,1-dimethylethyl ether
MS (FAB): 535 (M + H ⁺ , 100%).

iii) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (3,3-Dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2, 3-dihydroxycyclopentyl] -2-propenoic acid
MS (FAB): 439 (M + H ⁺ , 100%).

Example 12
[1R- (1α, 2β, 3β, 4α)] -N- [3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d ] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] -L- aspartic acid
a) [1R- (1α, 2β, 3β, 4α)] -4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3 -yl] -2,3-dihydroxycyclopentane propanoic acid
Obtained by the method of example 3 b) using the product of stage 10 b).

MS (FI): 467 (M + H ⁺ , 100%).

b) [1R- (1α, 2β, 3β, 4α)] -N- [3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] - L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of example 9 a) using the product of stage a).

MS (FI): 694 (M + H ⁺ , 100%).

c) [1R- (1α, 2β, 3β, 4α)] -N- [3- [4- [7- (Hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5 -d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] -L- aspartic acid
Obtained by the method of example 2 b) using the product of stage b).

NMR δ H (d ₆ -DMSO): 8.90 (1H, br), 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, m), 2.28 (1H, m), 2.20 (2H, m), 1.93 (1H, m), 1.77 (1H, m), 1.62 (3H, m), 1.59 (3H, m), 1.33 (6H , m), 1.00 (3H, t), 0.88 (3H, t).

Example 13
[1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [5 - [(3,3,3-Trifluoropropylthio) -7- [2- (methylthio) ethylamino] - 3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L- aspartic acid, monoammonium salt
a) 2 - [(3,3,3-Trifluoropropyl) thio] -4,6 (1H, 5H) -pyrimidinedione
Obtained by the method of example 1 a).

MS (PI, negative ionization): 239 (M-H ⁺ ), 143 (100%).

 b) 2 - [(3,3,3-Trifluoropropyl) thio] -6-hydroxy-5-nitro-4 (1H) -pyrimidinone.

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

MS (PH, negative ionization): 284 (M-H ⁺ , 100%).

c) 4,6-Dichloro-2 - [(3,3,3-trifluoropropyl) thio] -5- nitropyrimidine
Obtained by the method of example 1 c) using the product of stage b).

NMR δ H (CDCl ₃ ): 3.30 (2H, m), 2.60 (2H, m).

d) [3aS- (3aα, 4β, 7β, 7aα)] -5- [6-Chloro-5-nitro-2- (3,3,3-Trifluoropropyl) thio] - pyrimidin-4-yl tetrahydro-2, 2-dimethyl-4,7-methano-1,3-dioxolo [4, 5th] pyrimidin-6 (3aH) -one
Obtained by the method of example 1 c) using the product of stage b).

NMR δ H (CDCl ₃ ): 4.77 (1H, s), 4.73 (1H, d), 4.56 (1H, d), 3.33 (2H, m), 3.05 (1H, s), 2.58 (2H, m), 2.33 (1H, d), 2.20 (1H, t), 1.53 (3H, s), 1.36 (3H, s).

e) [3aS (3aα, 4α, 7α, 7aα)] -5- [5-amino-6-chloro-2- (3,3,3-trifluoropropyl) thio] pyrimidin-4-yl] tetrahydro-2, 2-dimethyl-4,7-methano-1,3-dioxolo [4,5-e] pyrimidin-6 (3aH) -one
Obtained by the method of example 1 e) using the product of stage d).

MS (FI): 439 (M + H ⁺ , 100%).

f) [3aR- (3aα, 4α, 6α, 6aα)] -6 - [[5-amino-6-chloro-2 - [(3,3,3-trifluoropropyl) thio] -4-pyrimidinyl] amino] tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
Obtained by the method of example 1 f) using the product of stage e).

MS (FI): 443 (M + H ⁺ , 100%).

g) [3aR- (3aα, 4α, 6α, 6aα)] -6- [5 - [(3,3,3-trifluoropropyl) thio] -7 - [(2- (methylthio) ethylamino] -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-methanol
Obtained by the method of example 1 g) using the product of stage f).

MS (FI): 509 (M + H ⁺ , 100%).

h) [3aR- (3aα, 4α (E), 6α, 6aα)] -3- [6- [5 - [(3,3,3-Trifluoropropyl) thio] -7 - [(2- (methylthio) ethylamino ] -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -2- propenoic acid, 1,1-dimethylethyl ether
Obtained by the method of example 1 i) using the product of stage g).

MS (FI): 605 (M + H ⁺ ), 549 (100%).

h) [1R- (1α (E), 2β, 3β, 4α)] -3- [4- [5 - [(3,3,3-Trifluoropropyl) thio] -7 - [(2-methylthio) ethylamino] -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid
Obtained by the method of example 1 j) using the product of stage h).

MS (FI): 509 (M + H ⁺ , 100%).

j) [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [5 - [(3,3,3-Trifluoropropyl) thio] -7 - [(2- ( methylthio) ethylamino] -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] 2,3-dihydroxycyclopentyl] -2-propenoyl] -L- aspartic acid, bis (1,1- dimethylethyl) ether
Obtained by the method of example 9 a) using the product of stage i).

MS (FI): 736 (M + H ⁺ ), 624 (100%).

j) [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [5 - [(3,3,3-Trifluoropropyl) thio] -7 - [(2- methylthio) ethylamino] -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L- aspartic acid, monoammonium salt
Obtained by the method of example 2 b) using the product of stage j).

NMR δ H (d ₆ -DMSO): 7.90 (1H, d), 6.76-6.68 (1H, dd), 6.15 (1H, d), 4.99 (1H, m), 4.30 (2H, m), 3.71 (2H, t), 3.30 (2H, m), 2.74 (5H, m), 2.50 (1H, m), 2.42 (2H , m), 2.11 (3H, s), 1.98 (1H, m).

Example 14
(E) -1- [7- (Butylamino) -5- (propylthio) -3H- 1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D-ribohept-5-enofuranuronic acid
a) 2,6-Bis (propylthio) -4,5-pyrimidinediamine
Propyl iodide (2.52 ml) was added to a stirred solution of 4,5-diamino-2,6-dimercaptopyrimidine (2.0 g) in a 1 N potassium hydroxide solution (26.4 ml). After stirring for 24 hours, the solid was collected by filtration to obtain the title compound as a pink solid (2.2 g).

MS (EU): 258 (M ⁺ , 100%).

b) 5,7-Bis (propylthio) -1H-1,2,3-triazolo [4,5-d] pyrimidine
A solution of sodium nitrite (0.6 g) in water (7 ml) was added to a stirred suspension of the product of stage a) (2.0 g) in a mixture of acetic acid: water (1: 1, 90 ml) at 50 ^° C. The reaction mixture stirred for 1 hour at 50 ^° C., the solid was collected by filtration to obtain the title compound.

MS (EU): 269 (M ⁺ ), 43 (100%).

c) 5,7-Bis (propylthio) -3- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine
Hydrogen bromide gas was bubbled into an ice-cooled solution of 1-O-acetyl-2,3,5-tri-O-benzoyl-β-D-ribofuranose (2.02 g) in dichloromethane (15 ml) for 15 minutes. 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 (3 x 50 ml). Sodium hydride (60%, 0.19 g) was added to a stirred suspension of the product of step b) (1.08 g) in acetonitrile (29 ml). After stirring for 15 minutes at room temperature, the bromosugar described above was added in acetonitrile (10 ml) and stirring was continued for 24 hours. The reaction mixture was partitioned between ethyl acetate and water, the organic layer was dried and concentrated. Chromatography (SiO ₂ dichloromethane: 39: 1 diethyl ether as eluent) afforded a mixture of 5,7-bis (propylthio) -3- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H- 1,2,3-triazolo [4,5-d] pyrimidine [MS (BBA): 714 (M + H ⁺ ), 105 (100%)] and 5.7-bis (propylthio) -2- (2, 3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine [MS (BBA): 714 (M + H ⁺ ), 105 ( 100%)] (1.9 g). Further elution afforded 5,7-bis (propylthio) -1- (2,3,5-tri-O-benzoyl-β-D-ribofuranosyl) -3H-1,2,3-triazolo [4,5-d] pyrimidine as a colorless foam (0.46 g). [MS (FAB): 714 (M + H ⁺ ), 105 (100%)].

d) N-Butyl-5- (propylthio) -3- (β-D-ribofuranosyl) -3H-1,2, 3-triazolo [4,5-d] pyrimidin-7-amine
n-Butylamine (7.37 g) was added to a solution of the mixture of isomers from step c) (9.0 g) in 1,4-dioxane (100 ml) and water (30 ml). 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 under reflux for 30 minutes. After cooling to room temperature, acetic acid was added to pH 7 and the solution was concentrated. Chromatography (SiO ₂ , chloroform: 85:15 isopropyl alcohol as eluent) afforded the title compound as a colorless glassy substance (2.0 g).

MS (Electrospray): 399 (M + H ⁺ , 100%).

e) N-Butyl-5- (propylthio) -3- (2,3-ethoxymethylene-β-D-ribofuranosyl) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-7-amine
A solution of the product of step d) (0.40 g) in 1,4-dioxane (5 ml) was treated with trichloroacetic acid (0.44 g) and triethylorthoformate (0.44 g). The resulting solution was heated for 90 minutes at 50 ^° C. The cooled solution was diluted with dichloromethane (100 ml), washed with saturated sodium bicarbonate solution (50 ml) and water (50 ml), then dried and concentrated. Chromatography (SiO ₂ , hexane: ethyl acetate 2: 1 as an eluent) gave the title compound as a colorless solid (0.32 g).

MS (FAB): 455 (M + H ⁺ ), 267 (100%).

f) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-ribohept-5-enofuranoronic acid, ethyl ether
A stirred solution of the product of step e) (3.25 g), pyridine (0.57 g) and trifluoroacetic acid (0.41 g) in DMSO (30 ml) was treated with 1,3-dicyclohexylcarbodiimide (4.42 g) and the mixture was stirred at room temperature for 24 hours. Carboethoxymethylene triphenylphosphorane (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 saturated sodium bicarbonate solution (200 ml), dried and concentrated. Chromatography (SiO ₂ , hexane: ethyl acetate 5: 1 as an eluent) gave an intermediate which was dissolved in 80% acetic acid (aqueous) (25 ml) and heated for 2 days at 36 ^° C. The solution was concentrated and the residue was purified by chromatography ( SiO ₂ , hexane: ethyl acetate 2: 1 as eluent) to give the title compound as a colorless solid (1.84 g).

MS (FAB): 467 (M + H ⁺ ), 267 (100%).

g) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 3 c) using the product of stage f).

NMR δ H (d ₆ -DMSO): 9.10 (1H, d), 6.82 (1H, dd), 6.15 (1H, d), 5.89 (IH, d), 4.76 ( 1H, t), 4.60 (1H, t), 4.39 (1H, t), 3.50 (2H, m), 3.08 (2H, m), 1.69 (2H, m), 1.61 (2H, m), 1.34 (2H, m), 0.98 (3H, t), 0.91 (3H, t).

MS (FAB): 439 (M + H ⁺ ), 267 (100%).

Example 15
(E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6 -tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid
a) (E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1, 5,6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of Example 2 a) using the product of Example 14.

MS (Electrospray): 666 (M + H ⁺ , 100%).

b) (E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1, 5,6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid
Obtained by the method of Example 2 b) using the product of stage a).

NMR δ H (d ₆ -DMSO): 12.57 (2H, br), 9.09 (1H, t), 8.42 (1H, d), 6.70 (1H, dd), 6.13 ( 2H, m), 5.78 (1H, d), 5.60 (1H, d), 4.71 (1H, m), 4.56 (2H, m), 4.40 (1H, q), 3.07 (2H, m), 2.63 (2H, m), 1.68 (2H, m), 1.60 (2H, m), 1.35 (2H, m), 0.98 (3H , t), 0.91 (3H, t).

Example 16
The following compound was obtained according to the method of Examples 14 and 15:
(E) -N- [1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt
a) 5- (Propylthio) -3- (β-D-ribofuranosyl) -3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine
A solution of the mixture of isomers from Example 14 c) (12.0 g) in methanol (1 L) was cooled to 0 ^° C. and saturated with gaseous ammonia. The solution was stirred at room temperature for 72 hours, then concentrated. Chromatography (SiO ₂ , dichloromethane: methanol 14: 1 as eluent) gave the title compound as a colorless solid (4.94 g).

MS (Electrospray): 343 (M + H ⁺ , 100%).

b) 5- (Propylthio) -3- [2,3-O- (ethoxymethylene) - β-D-ribofuranosyl] -3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine
MS (Electrospray): 399 (M + H ⁺ , 100%).

c) (E) -1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid, ethyl ether
MS (Electrospray): 411 (M + H ⁺ , 100%).

d) (E) -1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid, ethyl ether
MS (Electrospray): 383 (M + H ⁺ , 100%).

e) (E) -N- [1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1.5, 6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
MS (Electrospray): 610 (M + H ⁺ , 100%).

f) (E) -N- [1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1.5, 6-trideoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt
NMR δ H (d ₆ -DMSO): 8.53 (1H, ss), 8.18 (1H, ss), 6.66 (1H, dd), 6.62 (1H, d), 6.15 ( 1H, d), 5.78 (1H, t), 4.54 (1H, t), 4.39 (1H, t), 4.25 (1H, m), 3.05 (2H, m), 2.53-2.25 (2H, m), 1.68 (2H, m), 0.97 (3H, t).

Example 17
(E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6 - trideoxy-β-D-ribohept-5-enofuranuronoyl] -L-ac-paraginic acid, monoammonium salt
a) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-ribogept-5-enofuranoic acid, ethyl ether
Obtained by the method of Example 3 b) using the product of stage 14 f).

MS (Electrospray): 469 (M + H ⁺ , 100%).

b) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 3 c) using the product of stage a).

MS (Electrospray, negative ionization): 439 (MH ⁺ , 100%).

c) (E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1, 5, 6-trideoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of Example 2 a) using the product of stage b).

MS (Electrospray): 668 (M + H ⁺ , 100%).

d) (E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1, 5,6-tridesoxy-β-D-ribohept-3-enofuranuronoyl] -L-aspartic acid, monoammonium salt
Obtained by the method of Example 2 a) using the product of stage c).

NMR δ H (d ₆ -DMSO): 9.07 (1H, t), 7.69 (1H, d), 6.04 (1H, d), 5.50 (2H, br s), 4.76 (1H, t), 4.18 (2H, m), 3.91 (1H, m), 3.49 (2H, q), 3.08 (2H, t), 2.46-2.23 ( 2H, m), 2.18 (2H, t), 1.93 (1H, m), 1.70 (3H, m), 1.60 (2H, m), 1.34 (2H, m), 0.99 (3H, t); 0.91 (3H, t).

Example 18
(E) -N- [1,5,6-Tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3- silt] - β - D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt
a) 3- (5-O-Benzoyl-β-D-ribofuranosyl) and hexyl-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine
Obtained by the method of Example 14 d) using n-hexylamine.

MS (FAB): 531 (M + H ⁺ ), 295 (100%).

b) 3- [5-O-Benzoyl-2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -N-hexyl-5- (propylthio) -3H-1,2,3-triazolo [ 4, 5-d] pyrimidin-7-amine
The product of step a) (4.93 g) in acetone (120 ml) containing 2,2-dimethoxypropane (11.4 ml) was treated with p-toluenesulfonic acid (4.4 g). The resulting solution was stirred for 2 hours at room temperature, made basic with triethylamine (3.25 ml) and concentrated. Chromatography (SiO ₂ , cyclohexane: ethanol 95: 5 as eluent) gave the title compound (5.03 g).

MS (Electrospray): 571 (M + H ⁺ , 100%).

c) N-Hexyl-3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine-7-amine
A solution of the product of step b) (5.02 g) in a 0.1 M solution of sodium methoxide in methanol (88 ml) was heated under reflux for 30 minutes. Acetic acid (1 ml) was added and the reaction was concentrated. Chromatography (SiO ₂ , dichloromethane: acetonitrile 95: 5 as eluent) gave the title compound (3.63 g).

MS (Electrospray): 467 (M + H ⁺ , 100%).

d) (E) -1,5,6-Tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3- il] -2,3-O- (1-methylethylidene) β-D-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1 i) using the product of stage c).

MS (FAB): 563 (M + H ⁺ , 100%).

f) (E) -1,5,6-Tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl ] - β-D- ribohept-5-enofuranuronic acid
Obtained by the method of Example 1 j) using the product of stage d).

MS (FAB): 467 (M + H ⁺ ), 295 (100%).

f) (E) -N- [1,5,6-Tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine -3-yl] - β - D-ribohept-5-enofuranuronoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of Example 9a) using the product of stage e).

MS (FAB): 694 (M + H ⁺ ), 295 (100%).

g) (E) -N- [1,5,6-Tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine- 3-yl] - β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt
Obtained by the method of Example 2 b) using the product of stage f).

MS (FAB): 582 (M + H ⁺ ), 295 (100%).

NMR δ H (d ₆ -DMSO): 8.74 (1H, t), 8.00 (1H, m), 6.66 (1H, dd), 6 6.23 (1H, d), 6.15 (1H, m), 4.76 (1H, m), 4.55 (1H, t), 4.40 (1H, t), 4.27 (1H, t), 3.50 (2H, m) , 3.07 (2H, m), 2.51 (2H, m), 1.68 (4H, m), 1.30 (6H, m), 0.98 (3H, m), 0.87 ( 3H, m).

Example 19
(E) -1- [7- (N-Butyl-N-methylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] 1,5 , 6-tridesoxy-β-D-ribohept-5-enofuranuronic acid
a) N-Butyl-N-methyl-5- (propylthio) -3- (β-D-ribofuranosyl) -3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine
Obtained by the method of Example 14 d) using N-methyl-N-butylamine.

MS (FAB): 413 (M + H ⁺ ), 281 (100%).

b) N-Butyl-N-methyl-5- (propylthio) -3- [2,3, O- (1-methylethylidene) - β-D-ribofuranosyl] -3H-1,2,3-triazolo [4, 5-d] pyrimidine-7-amine
Obtained by the method of Example 18 b) using the product of stage a).

MS (FAB): 453 (M + H ⁺ ), 281 (100%).

c) (E) -1- [7- (N-Butyl-N-methylamino) -5- (propylthio) -3H- 1,2,3-triazolo [4,5-d] pyrimidin-3-yl] - 1,5,6-tridesoxy-2,3-O- (1-methylethylidene) - β-D-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1i) using the product of stage b).

MS (FAB): 549 (M + H ⁺ , 100%).

d) (E) -1- [7- (N-Butyl-N-methylamino) -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] - 1,5,6-tridesoxy-β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 1j) using the product of stage c).

MS (FAB): 453 (M + H ⁺ , 100%).

NMR δ H (d ₆ -DMSO): 6.51 (1H, dd), 6.12 (1H, d), 5.83 (1H, d), 4.71 (1H, t), 4.51 ( 1H, t), 4.31 (1H, m), 3.76 (2H, m), 3.71 (3H, s), 3.08 (2H, m), 1.69 (4H, m), 1.61 (2H, m), 1.34 (2H, m), 0.94 (6H, m).

Example 20
(E) -N- [1- [7- (Butylamino) -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6 -tridesoxy- β -D- ribohept-5-enofuranuronoyl] -L-aspartic acid
a) 3- (2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl) -5,7-bis (methylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine and
2- (2,3,5-Tri-O-benzoyl-β-D-ribofuranosyl) -5,7-bis (methylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine
Obtained according to the procedure of Example 14c) using 5,7-bis (methylthio) -1H-triazolo [4,5-d] pyrimidine (obtained according to the method described by JAMontgomery, ATShortancy, G. Arnett, WHShannon, J.Med.Chem ., 1977, 20, 401). Chromatography (SiO ₂ , dichloromethane: 99: 1 ethyl acetate as eluent) gave the title compound (13.3 g).

MS (Electrospray): 467 (M + H ⁺ , 100%).

b) N-Butyl-3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -5- (methylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine-7-amine
n-Butylamine (13.5 ml) was added to a solution of the mixture of isomers from step a) (22.5 g) in a mixture of dioxane (175 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 at the boil 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 (5.91 g) and 2,2-dimethoxypropane (50 ml) 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 (500 ml), the organic phase was dried and concentrated. Chromatography (SiO ₂ , hexane: ethyl acetate 7: 3 as eluent) afforded the title compound as a colorless solid (3.67 g).

MS (Electrospray): 411 (M + H ⁺ , 100%).

c) (E) -1- [7- (Butylamino) -5- (methylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-2,3-O- (1-methylethylidene) - β D-ribohept-5-enofuranuronic acid, ethyl ether
Obtained by the method of Example 1 i) using the product of stage b) and carbethoxymethylene triphenylphosphorane.

MS (FAB): 479 (M + H ⁺ , 100%).

d) (E) -1- [7- (Butylamino) -5- (methylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-ribohept-5-enofuranuronic acid, ethyl ether
The product of step c) (1.4 g) was dissolved in a 2 M solution of HCl in methanol (75 ml) and the reaction mixture was stirred for 15 min at room temperature, then concentrated. The residue was dissolved in ethyl acetate (300 ml), washed with saturated sodium bicarbonate solution (3 x 100 ml), dried and concentrated. Chromatography (SiO ₂ , dichloromethane: methanol 97: 3 as eluent) afforded the title compound as a colorless solid (1.10 g).

MS (FAB): 439 (M + H ⁺ ), 239 (100%).

e) (E) -1- [7- (Butylamino) -5- (methylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 3c) using the product of stage d).

MS (FAB): 411 (M + H ⁺ ), 154 (100%).

f) (E) -N- [4- [7- (Butylamino) -5- (methylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1.5 , 6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, bis (1,1-dimethylethyl) ether
Obtained by the method of Example 2 a) using the product of stage e).

MS (FAB): 638 (M + H ⁺ ), 239 (100%).

g) (E) -N- [1- [7- (Butylamino) -5- (methylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1, 5,6-tridesoxy-β-D-ribohept-3-enofuranuronoyl] -L-aspartic acid
Obtained by the method of Example 2 b) using the product of stage f).

MS (FAB): 526 (M + H ⁺ ), 239 (100%).

Example 21
(E) -1- [5-Butyl-7- (butylamino) -3H-1,2,3-triazolo [1,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy-β- D-ribohept-5-enofuranuric acid.

a) 5-Butyl-3,4-dihydro-3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -7H-1,2,3-triazolo [4,5-d] pyrimidin-7-one
Sodium (4.6 g) was dissolved in ethanol (200 ml), then 5-amino-1- [2,3-O- (1-methylethylidene) -β-D-ribofuranosyl] -1H- 1,2,3 was added triazole-4-carboxamide (prepared as described by G. Biagi et al., Farmaco 1992, 47, 525) (6.0 g) and the mixture was refluxed. Methyl valerate (10.5 ml) was added and refluxed for 17 hours. The mixture was neutralized using Dowex 50x8-200 (H ⁺ form), filtered, and the filtrate was concentrated. The residue was dissolved in ethanol, acetic acid was added and the solution was concentrated. Chromatography (SiO ₂ , hexane: ethyl acetate 7: 3 as eluent) gave the title compound as a colorless oil (3.08 g).

MS (FAB): 366 (M + H ⁺ ).

b) 5-Butyl-3,4-dihydro-3- [5-O-acetyl-2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -7H-1,2,3-triazolo [ 4,5-d] pyrimidin-7-one
Triethylamine (0.42 g) and acetyl chloride (0.3 g) were added sequentially to an ice-cooled solution of the product from step a) (1.41 g) in dichloromethane (50 ml). The mixture was stirred for 30 minutes at 5 ^° C., then washed with a saturated sodium chloride solution, dried and concentrated. Chromatography (SiO ₂ , dichloromethane: methanol 95: 5 as eluent) gave the title compound (1.2 g).

MS (EU): 408 (M + H ⁺ ).

c) 5-Butyl-7-chloro-3- [5-O-acetyl-2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -3H-1,2,3-triazolo [4, 5-d] pyrimidine
The product of step b) (1.19 g) and DMF (299 mg) in chloroform were heated under reflux, thionyl chloride (3.47 g) was added and refluxed for 45 minutes. After cooling in an ice bath, the mixture was slowly added to the stirred saturated sodium bicarbonate solution. The mixture was extracted with dichloromethane (3 x 200 ml), the combined extracts were dried, filtered and concentrated. Chromatography (SiO ₂ , hexane: 5: 1 ethyl acetate as eluent) afforded the title compound (1.14 g).

MS (EU): 427, 425 (M + H ⁺ ).

d) N, 5-Dibutyl-3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -3H-1,2,3-triazolo [4,5-d] pyrimidin-7- amine
Obtained by the method of Example 1h) using the product of stage c).

MS (EU): 420 (M ⁺ ).

f) (E) -1- [5-Butyl-7- (butylamino) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -1,5,6-trideoxy- 2,3-O- (1-methylethylidene) -β-D-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1 i) using the product of stage d).

MS (FAB): 517 (M + H ⁺ , 100%).

f) (E) -1- [5-Butyl-7- (butylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-O-ribohept-5-enofuranuronic acid
Obtained by the method of Example 1 j) using the product of stage e).

NMR δ H (d ₆ -DMSO): 8.87 (1H, d), 6.71 (1H, dd), 6.20 (1H, m), 5.89 (1H, d), 4.75 ( 1H, m), 4.56 (IH, t), 4.37 (1H, t), 3.54 (2H, q), 2.73 (2H, t), 1.74 (2H, m), 1.62 (2H, m), 1.35 (4H, m), 0.91 (6H, t).

Example 22
(E) -1- [7-Butyl-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy-β - D-ribohept-5-enofuranuronic acid
a) 5-amino-1- [5-O - [(1,1-dimethylethyl) dimethylsilyl] -2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -1H-1,2,3 triazole-4-carboxamide
A solution of 5-amino-1- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] - 1H-1,2,3-triazole-4-carboxamide (prepared as described by G. Biagi et al. Farmaco, 1992, 47, 525) (10.0 g), imidazole (2.20 g) and tert-butyldimethylsilyl chloride (4.98 g) in DMF (200 ml) were stirred for 16 hours at room temperature. The solution was concentrated and the residue was purified (SiO ₂ , dichloromethane: ethyl acetate 1: 1 as eluent) to obtain the title compound.

MS (EU): 398 (M-CH ₃ ⁺ ), 73 (100%).

b) 3,6-Dihydro-3- [5-O - [(1,1-dimethylethyl) dimethylsilyl] - 2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -5-mercapto-7H -1,2, 3-triazole [4,5-d] pyrimidin-7-one
The product of step a) (26.0 g) in DMF (100 ml) was added over 1 hour to a stirred suspension of sodium hydride (60%, 2.52 g) in DMF (200 ml). 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 (FAB): 456 (M + H ⁺ ), 69 (100%).

c) 3- [5-O - [(1,1-Dimethylethyl) dimethylsilyl] -2,3-O- (1-methylethylidene) β-D-ribofuranosyl] -3,4-dihydro-5- (propylthio) - 7H-1,2,3-) triazolo [4,5-d] pyrimidin-7-one
The product of step b) (19.3 g) was added to a stirred suspension of sodium hydride (60%, 1.41 g) in DMF (200 ml). After 15 minutes, iodopropane (3.55 g) was added, the mixture was stirred for 1 hour, then concentrated. The residue was partitioned between water (1 L) and dichloromethane (1 L). The organic layer was dried, concentrated and the title compound (18 g) was obtained.

MS (FAB): 498 (M + H ⁺ ), 73 (100%).

d) 3- [2,3-O- (1-Methylethylidene) - β-D-ribofuranosyl] -3,4-dihydro-5- (propylthio) -7H-1,2,3-triazolo [4,5- d] pyrimidin-7-one
Tributylammonium fluoride (1 M in THF, 40.6 ml) was added to a stirred solution of the product of step c) (20.2 g) in TTF (300 ml) 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 (1 L). The organic phase was dried, concentrated and the title compound (14.1 g) was obtained.

MS (Electrospray): 382 (MH ⁺ , 100%).

e) 3- [5-O-Acetyl-2,3-O- (1-methylethylidene) -β-D-ribofuranosyl] - 3,4-dihydro-5- (propylthio) -7H-1,2,3- triazolo [4,5-d] pyrimidin-7-one
Obtained by the method of Example 21 b) using the product of stage d).

MS (Electrospray): 443 (M + H ⁺ , 100%).

f) 3- [5-O-Acetyl-2,3-O- (1-methylethylidene) -β-D-ribofuranosyl] -7-chloro-5- (propylthio) -3H-1,2,3-triazolo [ 4,5-d] pyrimidine
Obtained by the method of Example 21 c) using the product of step e).

MS (FAB): 444, 446 (M + H ⁺ ).

g) 3- [5-O-Acetyl-2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] - 7-butyl-5- (propylthio) -3H-1,2,3-triazolo [ 4,5-d] pyrimidine
Obtained by the method of Example 21 c) using the product of step e).

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

MS (FAB): 466 (M + H ⁺ ).

7-Butyl-3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine
Obtained by the method of Example 16 a) using the product of stage q).

MS (FAB): 424 (M + H ⁺ ).

i) (E) -1- [7-Butyl-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1 i) using the product of stage h).

MS (FAB): 520 (M + H ⁺ ).

j) (E) -1- [7-Butyl-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 1i) using the product of stage h).

NMR δ H (d ₆ -DMSO): 7.00 (1H, d), 6.52 (1H, s), 6.01 (1H, d), 5.30 (2H, br), 4.94 ( 1H, s), 4.56 (1H, t), 4.76-4.81 (2H, d), 3.12 (4H, br s), 1.80 (2H, q), 1.70 ( 2H, q), 1.37 (2H, q), 0.99 (3H, t), 0.89 (3H, t).

Example 23
(E) -N- [1- [5,7-Di (butylamino) -3H-1,2,3-triazolo [4,5- (1] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D- riboheptofuranuronoyl] -L-ac paraginic acid, monoammonium salt
a) (E) -N- [1- [7-Butylamino-5- (methylsulfonyl) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1.5, 6-trideoxy-β-D-riboheptofuranuronoyl] -L-aspartic acid, 1,1-dimethylethyl ether
3-Chloroperoxybenzoic acid (50%, 0.12 g) in ethanol (1 ml) was added over 1 hour to a stirred solution of the product of Example 17 c) (0.1 g) in ethanol. After stirring for 16 hours at room temperature, the solution was diluted with dichloromethane (50 ml), then washed with an aqueous solution of sodium metabisulfite (30 ml) and an aqueous solution of sodium carbonate (2 x 20 ml). The organic layer was dried, concentrated, and the title compound (90 mg) was obtained.

MS (FAB): 700 (M + H ⁺ ), 299 (100%).

b) (E) -N- [1- [5,7-Di (butylamino) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- trideoxy-β-D-riboheptofuranuronoyl] - L-ac paraginic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1 h) using the product of stage a).

MS (FAB): 665 (M + H ⁺ , 100%).

c) (E) -N- [1- [5,7-Di (butylamino-3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D-riboheptofuranuronoyl] -L- aspartic acid, monoammonium salt
Obtained by the method of Example 2 b) using the product of stage b).

MS (Electrospray): 553 (M + H ⁺ , 100%).

Example 24
(Z) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D- ribohept-5-enofuranuric acid
a) N-Butyl-5- (propylthio) -3- [2,3-O- (1-methylethylidene) - β-D-ribofuranosyl] -3H-1,2,3-triazolo [4,5-d] pyrimidine-7-amine
Obtained by the method of Example 18 b) using the product of stage 14e).

MS (FAB): 443 (M + H ⁺ ), 267 (100%).

b) (Z) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-2,3-O- (1-methylethylidene) - β-D-ribohept-5-enofuranuronic acid, 1,1-dimethylethyl ether
Obtained by the method of Example 1i) using the product of step a), wherein the title compound was isolated as a minor product.

MS (FAB): 535 (M + H ⁺ , 100%).

c) (Z) -1- [7- (Butylamino-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy - β-D-ribohept-5-enofuranuronic acid
Obtained by the method of Example 1 j) using the product of stage b).

MS (FAB): 439 (M + H ⁺ ), 267 (100%).

Example 25
N-Butyl-5- (propylthio) -3- [5,6-dideoxy-6- (1H-tetrazol-5-yl) - β-D-ribohexofuranosyl] -3H-1,2,3-triazolo [4, 5-d] pyrimidin-7-amine
a) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-2,3-O- (1-methylethylidene) - β-D-ribohept-5-enofuranurononitrile
Obtained by the method of Example 1 i) using the product of step 24a) and (triphenylphosphonarylidene) acetonitrile.

MS (FAB): 460 (M + H ⁺ , 100%).

b) (E) -1- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-2,3-O- (1-methylethylidene) - β-D-riboheptofuranurononitrile
Obtained by the method of Example 8 b) using the product of stage a).

MS (FI): 462 (M + H ⁺ , 100%).

c) N-Butyl-5- (propylthio) -3- [5,6-dideoxy-2,3-O- (1-methylethylidene) -6- (1H-tetrazol-5-yl) -β-D-ribohexafuranosyl - 3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine
Azidotrimethylsilane (0.30 g) and dibutyltin oxide (32 mg) were added to a solution of the product of stage b) (0.60 g) in toluene (6 ml), 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 (SiO ₂ , ethyl acetate: isohexane: acetic acid 100: 100: 1 as eluent) to obtain the title compound (0.26 g).

MS (FAB): 505 (M + H ⁺ ), 267 (100%).

d) N-Butyl-5- (propylthio-3- [5,6-dideoxy-6- (1H-tetrazol-5-yl) - β-D-ribohexofuranosyl] -3H-1,2,3-triazolo [4 , 5-d] pyrimidine-7-amine
Obtained by the method of Example 1 j) using the product of stage c).

MS (FAB): 465 (M + H ⁺ ), 267 (100%).

NMR δ H (d ₆ -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 (1H, m), 3.50 (2H, m), 3.06 (2H, m), 2.92 (2H, m), 2.05 (2H, m), 1.63 (4H, m), 1.34 (2H, m), 0.97 (3H, t), 0.91 (3H, t).

Example 26
1,5,6-Tridesoxy-1- [5,7-bis (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] - β-D-riboheptofuranuronic acid sodium salt
a) (E) -1,2,3-Tri-O-acetyl-5,6-dideoxy-β-D-ribohept-5-enofuranuronic acid, ethyl ether
(E) -methyl-5,6-dideoxy-2,3-O- (1-methylethylidene) -β-D-ribohept-5-enofuranosiduronic acid ethyl ester (prepared as described by AJCooper, RG Salomon, Tetrahedron Lett., 1990 , 31, 3813) (88.0 g) was heated at 80 ^° C. in a mixture of acetic acid (256 ml) and water (64 ml) for 16 hours at room temperature. Evaporation gave a residue, which was dissolved in pyridine (160 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 HCl. Drying and evaporation gave an oil which was purified by chromatography (SiO ₂ , isohexane: ethyl acetate 5: 1 as eluent) to give the title compound (5.34 g).

MS (FAB + RbI): 431, 429 (M + Rb ⁺ ), 285 (100%).

b) 1,2,3-Tri-O-acetyl-5,6-dideoxy-β-D-riboheptofuranuronic acid, ethyl ether
Obtained by the method of Example 8 b) using the product of stage a).

MS (FAB + RbI): 433, 431 (M + Rb ⁺ ), 185 (100%).

 c) 2,3-Di-O-acetyl-1,5,6-tridesoxy-1- [5,7-bis (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidine- 3-yl] -β-D-riboheptofuranuronic acid, ethyl ether, and 2,3-di-O-acetyl-1,5,6-tridesoxy-1- [5,7-bis (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-2-yl] -β-D-riboheptofuranuronic acid, ethyl ether.

The product of stage b) (1.00 g) and the product of stage 14 b) (0.78 g) were mixed with p-toluenesulfonic acid (12 mg) and thoroughly mixed under vacuum of a water-jet pump. The mixture was immersed in an oil bath heated to 140 ^° C. Heating was continued for 10 minutes, then the flask was cooled and the reaction mixture was treated with chloroform. Washing with a saturated sodium bicarbonate solution, drying, evaporation and chromatography (SiO ₂ , dichloromethane-ethyl acetate 15: 1 as eluent) gave the title compounds (5.34 g) as an indivisible mixture.

d) 1,5,6-Tridesoxy-1- [5,7-bis (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] - β -D- riboheptofuranuronic acid, sodium salt
Obtained by the method of Example 3 c) using the product of stage c).

MS (FAB + RbI): 433, 431 (M + Rb ⁺ ).

Pharmaceutical Compositions
The novel compounds of the present invention can be administered parenterally, intravenously, by inhalation, or orally. The preferred route of administration is intravenous infusion.

 The dose depends on the route of administration, the severity of the disease, the age and weight of the patient, as well as other factors that are usually taken into account by the hospital’s staff doctor when determining the individual regimen and dose level most appropriate 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 inhaled compositions - untreated 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 excipients. In particular, chelating agents or passivating agents, antioxidants, toning agents, pH adjusting agents and buffering agents can be used. Solutions containing a compound of formula (1), if necessary, can be evaporated, for example, by freeze-drying or spray drying, to obtain a solid composition that can be reconstituted before use. The compositions may also contain suitable preservative, stabilizing and wetting agents, dissolution promoting agents, for example, a water-soluble cellulose polymer, such as hydroxypropyl methylcellulose, or a water-soluble glycol, such as propylene glycol, sweetening and coloring agents and perfumes. If necessary, the compounds can be formulated as a sustained release form.

 According to another aspect, the invention relates to the use of a compound of formula (1) or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of disorders associated with platelet aggregation.

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

 Pharmaceutically acceptable salts of the compounds of formula (1) include alkali metal salts, for example, sodium and potassium salts; alkaline earth metal salts, for example, calcium and magnesium salts; salts of group III elements, for example, aluminum salts; and ammonium salts. Salts with suitable organic bases, for example, hydroxylamine salts; lower alkyl amines, for example methylamine or ethylamine; with substituted lower alkyl amines, for example, hydroxy substituted alkyl amines; or with monocyclic nitrogen-containing heterocyclic compounds, for example piperidine or morpholine; and salts with amino acids, for example arginine, lysine, etc. or their N-alkyl derivatives; or with amino sugars, for example, N-methyl-D-glucamine or glucosamine. The above salts are only examples of salts that can be used in accordance with the present invention, and their list should not be construed as exhaustive.

 Preferred pharmaceutically acceptable salts of the compounds of formula (1) are alkali metal salts and ammonium salts, more preferably sodium salts and monoammonium salts.

Biological test
The effectiveness of the compounds of the present invention as inhibitors of platelet aggregation was determined by their ability to act as antagonists of the P _2T receptor, as shown in the following text.

Quantification of agonistic / antagonistic activity against the P _2T receptor of washed human platelets.

Cooking
Human venous blood (100 ml) was distributed equally between 3 tubes, each containing 3.2% trisodium citrate (4 ml) as an anticoagulant. The tubes were centrifuged for 15 min at 240 G to obtain platelet rich plasma (POT), to which 300 ng / ml prostacyclin was added in order to stabilize platelets during the washing operation. A red cell-free POT was obtained by centrifugation for 10 min at 125 G and subsequent centrifugation for 15 min at 640 G. The supernatant was discarded and the platelet cake was resuspended in a modified, calcium-free Tyrode (tubing) solution (10 ml ) having the composition: NaCl 137 mM, NaHCO ₃ 11.9 mM, NaH ₂ PO ₄ 0.4 mM, KCl 2.7 mM, MgCl ₂ 1.1 mM, dextrose 5.6 mM, saturated with a gaseous mixture of 950 O ₂ / 5% CO ₂ and kept at 37 ^o C. After adding another 300 ng / ml PG I _{2, the} combined suspension was centrifuged again for 15 min at 640 G. the cage fluid was discarded, and the platelets were resuspended first in 10 ml of tubing, then another tubing was added to bring the final platelet count to 2 x 10 ⁵ / ml. This final suspension was stored in a 60 ml syringe at 3 ^° C without air. To allow recovery of normal function after inhibition of PG I ₂ , platelets were used to study aggregation no earlier than 2 hours after the final resuspension.

In all studies, 3 ml aliquots of platelet suspensions were added to tubes containing CaCl ₂ solution (60 μl of a 50 mM solution, final concentration 1 mM). Human fibrinogen (Sigma, F 4883) and 8-sulfophenylteophylline (8-CFT) were added to block any antagonistic activity of the compounds with respect to P ₁ ) to obtain final concentrations of 0.2 mg / ml (60 μl of a coagulating protein solution in saline with a concentration of 10 mg / ml) and 300 nM (10 μl of a 15 mm solution in 6% glucose), respectively. Platelets or buffer, respectively, were added, in a volume of 150 μl, to individual 96-well plate cells. All measurements were made thrice with platelets from each donor.

Test report
a) Assessment of agonistic / antagonistic activity
Aggregated reactions in a 96-well plate using a change in absorbance are fixed with a recording device on the plate at 660 nm.

 The absorption of each cell in the tablet was fixed at 660 nm to establish a base figure. Saline or an appropriate solution of the test compound was added to each well in a volume of 10 μl to obtain a final concentration of 0.001, 0.1, 1, 10, or 100 mM. The tablet was then shaken for 5 min on a rotary shaker at position 10 and absorbance was fixed at 660 nm. Aggregation at this point is an indicator of the agonistic activity of the test compound. Then, physiological saline or ADP (30 mM; 10 μl 450 mM solution) was added to each well and the plate was shaken for another 5 min until the absorbance was fixed again at 660 nm.

 Agonistic activity was evaluated as% inhibition of the control response to ADP. The compounds of the present invention showed anti-aggregation activity when tested according to the above procedure.

Example Number - pIC ₅₀
1 - 7.60
2 - 9.30
3 - 5.85
4 - 7.14
5 - 7.04
6 - 7.00
7 - 7.15
8 - 6.24
10 - 5.93
14 - 7.39
pIC ₅₀ is log ₁₀ IC ₅₀ , where IC ₅₀ is the concentration of antagonist required for 50% inhibition of aggregation.

Claims (17)

1. Derivatives of 3H-1,2,3-triazolo- [4,5-d] pyrimidine of the general formula I

in which B represents O or CH ₂ ;
X is selected from NR ¹ R ² , SR ¹ and C ₁ -C ₇ alkyl;
Y is selected from SR ¹ , NR ¹ R ^2, and C ₁ -C ₇ alkyl;
R ¹ and R ² each independently represents H or C ₁ -C ₇ alkyl or R ¹ represents C ₁ -C ₇ alkyl optionally substituted in the alkyl chain by one O or S atom or one or more halogens, and R ² represents hydrogen ;
R ³ and R ⁴ represent hydrogen or R ³ and R ⁴ together form a bond;
A represents COOH, C (O) NH (CH ₂ ) _p COOH, C (O) N [(CH ₂ ) _q -COOH] ₂ , C (O) NHCH (COOH) (CH ₂ ) _r COOH or 5-tetrazolyl in which p, q and r are each independently 1, 2 or 3,
and their pharmaceutically acceptable salts or esters. 2. The compound of formula I according to claim 1, where X represents NR ¹ R ² ; Y represents SR ¹ ; A represents C (O) NHCH (COOH) (CH ₂ ) _r COOH and where R ¹ , R ² and r are defined in claim 1. 3. The compound according to claim 2, where X represents NR ¹ R ² where R ¹ represents hydrogen and R ^{2 is} defined in claim 1; Y is SR ¹ , where R ¹ is C ₁ -C ₅ alkyl optionally substituted with one or more halogens; A represents C (O) NHCH (COOH) (CH ₂ ) COOH. 4. The compound according to claim 1, which is a
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7-butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d ] -pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt;
[1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7-butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4, 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid, disodium salt;
[1S- (1α, 2β, 3β, 4α)] -4- [7-butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3- yl] -2,3-dihydroxycyclopentane propanoic acid, sodium salt;
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7-butylamino) -5- (pentylthio) -3H-1,2,3-triazolo- [4,5-d ] -pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt;
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo- [4,5- d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid, sodium salt;
[1S- (1α, 2β, 3β, 4α)] -4- [7-butylamino) -5- (pentylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3- yl] -2,3-dihydroxycyclopentane propanoic acid, sodium salt;
[1S- (1α, 2β, 3β, 4α)] -4- [7- (ethylamino) -5- (pentylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3 -yl] -2,3-dihydroxycyclopentane propanoic acid, sodium salt;
[1R- (1α, 2α, 3β, 5β)] -3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3 -yl] -5- [2- (1H-tetrazol-5-yl) ethyl-1,2-cyclopentadiol;
[1R- (1α, 2β, 3β, 4α)] -N- [3- [4- [7-butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d ] -pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] -L-aspartic acid;
[1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7-hexylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4, 5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid;
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (3,3-dimethylbutylamino) -5- (propylthio) -3H-1,2,3-triazolo- [ 4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid;
[1R- (1α (E), 2β, 3β, 4α)] -3- [4- [7- (2-methoxy) ethylamino) -5- (propylthio) -3H-1,2,3-triazolo- [ 4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoic acid;
[1R- (1α, 2β, 3β, 4α)] -N- [3- [4- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5- d] pyrimidin-3-yl] -2,3-dihydroxycyclopentylpropanoyl] -L-aspartic acid;
[1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [5- (3,3,3-trifluoropropyl) thio] -7- [2- (methylthio) ethylamino ] -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid, a monoammonium salt;
(E) -1- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-β-D-ribohept-5-enofuranuronic acid;
(E) -N- [1- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1.5 , 6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid;
(E) -N- [1- [7-amino-5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6 -tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt;
(E) -N- [1- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1.5 , 6-tridesoxy-β-D-riboheptofuranuronoyl] -L-aspartic acid, monoammonium salt;
(E) -N- [1,5,6-tridesoxy-1- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidine- 3-yl] -β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid, monoammonium salt;
(E) -1- [7- (N-butyl-N-methylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] - 1,5,6-tridesoxy-β-D-ribohept-5-enofuranuronic acid;
(E) -N- [1- [7- (butylamino) -5- (methylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1.5 6-Tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid;
(E) -1- [5-butyl-7- (butylamino) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid;
(E) -1- [7-butyl-5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6-trideoxy- β-D-ribohept-5-enofuranuronic acid;
(E) -N- [1- [5,7-di (butylamino) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6- tridesoxy-β-D-riboheptofuranuronoyl] -L-aspartic acid, monoammonium salt;
(Z) -1- [7-butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -1,5,6-tridesoxy β-D-ribogep-5-enofuranuronic acid;
N-butyl-5- (propylthio) -3- [5,6-dideoxy-6- (1H-tetrazol-5-yl) -β-D-ribohexofuranosyl] -3H-1,2,3-triazolo- [4 , 5-d] pyrimidin-7-amine or 1,5,6-tridesoxy-1- [5,7-bis (propylthio) -3H-1,2,3-triazolo- [4,5-d] - pyrimidin-3-yl] -β-D-riboheptofuranuronic acid, sodium salt.  5. The compound according to claim 4, which is (E) -N- [1- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo- [4,5-d] -pyrimidin-3-yl] -1,5,6-tridesoxy-β-D-ribohept-5-enofuranuronoyl] -L-aspartic acid.  6. The compound according to claim 4, which is [1R- (1α, 2β, 3β, 4α)] - N- [3- [4- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazolo- [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] propanoyl] -L-aspartic acid.  7. The compound according to claim 4, which is [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [7- (hexylamino) -5- (propylthio) -3H -1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid.  8. The compound according to claim 4, which is [1R- (1α (E), 2β, 3β, 4α)] -N- [3- [4- [5 - [(3,3,3-trifluoropropyl) thio ] -7- [2- (methylthio) ethylamino] -3H-1,2,3-triazolo- [4,5-d] pyrimidin-3-yl] -2,3-dihydroxycyclopentyl] -2-propenoyl] -L-aspartic acid, monoammonium salt.  9. The compound of formula I according to claim 1 in the form of a salt.  10. The compound according to claim 9, which is an alkali metal salt or ammonium salt of the compounds of formula I according to claim 1.  11. The compound according to p. 10, which is the sodium salt of the compounds of formula I according to claim 1.  12. The compound of claim 10, which is a monoammonium salt of the compounds of formula I according to claim 1.  13. The compound of formula I according to claim 1, which is in any one of its tautomeric, enantiomeric or diastereomeric forms. 14. The compound of formula I according to claim 1, where B, X, Y, R ¹ , R ² , R ³ and R ^{4 are} defined in claim 1 and A is selected from COOR ¹¹ , C (O) NH (CH ₂ ) _p COOR ¹¹ , C (O) N [(CH ₂ ) _q COOR ¹¹ ] ₂ or C (O) NHCH (COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ , where p, q and r are 1, 2 or 3 and R ¹¹ represents lower alkyl.  15. The compound of formula I according to claim 1 to prevent platelet aggregation.  16. A pharmaceutical composition having platelet aggregation inhibitory activity, comprising a compound of formula I according to claim 1 as an active ingredient together with a pharmaceutically acceptable carrier. 17. A method for producing a compound of formula I according to claim 1, comprising (i) reacting a compound of formula I, wherein X is SR ¹ , NR ¹ R ^2, or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; R ¹ and R ^{2 are} defined in formula I; B represents O or CH ₂ ; R ³ and R ⁴ represent hydrogen or together form a bond, and A represents COOH, with a compound of the structure NH ₂ (CH ₂ ) _p COOR ¹¹ , NH [(CH ₂ ) _q COOR ¹¹ ] ₂ or NH ₂ CH (COOR ¹¹ ) ( CH ₂ ) _r COOR ¹¹ , where p, q and r are 1, 2 or 3 and R ¹¹ is lower alkyl, using peptide synthesis methods, to obtain a compound of formula I, where X is SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² or C ₁ -C ₇ alkyl; R ¹ and R ^{2 are} defined in formula I; B represents O or CH ₂ ; R ³ and R ⁴ represent hydrogen or together form a bond, and A represents C (O) NH (CH ₂ ) _p COOR ¹¹ , C (O) N [(CH ₂ ) _q COOR ¹¹ ] ₂ or C (O) NHCH ( COOR ¹¹ ) (CH ₂ ) _r COOR ¹¹ , where p, q and r are 1, 2 or 3 and R ¹¹ represents lower alkyl; (i) a deesterification of a product of formula I of step (i) to give a compound of formula I, wherein B is O or CH ₂ ; X represents NR ¹ R ² , SR ¹ or C ₁ -C ₇ alkyl; Y represents SR ¹ , NR ¹ R ² , or C ₁ -C ₇ alkyl; R ¹ and R ² each independently represents H or C ₁ -C ₇ alkyl; R ³ and R ⁴ both represent hydrogen or R ³ and R ⁴ together form a bond and A represents C (O) NH (CH ₂ ) _p COOH, C (O) N [(CH ₂ ) _q COOH] ₂ or C (O ) NHCH (COOH) (CH ₂ ) _r COOH, where p, q and r are each independently 1.2 or 3;
Priority on points:
07/04/1996 - according to claims 1, 2, 4, 5 and 7 - 17;
07/11/1995 - according to claim 3;
11/08/1995 - according to claim 6.