MXPA00000681A - Novel compounds - Google Patents

Abstract

The invention provides new triazolo[4,5-i(d)]pyrimidine compounds of formula (I), their use as medicaments, compositions containing them and processes for their preparation.

Description

NOVEL COMPOUNDS OF TRIAZOL [, 5-d] PYRIMIDINE DESCRIPTION OF THE INVENTION The present invention provides novel triazole [4,5-d] pyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation. - Platelet adhesion and aggregation are initiation events in arterial thrombosis. Although the process of adhesion of platelets in the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates may precipitate acute thrombotic occlusion of vital vascular beds, leading to with high morbidity such as myocardial infarction and non-stable angina. The success of interventions used to avoid or alleviate these conditions, such as thrombolysis and angioplasty, is also compromised by platelet-mediated occlusion or re-occlusion. A number of convergent trajectories that lead to platelet aggregation. Whatever the initial stimulus, the final common event is a crosslinking of platelets by fibrinogen binding to REF: 32471 a membrane binding site, glycoprotein Ilb / IIIa (GPIIb / IIIa). The high anti-platelet efficacy of antibodies or antagonists for GPIIb / IIIa is explained by their interference with this final common event. However, this efficacy can also explain the problems that have been observed with this kind of agent. Thrombin can produce platelet aggregation greatly independently of other trajectories but substantial amounts of thrombin are unlikely to occur without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again they can cause excessive bleeding since they function both as anti-platelet agents and as anticoagulants (The TIMI 9a Investigators (1994), Ci rc ul a ti on 90, pp. 1624-1630, The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) in Iñvestigators (1994) Ci rcul a ti on 90, pp. 1631-1637, Neuhaus KL et al. (1994) Ci rcul a ti on 90, pp. 1638-1642). It has been discovered that ADP acts as a key mediator of thrombosis. A pivotal role for ADP is supported by the fact that other agents, such as adrenaline and 5-hydroxytryptamine (5HT, serotonin) will only produce aggregation in the presence of ADP. The limited anti-thrombotic efficacy of aspirin may reflect the fact that this blocks only one source of ADP which is that released in a thromboxane-dependent manner following the adhesion of platelets (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). Aspirin has no effect on the aggregation produced by other sources of ADP, such as damaged cells or ADP released under turbulent blood flow conditions. The aggregation of platelets induced by ADP is mediated by the P2r receptor subtype located only in the platelet membrane. Recently it has been shown that antagonists in this receptor offer significant improvements over other anti-thrombotic agents. Accordingly, there is a need to discover P2t antagonists as anti-thrombotic agents. It has now been found that a series of triazole [4,5-d] pyrimidine derivatives are P? T antagonists. In a first aspect the invention therefore provides a compound of the formula (I): wherein: R1 is an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl, each group being optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11 or alkyl of 1 to 6 carbon atoms (optionally substituted by itself by one or more halogen atoms); R2 is alkyl of 1 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, cycloalkyl of 3 to 8 carbon atoms, aryl (optionally substituted by one or more alkyl groups and / or atoms) of halogen), or alkyl of 1 to 6 carbon atoms; or R2 is a cycloalkyl group of 3 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, alkyl of 1 to 6 carbon atoms or phenyl (the last two being optionally substituted by one or plus its selected halogen constituents, N02, C (0) Rf OR 'SR NR12R13, phenyl and alkyl of 1 to 6 carbon atoms which is optionally substituted by one or more halogen atoms); one of R3 or R4 is hydroxy and the other is hydrogen, hydroxy or NR9R10; R5 is (CH2) nNR14R15 where n is 0 to 6 and R14 and R15 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R5 is CONR16R17 where R16 is hydrogen or alkyl of 1 to 6 carbon atoms, and R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms each of which is substituted by NR18R19 and optionally substituted by phenyl, or R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms substituted by phenyl which is substituted by NR18R19 where R18 and R19 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R17 is a 5- to 8-membered saturated heterocycle containing one or more nitrogen atoms and optionally substituted on nitrogen by hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R16 and R17 together with the nitrogen atom to which they are attached form a ring of 5 to 8 members which is replaced by NR18R19 as defined above; or RJ together with R forms a 6-membered ring containing the two nitrogen atoms in which R17 and R18 are as defined above; or R5 is (CH2) PNR20CO (CH2) q0R21 or (CH2) PNR22 (CH2) qNR23COR24 where p and q are independently 1 to 4 and R20, R21, R22, R23 and R24 are independently alkyl of 1 to 4 carbon atoms or phenyl; or R5 is CH = CHCH2NR25R26 where R25 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl and R26 is hydrogen or (CH2) and NR27R28 where y is 2-4 and R27 and R28 are independently hydrogen, alkyl of 1 to 6 atoms carbon or phenyl; R8, R9, R10 and R11 are independently hydrogen or alkyl of 1 to 6 carbon atoms; and R and R, 13 are independently hydrogen, alkyl of 1 to 6 carbon atoms or acyl groups; or a pharmaceutically acceptable salt or solvate thereof. The alkyl groups, either alone or as part of another group, can be straight or branched chains. The compounds of formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these stereoisomeric forms and to mixtures thereof including racemic mixtures. The invention also extends to any tautomeric forms and mixtures thereof.

Preferably the compound of the formula (I) has the following stereochemistry: Suitably R1 is an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl, each group being optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11 or alkyl from 1 to 6 carbon atoms (optionally substituted by itself by one or more halogen atoms). Preferably R1 is alkyl of 1 to 8 carbon atoms. Most preferably R1 is propyl. Suitably R2 is alkyl of 1 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, cycloalkyl of 3 to 8 carbon atoms, aryl (optionally substituted by one or more alkyl groups and / or halogen atoms), or alkyl of 1 to 6 carbon atoms; or R2 is a cycloalkyl group of 3 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, alkyl of 1 to 6 carbon atoms or phenyl (the last two being optionally substituted by one or more substituents selected from halogen, N02, C (0) R8, OR8, SR11, NR12R13, phenyl and alkyl of 1 to 6 carbon atoms). Preferably R2 is alkyl of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms optionally substituted by phenyl. More preferably R2 is butyl or cyclopropyl substituted by phenyl. Suitably one of R3 or R4 is hydroxy and the other is hydrogen, hydroxy or NR9R10. Preferably both R3 and R4 are hydroxy. Suitably R5 is (CH2) nNR1 R15 where n is 0 to 6 and R14 and R15 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R5 is CONR16R17 where R16 is hydrogen or alkyl of 1 to 6 carbon atoms, and R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms each of which is substituted by NR18R19 and optionally substituted by phenyl, or R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms substituted by phenyl which is substituted by NR18R19 where R, 18 and R are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R17 is a 5- to 8-membered saturated heterocycle containing one or more nitrogen atoms and optionally substituted on nitrogen by hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R16 and R17 together with the nitrogen atom to which they are attached form a ring of 5 to 8 members which are substituted by NR18R19 as defined above; or R16 together with R19 form a ring of 6 to 8 members containing the two nitrogen atoms in which R17 and R18 are as defined above; or R5 is (CH2) p-NR20C0 (CH2) qOR21 or (CH2) PNR22 (CH2) qNR23COR24 where p and q are independently 1 to 4 and R20, R21, R22, R23 and R24 are independently alkyl, of 1 to 4 carbon atoms or phenyl; or R5 is CH = CHCH2NR25R26 where R25 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl and R26 is hydrogen or (CH2) and NR27R28 where y is 2-4 and R27 and R28 are independently hydrogen, alkyl of 1 to 6 atoms carbon or phenyl. Preferably R5 is (CH2) nNH2 where n is 0, 1 or 2, CONR16R17 where R? E is hydrogen and R17 is alkyl of 1 to 5 carbon atoms optionally substituted by NR18R19 where R18 and R19 are both hydrogen, or one is alkyl from 1 to 6 carbon atoms, in particular methyl, and the other is phenyl, or R5 is CONR16R17 where R16 is hydrogen and R17 is CH2phenyl or a cyclohexyl group each substituted by amino, or R5 is CONR16R17 where R16 and R17 form a piperazine ring, or R5 is CH = CHCH2NR25R26 where R25 and R26 are both hydrogen or R25 is hydrogen and R26 is (CH2) 2NH2, or R5 is CH2R20CO (CH2) 2OR21 where R20 and R21 are alkyl of 1 to 4 carbon atoms, preferably ethyl and methyl respectively, or R5 is CH2NH (CH2) 2NHCOR24 where R24 is alkyl of 1 to 4 carbon atoms, in particular methyl. More preferably the R5 groups are those exemplified herein. Particularly preferred compounds of the invention include: [S- (la, 2β, 3β, 4a)] -4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole trifluoroacetate [4] , 5-d] pyrimidin-3-yl] -2, 3-dihydroxy-N- [[3- (N-methyl-N-phenyl) amino] propyl] -cyclopentanecarboxamide, Trifluoroacetate of [S- (la, 2ß, 3ß, 4a)] -N- [5-aminopentyl] -4- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl ] -2, 3-dihydroxy-cyclopentanecarboxamide, Trifluoroacetate of [ΔS- (la, 2β, 3β, 4a)] -N- [3-aminopropyl] -4- [7- (butylamino) -5- (propylthio) -3H -l, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -2, 3-dihydroxy-cyclopentane-carboxamide, Trifluoroacetate of [ÍS- (la, 2ß, 3ß, 4a)] -N- [(3-amino phenyl) methyl] -4- [7- (butylamino) -5-) propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -2, 3-dihydroxy-cyclopentanecarboxa ida, [S] - (la, 2β, 3β, 4a (ÍS *, 2R *)]] - N- [3-aminopropyl] -2,3-dihydroxy-4- [7- [ 2- (phenylcyclopropyl) -amin or] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, Bis (trifluoroacetate) of [1 S- (la, 2ß, 3ß, 4a (1S *, 2R *)]] - N - [4-aminocyclohexyl] -2,3-dihydroxy-4- [7- [2- (phenylcyclopropyl) amino] -5- (propylthio) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, [lS- (la, 2a, 3ß, 5ß)] -3-amino-5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß, 5ß)] - 3 - (Aminomethyl) -5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol , [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3-amino-5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1, 2, 3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß, 5ß (lS *, 2R *)]] -3 - (Ethylamino) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan- 1, 2-diol, [lS- (la, 2a, 3β, 5β (lR *, 2S *)]] -3- [(Methylamino) ethyl] -5- [7- [(2-phenylcyclopropyl) amino] - 5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3- [(Ethylamino) methyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4,5] -d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3- (A inomethyl) -5- [7 - [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclope-tan-1,2-diol, [lS - (la, 2a, 3β, 5β (lS *, 2R *)]] -3- (2-Aminoethyl) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1 , 2, 3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß (E), 5β (IS *, 2R *)] ]-3- (3-Aminoprop-1-eni 1) -5- [7- [(2-phenylcyclopropyl) amino] -5 - (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine- 3-yl] -cyclopentan-1,2-diol, N-Ethyl-N- [[R- [la, 2β, 3β, 4a (lR *, 2S *)]] -2,3-dihydroxy-4 - [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentylmethyl] -3-methoxy-propanamide, Ditrifluoroacetate [1 S- [la, 2a, 3ß (E ), 5β (1S *, 2R *)]] -3- [3- [(2-dimethylaminoethyl) amino] -prop-1-enyl] -5- [7- [(2-phenylcyclopropyl) amino] -5 - (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [IR- [la, 2ß, 3ß, 4a (lR * , 2S *)]] -N- [2- [2, 3-dihydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4 , 5-d] irimidin-3-yl] -cyclopethylmethyl-yl] -ethyl] -acetamide, [lS- [la, 2a, 3a, 5β (lS *, 2R *)]] - 3-Amino- 5- [ 7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, l- [[lS- [la, 2β, 3β, 4a (lS *, 2R *)]] -2, 3-Dihydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H- 1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentylcarbonyl] -piperazine or pharmaceutically acceptable salts or solvates thereof. According to the invention there is further provided a process for the preparation of a compound of the formula (I) comprising: (a) for compounds wherein R5 is CONHR16R17 of reaction of a compound of the formula (II): (II) wherein R1, R2, R3 and R4 are as defined in formula (I) or are protected derivatives thereof, with a compound of the formula. (III): HNR16R17 (III) where R16 and R17 are as defined in formula (I), or (b) for compounds of formula (I) wherein R5 is amino, perform a rearrangement of Curtis in a compound of formula (II) as defined above , o and optionally after the same (a) or (b) in any order: • converting one or more functional groups to additional functional groups • removing any protecting groups • forming a pharmaceutically acceptable salt or solvate. The reaction of a compound of the formula (II) with a compound of the formula (III) can be carried out using coupling chemistry, for example in the presence of a coupling agent using known methods of peptide synthesis (see M. Bodanszky and A. Bodanszky, The Practice of Peptide Synthesis, Springer-Verlag, 1984). Suitable coupling agents include 1,1 '-carbonyldiimidazole and dicyclohexylcarbodiimide; the preferred coupling agent is bromo-trispyrrolidino-phosphonium hexafluorophosphate, used in the presence of N, N-diisopropylethylamine. The reaction is preferably carried out in N, -dimethyl formamide (DMF) or tetrahydrofuran (THF) and preferably at a temperature from -15 ° to 120 ° C, more preferably at a temperature from 0 ° C to room temperature. The compounds of the formula (II) can be prepared by oxidizing a compound of the formula (IV): wherein R1, R2, R3 and R4 are as defined in formula (I) or are protected derivatives thereof using known reagents such as pyridinium dichromate or chromium (IV) oxide. A compound of the formula can be prepared (IV) by reacting a compound of the formula (V): wherein R1 is as defined in formula (I), P1, P2 and P3 are hydrogen or are the same or different protecting groups. L1 is a leaving group, for example a halogen atom, with NH2R2 or a salt of NH2R2 wherein R2 is as defined above, in the presence of a base. Suitable salts of NH2R2 include hydrochlorides. Suitable bases include an organic base such as triethylamine or an inorganic base such as potassium carbonate. A compound of the formula (V) can be prepared by diazotizing a compound of the formula (VI): wherein R1, L1, P1, P2 and P3 are as defined above, with a metal nitrite, for example an alkali metal nitrite, especially sodium nitrite in dilute aqueous acid, for example 2M HCl, or with a nitrite of alkyl of 1 to 6 carbon atoms in an inert solvent, at a temperature from -20 to 100 ° C; the preferred conditions are isoamyl nitrite in acetonitrile at 80 ° C. A compound of the formula (VI) can be prepared wherein P 1 is OH by reducing a compound of the formula (VII): wherein R1, L1, P2 and P3 are as defined above. The reduction of the nitro group can be carried out for example using hydrogenation with a transition metal catalyst at a temperature around room temperature, for example palladium or carbon under a hydrogen atmosphere, preferably at a pressure of 1 to 5 atmospheres, in a solvent, for example ethanol, or using iron in an acidic solvent such as acetic acid at a temperature of about 100 ° C. The reduction of the lactam can be carried out using complex metal hydrides such as lithium-aluminum hydride in a suitable solvent such as ether. The reduction is preferably carried out using sodium borohydride in methanol. A compound of the formula can be prepared (VII) by reacting a compound of the formula (VIII): wherein L1 and R1 are as defined above and L2 is a leaving group, for example a halogen atom, wherein L1 and L2 are preferably the same, with a compound of the formula (IX): wherein P2 and P3 are as defined above, in the presence of a base such as alkyl of 1 to 6 carbon atoms-M or MH wherein M is a metal ion, for example butyllithium, in an inert solvent, such as tetrahydrofuran (THF), at a temperature of about -10 to about 100 ° C. Preferably, sodium hydride in THF is used at room temperature. Preferably the compound of the formula (IX) has the following stereochemistry to give a compound of the formula (la): (Ka) A compound of the formula (II) can also be prepared from a compound of the formula (VII) ~ by reduction of the nitro group, as described above, followed by hydrolysis. The hydrolysis can be carried out using a mineral acid such as HCl or a strong organic acid such as trifluoroacetic acid. Preferably the reduction and hydrolysis are carried out simultaneously using iron in an alcohol solvent, for example ethanol, which contains an alkaline earth halide such as calcium chloride at a temperature of about 80 ° C. The resulting intermediate can be converted to compounds of formula (II) using methods described above. All novel intermediaries form a further aspect of the invention. Protective groups can be added and removed using known reaction conditions. The use of protecting groups is fully described in "Protective Groups in Organic Chemistry", edited by F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis" 2nd edition, T Greene & P G M Wutz, Wiley-Interscience (1991). The ester protecting groups can be removed by basic hydrolysis, for example using a metal hydroxide, preferably an alkali metal hydroxide, such as sodium hydroxide or lithium hydroxide, or quaternary ammonium hydroxide in a solvent, such as aqueous ethanol. or aqueous tetrahydrofuran, at a temperature of 10 ° to 100 ° C, preferably the temperature is around room temperature; or by acid hydrolysis using a mineral acid such as HCl or a strong organic acid such as trichloroacetic acid in a solvent such as aqueous 1,4-dioxane. The trialkylsilyl protecting groups can be eliminated by the use of, for example, a fluoride ion source, for example tetra-n-butylammonium fluoride or hydrogen fluoride. The benzyl groups can be removed by hydrogenolysis using a transition metal catalyst, for example palladium on carbon, under a hydrogen atmosphere, at a pressure of from 1 to 5 bar, in a solvent, such as acetic acid. The compounds of the formula (I) can be converted to additional compounds of the formula (I) by interconverting the functional groups using known procedures. For example: (a) for compounds of the formula (I) wherein R5 is CH2NH2, treating a compound of the formula (I) wherein R5 is CH2Hal where Hal is halogen with sodium azide followed by reduction, (b) for compounds of the formula (I) wherein R5 is (CH2) 2NH2, treating a compound of the formula (I) wherein R5 is CH2Hal where Hal is halogen with a cyanide, followed by reduction, (c) for compounds of the formula (I) wherein R5 is (CH2) NR14R15, treating a compound of the formula (I) wherein R5 is (CH2) nNH2 with an appropriate ketone in the presence of a reducing agent, (d) for compounds of the formula (I) wherein R5 is CH = CH.CH2NR22R23 R; R "are as defined above, can be prepared by treatment of a compound of the formula (I) wherein R5 is CH = CHCH2L with a compound of the formula HNR22R23, where L is a leaving group such as bromine, chlorine or mesylate and R22 and R23 are as defined above, (e) for compounds of the formula (I) wherein R5 is CH = CHCH2L can be prepared from the compounds of the formula (I) wherein R5 is CH = CHCH2OH by standard methods, (f) for compounds of the formula (I) wherein R5 is CH = CHCH2OH can be prepared from the compounds of the formula (I) wherein R5 is CH = CHC02R30 and R30 is alkyl of 1 to 6 carbon atoms, reduction, for example using DIBAL-H The compounds of the formula (I) wherein R5 is CH = CEC02R30 and R30 is alkyl of 1 to 6 carbon atoms can be prepared as described in WO97 / 03084. of the compounds of the formula (I) by reacting the free acid, or a salt thereof, or the free, or a salt or a derivative thereof, with one or more equivalents of the appropriate base (for example ammonium hydroxide optionally substituted by alkyl of 1 to 6 carbon atoms or an alkali metal or alkaline earth metal hydroxide) or acid ( for example a hydrohalic acid (especially HCl), sulfuric, oxalic or phosphoric 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, THF or diethyl ether, which can be removed in vacuo, or by lyophilization. The reaction can also be a metathetic process or it can be carried out in an ion exchange resin. Non-toxic physiologically acceptable salts are preferred, although other salts may be useful, for example in isolating or purifying the product.

The compounds of the invention act as antagonists of the P2r receptor. Accordingly, the compounds are useful in therapy, especially in adjunctive therapy, particularly they are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, anti-thrombotic agents or in the treatment or prophylaxis of unstable angina, coronary angioplasty (PTCA), myocardial infarction, perithrombolysis, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic infarction, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic diseases such as angioplasty, endarterectomy, placement of the stent, coronary and other vascular graft surgery, thrombotic complications of surgery or mechanical damage such as tissue recovery followed by accidental or surgical trauma, reconstructive surgery that includes skin and muscle bumps, conditions with a component of or of platelets / diffuse thrombotic such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, haemolytic uremic syndrome, thrombotic complications of septicemia, adult respiratory failure syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopenia and pre-eclampsia / eclampsia, or thrombosis venous such as deep vein thrombosis, veno-occlusive disease, haematological conditions such as myeloproliferative disease, including thrombocythemia; or in the prevention of mechanically induced platelet activation in vi ve, such as cardio-pulmonary by-pass (prevention of microthromboembolism), activation of mechanically induced platelets in vi tro, such as use in the preservation of blood products, by example, platelet concentrates, or short circuit occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to vascular damage / inflammation such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease, and organ graft rejection, conditions such as migraine , Raynaud's phenomenon, formation / progression of atheromatous plaques, vascular stenosis / restenosis and asthma, in which factors derived from platelets are implicated in the disease process. According to the invention, there is further provided the use of a compound according to the invention in the manufacture of a medicament for the treatment of the above disorders. In particular, the compounds of the invention are useful for treating myocardial infarction, thrombotic infarction, temporary ischemic attacks, peripheral vascular disease and angina, especially unstable angina. The invention also provides a method for the treatment of the above disorders comprising administering to a patient suffering therefrom, a therapeutically effective amount of a compound according to the invention. The compounds can be administered topically, for example, to the lung and / or the respiratory tract, in the form of solutions, suspensions, HFA aerosols and dry powder formulations.; or systematically, for example, by oral administration in the form of tablets, pills, capsules, syrups, powders or granules, or by parenteral administration in the form of sterile parenteral solutions or suspensions, by subcutaneous administration, or by rectal administration in the form of suppositories or transdermally. The compounds of the invention can be administered or taken as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant or carrier. Particularly preferred are compositions that do not contain material capable of causing an adverse reaction, for example allergic.

The dry powder and aerosol formulations of Pressurized HFA's of the compounds of the invention can be administered by oral or nasal inhalation.

For the inhalation of the compound, it is finely divided into a desirable form. The compounds of the invention can also be administered by means of a dry powder inhaler. The inhaler can be a single or multiple dose inhaler, and can be a dry powder inhaler for acute breathing. One possibility is to mix the finely divided compound with a carrier substance, for example a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers include sugars and starch. Alternatively, the finely divided compound can be coated by another substance. The powder mixture can also be supplied in hard gelatin capsules, each containing the desired dose of the active compound. Another possibility is to process the finely divided powder into spheres that are broken during the inhalation process. This spheronized powder can be filled into the drug container of a multi-dose inhaler, for example which is known as the Tubuhaler® in which the dosage unit measures the desired dose which is then inhaled by the patient. With this system the active compound with or without a carrier substance is supplied to the patient. The pharmaceutical composition comprising the compound of the invention may conveniently be in tablets, pills, capsules, syrups, powders or granules for oral administration; sterile or subcutaneous parenteral solutions, suspensions for parenteral administration or suppositories for rectal administration. For oral administration the active compound can be mixed with an adjuvant or a carrier, for example lactose, sucrose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatin or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffins and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, can be coated with a concentrated sugar solution which may contain eg gum arabic, gelatin, talcum, titanium dioxide, and the like. Alternatively, the tablet can be coated with a suitable polymer dissolved in either an easily volatile organic solvent or an aqueous solvent. For the preparation of soft gelatin capsules, the compound can be mixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatin capsules may contain granules of the compound used, either the excipients mentioned above for tablets, for example, lactose, sucrose, sorbitol, mannitol, starches, cellulose derivatives or gelatin. Also the liquid or semiliquid formulations of the drug can be filled into hard gelatin capsules. The liquid preparations. for oral application they may be in the form of syrups or suspensions, for example solutions containing the compound, the remainder being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain coloring agents, flavoring agents, saccharin and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in the art. The invention is illustrated by the following examples. In the examples the NMR spectra are measured on a Varian Unity Inova 300 or 400 spectrometer and the EM spectra are measured as follows: El spectra are obtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, the FAB spectra are obtained In a VG70-250SEQ spectrometer, the ESI and APCI spectra are obtained on a Finnigan Mat SSQ7000 spectrometer or a Micromass Platform spectrometer. The separations of preparative CLAP are generally carried out using a Novapak® column, Bondapak® or Hypersil® packaged with reverse phase silica BDSC-18. The flash chromatography (indicated in the Examples as (Si02) is carried out using Fisher Matrix silica, 35-70 μm, the organic solids are dried over magnesium sulfate or sodium sulfate and the drying agent is removed by filtration. showing the presence of rotamers in the proton nmr, only chemical changes are cited for most rotamers.

Example 1 Trifluoroacetate of [ΔS- (la, 2β, 3β, 4a)] -4- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazole [4,5-d] pyrimidine -3-yl] -2,3-dihydroxy-N- [[3- (N-methyl-N-phenyl) amino] propyl] -cyclopencarboxamide a) 4,6-Dihydroxy-2- (propylthio) pyrimidine Propyl iodide (136 ml) is added to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine (200 g) in water (800 ml), containing hydroxide of sodium (55.6 g). The reaction mixture is stirred for 2 weeks, then it is concentrated to a half volume, 2 N hydrochloric acid is added and the product is isolated by filtration (167 g). MS (El) 186 (M +, 100%). b) 4,6-Dihydroxy-5-ni ro-2- (propyl) pyrimidine The product from step a) (70 g) is slowly added to ice-cold fuming nitric acid. (323 ml). The reaction mixture is stirred for 1 hour then it is drained on ice and the product is isolated by filtration (65 g). MS (El) 231 (M +), 41 (100%). s) 4,6-Dichloro-5-n-ro-2- (propyl io) pyrimidine N, N-diethylaniline (150 ml) is added in drops to a stirred suspension of the product from step b) (134 g) in Phosphoryl chloride (500 ml) then the resulting solution is heated to reflux for 1 hour. The cooled reaction mixture is drained on ice, then extracted with diethyl ether (3 × 500 ml). The combined extracts are dried and concentrated. Chromatography (SiO2, isohexane: diethylether, 19: 1 as eluent) gives the subtitle compound (128 g). MS (El) 271, 269, 267 (M +), 41 (100%). d) [3aS- (3aa, 4β, 7β, 7aa)] -5- [6-Chloro-5-nitro-2- (propylthio) -pyrimidin-4-yl] tetrahydro-4,7-methane-2,2 dimethyl-1,3-dioxol [4,5-c] pyridin-6 (3aH) -one Sodium hydride (60%, 4.00 g) is added in portions to [3aS- (3aa, 4β, 7β, 7aa) ] tetrahydro-2,2-dimethyl-4,7-methano-l, 3-dioxol [4, 5-c] pyridin-6 (3aH) -one (18.3 g) in THF (500 ml). The solution is added in drops under stirring for 1 hour to the product of step c) (54.0 g) in THF (500 ml). The reaction mixture is stirred at room temperature for 45 minutes then concentrated and purified by chromatography (SiO2, dichloromethane: isohexane, 3: 2 as eluent) to yield the subtitle compound (79.2 g). MS (APCI) 417, 415 (M + H +), 415 (100%). e) Acid [3aR- (3aa, 4a, 6a, 6aa)] -6- [[5-amino-6-chloro-2- (propyl) -4-pyrimidinyl] amino] te rahydro-2,2-dimethyl 4H-cyclopenta-l, 3-dioxol-4-carboxylic acid Iron powder (10.0 g) is added to a stirred solution of the product from step d) (10.0 g), and calcium chloride in ethane l (140 ml). The reaction mixture is heated at reflux for 10 minutes then filtered through Celite, washed several times with hot ethanol. The filtrate is concentrated to produce the desired product (9.3 g). MS (FAB) 405, 403 (M + H +), 405 (100%). f) Acid [3aR- (3aa, 4a, 6a, 6aa)] -6- [7-chloro-5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidin-3- il] -te rahydro-2, 2-dimethyl-4H-cyclopenta-l, 3-dioxol-4-carboxylic acid Isoamyl nitrite (6.02 ml) is added to a solution of the product of step e) (9.28 g) in acetonitrile (80 ml) and the solution is heated at 70 ° C for 1 hour. Concentrate and purify the cooled reaction mixture (SiO2, ethyl acetate: isohexane 2: 1 as eluent) to yield the subtitle compound (7.9 g). MS (FAB) 416, 414 (M + Ht), 414 (100%). g) Acid [3aR- (3aa, 4a, 6a, 6aa)] -6- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine- 3-yl] tetrahydro-2, 2-dimethyl-4H-cisl open ta-1,3-dioxol-4-carboxylic product A mixture of the product of step f) (5.52 g) and n-butylamine (5 ml) is stirred. in 1,4-dioxane (25 ml) at room temperature for 1 hour. The reaction mixture is concentrated and the residue is purified (Si02, dichloromethane: ethyl acetate 2: 1 as eluent) to yield the subtitle compound (2.2 g). MS (FAB) 451 (M + H +, 100%). h) [3aR- (3aa, 4a, 6a, 6aa)] -6- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3 -yl] -tetrahydro-2,2-dimethyl-N- [3- (N-methyl-N-phenylamino) propyl] -4H-cyclopenta- [d] -1,3-dioxol-4-carboxamide It is added to a solution of the product from step g) (0.24 g), bromo-trispyrrolidino-phosphonium hexafluorophosphate (0.32 g) and N, N-di isopropylethylamine (0.28 ml) in N, N-dimethylformamide (8 ml) to N- (3-aminopropyl) -N-methylaniline (0.1 g). The mixture is stirred at room temperature for 2 hours, concentrated and purified (SiO2, ethyl acetate: petrol 3: 2) to yield the subtitle compound (0.23 g). MS (APCI) 597 (M + H +, 100%). i) Trifluoroacetate of [ÍS- (la, 2ß, 3ß, 4a)] -4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine -3-yl] -2,3-dihydroxy-N- [3- [(N-methyl-N-enyl) amino] propyl] -ci cl open tancarboxamide A solution of the product from step h) is stirred (0.22 g) in trifluoroacetic acid (8 ml) and water (1 ml) at room temperature for 2 hours, then concentrate and purify (CLAP, Novapak® C18 column, 0.1% aqueous ammonium acetate: methanol, 30 gradient elution: 70 to 0: 100 for 15 minutes) to yield the title compound (0.12 g). MS (APCI) 557 (M + H +, 100%) dH NMR (ds-DMSO) 9.00 (1H, t), 8.00 (1H, t), 7.21 (2H,), 6.85 (3H, m), 4.95 (1H , m), 4.41 (1H, m), 4.15 (1H, m), 3.90 (2H, m), 3.51 (2H, c), 3.38 (2H, m), 3.11 (4H, m), 2.92 (3H, m), 2.78 (1H, m), 2.36-2.25 (2H, m), 1.73-1.58 (6H, m), 1.36 (2H, m ), 1.00 (3H, t), 0.91 (3H, t).

Using 2 [Tris] - (la, 2ß, 3ß, 4a)] -N- [5-Aminopene] -4- [7- (butylamino) -5- (propylthio) -3H-1, 2,3 -triazol [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentanecarboxamide It is prepared according to the method of example 1 step (h) using the product of example 1 step (g) and 1, 5 -diaminopentane followed by the method of example 1 step (i). MS (APCI) 495 (M + H +, 100%) dH NMR (de-DMSO) 4.91 (1H, m), 4.47 (1H, t), 4.31 (1H, t), 3.75 and 3.37 (2H, m), 3.09 (2H, t), 2.95 (2H, m), 2.80 (3H, m), 2.45 (1H, m), 1.48 (8H, broad m), 1.24 (4H, m), 0.83 (3H, t), 0.75 (3H, t).

Example 3 [1S- (la, 2ß, 3ß, 4a)] -N- [3-Aminopropyl] -4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole trifluoroacetate] [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentanecarboxamide a) [3aR- (3aa, 4a, 6a, 6aa)] -6- [7- (Butylamino) -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3 -yl] -N- [[[1,1-dimethylethoxy) carbonyl] amino] propyl] -tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-carboxamide It is prepared according to the method of Example 1 step (h) using the product of example 1 step (g) and acid (3-aminopropyl) -carbamic acid, 1,1-dimethyl-ethyl ester ter. MS (APCI) 495 (M + H ", 100%) b) Trifluoroacetate of [ÍS- (la, 2ß, 3ß, 4a)] -N- [3-Aminopotyl] -4- [7- (butylamino) -5- (propylthio) -3H-1, 2, 3- triazol [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentanecarboxamide It is prepared according to the method of example 1 step (i) using the product of step (a). MS (APCI) 465 (MH ", 100%) dH NMR (de-DMSO) 9.01 (1H, t), 8.14 (1H, t), 7.75 (3H, broad s), 5.21 (1H, broad s), 5.04 (1H, broad s), 4.96 (1H, m), 4.41 (1H, m), 4.13 (1H, m), 3.50 (2H, c), 3.13 (4H, m), 2.77 (3H, m), 2.29 (2H, m), 1.68 (6H, m), 1.34 (2H, sextet), 0.99 (3H, t), 0.91 (3H, t).

EXAMPLE 4 Trifluoroacetate of [ΔS- (la, 2β, 3β, 4a)] -N- [(3-aminophenyl) -4- [7- (butylamino) -5- (propylthio) -3H-1, 2, 3- triazol [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopecarboxamide a) [3aR- (3aa, 4a, 6a, 6aa)] -N- [(Aminophenyl) methyl] -6- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazole [ 4, 5-d] pyrimidin-3-yl] -tetrahydro-2,2-dimethyl-4H-cyclopenta-l, 3-dioxol-4-carboxamide It is prepared according to the method of example 1 step _ (h) using the product of example 1 step (g) and 3-aminobenzylamine. MS (APCI) 555 (M + H ", 100%) b) Trifluoroacetate of [ÍS- (la, 2ß, 3ß, 4a)] -N- [(3-Aminophenyl) -methyl] -4 - [7- (butylamino) -5- (propylthio) -3H-1, 2 , 3-triazol [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentanecarboxamide It is prepared according to the method of example 1 step (i) using the product of step (a). APCI) 515 (M + H +, 100%) dH NMR (de-DMSO) 8.99 (1H, t), 8.54 (6.95 (1H, m), 6.48-6.43 (3H, m), 5.30 (2H, broad s) , 5.13 (1H, broad s), 5.00-4.93 (2H, m), 4.45 (1H, broad m), 4.16 (3H, d), 3.52-3.47 (2H, m) plus rotamer at 3.90, 3.13-3.07 ( 2H,), 2.86-2.81 (1H, m), 2.37-2.24 (2H,), 1.73-1.56 (4H, m), 1.39-1.32 (2H, m), 0.98 (3H, t).

T emp 5 Trifluoroacetate of [S S- (la, 2β, 3β, 4a (ÍS *, 2R *)]] -N- [3-aminopropyl] -2,3-dihydroxy-4- [7- [2- (f-nylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, a) Acid [3aR- (3aa, 4a, 6a, 6aa (lR *, 2S *))] -tetrahydro-2,2-dimethyl-6- [7- [2- (phenylcyclopropyl) amino] -5- (propylthio) ) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-l, 3-dioxol-carboxylic acid It is prepared according to the method of example 1 step ^ ( g) from the product of the example 1 stage (f) and (lR-trans) -2-f-enyl-cyclopropanamine, [R- (R *, R *)] ~ 2,3-dihydroxybutadiate (1: 1) (prepared as described by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044) MS (APCI) 511 (M + H ", 100% b) [3aR- (3aa, 4a, 6a, 6aa (lR *, 2S *))] -Tetrahydro-2, 2 -dimethyl-N- [3- [[(1,1-dimethylethoxy) carbonyl] amino] propyl ] -6- [7- [(2- (phenylcyclopropyl) amino] -5- (propylthio) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] -tetrahydro-2 , 2-dimethyl-4H-cyclopenta-1, 3-dioxol-4-carboxamide It is prepared according to the method of example 1 step (h) using the product of step (a) and 1,1-dimethylethyl ester of the acid (3). -aminopropyl) -carbamic MS (APCI) 667 (M + H +) c) Trifluoroacetate of [ΔS- (la, 2β, 3β, 4a (1S *, 2R *)]] - N - [3-aminopropyl] -2,3-dihydroxy-4- [7- [(2-phenylcyclopropyl)] amino] -5- (propyl thio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, is prepared according to the method of example 1 step (i) using the product of step (b) .MS (APCI) 527 (M + H +) RMN dH (d6-DMS0) 9.36 (1H, d), 8.12 (1H, t), 7. 69 (3H, broad s), 7.31-7.16 (5H, m), 5.20 (1H, broad s), 4.97 (2H, m), 4.41 (1H, t), 4.12 (1H, t), 3. 25-3.04 (3H, m), 3.02-2.72 (5H, m), 2.42-2.08 (3H,), 1.77-1.40 (5H, m), 1.33 (1H, m), 0.81 (H, 3t).

EXAMPLE 6 Bis (trifluoroacetate) of [ΔS- (la, 2β, 3β, 4a (1S *, 2R *)]] - N- [trans-4-aminociclohexyl] -2, 3-dihydroxy-4- [7- [ (2-phenylcislopropyl) amino] -5- (propylthio) -3H-1,2,3-triazol [4, 5-d] pyrimidin-3-yl] -cicl open ancarboxamide, a) [3aR- (3aa, 4a, 6a, 6aa (IR *, 2S *))] -N- [trans-4- [[(1,1-dimethylethoxy) carbonyl] amino] cyclohexyl] etrahydro-2, 2 -dimethyl -6- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopen al, 3-dioxol-4-car boxami da is prepared according to the method of example 1 step (h) using the product of the example 5 stage (a) and 1, 1-dimethylethyl ester of trans- (4-aminocyclohexyl) carbamic acid, (prepared as described by J. Smith et al., J. Org. Chem., 1996, 61, 8811). MS (APCI) 707 (M + H +, 100%) b) Bis (trifluoroacetate) of [SS- (la, 2β, 3β, 4a (SS *, 2R *)]] - N - [trans-4-aminocislohexyl] -2,3-dihydroxy-4- [7- [ (2-phenyl cyclopropyl) amino] -5- (propylthio) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -sicl open ancarboxy, is prepared according to the method of Example 1 step (i) using the product, from step (c).

MS (APCI) 567 (M + H +, 100%) dH NMR (d6-DMSO) 9.36 (1H, d), 7.88 (1H, d), 7. 83 (3H, broad s), 7.29 (2H, m), 7.18 (3H, m), 4.98 (1H, c), 4.45 (1H, m), 4.08 (1H, t), 3.48 (1H, m), 3.25-2.74 (5H, m), 2.40-2.07 (3H, m), 2.00-1.72 (5H , m), 1.53-1.19 (7H, m), 0.81 (3H, t).

Example 7 [SS- (la, 2a, 3ß, 5ß)] -3-Amino-5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] ] pyrimidin-3-yl] -ci cl open tan -1, 2 -diol, a) 1, 1-Dimethylethyl ester of [3aR- [3aa, 4a, 6a, 6aa]] -6- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -tetrahydro-2, 2-dimethyl-4H-cyclopenta [d] -1,3] -diazol-4-yl] -carbamic acid To a solution of the product of example 1 step (g) (0.25 g) in tert-butanol (5 ml) were added diphenylphosphoryl azide (0.15 g) and triethylamine (0.056 g). The mixture is heated at reflux for 10 hours and concentrated. The residue is dissolved in ethyl acetate and washed with 5% aqueous citric acid, brine and aqueous sodium bicarbonate, dried and concentrated. Purification (Si02 / ethyl acetate: isohexane 1: 9 to 2: 8 as eluent) of the subtitle compound (0.13 g) is produced.

MS (APCI) 522 (M + H ~, 100%) b) [lS- (la, 2a, 3ß, 5ß)] -3-Amino-5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] ] pyrimidin-3-yl] -sicl open tan -1, 2-diol, is prepared according to the method of example 1 step (i) using the product of step (a). MS (APCI) 382 (M + H +), 100%) dH NMR (de-DMSO) 9.08 (1H, t), 8.50 (3H, s), . 00 (3H, m), 4.46 (1H, t), 4.14 (1H, t), 3.50 (3H,), 3.08 (2H, m), 2.64 (1H, m), 2.14 (1H, m), 1.72 (2H, m), 1.61 (2H, m), 1.34 (2H, m), 1.00 (3H, t), 0. 91 (3H, t).

Example 8 [SS- (la, 2a, 3ß, 5ß)] -3- (Aminomethyl) -5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5] -d] pyrimidin-3-yl] -cyclopentan-1,2-diol a) N-Butyl-3- [[3aS- (3aa, 4a, 6a, 6aa)] -6-tetrahydro-6- (iodomethyl) -2,2-dimethyl-4H-cyclopenta-1, 3-dioxol-4 -yl] -5- (propylthio) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-7-amine To a solution of [3aR- (3aa, 4a, 6a, 6aa)] - 6 - [7- (but i lamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -tetrahydro-2, 2-dimethyl-4H- Cyclopenta-1,3-dioxol-4-methanol (prepared as described in WO 97/03084) (1 g) in dichloromethane (30 ml) at -60 ° C is added to a solution of methyltriphenoxyphosphonium iodide (3.12 g) in dichloromethane (40 ml). After 4 hours the mixture is diluted with dichloromethane and washed with aqueous sodium thiosulfate and sodium bicarbonate. The purification (Si02, dichloromethane: ethyl acetate 4: 1 as eluent) of the subtitle compound (1.4 g) is produced. MS (APCI) 547 (M + H +, 100%) b) 3- [[3aS- (3aa, 4a, 6a, 6aa)] -6- (Azidomethyl) -tetrahydro-2,2-dimethyl-4H-cyclopenta-l, 3-dioxol-4-yl] -N- butyl-5- (propylthio) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-7-amine A mixture of the product of step (a) (0.3 g) and sodium azide ( 0.1 g) in N, N-dimethylformamide (10 ml) at 80 ° C for 2 hours. Water is added and the product is extracted with dichloromethane. The purification (Si02, dichloromethane: ethyl acetate 9: 1 as eluent) of the subtitle compound (0.2 g) is produced. MS (APCI) 462 (M + H +, 100%) c) 3- [[3aS- (3aa, 4a, 6a, 6aa)] -6- (Aminomethyl) -tetrahydro-2,2-dimethyl-4H-cyclopenta- 1, 3-dioxol-4-yl] -N-butyl-5- (propylthio) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-7-amine A solution of the product from step (b) (0.3 g) in ethanol (50 ml) containing acetic acid (0.5 ml) in a 10% Pd / C catalyst at 1 atmosphere of hydrogen pressure for 18 hours. The mixture is filtered, concentrated and purified (Si02, ethyl acetate to methanol as eluent) to yield the subtitle compound (0.1 g). MS (APCI) 436 (M + H +, 100%) d) [SS- (la, 2a, 3ß, 5ß)] -3- (Aminomethyl) -5- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazole [4, 5] -d] pi imidin-3-yl] -cyclopentan-1,2-diol It is prepared according to the method of example 1 step (i) using the product of step (c). MS (APCI) 396 (M + H +, 100%) dH NMR (de-DMSO) 5.06 (1H,), 4.80 (1H, broad), 4.50 (1H, t), 4.19 (1H, t), 3.55 ( 2H, t), 3. 35-3.15 (2H, m), 3.12 (2H, t), 2.67 (1H, m), 2.47 (1H, m), 1.99 (1H, m), 1.75-1.60 (4H, m), 1.40-1.30 (2H,), 0.99 (3H, t), 0.90 (3H, t).

Example 9 [ΔS- (la, 2a, 3β, 5β (1S *, 2R *)]] -3-Amino-S- [7 - [(2-f-enyl-cyclopropyl) -amino] -5- (propylthio) - 3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl] - ci cl open tan -1, -diol a) 1, 1-Dimethylethyl ester of [3aR- [3aa, 4a, 6a, 6aa (IR *, 2S *)]] - [6- [7- [(phenylcyclopropyl) amino] -5- (propylthio) -3H] -1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -tetrahydro-2,2-dimethyl-4H-cyclopenta-l, 3-dioxol-4-yl] carcharide is prepared according to method of example 7 step (a) using the product of the example 5 step (a) EM (APCI) 582 (M + H +, 100% b) [lS- (la, 2a, 3β, 5β (1S *, 2R *)]] -3-Amino-5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1 , 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol It is prepared according to the method of example 1 step "(i) using the product of step (a) MS (APCI) 442 (M + H +, 100%) dH NMR (d6-DMS0) 9.42 (1H, d 4.2Hz), 8.21 (3H, broad s), 7.35-7.16 (5H, m), 4.95 (1H , c 6.4Hz), 4.43 (1H, t 6.0Hz), 3.50 (1H, broad), 3.22 (1H, m), 2.95 (1H, m), 2.80 (1H, m), 2.65 (1H, m), 2.10 (2H, m), 1.50 (3H, m), 1.34 (1H, m), 0.78 (3H, t, 7.6Hz) Example 10 [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3- (E-tilamino) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) - 3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol To a solution of the product of example 9 step (b) (0.72 g) in methanol (20 ml) was adjust to pH 5 using acetic acid, add acetaldehyde (60 μl) and sodium cyanoborohydride (74 mg). The reaction is stirred at room temperature for 12 hours then taken to pH 14 with sodium hydroxide solution and extracted with ethyl acetate. The organic phase is dried and concentrated, then purified (CLAP, Novapak® C18 column, aqueous ammonium acetate: 0.1% acetonitrile, 60:40 isocratic elution). to produce the title compound (0.21 g). MS (APCI) 470 (M + H +, 100%) dH NMR (d6-DMSO) 9.66 (1H, d 4.4Hz), 9.16 (2H, broad m), 7.50 (2H, m), 7.40 (3H, m) , 5.17 (1H, c 7.2Hz), 4.66 (1H, t 6.4Hz), 4.44 (1H, t 5.6 Hz), 3.75 (1H, m), 3.46 (1H, m), 3.30 (2H, m), 3.16 (1H, m), 3.05 (1H, m), 2.90 (1H, m), 2.35 (2H,), 1.77 (1H, m), 1.68 (2H, m), 1.56 (1H, m), 1.44 (3H , t 7.2Hz), 1.00 (3H, t 7.2Hz).

Example 11 [lS- [la, 2a, 3β, 5β (1R *, 2S *)]] -3- [(Methylamino) methyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -scyclopen an-1,2-diol a) [3aR- [3aa, 4a, 6a, (ÍS *, 2R *), 6aa]] -Tetrahydro-2,2-dimethyl-6- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-1,3-dioxol-4-methanol It is prepared according to the method of example 5, step ~ a) using [S- (R *, R *)] -2, 3-dihydroxybutanedioate of (SS-trans) -2-f-enyl-cyclopropanamine, (1: 1) MS (APCI) 497 (M + H +, 100 %) b) 3- [[3aS- (3aa, 4a (1R *, 2S *), 6a, 6aa)] -Tetrahydro-6- (iodomethyl) -2, 2-dimethyl-4H-cyclopenta-l, 3-dioxol- 4 -yl] -N- (2-phenylcyclopropyl) -5- (propylthio) -3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-ai is prepared according to the method of example 8 , stage a) using the product of stage a). MS (APCI) 606 (M + H +, 100%) c) [SS- [la, 2a, 3β, 5β (1R *, 2S *)]] -3- (Yodomethyl) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H -1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol A solution of the product from the step is treated (b) (0.34 g) in a mixture of methanol (5 ml) and tetrahydrofuran (5 ml) with aqueous hydrochloric acid 2M (2 ml). The reaction mixture is allowed to stand for 6 hours at room temperature. This mixture is emptied in saturated aqueous sodium bicarbonate solution (200 ml), extracted with ethyl acetate (200 ml) and the extract dried and concentrated. Purification (Si02, methanol: chloroform 1:49 as eluent) of the subtitle compound (0.26 g) occurs. MS (APCI) 567 (M + H +, 100%) d) [SS- [la, 2a, 3β, 5β (1R *, 2S *)]] -3- [(Methylamino) methyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -scyclopentan-1,2-diol. Treat a solution of the product of step (c) (0.25 g) in sulfoxide. of dimethyl (3 ml) with a 40% aqueous methylamine solution (1 ml). The reaction mixture is allowed to stand for 18 hours at room temperature then it is drained in ethyl acetate (200 ml), washed with a saturated solution of aqueous brine. (3 x 100 ml), dried and concentrated. The purification (Si02, methanol: chloroform 1: 4 as eluent) of the subtitle compound (0.27 g) is produced.

MS (APCI) 470 (M + H +, 100%) dH NMR (ds-DMSO) 9.32 (1H, d), 7.31-7.15 (5H, m), 4.96 (2H, c), 4.42-4.39 (1H, m ), 3.84 (1H, t), 3. 22-3.18 (1H, m), 2.95-2.85 (2H, m), 2.70-2.64 (1H, m), 2.34-2.27 (4H,), 2.17-2.11 (2H, m), 1.85-1.75 (1H, m), 1.54-1.47 (3H, m), 1.36-1.31 (1H, m), 0.82 (3H, t).

E jep lo 12 [ÍS- (la, 2a, 3ß, 5ß (1S *, 2R *)]] -3- [(E -tylamino) methyl] -5- [7- [(2-enyl cyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclo open an -1, 2 -diol a) [3aR- [3aa, 4a, 6a, (IR *, 2S *), 6aa]] -Te trahydro-2, 2-dimethyl-6- [7- [(2-phenylcyclopropyl) amino] -5- ( propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-l, 3-dioxol-4-methanol N, N-diisopropylethylamine (21 ml) is added to a solution of [3aR- [3aa, 4a, 6a, 6aa]] - 6- [7-chloro-5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-3] -yl] -tetrahydro-2, 2-dimethyl-4H-cyclopenta-l, 3-dioxol-4-methanol (prepared as described in WO 9703084) (55 g) and [R- (R *, R *)] -2, 3-dihydroxybutanedioate of (1R-trans) -2-phenyl-cyclopropanamine (1: 1) (prepared as described by LA Mitscher et al., J. Med. Chem. 1986, 29, 2044) (11.3 g) in dichloromethane (500 ml). The reaction mixture is stirred at room temperature for 3 hours, then washed with water, dried and evaporated.

The residue is purified (Si02 / ethyl acetate: dichloromethane 3: 7 as eluent) to yield the subtitle compound (19 g). MS (APCI) 497 (M + H +, 100%) b) 3- [[3aS- [3aa, 4a (ÍS *, 2R *), 6a, 6aa]] -Tetrahydro-6- (iodomethyl) -2, 2-dimethyl-4H-cyclopenta-l, 3-dioxol- 4-yl] -N- (2-phenylcyclopropyl) -5- (propylthio) -3H-1,2,3-triazolo [, 5-d] pyrimidin-7-amine It is prepared according to the method of example 8, step (a), using the product of stage a). MS (APCI) 606 (M + H +, 100%) c) [lS- [la, 2a, 3β, 5β (lS *, 2R *)]] -3- (Yodomethyl) -5- [7- [(2-enylcyclopropyl) amino] -5- (propylthio) -3H -1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol It is prepared according to the method of example 11, step (c), using the product of the step b) MS (APCI) 567 (M + H +, 100%) d) [ΔS- [la, 2a, 3β, 5β (1S *, 2R *)]] -3- [(Ethylamino) methyl] -5- [7- [(2-phenylcislopropyl) amino] -5- (propylthio) -3H-1,2,3-t-aiazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol It is prepared in accordance to the method of example 11, step (c), using the product of step c) and aqueous ethylamine. MS (APCI) 484 (M + H +, 100%) dH NMR (de-DMSO) 9.35 (1H, d), 7.31-7.15 (5H, m), 5.03-4.97 (2H, m), 4.42 (1H, c ), 3.86 (1H, t), 3.23-3.19 (1H, m), 3.00-2.80 (2H, m), 2.80-2.70 (1H, m), 2.64-2.57 (3H, m), 2.40-2.25 (1H , m), 2.15-2.12 (2H, m), 1.85-1.78 (1H,), 1.54-1.47 (2H, m), 1.32-1.28 (1H, m), 1.11-1.01 (4H, m), 0.86- 0.80 (3H, m).

EXAMPLE 13 Hydrochloride salt of [ΔS- (la, 2a, 3β, 5β (ÍS *, 2R *)]] -3- (aminomethyl) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) ) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol a) [ÍS- (la, 2a, 3β, 5β (1S *, 2R *)]] -3-Azidomethyl -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1 , 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol A solution of the product of Example 12, step (c) (0.9 g) in dimethyl sulfoxide ( 5 ml) with sodium azide (0.125 g) and the reaction mixture is stirred at room temperature for 7 hours, then it is poured into ethyl acetate (200 ml), washed with brine (3 x 100 ml), The residue is triturated with diethyl ether to yield the title compound (0.64 g), MS (APCI) 482 (M + H +, 100%). b) Hydrochloride salt of [ΔS- (la, 2a, 3β, 5β (ÍS *, 2R *)]] -3- (aminomethyl) -5- [7- [(2-enylcyclopropyl) amino] -5- (propyl) thio) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol A solution of the product of the step is treated (a) (0.22 g) in ethanol (7 ml) with 10% palladium on charcoal (0.03 g) and the resulting suspension is stirred under 4 atmospheres of hydrogen pressure for 24 hours. The reaction mixture is then filtered and the resulting solution treated with excess ethereal hydrochloric acid to precipitate a white solid. The solid is filtered off and washed with ethyl acetate to yield the title compound (0.13 g). MS (APCI) 456 (M + H +, 100%) dH NMR (de-DMSO) 9.39 (1H, d), 8.02 (3H, s), 7.31-7.18 (5H, m), 4.96 (1H, c), 4.33 (1H, t), 3.96 (1H, t), 3.22-3.19 (1H, m), 3.15-3.05 (1H, m), 2.95-2.80 (3H, m), 2.33-2.28 (2H, m), 2.13-2.11 (1H, m), 1.87-1.79 (1H, m), 1.55-1.45 (3H,), 1.35-1.31 (1H,), 0.81 (3H, t).

EXAMPLE 14 Hydrochloride of [ΔS- (la, 2a, 3β, 5β (ÍS *, 2R *)]] -3- (2-aminoethyl) -5- [7- [(2-enylcyclopropyl) amino] -5- ( propylthio) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopen-1, 2-diol a) [3aR- [3aa, 4a, 6a, (IR *, 2S *), 6aa]] -Tetrahydro-2, 2-dimethyl-6- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-l, 3-dioxol-4-acetoni tryl The product of example 12, step (b) is treated ) (1.25 g) in dimethyl sulfoxide (10 ml) with sodium cyanide (0.22 g) and the reaction mixture is stirred for 6 hours. The mixture is poured into ethyl acetate (200 ml), washed with brine (3 x 100 ml), dried and concentrated. The purification (Si02, ethyl acetate: isohexane 1: 2 as eluent) of the subtitled compound (0.88 g) is produced. MS (APCI) 506 (M + H +, 100%) b) [3aR- [3aa, 4a, 6a, (IR *, 2S *), 6aa] -Tetrahydro-2, 2-dimethyl-6- [7- [ (2-phenylcyclopropyl) amino] -5- (propylsulfonyl) -3H-1,2,3-triazolo [, 5-d] pyrimidin-3-yl] -4H-cyclopenta-l, 3-dioxol-4-acetonitrile treat a solution of the product from step (a) (0.88 g) in ethanol (20 ml) with 3-chloroperoxybenzoic acid (1.58 g of material classified at 57%). The reaction mixture is stirred at room temperature for 18 hours, then concentrated. The residue is dissolved in ethyl acetate (200 ml), washed with a saturated aqueous solution of sodium metabisulfite (100 ml) followed by saturated aqueous sodium bicarbonate (3 x 100 ml) then dried and concentrated. The purification (Si02, ethyl acetate: isohexane 1: 1 as eluent) of the subtitle compound (0.89 g) is produced. MS (APCI) 538 (M + H ", 100%) c) Acetate salt of 3 - [[3aS- (3aa, 4a (IS *, 2R *), 6a, 6aa]] -6- (2-aminoethyl) -tetrahydro-2,2-dimethyl-4H-cislopenta- 1, 3-dioxol-4-yl] -N- [(2-phenylcyclopropyl) amino] -5- (propylsulfonyl) -3H-1, 2,3-triazole [4, 5-d] pyrimidin-7-amine Treat a solution of the product from step (b) (0.82 g) in glacial acetic acid (7 ml) with platinum oxide (0.15 g) and stir the resulting suspension under 4 atmospheres of hydrogen pressure for 20 hours. and then the reaction mixture is concentrated, trituration of the residue with diethyl ether gives the subtitle compound which is collected by filtration (0.75 g), MS (APCI) 542 (M + H +, 100%). d) 3- [[3aS- (3aa, 4a (1S *, 2R *), 6a, 6aa]] -6- (2-Aminoethyl) -tetrahydro-2, 2-dimethyl-4H-cyclopenta-1, 3- dioxol-4 -yl] -N- [(2-phenylcislopropyl) amino] -5- (propyl io) -3H-1,2,3-triazole [4,5-d] pyrimidin-7-amine A solution is added from the product of step- (c) (0.74 g) in N, N-dimethylformamide (DMF) (5 ml) to a solution of sodium propantholate (1.4 g) in DMF (10 ml) .The reaction mixture is stirred at room temperature for 1 hour, then it is poured into a saturated solution of brine (100 ml), then extracted with ethyl acetate (2 x 100 ml) The combined organic materials are washed with brine (3 x 100 ml) then dried and concentrated, purification (Si02, methanol: chloroform 1: 4 as eluent) of the subtitle compound (0.58 g), MS (APCI) 510 (M + H +, 100%) e) Hydrochloride of [S] - [la, 2a, 3β, 5β (ÍS *, 2R *)]] -3- (2-amino-yl) -5- [7- [(2-nylcyclopropyl) amino] -5- (propylthio) -3H -1, 2, 3-triazole [4,5-d] pyrimidine-3 -yl] -cyclopentan-1,2-diol A solution of the product of the step is treated (d) (0.52 g) in methanol (5 ml) with 2 molar aqueous hydrochloric acid (2 ml) and let the reaction stand for 6 hours, then concentrate. Purification occurs (CLAP, Novapak® C18 column, trifluoroacetic acid: 0.1% aqueous acetonitrile, gradient elution 70:30 to 0: 100 over 15 minutes) of the title compound (0.13 g). MS (APCI) 470 (M + H +, 100%) dH NMR (de-DMSO) 9.36 (1H, d), 7.90 (3H, s), 7.31-7.15 (5H,), 4.93 (1H, c), 4.31 (1H, t), 3.81 (1H, t), 3.22-3.18 (1H, m), 2.95-2.82 (4H, m), 2.44- 2.38 (1H, m), 2.13-2.11 (1H, m), 2.03-2.01 (1H,), 1. 91-1.86 (1H, m), 1.74-1.64 (2H, m), 1.55-1.47 (3H, m), 1.35-1.31 (1H, m), 0.82 (3H, t).

EXAMPLE 15 Hydrochloride of [ΔS- (la, 2a, 3β (E), 5β (ÍS *, 2R *)]] -3- (3-aminoprop-1-enyl) -5- [7- [(2-phenylscyclopropyl) ) mino] -5- (propylthio) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol a) Ethyl ester of 3- [3aR-] [3aa, 4a (E), 6a (IR *, 2S *), 6aa]] -3- [tetrahydro-2, 2-dimethyl-6- [7- [(2-phenylcyclopropyl) amino] -5- (propyl) io) -3H-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-1,3-dioxol-4-yl] -2-propenoic The product of the example is treated 12, stage (a) (1.60 g) in dimethyl sulfoxide (15 ml) with pyridine (0.25 g) followed by trifluoroacetic acid (0.18 g) and N, N-dicyclohexylcarbodiimide (1.99 g). The reaction mixture is stirred at room temperature for 5 hours, then carbethoxymethylenetriphenylphosphorane (1.82 g) is added and stirring is continued for an additional 18 hours. The mixture is then diluted with ethyl acetate (300 ml) and cooled in an ice bath, before adding oxalic acid (1.59 g). After 30 minutes the mixture is filtered and the resulting solution is washed with saturated aqueous sodium bicarbonate solution (2 x 100 ml) followed by saturated aqueous brine (2 x 100 ml). The purified ethyl acetate solution (SiO2, ethyl acetate: isohexane 1: 4 as eluent) is concentrated to yield the subtitle compound (1.52 g). MS (APCI) 565 (M + H +, 100%) b) 3- [[3aR- [3aa, 4a (E), 6a (1R *, 2S *), 6aa]] -Tetrahydro-2, 2 -dimethyl -6- [7- [(2-phenylscyclopropyl) amino] -5- (propyl io) -3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] -4 H -cylopenta-1,3-dioxol-4-yl] -2-propenol treats a solution of the product of the stage (a) (1.45 g) in tetrahydrofuran (40 ml) at -78 ° C with DIBAL-H® (1.5 M toluene solution, 7.0 ml). The mixture is stirred at 0 ° C for 1 hour, then methanol is added (1 ml) and the reaction mixture was poured into diluted aqueous sodium hydroxide solution (100 ml). This mixture is extracted with ethyl acetate (100 ml) and the extract is washed with aqueous brine being concentrated before. The purification (Si02, ethyl acetate: isohexane 1: 1 as eluent) of the subtitle compound (1.20 g) is produced. MS (APCI) 523 (M + H +, 100%). c) 3- [[3aS- [3aa, 4a (E), 6a (1S *, 2R *), 6aa]] -Tetrahydro-6- (3-iodo-prop-l-enyl) -2, 2-dimethyl 4H-cyclopenta-l, 3-dioxol-4-yl] -N- (2-phenylscyclopropyl) -5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-7- amine It is prepared according to the method of example 8, step (a), using the product of step (b). EM (APCI) 633 (M + H ", 100%) d) 3- [[3aS- [3aa, 4a (1S *, 2R *), 6a (E), 6aa]] -6- (3-Aminoprop-1-enyl) -tetrahydro-2, 2-dimethyl-4H -cyclopenta-1, 3-dioxol-4-yl] -N- [(2-enylcyclopropyl) amino] -5- (propylthio) -3H-1, 2,3-triazole [4, 5-d] pyrimidine-7 -amine Treat a solution of the product from step (c) (0.60 g) in methanol (5 ml) / tetrahydrofuran (5 ml) with concentrated aqueous ammonia (2 ml). The reaction mixture is allowed to stand for 7 hours at room temperature, then it is concentrated and purified (SiO 2, methanol: chloroform 1: 4 as eluent) to yield the subtitle compound (0.21 g). MS (APCI) 522 (M + H +, 100%) e) [ÍS- (la, 2a, 3β (E), 5β (ÍS *, 2R *)]] -3- (3-aminoprop-1-enyl) -5- [7- [(2-phenylcyclopropyl)] hydrochloride ) amino] -5- (propyl io) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol It is prepared according to the method of example 14 , step (e), using the product of step (d) EM (APCI) 482 (M + H +, 100%) dH NMR (de-DMSO) 9.37 (1H, d), 8.04 (3H, s), 7.31-7.15 (5H, m), 5.98-5.93 (1H, m), 5.63-5.58 (1H, m), 4.31 (1H, t), 3.89 (1H, t), 3.43 (2H, t), 3.21- 3.18 (1H, m), 2.94-2.83 (2H, m), 2.72-2.69 (1H, m), 2.44-2.39 (1H, m), 2.18-2.10 (1H, m), 1.98-1.85 (1H, m ), 1.54-1.46 (3H, m), 1.36-1.32 (1H, m), 0.81 (3H, t).

Example 16 N-Ethyl-N- [[IR- [la, 2β, 3β, 4a (1R *, 2S *)]] -2, 3-dihydroxy -4 - [7- [(2-phenylcyclopropyl) amino] - 5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentylmethyl] -3-ethoxy-propanamide It is prepared according to the method of example 1, step h) using the product of Example 12 and acid 3 - . 3-methoxy-propionic. MS (APCI) 570 (M + H 100%) dH NMR (d6-DMSO) 9.34 (1H, d), 7.31-7.15 (5H, m), 5.16-4.73 (3H, m), 4.50-4.40 (1H, m), 3.85-3.78 (1H, m), 3.65-3.60 (1H, m), 3.55 (2H, t), 3.40-3.35 (2H, m), 3.20 (3H, s), 2.95-2.85 (2H, m), 2.60-2.55 (2H,), 2.32-2.28 (2H, m), 2.16-2.14 (1H,), 1.80-1.70 (1H, m), 1.55-1.50 (2H, m), 1.38-1.35 ( 1H, m), 1. 18-1.10 (2H, m), 1.07-1.00 (1H, m), 0.84-0.80 (3H, m).

Example 17 Ditrifluoroacetate of [ΔS- [la, 2a, 3β (E), 5β (SS *, 2R *)]] 3- [3- [(2-dimethylaminoethyl) amino] -prop-1-enyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopen-1, 2-diol a) 3- [[3aS- [3aa, 4a (1S *, 2R *), 6 (E), 6aa]] -6- [3- [(2-dimethylaminoethyl) mino] -prop-1-ethyl] - tetrahydro-2, 2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl] -N- [(2-phenylcislopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [ 4, 5-d] pyrimidin-7-amine A solution of the product of example 15, step (c) (0.50 g) in dichloromethane (6 ml) is treated with N, N-dimethylethylenediamine (0.10 g) and left to stand on. room temperature for 2 hours. The solution is then concentrated and the residue triturated with diethyl ether (20 ml) to yield the subtitle compound (0.45 g). MS (APCI) 593 (M + H +, 100%) b) [ΔS- [la, 2a, 3β (E), 5β (1S *, 2R *)]] -3- [3- [(2-dimethylaminoethyl) amino] -prop-1-enyl] ditrifluoroacetate 5- [7 - [(2-phenylcislopropyl) amino] -5- (propyl) -313-1,2, 3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentan-1, 2 - diol Prepare from the product of step (a) according to the method of Example 14, step (e). MS (APCI) 553 (M + H +, 100%) dH NMR (de-DMSO) 9.37 (1H, d), 8.21 (3H, s), 7.32-7.16 (5H, m), 6.21-6.18 (1H, m ), 5.80-5.75 (1H,), 5.01-4.99 (1H, m), 4.32 (1H, t), 4.03-3.96 (3H, m), 3.46-3.43 (2H, m), 3.36-3.32 (2H, m), 3.22-3.20 (1H, m), 3.04 (6H, s), 2.95-2.78 (3H, m), 2.13-2.10 (1H,), 2.02-1.95 (1H, m), 1.54-1.45 (3H, m), 1.35-1.32 (1H, m), 0.80 (3H, t).

Example 18 [IR- [la, 2β, 3β, 4a (1R *, 2S *)]] - N- [2- [2, 3-dihydroxy-4 - [7- [(2-phenylcyclopropyl) amino] -5 - (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentylmethylamino] ethyl] -acetamide A solution of the product of example 12, step (c) (0.70) is treated. g) in dimethyl sulfoxide (3 ml) with N-acetylethylenediamine (0.38 g) and then heated at 65 ° C for 3 hours. The mixture is then diluted with ethyl acetate (100 ml) and this solution is washed with saturated aqueous brine (2 x 100 ml). The organic phase is allowed to stand for 1 hour and the resulting white precipitate is isolated to yield the title compound (0.23 g). MS (APCI) 541 (M + H *, 100%) dH NMR (de-DMSO) 9.33 (1H, d), 7.80 (1H, s), 7.31-7.15 (5H, m), 5.02-4.97 (2H, m), 4.78 (1H, s), 4.41 (1H, c), 3.84 (1H, t), 3.20-3.18 (1H, m), 3.13-3.09 (2H, m), 2.95-2.83 (2H, m) , 2.71-2.69 (1H, m), 2.60-2.53 (2H, m), 2.34-2.32 (1H,), 2.14-2.09 (2H,), 1.53-1.48 (3H,), 1.33-1.31 (1H, m ), 0.82 (3H, t).

EXAMPLE 19 Hydrochloride of [SS- [1,2a, 3a, 5β (SS *, 2R *)]] - 3-amino-5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H -1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -cyclopen-an-1,2-diol a) (IR-cis) -Bis (1,1-dimethylethyl) -4-hydroxy-2-cis-pentyl-imidodicarbonate It is added to a suspension of sodium hydride washed with ether (dispersion in 60% oil, 0.3 g) in THF ( 30 ml) bis- (1,1-dimethylethyl) ester of the imidodicarbonic acid (1.84 g). The mixture is stirred at 40 ° C for 1 hour. It is then added to the mixture at room temperature (1 S-cis) -4-acetoxy-2-cyclopenten-ol (0.5 g) and tetrakis (triphenylphosphine) palladium (O) (0.185 g). The reaction mixture is stirred for 24 hours and purified (Si02, ethyl acetate: hexane 1: 9 as eluent) to give the subtitle compound as a colorless solid (0.9 g). NMR dH (d6-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J = 12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J = 12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J = 8.0, 1.8 Hz), 4.91 (1H, d, J = 5.4 Hz), 5.71-5.77 (2H, m). b) [1R- (la, 2ß, 3ß, 4a) -2,3,4-trihydroxysyclopentylimido-dicarboxylic acid (1, 1-dimethylethyl) ether The subtitle compound is prepared according to the method of example 1 step (f) using the product of stage (a). NMR dH (de-DMSO) 1.44 (18H, s), 1.46-1.60 (1H, m), 1.97-2.05 (1H, m), 3.55-3.58 (1H, m), 3.66-3.73 (1H, m), 4.11-4.21 (2H, m), 4.54 (1H, d, J = 4.8 Hz), 4.56 (1H, d, J = 5.9 Hz), 4.82 (1H, d, J = 4.6 Hz) c) Hydrochloride of [3aR- (3aa, 4a, 6, 6aa)] -6-amino-2, 2-dime yl-rahydro-4H-cyclopenal, 3-dioxol-4-ol The product of the step (b) (17.37 g) in 6M HCl (100 ml) and methanol (500 ml) for 18 hours. The mixture is vaporated and then azeotroped with toluene (4 x 200 ml) to give a colorless powder (8.67 g). This solid is suspended in acetone (250 ml), added 2, 2-dimethoxypropane (25 ml) and concentrated HCl (0.2 ml) and the reaction is heated under reflux for 2 hours. The mixture is cooled, evaporated and azeotroped with toluene (3 x 200 ml). The residue is dissolved in 20% aqueous acetic acid and stirred for 2 hours. The mixture is evaporated and azeotroped with toluene (4 x 200 ml) to give the subtitle compound as a colorless solid (10.1 g). MS (APCI) 174 (M + H +, 100%) d) [3aR- (3a, 4a, 6a, 6aa)] -6- [[6-Chloro-5-nitro-2- (propyl thio) -pi imidin-4-yl] amino] -tetrahydro-2, 2 -dime il-4H-cyclopenta-l, 3-dioxol-4 -ol A solution of the product from step (c) (10.0 g) and N, N-diisopropylethylamine (35 ml) in THF (600 ml) is stirred by 1 hour. The mixture is filtered and the solution is added for 1 hour to a solution of 4,6-dichloro-5-nitro-2- (propylthio) -pyrimidine (prepared as described in WO 9703084) (25.57 g) in THF (1000 ~ ml) and stirred for an additional hour. The mixture is washed with water and the organic layers are dried (MgSO), evaporated and purified (SiO2, isohexane-ethyl acetate as eluent) for the subtitle compound (14.22 g). MS (APCI) 405 (M + H ~, 100%) e) [3aR- (3aa, 4a, 6a, 6aa)] -6- [(5-Amino-6-chloro-2-propylthiopyrimidin-4-yl) amino] -te rahydro-2, 2-dimethyl-4H- Cyclopenta-1, 3-dioxol-4-ol Iron powder (2.30 g) is added to a stirred solution of the product of step (d) (2.61 g) in acetic acid (100 ml). The reaction mixture is stirred at room temperature for 2 hours, concentrated to a half volume, diluted with ethyl acetate and washed with water. The organic phase is dried and concentrated to yield the subtitle compound (2.28 g). MS (APCI) 375 (M + H ~, 100%) f) [3aR- (3aa, 4a, 6a, 6aa)] -6- [7-Chloro-5- (propylthio) -3H-1,2,3-triazole [4, 5-d] -pyrimidin-3- il] -tetrahydro-2, 2-dimethyl-4H-cyclopen a-1,3-dioxol-4-ol is prepared according to the method of example 1, step (f) using the product of step (e). MS (APCI) 386 (M + H +, 100%) g) (lR-trans) -N- [(2,4-Dimethoxy-enyl) methyl] -2-phenyl-cyclopropanamine A solution of [R- (R *, R *)] -2, 3-dihydroxybutanedioate of (IR-trans) -2-phenyl-cyclopropanamine, (1: 1) (prepared as described by LA Mitscher et al., J. Med. Chem. 1986, 29, 2044) (1.92 g) in 1N aqueous NaOH ( 50 ml) for 10 minutes and extracted with dichloromethane. The extract is dried, evaporated and the residue dissolved in methanol (30 ml). To this solution is added 2,4-dimethoxybenzaldehyde (1.12 g) and the pH is adjusted to 5 with acetic acid. Sodium cyanoborohydride (0.46 g) is added. The mixture is stirred overnight, basified with 2N NaOH and extracted with ethyl acetate. The extract is dried, evaporated and purified (Si02, methanol: dichloromethane: 0.880 ammonia 2: 98: 0.1 as eluent) to yield the subtitle compound (1.10 g). NMR dH (CDC13) 7.23-6.97 (6H, m), 6.49-6.41 (2H, m), 3.73 (3H, s), 3.69 (3H, s), 3.66 (2H, s), 2.21-2.16 (1H, m), 1.82-1.76 (1H,), 1.01-0.87 (2H,). h) [3aR- (3aa, 4a, 6a (1R *, 2S *), 6aa)] -6- [7- [N - [(2,4-Dimethoxy-nyl) methyl] - (2-enylcyclopropyl) amino] -5- (propyl io) -3H-1, 2,3-triazolo [4, 5-d] -pyrimidin-3-yl] -te rahydro-2,2-dimethyl-4H-cyclopen-1, 3 -dioxol-4-ol The subtitle compound is prepared using the method of example 12, step (a), from the compound of step (g) and the product of step (f). EM (APCI) 633 (M + H ", 100%) i) [3aR- (3aa, 4a, 6a (IR *, 2S *), 6aa)] - [ehydro-2, 2-dimethyl-6- [7- [N- (2,4-dimethoxyphenyl) methyl- ( 2-f nylcyclopropyl) amino] -5- (propylthio) -313-1,2,3-triazole [4, 5-d] -pyrimidxn-3-y1] -4 H -syclopenta-l, 3-dioxol-4- il] trifluoromethanesulfonic acid ester. Triflic anhydride (0.08 ml) is added to a solution of the product of step (h) (147 mg) and pyridine (0.08 ml) in dichloromethane (2 ml) and stirred for 18 hours. Water is added and the mixture is extracted with dichloromethane. Dry the organic layer (MgSO4), evaporate and purify (Si02, petrol: ether 3: 2 as eluent) to give the subtitle compound as a white foam (166 mg). MS (APCI) 765 (M + H +, 100%) j) 3- [[3aS- [3aa, 4a (1S *, 2R *), 6β, 6aa)] -6-Amino-tetrahydro-2, 2-dimethyl-H-cyclopenta-1,3-dioxol-4- il] -N- [(2,4-di ethoxyphenyl) methyl] -N- (2-phenylcyclopropyl) -5- (propyl thio) -3H-1, 2,3-triazole [4,5-d] -pyrimidine -7-amine A solution of the product from the stage is stirred (i) (957 mg) and sodium azide (289 mg) in DMSO (10 ml) for 18 hours. Water is added and the mixture is extracted with ether. The organic layers are evaporated and the residue is taken up in THF (15 ml) / water (1 ml). Triphenylphosphine is added (326 mg) and the solution is stirred for 24 hours. The solvent is removed in va cuo and the residue is purified (Si02, dichloromethane: methanol 9: 1 as eluent) to give the subtitle compound (424 mg). MS (APCI) 632 (M + H +, 100%) k) [ÍS- [la, 2a, 3a, 5β (ÍS *, 2R *)]] -3-amino-5- [7- [(2)] hydrochloride phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol A solution of the product of the Step (j) (252 mg) in 5M HCl (6 ml) / methanol (10 ml) for 3 days at 20 ° C then at 50 ° C for 6 hours. The in va cuo solvent is removed and the residue is purified (Si02, dichloromethane: methanol: ammonia 40: 7: 1 as eluent) to yield a solid which is dissolved in dichloromethane (2 ml) / ethyl acetate (2 ml) and a solution of 1M HCl in ether is added. The resulting precipitate is collected and dried to give the title compound (59 mg). p.f. 225-7 ° C. MS (APCI) 442 (M + H +, 100%). NMR dH (d6-DMSO) 9.39 (1H, d), 8.18-8.13 (3H,), 7. 33-T.14 (5H, m), 5.26 (6H, broad), 5.16 (1H, c), 4.57 (1H, dd), 4.15-4.13 (1H, m), 3.92-3.80 (1H, m), 3.23-3.19 (1H, m), 2.97-2.79 (2H, m), 2.38 (2H, t), 2.16-2.10 (1H, m), 1.57-1.29 (3H, m), 0.82 (3H, t).

Example 20 l- [[lS- [la, 2β, 3β, 4a (1S *, 2R *)]] -2, 3-Dihydroxy -4 - [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -313-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopen-1-ylcarbonyl] -piperazine a) 1,1-dimethylethyl ester of 4 - [[lS- [la, 2ß, 3β, 4a (lS *, 2R *)]] -tetrahydro-2,2-dimethyl -6- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -4H-cyclopenta-l, 3-dioxol-4-carbonyl] -piperazine-1-carboxylic acid It is prepared according to the method of example 1 step (h) using the product of Example 5 stage (a) and 1, 1-dimethylethyl ester of 1-piperazinecarboxylic acid. MS (APCI) 679 (M + H +, 100%) b) l- [[ÍS- [la, 2ß, 3ß, 4a (1S *, 2R *)]] -2, 3-Dihydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) ) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentylcarbonyl] -piperazine It is prepared according to the method of example 1 step (i) using the product from step ( to) . MS (APCI) 539 (M + H +, 100%) dH NMR (de-DMSO) 9.36 (1H, d), 7.56-7.31 (5H,), 5.25-5.10 (2H, m), 5.04-5.01 (1H, m), 4.50-4.38 (1H, m), 4.14 (1H, broad s), 3.36-3.30 (7H, m), 2.97-2.92 (1H, m), 2.86-2.81 (1H,), 2.37-2.32 ( 3H, m), 2.15-2.10 (2H,), 1.53-1.45 (3H, m), 1.38-1.31 (1H,), 0.86 (3H, t) Pharmacological data The preparation for the assay of the agonist / antagonist activity of the P 7 receptor on washed human platelets for the compounds of the invention is carried out as follows. Human venous blood (100 ml) is divided equally between 3 tubes, each containing 3.2% trisodium citrate (4 ml) as anti-coagulant. The tubes are centrifuged for 15 minutes at 240G to obtain a platelet-rich plasma (PRP) to which 300 ng / ml of prostacyclin are added to stabilize the platelets during the washing procedure. Red cell-free PRP is obtained by centrifugation for 10 minutes at 125G followed, by additional centrifugation for 15 minutes at 640G. The supernatant is discarded and the platelet pellet is resuspended in modified Calcium Free Tyrode's solution (10 ml) (CTF), composition: 137 mM NaCl, 11.9 mM NaHCO 3, 0.4 M NaH 2 P0 4, 2.7 mM KCl, 1.1 mM MgCl 2, 5.6 mM dextrose, gas with 95% 02/5% C02 is added and maintained at 37 ° C. After the addition of 300 ng / ml of additional PGI2, the stagnant suspension is centrifuged once more for 15 minutes at 640G. The supernatant is discarded and the platelets resuspended initially in 10 ml of CFT with additional CFT added to adjust the final platelet count to 2xl05 / ml. This final suspension is stored in a 60 ml syringe at 3 ° C with air excluded. To allow the recovery of PGI2 inhibition from normal function, platelets are used in aggregation studies not earlier than 2 hours after the final resuspension. In all studies, 3 ml aliquots of platelet suspension are added to tubes containing CaCl 2 solution (60 μl of 50 mM solution with a final concentration of 1 mM). The human fibrinogen (Sigma, F 4883) and 8-sulphophenylteophylline (8-SPT which is used to block any agonist activity of Pi of compounds) are added to give final concentrations of 0.2 mg / ml (60 μl of 10 mg / ml solution of aglo erable protein in saline) and 300 nM (10 μl of 15 mM solution in 6% glucose), respectively. Platelets or cushion as appropriate are added in a volume of 150 μl to the individual wells of a 96-well plate. All measurements are made in triplicate in platelets of each donor. The agonist / antagonist potency is evaluated as follows. Aggregation responses are measured in 96-well plates using the change in absorbance given by the plate reader at 660 nm. It uses either a Bio-Tec Ceres 900C or a Dynatech MRX as the plate reader. The absorbance of each well in the plate is read at 660 nm to establish a baseline figure. The saline solution or the appropriate solution of the compound tested is added to each well in a volume of 10 μl to give a final concentration of 0, 0.01, 0.1, 1, 10 or 100 mM. The plate is then stirred for 5 minutes on an orbital shaker set at 10 and the absorbance at 660 nm is read. The aggregation at this point was indicative of agonist activity of the test compound. The saline solution or ADP is then added (30 M; 10 μl of 450 mM) to each well and the plate is shaken for an additional 5 minutes before reading the absorbance again at 660 nm. The antagonist potency is estimated as a% inhibition of the control ADP response to obtain an IC5o. The exemplified compounds have pIC50 values of more than 5.0. It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (12)

CLAIMS Having described the invention as antecexle, the content of the following claims is claimed as property:

1. A compound of the formula (I) characterized in that: R1 is an alkyl group of 1 to 6 carbon atoms, cycloalkyl of 3 to 8 carbon atoms or phenyl, each group being optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11 or alkyl of 1 to 6 carbon atoms (optionally substituted by itself by one or more halogen atoms); R2 is alkyl of 1 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, cycloalkyl of 3 to 8 carbon atoms, aryl (optionally substituted by one or more alkyl groups and / or atoms) halogen), or alkyl of 1 to 6 carbon atoms; or R2 is a cycloalkyl group of 3 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR8, NR9R10, SR11, alkyl of 1 to 6 carbon atoms or phenyl (the last two being optionally substituted by one or more substituents selected from halogen, N02, C (0) R8, OR8, SR11, NR12R13, phenyl and alkyl of 1 to 6 carbon atoms which is optionally substituted by one or more halogen atoms); one of R3 or R4 is hydroxy and the other is hydrogen, hydroxy or NR9R10; R5 is (CH2) nNR14R15 where n is 0 to 6 and R14 and R15 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R is CONR1 R where R 16 is hydrogen or alkyl of 1 to 6 carbon atoms, and R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms each of which is replaced by NR18R19 and optionally substituted by phenyl, or R17 is alkyl of 1 to 6 carbon atoms or cycloalkyl of 3 to 6 carbon atoms substituted by phenyl which is substituted by NR18R19 where R18 and R19 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R17 is a 5- to 8-membered saturated heterocycle containing one or more nitrogen atoms and optionally substituted on nitrogen by hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; or R16 and R17 together with the nitrogen atom to which they are attached form a ring of 5 to 8 members which is replaced by NR18R19 as defined above; or R16 together with R19 forms a 6 to 8 member ring containing the two nitrogen atoms in which R17 and R18 are as defined above; or R5 is (CH2) PNR20CO (CH2) qOR21 or (CH2) PNR22 (CH2) qNR23COR24 where p and q are independently 1 to 4 and R20, RZ1, R22, R23 and R24 are independently alkyl of 1 to 4 carbon atoms or phenyl; or R5 is CH = CHCH2NR25R26 where R25 is hydrogen, alkyl of 1 to 6 carbon atoms or phenyl and R2 is hydrogen or (CH2) and NR2 'R2a where y is 2-4 and R2' and R28 are independently hydrogen, alkyl of 1 to 6 carbon atoms or phenyl; R8, R9, R10 and R ?: are independently hydrogen or alkyl of 1 to 6 carbon atoms; and R12 and R13 are independently hydrogen, alkyl of 1 to 6 carbon atoms or acyl groups; or a pharmaceutically acceptable salt or solvate thereof.

2. A compound according to claim 1, characterized in that it has the following stereochemistry:

3. A compound according to claim 1 or 2, characterized in that R1 is alkyl of 1 to 8 carbon atoms.

4. A compound according to any of claims 1 to 3, characterized in that R 2 is alkyl of 1 to 6 carbon atoms or a cycloalkyl group of 3 to 8 carbon atoms substituted phenyl.

5. A compound according to any of claims 1 to 4, characterized in that R3 or R4 are hydroxy.

6. A compound according to any of claims 1 to 5, characterized in that R5 is (CH2) nNH2 where n is 0.1 16, CONR16R17 where R16 is hydrogen and R17 is alkyl of 1 to 5 carbon atoms optionally substituted by NR18R19 where R18 and R19 are both hydrogen, or one is alkyl of 1 to 6 carbon atoms, in particular methyl, and the other is phenyl, or R5 is C0NR16R17 where R16 is hydrogen and R17 is CH2phenyl or a cyclohexyl group each substituted by amino, or R5 is C0NR16R17 where R16 and R17 form a piperazine ring, or R5 is CH = CHCH2NR25R26 where R25 and R26 are both hydrogen or R, is hydrogen and R is (CH2) 2NH2, R ° is CH2R, 2'0? C0 (CH2) 20R .2¿1I where R 2? O? and R 1 are to the one of 1 to 4 carbon atoms, or R is CH 2 NH (CH 2) 2NHCOR where R > 24 is alkyl of 1 to 4 carbon atoms.

7. A compound according to claim 1, characterized in that it is: [ÍS- (la, 2ß, 3ß, 4a)] -4- [7- (butylamino) -5- (propylthio) -3H-1, trifluoroacetate. , 3-triazolo [4,5-d] pyrimidin-3-yl] -2, 3-dihydroxy-N- [[3- (N-methyl-N-phenyl) amino] propyl] -cyclopentanecarboxamide, Trifluoroacetate [] - (la, 2ß, 3ß, 4a)] -N- [5-aminopentyl] -4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] ] pyrimidin-3-yl] -2, 3-dihydroxy-cyclopentanecarboxamide, Trifluoroacetate of [-S- (la, 2ß, 3ß, 4a)] -N- [3-aminopropyl] -4- [7- (butylamino) -5 - (propylthio) -3H-l, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -2,3-dihydroxy-cyclopentanecarboxamide, Trifluoroacetate of [S- (la, 2ß, 3ß, 4a) ] -N- [(3-aminophenyl) methyl] -4- [7- (butylamino) -5-) propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl] -2, 3-dihydroxy-cyclopentaneboxboxamide, Trifluoroacetate of [1 S- (la, 2β, 3β, 4a (1S *, 2R *)]] - N- [3-amino-ropil] -2, 3-dihydroxy-4 - [7- [2- (fenilcycle propyl) -amino] -5- (propylthio) -3H-1,2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, Bis (trifluoroacetate) of [S- (la, 2ß, 3β, 4a (ΔS *, 2R *)]] - N - [4-aminociclohexyl] -2, 3-dihydroxy-4- [7- [2- (phenylcyclopropyl) amino] -5- (propylthio) -3H-1 , 2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentanecarboxamide, [lS- (la, 2a, 3ß, 5ß)] -3-Amino-5- [7- (butylamino) -5 - (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß, 5ß)] - 3- (Aminomethyl) -5- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-2, 2- diol, [ÍS- (la, 2a, 3β, 5β (ÍS *, 2R *)]] -3-amino-5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1 , 2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß, 5ß (lS *, 2R *)]] - 3 - (Ethylamino) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan- 1,2-diol, [lS- (la, 2a, 3ß, 5ß (lR *, 2S *)]] - 3- [(Methylamino) methyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidin-3-yl] ] -cyclopentan-1,2-diol, [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3- [(Ethylamino) methyl] -5- [7- [(2-phenylcyclopropyl)] ) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3ß , 5β (lS *, 2R *)]] -3- (Aminomethyl) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [lS- (la, 2a, 3β, 5β (lS *, 2R *)]] -3- (2-aminoethyl) -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, [ lS- (la, 2a, 3β (E), 5β (lS *, 2R *)]] -3- (3-Aminoprop-1-enyl) -5- [7- [(2-phenylcyclopropyl) amino] -5 - (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, N-Ethyl-N- [[R- [la, 2] , 3ß, 4a (lR *, 2S *)]] -2, 3-dihydroxy-4 - [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) - 3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopenti-methyl] -3-methoxy-propanamide, Ditrifluoroacetate of [ΔS- [la, 2a, 3β (E), 5β (ΔS *, 2R *)]] -3- [3- [(2-dimethylaminoethyl) amino] -prop-1-enyl] -5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H -l, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclope tan-1,2-diol, [IR- [la, 2ß, 3ß, 4a (lR *, 2S *)] ] -N- [2- [2, 3-dihydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-.1,2,3-triazole [4,5-d] ] pyrimidin-3-yl] -cyclopentylmethylamino] ethyl] -acetamide, [1S- [la, 2a, 3a, 5β (ÍS *, 2R *)]] -3-Amino-5- [7- [(2-phenylcyclopropyl amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1,2-diol, l - [[lS- [la, 2ß, 3ß, 4a (lS *, 2R *)]] - 2,3-Dihydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -cyclopenti-1-carbonyl] -piperazine or pharmaceutically acceptable salts or solvates thereof.

8. A pharmaceutical composition, characterized in that it comprises a compound, according to any of claims 1 to 7 in combination with a pharmaceutically acceptable diluent, adjuvant or carrier.

9. A compound according to any of claims 1 to 7, characterized in that it is for use in therapy.

10. A compound according to any of claims 1 to 7, characterized in that it is for use in the treatment or prevention of myocardial infarction, thrombotic infarction, temporary ischemic attacks, peripheral vascular disease and angina.

11. A compound according to any of claims 1 to 7, characterized in that it is for use in the treatment or prevention of angina.

12. A process for the preparation of a compound of the formula (I), characterized in that it comprises: (a) for compounds where R5 is CONHR16R17 of reaction of a compound of the formula (II): (II) wherein R1, R2, R3 and R4 are as defined in formula (I) or are protected derivatives thereof, with a compound of formula (III): HNR16R17 (III) where R16 and R17 are as defined in formula (I), or (b) for compounds of formula (I) wherein R5 is amino, perform a rearrangement of Curtis in a compound of formula (II) as defined above , o and optionally after the same (a) or (b) in any order: • converting one or more functional groups to additional functional groups • removing any protecting groups • forming a pharmaceutically acceptable salt or solvate.