MXPA00000683A - 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 TRIAZO [, 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 platelet crosslinking by fibrinogen binding to REF: 32473 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 Inves tigators (1994), Ci rc ul a ti on 90 , pp. 1624-1630, The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) lia Investigators (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 antithrombotic agents. Accordingly, there is a need to discover P? T antagonists as antithrombotic agents. It has now been found that a series of triazole [4,5-d] pyrimidine derivatives are P r 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, OR0, NR7R8, SR9 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, OR6, NR7R8, SR9, 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, OR6, NR7R8, SR9, 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) R6, OR6, SR9, NR10R11, 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 hydrogen and the other is hydroxy; X is OH or NHR5; R5 is an alkyl group of 1 to 6 carbon atoms substituted by COOH or C (0) NR7R8 and optionally by one or more additional substituents selected from halogen, OR12, C (NH) NR13R14, C (0) NR1 R16, phenyl ( optionally substituted by one or more groups selected from halogen, N02, C (0) R6, OR6, NR7R8, SR9 and alkyl of 1 to 6 carbon atoms) or alkyl of 1 to 6 carbon atoms (optionally substituted by one or more hydroxy or phenyl groups); or R5 is a lactam ring of the formula (i): wherein Q is a portion of (CH2) m where m is 1, 2 or 3, Z is O, C (O) or CH2 and R18 is hydrogen or alkyl of 1 to 6 carbon atoms; R6, R9, R12, R13, R14, R15 and R16 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R7 and R8 are independently hydrogen, alkyl of 1 to 6 carbon atoms (optionally substituted by one or more phenyl groups) or phenyl groups; and R 10 and R 11 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 the formula (I) are capable of existing in stereoisomeric forms including enantiomers and the invention extends to each of these forms is tereosisomeric 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, OR6, NR7R8, SR9 or alkyl of 1 to 6 carbon atoms (optionally substituted by itself by one or more halogen atoms). Preferably R1 is alkyl of 1 to 6 carbon atoms or phenyl substituted by alkyl of 1 to 6 carbon atoms which is substituted by one or more fluorine atoms. Most preferably R1 is propyl or phenyl substituted by trifluoromethyl. Suitably R2 is alkyl of 1 to 8 carbon atoms optionally substituted by one or more substituents selected from halogen, OR °, NR7R8, SR9, 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, OR6, NR7R8, SR9, 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) R6, OR6, SR9, NR10R? a, phenyl and alkyl of 1 to 6 carbon atoms which is optionally substituted by one or more halogen atoms). Aryl groups include naphthyl and phenyl. Preferably R2 is alkyl of 1 to 8 carbon atoms, in particular alkyl of 4 to 6 carbon atoms, or cycloalkyl of 3 to 8 carbon atoms optionally substituted by phenyl. Most preferably R2 is butyl or cyclopropyl optionally substituted by phenyl. Suitably one of R3 or R4 is hydrogen and the other is hydroxy. Preferably R3 is hydroxy and R4 is hydrogen. Suitably X is OH or NHR5 where R5 is an alkyl group of 1 to 6 carbon atoms substituted by COOH or C (0) NR7R8 and optionally by one or more additional substituents selected from halogen, OR12, C (NH) NR13R14, C ( 0) NR15R16, phenyl (optionally substituted by one or more groups selected from halogen, N02, C (0) R6, OR6, NR7R8, SR9 and alkyl of 1 to 6 carbon atoms) or alkyl of 1 to 6 carbon atoms ( optionally substituted by one or more hydroxy or phenyl groups or R5 is a lactam ring of the formula (i) Acyl groups include C (0) -alkyl of 1 to 6 carbon atoms Preferably X is OH or NHR5 where R5 is alkyl of 1 to 6 carbon atoms substituted by COOH and optionally further substituted by alkyl of 1 to 6 carbon atoms substituted by OH Most preferably X is OH or NHR5 where R5 is CH2COOH or CH (CH2OH) C02H. Preferred of the invention include: [lS- (la, 3a, 4ß)] - 3- [7- (butyl amino) -5- (propyl) acid uncle) -3H-1, 2, 3-triazolo [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid, [lS- (la, 3a, 4ß)] - 3- [7- (buti lamino) -5- [[4- (tri? uorornethyl) phenyl] thio] -3H-l, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid, N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- [[ 4- (trifluoromethyl) -phenyl] thio] -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopent and learbonyl] -L-serine, N- [ 1S, 3R, 4S) -3- [7- (Butylamino) -5- [[4- (trifluoromethyl) -phenyl] thio] -3H-1,2,3-triazole [4,5-d] pyrimidine-3 -yl] -4-hydroxy-cyclopentylcarbonyl] -glycine, Acid [lS- [la, 3ß, 4a (lS *, 2R *)]] - 3-hydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxylic acid, N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentyl-carbonyl] -glycine, Acid [1S- (la, 3a, 4ß)] -3- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid [1S- (la, 2β, 4a)] - 3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazol [4, 5-d] pyrimidin-3-yl] - 2-hydroxy-cyclopentanecarboxylic , and pharmaceutically acceptable salts thereof. According to the invention there is further provided a process for the preparation of a compound of the formula (I) which comprises oxidizing a compound of the formula (II): wherein R1, R2, R3 and R4 are as defined in formula (I) or are protected derivatives thereof, and optionally thereafter in any order: • converting a compound of formula (I) into an additional compound of the formula (I) • removing any protecting groups • forming a pharmaceutically acceptable salt or solvate.

Oxidated compounds of formula (II) can be oxidized using known reagents such as pyridinium dichromate or chromium (VI) oxide. Compounds of the formula (II) can be prepared wherein R3 is hydroxy and R4 is hydrogen by dehalogenating compounds of the formula (IV): where R1 and R2 are as defined in formula (II) and X is halogen. Preferably X is bromine. The reaction can be carried out using known reagents such as tributyltin hydride. The hydroxy groups may be protected if necessary in compounds of the formula (IV). Compounds of the formula can be prepared (IV) from the corresponding epoxide of the formula (V): where R1 and R2 are as defined in formula (II) by -the treatment with HCl or HBr. Compounds of the formula (V) can be prepared from the corresponding diol, for example by treating the diol with 2-acetoxy-2-methylpropionyl bromide, followed by a base such as Amberlite® hydroxide resin. Compounds of the formula (II) can be prepared wherein R3 is hydrogen and R4 is hydroxy by dehydroxylating compounds of the formula (VI): where R1 and R2 are as defined in formula (II) and P1 and P2 are suitable protecting groups. The reaction can be carried out using treatment compounds of the formula (VI) with 1,1-thiocarbonyl-diimidazole followed by a trialkyl hydride. Compounds of the formula (VI) can be prepared by selective protection of the corresponding triols of the formula (VII): where R1 and R2 are as defined in formula (II).

Suitable reagents include 1,3-dichloro-1,1 ', 3,3'-tetraisopropyldisiloxane. A compound of the formula can be prepared (VII) by reacting a compound of the formula (VIII): 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 R 2 is as defined above, in the presence of a base Suitable salts of NH 2 R 2 include hydrochlorides Suitable bases include tertiary organic bases such as triethylamine or an inorganic base such as potassium carbonate. compound of the formula (VIII) diazotizing a compound of the formula (IX): (IX) 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 an alkyl nitrite 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 (IX) can be prepared wherein P 1 is OH by reacting a compound of the formula (X): wherein R1, L1, P2 and P3 are as defined in the above. The reduction of the nitro group can be performed, for example, by 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. Reduction of the lactam can be carried out using complex metal hydrides such as lithium-aluminum hydride in a solvent such as ether or preferably using sodium borohydride in a suitable solvent such as methanol. A compound of the formula can be prepared (X) by reacting a compound of the formula (XI): wherein L1 and R1 are as defined in the 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 (XII): wherein P2 and P3 are as defined in the 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 from -10 to 100 ° C. Preferably, sodium hydride in THF is used at room temperature. Preferably the compound of the formula (XII) has the following stereochemistry in such a way that the reaction schemes described in the above produce a compound having the stereochemistry of formula (la): (XHa) 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 W F McOmie, Plenum Press (1973), and "Protective Groups in Organic Synthesis" 2nd edition, T Greene & P G M utz, iley-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 may be removed 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 salts of the compounds of the formula (I) can be formed by reacting the free acid, or a salt thereof, or the free base, 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 eliminated in va cuo, 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.

Compounds of the formula (I) can be converted to additional compounds of the formula (I) using standard chemistry. For example, compounds of the formula (I) wherein X is NHR5 can be prepared from the compounds of the formula (I) wherein X is OH using coupling chemistry, for example in the presence of a coupling agent using known methods of the invention. Peptide synthesis (see M. Bodanszky and A. Bodanszky, The Practice Synthesis, Springer-Verlag, 1984). Suitable coupling agents include 1,1'-carbonyldiimidazole and dicyclohexylcarbodiimide; the preferred coupling agent is bromo-tris-pyrrolidino-phosphono hexafluorophosphate, used in the presence of N, N-diethyl-isopropylamine. The reaction is preferably carried out in N, N-dimethylformamide (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. All novel intermediaries form a further aspect of the invention. The compounds of the invention act as P? Receptor antagonists? - Accordingly, the compounds are useful in therapy, especially in adjunctive therapy, particularly are indicated for use as: inhibitors of platelet activation, aggregation and degranulation, promoters of platelet disaggregation, 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, transient ischemic infarcts, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic diseases such as angioplasty, endarterectomy, stenting, 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 and includes skin and muscle bumps, conditions with a diffuse platelet / thrombotic intake component such as disseminated intravascular coagulation, thrombotic thrombocytopenic purpura, hemolytic uremic syndrome, thrombotic complications of septicemia, adult respiratory distress syndrome, anti-inflammatory syndrome, - phospholipids, heparin-induced thrombocytopenia and pre-eclampsia / eclampsia, or venous thrombosis such as deep vein thrombosis, veno-occlusive disease, haematological conditions such as myeloproliferative disease, including thrombocythemia, sickle cell disease; or in the prevention of mechanically induced platelet activation in vi ve, such as cardio-pulmonary bypass and oxygenation of the extracorporeal membrane (prevention of microthromboembolism), activation of mechanically induced platelets in vi tro, such as use in the preservation of blood products, for example, platelet concentrates, or short circuit occlusion such as in renal dialysis and plasmapheresis, thrombosis secondary to damage / vascular inflammation such. such as vasculitis, arteritis, glomerulonephritis, inflammatory bowel disease and rejection of organ graft, conditions such as migraine, Raynaud's phenomenon, conditions in which platelets can contribute to the process of fundamental inflammatory disease in the vascular wall such as formation / progression of atheromatous plaques, estensis / restenosis and in other inflammatory conditions such as asthma, in which factors derived from platelets and platelets are implicated in the process of immunological diseases.

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, aerosols of HFA 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 pressurized HFA aerosol formulations 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 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 polyvinyl pyrrolidone. , 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 gelatine 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 semi-liquid formulations of the drug can be filled into hard gelatin capsules. Liquid preparations for oral application - 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, which should not be construed as limiting the invention. 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. Preparative CLAP separations are usually performed using a Novapak®, Bondapak® or Hypersil® column packed with reverse phase silica BDSC-18. Instant chromatography (indicated in the Examples as (Si02) is made using Fisher Matrix silica, 35-70 μm. For compounds that show the presence of rotamers in the proton NMR, only chemical changes are cited for most rotamers.

Example 1 Acid [ÍS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [, 5-d] pyrimidin-3-yl ] - -hydroxy-cyclopentanecarboxylic acid a) [lS- (la, 2a, 3ß, 5ß)] - 5- [7- (Butylamino) -5- (propylthio) -3H-1, 2,3-triazole [, 5-d] pyrimidin-3- il] -3-hydroxymethyl) -cyclopentan-1,2-diol A solution of [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-4H-cyclopenta-1,3-dioxol-4-methanol (prepared as described in WO 97 / 03084) (5.0 g) in methanol (50 ml) and IN HCl (50 ml) is stirred at room temperature for 2 hours. Water is added and the product is collected by filtration and dried (4.51 g). MS (APCI) 397 (M + H *) b) [lR- (la, 2a, 4a, 5a)] - 4- [7- (Butylamino) -5- (propylthio) -3H-1, 2,3-triazole [, 5-d] pyrimidin-3- il] -6-oxabicyclo- [3.1.0] hexane-methanol A solution of the product from the stage is stirred (a) (4.3 g) and 2-acetoxy-2-methylpropionyl bromide (7.7 ml) in acetonitrile (200 ml) overnight at room temperature. The mixture is concentrated and partitioned between ethyl acetate and aqueous sodium bicarbonate. The organic phase is dried, concentrated and the residue is dissolved in methanol (500 ml) then Amberli te®IR8 (400) OH "is added in the form of a resin (50 g) The mixture is stirred overnight, filtered and concentrated The purification (Si02, ethyl acetate: dichloromethane 1: 1 as eluent) of the subtitle compound (3.2 g) is carried out MS (APCI) 379 (M + H +) c) [IR- (la, 2a, 3β, 4a)] -2-Bromo-4- [7- (butylamino) -5- (propylthio) -3H-1, 2,3-triazole [, 5-d] pyrimidin-3-yl] -3-hydroxy-cyclopentanemethane 1 To a solution, from the product of step (b) (3.2 g) in chloroform (20 ml), 48% hydrobromic acid (20 ml) is added. The mixture is stirred at room temperature for 15 minutes, concentrated and treated with water (100 ml). The product is collected by filtration (3.3 g). MS (APCI) 459/461 (M + H +) d) (lS-la, 3a, 4β) -3- (Butylamino) -5- (propyl io) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4- hydroxy-cyclopentanemethanol To a solution of the product of step (c) (0.5 g) in toluene (30_ml) at 80 ° C, tributyltin hydride (0.35 ml) and 2, 2'-azobis (2-methylpropionitrile) (10 g) are added. mg). The mixture is heated at 80 ° C for 30 minutes, cooled and the product is collected by filtration (0.34 g). MS (APCI) 381 (M + H +) e) [IR- (la, 2ß, 4ß)] -4- [[[Bis (4-methoxyphenyl) phenyl-methyl] oxy] methyl] -2- [7- (butyl mino) -5- (propyl) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopentan-1-ol A mixture of the product from the stage is stirred (d) (7.1 g), 4,4 '-dimethoxytriphenyl chloride (6.31 g) and 4-dimethylaminopyridine (2.32 g) in dichloromethane (300 mL) at room temperature for 48 hours and purified (Si02, ethyl acetate: diclpromethane 3:97 to 10:90 as eluent) to yield the subtitle compound (10.1 g). MS (FAB) 683 (M + H +) f) 3- [[IR- (la, 2ß, 4a)] - 4 - [[[Bis (-methoxyphenyl) phenyl-methyl] oxy] methyl] -2- [[(1,1-dimethylthyl) dimethylsilyl]] -oxi] -cyclopent-1-yl] -N-butyl-5- (propylthio) -3H-1,2,3-triazolo [4,5-d] pyrimidin-7-amine A mixture of the product of the stage (e) (10.1 g), t-butyldimethylsilyl chloride (2.67 g) and imidazole (1.16 g) in N, N-dimethylformamide (300 ml) at room temperature for 48 hours, concentrate and purify (SiO2, ethyl acetate : dichloromethane 5:95 as eluent) to yield the subtitle compound (10.0 g). EM (El) 796 (M +) g) [lS- (la, 3a, 4ß)] - 3- [7- (Butylamino) -5- (propylthio) -3H-1,2, 3-riazol [4, 5-d] pyrimidin-3-yl ] -4- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -cislopentanme year1 It is added to a solution of the product from step "(f) (10.0 g) in nitromethane / ethanol (95: 5, 230 ml) Anhydrous zinc bromide (27.5 g) The mixture is stirred at room temperature for 1 hour and is poured into water (11) containing ammonium acetate (100 g) The product is extracted with ethyl acetate and purified ( Si02, ethyl acetate: dichloromethane 1: 9 as eluent) to yield the subtitle compound (5.6 g) MS (APCI) 495 (M + H +) h) Acid [lS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidin-3- il] -4- [[(1,1-di-ethylene-yl) -dimethylsilyl] oxy] -cyclopentanecarboxylic A mixture of the product of step (g) (5.5 g) and pyridinium dichromate (55 g) in N, N is stirred. dimethylformamide (300 ml) at room temperature for 7 hours. The mixture is poured into water (11) and the product is collected by filtration and purified (Si02, ethyl acetate: dichloromethane 2: 8 as eluent) to yield the subtitle compound (4.6 g). MS (APCI) 509 (M + H +) i) Acid [lS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidin-3- yl] -4-hydroxy-cyclopentanecarboxylic acid. To a solution of the product of step (h) (4.3 g) in tetrahydrofuran (100 ml) tetrabutylammonium fluride (20 ml, 1M solution in tetrahydrofuran) is added and the mixture is stirred at room temperature. Atmosphere during the night. The mixture is poured into water and the product is collected by filtration, then purified by recrystallization (ethyl acetate / isohexane) (2.1 g). MS (APCI) 395 (M + H +) Example 2 Acid [lS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- [[4- (trifluoromethyl) enyl] thio] -3H-1,2,3-triazole [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid a) Acid [ÍS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- (propylsulfonyl) -3H-1, 2,3-triazolo [4, 5-d] pyrimidin-3-yl] - -hydroxy-acarboxylic cyclopene It is added to a solution of the product of Example 1, step (i) (0.5 g) in acetonitrile / water (3: 2, 100 ml) Oxone® (5 g). The mixture is stirred at room temperature for 30 minutes. Water is added and the mixture is extracted with ethyl acetate. The extract is concentrated to produce the product (0.5 g). MS (APCI) 427 (M + H +) b) Acid [ÍS- (la, 3a, 4ß)] -3- [7- (butylamino) -5- [[4- (trifluoromethyl) phenyl] thio] -3H-1, 2,3-triazole [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid It is added to a suspension of sodium hydride (60%, 0.18 g) in N, N-dimethylformamide (30 ml) 4- (tri fluoromethyl) thiophenol (0.8 g). The mixture is stirred for 30 minutes then the product of the stage is added (a) (0.5 g). The mixture is heated at 80 ° C for 2 hours, cooled and drained in water. The product is extracted with ethyl acetate and purified (Si02, ethanol: dichloromethane 1: 9 as eluent). Further purification occurs (CLAP, Novapak®C18 column, ammonium acetate: 0.1% aqueous acetonitrile, 40:60 gradient elution at 0: 100 for 15 minutes) of the subtitle compound (0.145 g). MS (APCI) 497 (M + H +) NMR (de-DMSO) 12.29 (1H, s), 9.10 (1H, t), 7.84 (4H, c), 5.29 (1H, d), 4.83 (1H, m) , 4.49 (1H, m), 3.19 (2H, m), 3.05 (1H,), 2.49-2.30 (2H, m), 2.15 (1H, m), 1.95 (1H,), 1.34 (1H,), 1.10 (2H, m), 0.78 (3H, t).

Example 3 N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- [[4- (trifluoromethyl) -enyl] thio] -3H-1, 2,3-triazole [4, 5 d] pyrimidin-3-yl] -4-hydroxy-cyclopentylcarbonyl] -L-serine N, N-diisopropylethylamine (1.0 ml) is added to a solution of L-serine t-butylester hydrochloride (0.5 g), hexafluorophosphate bromo-tris-pyrrolidino-fos phonium (1.0 g) and the product of the example 2 (0.3 g) in tetrahydrofuran (20 ml). The reaction mixture is stirred at room temperature for 1 hour, then it is poured into water and extracted with ethyl acetate. The extract is concentrated and the residue is dissolved in trifluoroacetic acid / dichloromethane (1: 1). 100 mi). After 1 hour the mixture is concentrated and the residue is purified (CLAP, Novapak® C18 column, ammonium acetate: 1.0% aqueous acetonitrile, gradient elution from 10:90 to 0: 100 for 15 minutes) to produce the title (0.17 g). MS (APCI) 584 (M + H +) NMR (d6-DMSO) 9.12 (1H, t), 8.08 (1H, d), 7.83 (4H, c), 5.24 (1H, d), 4.89 (1H, broad) ), 4.80 (1H, m), 4.55 (1H, m), 4.30 (1H,), 3.65 (2H, m), 3.15 (3H,) ", 2.34 (2H, m), 2.08 (1H, m), 1.83 (1H, m), 1. 34 (1H, m), 1.10 (2H, m), 0.77 (3H, t).

Use 4 N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- [[4- (trifluoromethyl) -phenyl] thio] -3H-l, 2,3-triazole [4, 5 -d] pyrimidin-3-yl] -4-hydroxy-cyclopentylcarbonyl] -glycine It is prepared according to the method of example 2 using the product of example 1 and glycine methyl ester hydrochloride. MS (APCI) 554 (M + H +) NMR (d6-DMSO) 9.11 (1H, t), 8.24 (1H, t), 7.55 (4H, c), 5.26 (1H, d), 4.80 (1H, m), 4.55 (1H, m), 3.75 (2H, m), 3.16 (2H, m), 3.01 (1H, m), 2.28 ( 2H, m), 2.13 (1H, m), 1.81 (1H,), 1.36 (2H, m), 1.12 (2H, m), 0.77 (3H, t).

EXAMPLE 5 Acid [ΔS- [la, 3β, 4a (1S *, 2R *)]] - 3-hydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propyl io -3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxylic acid a) [3aR- [3aa, 4a, 6a, (IR *, 2S *), 6aa]] -Tetrahydro-2,2-dimethyl-6- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio ) -3H-1,2,3-triazolo [, 5-d] pyrimidin-3-yl] -4H-cyclopen al, 3-dioxol-4-methanol N, -diisopropylethylamine (21 ml) is added to a solution of [3aR- [3aa, 4a, 6a, 6aa]] - 6- [7-chloro-5- (propylthio) -3H-1,2,3-triazolo [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 (1R-trans) -2-phenyl-cyclopropanamine dihydroxybutanedioate (1: 1). (prepared as described by L.A. 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. The reaction mixture is 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 +) b) [ΔS- [la, 2a, 3β, 5β (1S *, 2R *)]] -3-Hydroxymethyl-5- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -cyclopen-1,2-diol It is prepared according to the method of example 1 step (a ) using the product of step (a). MS (APCI) 457 (M + H +) c) [R- [la, 2a, 4a (lR *, 2S *), 5a]] -4- [7- [(2-Phenylcyclopropyl) -amino] -5- (propylthio) -3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] -6-oxabicyclo [3.1.0] hexan-2-methanol It is prepared according to the method of example 1 step (b) using the product from step ( b) MS (APCI) 439 (M + H +) d) [IR- [la, 2a, 3β, 4a (1R *, 2S *)]] -2-Bromo-3-hydroxy-4- [7- [(2-enylcyclopropyl) amino] -5- (propyl) ) -3H-1,2,3-triazole [4, 5-d] pyrimidxn-3-yl] -cislopentanme year1 It is prepared according to the method of example 1 step (c) using the product of step (c). EM (APCI) 519/521 (M + H +) e) [lS- [la, 3β, 4a (lS *, 2R *)]] -3-Hxdroxy -4 - [7- [(2-phenylcyclopropyl) amino] -5- (propyl) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentanemethanol It is prepared according to the method of example 1 step (d) using the product from step (d). MS (APCI) 441 (M + H +) f) [IR- [la, 2β, 4β (1R *, 2S *)]] -4- [[[Bis (4-methoxyphenyl) -phenylmethyl] oxy] methyl] -2- [7- [(2-phenylcyclopropyl)] ) -amino] -5- (propylthio) -3H-1, 2, 3-tri zol [, 5-d] pyrimidin-3-yl] -cyclopentan-1-ol It is prepared according to the method of example 1 step ( e) using the product of stage (e). MS (APCI) 743 (M + H +) g) 3 - [[1R, 2R, 4S] -4 - [[[Bis (4-methoxyphenyl) enylmethyl] -oxy] methyl] -2- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -cyclopentan- 1-yl] -N- [[IR- (trans)] - (2-phenylcyclopropyl) -amino] -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine-7 -amine It is prepared according to the method of example 1 step (f) using the product of step (f). NMR (d6-DMSO) 7.76-7.11 (18H, m), 6.70 (1H, broad s), 5.32 (1H, d), 5.04 (1H,), 4.00 (6H, s), 3. 52 (1H, m), 3.42-3.20 (4H, m), 2.92 (1H, m), 2.78 (1H, m), 2.52 (1H, m), 2.42 (1H, m), 2.30-2.10 (2H, m), 1.98 (2H, m), 1.72 (2H, m), 1.20 (3H, t), 1.00 (9H, s), 0.13 (3H, s), 0.00 (3H, s). h) [ΔS- [la, 3β, 4a (ÍS *, 2R *)] -3- [[1,1-Dimethylethyl) dimethylsilyl] -oxy] -4- [7- [(2-enylcyclopropyl) amino] - 5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -syclopentanemethane 1 It is prepared according to the method of example 1 step (g) using the product from step ( g). MS (APCI) 555 (M + H +) i) Acid [ÍS- [la, 3β, 4 (1S *, 2R *)]] -3 - [[1,1-Dimethylethyl) -dimethylsilyl] oxy] -4- [7- [(2-phenylcyclopropyl) amino] ] -5- (propyl io) -3H-1, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -cyclopentanecarboxylic acid It is prepared according to the method of example 1 step (h) using the product from the stage (h). MS (APCI) 569 (M + H +) j) Acid [ΔS- [la, 3β, 4a (1S *, 2R *)]] -3-hydroxy-4 - [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1, 2,3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxylic acid It is prepared according to the method of example 1 step (i) using the product of step (i). MS (APCI) 455 (M + H +) NMR (d6-DMS0) 12.30 (1H, s), 9.34 (1H, d), 7.31-7.16 (5H, m), 5.32 (1H, d), 4.84 (1H, m), 4.57 (1H, m), 3.20 (1H, m), 3.10 (1H, m), 2.85 (2H, 2x m), 2.48 (2H, m), 2.25 (1H, m), 2.15 (1H, m), 1.95 (1H,), 1.52 (3H, m), 1.35 (1H,), 0.81 (3H, t).

Use 6 N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentyl-carbonyl] -glycine It is prepared according to the method of example 3 using the product of example 1 and ter-butyl esters of glycine. MS (APCI) 450 (M-H +) NMR (d6-DMSO) 8.99 (1H, t), 8.11 (1H, m), 5.28 (1H, m), 4.86-4.78 (1H, m), 4.60-4.58 (1H, m), 3.50- 3.47 (1H, m), 3.70-3.68 (2H, d) ,. 3.16-3.01 (3H, m), 2.41-2.18 (3H, m), 1.90-1.58 (5H, m), 1.40-1.28 (2H, m), 1.01-0.90 (6H, 2x t).

Example 7 Acid [lS- (la, 3a, 4ß)] -3- [7- (hexylamino) -5- (propylthio) 3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] - -hydroxy-cyclopentanecarboxylic acid a) Methyl ester of [ÍS- (la, 3a, ß)] -3- [[5-amino-6-chloro-2- (propyl io) -pyrimidxn-4-yl] amino] -4-hydroxy-cyclopentanecarboxylic acid A solution of methyl ester hydrochloride [lS- (la, 3a, 4ß)] - 3-amino-4-hydroxycyclopentane-carboxylic acid (Prepared as described by S. Roberts et al., J. Chem. Soc. Perkin Trans. 1, 1992, 1021) (1.90 g), 4,6-dichloro-5-nitro-2-propylthiopyrimidine (prepared as described in WO 9703084) (5.23 g) and triethylamine (6.6 ml) in n-butanol (95 ml) is heated to reflux for 3 hours. The mixture is concentrated and purified (Si02, diethylether: isohexane 1: 3 as eluent) to yield the subtitle compound (3.36 g). MS (APCI) 389 (M-H +, 100%) b) Methyl ester of [ÍS- (la, 3a, 4ß)] -3- [7-chloro-2- (propl io) -3H-1,2,3-triazol [, 5-d] pyrimidin-3 -yl] -4-hydroxy-cyclopencarboxylic acid It is added to a solution of the product of step (a) (2.90 g) in glacial acetic acid (100 ml) iron powder (2.1 g). After 2 hours the mixture is neutralized with saturated aqueous sodium bicarbonate and extracted with dichloromethane, then concentrated. The intermediate is dissolved in acetonitrile (150 ml) and isoamylnitrite (1.20 ml) is added. The solution is heated at 60 ° C for 1 hour, then it is evaporated to give the subtitled compound without purification (2.82 g).

MS (APCI) 429 (M + H +) c) Methyl ester of [ÍS- (la, 3a, 4ß)] -3- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine- 3-yl] -4-hydroxy-cyclopentanecarboxylic acid A solution of the product from step (b) (1.3 g) and n-hexylamine (0.43 ml) in 1,4-dioxane (20 ml) is stirred at room temperature for 20 minutes. hours and evaporated to give the subtitle compound (0.90 g). MS (APCI) 435 (M-H +, 100%) d) Acid [ÍS- (la, 3a, 4ß)] -3- [7- (hexylamino) -5- (propyl thio) -3H-1, 2,3-triazole [4,5-d] pyrimidxn-3 -yl] -4-hydroxy-cyclopentanecarboxylic acid A solution of the product of step (c) (0.88 g) in methanol (5 ml) is added to a solution of lithium hydroxide monohydrate (0.18 g) in water (20 m). The mixture is stirred at room temperature by 3 hours and concentrates. Purification occurs (CLAP, Novapak® C18 column, trifluoroacetic acid: aqueous 0.1% methanol, gradient elution 70:30 at 20:80 for 20 minutes) of the title compound (0.16 g). MS (APCI) 423 (M + H +, 100%) NMR (de-DMSO) 8.99 (1H, t), 5.31 (1H, m), 4. 89-4.80 (1H, m), 4.59-4.52 (1H, m), 3.49-3.44 (2H, m), 3.14-3.00 (2H, m), 2.44-2.41 (2H, m), 2.33-2.24 (1H,), 1.94-1.84 (1H, m), 1.76-1.55 (4H, m), 1.29 (6H, m), 1.06 (3H, t), 0.86 (3H, t).

Example 8 Acid [lS- (la, 2ß, 4a)] -3- [7- (butylamino) -5- (propylthio) 3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] -2-hydroxy-cyclopentanecarboxylic acid a) [6aR- (6aa, 8β, 9a, 9aβ)] -8- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazole [4,5-d] pyrimidine-3 -yl] -hexahydro-2,2,4,4-tetrakis (1 -melethyl) -cyclopenta [f] -l, 3,5,2,4-trioxadisilocin-9-ol A mixture of the product of the example is stirred 1 stage (a) (0.3 g), imidazole (0.20 g) and 1,3-dichloro-1,1 ', 3,3' -tetraisopropyldisiloxane (0.26 ml) in N, N-dimethylformamide (5 ml) at room temperature for 2 hours, concentrate and purify (SiO2, ethyl acetate: dichloromethane 5:95 as eluent) to yield the subtitle compound (0.21 g). MS (APCI) 639 (M + H +) b) O- [8- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazole- [4,5-d] pyrimidine-3 -yl] -hexahydro-2, 2,4, 4-tetrakis (1-methylethyl) -syclopenta [f] -l, 3,5,2,4-trioxadisilocin-9-yl] ester of the acid [6aR- (6aa , 8ß, 9a, 9aß)] -lH-imidazole-1-carbonothioic acid It is added to a solution of the product of step (a) (3.1 g) in N, N-dimethylformamide 1,1'-thiocarbonyldiimidazole (0.95 g). The reaction mixture is heated at 80 ° C for 6 hours, concentrated and purified (SiO 2, ethyl acetate: dichloromethane 2: 8 as eluent) to yield the subtitle compound (3.4 g). MS (APCI) 749 (M + H +, 100%) c) [ÍS- (la, 2ß, 4a)] -4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazole- [4,5-d] pyrimidin-3- il] -2-hydroxy-cyclopentanemethane.1 To a solution of the product from step (b) (3.0 g) in toluene (60 ml), AIBN (50 mg) and tributyltin hydride (6.3 ml) are added. The reaction mixture is heated at 80 ° C for 1 hour, concentrated and purified (SiO2, ethyl acetate: dichloromethane 5:95 as eluent). The intermediate is dissolved in tetrahydrofuran (50 ml) and treated with tetrabutylammonium fluride (1.0M solution in tetrahydrofuran, 3 ml). After 2 hours the solution is concentrated and purified (Si02, methanol: dichloromethane 1: 9 as eluent) to yield the subtitle compound (0.98 g). MS (FAB) 381 (M + H +) d) [IR- (la, 2ß, 4ß)] -2- [[[Bis (4-methoxy phenyl) phenylmethyl] oxy] -methyl] -4- [7- (butylamino) -5- (propylthio) -3H -1, 2,3-triazole- [, 5-d] pyrimidin-3-yl] -cyclo open tan-1 -ol It is prepared according to the method of example 1 step (e) using the product from step (c) ). MS (FAB) 683 (M + H +) e) 3- [[IR- (la, 3a, 4ß)] -3- [[[Bis (4-methoxy-enyl) f -methylmethyl] -oxy] methyl] -4- [[(1,1-dimethyl)] dimethylsilyl] oxy] -cyclopent-1-yl] -N-butyl-5- (propylthio) -3H-1,2,3-triazole- [4,5-d] pyrimidin-7 -amine It is prepared according to the method of example 1 step (f) using the product of step (d). MS (FAB) 797 (M + H +), 303 (100%). f) [ÍS- (la, 2ß, 4a)] -4- [7- (Butylamino) -5- (propylthio) -3H-1,2,3-triazole- [4,5-d] pyrimidin-3- il] -2- [[(1,1-dimethylethyl) dimethylsilyl] oxy] -sicl open tanme anol It is prepared according to the method of example 1 step (g) using the product from step (e). MS (APCI) 495 (M + H +) g) 1,1-dimethylester of [ÍS- (la, 2ß, 4a)] -4- [7- (b-thylamino) -5- (propylthio) -3H-1, 2, 3-tri-zol- [4] , 5-d] pyrimidin-3-yl] -2- [[(1,1-dimethylethyl) dimethylsilyl] -oxy] -cyclopentanecarboxylic acid. Chromium (VI) oxide (0.58 g) is added to a pyridine solution (0.92 ml). ) in dichloromethane / N, -dimethylformamide 4: 1 (30 ml) and the mixture is stirred for 15 minutes. The product of step (f) (0.07 g) is added to this solution followed by acetic anhydride (0.92 ml) and tert-butanol (10.5 ml). The reaction mixture is stirred for 48 hours and emptied into water. The product is extracted with dichloromethane and purified (Si02, methanol: dichloromethane 1: 9 as eluent) to yield the subtitle compound (0.45 g). MS (APCI) 565 (M + H +) h) Acid [IS- (la, 2ß, 4a)] -4- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole - [4,5-d] pyrimidine-3 -yl] -2-hydroxy-cyclopentanecarboxylic A solution of the product from step (g) (0.44 g) in dichloromethane / trifluoroacetic acid 1: 1 (50 ml) is stirred at room temperature for 4 hours, dried and purified (CLAP). , Novapak® C18 column, ammonium acetate: 0.1% aqueous methanol, gradient elution 70:30 to 0: 100 for 20 minutes) to give the title compound (0.12 g). MS (APCI) 395 (M + H +) NMR (dß-DMSO) 9.87 (1H, t), 5.29 (2H, m), 4.54 (1H, m), 3.49 (2H, m), 3.13 (2H, m). , 2.76 (1H, m), 2.56 (1H, m), 2.38 (2H, m), 2.16 (1H, m), 1.70 (2H, m), 1.66 (2H, m), 1.56 (2H, m), 0.97 (3H, t), 0.89 (3H, t).

Pharmacological data The preparation for the assay of agonist / antagonist activity of the P27 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 Calcium Free Tyrode solution, modified (10 ml) (CTF), composition: 137 mM NaCl, 11.9 mM NaHCO3, 0.4 mM NaH P0, 2.7 mM KC1, 1.1 mM MgCl2. , dextrose 5.6 mM, gas is added with 95% 02/5% C02 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 syringe of 60 ml 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, aliquots of 3 ml of platelet suspension are added to tubes containing CaCl solution (60 μl of 50 mM solution with a final concentration of 1 mM). The human fibrinogen (Sigma, F 4883) and 8-sul phenophenylteophylline (8-SPT used to block any Pi agonist activity of compounds) are added to give final concentrations of 0.2 mg / ml (60 μl of 10 mg / ml solution of agglomerable protein in saline solution) and 300 nM (10 μl of 15 mM solution in 6% glucose), respectively. Platelets or buffer as appropriate are added in a 150 μl volume 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 or ADP (30 mM; 10 μl of 450 mM) is then added 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 above, 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, OR6, NR7R8, SR9 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, OR6, NR7R8, SR9, 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, OR6, NR7R8, SR9, 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) R6, OR6, SR9, NR10Rn, 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 hydrogen and the other is hydroxy; X is OH or NHR5; R5 is an alkyl group of 1 to 6 carbon atoms substituted by COOH or C (0) NR7R8 and optionally by one or more additional substituents selected from halogen, OR12, C (NH) NR13R14, C (O) NR15R16, phenyl (optionally substituted by one or more groups selected from halogen, N02, C (0) R6, OR6, NR7R8, SR9 and alkyl of 1 to 6 carbon atoms) or alkyl of 1 to 6 carbon atoms (optionally substituted by one or more groups hydroxy or phenyl); or R5 is a lactam ring of the formula (i): where Q is a portion of (CH2) m where m is 1, 2 or 3, Z is O, C (O) or CH2 and R18 is hydrogen or alkyl of 1 to 6 carbon atoms; R6, R9, R12, R13, R14, R15 and R16 are independently hydrogen or alkyl of 1 to 6 carbon atoms; R7 and R8 are independently hydrogen, alkyl of 1 to 6 carbon atoms (optionally substituted by one or more phenyl groups) or phenyl groups; and R 10 and R 11 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 6 carbon atoms or phenyl substituted by alkyl of 1 to 6 carbon atoms which is substituted by one or more fluorine atoms.

4. A compound according to any of claims 1 to 3, characterized in that R2 is alkyl of 1 to 8 carbon atoms ..

5. A compound according to any of claims 1 to 4, characterized in that R3 is hydroxy and R4 is hydrogen.

6. A compound according to any of claims 1 to 5, characterized in that X is OH or NHR5 where R5 is alkyl of 1 to 6 carbon atoms substituted by COOH and optionally further substituted by alkyl of 1 to 6 carbon atom substituted by OH .

7. A compound according to claim 1, characterized in that it is: [lS- (la, 3a, 4ß)] - 3- [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazole acid [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid, [lS- (la, 3a, 4ß)] - 3- [7- (butylamino) -5- [[4- (trifluoromethyl)] ) phenyl] thio] -3H-1, 2, 3-triazol [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid, N- [lS, 3R, 4S) -3- [7 - (Butylamino) -5- [[4- (tri fluoromethyl) -phenyl] thio] -3H-l, 2,3-triazolo [4,5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentylcarbonyl] -L-serine, N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- [[4- (trifluoromethyl) -phenyl] thio] -3H-1, 2, 3-triazole [4 , 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentylcarbonyl] -glycine, Acid [SS- [la, 3β, 4a (SS *, 2R *)]] -3-hydroxy-4- [7- [(2-phenylcyclopropyl) amino] -5- (propylthio) -3H-1, 2 , 3-triazol [4, 5-d] pyrimidin-3-yl] -cyclopentanecarboxylic acid, N- [lS, 3R, 4S) -3- [7- (Butylamino) -5- (propylthio) -3H-1, 2 , 3-triazol [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentyl-carbonyl] -glycine, Acid [ÍS- (la, 3a, 4ß)] -3- [7- (hexylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -4-hydroxy-cyclopentanecarboxylic acid, acid [IS- (la, 2ß, 4a)] -3 - [7- (butylamino) -5- (propylthio) -3H-1,2,3-triazolo [4, 5-d] pyrimidin-3-yl] -2-hydroxy-cyclopentanecarboxylic acid, and pharmaceutically acceptable salts 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 the treatment of angina.

11. A method for treating a disease in platelet aggregation, characterized in that it comprises administering to a patient suffering from such disorder, a therapeutically effective amount according to any of claims 1 to 7.

12. A process for the preparation of a compound of the formula (I), characterized in that it comprises oxidizing a compound of the formula (II): wherein R1, R2, R3 and R4 are as defined in formula (I) or are protected derivatives thereof, and optionally thereafter in any order: • converting a compound of formula (I) into an additional compound of the formula (I) • removing any protecting groups • forming a pharmaceutically acceptable salt or solvate.