FIELD OF THE INVENTION 0001 The present invention provides new triazolo4,5-dpyrimidine compounds, their use as medicaments, compositions containing them and processes for their preparation.

BACKGROUND OF THE INVENTION 0002 Platelet adhesion and aggregation are initiating events in arterial thrombosis. Although the process of platelet adhesion to the sub-endothelial surface may have an important role to play in the repair of damaged vessel walls, the platelet aggregation that this initiates can precipitate acute thrombotic occlusion of vital vascular beds, leading to events with high morbidity such as myocardial infarction and unstable angina. The success of interventions used to prevent or alleviate these conditions, such as thrombolysis and angioplasty is also compromised by platelet mediated occlusion or re-occlusion. 0003 A number of converging pathways lead to platelet aggregation. Whatever the initial stimulus, the final common event is a cross-linking of platelets by binding of fibrinogen to a membrane-binding site, glycoprotein Ub/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 may also explain the bleeding problems that have been observed with this class of agent. Thrombin can produce platelet aggregation largely independently of other pathways but substantial quantities of thrombin are unlikely to be present without prior activation of platelets by other mechanisms. Thrombin inhibitors such as hirudin are highly effective anti-thrombotic agents, but again may produce excessive bleeding because they function as both anti-platelet and anti-coagulant agents (The TIMI 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators (1994) Circulation 90, pp. 1631-1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642). 0004 It has been found that adenosine 5-diphosphate (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 a-gregation in the presence of ADP. The limited anti-thrombotic efficacy of aspirin may reflect the fact that it blocks only one source of ADP which is that released in a thromboxane-dependent manner following platelet adhesion (see e.g. Antiplatelet Trialists' Collaboration (1994), Br. Mecl. J. 308, pp. 81-106 and Antiplatelet Trialists' Collaboration (1994), Br. Med. J. 308, pp. 159-168). Aspirin has no effect on aggregation produced by other sources of ADP, such as damaged cells or ADP released under conditions of turbulent blood flow. 0005 ADP-induced platelet aggregation is mediated by the P2T receptor subtype located on the platelet membrane. The P2T receptor (also known as P2YADP or P2TAC) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloned. The pharmacological characteristics of this receptor have been described, for example, in the references by Humphries et al., Br. J. Pharmacology (1994), 113, 1057-1063, and Fagura et al., Br. J. Pharmacology (1998) 124, 157-164. Recently it has been shown that antagonists at this receptor offer significant improvements over other anti-thrombotic agents (see J. Med. Chem. (1999) 42, 213). Accordingly there is a need to find further P2T (P2YADP or P2TAC) antagonists as anti-thrombotic agents. 0006 International Patent Application WO 9905143 discloses generically a series of triazolo4,5-dpyrimidine compounds having activity as P2T (P2YADP or P2TAC) antagonists. It has now been found that certain compounds within the scope of International Patent Application WO 9905143 but not specifically disclosed therein exhibit high potency combined with surprisingly high metabolic stability and bioavailibility, such that the predicted therapeutic dose for prolonged inhibition of aggregation in man shows advantage.

DESCRIPTION OF THE INVENTION 0007 In a first aspect the invention therefore provides a compound of formula (I): 1

0008 wherein: 0009 R1 is C3-5 alkyl optionally substituted by one or more halogen atoms; 0010 R2 is a phenyl group, optionally substituted by one or more fluorine atoms; 0011 R3 and R4 are both hydroxy; 0012 R is XOH, where X is CH2, OCH2CH2 or a bond; 0013 or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt. 0014 provided that: 0015 when X is CH2 or a bond, R1 is not propyl. 0016 when X is CH2 and R1 is CH2CH2CF3, butyl or pentyl, the phenyl group at R2 must be substituted by fluorine. 0017 when X is OCH2CH2 and R1 is propyl, the phenyl group at R2 must be substituted by fluorine. 0018 Alkyl groups, whether alone or as part of another group are straight chained and fully saturated. 0019 Suitably R1 is a C3-5 alkyl optionally substituted by one or more fluorine atoms. Preferably R1 is C3-5 alkyl optionally substituted on the terminal carbon by three fluorine atoms. More preferably R1 is 3,3,3,-trifluoropropyl, butyl or propyl. 0020 Suitably R2 is phenyl or phenyl substituted by one or more fluorine atoms. Preferably R2 is phenyl, 4-fluorophenyl or 3,4-difluorophenyl. 0021 Suitably R is XOH where X is CH2, OCH2CH2 or a bond. 0022 Preferably R is CH2OH or OCH2CH2OH. 0023 Particularly preferred compounds include: 0024 1R-1,2,3(1R*,2S*),5-3-7-2-(4-Fluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol; 0025 1R-1,2,3(1R*,2S*),5-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol; 0026 1S-(1,2,3(1S*,2R*),5-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; 0027 1R-1,2,3(1R*,2*),5-3-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol; 0028 1S-1,2,3,4(1S*,2R*)-4-5-(Butylthio)-7-2-(4-fluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-cyclopentane-1,2,3-triol; 0029 1S-(1,2,3(1S*,2R*),5-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol; 0030 1S-1,235(1S*,2R*)-3-(2-Hydroxyethoxy)-5-7-(2-phenylcyclopropyl)amino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-cyclopentane-1,2-diol 0031 1S-1,2,3,4(1S*,2R*)-4-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-ylcyclopentane-1,2,3-triol; 0032 1S-1,2,3(1S*,2R*),5-3-5-(Butylthio)-7-(2-phenylcyclopropyl)amino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(2-hydroxethoxy)-cyclopentane-1,2-diol; 0033 and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts. 0034 According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises: 0035 (a) reacting a compound of formula (II): 2

0036 where R, R1, R3 and R4 are as defined in formula (I), or are protected derivatives thereof, or R3 and R4 together form a bond in the 5-membered ring, or R is CH2CH2OR, where R is C1-6 alkyl or benzyl, and L is a leaving group such as halogen or SR, with a compound of formula (I): 3

0037 where R2 is as defined in formula (I), or is a protected derivative thereof, 0038 or where X is a bond: 0039 (b) hydroxylation of a compound of formula (IV): 4

0040 where R1 is defined in formula (I) and R8 is H or CH2CH2OP3 where P3 is H or a protecting group or R8 is CH2COOR where R is C1-6 alkyl or benzyl, and Z is NH2 or 5

0041 where R2 is defined in formula (I). 0042 and for both (a) and (b) optionally thereafter and in any order: 0043 converting one or more functional groups into further functional groups; 0044 removing any protecting groups; 0045 forming a pharmaceutically acceptable salt or solvate, or a solvate of such a salt. 0046 Compounds of formula (II) can be reacted with amines of formula (III) in the presence of a base, such as a tertiary organic amine, in an inert solvent, such as dichloromethane, at ambient or elevated temperature. Other suitable bases include inorganic bases such as potassium carbonate. 0047 The hydroxy groups R3 and R4 can be protected as groups OP1 and OP2 where P1 and P2 are protecting groups. Examples of suitable protecting groups in compounds of formula (II) are C1-6 alkyl (preferably methyl), benzyl, (C1-6alkyl)3Si (preferably t-butyldimethylsilyl), and a C(O)C1-6alkyl group such as acetyl. Preferably the two groups P1 and P2 together with the atoms to which they are attached form an alkylidene ring such as a methylidene or isopropylidene ring. Alternatively P1 and P2 can form an alkoxymethylidene ring such as ethoxymethylidene. 0048 Protecting 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 J W F McOmie, Plenum Press (1973), and Protective Groups in Organic Synthesis, 2nd edition, T W Greene & P G M Wutz, Wiley-Interscience (1991). 0049 Ester protecting groups can be removed by basic hydrolysis, for example by 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 from 10 to 100 C., preferably the temperature is around room temperature, or by acidic 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. Trialkylsilyl protecting groups can be removed by the use of, for example, a fluoride ion source, for example tetra-n-butylammonium fluoride or hydrogen fluoride. When one or both of P1 and P2 are C1-6 alkyl, deprotection can be achieved using boron tribromide. Benzyl groups can be removed by hydrogenolysis using a transition metal catalyst, for example palladium on charcoal, under an atmosphere of hydrogen, at a pressure of from 1 to 5 bar, in a solvent, such as acetic acid. 0050 A compound of formula (II) can be prepared by diazotising a compound of formula (V): 6

0051 wherein R1 is as defined in formula (I), and R is as defined in formula (I), or is a protected derivative thereof, or is OCH2CO2R, where R is C1-6 alkyl or benzyl, and L is as defined above and R3 and R4 are as defined in formula (I) or are protected derivatives thereof or R3 and R4 together form a bond in the 5-membered ring, 0052 with a metal nitrite, for example an alkali metal nitrite, especially sodium nitrite in dilute aqueous acid, for example 2M HCl, or with a C1-6-alkyl nitrite, in an inert solvent, at a temperature of from about 20 to about 100 C. Preferred conditions are isoamyl nitrite in acetonitrile at about 80 C. 0053 A compound of formula (V) wherein R is CH2OH, R3 and R4 are hydroxyl or protected derivatives thereof and L is as defined above, can be prepared by reducing a compound of formula (VI): 7

0054 wherein R1, L, P1 and P2 are as defined above. 0055 The reduction of the nitro group can be carried out for example by using hydrogenation with a transition metal catalyst at a temperature around room temperature, for example palladium on charcoal under an atmosphere of hydrogen, preferably at a pressure from 1 to 5 atmospheres, in a solvent, for example ethanol, or by using iron in an acidic solvent such as acetic acid at a temperature of about 100 C. 0056 Reduction of the lactam can be carried out using complex metal hydrides such as lithium aluminium hydride in a solvent such as ether or preferably, by using sodium borohydride in a suitable solvent such as methanol. 0057 A compound of formula (VI) can be prepared by reacting a compound of formula (VII): 8

0058 wherein L and R1 are as defined above and L1 is a leaving group, for example a halogen atom, wherein L and L1 are preferably the same, with a compound of formula (VIII): 9

0059 wherein P1 and P2 are as defined above, in the presence of a base such as C1-6-alkyl-M or MH wherein M is a metal ion, for example n-butyl lithium, in an inert solvent, such as tetrahydrofuran, at a temperature of from about 10 to about 100 C. Preferably sodium hydride is used in tetrahydrofuran at room temperature. 0060 One or more functional groups can be converted into further functional groups using standard chemistry. A compound where X is a bond can be converted to a compound where X is O(CH2)2 by treatment with base followed by LY where L is a leaving group and Y is (CH2)2OH or a protected version thereof or Y is CH2COOR where R is C1-6 alkyl or benzyl. A compound where R is CH2CH2OR may be converted into a compound where R is O(CH2)2OH by reduction, for example using DIBAL-H. The group SR1 can be interconverted by oxidation of the sulfur, for example using oxone or mCBPA, followed by treatment with a compound R1-SM where R1 is a different R1 group and M is a metal such as sodium. Alternatively the product of the sulfur oxidation may be treated with MSH where M is a metal such as sodium, followed by treatment with a base and R1X where R1 is a different R1 group and X is a leaving group. Suitable bases include N,N-diisopropylethylamine. 0061 A compound of formula (II) where R, R1, R3, and R-are as defined in formula (I) or are protected derivatives thereof, or R3 and R4 together form a bond in the 5-membered ring or R is OCH2CO2R where R is C1-6 alkyl or benzyl, and L is a leaving group such as halogen, may be converted into a compound of formula (II) where R, R1, R3, and R4 are defined above and L is NH2 by treatment with a diazotizing agent in the presence of a halogenating agent, preferably isoamyl-nitrite and carbon tetrabromide. 0062 A compound of formula (II) where R, R1, R3, and R4 are defined above and L is NH2 may be prepared by treating a compound of formula (II) where R, R1, R3, and R4 are as defined above and L is a leaving group such as halogen, with ammonia in a solvent such as methanol. 0063 Compounds of formula (V) can also be prepared by treating a compound of formula (XI) R _ONH 2 10

0064 where R, R3 and R4 are as defined in formula (I) or are protected derivatives thereof or R is OCH2CO2R where R is C1-6 alkyl or benzyl, or R3 and R4 together form a bond in the 5-membered ring, 0065 with a compound of formula (VII) as defined above, followed by reduction of the nitro group. The reaction is carried out in an inert solvent such as dichloromethane or 1,4-dioxane, in the presence of a non-nucleophilic base, such as N,N-diisopropylamine, at a tempeature of about 20 C. to about 150 C., preferably at ambient temperature. 0066 Compounds of formula (II) where R is as defined in formula (I), R3 and R4 together form a bond in the 5-membered ring, and L is SR1, or a protected derivative thereof, can be prepared by reacting a compound of formula (XII): 11

0067 where R1 groups are as defined in formula (I), 0068 with a compound of formula (XIII): 12

0069 in which R7 is H or a protected derivative thereof. The reaction can be carried out in the presence of a suitable transition metal complex, preferably tetrakistriphenylphosphine palladium(0). 0070 Compounds of formula (XII) can be prepared from compounds of formula (XIV): 13

0071 by reacting with a compound R1X where R1 is as defined in formula (I) and X is a leaving group such as halo, followed by cyclisation. 0072 Compounds of formula (XI) where R is OH or a protected version thereof and R3 and R4 are as defined in formula (I) or are protected derivatives thereof may be prepared from compounds of formula (XIII) where R7 is H or a protecting group by treatment with a bisester of imidodicarbamic acid using palladium catalysis followed by hydroxylation of the double bond, and optionally, deprotection of the nitrogen. Preferably imidodicarbonic acid, bis-(1,1-dimethylethyl)ester and tetrakistriphenylphosphine palladium(0) are used followed by osmium tetroxide and deprotection using hydrochloric acid in methanol. 0073 Compounds of formula (XI), where R is OCH2CO2R where R is C1-6 alkyl and R3 and R4 together form a bond in the 5-membered ring, may be formed from compounds of formula (XIII), where R7 is H or a protecting group, by treatment with an azide in the presence of a palladium catalyst, followed by reduction of the azide and alkylation of the alcohol as described previously. 0074 Compounds of formula (XI) where R is OCH2CH2OH and R3 and R4 are as defined in formula (I) or are protected derivatives thereof may be prepared from compounds of formula (XI) where R is OH and R3 and R4 are as defined in formula (I) or are protected derivatives thereof, by protection of the nitrogen, alkylation of the alcohol using a 2-halo-acetic acid ester, followed by reduction of the ester and deprotection of the nitrogen. We prefer protection of the nitrogen as a carbobenzyloxy derivative using benzyl chloroformate followed by alkylation of the alcohol using ethyl bromoacetate and potassium t-butoxide, reduction of the ester using lithium borohydride in tetrahydrofuran and deprotection of the nitrogen by hydrogenation in the presence of palladium on carbon. In addition we prefer the case where the alcohols R3 and R4 are protected as an isopropylidene ring. 0075 The amines of formula (m) can be prepared using procedures described in H Nishiyama et al, Bull. Chem. Soc., Jpn., 1995, 68, 1247, P. Newman, Optical Resolution Procedures for Chemical Compounds, Vol. 1. Amines and Related Compounds; Optical Resolution and Information Centre: Manhattan College, Riverdale, N.Y., 1978, p 120, J. Vallgarda et al, J. Chem. Soc. Perkin 1, 1994, 461 or in International Patent Application WO 9905143. 0076 All novel intermediates form a further aspect of the invention. 0077 Salts of the compounds of formula (I) may 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 C1-6-alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a to hydrohalic (especially HCl), sulphuric, oxalic or phosphoric acid). The reaction may be carried out in a solvent or medium in which the salt is insoluble or in a solvent in which the salt is soluble, e.g. water, ethanol, tetrahydrofuran or diethyl ether, which may be removed in vacuo, or by freeze drying. The reaction may also be a metathetical process or it may be carried out on an ion exchange resin. The non-toxic physiologically acceptable salts are preferred, although other salts may be useful, e.g. in isolating or purifying the product. 0078 The compounds of the invention act as P2T (P2YADP or P2TAC) receptor antagonists. Accordingly, the compounds are useful in therapy, including combination therapy, particularly they 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, primary arterial thrombotic complications of atherosclerosis such as thrombotic or embolic stroke, transient ischaemic attacks, peripheral vascular disease, myocardial infarction with or without thrombolysis, arterial complications due to interventions in atherosclerotic disease such as angioplasty, including coronary angioplasty (PTCA), endarterectomy, stent placement, coronary and other vascular graft surgery, thrombotic complications of surgical or mechanical damage such as tissue salvage following accidental or surgical trauma, reconstructive surgery including skin and muscle flaps, conditions with a diffuse thrombotic/platelet consumption component such as disseminated intravascular coagulation, thrombotic thrombocytopaenic purpura, haemolytic uraemic syndrome, thrombotic complications of septicaemia, adult respiratory distress syndrome, anti-phospholipid syndrome, heparin-induced thrombocytopaenia and pre-eclampsia/eclampsia, or venous thrombosis such as deep vein thrombosis, venoocclusive disease, haematological conditions such as myeloproliferative disease, including thrombocythaemia, sickle cell disease; or in the prevention of mechanically-induced platelet activation in vivo, such as cardiopulmonary bypass and extracorporeal membrane oxygenation (prevention of microthromboembolism), mechanically-induced platelet activation in vitro, such as use in the preservation of blood products, e.g. platelet concentrates, or shunt 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, conditions in which platelets can contribute to the underlying inflammatory disease process in the vascular wall such as atheromatous plaque formation/progression, stenosis/restenosis and in other inflammatory conditions such as asthma, in which platelets and platelet-derived factors are implicated in the immunological disease process. Further indications include treatment of CNS disorders and prevention of the growth and spread of tumours. 0079 According to the invention there is further provided the use of a compound according to the invention as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of the above disorders. In particular the compounds of the invention are useful for treating myocardial infarction, thrombotic stroke, transient ischaemic attacks, peripheral vascular disease and stable and unstable angina, especially unstable angina. The invention also provides a method of treatment or prevention of the above disorders which comprises administering to a person suffering from or susceptible to such a disorder a therapeutically effective amount of a compound according to the invention. 0080 The compounds may be administered topically, e.g. to the lung and/or the airways, in the form of solutions, suspensions, HFA aerosols and dry powder formulations; or systemically, e.g. 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. 0081 The compounds of the invention may be administered on their own or as a pharmaceutical composition comprising the compound of the invention in combination with a pharmaceutically acceptable diluent, adjuvant and/or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction. 0082 Dry powder formulations and pressurised HFA aerosols of the compounds of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The compounds of the invention may also be administered by means of a dry powder inhaler. The inhaler may be a single or a multi dose inhaler, and may be a breath actuated dry powder inhaler. 0083 One possibility is to mix the finely divided compound with a carrier substance, e.g. a mono-, di- or polysaccharide, a sugar alcohol or another polyol. Suitable carriers include sugars and starch. Alternatively the finely divided compound may be coated by another substance. The powder mixture may also be dispensed into hard gelatine capsules, each containing the desired dose of the active compound. 0084 Another possibility is to process the finelv divided powder into spheres which break up during the inhalation procedure. This spheronized powder may be filled into the drug reservoir of a multidose inhaler, e.g. that known as the Turbuhaler in which a dosing unit meters the desired dose which is then inhaled by the patient. With this system the active compound with or without a carrier substance is delivered to the patient. 0085 The pharmaceutical composition comprising the compound of the invention may conveniently be tablets, pills, capsules, syrups, powders or granules for oral administration; sterile parenteral or subcutaneous solutions, suspensions for parenteral administration or suppositories for rectal administration. 0086 For oral administration the active compound may be admixed with an adjuvant or a carrier, e.g. lactose, saccharose, sorbitol, mannitol, starches such as potato starch, corn starch or amylopectin, cellulose derivatives, a binder such as gelatine or polyvinylpyrrolidone, and a lubricant such as magnesium stearate, calcium stearate, polyethylene glycol, waxes, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain e.g. gum arabic, gelatine, talcum, titanium dioxide, and the like. Alternatively, the tablet may be coated with a suitable polymer dissolved either in a readily volatile organic solvent or an aqueous solvent. 0087 For the preparation of soft gelatine capsules, the compound may be admixed with e.g. a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above mentioned excipients for tablets, e.g. lactose, saccharose, sorbitol, mannitol, starches, cellulose derivatives or gelatine. Also liquid or semisolid formulations of the drug may be filled into hard gelatine capsules. 0088 Liquid preparations for oral application may be in the form of syrups or suspensions, for example solutions containing the compound, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavourin-agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

EXAMPLES 0089 The invention is illustrated by the following non-limiting examples. 0090 In the examples the NMR spectra were measured on a Varian Unity Inova 300 or 400 spectrometer and the MuS spectra were measured as follows: EI spectra were obtained on a VG 70-250S or Finnigan Mat Incos-XL spectrometer, FAB spectra were obtained on a VG70-250SEQ spectrometer, ESI and APCI spectra were obtained on Finnigan Mat SSQ7000 or a Micromass Platform spectrometer. Preparative HPLC separations were generally performed using a Novapak, Bondapak or Hypersil column packed with BDSC-18 reverse phase silica. Flash chromatography (indicated in the Examples as (SiO2)) was carried out using Fisher Matrix silica, 35-70 m. For examples which showed the presence of rotamers in the proton NMR spectra only the chemical shifts of the major rotamer are quoted.

Example 1 0091 1R-1,2,3(1R*,2S*),5-3-7-2-(4-Fluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0092 a) 3aS-1(E),3a,6,7a-1-3-(4-Fluorophenyl)-1-oxo-2-propenyl-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide 0093 A mixture of 3-(4-fluorophenyl)-2-propenoic acid (3.0 g) and thionyl chloride (5.0 ml) was stirred at 70 C. for 1 hour, the reaction mixture was then concentrated under reduced pressure. The residue was azeotroped twice with dichloromethane then dissolved in toluene (10 ml). To a suspension of sodium hydride (60% dispersion in oil; 0.99 g) in toluene (40 ml) was added a solution of 3aS-(3a,6,7a)-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide (3.89 g) in toluene (40 ml) and the mixture stirred for 30 minutes. To the reaction mixture was then added the solution described above and the resulting suspension was stirred for 16 hours. Water (200 ml) was added, the organics collected and the aqueous extracted into dichloromethane (3100 ml). The organics were combined, dried and concentrated. Recrystallisation (ethanol) gave the subtitle compound as colourless needles (5.92 g). 0094 MS (APCI) 364 (MH,100%) 0095 b) 3aS-1(1S*,2S*),3a,6,7a-1-2-(4-Fluorophenyl)cyclopropylcarbonyl-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide 0096 A solution of diazomethane (2.9 g) in ether (150 ml) (prepared as described in Vogel's Textbook of Practical Organic Chemistry, Fifth Edition, Longman Scientific and Technical, p432) was added to a solution of the product of step a) (5.90 g) and palladium(II) acetate (18 mg) in dichloromethane (350 ml) at 0 C. and the reaction mixture stirred at 0 C. for 5 hours. Acetic acid (5 ml) was added and the reaction mixture was then washed with saturated sodium bicarbonate solution (200 ml) and the organics filtered through a plug of silica. After concentrating in vacuo, the residue was recrystallised (ethanol) to give the subtitle compound as colourless needles (3.81 g). 0097 MS (APCI) 378 (MH,100%) 0098 c) (1R-trans)-2-(4-Fluorophenyl)-cyclopropanecarboxylic Acid 0099 A suspension of the product from step b) (3.74 g) and lithium hydroxide monohydrate (4.11 g) in tetrahydrofuran (100 ml)/water (3 ml) was stirred at 50 C. for 24 hours. The reaction mixture was concentrated in vacuo, and the residue dissolved in water (100 ml), acidified with 2N HCl and extracted into dichloromethane (375 ml). The organics were dried and concentrated. Purification (SiO2, isohexane:diethylether 2:1 as eluant) gave the subtitle compound as a colourless solid (1.78 g). 0100 MS (APCI) 179 (MH,100%) 0101 d) (1R-trans)-2-(4-Fluorophenyl)cyclopropanamine, R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) 0102 To a solution of the product from step c) (1.78 g) and triethylamine (2.7 ml) in acetone/water (10:1, 23 ml) at 0 C. was added ethyl chloroformate (2.0 ml) over 5 min. The solution was maintained at 0 C. for 30 minutes before addition of sodium azide (1.52 g) in water (6 ml). After a further hour, water (350 ml) was added and the reaction mixture extracted with toluene (3100 ml). The organic extracts were combined and dried, then heated at reflux for 2 hours behind a blast screen. After cooling the solution, 6N HCl (50 ml) was added and the mixture heated at reflux for 3 hours. Water (150 ml) was added and the aqueous phase basified with 2N NaOH (aq), then extracted into dichloromethane (3100 ml). The organic phase was dried and concentrated. The amine was dissolved in ethanol (5 ml) and a solution of L-tartaric acid (1.48 g) in ethanol (20 ml) was added. After 20 minutes the solid was collected affording the subtitle compound as colourless needles (1.12 g). 0103 NNIR H (d6-DMSO) 1.07-1.39 (1H, m), 1.22-1.29 (1H, m), 2.16-2.23 (1H, m), 2.64-2.70 (1H, m), 3.95 (2H, s), 7.06-7.19 (4H, m) 0104 e) 3aR-3a,4,6(1R*,2*),6a-6-7-2-(4-Fluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0105 N,N-Diisopropylethylamine (1.29 g) was added to a solution of 3aR-(3a,4,6,6a)-6-7-chloro-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (1.0 g) and the product of step d) (0.75 g) in dichloromethane (25 ml). The reaction mixture was stirred at room temperature for 3 hours, then washed with water, dried and evaporated. The residue was purified (SiO2, ethyl acetate:isohexane 1:1 as eluent) to afford the subtitle compound (1.25 g). 0106 MS (APCI) 515 (MH, 100%) 0107 f) 3aR-3a,4,6(1R*,2S*),6a-6-7-2-(4-Fluorophenyl)cyclopropylamino-5-(propylsulphonyl)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0108 3-Chloroperoxybenzoic acid (70%, 1.8 g) was added to a suspension of the product of step e) (1.25 g) in ethanol (25 ml) and the resulting solution stirred at room temperature for 2 hours. The reaction mixture was concentrated and the residue taken up in ethyl acetate (500 ml), washed with 10% aqueous sodium metabisulfite solution (2100 ml) and 10% aqueous sodium bicarbonate solution (2100 ml) then dried and concentrated to afford the subtitle compound (1.4 g). 0109 MS (APCI) 547 (MH, 100%) 0110 g) 3aR-3a,4,6(1R*,2S*),6a-6-7-2-(4-Fluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropy)lthio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl)-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0111 Sodium hydrosulfide hydrate (1.4 g) was added to a solution of the product of step f) (1.4 g) in dimethyl sulphoxide (20 ml) and the solution stirred at room temperature for 1.5 hours. Brine (150 ml) was added and the mixture acidified with acetic acid then extracted with ethyl acetate (3100 ml). The organic phase was dried and concentrated and the residue azeotroped with toluene (3100 ml). The residue was dissolved in N,N-dimethylformamide (20 ml) then N,N(-diisopropylethylamine (0.33 g) and 3,3,3-trifluoropropylbromide (0.48 g) added. After stirring at 50 C. for 30 minutes the reaction mixture was diluted with ethyl acetate (100 ml) then washed with aqueous brine (3100 ml), dried and concentrated then the residue purified (SiO2, isohexane:ethyl acetate 1:1 as eluant) to afford the subtitle compound (1.4 g). 0112 MS (APCI) 569 (MH, 100%) 0113 h) 1R-1,2,3(1R*,2S*),5-3-7-2-(4-Fluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0114 A solution of the product from step g) (1.4 g) in trifluoroacetic acid (10 ml) and water (2 ml) was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate (400 ml) then washed with sodium bicarbonate solution (400 ml), dried and evaporated. The residue was purified (SiO2, methanol:chloroform 3:47 as eluant) to afford the title compound (0.44 g). 0115 MS (APCI) 529. (MH,100%) 0116 NMR H (d6-DMSO) 9.42 (1H, d), 7.27-7.22 (2H, m), 7.14-7.08 (2H, m), 5.01-4.95 (2H, m), 4.73-4.70 (2H, m), 4.44-4.41 (1H, m), 3.87-3.84 (1H, m), 3.50-3.45 (2H, m), 3.26-3.13 (3H, m), 2.60-2.55 (1H, m), 2.28-2.20 (2H, m), 2.10-2.06 (1H, m), 1.90-1.80 (1H, m), 1.49-1.46 (1H, m), 1.33-1.30 (1H, m).

Example 2 0117 1R-1,2,3(1R*,1S*),5-3-(7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0118 a) 3aS-1(E),3a,6,7a-1-3-(3,4-Difluorophenyl)-1-oxo-2-propenyl-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide 0119 The subtitle compound was prepared according to the method of Example 1, step a) using 3-(3,4-difluorophenyl)-2-propenoic acid. 0120 MS (APCI) 382 (MH, 100%) 0121 b) 3aS-1(1S*,2S*),3a,6,7a-1-2-(3,4-Difluorophenyl)cyclopropylcarbonyl-hexahydro-8,8-dimethyl-3H-3a,6-methano-2,1-benzisothiazole-2,2-dioxide 0122 The subtitle compound was prepared according to the method of Example 1, step b) using the product of step a). 0123 MS (APCI) 396 (MH, 100%) 0124 c)(1R-trans)-2-(3,4-Difluorophenyl)-cyclopropane Carboxylic Acid 0125 The subtitle compound was prepared according to the method of Example 1, step c) using the product of step b). 0126 NMR H (CDCl3) 7.06 (1H, dt, J10.0, J8.5 Hz), 6.93-6.80 (2H, m), 2.58-2.52 (1H m), 1.88-1.82 (1H, m), 1.66 (1H, dt, J9.2, J5.2 Hz), 1.34 (1H, ddd, J8.5, J6.5, J4.8 Hz). 0127 d)(1R-trans)-2-(3,4-Difluorophenyl)cyclopropanamine, R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) 0128 The subtitle compound was prepared according to the method of Example 1, step d) using the product of step c). 0129 MS (APCI) 170 (MH, 100%) 0130 e)3aR-3a,4,6(1R*,2S*),6a-6-7-2-(3,4-Difluorophenyl)cyclopropylamno-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0131 Isoamyl nitrite (5.1 ml) was added to a solution of 3aR-(3a,4,6,6a)-6-5-amino-6-Chloro-2-(3,3,3-trifluoropropyl)thio-4-pyrimidinyl-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084) (8.1 g) in acetonitrile (1000 ml) and the solution heated at 70 C. for 1 hour. The cooled reaction mixture was concentrated and purified (SiO2, dichloromethane:ethyl acetate 4:1 as eluant) to afford an intermediate which was converted to the subtitle compound by the method of example 1, step e) using the product of step d). 0132 MS (APCI) 587 (MH, 100%) 0133 f) 1R-1,2,3(1R*,2S*),5-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5 dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0134 Prepared according to the method of example 1, step h) using the product of step e). 0135 MS (APCI) 547 (MH, 100%) 0136 NMR H (d6-DMSO) 9.43 (1H, d), 7.35-7.28 (2H, m), 7.14-7.02 (1H, m), 5.01-4.96 (2H, m), 4.72-4.69 (2H, m), 4.42 (1H, q), 3.87-3.84 (1H, m), 3.50-3.44 (2H, m), 3.25-3.12 (3H, m), 2.58-2.50 (2H, m), 2.28-2.21 (3H, m), 1.85-1.80 (1H, m), 1.52-1.50 (1H, m), 1.39-1.37 (1H, m).

Example 3 0137 1S-(1,2,3(1S*,2R*),5)-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol, 0138 a) (1R-cis)-Bis(1,1-dimethylethyl)-4-hydroxy-2-cyclopentenylimidodicarbonate 0139 To a suspension of ether washed sodium hydride (60% dispersion in oil; 0.31 g) in tetrahydrofuran (30 ml) was added imidodicarbonic acid bis-(1,1-dimethylethyl)ester (1.84 g). The mixture was stirred at 40 C. for 1 hour. To the mixture, at ambient temperature, was then added (1S-cis)-4-acetoxy-2-cyclopenten-1-ol (0.5 g) and tetrakis(triphenylphosphine)palladium(0) (0.18 g). The reaction mixture was stirred for 24 hours then purified (SiO2, ethyl acetate:hexane 1:9 as eluant) to give the subtitle compound as a colourless solid (0.90 g). 0140 NMR H (d6-DMSO) 1.43 (18H, s), 1.61 (1H, ddd, J12.3, 7.7, 6.4 Hz), 2.54 (1H, dt, J12.6, 7.4 Hz), 4.51-4.57 (1H, m), 4.86 (1H, tq, J8.0, 1.8 Hz), 4.91 (1H, d, J5.4 Hz), 5.71-5.77 (2H, m). 0141 b) 1R-(1,2,3,4)-2,3,4-Trihydroxy-cyclopentenylimidodicarbonic Acid, bis(1,1-dimethylethyl) Ester 0142 To a solution of the product of step a) (17.1 g) in tetrahydrofuran (500 ml)/water (50 ml) was added N-methylmorpholine-N-oxide (9.4 g) followed by osmium tetroxide (10 ml, 2.5% solution in t-butanol). The mixture was stirred at room temperature for 4 days then treated with sodium hydrosulphite (6.0 g). The suspension was filtered through celite and the product purified (SiO., ethyl acetate:hexane 1:1 as eluant) to afford the subtitle compound (19.1 g) 0143 NMR H (d6-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, J4.8 Hz), 4.56 (1H, d, J5.9 Hz), 4.82 (1H, d, J4.6 Hz) 0144 c) 3aR-(3a,4,6,6a)-6-Amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, Hydrochloride 0145 The product from step b) (17.4 g) in 6M HCl (100 ml)/methanol (500 ml) was stirred for 18 hours. The mixture was evaporated and then azeotroped with toluene (4200 ml) to give a colourless powder (8.7 g). This solid was suspended in acetone (250 ml) containing 2,2-dimethoxypropane (25 ml) and cHCl (0.2 ml) then heated under reflux for 2 hours. The mixture was cooled, evaporated and azeotroped with toluene (3200 ml). The residue was dissolved in 20% aqueous acetic acid and stirred for 2 hours. The mixture was evaporated and azeotroped with toluene (4200 ml) to afford the subtitle compound (10.1 g). 0146 MS (APCI) 174 (MH, 100%) 0147 d) 3aR-(3a,4,6,6a)-6-6-Chloro-5-nitro-2-(propylthio)-pyrimidin-4-ylamino-tetrahydro-2,2-dimethyl4H-cyclopenta-1,3-dioxol-4-ol 0148 A solution of the product from step c) (10.0 g) and NN-diisopropylethylamine (35 ml) in tetrahydrofuran (600 ml) was stirred for 1 hour. The mixture was filtered and the solution was added over 1 hour to a solution of 4,6-dichloro-5-nitro-2-(propylthio)-pyrimidine (prepared as described in International Patent Application WO 9703084) (25.6 g) in tetrahydrofuran (1000 ml) and stirred for a further 2 hours. The solvent volume was reduced in vacuo and ethyl acetate was added (1000 ml). The mixture was washed with water and the organic layers were dried, evaporated and purified (SiO2, isohexane-ethyl acetate as eluant) to afford the subtitle compound (14.2 g). 0149 MS (APCI) 405 (MH, 100%) 0150 e) 3aR-(3a,4,6,6a)-6-5-Amino-6-Chloro-2-(propylthio)-pyrimidin-4-ylamino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0151 Iron powder (3.0 g) was added to a stirred solution of the product of step d) (2.7 g) in acetic acid (100 ml). The reaction mixture was stirred at room temperature for 2 hours, concentrated to half volume, diluted with ethyl acetate and washed with water. The organic phase was dried and concentrated to afford the subtitle compound (2.0 g). 0152 MS (APCI) 375 (MH, 100%) 0153 f) 3aR-(3a,4,6,6a)-6-7-Chloro-5-(propylthio)-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0154 Isoamyl nitrite (1.1 ml) was added to a solution of the product of step e) (2.0 g) in acetonitrile (100 ml) and the solution heated at 70 C. for 1 hour. The cooled reaction mixture was concentrated and purified (SiO2, ethyl acetate:isohexane 1:3 as eluant) to afford the subtitle compound (1.9 g). 0155 MS (APCI) 386 (MH, 100%) 0156 g) 3aR-(3a,4,6,6a)-6-7-Amino-5-(propylthio)-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0157 The product of step f) (13.2 g) in tetrahydrofuran (200 ml) containing 0.88 ammonia (5 ml) was stirred for 2 hours then concentrated to dryness and the residue partitioned between water and ethyl acetate. The organics were dried and then concentrated to afford the subtitle compound (12.5 g). 0158 MS (APCI) 367 (MH, 100%). 0159 h) 3aR-(3a,4,6,6a)-6-7-Amino-5-(propylthio)-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-oloxyacetic Acid, Methyl Ester 0160 To a solution of the product of step g) (0.50 g) in tetrahydrofuran (25 ml) at 0 C., was added butyllithium (0.62 ml of 2.5N in hexanes). After 20 minutes, the suspension was treated with a solution of trifluoromethanesulfonyloxy-acetic acid methyl ester (0.34 g) (prepared according to the method of Biton, Tetrahedron, 1995, 51, 10513) in tetrahydrofuran (10 ml). The resulting solution was allowed to warm to room temperature then concentrated and purified (SiO2, ethyl acetate:hexane 4:6 as eluant) to afford the subtitle compound (0.25 g). 0161 MS (APCI) 439 (MH, 100%). 0162 i) 3aR-(3a,4,6,6a)-6-7-Bromo-5-(propylthio)-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-oloxyacetic Acid, Methyl Ester 0163 The product from step h) (1.1 g) and isoamylnitrite (2.4 ml) in bromoform (30 ml) was heated at 80 C. for 30 minutes. The cooled reaction mixture-was purified (SiO2, ethyl acetate:isohexane 1:4 as eluant) to afford the subtitle compound (0.44 g). 0164 MS (APCI) 502/4 (MH), 504 (100%). 0165 j) 3aR-3a,4,6(1R*,2S*),6a-6-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxyacetic Acid, Methyl Ester 0166 To a mixture of the products from step i) (0.80 g) and Example 2, step d) (0.61 g) in dichloromethane (25 ml) was added N,N-diisopropylethylamine (0.85 ml). The resulting solution was stirred at room temperature for 16 hours then concentrated in vacuo. Purification (SiO2, isohexane:ethylacetate 3:1 as eluant) gave the subtitle compound as a colourless foam (0.77 g). 0167 MS (APCI) 591 (MH, 100%) 0168 k) 3aR-3a,4,6(1R*,2S*),6a-2-6-(7-2-(3,4-Difluorophenyl) cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy-ethanol 0169 DIBAL-H (1.0M solution in hexanes, 5.15 ml) was added to an ice-cooled solution of the product of step j) (0.76 g) in tetrahydrofuran (1 ml) and the solution stirred at this temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate (75 ml). A saturated aqueous solution of sodium potassium tartrate (75 ml) was added and the mixture stirred vigorously for 16 hours. The organics were collected and the aqueous re-extracted with ethyl acetate (250 ml). The combined organics were dried and concentrated and the residue purified (SiO2, isohexane:ethylacetate 1:1 as eluant) to give the subtitle compound (0.63 g). 0170 MS (APCI) 563 (MH,100%) 0171 l) 1S-1,2,3(1S*,2R*),5-3-7-(2-(3,4-Difluorophenyl)cyclopropylamino)-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol 0172 Prepared according to the method of example 1, step h) using the product of step k). 0173 MS-(APCI) 523 (MH, 100%) 0174 NMR H (d6-DMSO) 8.95 (1H, d, J3.3 Hz), 7.39-7.21 (2H, m), 7.10-7.00 (1H, m), 5.12 (1H, d, J6.4 Hz), 5.05 (1H, d, J3.6 Hz), 4.96 (1H, q, J9.0 Hz), 4.62-4.54 (2H, m), 3.95 (1H, br s), 3.79-3.73 (1H, m), 3.55-3.47 (4H, m), 3.20-3.13 (1H, m), 2.98-2.81 (2H, m), 2.63 (1H, dt, J13.6, 8.5 Hz), 2.29-2.21 and 2.16-2.69 (1H, m), 2.07-2.00 (1H, m), 1.73-1.33 (4H, m), 0.99 (3H, t, J7.4 Hz).

Example 4 0175 1R-1,2,3(1R*,2S*),5-3-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0176 a) 3aR-(3a,4,6,6a)-6-7-Amino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0177 Prepared according to the method of Example 3, step g) using 3aR-(3a,4,6,6a)-6-7-chloro-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol (prepared as described in International Patent Application WO 9703084). The crude product was purified (SiO2, methanol:dichloromethane 1:19 as eluant) to give the subtitle compound. 0178 MS (APCI) 381 (MH, 100%). 0179 b) 3aR-(3a,4,6,6a)-6-7-Amino-5-(propylsulfonyl)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0180 Prepared according to the method of example 1, step f) using the product of step a). 0181 MS (APCI) 413 (MH, 100%). 0182 c) 3aR-(3a,4,6,6a)-6-7-Amino-5-(butylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol 0183 1-Butanethiol (2.38 ml) in DMF (25 ml) was added to a suspension of sodium hydride (60%, 1.09 g) in DMF (50 ml). After 1 hour a solution of the product of step b) (3.66 g) in DMF (65 ml) was added dropwise and the resulting mixture was stirred overnight. The reaction mixture was added slowly to saturated aqueous sodium bicarbonate (1000 ml) and then extracted into ethyl acetate (3200 ml). The organic phase was dried (MgSO4) and concentrated in vacuo and the residue purified (SiO2, methanol:dichloromethane 1:19 as eluant) to give the subtitle compound (3.32 g). 0184 MS (APCI) 395 (MH, 100%). 0185 d) 3aR-(3a,4,6,6a)-6-7-Amino-5-(butylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate 0186 To a solution of the product from step c) (3.3 g) in dichloromethane (50 ml), was added pyridine (2.7 ml), 4-dimethylaminopyridine (0.4 g) and acetic anhydride (2.0 ml). The mixture was stirred at room temperature overnight, concentrated in-vacuo and purified (SiO2, diethyl ether:isohexane 3:2 as eluent) to give the subtitle compound (2.7 g). 0187 MS (APCI) 437 (MH, 100%). 0188 e) 3aR-(3a,4,6,6a)-6-7-Bromo-5-(butylthio)-3H-1,2,3-triazolo4,5-dpyrimidin. 3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate 0189 Prepared according to the method of example 3, step i) using the product of step d). 0190 MS (APCI) 500/502 (MH), 500 (100%). 0191 f) 3aR-3a,4,6(1R*,2S*),6a-6-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxole-4-methanol, acetate 0192 Prepared according to the method of example 3, step j) using the product of example 2, step d) and the product of step e). 0193 MS (APCI) 589 (MH, 100%). 0194 g) 1R-1,2,3(1R*,2S*),5-3-(5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(hydroxymethyl)-cyclopentane-1,2-diol 0195 The product of step f) (0.64 g) in 80% aqueous acetic acid (30 ml) was heated at 80 C. for 1 hour. The cooled mixture was poured into saturated sodium bicarbonate solution and extracted into ethyl acetate. The organic phase was dried and concentrated in vacuo to give a gum which was dissolved in methanol (50 ml)/10% aqueous potassium carbonate solution (3 ml). The solution was stirred for 30 minutes, neutralised with acetic acid, and concentrated in vacuo. Purification (SiO2, methanol:dichloromethane 1:19 as eluent) gave a solid which was recrystallised (acetonitrile) to give the title compound (0.25 g). 0196 MS (APCI) 507 (MH, 100%). 0197 NMR 5H (d6-DMSO) 9.34 (1H, br), 7.40-7.23 (2H, m), 7.11-7.00 (1H, m), 5.06-4.93 (2H, m), 4.764.67 (2H, m), 4.484.38 (1H, m), 3.91-3.84 (1H, m), 3.56-3.39 (2H, m), 3.21-3.08 (1H, m), 3.03-2.83 (2H, m), 2.32-2.17 (1H, m), 2.17-2.03 (2H, m), 1.91-1.77 (1H, m), 1.71-1.32 (4H, m), 1.32-1.17 (2H, m), 0.81 (3H, t).

Example 5 0198 1S-1,2,3,4(1S*,2R*)-4-5-(Butylthio)-7-2-(4-fluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-cyclopentane-1,2,3-triol 0199 a) 3aR-3a,4,6,6a(1S*,2R*)-6-(7-(4-Fluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0200 Prepared according to the method of example 1, step e) using the product of example 1, step d) and the product of example 3 step f). 0201 MS (APCI) 501 (MH, 100%). 0202 b) 3aR-3a,4,6,6a(1S*,2R*)-6-7-(4-Fluorophenyl)cyclopropylamino-5-(propylsulphonyl)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0203 Prepared according to the method of example 1, step f) using the product of step a). 0204 MS (APCI) 532 (MH, 100%). 0205 c) 3aR-3a,4,6,6a(1S*,2R*)-6-7-(4-Fluorophenyl)cyclopropyamino-5-(butylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0206 Prepared according to the method of example 4 step c) using the product of step b). 0207 MS (APCI) 515 (MH, 100%). 1S-1,2,3,4(1S*,2R*)-4-(5-(Butylthio)-7-2-(4-fluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5 dpyrimidin-3-yl-cyclopentane-1,2,3-triol 0208 Prepared according to the method of example 1 step h) using the product of step c). 0209 MS (APCI) 575 (MH, 100%). 0210 NMR H (d6-DMSO) 7.26-7.22 (2H, m), 7.11 (2H, t), 4.99-4.90 (1H, m), 4.67-4.63 (1H, m), 3.93 (1H, s), 3.77 (1H, bs), 3.35-3.13 (1H, m), 3.00-2.80 (2H, m), 2.59-2.51 (1H, m), 2.15-2.11 (1H, m), 1.91-1.86 (1H, m), 1.53-1.41 (3H, m), 1.35-1.30 (1H, m), 1.22 (2H, sex), 0.80 (3H, t).

Example 6 0211 1S-(1,2,3(1S*,2R*),5)-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5 dpyrimnidin-3-yl-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol 0212 a) 1S-(1,2,3(1S*,2R*),5)-3-7-2-(3,4-Difluorophenyl)cyclopropylaiino-5-(propylsulphonyl)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol 0213 The subtitle compound was prepared according to the method of Example 1, step f) using the product of Example 3, step 1. 0214 MS(APCI) 555(MH, 100%) 0215 b) 1S-(1,2,3(1S*,2R*),5)-3-7-2-(3,4-Difluorophenyl)cyclopropylamino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimiidin-3-yl)-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol 0216 The title compound was prepared according to the method of Example 1, step g) using the product of step a). 0217 MS(APCI) 555 (MH, 100%) 0218 NMR H (d6-DMSO) 9.45 (1H, d), 7.36-7.05 (3H, m), 5.05 (1H, d), 5.02 (1H, d), 4.95 (1H, m), 4.60 (2H, m), 3.95 (1H, m), 3.86 (1H, m), 3.47 (4H, m), 3.30-3.11 (3H, m), 2.63-2.49 (3H, m), 2.19 (1H, m), 2.00 (1H, m), 1.53 (1H, m), 1.40 (1H, m).

Example 7 0219 1S-1,2,3,5(1S*,2R*)-3-(2-Hydroxyethoxy)-5-7-(2-phenylcyclopropyl)amino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-cyclopentane-1,2-diol 0220 a) (1S-cis)-2-4-6-Chloro-5-nitro-2-(3,3,3-trifluoropropyl)thiol-4-pyrimidinylamino-2-cyclopenten-1-yloxy-acetic Acid, Ethyl Ester 0221 A solution of sodium azide (4.70 g) in degassed water (25 ml) was added to a solution of (1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate (9.99 g) in tetrahydrofuran (60 ml) and stirred for 10 min. Tetrakis(triphenylphosphine)palladium(0) (365 mg) was added and stirred for 10 min. The aqueous layer was separated and extracted twice with ethyl acetate. The combined organic layers were dried (MgSO4), concentrated and purified on a short column (SiO2, ethyl acetate:isohexane 1:2 as eluant) to afford a yellow oil. This was dissolved in tetrahydrofuran (25 ml) and slowly added to a suspension of sodium hydride (2.94 g, 60% dispersion in oil) in tetrahydrofuran (60 ml) at 78 C. A solution of ethyl bromoacetate (8.2 ml) in tetrahydrofuran (5 ml) was added and the mixture was allowed to warm to 20 C. and stirred for 30 min. Aqueous ammonium chloride solution was added and the mixture was extracted with ether. The organic layers were dried (MgSO4), concentrated and purified (SiO2, ether:isohexane 1:5 as eluant) to afford a colourless oil. A solution of this oil and triphenylphosphine (17.89 g) in tetrahydrofuran (90 ml) was stirred for 10 min. Water (15 ml) was added and the solution was stirred for 18 hours. The solvent was removed in vacuo and the residue azeotroped with toluene then purified (SiO2, ethyl acetate then ethyl acetatemethanolammonia (90:9:1) as eluant) to afford a pale yellow oil (7.14 g). 0222 A solution of this compound in tetrahydrofuran (50 ml) was added over 25 min to a solution of 4,6-dichloro-5-nitro-2-(3,3,3-trifluoropropyl)thio pyrimidine (prepared as described in International Patent Application WO 9703084) (24.8 g) and N,N-diisopropylethylamine (77.5 ml) in dry tetrahydrofuran (100 ml) and then stirred for 30 minutes. Water was added and the mixture was extracted with ether (three times). The organic layers were dried (MgSO4), concentrated and purified (SiO., ethyl acetate:isohexane 1:4 as eluant) to afford the subtitle compound (7.39 g). 0223 MS (APCI) 367/9 (M-(EtO2CCH2O)), 367 (100%) 0224 b) (1S-cis) 2-4-7-Chloro-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5d-pyrimidin-3-yl-2-cyclopenten-1-yloxy-acetic Acid, Ethyl Ester 0225 Prepared according to the method of example 3, steps e) and f) using the product of step a). 0226 MS (APCI) 348/50 (M-(EtO2CCH2O)), 348 (100%). 0227 c) 1S-(cis) 2-4-7-Amino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-2-cyclopenten-1-yloxy-acetic Acid, Ethyl Ester 0228 Prepared according to the method of example 3, step g) using the product of step b). 0229 MS (APCI) 433 (MH, 100%). 0230 d) 1S-(cis) 2-4-7-Amino-5-(3,3,3-trifluoropropyl)thiol-3H-1,2,3-triazolo(4,5-dpyrimidin-3-yl-2-cyclopenten-1-yloxy-1-ethanol 0231 Prepared according to the method of example 3, step k) using the product of step c). 0232 MS (APCI) 391 (MH, 100%). 0233 e) 3aR-(3a,4,6,6a)-2-6-7-Amino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxyethanol 0234 A solution of the product from step d) (454 mg), osmium tetroxide (0.17 ml of 0.1M solution in t-butanol), N-methylmorpholine N-oxide (210 mg) and pyridine (0.09 ml) in acetone (5 ml) and water (1 ml) was heated at 70 C. for 5 hours. Sodium hydrosulfite (330 mg) in water (1 ml) was added, the solvent was remove in vacuo and the residue azeotroped with toluene. A solution of this and p-toluenesulfonic acid (50 mg) in acetone (5 ml) and 2,2-dimethoxypropane (2 ml) was stirred for 3 h. The solvent was remove in vacuo, aq sodium hydrogen carbonate solution added and the mixture was extracted with ethyl acetate. The organic layers were dried (MgSO4), concentrated and purified (SiO2,isohexane:acetone 5:2 as eluant) to afford the subtitle compound as a white solid (367 mg). 0235 MS (APCI) 465 (MH, 100%) 0236 f) 3aR-(3a,4,6,6a)-2-6-7-Bromo-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-d-pyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxyethanol 0237 Prepared according to the method of Example 3, step i) using the product of step e). 0238 MS (APCI) 528/30 (MH), 528 (100%) 0239 g) 3aR-3a,4,6(1R*,2S*),6a-2-6-(7-Phenylcyclopropyl)amino-S-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-1,3-dioxol-4-yloxyethanol 0240 Prepared according to the method of Example 3, step j) using the product of step f) and (1R-trans)-2-phenyl-cyclopropanamine, R-(R*,R*)-2,3-dihydroxybutanedioate (1:1) (prepared as described by L. A. Mitscher et al., J. Med. Chem. 1986, 29, 2044). 0241 MS (APCI) 581 (MH, 100%) 0242 h) 1S-1,2,3,5(1S*,2R*)-3-(2-Hydroxyethoxy)-5-7-(2-phenylcyclopropyl)amino-5-(3,3,3-trifluoropropyl)thio-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-cyclopentane-1,2-diol Prepared according to the method of Example 1, step h) using the product of step g). 0243 MS (APCI) 540 (MH, 100%). 0244 NMR H (d6-DMSO) 7.35-7.16 (5H, m), 4.97 (1H, q), 4.62-4.54 (1H, m), 3.98-3.92 (1H, m), 3.78-3.72 (1H, m), 3.55-3.44 (4H, m), 3.26-3.19 (2H, m), 3.16-3.07 (1H, m), 2.70-2.61 (1H, m), 2.58-2.52 (1H, m), 2.23-2.18 (1H, m), 2.05-1.97 (1H, m), 1.86 (1H, s), 1.54-1.46 (1H, m), 1.38-1.30 (1H, m).

Example 8 0245 1S-1,2,3,4(1S*,2R*)-4-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5 dpyrimidin-3-ylcyclopentane-1,2,3-triol 0246 a) 3aR-3a,4,6(1R*,2S*),6a-6-(7-((3,4-Difluorophenyl)cyclopropylamino-5-(propylthio)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0247 The subtitle compound was prepared according to the method of Example-1, step e) using the product of Example 3, step f) and the product of example 2, step d). 0248 MS (APCI) 519 (MH, 100%). 0249 b) 3aR-3a,4,6(1R*,2S*),6a-6-7-(3,4-Difluorophenyl)cyclopropylaxino-5-(propylsulfonyl)-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0250 The subtitle compound was prepared according to the method of Example 1, step f) using the product of step a). 0251 MS (APCI) 551 (MH, 100%). 0252 c) 3aR-3a,4,6(1R*,2S*),6a-6-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol 0253 The subtitle compound was prepared according to the method of Example 4, step c) using the product of step b). 0254 MS (APCI) 533 (MH, 100%) 0255 d) 1S-1,2,3,4(1S*,2R*)-4-5-(Butylthio)-7-2-(3,4-difluorophenyl)cyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-ylcyclopentane-1,2,3-triol 0256 The title compound was prepared according to the method of Example 1, step h) using the product of step c). 0257 NMR H (d6-DMSO) 7.15-6.98 (3H, m), 6.67 (1H, s), 5.11-5.09 (1H, m), 4.82-4.76 (1H, m), 4.34-4.21 (3H, m), 3.7 (1H, s), 3.2-2.92 (4H, m), 2.77 (1H, m), 2.42-2.36 (1H, m), 2.2-2.18 (1H, m), 1.42-1.25 (6H, m), 0.9 (3H, q). 0258 MS (APCI) 493 (MH, 100%)

Example 9 0259 1S-(1,2,3(1S*,2R*),5-3-5-(Butylthio)-7-(2-phenylcyclopropyl)a-no-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-5-(2-hydroxethoxy)-cyclopentane-1,2-diol 0260 a) 3aS-(3a,4,6,6a)-Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl-carbamic Acid, Phenylmethyl Ester 0261 Potassium carbonate (39.3 g) was added to a suspension of 3aR-(3a,4,6,6a)-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, hydrochloride, (prepared as described in WO 9905142) (27.1 g) in 4-methyl-2-pentanone (SOOml). Water (150 ml) was then added followed by dropwise addition of benzyl chloroformate (23.1 g). The reaction mixture was stirred at room temperature for 4 hours before the organic phase was separated. The aqueous phase was extracted with 4-methyl-2-pentanone (250 ml). The combined organics were concentrated and the residue was purified (SiO2, dichloromethane:methanol, 95:5 to 90:10 as eluant) to give the subtitle compound (39.23 g). 0262 NMR H (CDCl3) 7.32 (5H, m), 5.65 (1H, br s), 5.10 (2H, br s), 4.59 (1H, d), 4.48 (1H, d), 4.27 (1H, m), 4.19 (1H, br m), 2.24 (1H, br s), 1.69 (1H, d), 1.41 (3H, s), 1.26 (3H, s). 0263 b) 3aS-(3a,4,6,6a)-2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl-carbamic Acid, Phenylmethyl Ester 0264 Potassium tert-butoxide (3.6 g) in tetrahydrofuran (20 ml) was added over 5 minutes to a solution of the product from step a) (39.23 g) in tetrahydrofuran (200 ml). After 15 minutes, ethyl bromoacetate (3.7 ml) in tetrahydrofuran (10 ml) was added dropwise. The mixture was stirred at 0 C. for 10 minutes, then further ethyl bromoacetate was added (3.7 ml4). The reaction mixture was stirred at 0 C. a further 2 hours. Lithium borohydride (2.79 g) was then added portionwise to the resulting suspension and the reaction mixture was stirred at <5 C. for 16 hours. Glacial acetic acid (23 g) was added dropwise to the cold mixture. After stirring for 30 minutes, water (100 ml) was added dropwise and the resulting mixture was stirred for 30 minutes. The phases were then separated and the aqueous phase was extracted with ethyl acetate. The combined organics were washed with saturated sodium bicarbonate and brine, dried and concentrated. The residue was purified (SiO2, ethyl acetate:hexane, 25:75 to 50:50 as eluant) to give the subtitle compound (38.6 g). 0265 MS (APCI) 218 (MH, 100%). 0266 c)) 3aR-(3a,4,6,6a)-2-6-Amino-2, 2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yloxy-ethanol 0267 A slurry of 5% palladium on charcoal (4 g) in ethanol was added to a solution of the product from step b) (39.96 g) in ethanol (250 ml) and the mixture was hydrogenated at 1.2 bar for 20 hours. The catalyst was filtered off and the filtrate was concentrated to give the subtitle compound (23.65 g). 0268 MS (APCI) 160 (MH, 100%). 0269 d) 2-(Butylthio)-4,6-dichloropyrimidine-5-amine 0270 The subtitle compound was prepared according to the method of example 3, step e) using 2-(butylthio)-4,6-dichloro-5-nitro-pyrimidine (prepared as described in DE 2223644). 0271 NMR H (CDCl3) 4.20 (2H, br s), 3.10 (2H, t), 1.70 (2H, m), 1.47 (2H, m), 0.95 (3H, t). 0272 e) 3aR-(3a,4,6,6a)-2-6-5-Amino-2-(butylthio)-6-chloro-pyrimidin-4-ylamino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxyethanol 0273 The subtitle compound was prepared according to the method of example 3, step d) using the products of steps c) and d). 0274 MS (APCI) 433 (MH, 100%). 0275 f) 3aR-3a,4,6(1R*,2S*),6a-2-6-5-(Butylthio)-7-chloro-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ylloxy-ethanol 0276 The subtitle compound was prepared according to the method of Example 3, step f) using the product of step e). 0277 NMR H (CDCl3) 5.53 (1H, m), 5.21 (1H, m), 4.88 (1H, d), 4.05 (1H, m), 3.59 (4H, m), 3.24 (2H, t), 2.70 (1H, m), 2.53 (1H, m), 2.13 (1H, t), 1.79 (2H, m), 1.55 (5H, m), 1.37 (3H, s), 0.98 (3H, t). 0278 g) (3aR-3a,4,6(1R*,2S*),6a-2-6-5-(Butylthio)-7-2-phenylcyclopropylamino-3H-1,2,3-triazolo4,5-dpyrimidin-3-yl-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yloxy-ethanol 0279 The subtitle compound was prepared according to the method of Example 3, step j) using the product of step f). 0280 MS (APCI) 541 (MH, 100%). 0281 h) 1S-1,2,3(1S*,2R*),5-3-5-(Butylthio)-7-(2-phenylcyclopropyl)anino-3H-1,2,3-triazolo4,5-dpyrirridin-3-yl-5-(2-hydroxethoxy)-cyclopentane-1,2-diol 0282 The title compound was prepared according to the method of example 1, step h) using the product of step g). 0283 MS (APCI) 501 (MH, 100%) 0284 NMR H (d6-DMSO) 9.33 (1H, d), 7.30 (2H, m), 7.18 (3H, m), 5.12 (1H, d), 5.04 (1H, d), 4.96 (1H, q), 4.59 (2H, m), 3.94 (1H, s), 3.76 (1H, m), 3.51 (4H, m), 3.22 (1H, m), 2.98 (1H, m), 2.86 (1H, m), 2.65 (1H, m), 2.14 (1H, m), 2.05 (1H, m), 1.21-1.53 (6H, m), 0.80 (3H, t). 0285 Pharmacological Data 0286 The preparation for the assay of the P2T (P2YADP or P2TAC) receptor agonist/antagonist activity in washed human platelets for the compounds of the invention was carried out as follows. 0287 Human venous blood (100 ml) was divided equally between 3 tubes, each containing 3.2% trisodium citrate (4 ml) as anti-coagulant. The tubes were centrifuged for 15 minutes at 240G to obtain a platelet-rich plasma (PRP) to which 300 ng/ml prostacyclin was added to stabilize the platelets during the washing procedure. Red cell free PRP was obtained by centrifugation for 10 minutes at 125G followed by further centrifugation for 15 minutes at 640G. The supernatant was discarded and the platelet pellet resuspended in modified, Calcium Free Tyrode solution (10 ml) (CFT), composition: NaCl 137mM, NaHCO3 11.9mM, NaH2PO4 0.4 mM, KCl 2.7 mM, MgCl2 1.1 ml, dextrose 5.6 mM, gassed with 95% O2/5% CO2 and maintained at 37 C. Following addition of a further 300 ng/ml PGI2, the pooled suspension was centrifuged once more for 15 minutes at 640G. The supernatant was discarded and the platelets resuspended initially in 10 ml CFT with further CFT added to adjust the final platelet count to 2105/ml. This final suspension was stored in a 60 ml syringe at 3 C. with air excluded. To allow recovery from PGI2-inhibition of normal function, platelets were used in aggregation studies no sooner than 2 hours after final resuspension. 0288 In all studies, 3 ml aliquots of platelet suspension were added to tubes containing CaCl2 solution (60 l of 50 mM solution with a final concentration of 1 mM). Human fibrinogen (Sigma, F 4883) and 8-sulphophenyltheophylline (8-SPT which was used to block any Pi-agonist activity of compounds) were added to give final concentrations of 0.2 mg/ml (60 l of 10 mg/ml solution of clottable protein in saline) and 300 nM (10 l of 15 multi solution in 6% glucose), respectively. Platelets or buffer as appropriate were added in a volume of 150 l to the individual wells of a 96 well plate. All measurements were made in triplicate in platelets from each donor. 0289 The agonist/antagonist potency was assessed as follows. 0290 Aggregation responses in 96 well plates were measured using the change in absorbance given by the plate reader at 660 nm. Either a Bio-Tec Ceres 900C or a Dynatech MRX were used as the plate reader. 0291 The absorbance of each well in the plate was read at 660 nm to establish a baseline figure. Saline or the appropriate solution of test compound was added to each well in a volume of 10 l to give a final concentration of 0, 0.01, 0.1, 1, 10 or 100 mM. The plate was then shaken for 5 min on an orbital shaker on setting 10 and the absorbance read at 660 nm. Aggregation at this point was indicative of agonist activity of the test compound. Saline or ADP (30 mM; 10 l of 450 mM) was then added to each well and the plate shaken for a further 5 min before reading the absorbance again at 660 nm. 0292 Antagonist potency was estimated as a % inhibition of the control ADP response to obtain an IC50. Compounds exemplified have pIC50 values of more than 5.0.