EP1232172A1

EP1232172A1 - Novel ribose compounds

Info

Publication number: EP1232172A1
Application number: EP00980179A
Authority: EP
Inventors: David AstraZeneca R & D Charnwood HARDERN; Anthony AstraZeneca R & D Charnwood INGALL; Paul AstraZeneca R & D Charnwood WILLIS
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 1999-11-15
Filing date: 2000-11-14
Publication date: 2002-08-21
Also published as: JP2003514827A; SE9904128D0; WO2001036438A1; AU1747501A

Abstract

The invention provides novel ribose compounds of formula (I); their use as medicaments, compositions containing them and processes for their preparation.

Description

NOVEL RIBOSE COMPOUNDS

FIELD OF THE INVENTION

The present invention provides novel ribose analogues, their use as medicaments, compositions containing them and processes for their preparation.

BACKGROUND OF THE INVENTION

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 platelet-mediated occlusion or re-occlusion also compromises angioplasty.

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 Ilb/πia (GPEb fla). The high anti-platelet efficacy of antibodies or antagonists for GPnb/Tfla 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 T I 9a Investigators (1994), Circulation 90, pp. 1624-1630; The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) Ha Investigators (1994) Circulation 90, pp. 1631- 1637; Neuhaus K. L. et. al. (1994) Circulation 90, pp. 1638-1642). It has been found that ADP acts as a key mediator of thrombosis. ADP-induced platelet aggregation is mediated by the P ₇- receptor subtype located on the platelet membrane. The P₂r receptor (also known as P2Y_ADP or P2T_Ac) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor. 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). There is a need to find P_2r (P2Y_ADp or P2T_AC) antagonists as anti- thrombotic agents.

DESCRIPTION OF THE INVENTION

In a first aspect the invention provides a compound of formula (I):

(D wherein:

R¹ is either alkyl C_1-6 substituted by OH or COR⁴; R² is alkyl C_1-6 or haloalkyl Cι.₆; R³ is cycloalkyl C₃.₆ optionally substituted by R⁵; R⁴ is OR⁶ or NHR⁶; R⁵ is phenyl optionally substituted by one or more groups selected from alkyl Cι_-6, halogen and OR⁶;

R⁶ is H or alkyl Cι.₆; or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

Preferably the compound of formula (I) has the following stereochemistry:

(la)

where R¹, R² and R³ are as defined above

When R 3 is R⁵ , where R 5 is defined above, the stereochemistry is preferably

Suitably, R¹ is CH₂OH, (CH₂)₂OH, COOH or CONHEt.

Suitably, R² is alkyl C₃ optionally substituted by three halogen atoms.

Particularly preferred compounds of the invention include: (lΛ-trαπ5)-N-(2-Phenylcyclopropyl)-5-(propylthio)-3-(β-D-ribofurarosyl)-3H^:[ 1 ,2,3]- triazolo[4,5-J]pyrimidin-7-amine;

(li?-tr n5)-N-[2-(4-Chlorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-

[l,2,3]-triazolo[4,5-J]pyrimidin-7-amine; (li?-rr πs)-N-[2-(3,4-Difluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-

3H-[ 1 ,2,3]-triazolo[4,5-Jlpyrimidin-7-amine;

(l ?-trαn5)-N-[2-(4-Methoxyphenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-

[ 1 ,2,3]-triazolo[4,5-J]pyrimidin-7-amine;

(lΛ-tr n5)-N-[2-(4-Fluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H- [l,2,3]-triazolo[4,5-J]pyrimidin-7-amine;

(l ?-tr π5)-N-(2-Phenylcyclopropyl)-5-(3,3,3-trifluoropropylthio)-3-(β-D-ribofuranosyl)-

3H-[ 1 ,2,3]-triazolo[4,5-<i]pyrimidin-7-amine;

(l/?-tran5)-3-(5-Deoxy-β-D-π^'bo-hexofuranosyl)-N-(2-phenylcyclopropyl)-5-(propylthio)-

3H-[ 1 ,2,3]-triazolo[4,5-J]pyrimidin-7-amine; (li?-traπ5)-l-Deoxy-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[ 1,2,3]- triazolo[4,5-J]pyrimidin-3-yl]-β-D-ribofuranuronic acid;

(li?-tr n5)-l-Deoxy-N-ethyl-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[ 1,2,3]- triazolo[4,5-d]pyrimidin-3-yl]-β-D-ribofuranuronamide;

or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

According to the invention there is further provided a process for the preparation of a compound of formula (I) which comprises:

a. For compounds of formula (I) where R¹ is CΗ OΗ, reacting a compound of formula (II):

(n)

where R² is defined above and P is a protecting group, preferably benzoyl, with R³NH , where R³ is defined above, and a base, preferably triethylamine or NN-di- isopropylethylamine, in the presence of dipolar aprotic solvent, preferably N,N- dimethylformamide or an alcohol, preferably n-butanol, at a temperature between about 100 and about 150°C, and optionally thereafter removing any protecting groups.

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).

When and when R is phenyl, it may be prepared as described in L.A.

Mitscher et al, J. Med. Chem., 1986, 29, 2044. When R⁵ is phenyl substituted by one or more groups selected from Cj.₆ alkyl, halogen and OR⁶ it may be prepared as described in International Patent Application WO 9905143.

A compound of formula (II) can be prepared by reacting a compound of formula (HI):

⁽in⁾ where R² is defined above, with l-0-acetyl-2,3,4-tri-0-benzoyl-β-D-ribofuranose and an acid, preferably p-toluenesulphonic acid, at a temperature between about 100 and about 150°C.

A compound of formula (HI) can be prepared by reducing a compound of formula (IV):

(IV)

where R² is defined above, with a metal, preferably iron powder, in the presence of an acid, preferably acetic acid, followed by diazotization using a Cι_-6 alkyl nitrite, preferably iso- amyl nitrite, in the presence of an inert dipolar aprotic solvent, preferably acetonitrile, at a temperature between about 20 and about 100°C.

A compound of formula (IV) can be prepared by reacting a compound of formula (V):

(V)

where R" is defined above, with aqueous ammonia in the presence of an inert ethereal solvent, preferably 1,4-dioxane, at a temperature between about 0 and about 50°C. The compound of formula (V) may be prepared as described in International Patent Application WO 9828300.

b. For compounds of formula (I) where R¹ is CH₂OH, interconverting R² by reacting a compound of formula (VI):

(VI)

where R"" and R are as defined above, i) with sodium hydrosulphide (NaSH) in the presence of a dipolar aprotic solvent, preferably N,N-dimethylformamide, at a temperature between about 0 and about 50°C and treating the product of this reaction with an alkyl halide (R² X), preferably l-bromo-3,3,3- trifluoropropane, in the presence of a dipolar aprotic solvent, preferably N,N- dimethylformamide, at a temperature between about 0 and about 50°C, or ii) with a sodium alkylthiolate (R SΝa) in the presence of a dipolar aprotic solvent, preferably N,N-dimethylformamide, at a temperature between about 0 and about 50°C, where R² is different from the R" being interconverted.

A compound of formula (VI) may be made by the oxidation of a compound of formula (VII):

(vπ)

where R" and R are as defined above, with a peracid, preferably m-chloroperoxybenzoic acid, in the presence of a chlorocarbon solvent, preferably dichloromethane, at a temperature between about 0 and about 50°C.

The preparation of the compound of formula (VII) was described above in step a.

c. For compounds of formula (I) where R¹ is (CH₂)₂OH, reducing a compound of formula (VIE):

where P and P are protecting groups, preferably CMe₂, and R² and R³ are as defined above, with a metal hydride, preferably di-isobutylaluminiumhydride, in the presence of an inert solvent, preferably toluene, at a temperature between about 0 and about 50°C and optionally thereafter removing any protecting groups. Preferably the protecting groups are removed by reaction with trifluoroacetic acid, using water or aqueous acetonitrile as solvents, at a temperature between about 0 and about 100°C.

A compound of formula (VHI) can be made by reacting a compound of formula (IX):

( X)

where P, P , R^" and R are as defined above, with silver (I) oxide in the presence of an alcohol, preferably methanol, at a temperature between about 20 and about 80°C.

A compound of formula (IX) can be made by reacting a compound of formula (X):

(X)

where P, P , R² and R³ are as defined above, with an alkylchloroformate, preferably iso- butylchloroformate, in the presence of a base, preferably N-methylmorpholine, followed by reaction with diazomethane in the presence of an ethereal solvent, preferably a mixture of tetrahydrofuran and diethylether, at a temperature between about -10 and about 20°C

A compound of formula (X) can be made by oxidising a compound of formula (XI):

(XI) where P, P , R² and R³ are as defined above, preferably with pyridinium dichrσmate, in the presence of an inert dipolar aprotic solvent, preferably N,N-dimethylformamide, at a temperature between about 0 and about 50°C.

A compound of formula (XI) can be made by reacting a compound of formula (VII) with a ketal or acetal, preferably 2,2-dimethoxypropane in acetone, and an acid, preferably p- toluenesulphonic acid, at a temperature between about 0 and about 100°C. The preparation of the compound of formula (VII) was described above.

d. For compounds of formula (I) where R¹ is COOH, deprotecting a compound of formula (X) using an acid, preferably trifluoroacetic acid, in water or aqueous acetonitrile, at a temperature between about 0 and about 100°C.

e. For compounds of formula (I) where R¹ is COΝHR⁶, activating the carboxylic group of a compound of formula (X) with a suitable activating reagent, preferably benzotriazolyl-1- yloxytris(dimethylamino)phosphonium hexafluorophosphate, and reaction with R⁶ΝH₂, where R⁶ is defined above, in the presence of a base, preferably N,N-di- isopropylethylamine in inert ethereal solvent, preferably tetrahydrofuran, at a temperature between about 0 and about 50°C and optionally thereafter removing any protecting groups. Preferably the protecting groups are removed using trifluoroacetic acid in water or aqueous acetonitrile at a temperature between about 0 and about 100°C.

Compounds of formulae (II), (VI), (VII), (VIE) and (X) form a further aspect of the invention.

Salts of the compounds of formula (I) may be formed by reacting the free base, or a salt or a derivative thereof, with one or more equivalents of the appropriate acid (for example a hydrohalic (especially HC1), 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.

The compounds of the invention act as P ₇- (P2Y_ADp or P2T_Ac) 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, coronary revascularisation procedures including angioplasty (PTCA), myocardial infarction, perithrombolysis, 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, 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 cardio-pulmonary 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.

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 a therapeutically effective amount of a compound according to the invention to a person suffering from or susceptible to such a disorder.

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.

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 or carrier. Particularly preferred are compositions not containing material capable of causing an adverse, e.g. an allergic, reaction.

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.

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.

Another possibility is to process the finely 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.

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.

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. 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.

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, flavouring agents, saccharine and carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

EXAMPLES

The invention is illustrated by the following non-limiting examples.

In the examples the NMR spectra were measured on a Varian Unity Inova 300 or 400 spectrometer and the MS spectra were measured as follows: El 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 (Si0₂)) was carried out using Fisher Matrix silica, 35-70 μm. 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

(lR-trα/w)-N-(2-Phenylcyclopropyl)-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-[l,2,3]- triazolo[4,5-rf]pyrimidin-7-amine a) 6-Chloro-5-nitro-2-(propylthio)pyrimidin-4-amine

A stirred solution of 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine (prepared as described in WO9828300) (2.6g) in 1,4-dioxane (50ml) was treated with concentrated ammonia solution (1ml) at room temperature for 24 hours. The reaction mixture was concentrated in vacuo and the residue triturated with hexane to give the sub-title compound (2.2g).

MS (APCI) 247/9 (M-H⁺, 100%).

b) 7-Chloro-5-(propylthio)-3H-[l,2,3]triazolo[4,5-d]pyrimidine

Iron powder (5g) was added in portions over 2 hours to a solution of the product from step a) (5g) in acetic acid (200ml) at 25 °C and the suspension stirred for a further 2 hours. The reaction mixture was neutralised with sodium bicarbonate solution and extracted with dichloromethane. The organic extract was dried (MgSO ) and concentrated in vacuo. The resultant oil was dissolved in acetonitrile (25ml), isoamyl nitrite (7.5ml) added and the solution stirred at 65 °C for 1 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (Si0 , dichloromethane followed by ethyl acetate as eluants) to give the sub-title compound (5g).

MS (APCI) 228/30 (M+H⁺, 100%).

c) 2,3,5-Tri-0-benzoyl-l-deoxy-l-[7-chloro-5-(propylthio)-3H -[l,2,3]-triazolo[4,5- d]pyrimidin-3-yl]-β-D-ribofuranose (together with 2,3,5-tri-0-benzoyl-l-deoxy-l-[7- chloro-5-(propylthio)-3H -[l,2,3]-triazolo[4,5-d]pyrimidin-2-yI]-β-D-ribofuranose and 2,3,5-tri-0-benzoyl-l-deoxy-l-[7-chIoro-5-(propylthio)-3H -[l,2,3]-triazolo[4,5- d]pyrimidin-l-yI]-β-D-ribofuranose)

A mixture of the product from step b) (8g), l-0-acetyl-2,3,4-tri-CM_>enzoyl-β-D- ribofuranose (16g) and p-toluenesulphonic acid were heated together in vacuo at 120°C for 30 minutes. The cooled reaction mixture was purified by chromatography (SiO₂, dichloromethane:ethyl acetate 9: 1 as eluant) to give the sub-title compound ( 15g) as the major fraction in a mixture of isomers (used without further purification).

d) (lR-trαns)-N-(2-Phenylcyclopropyl)-5-(propyIthio)-3-(2,3,5-tri-0-benzoyl-β-D- ribofuranosyl)]-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

A mixture of the products from step c) (3.37 g), (l/?-trαrcs)-2-phenylcyclopropylamine [R- (7?*J?*)]-2,3-dihydroxybutanedioate (1 : 1) (prepared as described by L.A. Mitscher et al, J. Med. Chem., 1986, 29, 2044) (1.5g) and diisopropylethylamine (3 ml) in dichloromethane (60 ml) was stirred at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO₂, ethyl acetateύsohexane 1:4 as eluant) to afford the sub-title compound (3.4 g).

MS (APCI) 771 (M+H⁺, 100%).

e) (lR-trα«s)-N-(2-Phenylcyclopropyl)-5-(propylthio)-3-(β-D-ribofuranosyI)-3H- [l,2,3]-triazoIo[4,5-d]pyrimidin-7-amine

A mixture of the product from step a) (3 g) and sodium methoxide (lg) in methanol (20ml) was stirred 25 °C for 2 hours. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO₂, dichloromethane followed by methanohdichloromethane 1 :9 as eluants) to afford the title compound (lg).

MS (APCI) 459 (M+Η⁺, 100%).

ΝMR δH (d₆-DMSO) 9.4 (IH, d), 7.41-7.10 (5H, m), 6.06 (IH, d), 5.55 (IH, d), 5.26 (IH, d), 4.83-4.80 (2H, m), 4.29-4.25 (IH, m), 3.98 (IH, m), 3.60-3.58 (IH, m), 3.50-3.44 (IH, m), 3.21 (IH, m), 3.00-2.80 (2H, m), 2.25-2.1 (2H, m), 1.80-1.30 (3H, m), 0.90 (3H, t).

Example 2 (lR-trαns)-N-[2-(4-Chlorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)- 3H-[l,2,3]-triazolo[4,5-£Tlpyrimidin-7-amine

a) (lR-trαns)-N-[2-(4-Chlorophenyl)cyclopropyl]-5-(propylthio)-3-(2,3,5-tri-0- benzoyl-β-D-ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

The sub-title compound was prepared by the method of example 1, step d) using (IR- tr /w)-2-(4-chlorophenyl)cyclopropylamine (prepared as described in International Patent Application WO 9905143).

MS (APCI) 805 (M+H⁺, 100%).

b) (lR-trα w)-N-[2-(4-Chlorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

The title compound was prepared by the method of example 1 , step e) using the product from step a).

MS (APCI) 493 (M+Η⁺, 100%).

ΝMR δH (d₆-DMSO) 9.5 (IH, d), 7.34-7.33 (2H, d), 7.24-7.21 (2H, d), 6.06 (IH, d), 5.58 (IH, d), 5.26 (IH, d), 4.83-4.80 (2H, m), 4.29-4.25 (IH, m), 3.98 (IH, m), 3.60-3.58 (IH, m), 3.50-3.40 (IH, m), 3.21 (IH, m), 3.00-2.80 (2H, m), 2.20-2.10 (IH, m), 1.80-1.30 (4H, m), 0.80 (3H, t)

Example 3

(lR-trαns)-N-[2-(3,4-Difluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine a) (lR-trαn5)-N-[2-(3,4-Difluorophenyl)cyclopropyl]-5-(propylthio)-3-(2,3,5-tri-0- benzoyl-β-D-ribofuranosyl)-3H-[l,2,3]-triazoIo[4,5-rf]pyrimidin-7-amine

The sub-title compound was prepared by the method of example 1 step d) using (IR-trans)- 2-(3,4-difluorophenyl)cyclopropylamine [Λ-(i?*J?*)]-2,3-dihydroxybutanedioate (1 : 1) (prepared as described in International Patent Application WO 9905143).

MS (APCI) 806 (M+Η⁺, 100%).

b) (lR-trαns)-N-[2-(3,4-Difluorophenyl)cydopropyl]-5-(propylthio)-3-(β-D- ribofuranosyI)-3H-[l,2,3]-triazoIo[4,5-rf]pyrimidin-7-amine

MS (APCI) 495 (M+Η⁺, 100%)

NMR δH (CDC1₃ + d₆-DMSO) 8.05 (IH, d), 7.14-6.90 (3H, d), 6.36 (IH, d), 5.18-5.14 (IH, d), 4.96-4.90 (IH, m), 4.68-4.64 (IH, m), 4.5 (IH, s), 4.39 (IH, d), 4.29-4.25 (IH, m), 4.0-3.90 (IH, m), 3.80-3.70 (IH, m), 3.21 (IH, m), 3.10-2.80 (2H, ), 2.20-2.10 (IH, m), 1.60-1.30 (4H, m), 0.80 (3H, t)

Example 4

(lR-trα/i5)-N-[2-(4-Methoxyphenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)- 3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

a) (lR-trαns)-N-[2-(4-Methoxyphenyl)cyclopropyl]-5-(propylthio)-3-(2,3,5-tri-0- benzoyl-β-D-ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine The sub-title compound was prepared by the method of example 1, step d) using (IR- trans)-2-(4-methoxyphenyl)cyclopropylamine [i?-(i?*,i?*)]-2,3-dihydroxybutanedioate (1 : 1) (prepared as described in International Patent Application WO 9905143).

MS (APCI) 801 (M+H⁺, 100%).

b) (lR-trαns)-N-[2-(4-Methoxyphenyl)cyclopropyl]-5-(propylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazoIo[4,5-£T|pyrimidin-7-amine

The title compound was prepared by the method of example 1, step e) using the product from step a).

MS (APCI) 489 (M+H⁺, 100%).

NMR δH (d₆-DMSO) 9.4 (IH, d), 7.15-7.10 (2H, d), 6.87-6.85 (2H, d), 6.06 (IH, d), 5.55 (IH, d), 5.26 (IH, d), 4.83-4.80 (2H, m), 4.29-4.25 (IH, m), 3.98 (IH, m), 3.72 (3H, s), 3.60-3.58 (IH, m), 3.58-3.44 (IH, m), 3.12-3.10 (IH, m), 3.0-2.85 (2H, m), 2.15-2.07 (IH, m), 1.80-1.20 (4H, m), 0.84 (3H, t).

Example 5

(li?-trαns)-N-[2-(4-Fluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)- 3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

a) (lR-tr ns)-N-[2-(4-Fluorophenyl)cyclopropyl]-5-(propylthio)-3-(2,3,5-tri-0- benzoyl-β-D-ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

The sub-title compound was prepared by the method of example 1, step d) using (IR- tra/25)-2-(4-fluorophenyl)cyclopropylamine (prepared as described in International Patent Application WO 9905143). MS (APCI) 789 (M+H⁺, 100%).

b) (lR-trαns)-N-[2-(4-Fluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

MS (APCI) 477 (M+Η⁺, 100%).

NMR δH (d₆-DMSO) 9.4 (IH, d), 7.35-7.20 (2H, d), 7.15-7.10 (2H, d), 6.70 (IH, d), 5.55 (IH, d), 5.26 (IH, d), 4.85-4.80 (2H, m), 4.29-4.25 (IH, m), 3.98 (IH, m), 3.65-3.58 (IH, m), 3.50-3.40 (IH, m), 3.20-3.00 (IH, m), 3.00-2.80 (2H, m), 2.20-2.10 (IH, m), 1.80-1.20 (4H, m), 0.84 (3H, t).

Example 6

(lR-trαns)-N-(2-Phenylcyclopropyl)-5-(3,3,3-trifluoropropylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazoIo[4,5-rf]pyrimidin-7-amine

a) (lR-trα«s)-N-(2-PhenyIcyclopropyl)-5-(propylsuIphonyl)-3-(β-D-ribofuranosyl)-3H- [l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

A mixture of the product from example 1 (0.6g) and m-chloroperbenzoic acid (0.9g) was stirred in dichloromethane (20ml) solution for 1 hour. The reaction mixture was washed with aqueous sodium bicarbonate and the organic phase concentrated in vacuo. The residue was purified by chromatography (SiO₂, ethyl acetateύsohexane 1:4 as eluant) to afford the sub-title compound (0.6 g).

MS (APCI) 491 (M+H⁺, 100%). b) (lR-trαns)-N-(2-PhenylcyclopropyI)-5-(3,3,3-trifluoropropylthio)-3-(β-D- ribofuranosyl)-3H-[l,2,3]-triazoIo[4,5-rf]pyrimidin-7-amine

To the product from step a) (0.5g) in dimethylformamide (5ml) solution was added sodium hydrosulphide (0.2g) over 15 minutes. l-Bromo-3,3,3-trifluoropropane (1ml) was added and the mixture stirred for 4 hours at 25 °C. Water was added and the product extracted into ethyl acetate. The organic phase was concentrated in vacuo and the residue purified by chromatography (SiO₂, ethyl acetateύsohexane 1 :4 as eluant) to afford the title compound (O.lg).

MS (APCI) 513 (M+Η⁺, 100%).

NMR δH (d₆-DMSO) 9.54 (IH, d), 7.31-7.10 (5H, m), 6.07 (IH, d), 5.55 (IH, d), 5.26 (IH, d), 4.85-4.80 (2H, m), 4.25-4.07 (IH, m), 4.00-3.95 (IH, m), 3.60-3.50 (IH, m), 3.50-3.40 (IH, m), 3.30-3.00 (3H, m), 2.30-2.21 (2H, m), 1.80-1.20 (3H, m).

Example 7

(lR-trαns)-3-(5-Deoxy-β-D-π^'6o-hexofuranosyl)-N-(2-phenylcycIopropyl)-5- (propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-7-amine

a) (lR-trα/w)-3-[2,3-0-(l-Methylethylidene)-β-D-ribofuranosyl]-N-(2- phenylcyclopropyl)-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

To a solution of (li^trαns)-N-(2-phenylcyclopropyl)-5-(propylthio)-3-(β-D-ribofuranosyl)- 3H-[l,2,3]-triazolo[4,5-J]pyrimidin-7-amine (prepared as described in Example 1) (3.1g) in dry acetone was added 2,2-dimethoxypropane (8ml) followed by /7-toluenesulphonic acid (1.6g). The mixture was stirred for 1 hour, neutralised by the addition of triethylamine and the mixture evaporated. The residue was partitioned between water (50ml) and dichloromethane (50ml). The organic extract was concentrated in vacuo and the residue purified by chromatography (SiO₂, ethyl acetate: isohexane 1 :2 as eluant) to afford the subtitle compound (3.0g).

MS (APCI) 500 (M+H⁺, 100%).

b) (lR-trαns)-l-Deoxy-2,3-0-(l-methyIethylidene)-l-[7-(2-phenylcyclopropylamino)-5- (propylthio)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-3-yl]-β-D-ribofuranuronic acid

A mixture of the product from step a) (3.0g) and pyridinium dichromate (30g) in dry dimethylformamide (30 ml) was stirred for 48 hours. The mixture was poured into water (500ml) and extracted with ethyl acetate, washed with 10% sodium metabisulfite solution. The organic layer was dried, concentrated in vacuo and the residue purified by reverse phase HPLC (NovapakCis, acetonitrile:0.1% aqueous ammonium acetate, 35:65 as eluant) to afford the sub-title compound (2.1g).

MS (APCI) 513 (M+H⁺, 100%).

c) [3aR-[3aα,4α,6α (lR*,2S*),6aα]]-2-Diazo-l-[2,2-Dimethyl-6-[7-(2- phenylcyclopropylamino)-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-d]pyrimidin-3- yl]tetrahydrofuro[3,4-d][l,3]dioxol-4-yl]ethanone

To an ice-cold mixture of the product from step b) (300mg) and N-methylmorpholine (0.059ml) in dry tetrahydrofuran (10 ml) was added isobutylchloroformate (0.076ml) dropwise. The mixture was allowed to attain room temperature and stirred for an additional 30 mins. This mixture was then added slowly to an ethereal solution of diazomethane (3.0g). After 1 hour the mixture was concentrated in vacuo and the residue purified by chromatography (Si0₂, dichloromethane as eluant) to afford the sub-title compound (0.3g).

MS (APCI) 509 (M+H⁺-Ν₂, 100%). d) (lR-trαns)-l,5-Dideoxy-2,3-0-(l-methylethy!idene)-l-[7-(2- phenylcycIopropyl)amino-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-3-yI]-β- D-πio-hexofuranuronic acid, methyl ester

A mixture of the product from step c) (0.3g), methanol (50 ml) and silver (I) oxide (0.3 g) was heated under reflux for 8 hours. The reaction mixture was filtered through Celite and the filtrate concentrated in vacuo. The residue was purified by reverse phase ΗPLC (NovapakCis, acetonitrile:0.1% aqueous ammonium acetate, 60:40 as eluant) to afford the sub-title compound (0.18g).

MS (APCI) 541 (M+Η⁺, 100%).

e) (lR-trα/w)-3-[5-Deoxy-2,3-0-(l-methylethylidene)-β-D-π^' >o-hexofuranosyl)]-N-(2- phenylcyclopropyI)-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-7-amine

To an ice cooled solution of the product from step d) (0.18g) in toluene (10 ml) was added diisobutylaluminium hydride (1.5 M in toluene, 2.2 ml). The mixture was stirred for 30 min, quenched with water (1 ml), concentrated in vacuo and the residue purified by chromatography (Si0₂, dichloromethane as eluant) to afford the sub-title compound (0.085g).

MS (APCI) 513 (M+H⁺, 100%).

f) (lR-trαns)-3-[5-Deoxy-(β-D-π »o-hexofuranosyl)]-N-(2-phenylcyclopropyl)-5- (propylthio)-3H-[1_.2_.3]-triazolo[4,5-rf]pyrimidin-7-amine

A mixture of the product from step e) (85 mg), trifluoroacetic acid (0.1 ml) and water (0.01 ml) was stirred for 15 minutes. The reaction mixture was concentrated in vacuo and the residue purified by chromatography (SiO₂. diethyl ether as eluant) to afford the title compound (0.035g). MS (APCI) 473 (M+H⁺, 100%).

NMR δH (d₆-DMSO) 9.41 (IH, d), 7.31-7.16 (5H, m), 6.05 (IH, d), 5.54 (IH, d), 5.23 (IH, d), 4.79-4.76 (2H, m), 4.47 (IH, t), 4.23 (IH, m), 4.08-4.05 (IH, m), 3.46-3.40 (2H, m), 5 3.19 (IH, m), 2.98-2.87 (2H, m), 2.15 (IH, m), 1.93-1.70 (2H, m), 1.54-1.47 (3H, m), 1.36- 1.31 (lH, m), 0.82 (3H, t).

Example 8

l o (lR-trans)-l -Deoxy-1 -[7- [(2-phenylcyclopropyl)amino] -5-(propylthio)-3H- [1 ,2,3] - triazolo[4,5-rf]pyrimidin-3-yl]-β-D-ribofuranuronic acid

A solution of the product from Example 7, step b) (0.4 lg) in trifluoroacetic acid (3.6ml) was treated with water (0.4ml) and allowed to stand at room temperature for 30 minutes. 15 The mixture was diluted with ethyl acetate (300ml) and the solution stirred with a slight excess of cold, aqueous sodium bicarbonate solution. The mixture was acidified by addition of a slight excess of acetic acid, the ethyl acetate layer was separated, dried and concentrated in vacuo. The residue was purified by chromatography (Si0_2, acetic acid:methanol:chloroform 1 :6:93 as eluant) to afford the title compound (0.29g).

20

MS (APCI) 473 (M+H⁺, 100%).

NMR δH (d₆-DMSO) 9.43 (IH, d), 7.32-7.16 (5H, m), 6.13 (IH, d), 5.76-5.72 (2H, m), 4.93-4.91 (IH, m), 4.63-4.61 (IH, m), 4.39 (IH, d), 3.22-3.20 (IH, m), 3.01-2.92 (IH, m), 25 2.88-2.79 (IH, m), 2.16-2.13 (IH, m), 1.54-1.30 (4H, m), 0.79 (3H, t).

Example 9

(lR-trαn^)-l-Deoxy-N-ethyl-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H- 30 [l,2,3]-triazolo[4,5-rf]pyrimidin-3-yl]-β-D-ribofuranuronamide a) (l/?-trαn5)-l-Deoxy-N-ethyl-2,3-0-(l-methylethylidene)-l-[7-[(2- phenylcyclopropyl)amino]-5-(propylthio)-3H-[l,2,3]-triazolo[4,5-rf]pyrimidin-3-yl]-β-

D-ribofuranuronamide

To a solution of the product from Example 7, step b) (0.4 lg) in anhydrous tetrahydrofuran (10ml) was added benzotriazol-l-yloxytris(dimethylamino) phosphonium hexafluorophosphate (0.39g) followed by N,N-diisopropylethylamine (0.1 lg) and the resultant solution was stirred at room temperature for 40 minutes. The reaction mixture was then treated with a 70% solution of aqueous ethylamine (0.5ml) and stirring continued for a further 1 hour at room temperature. The mixture was neutralised by addition of acetic acid and then partitioned between ethyl acetate (200ml) and a saturated solution of aqueous sodium bicarbonate (200ml). The ethyl acetate layer was washed with brine (3 x 200ml) and concentrated in vacuo. The residue was purified by chromatography (SiO₂, ethyl acetate: isohexane 2:3 as eluant) to afford the sub-title compound (0.39g).

MS (APCI) 540 (M+Η\ 100%).

b) (lR-trαn5)-l-Deoxy-N-ethyl-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H- [l,2,3]-triazolo[4,5-rf]pyrimidin-3-yl]-β-D-ribofuranuronamide

A solution of the product from step b) (0.38g) in trifluoroacetic acid (3.6ml) was treated with water (0.4ml) and allowed to stand at room temperature for 30 minutes. The mixture was diluted with ethyl acetate (300ml) and the resultant solution washed with excess cold, saturated, aqueous sodium bicarbonate solution. The ethyl acetate layer was dried and concentrated in vacuo. The residue was purified by chromatography (SiO₂, methanolxhloroform 4:96 as eluant) to afford the title compound (0.2 lg).

MS (APCI) 500 (M+H⁺, 100%).

ΝMR δH (d₆-DMSO) 9.51 (IH, d), 7.85 (IH, t), 7.32-7.16 (5H, m), 6.17 (IH, d), 5.75 (IH, d), 5.65 (IH, d), 4.83 (IH, q), 4.41-4.37 (IH, m), 4.33 (IH, d), 3.25-3.22 (IH, m), 3.16- 3.09 (2H, m), 2.95-2.90 (IH, m), 2.82-2.77 (IH, m), 2.15-2.1 1 (IH, m), 1.57-1.42 (4H, m), 0.99 (3H, t), 0.78 (3H, t).

Pharmacological data

The preparation for the assay of the P₂τ (P2Y_ADP or P2T_A ) receptor agonist/antagonist activity in washed human platelets for the compounds of the invention was carried out as follows.

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 0.4mM, KC1 2.7 mM, MgCl₂ 1.1 mM, 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 2x10 /ml. This final suspension was stored in a 60 ml syringe at 3°C with air excluded. To allow recovery from PGI -inhibition of normal function, platelets were used in aggregation studies no sooner than 2 hours after final resuspension.

In all studies, 3 ml aliquots of platelet suspension were added to tubes containing CaCl₂ solution (60 μl of 50 mM solution with a final concentration of ImM). 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 μl of 10 mg/ml solution of clottable protein in saline) and 300 nM (10 μl of 15 mM solution in 6% glucose), respectively. Platelets or buffer as appropriate were added in a volume of 150 μl to the individual wells of a 96 well plate. All measurements were made in triplicate in platelets from each donor. The agonist/antagonist potency was assessed as follows

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 was used as the plate reader.

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 μl 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 μl 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.

Antagonist potency was estimated as a % inhibition of the control ADP response to obtain an IC₅₀. Compounds exemplified have pIC₅o values of more than 5.0.

Claims

1. A compound of formula (I):

(D

wherein:

R , ι i •s either alkyl .₆ substituted by OH or COR ; R² is alkyl Cι-₆ or haloalkyl .₆;

R³ is cycloalkyl C₃.₆ optionally substituted by R³;

R⁴ is OR⁶ or NHR⁶;

R⁵ is phenyl optionally substituted by one or more groups selected from alkyl Cι- , halogen and OR⁶; R⁶ is H or alkyl Cι_-6; or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt.

2. A compound according to claim 1 which is:

(la) where R , R^~ and R are as defined in claim 1.

3. A compound according to claim 2 in which R³ is where R⁵ is as defined in claim 1.

4. A compound according to any one of claims 1 to 3 in which R¹ is CH₂OH, (CH₂) OH, COOH or CONHEt.

5. A compound according to any one of claims 1 to 4 in which R^~ is alkyl C optionally substituted by three halogen atoms.

6. A compound according to claim 1 which is:

(li?-trαn5)-N-(2-Phenylcyclopropyl)-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-[ 1,2,3]- triazolo[4,5-J]pyrimidin-7-amine; (l/?-tr π5)-N-[2-(4-Chlorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-

[l,2,3]-triazolo[4,5-d]pyrimidin-7-amine;

(li?-tr π5^,)-N-[2-(3,4-Difluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-

3H-[ 1 ,2,3]-triazolo[4,5-J]pyrimidin-7-amine;

(li?-tran5)-N-[2-(4-Methoxyphenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H- [ 1 ,2,3]-triazolo[4,5-J]pyrimidin-7-amine; (l/?-tr «5)-N-[2-(4-Fluorophenyl)cyclopropyl]-5-(propylthio)-3-(β-D-ribofuranosyl)-3H-

[ 1 ,2,3]-triazolo[4,5-J]pyrimidin-7-amine;

(l/?-trαn5)-N-(2-Phenylcyclopropyl)-5-(3,3,3-trifluoropropylthio)-3-(β-D-ribofuranosyl)-

3H-[l,2,3]-triazolo[4,5-J]pyrimidin-7-amine; (lR-trfl/u)-3-(5-Deoxy-β-D-rιbo-hexofuranosyl)-N-(2-phenylcyclopropyl)-5-(propylthio)-

3H-[l,2,3]-triazolo[4,5-J|pyrimidin-7-amine;

(l/?-trαn5)-l-Deoxy-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[ 1,2,3]- triazolo[4,5-J]pyrimidin-3-yl]-β-D-ribofuranuronic acid;

(li"?-trαn5)-l-Deoxy-N-ethyl-l-[7-[(2-phenylcyclopropyl)amino]-5-(propylthio)-3H-[ 1,2,3]- triazolo[4,5-J]pyrimidin-3-yl]-β-D-ribofuranuronamide;

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 in combination with a pharmaceutically acceptable diluent, adjuvent or carrier.

8. A pharmaceutical composition for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease, comprising a compound according to any one of claims 1 to 6.

9. A pharmaceutical composition for use in the treatment or prevention of unstable or stable angina, comprising a compound according to any one of claims 1 to 6.

10. A compound according to any one of claims 1 to 6 for use in therapy.

1 1. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease.

12. A compound according to any one of claims 1 to 6 for use in the treatment or prevention of unstable or stable angina.

13. The use of a compound according to any one of claims 1 to 6 as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease.

14. The use of a compound according to any one of claims 1 to 6 as an active ingredient in the manufacture of a medicament for use in the treatment or prevention of unstable or stable angina

15. A method of treatment or prevention of a platelet aggregation disorder which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 6 to a person suffering from or susceptible to such a disorder.

16. A method of treatment or prevention of myocardial infarction, thrombotic stroke, transient ischaemic attacks, and/or peripheral vascular disease, which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 6 to a person suffering from or susceptible to such a condition.

17. A method of treatment or prevention of unstable or stable angina which comprises administering a therapeutically effective amount of a compound according to any one of claims 1 to 6 to a person suffering from or susceptible to such a condition.

18. A process for the preparation of a compound of formula (I) where R¹ is CH OH, which comprises reacting a compound of formula (II):

(ii)

where R^~ is defined in claim 1 and P is a protecting group, with R NH₂, where R is defined in claim 1, and a base in the presence of dipolar aprotic solvent or an alcohol, at a temperature between about 100 and about 150°C, and optionally thereafter removing any protecting groups.

19. A process for the preparation of a compound of formula (I) where R¹ is CH OH, which comprises interconverting R^" by reacting a compound of formula (VI):

(VI)

where R^" and R are as defined in claim 1, i) with sodium hydrosulphide (NaSH) in the presence of a dipolar aprotic solvent, at a temperature between about 0 and about 50°C and treating the product of this reaction with an alkyl halide (R² X) in the presence of a dipolar aprotic solvent, at a temperature between about 0 and about 50°C, or ii) with a sodium alkylthiolate (R² SNa) in the presence of a dipolar aprotic solvent, at a temperature between about 0 and about 50°C, where R² is different from the R² being interconverted.

20. A process for the preparation of a compound of formula (I) where R¹ is (CH₂)₂OH, which comprises reducing a compound of formula (VIE):

(vπi)

where P and P are protecting groups, and R² and R³ are as defined in claim 1 , with a metal hydride, in the presence of an inert solvent, at a temperature between about 0 and about 50°C and optionally thereafter removing any protecting groups.

21. A process for the preparation of a compound of formula (I) where R¹ is COOH, which comprises deprotecting a compound of formula (X):

(X)

where P and P are protecting groups, and R^" and R are as defined in claim 1, using an acid in water or aqueous acetonitrile, at a temperature between about 0 and about 100°C.

22. A process for the preparation of a compound of formula (I) where R is CONHR , which comprises activating the carboxylic group of a compound of formula (X) as defined in claim 21 , with a suitable activating reagent, and reacting the resultant compound with R NH , where R is defined in claim 1, in the presence of a base in inert ethereal solvent, at a temperature between about 0 and about 50°C, and optionally thereafter removing any protecting groups.

23. Compounds of formulae (II), (VI), (VII), (Vm) and (X):

(vπ)

(vm)

(X) where P and P are protecting groups, and R² and R³ are as defined in claim 1.