HK1061246B - Intermediates for the preparation of anti-thrombotic 4h-cyclopenta-1,3-dioxol derivatives - Google Patents

Description

FIELD OF THE INVENTION

The present invention provides new intermediates for preparing triazolo[4,5-d]pyrimidine compounds, 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 angioplasty is also compromised by platelet mediated occlusion or re-occlusion.

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 IIb/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).

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 aggregation 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. Med. 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.

ADP-induced platelet aggregation is mediated by the P _2T receptor subtype located on the platelet membrane. The P _2T receptor (also known as P2Y_ADP or P2T_AC) is primarily involved in mediating platelet aggregation/activation and is a G-protein coupled receptor which is as yet uncloaked. 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 P _2T (P2Y_ADP or P2T_AC) antagonists as anti-thrombotic agents.

International Patent Application WO 9905143 discloses generically a series of triazolo[4,5-d]pyrimidine compounds having activity as P_2T (P2Y_ADP or P2T_AC) 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

The invention therefore provides intermediates for preparing a compound of formula (I): wherein:

• R1 is C3-5 alkyl optionally substituted by one or more halogen atoms;
• R2 is a phenyl group, optionally substituted by one or more fluorine atoms;
• R3 and R4 are both hydroxy;
• R is XOH, where X is CH2, OCH2CH2 or a bond;

or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt. provided that:

• when X is CH2 or a bond, R1 is not propyl.
• when X is CH2 and R1 is CH2CH2CF3. butyl or pentyl, the phenyl group at R2 must be substituted by fluorine.
• when X is OCH2CH2 and R1 is propyl, the phenyl group at R2 must be substituted by fluorine.

Alkyl groups, whether alone or as part of another group are straight chained and fully saturated.

Suitably R¹ is a C_3-5 alkyl optionally substituted by one or more fluorine atoms. Preferably R¹ is C_3-5 alkyl optionally substituted on the terminal carbon by three fluorine atoms. More preferably R¹ is 3,33,-trifluoropropyl, butyl or propyl.

Suitably R² is phenyl or phenyl substituted by one or more fluorine atoms. Preferably R² is phenyl, 4-fluorophenyl or 3,4-difluorophenyl.

Suitably R is XOH where X is CH₂, OCH₂CH₂ or a bond.

Preferably R is CH₂OH or OCH₂CH₂OH.

Particularly preferred compounds include:

• [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(4-Fluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
• [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
• [1S-(1α,2α,3β(1S*,2R*),5β]]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxyethoxy)-cyclopentane-1,2-diol;
• [1R-[1α,2α,3β(1R*,2S*),5β]]-3-[5-(Butylthio)-7-[[2-(3,4-difluorophen)cycyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(hydroxymethyl)-cyclopentane-1,2-diol;
• [1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(4-fluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2,3-triol;
• [1S-(1α,2α.3β(1S*,2R*),5β)]-3-[7-[[2-(3,4-Difluorophenyl)cyclopropyl]amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydrocyethoxy)-cyclopentane-1,2-diol;
• [1S-[1α,2α,3β,5β(1S*,2R*)]]-3-(2-Hydroxyethoxy)-5-[7-(2-phenylcyclopropyl)amino]-5-[(3,3,3-trifluoropropyl)thio]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-cyclopentane-1,2-diol
• [1S-[1α,2β,3β,4α(1S*,2R*)]]-4-[5-(Butylthio)-7-[[2-(3,4-difluorophenyl)cyclopropyl]amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]cyclopentane-1,2,3-triol;
• [1S-[1α,2α,3β(1S*,2R*),5β]]-3-[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5-d]pyrimidin-3-yl]-5-(2-hydroxethoxy)-cyclopentane-1,2-diol:

and pharmaceutically acceptable salts or solvates thereof, or solvates of such salts.

There is further provided a process for the preparation of a compound of formula (I) which comprises:

1. (a) reacting a compound of formula (II): 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 C_1-6 alkyl or benzyl, and L is a leaving group such as halogen or SR, with a compound of formula (III): where R² is as defined in formula (I), or is a protected derivative thereof. or where X is a bond:
2. (b) hydroxylation of a compound of formula (IV):

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 C_1-6 alkyl or benzyl, and Z is NH₂ or where R² is defined in formula (I). and for both (a) and (b) optionally thereafter and in any order:

• converting one or more functional groups into further functional groups;
• removing any protecting groups;
• forming a pharmaceutically acceptable salt or solvate, or a solvate of such a salt.

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.

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 C_1-6 alkyl (preferably methyl), benzyl, (C_1-6alkyl)₃Si (preferably t-butyldimethylsilyl), and a C(O)C_1-6alkyl 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.

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 GM Wutz, Wiley-Interscience (1991).

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 C_1-6 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 I to 5 bar, in a solvent, such as acetic acid.

A compound of formula (ll) can be prepared by diazotising a compound of formula (V): 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 C_1-6 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, with a metal nitrite, for example an alkali metal nitrite, especially sodium nitrite in dilute aqueous acid, for example 2M HCl, or with a C_1-6-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.

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): wherein R¹, L, P¹ and P² are as defined above.

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.

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.

A compound of formula (VI) can be prepared by reacting a compound of formula (VII): wherein L and R¹ are as defined above and L' is a leaving group, for example a halogen atom, wherein L and L' are preferably the same, with a compound of formula (VIII): wherein P¹ and P² are as defined above, in the presence of a base such as C_1-6-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.

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 C_1-6 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 axone^™ 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.

A compound of formula (II) 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 OCH₂CO₂R' where R' is C_1-6 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.

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.

Compounds of formula (V) can also be prepared by treating a compound of formula (XI) where R, R³ and R⁴ are as defined in formula (I) or are protected derivatives thereof or R is OCH₂CO₂R' where R' is C_1-6 alkyl or benzyl, or R³ and R⁴ together form a bond in the 5-membered ring. 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.

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

Compounds of formula (XII) can be prepared from compounds of formula (XIV): 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.

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.

Compounds of formula (XI), where R is OCH₂CO₂R' where R' is C_1-6 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.

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-haloacetic 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.

The amines of formula (III) 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, NY, 1978. p120, J. Vallgarda et al, J. Chem. Soc. Perkin 1, 1994,461 or in International Patent Application WO 9905143 .

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 C_1-6-alkyl or an alkali metal or alkaline earth metal hydroxide) or acid (for example a 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.

The compounds prepared using the intermediates of the invention act as P _2T (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, 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 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 prepared using the intermediates 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 prepared using the intermediates 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 prepared using the intermediates according to the invention.

The compounds prepared using the intermediates 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 prepared using the intermediates 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.

Dry powder formulations and pressurised HFA aerosols of the compounds prepared using the intermediates of the invention may be administered by oral or nasal inhalation. For inhalation the compound is desirably finely divided. The compounds prepared using the intermediates 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 prepared using the intermediates 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, com 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: 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 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 [1S-[1α,2a,3β(1S*,2R*),5β]]-3[5-(Butylthio)-7-[(2-phenylcyclopropyl)amino]-3H-1,2,3-triazolo[4,5.d]pyrimidin-3-yl]-5-(2-hydroxethoxy)cyclopentane-1,2-diol a) [3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]carbamic acid, phenylmethyl ester

Potassium carbonate (39.3g) was added to a suspension of [3αR-(3aα,4α,6α,6aα)]-6-amino-tetrahydro-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-ol, hydrochloride, (prepared as described in WO 9905142 ) (27.1g) in 4-methyl-2-pentanone (500ml). Water (150ml) was then added followed by dropwise addition of benzyl chloroformate (23.1g). 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 (2x50ml). 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 (39.23g),

NMR δH (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, brs), 1.69 (1H, d), 1.41 (3H, s), 1.26 (3H, s).

b) [3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester

Potassium tert-butoxide (3.6g) in tetrahydrofuran (20ml) was added over 5 minutes to a solution of the product from step a) (39.23g) in tetrahydrofuran (200ml). After 15 minutes, ethyl bromoacetate (3.7ml) in tetrahydrofuran (10ml) was added dropwise. The mixture was stirred at 0°C for 10 minutes, then further ethyl bromoacetate was added (3.7ml x4). The reaction mixture was stirred at 0°C a further 2 hours. Lithium borohydride (2.79g) was then added portionwise to the resulting suspension and the reaction mixture was stirred at <5°C for 16 hours. Glacial acetic acid (23g) was added dropwise to the cold mixture. After stirring for 30 minutes, water (100ml) 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 (38.6g).

MS (APCI) 218 (M+H⁺, 100%).

c))[3aR-(3aα,4α,6α,6aα)]-2-[[6-Amino-2,2-dimethyl-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxyl-ethanol

A slurry of 5% palladium on charcoal (4g) in ethanol was added to a solution of the product from step b) (39;96g) in ethanol (350ml) 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 compounds (23.65g).

MS (APCI) 160 (M+H⁺, 100%).

Claims (1)

1. A compound selected from :

   [3aS-(3aα,4α,6α,6aα)]-[Tetrahydro-6-hydroxy-2,2-dimethyl-4H-cyclopenta-1,3-dioxol-4-yl]-carbamic acid, phenylmethyl ester;

   [3aS-(3aα,4α,6α,6aα)]-[2,2-Dimethyl-6-(2-hydroxyethoxy)-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]-carbanic acid, phenylmethyl ester: and

   [3aR-(3aα,4α,6α,6aα)]-2-[[6-Amino-2,2-dimethy-tetrahydro-4H-cyclopenta-1,3-dioxol-4-yl]oxy]-ethanol.