SE510812C2 - (-) - (3R) -3-methyl-4- (4- (4- (4-pyridyl) piperazin-1-yl) phenoxy) butyric acid as cellular adhesion inhibitor - Google Patents

Abstract

The novel optically active compound (-)-(3R)-3-methyl-4--4-[4-(4-pyridyl)-piperazine-1-yl]phenoxy butyric acid, and pharmaceutically-acceptable salts, esters, amides or solvates thereof. Processes for the preparation of the compound, pharmaceutical compositions containing the compound and its use to inhibit cellular adhesion, for example platelet aggregation.

Description

510 812 2 such as an enzyme or a receptor. The separate enantiomers may therefore possess different potencies as enzyme inhibitors or receptor antagonists. In addition to the rate and extent of absorption, the distribution, metabolism and excretion observed when one enantiomer is dosed to a warm-blooded animal may differ from that observed when the mirror image compound is dosed in this manner, namely, the enantiomers may possess different pharmacokinetic properties.

Furthermore, the stereochemical purity of an organic compound may also be of importance for the nature and extent of side effects that may be obtained when a pharmacologically active compound is dosed. Thus, one enantiomer may be a useful compound, while the other enantiomer may give rise to harmful side effects or toxicity. For example, it has been suggested that one of the enantiomers of thalidomide was a safe and effective sedative, while the other enantiomer controlled the teratogenic side effects of the racemic mixture.

The optically active compound of the present invention is an optical isomer of the racemic mixture (3RS)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]-phenoxy}butyric acid, [hereinafter the (3RS)-racemic mixture] which is described as the trifluoroacetic acid salt in Example 132 of WO 94/22834 and Example 203 of WO 94/22835. It is described therein that such compounds are useful in the treatment of a variety of diseases involving cell adhesion, such as the formation of blood thrombi following platelet aggregation. Blood thrombi can lead to diseases such as thrombosis, stroke, thrombotic events following unstable angina, myocardial infarction, atherosclerosis, thromboembolism and reocclusion during or after thrombolytic therapy.

The antiplatelet aggregating effect of the compounds is stated to be based on the ability of the compounds to inhibit the binding of adhesion molecules, such as fibrinogen and von Willebrand factor, to glycoprotein IIb/IIIa (hereinafter GPIIb/IIIa) which is held in the membrane of each platelet. The necessary activation and dimerization of e.g. the platelet-carrying fibrinogen thereby does not occur, and processes such as thrombus formation and platelet aggregation are inhibited. 3,510,812 As a possible aid in the search for compounds with improved therapeutic ratio, it is desirable to find a compound with increased potency compared to the compounds described in WO 94/22834 and WO 94/22835.

It is also known that there are several classes of adhesion molecules, such as integrins, selectins and cadherins. Integrins are found on leukocytes and platelets, and selectins are found on leukocytes and endothelial cells. Within each class of adhesion molecules there are many members. The integrin family includes, for example, GPIIb/IIIa which binds fibrinogen, integrin otvβ; which binds vitronectin and integrin otgβ1 which binds fibronectin. It is believed that the more useful therapeutic platelet aggregation inhibitors possess a selectivity of inhibitory effect between classes of adhesion molecules and between family members of each class of adhesion molecules. It is thus also desirable to find a compound which possesses this selectivity or which possesses higher selectivity than known platelet aggregation inhibitors.

It is also known that there are several classes of GPIIb/IIIa antagonists. Monoclonal antibody antagonists against GPIIb/IIIa have, for example, been produced. Small molecules that inhibit the binding of adhesion molecules to GPIIb/IIIa are also known, for example from US-A-5,039,805 and 5,084,446, from CA-A-2,008,161, 2,037,153 and 2,061,661, and from Alig et al., J. Med. Chem., 1992, 35, 4393. The structures of these compounds are usually based on the binding regions of the adhesion molecules, for example the amino acid sequence RGD (arginylglycylaspartate) in the structure of fibrinogen. It is believed that such compounds can be used to inhibit platelet aggregation and, for example, thrombus formation for a sufficient period of time, allowing healing of damaged tissue without the deleterious consequences of overly robust platelet aggregation processes.

It is a theoretical concern with the different classes of GPIIb/IIIa antagonists that inhibition of platelet aggregation may lead to a decrease in the blood coagulation rate and therefore an increase in bleeding events and times. 510 812 4 Although a small increase in bleeding times may be acceptable, some clinically relevant bleeding events, such as intracranial hemorrhage, may be life-threatening.

It is thus desirable to find a compound with the advantage of the potent GPIIb/IIIa antagonist activity described for the compound in Example 132 of WO 94/22834 which does not possess or which possesses to a lesser extent the disadvantages of increased bleeding times and/or adverse clinically relevant bleeding events associated with the known GPIIb/IIIa antagonists.

According to the present invention, there is provided the optically active compound (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy}butyric acid or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer. The (-)-(3R) compound possesses significantly better potency as a GPIIb/IIIa antagonist than the corresponding (+)-(3S) isomer (more than 10-fold more potent). The (-)-(3R) compound also possesses selectivity for inhibitory effect between classes of adhesion molecules and between family members of such classes. For example, the compound possesses activity against the binding of GPIIb/IIIa to fibrinogen (pIC50=7.65) but not the binding of otvß; to vitronectin (pIC50 less than 4) or the binding of ot5ß1 to fibronectin (pIC50 less than 4). The (-)-(3R) compound is consequently a novel, potent and selective fibrinogen receptor antagonist which significantly reduces the propensity or possibility of obtaining negative effects, such as excessive bleeding, associated with the administration of other fibrinogen receptor antagonists, such as the (3RS) racemic mixture.

Use of the (-)-(3R) compound also eliminates the tendency or possibility of adverse effects associated with the administration of the therapeutically less effective (+)-(3S) compound which is a component of the (3RS) racemic mixture. Use of the (-)-(3R) compound allows for a clearer structure-activity-toxicity analysis and provides an improved therapeutic relationship. It is therefore desirable to use the (-)-(3R) compound of the present invention rather than the (3RS) racemic mixture of Example 132 of WO 94/22834.

Particular pharmaceutically acceptable salts of the (-)-(3 R) compound of the invention include, for example, salts with acids which give physiologically acceptable anions, such as salts with mineral acids, for example, a hydrogen halide, such as hydrogen chloride or hydrogen bromide, sulfuric acid or phosphoric acid, and salts with organic acids, for example, trifluoroacetic acid. Other pharmaceutically acceptable salts include, for example, salts with inorganic bases, such as alkali metal and alkaline earth metal salts, for example, sodium salts, ammonium salts, and salts with organic amines and quaternary bases which form physiologically acceptable cations, such as salts with methylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, 1-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylaminonium hydroxide.

Particular pharmaceutically acceptable esters of the (-)-(3R) compound of the invention include, for example, ester derivatives of the carboxylic acid group of the compound of the invention, for example, esters formed with alcohols, such as (1-6C) alcohols (e.g. methanol, ethanol, propanol and tert-butanol), indanol, adamantol, (1-6C) alkanoyloxy(1-4C) alcohols (e.g. pivaloyloxymethanol) and (1-4C) alkoxycarbonyl-(1-4C) alcohols (e.g. methoxycarbonylmethanol).

Particular pharmaceutically acceptable amides of the (-)-(3R) compound of the invention include, for example, amide derivatives of the carboxylic acid group of the compound of the invention, for example, amides formed with amines such as ammonia, (1-4C)alkylamines (e.g. methylamine), di-(1-4C)alkylamines (e.g. dimethylamine, fl-ethyl-fl-methylamine and diethylamine), (1-4C)alkoxy-(2-4C)alkylamines (e.g. 2-methoxyethylamine), phenyl-(1-4C)alkylamines (e.g. benzylamine) and amino acids (e.g. glycine or an ester thereof).

Particular amides of the (-)-(3R) compound of the invention thus include -methyl-, -, -dimethyl-, -, -ethyl-N-methyl- and -diethylbutyranides. Particular pharmaceutically acceptable solvates of the (-)-(3R) compound of the invention include, for example, hydrates, e.g., a hemihydrate, monohydrate, dihydrate or trihydrate or an alternative amount thereof.

The phrase "substantially free of the (+)-(3S) stereoisomer", as used above, means that there is at least 90% by weight of the (-)-(3R) isomer and 10% by weight or less of the corresponding (+)-(3S) isomer. Preferably there is at least 95% by weight of the (-)-(3R) isomer and 5% by weight or less of the (+)-(3S) isomer. More preferably there is at least 99% by weight of the (-)-(3R) isomer and 1% by weight or less of the (+)-(3S) isomer. The (-)-(3R) compound of the invention or a pharmaceutically acceptable salt, ester, amide or solvate thereof may be prepared by any method known in the art for the preparation of such a compound. Suitable methods include asymmetric synthesis involving a suitable chiral intermediate and resolution of the (3RS) racemic mixture. Such processes constitute a further feature of the invention and include the following: a) Reaction of 4-[4-(4-pyridyl)piperazin-1-yl]phenol, or a reactive derivative thereof, with the chiral intermediate (3R)-4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof.

The reaction is conveniently carried out in the presence of a strong base, such as an alkali metal hydride, for example sodium hydride. Suitable solvents include amides, such as dimethylformamide. The reaction is conveniently carried out at a temperature in the range of 0-100°C.

Suitable esters of the chiral intermediate (3R)-4-hydroxy-3-methylbutyric acid include, for example, methyl, ethyl, propyl and tert-butyl esters. Suitable reactive derivatives thereof include, for example, (3R)-4-halogeno-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester), such as the 4-chloro and 4-bromo derivatives, (3R)-4-alkanesulfonyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester), such as the 4-methanesulfonyloxy derivative or (3R)-4-allylsulfonyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester), such as the 4-(p-toluenesulfonyloxy) derivative. b) Reaction of a compound of formula I where L is a leaving atom or group, with the chiral intermediate (3R)-3-methyl-4-[4-(piperazin-1-yl)phenoxy]butyric acid or an acid addition salt thereof.

Examples of values for L include halogen, such as chlorine or bromine, and cyano.

Examples of acid addition salts of (3R)-3-methyl-4-[4-(piperazin-1-yl)phenoxy]butyric acid include, for example, hydrochlorides.

The reaction may conveniently be carried out at a temperature in the range of -10 to 120°C, preferably 10-100°C. Suitable solvents include, for example, ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, alcohols such as ethanol, and hydrogen chloride.

Under certain circumstances, e.g. when an acid addition salt of (3R)-3-methyl-4-[4-(piperazin-1-yl)phenoxy]butyric acid is used as the starting material, the reaction can advantageously be carried out in the presence of a base. Examples of suitable bases include tertiary amines, such as triethylamine, and alkali metal hydroxides, carbonates and bicarbonates, such as sodium or potassium hydroxide, carbonate or bicarbonate 510 812 s c) Decomposition of an ester of formula II CH, O\/:\/CO2R WN II where R is a carboxyl protecting group.

R may be any conventional carboxyl protecting group which can be removed without disturbing other parts of the molecule. Examples of carboxyl protecting groups include (1-6C)alkyl groups (such as methyl, ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl group in any of which may optionally have one or two halogeno, (1-4C)alkyl, (1-4C)alkoxy or nitro.

The decomposition may be carried out using any of the conventional reagents and conditions known in the art for the conversion of carboxylic acid esters to carboxylic acids. Thus, for example, the decomposition may be carried out by base-catalyzed hydrolysis, for example, using an alkali metal hydroxide, such as lithium, potassium or sodium hydroxide, or a tertiary amine, such as triethylamine, in the presence of water. The base-catalyzed hydrolysis may be carried out in the presence of a solvent, such as an alcohol, such as methanol or ethanol, or an ether, such as tetrahydrofuran or dioxane. The decomposition may alternatively be carried out by acid-catalyzed hydrolysis, for example, using aqueous acetic acid or trifluoroacetic acid. The temperature is preferably in the range of -10 to 100°C, e.g. 10-50°C. When the alcohol residue is t-butyl, it can be removed by heating, e.g. at a temperature of 80-150°C, separately or in the presence of a suitable diluent, such as diphenyl ether or diphenyl sulfone. A benzyl group can be removed by catalytic hydrogenation, e.g. by hydrogenation in the presence of palladium on carbon at a temperature in the range of -10 to 100°C in the presence of a solvent, such as an alcohol, e.g. methanol or ethanol. d) Resolution of the (3 RS)-racemic mixture, (3 RS)-3-methyl-4-{4-[4-(4-pyridyl)-piperazin-1-yl]phenoxy}butyric acid.

The resolution of the butyric acid derivative of the (3 RS) racemic mixture can be carried out by conventional methods, for example by salt formation using an optically active base, followed by separation, for example by fractional crystallization of the two salts thus prepared and regeneration of the separated (-)-(3R) and (+)-(3S) compounds by acidification of the separated salts.

The resolution of the butyric acid derivative of the (3 RS) racemic mixture can also be carried out by the conventional methods of forming a diastereoisomeric pair of esters by reaction with an optically active alcohol, separating the esters, e.g. by chromatography, and regenerating the separate (-)-(3R) and (+)-(3 S) compounds by hydrolysis of the separated esters. An analogous route involving the preparation of a diastereoisomeric pair of amides can also be used.

The preparation of the (-)-(3R) compound and chiral intermediates is described in the following non-limiting examples, which are provided for illustrative purposes only.

Certain of the chiral intermediates defined above are novel, and according to a further aspect of the invention there is thus provided the compound tert-butyl-(3R)-3-methyl-4-hydroxybutyrate or a reactive derivative thereof, substantially free of the (3S)-stereoisomer. A particularly reactive derivative which may be mentioned is tert-butyl-(3R)-3-methyl-4-(p-toluenesulfonyloxy)butyrate.

The phrase "substantially free of the (3S) stereoisomer", as used above, has the same meaning as given in relation to the (-)-(3R) compound of the invention. When a pharmaceutically acceptable salt of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reacting said compound with a suitable acid or base using a conventional method. When a pharmaceutically acceptable ester or amide of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reacting said compound with a suitable alcohol or amine, as appropriate using a conventional method.

The ability of the (-)-(3R) compound of the invention to inhibit platelet aggregation and to inhibit the binding of fibrinogen to GPIIb/IIIa can be demonstrated using the standard test procedures (a) and (b) described in WO 94/22834, which test procedures are hereby incorporated by reference. The (-)-(3R) compound of the invention possesses activity against the adenosine diphosphate (ADP)-induced aggregation of human platelets with a pAg = 7.3 and against the binding of fibrinogen to GPIIb/IIIa with a pIC50 = 7.65.

As indicated above, the (-)-(3R) compound of the invention may be used in the therapy or prevention of diseases in which cell adhesion (especially platelet aggregation) is involved, e.g. venous or arterial thrombosis (e.g. pulmonary embolism, stroke and thrombotic events following unstable angina and transient ischemic attack), cerebral infarction, atherosclerosis, thromboembolism and reocclusion during and after thrombolytic therapy. The compounds may also be useful for the prevention of reocclusion and restenosis after percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass grafting. It should also be noted that the compounds may be useful in the treatment of other diseases mediated by the binding of adhesion molecules to GPIIb/IIIa, e.g. cancer.

According to a further aspect of the invention, there is provided the use of the (-)-(3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer as a medicament. 11 510 812 According to a further aspect of the invention, there is provided the use of the (-)-(3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer for the preparation of a medicament for the prevention or treatment of a disease involving platelet aggregation.

According to a further aspect of the invention, there is provided the use of the (-)-(3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer for the preparation of a medicament for the prevention or treatment of a disease involving the binding of fibrinogen to GPIIb/IIIa.

According to a further aspect of the invention, there is provided the use of the (-)-(3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer for the manufacture of a medicament for the prevention or treatment of thrombotic events following unstable angina. The (-)-(3R) compound of the invention is generally administered for this purpose by an oral, rectal, topical, intravenous, subcutaneous, intramuscular or inhalation route, such that a dose in the range of 0.01-50 mg/kg body weight is given, depending on the route of administration, the age and sex of the patient and the severity of the condition being treated. The (-)-(3R) compound of the invention is generally used in the form of a pharmaceutical composition comprising the (-)-(3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer, in admixture with a pharmaceutically acceptable diluent or carrier. Such a composition is provided as a further feature of the invention and may be in a variety of dosage forms. It may, for example, be in the form of tablets, capsules, solutions or suspensions for oral administration, in the form of creams or ointments or a transdermal (skin) patch for topical administration, in the form of a suppository for rectal administration, in the form of a sterile solution or suspension for administration by intravenous or intramuscular injection, in the form of an aerosol or nebulizer solution or suspension, for administration by inhalation, and in the form of a powder, together with pharmaceutically acceptable inert solid diluents, such as lactose, for administration by insufflation.

Depending on the route of administration, the composition may comprise, for example, 0.1-99.9% by weight of the (-)-(3R) compound of the invention.

The pharmaceutical compositions may be obtained by conventional methods using pharmaceutically acceptable diluents and carriers well known in the art. Tablets and capsules for oral administration may conveniently be formed with an enteric coating, for example comprising cellulose acetate phthalate, to minimize contact of the (-)-(3R)-compound of the invention with gastric acids. The (-)-(3R) compound of the invention may be co-administered or co-formulated with one or more agents known to be of value in the diseases or conditions to be treated, e.g. a known platelet aggregation inhibitor (e.g. aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a hypolipidemic agent, antihypertensive agent, thrombolytic agent (such as streptokinase, urokinase, pro-urokinase, tissue plasminogen activator and derivatives thereof), a beta-blocker or a vasodilator may also be advantageously present in a pharmaceutical composition of the invention for use in the treatment of a cardiovascular disease or condition.

In addition to its use in therapeutic medicine, the (-)-(3R) compound of the invention is also useful as a pharmacological tool in the development and standardization of test systems for evaluating the effects of adhesion molecules on laboratory animals, such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new drugs. The (-)-(3R) compound of the invention can also be used, due to its platelet aggregation inhibitory properties, to help store blood and maintain the viability of blood and blood vessels in warm-blooded animals (or parts thereof) undergoing artificial extracorporeal circulation, e.g. during limb or organ transplantation. When used for this purpose, the (-)-(3R) compound of the invention is generally administered so that a stable concentration in the range of e.g. 0.1-10 mg/l is achieved in the blood.

The invention is now illustrated by the following non-limiting examples, in which unless otherwise stated: concentrations and evaporations were carried out by rotary evaporation under vacuum, operations were carried out at room temperature, namely in the range of 18-26°C, column chromatography was carried out on silica gel (Merck 7736) available from E Merck and Co., Dannstadt, Germany, yields are given for illustration only and are not necessarily the maximum obtainable by diligent process development, proton NMR spectra were normally determined at 200 MHz or 250 MHz using tetramethylsilane (TMS) as internal standard and are expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for the designation of major peaks: s, singlet, m, multiplet, t, triplet, br, broad, d, doublet, and the following abbreviations have been used for particular organic solvents: THF for tetrahydrofuran, DMF for flfi-dimethylformamide and DMSO for dimethyl sulfoxide. 14 510 812 Example 1 f -)-( 3 R)-3 -methyl-4- 4-[4-(4-pyridyl)piperazin-1-ylphenoxy}butyric acid hydrochloride Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 4-[4-(4-pyridyl)piperazin-1-yl]phenol (15.5 g) in dry DMF (120 ml), and the mixture was stirred for 45 min. Tert-butyl-(3 R)-3-methyl-4-(p-toluenesulfonyloxy)butyrate (20 g) was added, and the mixture was stirred for 20 h. The mixture was evaporated, and the residue was partitioned between dichloromethane and water. The organic phase was washed with water, filtered through phase-separating paper (Whatman IPS) and evaporated. The residue was triturated under diethyl ether. The solid thus obtained was recrystallized from ethyl acetate, giving (-)-(3 R)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy}butyrate (10.6 g). mp 112-113°C, [ab = 5.5° (conc. = 1 g/100 ml methanol, 20°C, NMR (C003) ß s,3(2H,d), 6.s9(4H,m), 6.7(zH,m), 3.79(2H,d), 3_46(4H,m), 3.28(4H,m), 2.31-2.53(2H,m), 2.08-2.21(11-1,m), 1.44(9H,s), 1.07(31-1,d).

A mixture of tert-butyl-(-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy}butyrate (10.53 g) and 1N aqueous hydrochloric acid (250 ml) was stirred for 44 hours. 1N aqueous sodium hydroxide (250 ml) was added, and the mixture was cooled to 5°C. The mixture was filtered, and the filtrate was evaporated.

Water (150 ml) was added, and the resulting precipitate was isolated and washed successively with water, acetone and diethyl ether. The material thus obtained was stirred with 1N aqueous hydrochloric acid (25 ml) for 16 hours. The mixture was cooled to 5°C and filtered. The solid thus obtained was washed successively with water, acetone and diethyl ether and dried to give -(-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)piperazin-1-yl]phenoxy}butyric acid hydrochloride (7.9 g). 15 510 812 M.p. 203-205°C, [(110 = 6.2° (conc. = 1 g/100 m1 methanol, 20°C), NMR (dóDMSO) ö 13.8(1H,br), 12.1(1H,br), 8.72(2H,d), 7.28(2H,d), 6.9(4H,m), 3.8(6H,m), 3.18(1H,m), 2.23(1H,m), 1.0(3H,d), rn/e 356(M+H)+, HCI: C, 58.5, N, 10.2, Found: C, 58.3, H, 6.9, N, 10.2%.

The necessary chiral starting material was prepared as follows: Sodium bis(trimethylsilyl)amine (1M in THF, 170 ml) was added dropwise to a solution of (4S)-4-isopropyl-3-propionyloxazolidin-2-one (J. Am. Chem. Soc., 1981, 103, 2127; 28.4 g) in dry THF (500 ml) which had been cooled to -70°C and placed under an argon atmosphere. The rate of addition was adjusted so that the temperature of the reaction mixture did not exceed -67°C. The resulting solution was stirred at -70°C for 30 min. Tert-butyl bromoacetate (423 g) was added dropwise, and the solution was stirred at -70°C for 3 h. The solution was then allowed to warm to room temperature. The solvent was evaporated. and the residue was partitioned between diethyl ether and water. The organic phase was separated, filtered through phase separating paper (Whatman IPD) and evaporated. The residue was triturated under hexane at -40°C to give a solid (21.6 g). A second solid fraction (4.4 g) was obtained by evaporating the hexane solution and purifying the residue by silica gel filtration chromatography starting from hexane and progressing to 1/10 ethyl acetate/hexane. The two batches of solid were combined and recrystallized from hexane to give (4S)-3-[(2R)-3-tert-butoxycarbonyl-2-methylpropionyl]-4-isopropyloxazolidin-2-one (22.5 g).

Mp. 64-65°C, NMR(CDCl3) δ 4.41(1H,m), 4.21(2H,m), 4.12(1H,m), 2.79(1H,m), 2.28-2.4(2H,m), 1.41(9H,s), 1.16(3H,d), 0.9(6H,m). 510 812 16 Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38 g) were added sequentially to a stirred mixture of (4S)-3-[(2R)-3-tert-butoxycarbonyl-2-methylpropionyl]-4-isopropyloxazolidin-2-one (22.5 g), water (280 ml) and THF (800 ml) which had been cooled to 5°C. The resulting mixture was stirred at 5°C for 3 hours.

A saturated aqueous solution of sodium metabisulfite was added to destroy the excess hydrogen peroxide, and the solvent was evaporated. The residue was extracted with dichloromethane. The aqueous solution was acidified by the addition of an aqueous solution of citric acid and extracted with dichloromethane. The extracts were combined, washed with water and filtered through phase separating paper. The filtrate was evaporated to give 1-tert-butyl-(3R)-3-methylsuccinate as an oil (12.9 g).

NMR (CDCl 3 ) δ 2.9(1H,m), 2.64(1H,m), 2.37(1H,m), 1.4(9H,s), 1.23(3H,d).

Borane-dimethylsulfide complex (10M, 10.3 ml) was added over 15 min to a stirred mixture of 1-tert-butyl(3R)-3-methylsuccinate (12.9 g) and THF (200 ml) which had been cooled to -10°C and placed under argon gas. The mixture was stirred at -10°C for 30 min. The mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was cooled again to 5°C, and methanol (50 ml) was added portionwise.

The mixture was allowed to warm to room temperature and stirred for 30 min. The mixture was evaporated and the residue partitioned between dichloromethane (100 ml) and water (100 ml). The organic phase was filtered through phase separating paper and evaporated to give tert-butyl-(3R)-4-hydroxy-3-methylbutyrate as an oil (11 g).

NMR(CDCl3) δ 8.55(2H,m), 2.1-2.4(3H,m), 1.46(9H,s), 0.98(3H_d). p-Toluenesulfonyl chloride (13.2 g) was added portionwise to a stirred mixture of tert-butyl-(3R)-4-hydroxy-3-methylbutyrate (11 g), methylamine (21 ml) and dichloromethane (120 ml), and the mixture was stirred for 20 hours. The mixture was washed successively with water and dilute aqueous sodium carbonate solution. The organic solution was filtered through phase-separating paper and evaporated to give tert-butyl-(3R)-3-methyl-4-(p-toluenesulfonyloxy)butyrate as an oil (20 g).

NMR(CDCl 3 ) δ 7.6(2H,d), 7.33(2H,d), 3.92(2H,d), 2.45(3H,s), 2.18-2.47(2H,m), 2.0-2.15(1H,m), 1.42(9H,s), 0.95(3H,d).

Example 2 Illustrative pharmaceutical dosage forms suitable for presenting the compound of the invention for therapeutic or prophylactic use comprising the following, which may be obtained by conventional methods well known in the art: a) mg tablet active ingredient 1.0 lactose Ph. Eur. 93.25 croscarmellose sodium 4.0 corn starch paste 0.75 (5% w/v water-containing paste) magnesium stearate 1.0 b) Tablet II mg tablet active ingredient 50 lactose Ph. Eur. 223.75 croscarmellose sodium 6.0 corn starch 15.0 polyvinylpyrrolidone 2.25 (5% w/v water-containing paste) magnesium stearate 3.0 510 812 18 c) Tablet III mg tablet active ingredient 100 lactose Ph. Eur. 182.75 croscarmellose sodium 12.0 corn starch paste 2.25 (5% w/v water-containing paste) magnesium stearate 3.0 (d) Kagsel mg¿l_ active ingredient 10 lactose Ph.Eur. 488.5 magnesium stearate 1.5 (e) injection mg¿ml active ingredient (acid addition salt) 1.0 sodium chloride 9 0 purified water to 1.0 ml Example 3 The following is a description of a study of the effects of the (-)~(3R) compound of the invention and the corresponding (3RS) racemic mixture in the rat. Four groups of 10 Alderly Park Wistar rats (each group comprising 5 males and 5 females) were dosed orally with the (3RS) racemic mixture at daily doses of 0, 25, 100 or 500 mg/kg. Dosing continued for a total of seven days. The animals were sacrificed and examined. Adverse effects were noted in the livers of six of the group of 10 rats dosed at 500 mg/kg/day.

Four groups of 10 Alderly Park Wistar rats (each group containing 5 males and 5 females) were dosed orally with the (-)-(3R) compound of the invention at daily doses of 0, 50, 250 and 1000 mg/kg. The highest dose was not tolerated. After four or five days, four of the animals from this group were sacrificed. The remaining six animals were dosed at 500 mg/kg/day for the remainder of the study. Dosing continued for a total of fourteen days. The animals were sacrificed and examined. No adverse effects were noted in the livers of the group of rats dosed at 250 mg/kg/day. The six animals dosed at 1000 mg/kg/day for three or four days and then at 500 mg/kg/day for ten or eleven days also showed no adverse effect on the liver.

Based on such observations, it is apparent that the (-)-(3R) compound of the invention does not cause a significant negative effect on the rat liver at 500 mg/kg/day.

Indirectly, the (-)-(3R) compound is less toxic than the (3RS) racemic mixture.

Claims (1)

1. D.) 510 812 Patent claims. The optically active compound (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl] phenoxy} butyric acid or a pharmaceutically acceptable salt, ester, amide or a solvate thereof, substantially free of the (+) - (3S) stereoisomer. An optically active compound according to claim 1, wherein there is at least 90% by weight of the (-) - (3R) isomer and 10% by weight or less of the corresponding (+) - (3S) isomer. An optically active compound according to claim 1, wherein there is at least 95% by weight of the (-) - (3R) -isomer and 5% by weight or less of the corresponding (+) - (3S) -isomer. An optically active compound according to claim 1, wherein there is at least 99% by weight of the (-) - (3R) isomer and 1% by weight or less of the corresponding (+) - (3S) isomer. . An optically active compound according to any one of claims 1-4, wherein the pharmaceutically acceptable salt is in the form of a hydrochloride salt. . An optically active compound according to any one of claims 1-4, wherein the pharmaceutically acceptable ester is in the form of methyl, ethyl, propyl or tert-butyl ester. . An optically active compound according to any one of claims 1-4, wherein the pharmaceutically acceptable arnide is in the form of an N-methyl, N, N-dimethyl, N-ethyl-N-methyl or N, N-diethylbutyramide. . An optically active compound according to any one of claims 1-4, wherein the pharmaceutically acceptable solvate is in the form of a hydrate. A process for the preparation of the optically active compound or a pharmaceutically acceptable salt, an ester, amide or a solvate thereof, according to any one of the preceding claims, which comprises: a) reacting 4- [4- (4-pyridyl) piperazin-1-yl] phenol, or a reactive derivative thereof with the chiral intermediate (3R) -4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative thereof, b) reacting a compound of formula I wherein L is a leaving atom or group, with the chiral intermediate (3R) -3-methyl-4- [4- (piperazin-1-yl) phenoxy] butyric acid or an acid addition salt thereof, c) decomposing a ester of the formula II: Q 0 \ / \ / CO2R fr: where R is a carboxyl protecting group, d) dissolving the (3RS) -racemic mixture, (3RS) -3-methyl-4- {4- [4- (4) pyridyl) piperazin-1-yl] phenoxy} butyric acid, and when a pharmaceutically acceptable salt of the (-) - (3R) compound is required, reacting the resulting compound with an appropriate acid or base, and when a Pharmaceutically acceptable ester or amide of the (-) - (3R) compound is required, reacting the resulting compound with a suitable alcohol or amide. The optically active compound tert-butyl (3R) -3-methyl-4-hydroxybutyrate or a reactive derivative thereof, substantially free of the (3S) stereoisomer. A compound according to claim 10, wherein the reactive derivative is tert-butyl (3R) -3-methyl-4- (p-toluenesulfonyloxy) butyrate. A medicament composition, comprising the optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, as claimed in any one of claims 1 to 8, in admixture with a pharmaceutically acceptable diluent or carrier. Use of the optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, as claimed in any one of claims 1 to 8, for the manufacture of a medicament for the prevention or treatment of a disease comprising platelet aggregation. Use of the optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, according to any one of claims 1 to 8, for the manufacture of a medicament for the prevention or treatment of a disease comprising binding of fibrinogen to GPIIb / llla. Use of the optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, as claimed in any one of claims 1 to 8 for the manufacture of a medicament for the prevention or treatment of thrombotic events following unstable angina.