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 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 an enantiomer is dosed to a warm-blooded animal may differ from those observed when the mirror image form is dosed in this manner, namely the enantiomers may possess different pharmacokinetic properties.

In addition, the stereochemical purity of an organic compound may also be relevant to the properties 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 effect of the rechemical 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] described as the trifluoroacetic acid salt of 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 including cell adhesion, such as the formation of blood clots after 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 antithrombocyte 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 fi brigene and von Willebrand factor to glycoprotein IIb / IIIa (hereinafter GPIIb / IIIa) held in the membrane of each platelet. The necessary activation and dimerization of, for example, the platelet-bearing in brinogen thereby does not occur, and processes such as thrombus formation and platelet aggregation are inhibited. 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 classes of adhesion molecules, such as integrins, selectins and cadherins. Integrins are recovered on leukocytes and thymococytes, and selectins are recovered on leukocytes and endothelial cells. Within each class of adhesion molecules there are many members. The integrin group includes, for example, GPIIb / IIIa which binds fibrinogen, integrin and the like; which binds vitronectin and integrin otgßl which binds fi bronectin. 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. Thus, it is also desirable to find a compound that possesses this selectivity or that possesses higher selectivity than known platelet aggregation inhibitors.

It is also known that there are several classes of GPIIb / Illa antagonists. For example, monoclonal antibody antagonists to GPIIb / IIIa have been produced. In addition, 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 (arginyl glycyl aspartate) in the structure of the fi-bronogen. It is believed that such compounds can be used to inhibit platelet aggregation and, for example, thrombus formation for a sufficient time, allowing healing of damaged tissue without the detrimental consequence of robust platelet aggregation processes.

It is a theoretical matter regarding the different classes of GPIIb / IIIa antagonists that inhibition of platelet aggregation can lead to a decrease in the blood coagulation rate and therefore an increase in bleeding events and times. Although a small increase in bleeding times may be acceptable, certain clinically relevant bleeding events, such as intracranial haemorrhage, may be life-threatening.

Thus, it is desirable to find a compound having the benefit of the potent GPIIb / IIIa antagonist effect described for the compound of Example 132 in WO 94/22834 which does not possess or which has to a lesser extent possessed the disadvantages of increased bleeding times and / or harmful clinically relevant bleeding events such as has to do with the known GPIIb / IIla 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, an ester, amide or a 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 times more potent). The (-) - (3R) -f compound also possesses selectivity for inhibitory effect between classes of adhesion molecules and between family members of such classes. For example, the compound has activity against the binding of GPIIb / IIIa to in brinogen (pIC50 = 7.65) but not binding of otvß; to vitronectin (pICSO lower than 4) or binding of ot5ßl to fi bronectin (pIC50 lower than 4). Accordingly, the (--R) (3R) compound is a novel, potent and selective in brinogen receptor antagonist which significantly reduces the propensity or possibility of adverse effects, such as excessive bleeding associated with the administration of other fi brinogen receptor antagonists, such as the ( 3RS) -racernic mixture.

Use of the (-) - (3R) compound also eliminates the tendency or possibility to obtain adverse effects associated with the administration of the therapeutically less effective (+) - (3S) compound which is a component of the ( 3RS) - the racemic mixture. Use of the (-) - (3R) compound allows 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 in WO 94/22834.

Particularly pharmaceutically acceptable salts of the (-) - (3R) 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, eg triacetic acid. Other pharmaceutically acceptable salts include, for example, salts with inorganic bases, such as alkali metal and alkaline earth metal salts, such as sodium salts, ammonium salts, and salts with organic arnines and quaternary bases which form physiologically acceptable cations, such as salts with methylamine, dimethylamine, thymethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, 11-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylaminonium hydroxide.

Particularly 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, adamantole, (1-6C) alkanoyloxy (1-4C) alcohols (eg pivaloyloxymethanol) and (1-4C) alkoxycarbonyl- (1-4C) alcohols (eg methoxycarbonylmethanol).

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

Thus, particular amides of the (-) - (3R) -compound of the invention include fi-methyl-, fl, 1,1'-dimethyl-, 1,1'-ethyl-N_-methyl- and fic1-diethylbutyrainides. Particularly pharmaceutically acceptable solvates of the (-) - (3R) compound of the invention include, for example, hydrates, for example 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. There is preferably at least 95% by weight of the (-) - (3R) -isomer and 5% by weight or less of the (+) - (3S) -isomer. In particular, there is at least 99% by weight of the (-) - (3R) -isomer and 1% by weight or less of the (+) - (3S) -isomer. (-) - (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 comprising a suitable chiral intermediate and dissolution of the (3 RS) -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-halo-3-methylbutyric acid or an ester thereof (eg a methyl or ethyl ester), such as 4-chloro and 4-bromo derivatives, (3R) -4-alkanesulfonyloxy Methylbutyric acid or an ester thereof (eg a methyl or ethyl ester), such as the 4-methanesulfonyloxy derivative or (3R) -4-alkylsulfonyloxy-3-methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) ethyl ester), such as the 4- (p-toluenesulfonyloxy) derivative. b) Reaction of a compound of formula I wherein L is a linking 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, arnides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, alcohols such as ethanol, and VäflfCfl.

Under certain circumstances, for example when an acid addition salt of (3R) -3-methyl-4- [4- (piperazin-1-yl) phenoxy] butyric acid is used as starting material, the reaction can be advantageously 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 sc) Decomposition of an ester of formula II CH 2 O 3: \ / CO2R WN II where R is a carboxyl protecting group.

R may be any conventional carboxyl protecting group which can be removed without interfering with 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 halo, (1-4C) alkyl, (1 -4C) alkoxy or nitro.

The decomposition can be carried out using one of the conventional reagents and conditions known in the art for converting carboxylic acid esters to carboxylic acids. The decomposition can thus be carried out, for example, by base-catalyzed hydrolysis, for example using an alkali metal hydroxide, such as lithium, potassium or sodium hydroxide, or a tertiary arnin, such as triethylamine, in the presence of water. The base-catalyzed hydrolysis can be carried out in the presence of a solvent, such as an alcohol, for example methanol or ethanol, or an ether, such as tetrahydrofuran or dioxane. The decomposition can alternatively be carried out by acid-catalyzed hydrolysis, for example using aqueous acetic acid or trifluoroacetic acid. The temperature is in the range from -10 to 100 ° C, eg 10-50 ° C. When the alcohol residue is t-butyl, it can be removed by heating, eg 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, for example by hydrogenation in the presence of palladium on carbon at a temperature in the range of -10 to 10 ° C in the presence of a solvent such as an alcohol, eg methanol or ethanol . d) Dissolution of the (3 RS) -recemical mixture, (3 RS) -3-methyl-4- {4- [4- (4-pyridyl) -piperazin-1-yl] phenoxy} butyric acid.

The dissolution 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 acidifying the separated salts.

The dissolution 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, separation of the esters, for example by chromatography, and regeneration of the separate ( -) - (3R) - and (+) - (3S) - 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.

Some 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 (3S) ) - stereoisomers. A particularly reactive derivative which may be mentioned is ten-butyl- (3R) -3-methyl-4- (p-toluenesulfonyloxydbutyrate).

The phrase "substantially free of the (3S) stereoisomer", 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 teachable acid or base using a conventional method. When a pharmaceutically acceptable ester or arnide 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 GPIlb / IIIa can be demonstrated using the standard test procedures (a) and (b) described in WO 94/22834, which test procedures here are given for 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 pI50 = 7.65.

As indicated above, the (-) - (3R) compound of the invention can 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 palsy, atherosclerosis, thromboembolism and reocclusion during and after thrombolytic therapy. The compounds may also be useful for the prevention of reocclusion and restenosis following percutaneous transluminal coronary angioplasty (PTKA) and coronary artery bypass grafting. It should also be noted that the compounds may be useful in the treatment of other diseases mediated by binding of adhesion molecules to GPI1b / IIIIa, eg 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 from the (+) - (3S) -stereoisomer as a medicament. 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 preparation of a medicament for the prevention or treatment of a disease comprising 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, arnide or solvate thereof, substantially free of the (+) - (3S) stereoisomer for the preparation of a medicaments for the prevention or treatment of a disease comprising binding of fi brinogen 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 from the (+) - (3S) stereoisomer for the preparation of a drugs 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, so that a dose in the range of 0.01-50 mg / kg body weight is given. depending on the mode of administration, 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, an ester, ainide or a solvate thereof, substantially free from ( 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 a variety of dosage forms. It may, for example, be in the form of tablets, its capsules, solutions or suspensions for oral administration, in the form of a cream or ointment 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 nebuliser 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 mode of administration, the composition may, for example, comprise 0.1-99.9% by weight of the (-) - (3R) compound of the invention.

The drug compositions can 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 diseases or conditions intended to be treated, for example a known platelet aggregation inhibitor (eg aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a hypolipidemic agent, blood pressure lowering 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 medicament composition for use in the invention. cardiovascular disease or a 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 inhibiting 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, eg during limb or organ transplants. When used for this purpose, the (-) - (3R) compound according to the invention is generally administered so that a stable concentration in the range, eg 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 indicated: concentrations and evaporations were carried out by rotary evaporation in vacuo, procedures were carried out at room temperature, namely in the range 18-26 ° C, column chromatography was performed 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 that can be obtained by rapid process development, proton NMR spectra were normally determined at 200 MHz or 250 MHz using tetrarethylsilane (TMS) as internal standard and expressed as chemical shifts (delta values) in parts per million relative to TMS using conventional abbreviations for the designation of main peaks: s, singlet, m, multiplet, t, triplet, br, broad, d, doublet, and the following Abbreviations have been used for specific organic solvents: THF for tetrahydrofuran, DMF for flfi-dimethylformamide and DMSO for dimethylsulfoxide. Example 1 f -) - (3R) -3-Methyl-4- [4- [4- (4-pyridylpiperazin-1-yl] phenoxy} butyric acid hydrochloride Sodium hydride (60% dispersion in mineral oil, 2.44 g) 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 minutes. 3R) -3-Methyl-4- (p-toluenesulfonyloxy) butyrate (20 g) was added, and the mixture was stirred for 20 hours, the mixture was evaporated and the residue partitioned between dichloromethane and water, the organic phase was washed with water, It was filtered through phase separating paper (Whatman IPS) and evaporated, the residue was partitioned between diethyl ether, the solid thus obtained was recrystallized from ethyl acetate to give (-) - (3R) -3-methyl-4- {4- [4- (4) -pyridyl) piperazin-1-yl] phenoxy} butyrate (10.6 g), m.p. CO 3) δ s, 3 (2H, d), 6.9 (4H, m), 6.7 (zH, m), 3.79 (2H, d), 3.46 (4H, m), 3.28 ( 4H, m), 2.3l-2.53 (2H, m), 2.08-2.2l (1l-1m) 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 solution of hydrochloric acid (250 ml) was stirred for 44 hours. 1N aqueous sodium hydroxide solution (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) piperazine]. -y1] phenoxy} butyric acid hydrochloride (7.9 g). 15 510 812 M.p. 203-205 ° C, [(110 = 6.2 ° (conc. = 1g / 100 ml methanol, 20 ° C), NMR (dodMSO) , 8.72 (2H, d), 7.28 (2H, d), 6.9 (4H, m), 3.8 (6H, m), 3.18 (4H, t), 2.45 (1H, m), 2.23 (1H, m), 2.12 (1H, m), 1.0 (3H, d), m / e 356 (M + H) +, Calcd for C 20 H 25 N 3 O 3. H 2 O: C, 58.5, H, 6.8, 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) arnide (1M in THF, 170 ml) was added dropwise to a solution of (4S) -4-isopropyl-3-propionyloxazolidin-Z-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 minutes. Tert-butyl bromoacetate (423 g) was added dropwise, and the solution was stirred at -70 ° C for 3 hours. 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 partitioned between hexane at -40 ° C to give a solid (2.1l, 6 g). A second solid fraction (4.4 g) was obtained by evaporation; purification of the hexane solution and purification of the residue by tltration chromatography fi on silica gel starting from hexane and proceeding to 1/10 ethyl acetate / liexane. The two solid batches were combined and recrystallized from hexane to give (4S) -3 - [(2R) -3-tert-butoxycarbonyl-2-methylpropionyl] -4-isopropyloxazolidin-2-one (22.5 g ).

M.p. 64-65 ° C, NMR (CDCl 3) δ 4.4l (1H, m), 4.2l (2H, m), 4.1 (1H, m), 2.79 (1H, m), 2.28 -2.4 (2H, m), 1.41 (9H, s), 1.66 (3H, d), 0.9 (6H, m). Hydrogen peroxide (30%, 44 ml) and lithium hydroxide monohydrate (6.38 g) were added successively to a stirred mixture of (4S) -3 - [(2R) -3-tert-butoxycarbonyl-2-methylprot pionyl] -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 adding an aqueous solution of citric acid and extracted with the 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 (1.2.9 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 minutes to a stirred mixture of 1-tert-butyl (3R) -3-methylsuccinate (1.2.9 g) and THF (200 ml) which had been cooled to -10 ° C and placed under argonatinosphere. The mixture was stirred at -10 ° C for 30 minutes. The mixture was allowed to warm to room temperature and stirred for 1 hour. 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 minutes. The mixture was evaporated, and the residue was partitioned between diclonnetane (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 (CDCl 3) δ 8.55 (2H, m), 2.1-2.4 (3H, m), I, 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 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 drug 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 aqueous paste) magnesium stearate 1.0 b) Tablet II tablet active ingredient 50 lactose Ph. Eur. 223.75 croscarnellosnatnum 6.0 maize starch 15.0 polyvinylpyrrolidone 2.25 (5% w / v aqueous paste) magnesium stearate 3.0 510 812 18 c) Tablet III mg fi tablet active ingredient 100 lactose Ph. Eur. 182.75 croscarmellose sodium 12.0 maize starch paste 2.25 (5% w / v aqueous paste) magnesium stearate 3.0 (d) Kagsel mg¿l_ active ingredient 10 lactose Ph.Eur. 488.5 Magnesium stearate 1.5 (e) injection mg mg active ingredient (acid addition salt) 1.0 sodium chloride 90 purified water to 1.0 ml Example 3 The following is a description of a study of the effects of (-) ~ (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 male and 5 female rats) 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 liver of six in the group of 10 rats dosed at 500 mg / kg / day.

Four groups of 10 Alderly Park Wistar rats (each group comprising 5 male and 5 female rats) 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 19 510 812 or five days, four of the animals from this group were killed. 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 liver in the group if 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 negative effect on levem.

Based on such observations, it appears that the (-) - (3R) compound of the invention does not cause a significant adverse 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.