SK13097A3 - Optically active (-)-(3r)-3-methyl-4-{4-£4-(4-pyridyl)piperazin- -1-yl|phenoxy} butyric acid and its derivatives, preparation method thereof and their use - Google Patents

Abstract

The novel optically active compound (-)-(3R)-3-methyl-4-{4-[4-(4-pyridyl)-piperazin-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

Optically active (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) -piperazin-1-yl] phenoxy) butyric acid and its derivatives, process for their preparation and their use

Technical field

The present invention relates to a novel optically active (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) -piperazin-1-yl] phenoxy) butyric acid (hereinafter (-) - (3R) The compound (I) and pharmaceutically acceptable salts, esters, amides, or solvates thereof. The invention also relates to a process for the manufacture of this optically active compound, to pharmaceutical compositions containing it, and to its use for inhibiting cellular adhesion, for example, platelet aggregation.

BACKGROUND OF THE INVENTION

The organic compounds occur in optically active forms. These compounds have the ability to rotate the plane of plane-polarized light either clockwise (+) or left-handed (-). A typical optically active compound has an asymmetric or chiral atom, such as e.g. a tetrahedral carbon atom that attaches to four different atomic groups. Four different atoms or groups can be positioned around the asymmetric carbon atom in two ways, to form two chiral compounds that are structurally mirror-like to each other. These compounds are called stereoisomers or enantiomers. Enantiomers have identical physical and chemical properties except that they rotate the plane of polarized light by the same angle but in the opposite direction. The racemic mixture is a mixture of equal amounts of each enantiomer from a pair of enantiomers. This mixture does not cause the plane of plane-polarized light to rotate.

The stereochemical purity of the organic compound may be of importance in the field of pharmaceutical chemistry and pharmacology. Many macromolecules, e.g. the enzymes and receptors of warm-blooded animals, which are important for the maintenance of life, are built from chiral building blocks such as e.g. chiral amino acids. The individual enantiomers, which together form a racemic mixture of a pharmacologically active compound, can interact to varying extents with a chiral molecule such as e.g. enzyme or receptor. Therefore, the individual enantiomers may have different potencies as enzyme inhibitors or receptor antagonists. In addition, the rate and rate of absorption, distribution, metabolism and excretion observed when a single enantiomer is administered to a warm-blooded animal may differ from the observed rate and rate of absorption, distribution, metabolism and excretion when administered in a mirror form, i. enantiomers may exhibit various pharmacokinetic properties.

The stereochemical purity of the organic compound may be of importance for the nature and extent of the side effects that may occur when a pharmacologically active compound is administered. Thus, one enantiomer may be a useful compound, while the other enantiomer may cause deleterious side effects or toxicity. For example, one enantiomer of thalidomide is believed to be a safe and effective sedative while the other enantiomer is responsible for the teratogenic side effect of racemic mixtures.

The optically active compound of the invention is the optical isomer of the racemic mixture of (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 International Patent Application Ser. WO 94/22834 and in Example 203 of International Patent Application Ser. WO 94/22835. It is stated that these compounds are useful in the treatment of various diseases including cell adhesion, such as e.g. blood clot formation, which follows platelet aggregation. Blood clots can lead to diseases such as e.g. thrombosis, stroke, thrombotic conditions accompanying unstable angina, myocardial infarction, atherosclerosis, thromboembolism and reocclusion during or after thrombolytic treatment.

The antiplatelet effect of the compounds on platelets has been reported to be based on the ability of the compounds to inhibit binding of adhesion molecules such as e.g. fibrinogen; and von Willebrant's factor for glycoprotein IIb / IIIa (hereinafter GPIIb / IIIa), which occurs in the membrane of each platelet. As a result, the necessary activation and dimerization of e.g. platelets bearing fibrinogen and processes such as clot formation and platelet aggregation are inhibited.

As a possible aid in the research of compounds with an improved therapeutic percentage, it would be desirable to find a compound with enhanced efficacy compared to the compounds disclosed in International Patent Application Nos. 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 on leukocytes and endothelial cells. Each group of adhesion molecules has many members. Integrins include, e.g., GPIIb / IIa which binds fibrinogen, integrin alpha-beta, which binds vitronectin, and integrin alpha _with beta _{; L} , which binds fibronectin. More appropriately, therapeutic platelet aggregation inhibitors are expected to exhibit selectivity of inhibitory effect between groups of adhesion molecules and between members of each group of adhesion molecules. Thus, it would be desirable to find a compound having this selectivity or having a greater selectivity than known platelet aggregation inhibitors.

It is further known that there are several classes of GPIIb / IIIa antagonists. E.g. monoclonal antibodies were generated as GPIIb / III antagonists. In addition, small molecules that inhibit the binding of adhesion molecules to GPIIb / IIIa, e.g. U.S. Patent Nos. 5,039,805 and 5,084,446; Canadian Patent Applications Nos. 2,008,161, 2,037,153 and 2,061,661; and Alig et al., J. Med. Chem., 1992, 35, 4393. Usually, the structures of these compounds are based on the binding regions of the adhesion molecules, e.g. the amino acid sequence RGD (arginyl-glycyl-aspartate) in the fibrinogen structure. It is contemplated that such compounds may be used to inhibit platelet aggregation and e.g. for inhibiting clot formation for a sufficient period of time to allow the treatment of damaged tissue without the deleterious consequences of diseases from massive platelet aggregation processes. It is believed that, for the various classes of GPIIb / IIIa antagonists, inhibition of platelet aggregation may lead to a decrease in blood clotting rate and therefore to an increase in bleeding conditions and bleeding time. While a small increase in bleeding time might be acceptable, certain clinically significant bleeding conditions e.g. intracranial hemorrhage could be life-threatening.

It would therefore be desirable to find a compound exhibiting potent GPIIb / IIIa antagonistic activity described for the compound of Example 132 of International Patent Application Ser. WO 94/2834, which does not exhibit or exhibits to a lesser extent the disadvantages of increased bleeding time and / or harmful clinically significant bleeding conditions associated with known GPIIb / IIIa antagonists.

SUMMARY OF THE INVENTION The (-) - (3R) compound has significantly better potency than the GPIIb / IIIa antagonist than the corresponding (+) - (3S) -isomer (more than 10x more potent). The (-) - (3R) compound also exhibits selectivity of inhibitory effect between groups of adhesion molecules and between members of these groups. For example, the compound possesses activity against the binding of GPIIb / IIIa to fibrinogen (pIC _a = 7.65), but does not show binding activity to the alpha beta ^ ^ to vitronectin (pIC _go below 4) or to the binding of the alpha _and beta _g to fibronectin (pIC _with less than 4).

Accordingly, the (-) - (3R) compound is a novel, potent and selective fibrinogen receptor antagonist that substantially reduces the risk or possibility of adverse effects, such as e.g. excessive bleeding associated with administration of other fibrinogen receptor antagonists such as the (3RS) -racemic mixture. The use of the (-) - (3R) -compound also eliminates the risk or possibility of adverse effects associated with the administration of the therapeutically less active (+) - (3R) -compound, which forms part of the (3RS) -racemic mixture. The use of the (-) - (3R) compound allows a clearer structure-activity-toxicity analysis and provides an enhanced therapeutic effect. Therefore, it is desirable to use the (-) - (3R) -compounds of the invention in place of the (3RS) -racemic mixture of Example 132 of International Patent Application Ser. WO 94/22834.

Particular pharmaceutically acceptable salts of the (-) - (3R) -compounds of the invention include e.g. salts with acids providing physiologically acceptable anions such as e.g. salts with mineral acids, e.g. hydrohalic acids such as hydrochloric or hydrobromic acid> sulfuric acid or phosphoric acid and salts with organic acids, e.g. with trifluoroacetic acid. Other pharmaceutically acceptable salts include e.g. salts with inorganic bases such as e.g. alkali metal salts and alkaline earth metal salts, e.g. sodium salts, ammonium salts and salts with organic amines and quaternary bases forming physiologically acceptable cations such as e.g. salts with methylamine, dimethylamine, trimethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, N-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide.

Particular pharmaceutically acceptable esters of the (-) - (3R) -compounds of the invention include e.g. ester derivatives of the carboxyl group of a compound of the invention, e.g. esters of alcohols such as alcohols containing 1 to 6 carbon atoms (e.g., methanol, ethanol, propanol and tert-butanol), indanol, adamantanol, alkanoyloxy alcohols containing 1 to 6 carbon atoms in the alkanoyloxy moiety and 1 to 4 carbon atoms in the alcohol moiety (e.g. (pivaloyloxymethanol) and alkoxycarbonyl alcohols containing from 1 to 4 carbon atoms in the alkoxy moiety and from 1 to 4 carbon atoms in the alcohol moiety (e.g., methoxycarbonylmethanol).

Particular pharmaceutically acceptable amides of the (-) - (3R) -compounds of the invention include e.g. amide derivatives of the carboxyl group of a compound of the invention, e.g. amides formed with amines such as e.g. ammonia, C 1-4 alkylamines (e.g. methylamine), C 1-4 dialkylamines (e.g. dimethylamine, N-ethyl-N-methylamine and diethylamine) in each alkyl moiety, 1-4 alkoxyalkylamines in the alkoxy moiety carbon atoms and in the alkyl moiety 2 to 4 carbon atoms (e.g. 2-methoxyethylamine), phenylalkyamines containing in the alkyl moiety 1-4 carbon atoms (e.g. benzylamine) and amino acids (e.g. glycine or an ester thereof). Particular amides of the (-) - (3R) -compounds of the invention include N-methyl-, Ν, Ν-dimethyl-, N-ethyl-N-methyl and N, N-diethylbutyramides.

Particular pharmaceutically acceptable solvates of the (-) - (3R) -compounds of the invention include, for example, hydrates, for example, hemihydrate, monohydrate, dihydrate or trihydrate, or alternatively multiples thereof.

As used herein, the term substantially free of the (+) - (3S) -stereoisomer or substantially free of the (+) - (3S) -stereoisomer means that the compound contains at least 90 wt. % (-) - (3R) -isomer and 10 wt. or less of the corresponding (+) - (3S) -isomer. More preferably it comprises at least 95 wt. % (-) - (3R) -isomer and 5 wt. or less of the (+) - (3S) -isomer. Most preferably it comprises at least 99 wt. % (-) - (3R) -isomer and 1 wt. 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 using a suitable chiral intermediate and cleavage of the (3RS) -racemic mixture. These methods represent a further embodiment of the invention and include the following steps:

a) Reaction of 4- [4- (4-pyridyl) piperazin-1-yl] phenol or a reactive derivative thereof with (3R) -4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative or chiral intermediate thereof.

Preferably, the reaction is carried out in the presence of a strong base such as e.g. an alkali metal hydride, e.g. sodium hydride. Suitable solvents include amides such as dimethylformamide. Preferably, the reaction is carried out at a temperature ranging from 0 to 100 ° C.

Suitable (3R) -4-hydroxy-3-methylbutyric acid esters as chiral intermediate include e.g. methylethyl, propyl and tert-butyl esters. Suitable reactive derivatives include e.g. (3R) -4-halo-3-methylbutyric acid or its ester (e.g. methyl or ethyl ester) such as its 4-chloro or 4-bromo derivatives, (3R) -4-alkanesulfonyloxy-3-methylbutyric acid or its ester (e.g., methyl or ethyl ester) such as its 4-methanesulfonyloxy derivative or (3R) -4-arylsulfonyloxy-3-methylbutyric acid or ester (e.g., methyl or ethyl ester) such as its 4- (p-toluenesulfonyloxy) derivative.

b) Reaction of a compound of formula I (I) wherein L is a displaceable atom or group with (3R) -3-methyl-4- [4- (piperazin-1-yl) phenoxy] butyric acid or an acid addition salt thereof such as a chiral intermediate.

Examples of the meanings of L include halogens such as chlorine or bromine and cyano.

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

Preferably, the reaction is carried out at a temperature in the range of -10 to 120 ° C, preferably 10 to 100 ° C. Suitable solvents include e.g. ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, alcohols such as ethanol and water.

In 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 may preferably be carried out in the presence of a base. Examples of suitable bases include tertiary aroins such as triethylamine and alkali metal hydroxides and bicarbonates such as sodium or potassium hydroxide, carbonate or bicarbonate.

c) Decomposition of the ester of formula II

, R (II) wherein R is a carboxyl protecting group.

R can be any conventional carboxyl protecting group that can be removed without disturbing other parts of the molecule. Examples of carboxyl protecting groups include alkyl groups having 1 to 6 carbon atoms (such as methyl, ethyl, propyl or tert-butyl), phenyl and benzyl, wherein the phenyl radical in any of these groups may optionally have 1 or 2 atoms halogen, C 1 -C 4 alkyl, C 1 -C 4 alkoxy or nitro.

The decomposition can be carried out using any conventional reagent and under conditions known in the art for the conversion of carboxylic esters to carboxylic acids. Thus, the decomposition can be carried out, for example, by base-catalyzed hydrolysis, e.g. 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 can be performed in the presence of a solvent such as an alcohol e.g. methanol or ethanol, or an ether such as tetrahydrofuran or dioxane. Alternatively, the decomposition can be carried out by acid catalyzed hydrolysis, e.g. using aqueous acetic acid or trifluoroacetic acid. The temperature is preferably in the range of -10 to 100 ° C, e.g. from 10 to 50 ° C. When the alcohol moiety is a tert-butyl group, it can be removed by heating, for example, to a temperature in the range of from 80 to 150 ° C, either alone or in the presence of a suitable diluent such as diphenyl ether or diphenylsulfone. The benzyl group may be removed by catalytic hydrogenation, e.g. by hydrogenation in the presence of palladium on carbon at a temperature ranging from -10 to 100 ° C in the presence of a solvent such as an alcohol, e.g. methanol or ethanol.

d) Cleavage of the (3RS) -racemic mixture, (3RS) -3-methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl] phenoxy} butyric acid.

The cleavage of the (3RS) -racemic butyric acid derivative mixture may be carried out by known methods, e.g. salt formation using an optically active base followed by separation of the two salts thus formed, for example, by fractional crystallization and regeneration of the separated (-) - (3R) compound and the (+) - (3S) compound by acidifying the separated salts.

Cleavage of the (3RS) -racemic butyric acid derivative mixture can also be carried out by conventional methods of forming diastereomeric ester pairs, by reaction with an optically active alcohol, by separation of esters, e.g. chromatographic separation and recovery of the separated (-) - (3R) - compound and the (+) - (3RS) - compound by hydrolysis of the separated esters. An analogous procedure involving the preparation of diastereomeric amide pairs may also be used.

The preparation of the (-) - (3R) compound and the chiral intermediates is described in the examples, which are given by way of illustration only and are not intended to limit the scope of the invention in any way.

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

The term substantially free of the (3S) -stereoisomer as used hereinabove has the same meaning as given above for the (-) - (3R) -compound of the invention.

If a pharmaceutically acceptable salt of the (-) - (3R) -compound of the invention is required, e.g. reacting said compound with a suitable acid or base using a conventional method. If a pharmaceutically acceptable ester or amide of the (-) - (3R) -compound of the invention is desired, e.g. reacting said compound with a suitable alcohol or amine using a conventional method.

The ability of the (-) - (3R) -compounds of the invention to inhibit platelet aggregation and inhibit fibrinogen binding to GPIIb / IIIa can be demonstrated using standard test procedures (a) and (b) described in International Patent Application Ser. WO 94/22834.

(-) - (3R) compound of the invention possesses activity against platelet aggregation induced by human adenozíndifos11 dialkyl sulfate (ADP), p = 7.3 pA and the binding of fibrinogen to GPIIb / IIIa with _a pIC = 7.65.

As mentioned previously, the (-) - (3R) -compound of the invention can be used in the treatment or prevention of cellular adhesion diseases such as venous and arterial thromboses (e.g., pulmonary embolism, stroke and thrombotic conditions accompanying unstable angina) and transient ischemic attack), myocardial infarction, atherosclerosis, thromboembolism and reocclusion during and after thrombolytic therapy. These compounds may also be useful in preventing reocclusion and restenosis following percutaneous transluminal coronary angioplasty (PTCA) and after coronary erterial step bypass. It will also be appreciated that these 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 embodiment of the invention there is provided the use of a (-) - (3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof substantially free of the (+) - (3S) -stereoisomer as a medicament.

According to a further aspect of the invention there is provided a method of inhibiting platelet aggregation in a warm-blooded animal in need thereof, comprising administering an effective amount of a (-) - (3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of (+) - (3S) stereoisomer.

According to another embodiment of the invention there is provided a method of inhibiting fibrinogen binding to GPIIb / IIIa in a warm-blooded animal in need thereof, comprising administering an effective amount of a (-) - (3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of (+) - (3S) stereoisomer.

According to another embodiment of the invention, the inhibition of thrombotic conditions accompanying the present invention is a method of unstable an12 gin in a warm-blooded animal in need thereof, comprising administering an effective amount of a (-) - (3R) compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof. (+) - (3S) stereoisomer.

According to another embodiment of the invention, there is provided a method of inhibiting platelet aggregation in a warm-blooded animal in need thereof, substantially reducing the adverse effects associated with administration of a (3RS) -racemic composition comprising administering an effective amount of a (-) - (3R) compound or a pharmaceutically acceptable a salt, ester, amide or solvate substantially free of the (+) - (3S) -stereoisomer.

According to a further aspect of the invention there is provided the use of a (-) - (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 preventing or treating a disease caused by by platelet aggregation.

According to a further aspect of the invention there is provided the use of a (-) - (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 preventing or treating a disease caused by binding of fibrinogen to GPIIb / IIIa.

According to a further aspect of the invention there is provided the use of a (-) - (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 preventing or treating thrombotic conditions accompany unstable angina.

Generally, the (-) - (3R) -compound of the invention will be administered for this purpose by the oral, rectal, topical, intravenous, subcutaneous, intramuscular or inhalation route so that the dose administered is in the range of 0.01 to 50 mg / kg body weight. weight, depending on the route of administration, age and sex of the patient, and the severity of the condition being treated.

The (-) - (3R)-compound of the invention will generally be used in the form of a pharmaceutical composition comprising a (-) - (3R)-compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof, substantially free of (+) - (3S) -stereoisomer, in admixture with a pharmaceutically acceptable diluent or carrier. Such a composition constitutes another embodiment of the invention and may be in a variety of dosage forms. E.g. it may be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of a cream or ointment or a transdermal patch for topical administration; in the form of suppositories for rectal administration; in the form of sterile solutions or suspensions for administration by intravenous or intramuscular injection; in the form of an aerosol or nebulizer solution or suspension for 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 e.g. from 0.1 to 99.9 wt. The (-) - (3R) -compounds of the invention.

The pharmaceutical compositions can be obtained by conventional methods using pharmaceutically acceptable diluents or carriers known in the art. Tablets and capsules for oral administration may advantageously be coated with an enteric layer comprising, for example, cellulose acetate phthalate to minimize contact of the (-) - (3R) compound of the invention with stomach acids.

The (-) - (3R)-compound of the invention may be administered together or formulated together with one or more agents known to be of value in the treatment of the diseases or conditions to be treated. For example, a known platelet aggregation inhibitor (e.g., aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a hypolipidemic agent, an antihypertensive agent, a thrombolytic agent (such as a thrombolytic agent) may be suitably present in a pharmaceutical composition of the invention for use in the treatment of cardiac or vascular diseases or conditions. is a streptokinase, urokinase, prourokinase, tissue plasminogen activator and derivatives thereof), a beta-adrenergic blocker or a vasodilator.

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 to assess the effects of adhesion molecules in laboratory animals such as cats, dogs, rabbits, monkeys, rats, and rats. mice as part of research into new therapeutic agents. The (-) - (3R) -compound of the invention can also be used, due to its ability to inhibit platelet aggregation, as an aid in blood storage and to maintain blood and blood vessel viability in warm-blooded animals (or parts thereof) undergoing artificial extracorporeal circulation. , e.g. during limb or organ transplantation. When the (-) - (3R) -compound of the invention is used for this purpose, it will generally be administered so that the steady-state blood concentration is in the range of 0.1 to 10 mg / ml.

The invention is illustrated by the following examples, which are given by way of illustration only and are not intended to limit the scope of the invention in any way unless otherwise indicated:

(i) concentration and evaporation are carried out on a rotary evaporator under vacuum;

ii) the operations are carried out at room temperature, i. in the range of 18-26 ° C;

iii) column chromatography is performed on silica gel (Merck 7736) supplied by E Merck and Co., Darmstadt, Germany;

(iv) yields are given for illustration only and are not necessarily the maximum yields obtainable by a precise execution of the process;

(v) proton NMR spectra are normally determined at 200 MHz or 250 MHz using tetramethylsilane (TMS) as an internal standard and are expressed as chemical shifts (δ values) in ppm relative to tetramethylsilane using standard abbreviations to indicate the main signals: s - singlet, m - multiplet, t - triplet, br - broad signal, d - doublet.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

(-) - (3R) -3-Methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl] phenoxy} butyric acid hydrochloride

Sodium hydride (60% dispersion in mineral oil, 2.44 g) was added to a stirred suspension of 15.5 g of 4- [4- (4-pyridyl) piperazin-1-yl] phenol in 120 mL of dry dimethylformamide, and the mixture was stirred for 45 minutes. 20 g of tert-butyl (3R) -3-methyl-4- (p-toluenesulfonyloxy) butyrate are added and the mixture is stirred for 20 hours. The mixture was evaporated and the residue was partitioned between dichloromethane and water. The organic layer was washed with water, filtered through phase separation paper (Whatman IPS) and evaporated. The residue was triturated with diethyl ether. The solid thus obtained was recrystallized from ethyl acetate to give 10.6 g of tert-butyl - (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl]. ] phenoxy} butyrate, m.p. 112-113 ° C.

[α] _D = -5.5 ° (concentration = 1 g / 100 mL methanol; 20 ° C);

NMR (CDCl 3) δ: 8.3 (2H, d), 6.89 (4H, m), 6.7 (2H, m), 3.79 (2H, d), 3.46 (4H, m) m), 3.28 (4H, m), 2.31-2.53 (2H, m), 2.08-2.21 (1H, IU, 1.44 (9H, s), 1.07 ( 3H, d).

A mixture of 10.53 g of tert-butyl (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl] phenoxy} butyrate and 250 ml of 1N aqueous hydrochloric acid is stirred for 44 hours. 250 ml of 1N aqueous sodium hydroxide solution are added and the mixture is cooled to 5 ° C. The mixture was filtered and the filtrate was evaporated. 150 ml of water are added and the resulting precipitate is collected and washed successively with water, acetone and diethyl ether. The material so obtained was stirred with 25 ml of 1N aqueous hydrochloric acid 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 7.9 g of (-) - (3R) -3-methyl-4- (4- [4- (4-pyridyl) piperazine) hydrochloride. 1-yl] phenoxy) butyric acid, m.p. 203-205 ° C.

[α] _D = -6.2 ° (concentration = 1 g / 100 mL methanol; 20 ° C);

NMR (Perdeuterodimethylsulfoxide), δ: 13.8 (1H, broad signal), 12.1 (1H, broad signal), 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);

MS: m / e 356 (M + H) < + >;

Analysis for C HH 0O · HCl · H OO;

H, 6.8; N, 10.2. Found: C, 58.3; H, 6.9; N, 10.2;

The necessary chiral starting material is prepared as follows:

To a solution of 28.4 g of (4S) -4-isopropyl-3-propionyloxazolidin-2-one (J. Am. Chhem. Soc., 1981, 103, 2127) in 500 mL of dry tetrahydrofuran, which was cooled to -70 ° C and placed under an argon atmosphere, sodium bis (trimethylsilyl) amide (1M in tetrahydrofuran, 170 mL) was added dropwise. 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. 42.3 g of tert-butyl bromoacetate are added dropwise and the solution is stirred at -70 ° C for 3 hours. The solution was allowed to warm to room temperature. The solvent was evaporated and the residue was partitioned between diethyl ether and water. The organic phase is separated, filtered through phase separation paper (Whatman IPD) and evaporated. The residue was triturated with hexane at -40 ° C to give 21.6 g of a solid. A second portion (4.4 g) of solid was obtained by evaporation of the hexane solution and purification of the residue by silica gel filtration chromatography, eluting first with hexane and successively with a 1: 10 mixture of ethyl acetate and hexane. recrystallized from hexane to give 22.5 g of (4S) -3 - [(2R) -3-tert-butoxycarbonyl-2-methylpropionyl] -4-isopropyl-oxazolidin-2-one, 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).

% hydrogen peroxide (44 ml) and 6.38 g of lithium hydroxide monohydrate were added gradually to a stirred solution of 22.5 g of (4S) -3 - [(2R) -3-tert-butoxycarbonyl-2-methylpropionyl] -4-isopropyloxazolidine -2-one, 280 ml of water and 800 ml of tetrahydrofuran, cooled to 5 ° C. The resulting mixture was stirred at 5 ° C for 3 hours. A saturated aqueous solution of sodium pyrosulfite was added to react excess hydrogen peroxide and the solvent was evaporated. The residue was extracted with dichloromethane. The aqueous solution was acidified by addition of aqueous citric acid solution and extracted with dichloromethane. The extracts are combined, washed with water and filtered through phase separation paper. The filtrate was evaporated to give 12.9 g of 1-tert-butyl (3R) -3-methylsuccinate as an oil.

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

10M Borane-dimethylyl sulfide complex (10.3 ml) was added to a stirred mixture of 12.9 g of 1-tert-butyl (3R) -3-methylsuccinate and 200 ml of tetrahydrofuran over 15 minutes, cooled to -10 ° C and placed into the atmosphere of argon. 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 recooled to 5 ° C and 50 mL of methanol 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 100 mL of dichloromethane and 100 mL of water. The organic phase is filtered through phase separation paper and evaporated to give 11 g of tert-butyl (3R) -4-hydroxy-3-methylbutyrate as an oil.

NMR (CDCl3) Si values 3.55 (2H, m), 2.1-2.4 (3H, m), 1.46 (9Hs), 0.98 (3H, d).

13.2 g of p-toluenesulfonyl chloride are added portionwise to the stirred mixture of 11 g of tert-butyl (3R) -4-hydroxy-3-methylbutyrate, 21 ml of triethylamine and 120 ml of dichloromethane, and the mixture is stirred for 20 hours. The mixture was washed successively with water and dilute aqueous sodium carbonate solution. The organic solution was filtered through phase separation paper and evaporated to give 20 g of tert-butyl (3R) -3-methyl-4- (p-toluenesulfonyloxy) butyrate as an oil.

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 a compound of the invention for therapeutic or prophylactic use include the following forms, which may be obtained by conventional procedures known in the art:

a) Tablet I Active ingredient Lactose Ph. Eur. Croscarmellose sodium Corn starch paste (5% (w / v) aqueous Magnesium stearate

b) Tablet II Active Ingredient Lactose Ph. Eur. Sodium croscarmellose Corn starch Polyvinylpyrrolidone (5% (w / v) aqueous Magnesium stearate mg / tablet

1.0

93.25

4.0 paste) 0.75

1.0 mg / tablet

223.75

6.0

15.0 paste) 2.25

3.0

c) Tablet III

Active ingredient

Lactose Ph. Eur.

Sodium croscarmellose

Corn starch paste (5% (w / v) aqueous paste) mg / tablet

100

182,75

12.0

2.25

Magnesium stearate

(d) Capsules

Active ingredient Lactose

Magnesium stearate

(e) Injection

Active Ingredient (acid addition salt) Sodium chloride

3.0 mg / capsule

488.5

1.5 mg / ml

1.0

9.0

Purified water to 1.0 ml

Example 3

The following description deals with the study of the effects of the (-) - (3R) compound of the invention and the corresponding (3RS) -racemic mixture in rat. Four groups of 10 Alderley Park Wistar rats (each group comprised 5 males and 5 females) received an oral (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. Hepatic effects were noted in the liver of six animals of the group of 10 rats dosed at 500 mg / kg / day.

Four groups of Alderley Park Wistar rats (each group comprised 5 males and 5 females) were administered orally (-) - (3R) -compound of the invention at daily doses of 0, 50, 250 and 1000 mg / kg. The highest daily dose was not tolerated. After four or five days, four 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 14 days. The animals were sacrificed and examined. No adverse effects were noted in the liver of the 250 mg / kg / day group of rats. There were also no harmful effects on the liver in the six animals dosed at 1000 mg / kg / day for three or four days and then at 500 mg / kg / day for ten to eleven days.

Based on these observations, it can be seen that the (-) - (3R) -compound of the invention does not cause any significant deleterious effect on rat liver at a dosage of 500 mg / kg / day.

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

Tlf or 3 Q 'Cfl-

Claims (19)

Optically active (-) - (3R) -3-methyl-4- {4- [4- (4-pyridyl) -piperazin-1-yl] phenoxy} butyric acid or a pharmaceutically acceptable salt, ester, amide or solvate, substantially free of the (+) - (3S) -stereoisomer. The optically active compound of claim 1, wherein at least 90 wt. % (-) - (3R) -isomer and 10 wt. or less of the corresponding (+) - (3S) -isomer. The optically active compound of claim 1, wherein at least 95 wt. % (-) - (3R) -isomer and 5 wt. or less of the corresponding (+) - (3S) -isomer. An optically active compound according to claim 1, at least 99 wt. % (-) - (3R) -isomer and 1 wt. the corresponding (+) - (3S) -isomer. in which it is or less The optically active compound of any one of claims 1 to 4, which is a pharmaceutically acceptable hydrochloride. The optically active compound according to any one of claims 1 to 4, which is a pharmaceutically acceptable methyl ester, ethyl ester, propyl ester or tert-butyl ester. The optically active compound according to any one of claims 1 to 4, which is a pharmaceutically acceptable Ν-methyl-, N, N-dimethyl-, N-ethyl-N-methyl- or N, N-diethyl-butyramide. The optically active compound according to any one of claims 1 to 4, which is a pharmaceutically acceptable hydrate. A process for the preparation of an optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof according to any one of claims 1 to 8, characterized in that: (a) reacting 4- [4- (4-pyridyl) piperazin-1-yl] phenol or a reactive derivative thereof with (3R) -4-hydroxy-3-methylbutyric acid or an ester thereof, or a reactive derivative or chiral intermediate thereof, or that is b) reacting a compound of formula I (I) wherein L is a displaceable atom or group with (3R) -3-methyl-4- [4- (piperazin-1-yl) phenoxy] butyric acid or an addition salt thereof with with an acid as an intermediate or that is c) decomposes the ester of formula II CH ₃ , CO, R (II) wherein R is a carboxyl protecting group, or that is d) cleaving the (3RS) -racemic mixture, (3RS) -3-methyl-4- {4- [4- (4-pyridyl) piperazin-1-yl] phenoxy} butyric acid, and if a pharmaceutically acceptable salt is desired ( -) - (3R) compounds, reacting the resulting compound with a suitable acid or base, and if a pharmaceutically acceptable ester or amide of the (-) - (3)) compound is desired, reacting the resulting compound with a suitable alcohol or amide. Optically active tert-butyl (3R) -3-methyl-4-hydroxybutyrate or a reactive derivative thereof, substantially free of the (3S) -stereoisomer. The compound of claim 10, wherein the reactive derivative is tert-butyl (3R) -3-methyl-4- (p-toluenesulfonyloxy) butyrate. A pharmaceutical composition comprising an optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof according to any one of claims 1 to 8 in admixture with a pharmaceutically acceptable diluent or carrier. A method of inhibiting platelet aggregation in a warm-blooded animal in need of such treatment, comprising administering an effective amount of an optically active compound or a pharmaceutically acceptable salt, ester, amide or solvate thereof according to any one of claims 1 to 8. 14. A method of inhibiting platelet aggregation in a warm-blooded animal in need of such treatment, substantially reducing the adverse effects associated with the administration of a (3RS) -racemic composition, comprising administering an effective amount of an optically active compound or a pharmaceutically acceptable salt, ester thereof. , amide or solvate according to any one of claims 1 to 8. A method of inhibiting fibrinogen binding to GPIIb / IIIa in a warm-blooded animal in need of such treatment comprising administering an effective amount of an optically active compound or a pharmaceutically acceptable salt, ester, amide, or solvate thereof according to any one of claims 1 to 8. A method of inhibiting thrombotic conditions accompanying unstable angina in a warm-blooded animal in need of such treatment, comprising administering an effective amount of an optically active compound or a pharmaceutically acceptable salt, ester, amide, or solvate thereof according to any one of claims 1 to 8. Use of an 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 caused by platelet aggregation. Use of an 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 caused by fibrinogen binding to GPIIb / IIIa. Use of an 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 thrombotic conditions that accompany unstable angina.