Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
  • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
  • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D213/72—Nitrogen atoms
  • C07D213/74—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
  • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors

Definitions

• the present invention relates to the novel optically active compound (-)-(3R)-3-methyl-4- ⁇ 4- [4-(4-pyridyl)piperazin- 1 -yl]phenoxy ⁇ butyric acid, [hereinafter (-)-(3R)] and pharmaceutically-acceptable salts, esters, amides or solvates thereof.
• the invention also relates to processes for the preparation of the optically active compound, pharmaceutical compositions containing it and its use to inhibit cellular adhesion, for example platelet aggregation.
• Organic compounds can exist in optically active forms. Such compounds possess the property of being able to rotate the plane of plane-polarised light in either a dextrorotary [prefix (+)] or laevorotary [prefix (-)] manner.
• an optically active compound possesses an asymmetric or chiral atom such as a tetrahedral carbon atom which is bonded to four different atoms or groups. The four different atoms or groups can be arranged around the asymmetric carbon atom in two ways to give two chiral compounds which are structurally related as mirror images of one another. Such compounds are termed stereoisomers or enantiomers.
• Enantiomers have identical physical and chemical properties except that they rotate the plane of plane-polarised light by an equal amount but in opposite directions.
• a racemic mixture is a mixture of equal amounts of a pair of enantiomers. Such a mixture does not cause rotation of the plane of plane-polarised light.
• the stereochemical purity of an organic compound can be of importance in the fields of pharmaceutical chemistry and pharmacology.
• Many macromolecules such as the enzymes and receptors within warm-blooded animals which are involved in the maintenance of life are built up from chiral building blocks such as the chiral amino acids.
• the individual enantiomers which together make up a racemic mixture of a pharmacologically- active compound may interact to differing extents with a chiral macromolecule such as an enzyme or receptor.
• the individual enantiomers may therefore possess different potencies as enzyme inhibitors or receptor antagonists.
• the rate and extent of the absorption, distribution, metabolism and excretion observed when one enantiomer is dosed to a warm-blooded animal may differ from that observed when the mirror image form is so dosed, i.e. the enantiomers may possess different pharmacokinetic properties.
• the stereochemical purity of an organic compound may also be of importance to the nature and extent of the side effects which may be obtained when a pharmacologically-active compound is dosed.
• one enantiomer may be a useful compound whereas the other enantiomer may give rise to deleterious side effects or toxicity. It has, for example, been suggested that one of the enantiomers of thalidomide was a safe and effective sedative whereas the other enantiomer controlled the racemic mixture's teratogenic side effect.
• 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-l-yl]-phenoxy ⁇ butyric acid [hereinafter the (3RS)-racemic mixture] which is disclosed, as the trifluoroacetic acid salt, in Example 132 of International Patent Application No. WO 94/22834 and Example 203 of International Patent Application No. WO 94/22835. It is disclosed 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 accompanying unstable angina, myocardial infarction, atherosclerosis, thromboembolism and reocclusion during or after thrombolytic therapy.
• the anti-platelet aggregatory effect of the compounds is stated to be based on the compounds' ability to inhibit the binding of adhesion molecules such as fibrinogen and von Willebrand Factor to glycoprotein ⁇ b/Tfla (hereinafter GPIIb/Tfla) which is held within the membrane of each platelet.
• adhesion molecules such as fibrinogen and von Willebrand Factor to glycoprotein ⁇ b/Tfla (hereinafter GPIIb/Tfla) which is held within the membrane of each platelet.
• Integrins are found on leucocytes and platelets and selectins are found on leucocytes and endothelial cells. Within each class of adhesion molecules there are many members.
• the integrin family includes, for example, GP ⁇ b/LIa which binds fibrinogen, the integrin ⁇ v ⁇ 3 which binds vitronectin and the integrin a which binds fibronectin. It is believed that the more useful therapeutic platelet aggregation inhibitors will possess selectivity of inhibitory effect between classes of adhesion molecules and between family members of each class of adhesion molecules. Thus it would also be desirable to find a compound which possesses this selectivity or which possesses greater selectivity than known platelet aggregation inhibitors.
• GPHb/Tfla antagonists there are several classes of GPHb/Tfla antagonists. For example, monoclonal antibody antagonists to GP ⁇ b/IIIa have been raised.
• small molecules which inhibit the binding of adhesion molecules to GP ⁇ b/Tfla are also known, for example from US Patent Nos. 5,039,805 and 5,084,446, from Canadian Patent Application Nos. 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 based upon the binding regions of the adhesion molecules, for example the amino acid sequence RGD (arginyl glycyl aspartate) within the structure of fibrinogen.
• optically active compound (-)-(3R)-3-methyl-4- ⁇ 4-[4-(4-pyridyl)piperazin-J-yl]-phenoxy ⁇ butyric acid, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
• the (-)-(3R) compound possesses substantially better potency as a GPIIb/IHa antagonist than the corresponding (+)-(3S) isomer (greater than 10-fold more potent).
• the (-)-(3R) compound is a novel, potent and selective fibrinogen receptor antagonist that substantially reduces the liability or possibility of obtaining adverse 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 liability or possibility of obtaining adverse effects associated with the administration of the therapeutically less effective (+)-(3S) compound which is a constituent of the (3RS)-racemic mixture.
• Use of the (-)-(3R) compound allows a clearer structure-activity-toxicity analysis and provides an improved therapeutic ratio. It is therefore desirable to use the (-)-(3R) compound of the present invention rather that the (3RS)-racemic mixture of Example 132 of International Patent Application No. WO 94/22834.
• Particular pharmaceutically-acceptable salts of the (-)-(3R) compound of the invention include, for example, salts with acids affording physiologically-acceptable anions, such as salts with mineral acids, for example a hydrogen halide such as hydrogen chloride or hydrogen bromide, sulphuric 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 e.g.
• sodium salts, ammonium salts, and salts with organic amines and quaternary bases forming physiologically-acceptable cations such as salts with methylamine, dimethylamine, trm ethylamine, ethylenediamine, piperidine, morpholine, pyrrolidine, piperazine, ethanolamine, triethanolamine, N-methylglucamine, tetramethylammonium hydroxide and benzyltrimethylammonium hydroxide.
• esters of the (-)-(3R) compound of the invention include, for example, ester derivatives of the carboxylic acid group in the compound of the invention, for example esters formed with alcohols such as (l-6C)alcohols (e.g. methanol, ethanol, propanol and tert-butanol), indanol, adamantol, (l-6C)alkanoyloxy- (l-4C)alcohols (e.g. pivaloyloxymethanol) and (l-4C)alkoxycarbonyl-(l-4C)alcohols (e.g. methoxycarbony lmethanol) .
• alcohols such as (l-6C)alcohols (e.g. methanol, ethanol, propanol and tert-butanol), indanol, adamantol, (l-6C)alkanoyloxy- (l-4C)alcohols (e.g. pivaloyl
• Particular pharmaceutically-acceptable amides of the (-)-(3R) compound of the invention include, for example, amide derivatives of the carboxylic acid group in the compound of the invention, for example amides formed with amines such as ammonia, (l-4C)alkylamines (e.g. methylamine), di-(l-4C)alkylamines (e.g. dimethylamine, N- ethyl-N-methylamine and diethylamine), (l-4C)alkoxy-(2-4C)alkylamines (e.g. 2-methoxyethylamine), phenyl-(l-4C)alkylamines (e.g. benzylamine) and amino acids (e.g.
• amines such as ammonia, (l-4C)alkylamines (e.g. methylamine), di-(l-4C)alkylamines (e.g. dimethylamine, N- ethyl-N-methylamine and dieth
• amides of the (-)-(3R) compound of the invention include the N-methyl-, N,N-dimethyl-, N-ethyl-N-methyl- and N,N- diethyl-butyramides.
• Particular pharmaceutically-acceptable solvates of the (-)-(3R) compound of the invention include, for example, hydrates e.g. a hemi-hydrate, mono-hydrate, di-hydrate or tri-hydrate or an alternative quantity thereof.
• substantially free of the (+)-(3S) stereoisomer 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 may be prepared by any process known in the art for the preparation of such a compound. Suitable procedures include asymmetric synthesis involving an appropriate chiral intermediate and resolution of the (3RS)-racemic mixture. " Such procedures represent 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 performed in the presence of a strong base, such as an alkali metal hydride, for example, sodium hydride.
• a strong base such as an alkali metal hydride, for example, sodium hydride.
• Suitable solvents include amides, such as dimethylformamide.
• the reaction is conveniently performed at a temperature in the range of from 0 to 100 °C.
• Suitable esters of the chiral intermediate (3R)-4-hydroxy-3-methylbutyric acid include, for example, the 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-alkanesulphonyloxy-3-methylbutyric acid or an ester thereof (e.g.
• a methyl or ethyl ester such as the 4-methanesulphonyloxy derivative or (3R)-4-arylsulphonyloxy-3- methylbutyric acid or an ester thereof (e.g. a methyl or ethyl ester) such as the 4-(p- toluenesulphonyloxy) derivative, b) Reaction of a compound of formula I
• values for L include halogen, such as chlorine or bromine, and cyano.
• Examples of acid addition salts of (3R)-3-methyl-4-[4-(piperazin-l-yl)- phenoxyjbutyric acid include, for example, the hydrochlorides.
• the reaction may conveniently be effected at a temperature in the range of from -10 to 120 °C, preferably from 10 to 100 °C.
• Suitable solvents include, e.g. ethers such as tetrahydrofuran and dioxan, amides such as dimethylformamide, nitriles such as acetonitrile, halogenated hydrocarbons such as dichloromethane, alcohols such as ethanol and water.
• the reaction may advantageously be performed in the presence of a base.
• bases include tertiary amines, such as triethylamine, and alkali metal hydroxides, carbonates and bicarbonates, such as sodium or potassium hydroxide, carbonate or bicarbonate, c) Decomposition of an ester of formula II
• R is a carboxyl protecting group
• R may be any conventional carboxyl protecting group that may be removed without interfering with other parts of the molecule.
• carboxyl protecting groups include (l-6C)alkyl groups (such as methyl, ethyl, propyl or t-butyl), phenyl and benzyl, the phenyl moiety in any of which may optionally bear 1 or 2 of halogeno, (l-4C)alkyl, (l-4C)alkoxy or nitro.
• the decomposition may be carried out using any one of the conventional reagents and conditions known in the art for converting carboxylic esters into carboxylic acids.
• the decomposition may be performed by base catalysed 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 catalysed hydrolysis may be performed in the presence of a solvent such as an alcohol, e.g. methanol or ethanol, or an ether such as tetrahydrofuran or dioxan.
• the decomposition may be carried out by acid catalysed hydrolysis, e.g.
• aqueous acetic acid or trifluoroacetic acid The temperature is conveniently in the range of from -10 to 100°C, for example from 10 to 50°C.
• the alcohol residue is t-butyl, this may be removed by heating, e.g. at a temperature in the range of from 80 to 150°C, alone or in the presence of a suitable diluent such as diphenylether or diphenylsulphone.
• a benzyl group may be removed by catalytic hydrogenation, e.g. by hydrogenation in the presence of palladium on carbon at a temperature in the range of from -10 to 100°C in the presence of a solvent such as an alcohol, for example methanol or ethanol.
• the resolution of the butyric acid derivative of the (3RS)-racemic mixture may be carried out by conventional means, for example by salt formation using an optically active base followed by separation, for example by fractional crystallisation of the two salts so produced and regeneration of the separated (-)-(3R) and (+)-(3S) compounds by acidification of the separated salts.
• the resolution of the butyric acid derivative of the (3RS)-racemic mixture may also be carried out by the conventional means 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 may also be employed.
• a pharmaceutically-acceptable salt of 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 reaction of said compound with a suitable acid or base using a conventional procedure. When a pharmaceutically-acceptable ester or amide of the (-)-(3R) compound of the invention is required, it may be obtained, for example, by reaction of said compound with a suitable alcohol or amine as appropriate using a conventional procedure.
• the ability of the (-)-(3R) compound of the invention to inhibit platelet aggregation and to inhibit the binding of fibrinogen to GPIIb/TJIa may be demonstrated using the standard test procedures (a) and (b) disclosed in International Patent Application No. WO 94/22834, which test procedures are incorporated herein by way of reference.
• ADP adenosine diphosphate
• 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, for example venous or arterial thrombosis (e.g. pulmonary embolism, stroke and thrombotic events accompanying unstable angina and transient ischaemic attack), myocardial infarction, 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 (PTCA) and coronary artery bypass graft.
• PTCA percutaneous transluminal coronary angioplasty
• the compounds may be useful in the treatment of other diseases mediated by binding of adhesion molecules to GPIIb/IIIa, for example cancer.
• a method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatment which comprises administering an effective amount of the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
• a method of inhibiting binding of fibrinogen to GPHb/IIIa in a warm-blooded animal requiring such treatment which comprises administering an effective amount of the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
• a method of inhibiting thrombotic events accompanying unstable angina in a warm-blooded animal requiring such treatment comprises administering an effective amount of the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
• a method of inhibiting platelet aggregation in a warm-blooded animal requiring such treatment while substantially reducing adverse effects associated with the administration of the (3-RS)- racemic mixture which comprises administering an effective amount of the (-)-(3R) compound, or a pharmaceutically-acceptable salt, ester, amide or solvate thereof, substantially free of the (+)-(3S) stereoisomer.
• the (-)-(3R) compound of the invention will be administered for this purpose by an oral, rectal, topical, intravenous, subcutaneous, intramuscular or inhalation route, so that a dose in the range of from 0.01 to 50 mg/kg body weight will be given, depending upon the route of_administration, the age and sex of the patient, and the severity of the condition to be treated.
• the (-)-(3R) compound of the invention will generally be used in the form of a pharmaceutical composition
• 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 be in the form of tablets, capsules, solutions or suspensions for oral administration; in the form of cream 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 a 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.
• inert solid diluents such as lactose
• composition may comprise, for example, for 0.1 to 99.9% by weight of the (-)-(3R) compound of the invention.
• compositions may be obtained by conventional procedures 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 minimise contact of the (-)-(3R) compound of the invention with stomach acids.
• the (-)-(3R) compound of the invention may be co-adminstered or co-formulated with one or more agents known to be of value in the diseases or conditions intended to be treated, for example a known platelet aggregation inhibitor (e.g. aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), hypolipidemic agent, anti-hypertensive agent, thrombolytic agent (such as streptokinase, urokinase, prourokinase, tissue plasminogen activator and derivatives thereof), beta-adrenergic blocker or a vasodilator may usefully also be present in a pharmaceutical composition of the invention for use in treating a heart or vascular disease or condition.
• a known platelet aggregation inhibitor e.g. aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor
• hypolipidemic agent e.g. aspirin
• the (-)-(3R) compound of the invention is also useful as a pharmacological tool in the development and standardisation of test systems for the evaluation of the effects of adhesion molecules in laboratory animals such as cats, dogs, rabbits, monkeys, rats and mice, as part of the search for new therapeutic agents.
• the (-)-(3R) compound of the invention may also be used because of its platelet aggregation inhibitory properties in helping to store blood and to maintain the viability of blood and blood vessels in warm-blooded animals (or parts thereof) under-going artificial extracorporeal circulation, for example during limb or organ transplants.
• the (-)-(3R) compound of the invention will generally be administered so that a steady state concentration in the range, for example, 0.1 to 10 mg per litre is achieved in the blood.
• the aqueous solution was acidified by the addition of an aqueous citric acid solution 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 (12.9g).
• p-Toluenesulphonyl chloride (13.2 g) was added portionwise to a stirred mixture of tert-butyl (3R)-4-hydroxy-3-methylbutyrate (11 g), triethylamine (21 ml) and dichloromethane (120 ml) and the mixture stirred for 20 hours. The mixture was washed in turn 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-toluenesulphonyloxy)butyrate as an oil (20 g).
• Illustrative pharmaceutical dosage forms suitable for presenting the compound of the invention for therapeutic or prophylactic use include the following, which may be obtained by conventional procedures well known in the art:
• Active ingredient 1.0 Lactose Ph. Eur. 93.25 Croscarmellose sodium 4.0 Maize starch paste 0.75 (5% w/v aqueous paste) Magnesium stearate 1.0
• Active ingredient (acid addition salt) 1.0
• the (-)-(3R) compound is less toxic than the (3RS)-racemic mixture.

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