REDUCED PARTICLE SIZE FORM OF 1-(6-CHLORONAPHTH-2- YLSULPHONYL) -4-[4-(4PYRIDYL) BENZOYL] PIPERAZINE

Abstract: The invention relates to pharmaceutically acceptable salts of 1-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and reduced particle size forms of either the compound or a pharmaceutically acceptable salt thereof, which possess antithrombotic and anticoagulant properties and accordingly are useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of pharmaceutically-acceptable salts of the above compound and reduced particle size forms thereof, to pharmaceutical compositions containing them and to their use in the manufacture of medicaments for use in the production of an antithrombotic or anticoagulant effect in humans.

Description: - 1 - REDUCED PARTICLE SIZE FORM OF l-(6-CHLORONAPHTH-2- YLSULPHONYL) -4-[4-(4PYRIDYL) BENZOYL] PIPERAZINE The invention relates to pharmaceutically-acceptable salts of 1 -(6-chloronaphth- 2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine and reduced particle sized forms of either 5 the compound or a pharmaceutically-acceptable salt thereof, which possess antithrombotic and anticoagulant properties and accordingly are useful in methods of treatment of humans or animals. The invention also relates to processes for the preparation of pharmaceutically- acceptable salts of the above compound and reduced particle size forms thereof, to pharmaceutical compositions containing them and to their use in the manufacture of 0 medicaments for use in the production of an antithrombotic or anticoagulant effect in humans. The antithrombotic and anticoagulant effect produced by the compounds of the invention is believed to be attributable to their strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is one of a cascade of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the final 5 protease in the cascade and Factor Xa is the preceding protease which cleaves prothrombin to generate thrombin. Certain compounds are known to possess Factor Xa inhibitory properties and the field has been reviewed by R.B. Wallis, Current Opinion in Therapeutic Patents. 1993, 1173- 1179. Thus it is known that two proteins, one known as antistatin and the other known as tick 0 anticoagulant protein (TAP), are specific Factor Xa inhibitors which possess antithrombotic properties in various animal models of thrombotic disease. It is also known that certain non-peptidic compounds possess Factor Xa inhibitory properties. Of the low molecular weight inhibitors mentioned in the review by R.B. Wallis, all possessed a strongly basic group such as an amidinophenyl or amidinonaphthyl group. 5 We have now found that l-(6-chloronaphth-2-ylsulphonyl)-4- [4-(4-pyridyl)benzoyl]piperazine (hereinafter referred to as Compound 1) possesses Factor Xa inhibitory activity at concentrations which do not inhibit, or which inhibit to a lesser extent, the enzyme thrombin which is also a member of the blood coagulation enzymatic cascade. The trifluoroacetic acid addition salt of Compound 1 is disclosed as Example 7 of 0 PCT Application No. GB97/03033. - 2 - Compound 1 possesses activity in the treatment or prevention of a variety of medical disorders where anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions such as coronary artery and cerebro-vascular disease. Further examples of such medical disorders include various cardiovascular and cerebrovascular conditions such as myocardial infarction, the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes, vascular injury (including reocclusion and restenosis following angioplasty and coronary artery bypass surgery, thrombus formation after the application of blood vessel operative techniques or after general surgery such as hip replacement surgery, the introduction of artificial heart valves or on the recirculation of blood), cerebral infarction, cerebral thrombosis, stroke, cerebral embolism, pulmonary embolism, ischaemia and angina (including unstable angina). Compound 1 is also useful as an inhibitor of blood coagulation in an ex-vivo situation such as, for example, the storage of whole blood or other biological samples suspected to contain Factor Xa and in which coagulation is detrimental. We have found that Compound 1, i.e. the free base, has limited aqueous solubility and limited bioavailabilty when dosed orally. We have investigated pharmaceutically- acceptable salts of Compound 1 and also solid forms of both Compound 1 and pharmaceutically-acceptable salts of Compound 1 with reduced particle size to try to improve upon the physical properties of Compound 1. Our investigations have shown that pharmaceutically-acceptable salts of Compound 1 and reduced particle sized forms of Compound 1, and pharmaceutically-acceptable salts thereof, show improved physical properties. In particular the pharmaceutically-acceptable salts of Compound 1 showed improved physical properties such as aqueous solubility and oral bioavailabilty. In particular the reduced particle size form of a pharmaceutically-acceptable salt of Compound 1 showed an improved aqueous dissolution rate, oral bioavailabilty, and reduction in the variability in oral bioavailabilty when compared to Compound 1. Accordingly provided in the present invention is: (a) a reduced particle size form of a pharmaceutically-acceptable salt or a solvate thereof of Compound 1; (b) a reduced particle size form of Compound 1 or a solvate thereof; and - 3 - (c) a pharmaceutically-acceptable salt of Compound 1 or a solvate thereof. As used hereinafter the term "a Compound of the invention" refers to either one of features (a), (b) or (c) described above. 5 By the use of the term "reduced particle size" we refer to solid Compound 1, or a pharmaceutically-acceptable salt thereof, or a solvate of either thereof, reduced by suitable processing techniques to a solid of smaller particle size and, consequently, greater surface area. Any number of processing techniques known in the pharmaceutical field may be used to reduce solid particle size, such as grinding, milling and micronising, reference should be made 10 to Remington: The Science and Practise of Pharmacy, 19 th Ed., pages 1598-1602, for a more exhaustive review. The range of particle sizes preferred in this invention start from, in increasing preference, moderately fine powder, fine powder, very fine powder, microfine powder to, most preferably, superfine powder. 15 The above references to particle sizes are taken from the British Pharmacopoeia 1993, Volume II, Appendix XVII B, A193, and are reproduced below for reference. Moderately fine powder A powder all the particles of which pass through a sieve with a nominal mesh aperture of 20 355μm and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 250μm. Fine powder A powder all the particles of which pass through a sieve with a nominal mesh aperture of 25 180μm and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 125μm. Very fine powder A powder all the particles of which pass through a sieve with a nominal mesh aperture of 30 125μm and not more than 40.0% by weight pass through a sieve with a nominal mesh aperture of 45μm. - 4 - Microfine powder A powder of which not less than 90% by weight of the particles pass through a sieve with a nominal mesh aperture of 45 μm. Superfine powder A powder of which not less than 90% by weight of the particles pass through a sieve with a nominal mesh aperture of 1 Oμm. The particular sieves to be used in determining the particle size are described in British Pharmacopoeia 1993 Volume II, Appendix XVIIB, A193-A194, which part is incorporated herein by reference. Pharmaceutically-acceptable salts may be formed by reacting the basic moiety of Compound 1 with any one of a number of pharmaceutically-acceptable organic or inorganic acids and precipitating the salt from solution. A preferred pharmaceutically-acceptable salt of Compound 1 is the hydrochloride salt. In a more preferred from the chloride salt of Compound 1 is solvated, preferably hydrated, and in particular the hemihydrate form is preferred. A feature of the invention is a Compound of the invention, as described above, for use in medical therapy. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a Compound of the invention, as described above, in association with a pharmaceutically-acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for topical use, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal use, for example a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder such as a dry powder, a microcrystalline form or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. The amount of a Compound of the invention, as described above that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the host treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipient(s) which may vary from about 5 to about 98 percent by weight of the total composition. Dosage unit forms will generally contain about 1 mg to about 500 mg of an active ingredient. The invention also includes the use of a Compound of the invention, as described above in the production of a medicament for use in:- (i) producing a Factor Xa inhibitory effect; (ii) producing an anticoagulant effect; (iii) producing an antithrombotic effect; (iv) treating a Factor Xa mediated disease or medical condition; (v) treating a thrombosis mediated disease or medical condition; (vi) treating coagulation disorders; and/or (vii) treating thrombosis or embolism involving Factor Xa mediated coagulation. The invention also includes a method of producing an effect as defined hereinbefore or treating a disease or disorder as defined hereinbefore which comprises administering to a warm-blooded animal requiring such treatment an effective amount of form of a Compound of the invention, as described above. The size of the dose for therapeutic or prophylactic purposes of a form of a Compound of the invention, as described above, will naturally vary according to the nature and severity of the medical condition, the age and sex of the animal or patient being treated and the route of administration, according to well known principles of medicine. In using a Compound of the invention it will generally be administered so that a daily oral dose in the range, for example, 0.1 to 50 mg/kg body weight/day is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed, for example a dose for intravenous administration in the range, for example, 0.01 to 10 mg/kg - 6 - body weight/day will generally be used. Preferred oral daily doses include, for example, 0.1 to 10 mg/kg body weight/day. In general a preferred dose range for either oral or parenteral administration would be 0.01 to 10 mg/kg body weight/day. Compound 1 may conveniently be prepared by reacting (4-pyridyl)benzoic acid, or a reactive derivative thereof, for example the acylchloride derivative, with l-(6-chloronaphth-2-ylsulphonyl)piperazine, or a salt thereof, for example, the hydrochloride salt. The reaction is conveniently carried out in the presence of a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, potassium butoxide, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride, or an organometallic base such as an alkyl-lithium, for example n-butyl-lithium, or a dialkylamino-lithium, for example lithium di-isopropylamide, or, for example, an organic amine base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo[5.4.0]undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent, for example methylene chloride, chloroform, carbon tetrachloride, tetrahydrofuran, 1 ,2-dimethoxyethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethylsulphoxide or acetone, and at a temperature in the range, for example, -78° to 150°C, conveniently at or near ambient temperature. Processes for the preparation of the two intermediates above, as well as for Compound 1, may be found in PCT application number PCT/GB97/03033. Compound 1 or a Compound of the invention may be administered as a sole therapy or they may be administered in conjunction with other pharmacologically active agents such as a thrombolytic agent, for example tissue plasminogen activator or derivatives thereof or streptokinase. The compounds of the invention may also be administered with, for example, a known platelet aggregation inhibitor (for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidaemic agent or a known anti-hypertensive agent. The dissolution rates of material were tested in analagous methods as described in the Britsih Pharmacopoeia 1998 Appendix XIID A189-A191. The invention will now be illustrated in the following Examples. Example 1 Preparation of l-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyllpiperazine hydrochloride from free base: Free base 1 -(6-chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine (54.8g) was dissolved in dichloromethane (800ml) and a solution of HCl in ethyl acetate ( 50 ml of 3.1 M, 1.1 eq.) was added with stirring; the mixture was stirred for lhour, giving a copious precipitate. The solvent was removed in vacuo and the resulting colourless solid dried under a high vacuum. To the solid was added hot methanol (2.51), the suspension was brought to reflux (complete solution at this stage), filtered, and the volume then reduced on a steam bath until crystallisation started to occur; the solution was removed from the steam bath and allowed to crystallise to give l-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine as the hydrochloride salt hemihydrate, 46.6g as a colourless crystalline solid. M.p. 250°C ! H NMR(d 6 -DMSO): 2.9 - 3.2 (broad s, 4H), 3.3 - 3.8 (broad s, 4H), 7.4 (d, 2H), 7.7 (m, 3H), 7.8 (m, 3H), 8.2 (d, 1H), 8.3 (m, 2H), 8.5 (s, 1H), 8.7 (d, 2H) Microanalysis, found: C, 57.9; H, 4.5; N, 7.7; S, 6.2; Cl, 13.0 %; C26H23N3O3CIS. 1.0 HCl. 0.5 H 2 O requires: C, 58.0; H, 4.7; N, 7.8; S, 6.0; Cl, 13.2 % Mass spectrum (+ ive ESP) m/z 492/494 (M+H+). Example 2 Preparation of Reduced Particle Size Form of Example 1 The hemihydrate hydrochloride salt of compound 1 (Example 1) was fed at a controlled rate into a fluid energy mill (microniser), in which the salt was subjected to self attrition caused by high energy streams of gas. The particles produced were continuously classified, with the fines collected via a filter. The solid produced was measured as "Superfine Powder" (Reference: British Pharmacopoeia 1993 Vo.2 Appendix A193). - 8 - Example 3 Illustrative pharmaceutical dosage forms suitable for presenting a Compound of the invention for therapeutic or prophylactic use include the following tablet and capsule formulations, which may be obtained by conventional procedures well known in the art of pharmacy and are suitable for therapeutic use in humans: (a) Tablet I mg/tablet Compound Z* 1.0 Lactose Ph. Eur. 93.25 Croscarmellose sodium 4.0 Maize starch paste (5% w/v aqueous paste) 0.75 Magnesium Stearate 1.0 (b) Tablet II me/tablet Compound Z* 50 Lactose Ph. Eur 223.75 Croscarmellose sodium 6.0 Maize starch 15.0 Polyvinylpyrrolidone (5% w/v aqueous paste) 2.25 Magnesium stearate 3.0 (c) Tablet III mg/tablet Compound Z* 100 Lactose Ph. Eur. 182.75 Croscarmellose sodium 12.0 Maize starch paste (5% w/v aqueous paste) 2.25 Magnesium stearate 3.0 - 9 - (d) Capsule mg/capsule Compound Z* 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 Note * The active ingredient Compound Z is a Compound of the invention, as described above. The tablet compositions (a) - (c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate.

Claims: - 10 - CLAIMS 1. A reduced particle size form of either 1 -(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of l-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof. 2. 1 -(6-Chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine hydrochloride salt or a solvate thereof. 3. l-(6-Chloronaphth-2-ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine hydrochloride hemi-hydrate salt. 4. A superfine powder of either 1 -(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1 -(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof. 5. A microfine powder of either l-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of 1 -(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof. 6. A very fine powder of either l-(6-chloronaphth-2-ylsulphonyl)-4-[4-(4- pyridyl)benzoyl]piperazine or a pharmaceutically-acceptable salt of l-(6-chloronaphth-2- ylsulphonyl)-4-[4-(4-pyridyl)benzoyl]piperazine or a solvate of either thereof. 7. Use of any substance defined in any one of claims 1 to 7 in medical therapy. 8. A pharmaceutical composition comprising a substance as defined in any claim from 1 to 7 in association with a pharmaceutically-acceptable diluent or carrier. 9. The use of a substance as defined in any claim from 1 to 7 in the production of a medicament for use in treating a Factor Xa mediated disease or medical condition.

Inventors: ASHFORD MARIANNE, JAMES ROGER, ASHFORD, MARIANNE, JAMES, ROGER
Applicants: ASHFORD MARIANNE, JAMES ROGER, ZENECA LTD, ASHFORD, MARIANNE, JAMES, ROGER, ZENECA LIMITED
Application year: 1999
Main classification: C07D401
IPC codes: A61K31, A61P7, A61P43, C07D213