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
  • C07D213/24—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 substituted hydrocarbon radicals attached to ring carbon atoms
  • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • 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 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.
• 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.
• Compound 1 [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.
• 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).
• myocardial infarction the formation of atherosclerotic plaques, venous or arterial thrombosis, coagulation syndromes
• vascular injury including reo
• 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.
• Compound 1 i.e. the free base, has limited aqueous solubility and limited bioavailabilty when dosed orally.
• 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
• a Compound of the invention refers to either one of features (a), (b) or (c) described above. 5
• 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,
• a powder of which not less than 90% by weight of the particles pass through a sieve with a nominal mesh aperture of 45 ⁇ m.
• 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 O ⁇ m.
• compositions 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.
• 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.
• the above compositions may be prepared in a conventional manner using conventional excipients.
• 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:-
• 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.
• 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.
• a parenteral route 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.
• a suitable base such as, for example, an alkali or alkaline earth metal carbonate, alkoxide, hydroxide or hydride, for example sodium carbonate,
• 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.
• 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
• 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.
• 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.
• a known platelet aggregation inhibitor for example aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor
• hypolipidaemic agent for example aspirin, a thromboxane antagonist or a thromboxane synthase
• 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.
• 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 -
• 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:
• Maize starch paste (5% w/v aqueous paste) 0.75
• Maize starch paste (5% w/v aqueous paste) 2.25 Magnesium stearate 3.0 - 9 -
• 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.

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• Organic Chemistry (AREA)
• Chemical & Material Sciences (AREA)
• Health & Medical Sciences (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• General Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Engineering & Computer Science (AREA)
• Pharmacology & Pharmacy (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Pyridine Compounds (AREA)

Priority Applications (11)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

Country Status (16)

Cited By (4)

Citations (3)

• 1998
  • 1998-05-02 GB GBGB9809350.3A patent/GB9809350D0/en not_active Ceased
• 1999
  • 1999-04-27 JP JP2000547082A patent/JP2002513789A/ja active Pending
  • 1999-04-27 IL IL13940599A patent/IL139405A0/xx unknown
  • 1999-04-27 CA CA002331041A patent/CA2331041A1/en not_active Abandoned
  • 1999-04-27 PL PL99343705A patent/PL343705A1/xx not_active Application Discontinuation
  • 1999-04-27 CN CN99808217A patent/CN1308629A/zh active Pending
  • 1999-04-27 SK SK1652-2000A patent/SK16522000A3/sk unknown
  • 1999-04-27 EP EP99919395A patent/EP1084118A1/en not_active Withdrawn
  • 1999-04-27 BR BR9910176-9A patent/BR9910176A/pt not_active IP Right Cessation
  • 1999-04-27 WO PCT/GB1999/001316 patent/WO1999057112A1/en not_active Application Discontinuation
  • 1999-04-27 EE EEP200000638A patent/EE200000638A/xx unknown
  • 1999-04-27 HU HU0102394A patent/HUP0102394A3/hu unknown
  • 1999-04-27 AU AU37196/99A patent/AU3719699A/en not_active Abandoned
  • 1999-04-27 KR KR1020007012149A patent/KR20010043216A/ko not_active Application Discontinuation
• 2000
  • 2000-10-25 ZA ZA200006036A patent/ZA200006036B/en unknown
  • 2000-11-01 NO NO20005498A patent/NO20005498D0/no not_active Application Discontinuation

Patent Citations (3)

Non-Patent Citations (2)

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