MXPA00010676A - Reduced particle size form of 1-(6-chloronaphth-2- ylsulphonyl) -4-[4-(4pyridyl) benzoyl]piperazine - Google Patents

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

DK FORM REDUCED PARTICLE SIZE OF 1- (6-CLORONAFT-2-ILSULFONYL) -4- [4- (4-PYRIDYL) BENZOYL] PIPERAZINE DESCRIPTION OF THE INVENTION The invention relates to pharmaceutically acceptable salts in reduced particle size form of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) -benzoyl] piperazine and reduced particle size forms of any of the compounds or pharmaceutically acceptable salts thereof, which possesses antithrombotic and anticoagulant properties and in agreement are used in treatment methods for humans or animals. The invention also relates to the process for the preparation of pharmaceutically acceptable salts of the aforementioned compounds and the reduced particle size forms thereof, to pharmaceutical compositions containing them or using them in the manufacture of medicaments for use in the production of antithrombotic or anticoagulant effects in humans. The effect of antithrombotic and anticoagulant produced by the compound of the invention is believed to be attributable to its strong inhibitory effect against the activated coagulation protease known as Factor Xa. Factor Xa is one within a cascade of proteases involved in the complex process of blood coagulation. The protease known as thrombin is the last of the cascade and factor Xa is the protease that precedes it which adheres to prothrombin to generate thrombin. Some compounds are known to possess the inhibitory properties of factor Xa and in the field reviewed by R. B. Wallis, Current Opinion In Therapeutic Patents, 1993, 1173-1179. Therefore it is known that of two proteins, one is known as antistatin and the other as tick-binding protein (TAP), are specific inhibitors of Factor Xa which has antithrombotic properties in several animal models of thrombotic diseases ^ It is also known that some non-peptidic compounds have inhibitory properties of Factor Xa. Of the inhibitors of low-weight molecules mentioned in the summary by R.B. Wallis, all have a strong basic group such as the amidinophenyl group or amidinonaphthyl. It has been found that the reduced particle size forms of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine (which will be referred to as compound 1) possess inhibitory activity Factor Xa in concentrations that fail to inhibit, or inhibit in a lesser extent the enzyme thrombin, which is also a member of the enzymatic cascade of blood coagulation.

The additional trifluoroacetic acid salt of compound 1 is set forth as example 7 of PCT Application No. GB97 / 03033. • 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 neurovascular diseases. Later examples of these medical disorders include several cardiovascular and neurovascular conditions as infarction • to the myocardium, the formation of atherosclerotic platelets, veins or arteries with thrombosis, coagulation syndrome, vascular damage (including reocclusion and restenosis after angioplasty and artery bypass surgery) Coronary artery, thrombus formation after the application of operative techniques of blood vessels or after general surgery such as hip prosthesis operation, introduction of an artificial valve to the heart or in the recirculation of the • blood), cerebral infarction, cerebral thrombosis, infarction, cerebral embolism, pulmonary embolism, ischemia and angina (including unstable angina). Compound 1 is also used as an inhibitor in blood coagulation in ex vivo situations such as for example the storage of whole blood or other biological samples suspected of containing Factor Xa and in which coagulation is detrimental. It has been found that Compound 1, for example, the free base has a limited water solubility and bioavailability when administered orally. Pharmaceutically acceptable salts of Compound 1 and also solid forms of both of Compound 1 and pharmaceutically acceptable salts of Compound 1 have been investigated in the form of reduced particle size to try to improve the physical properties of Compound 1. Research has shown that Pharmaceutically acceptable salts of Compound 1 in the form of reduced particle size of Compound 1, and pharmaceutically acceptable salts thereof, exhibit improved physical properties. In particular the pharmaceutically acceptable salts of Component 1 show the improved physical properties such as their solubility in water and oral bioavailability. In particular the reduced particle size forms of the pharmaceutically acceptable salts of Compound 1 show improvement in dissolution rate in water, oral bioavailability and reduction of variability in oral bioavailability when compared to Compound 1. The present invention also provides the following: a) A reduced particle size form of pharmaceutically acceptable salts or a solvent of Compound 1; b) A reduced particle size form of Compound 1 or a solvent thereof; and c) A pharmaceutically acceptable salt of Compound 1 or a solvent thereof. The term "a compound of the invention" will be used later referring to any of the parentheses a, b or c described above. The use of the term "reduced particle size" refers to solid Compound 1, or a pharmaceutically acceptable salt thereof, or a solvent of any of these, reduced by appropriate processing techniques to a solid of smaller particle size and consequently , greater surface area. Any number of processing techniques known in the pharmaceutical field can be used to reduce the size of solid particles, as well as grind, pulverize or micronise, for a detailed review should refer to Remington: The Science and Practice of Pharmacy, 19th ed. pages 1598-1602. The preferred range of reduced particle size in this initial form of the invention, preferably ascending, moderately fine powder, fine powder, very fine powder, microfine powder to preferably super fine powder.

The above references to particle size are taken from British Pharmacopoeia 1993, Volume II Appendix XVII B, A 193 which are subsequently • mentioned for reference: 5 Moderately fine powder A powder where all its particles pass through a sieve with nominal net opening of 355 μm and not exceeding 40.0% of the weight through a sieve with nominal net opening. 250 μm. 10 Fine powder • A powder where all its particles pass through a sieve with nominal net opening of 180 μm and that does not pass more than 40.0% of the weight through a screen with a nominal opening of 125 μm net. 15 Very fine dust A powder where all its particles pass through a sieve with a nominal mesh opening of 125 μm and that does not pass more than 40.0% of the weight through a sieve with • nominal 45 μm network opening. 20 Microfine powder A powder where no more than 90.0% of the weight passes through a sieve with a nominal 45 μm net opening. Super fine powder A powder where no more than 90% of the weight passes through a sieve with a nominal 10 μm net opening.

The particular sieves that will be used to determine the particle size are described in British Pharmacopoeia 1993, Volume II, Appendix XVIIB, A193-A194, part of which is presented as a reference. The pharmaceutically acceptable salts can be formed by reacting a portion of Compound 1 with any number of organic or inorganic acids and precipitating the salt from the solution. The preferred pharmaceutically acceptable salt of Compound 1 is the hydrochloride salt. In a preferable form, the chloride salt of Compound 1 is soluble, preferably hydrated and in particular the hemihydrated form is preferable. A feature of the invention is a compound thereof, as described above for use in medical therapy. According to a later feature of the invention, a pharmaceutical composition comprising a compound of the invention is provided, as described above, in association with a pharmaceutically acceptable solvent or carrier. The Compound may be in a form suitable for oral administration, for example, a tablet, aqueous or oily solution, suspension or emulsion; for topical administration, for example a cream, ointment, gel or aqueous or oily solution or suspension; for nasal administration, for example an inhaler, sprinkler or nasal drops; for vaginal or anal administration, for example a suppository; for administration by inhalation, for example a fine powder such as a dry powder, a microcrystalline form or a liquid aerosol; for buccal or sublingual administration, for example a tablet or capsule; or for parenteral administration (including intravenous, subcutaneous, intravascular, intramuscular or infusion), for example a sterile aqueous or oily solution or suspension. In general, the aforementioned compounds can 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 dose form, will necessarily vary depending on the host treated and the particular route of administration. For example, a formulation created for oral administration to humans will generally contain, for example, 0.5 mg to 2 g of active agent compounded with an appropriate and convenient amount of excipient or excipients which may vary from about 5 to 98 percent by weight total of the compound. The dosage unit forms will generally contain about lmg to 500mg of an active ingredient.

The invention also includes the use of a compound of the invention, as described above in the manufacture of a medicament for use in: (i) The production of an inhibitory effect of Factor Xa; (ii) The production of an anticoagulant effect; (iii) The production of an antithrombotic effect; (iv) The treatment of a medical condition or disease mediated by Factor Xa; (v) The treatment of a medical condition or disease mediated by thrombosis; (vi) The treatment of coagulation disorders; and / or (vii) The treatment of an embolism or thrombosis related to coagulation mediated by Factor Xa. The invention also includes a method for producing an effect as defined above in the invention or for treating a disease or disorder as defined above, which comprises administering such treatment in an effective amount of a compound of the invention, as described above, to a warm-blooded animal that needs it. The dose size of a form of a compound of the invention for therapeutic or prophylactic purposes, 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 under treatment and the route of administration, according to the well-known principles of medicine. When using a compound of the invention it will generally be administered so that a daily oral dose is received in the range, for example, from 0.1 to 50 mg / kg per body weight / day, in divided doses if necessary. In general, lower doses will be administered when a parenteral route is used, for example a dose for intravenous administration in the range, for example from 0.01 to 10 mg / kg per body weight / day. Preferred daily oral doses include, for example, 0.1 to 10 mg / kg per body weight / day. In general, the range in the preferred oral or parenteral administration dose is 0.01 to 10 mg / kg per body weight / day. Compound 1 can conveniently be prepared by reacting (4-pyridyl) benzoic acid, or a reactive derivative thereof, for example the acylchloride derivative, with 1- (6-chloronaphth-2-ylsulfonyl) piperazine, or a salt thereof. same, for example, the hydrochloride salt. The reaction is conveniently carried out in the presence of an appropriate base such as, for example, an alkaline carbonate or an alkaline earth metal, alkoxide, hydroxide or hydride, for example sodium carbonate, potassium carbonate, sodium ethoxide, butoxide potassium, sodium hydroxide, potassium hydroxide, sodium hydride or potassium hydride or an organometallic base such as alkyllithium, for example n-butyl¬ • lithium or a dialkylamino lithium, for example lithium di-5-isopropylamide or for example, an organic amino base such as, for example, pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabicyclo [5.4.0 undec-7-ene The reaction will preferably be carried out in an inert solvent or diluent and Suitable, for example, methylene chloride, chloroform, • carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethisulfoxide or acetone, and at a temperature in a range, for example, -78 °. at 150 ° C, conveniently at or near room temperature. The processes for the preparation of the two aforementioned intermediates, as well as of Compound 1 can be found in the PCT application No. PCT / GB97 / 03033. • Compound 1 or a compound of the invention is can be administered as a single therapy or together with other pharmaceutically active agents, such as a thrombolytic agent, for example, a tissue plasminogen activator or derivatives thereof or streptokinase. The compounds of the invention can also be administered with, For example, a known inhibitor of platelet aggregation (e.g., aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor) a known hypolipidemic agent or known antihypertensive agent. The dissolution ranges of the material were tested in analogous methods as described in the British Pharmacopoeia 1998 Appendix XIID A189-A191. The invention will be illustrated with the following examples. Example 1 Preparation of 1- (6-chloronaphth-2-ylsulphonyl) -4- [4- (4-pyridyl) benzoyl) piperazine hydrochloride from a free base: The free base of 1- (6-chloronaft-2 -ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine (54.8g), was dissolved in dichloromethane (8OOml) and added by stirring a solution of HCl in ethyl acetate (50ml of 3.1M, 1.1 eq. .); the mixture was stirred for one hour resulting in copious precipitation. The solvent was removed in vacuo and the resulting colorless solid was dried under high vacuum. Hot methanol (2.51) was added to the solid, the solution was brought to reflux (the complete solution in this step), filtered and the volume was reduced in a steam bath until its crystallization began; the solution was removed from the steam bath and allowed to crystallize to obtain 1- (6-chloronaphth-2-ylsulfonyl) -4 [4- (4-pyridyl) benzoyl] piperazine as the hemihydrate hydrochloride salt, 46.6 gms of a solid colorless crystalline Mp250 ° C xHNMR (d6-DMSO): 2.9-3.2 (broad s, 4H), 3.3-3.8 (s broad, 4H), 7.4 (d, 2H), 7.7 (m, 3H), 7.8 (m, 3H) ) 8.2 (d, 1H), 8.3 (m, 2H), 8.5 (s, lH) 8.7 (d, 2H) Microanalysis found: C, 57.9; H, 4.5; N, 7.7; S, 6.2; Cl, 13.0%; C26H23N303C1S. 1.0HC1. 0.5H2O required: 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 the Reduced Particle Size Form of Example 1. The hemihydrated hydrochloride salt of Compound 1 (Example 1) was fed in a controlled rate to the fluid energy mill (MICRONIZER), in which the salt was subjected to an auto wear caused by high energy gas jet. The particles produced were classified continuously with the collection of the fine particles by means of a filter. The produced solid was measured as "super fine powder" (reference: British Pharmacopoeia 1993 Vo. 2 appendix A193). EXAMPLE 3 Illustrative dosage dosage forms of pharmaceutical dosage suitable for presenting a Compound of the invention for therapeutic or prophylactic use include the following tablet and capsule formulations, which can be obtained by conventional methods known in the pharmaceutical field and are suitable for the Therapeutic use in humans. (a) Tablet I mg / tablet Compound Z * 1.0 Lactose Ph. Eur. 93.25 Croscarmellose sodium 4.0 Corn starch paste (5% w / v aqueous paste) 0.75 Magnesium stearate 1.0 (b) Tablet II mg / tablet Compound Z * 50 Lactose Ph. Eur. 223.75 Croscarmellose sodium 6.0 Starch of corn 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 Corn starch paste (5% p / v of aqueous paste) 2.25 Magnesium stearate 3.0 (d) Capsule mg / capsule Compound Z * 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.5 Note * The active ingredient of Compound Z is a compound of the invention described above. The composition of tablet (a) - (c) may be enteric coated by conventional means, for example, with cellulose acetate phthalate.

Claims (9)

1. CLAIMS 1. A reduced particle size form of any of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) -benzoyl] piperazine or a pharmaceutically acceptable salt of 1- (6 -chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] -piperazine or a solvent of any of them.
2. 2. A 1- (6-chloronaphth-2-ylsulphonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hydrochloride salt or a solvent thereof.
3. 3. A hydrochloride salt of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hemihydrate.
4. 4. A very fine powder of either 1- (6-chloronaphth-2-ylsulfonyl) -A - [4- (4-pyridyl) benzoyl] piperazine or a pharmaceutically acceptable salt of 1- (6-chloronaphth-2-ylsulfonyl) ) - 4- [4- (4-pyridyl) benzoyl] piperazine or a solvent of any of them.
5. 5. A microfine powder of either l- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine or a pharmaceutically acceptable salt of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine or a solvent of any of them.
6. 6. A very fine powder of either 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine or a pharmaceutically acceptable salt of 1- (6-chloronaphth-2-ylsulfonyl) ) -4- [4- (4-pyridyl) benzoyl] piperazine or a solvent of any of them.
7. 7. The use of any substance in medical therapy defined according to any of claims 1 to 7.
8. The pharmaceutical composition characterized in that it contains a substance as defined according to any of claims 1 to 7 with a diluent or carrier pharmaceutically acceptable. 10
9. 9. The use of a substance in accordance with • any of claims 1 to 7 in the production of a medicament for use in the treatment of a disease or medical condition mediated by Factor Xa. •