SK16522000A3 - 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

Technical field

The present invention relates to pharmaceutically acceptable salts of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine and forms of the compound or a pharmaceutically acceptable salt thereof with reduced particle size having antithrombotic and anticoagulant properties, and accordingly are useful in the treatment of humans or animals. The invention also relates to a process for the preparation of pharmaceutically acceptable salts of said compound and reduced particle size forms thereof, to pharmaceutical compositions containing said salts, and to their use in the manufacture of a medicament for use in achieving antithrombotic and anticoagulant effects in humans.

BACKGROUND OF THE INVENTION

It is believed that the antithrombotic and anticoagulant effect induced by the compounds of the invention is attributable to their potent inhibitory effect on the activated coagulation protease known as factor Xa. This protease, referred to as factor Xa, is one of a cascade of proteases involved in the blood coagulation process. The final protease of this cascade is thrombin, where the protease referred to as factor Xa is a previous protease that cleaves prothrombin to form thrombin.

some compounds are known to have Factor Xa inhibitory properties and are described in 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 TAP anticoagulant protein, are specific Factor Xa inhibitors having antithrombotic properties in various animal models of thrombotic disease.

It is also known that some non-peptide compounds also have factor Xa inhibitory properties. All of the low molecular weight inhibitors disclosed in R. B. Wallis have a strong basic group such as, in particular, an amidinophenyl or amidinonaphthyl group.

It has now been found that 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine (hereinafter referred to as Compound 1) has factor A inhibitory activity at a concentration that it does not inhibit or inhibit to a lesser extent the enzyme thrombin, which is also a member of the enzyme cascade of the blood coagulation process.

The trifluoroacetate addition salt of compound 1 is described in Example 7 of PCT application no. GB 97/03033.

Compound 1 has efficacy in the treatment or prevention of various disorders for which anticoagulant therapy is indicated, for example in the treatment or prevention of thrombotic conditions, including coronary arterial and cerebrovascular diseases. Other examples of such physiological disorders include various cardiovascular and cerebrovascular conditions, such as myocardial infarction, atherosclerotic plaque formation, venous or arterial thrombosis, coagulation syndromes, vascular lesion (including reocclusion and restenosis after angioplasty surgery, cervical arthroplasty, and surgical arthroplasty) techniques or following general surgery such as hip replacement, insertion of an artificial heart valve, surgery in the bloodstream), cerebral infarction, cerebral thrombosis, stroke, brain embolism, pulmonary embolism, ischemia, and angina (including unstable angina).

Compound 1 is also useful as an inhibitor of blood clotting in ex vivo situations, including, for example, the storage of whole blood or other biological samples suspected of containing factor Xa and where coagulation would have a deleterious effect.

Compound 1, i. j. the free base has limited solubility in water and limited bioavailability when administered orally. The Applicant has searched for pharmaceutically acceptable salts of Compound 1 as well as solid forms of both Compound 1 and pharmaceutically acceptable salts of Compound 1 with reduced particle size in order to achieve improved physical properties of Compound 1.

The Applicant's studies have shown that the pharmaceutically acceptable salts of Compound 1 and the forms of Compound 1 and their pharmaceutically acceptable salts with reduced particle size are characterized by improved physical properties. In particular, the pharmaceutically acceptable salts of Compound 1 have such improved physical properties, the improvement being particularly related to their water solubility and oral bioavailability. In particular, the pharmaceutically acceptable salt form of Compound 1 having a reduced particle size has improved water dissolution rate, improved oral bioavailability, and improved oral bioavailability compared to Compound 1.

SUMMARY OF THE INVENTION

The subject of the invention is:

(a) a reduced particle size form of a pharmaceutically acceptable salt or solvate thereof of Compound 1;

(b) a reduced particle size form of Compound 1 or a solvate thereof; and

c) a pharmaceutically acceptable salt of Compound 1 or a solvate thereof.

The term "compound according to the invention" is to be understood as one of the substances mentioned in a), b) and c).

By "reduced particle size" is meant here a solid compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, the particles of which have been reduced by a suitable processing technique, resulting in a greater surface area of the particles. Any of the processing techniques known in the pharmaceutical art may be used to reduce the particle size, including, but not limited to, crushing, milling and micronizing, such disintegration techniques being described, for example, in Remington, The Science and Practice of Pharmacy, 19th Edition, 1598 -1602.

The range of particle sizes that are preferred in the present invention ranges in order of increasing convenience, from a mild powder, a fine powder, a very fine powder, a micro-fine powder to the most preferred superfine powder.

Qualitative particle size grades of the various types of powders are given in British Pharmacopoeia 1993, Vol. 2, Annex XVIIB, A193 and these species can be defined as follows.

Slightly fine powder

Powder in which all particles pass through a sieve with a nominal mesh size of 355 µm and a maximum of 40.0% by weight. passes through a sieve with a nominal mesh size of 250 µm.

Fine powder

Powder in which all particles pass through a sieve with a nominal mesh size of 180 µm and a maximum of 40.0% by weight. passes through a sieve with a nominal mesh size of 125 µm.

Very fine powder

Powder in which all particles pass through a sieve with a nominal mesh size of 125 µm and a maximum of 40.0% by weight. passes through a sieve with a nominal mesh size of 45 µm.

Microfine powder

Powder in which at least 90 wt. the particles pass through a sieve with a nominal mesh size of 45 µm.

Superfine powder

Powder in which at least 90 wt. the particles pass through a sieve with a nominal mesh size of 10 µm.

The individual sieves used to determine the particle size of each powder type are described in British Pharmacopoeia 1993, Vol. 2, Annex XVIIB, A193-A194.

Pharmaceutically acceptable salts may be obtained by reacting the basic residue of compound 1 with any of a number of pharmaceutically acceptable organic or inorganic acids and precipitating the obtained salt from solution. A preferred pharmaceutically acceptable salt of Compound 1 is the hydrochloride salt. Even more preferred is the hydrochloride salt of the compound in the form of a solvate, more preferably in the form of a hydrate, with the hemihydrate form being even more preferred.

The invention thus provides a compound of the invention for use in medical therapy.

A further object of the invention is a pharmaceutical composition comprising the described compound of the invention in combination with a pharmaceutically acceptable diluent or carrier.

Said composition may be in a form suitable for oral use, for example in the form of tablets, capsules, aqueous or oily solutions, suspensions or emulsions, or for topical use, for example in the form of an ointment, cream, gel or aqueous or oily solution or suspension or for nasal use, for example in the form of a snuff, nasal spray or nasal drops, or for vaginal or rectal administration, for example in the form of a suppository, or for administration by inhalation, for example in the form of finely disintegrated powder, especially dry powder, microcrystalline or aerosol, or for sublingual or buccal administration, for example in the form of tablets or capsules, or for parenteral administration (including intravenous administration, subcutaneous administration, intramuscular administration, intravascular administration or infusion), e.g. in the form of a sterile aqueous or oily solution or sus. board.

In general, said compositions may be prepared in a conventional manner using conventional excipients.

The amount of the compound of the invention described herein, which is mixed with one or more excipients to obtain a unit dosage form will necessarily vary depending on the subject being treated and the route of administration chosen. For example, a formulation intended for oral administration to humans will generally contain, for example, 0.5 to 2 g of active ingredient mixed with an appropriate and appropriate amount of excipient or excipients, which may range from about 5 to about 98% by weight based on the total. weight of the composition. Unit dosage forms will generally contain about 1 mg to about 500 mg of the active ingredient.

The present invention also provides the use of a compound of the present invention for the manufacture of a medicament for use in:

i) inducing factor Xa inhibitory effect, ii) inducing anticoagulant effect, iii) inducing antithrombotic effect, iv) treating factor Xa mediated disease or condition,

(v) treating a disease or condition associated with thrombosis; (vi) treating coagulation disorders; and / or (vii) treating thrombosis or embolism in which factor Xa-mediated coagulation is applied.

The invention also encompasses a method of inducing an effect as defined above or treating a disease or condition as defined above, comprising administering to a warm-blooded animal in need of such treatment an effective amount of a disclosed form of a compound of the invention.

The dosage size for therapeutic or prophylactic purposes of the form of the compound of the invention described above will naturally vary depending on the nature and severity of the disease or condition being treated, the age and sex of the animal or human patient, and the route of administration chosen. applied in medicine. In a practical application, the compound of the invention will generally be administered in an amount such that the patient receives a daily oral dose in the range, for example, 0.1 to 50 mg / kg body weight per day, optionally in several sub-doses. Generally, lower doses will be administered when parenteral administration is used, for example, the dose for intravenous administration is, for example, in the range of 0.01 to 10 mg / kg body weight per day. For example, preferred oral daily dosages include 0.1 to 10 mg / kg body weight per day. In general, the preferred application range for oral or parenteral administration is from 0.01 to 10 mg / kg body weight per day.

Compound 1 can be prepared by reacting (4-pyridyl) benzoic acid or a reactive derivative thereof, such as an acyl chloride derivative, with 1- (6-chloronaphth-2-ylsulfonyl) piperazine, or a salt thereof, such as the hydrochloride salt. This reaction is usually carried out in the presence of a suitable base such as 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 hydride a potassium or organometallic base such as an alkyl lithium such as n-butyl lithium or a dialkylaminolithium such as 11thium diisopropylamide or an organic amine such as pyridine, 2,6-lutidine, collidine, 4-dimethylaminopyridine, triethylamine, morpholine or diazabiclo [ 5.4.0] undec-7-ene. The reaction is also preferably carried out in a suitable inert solvent or diluent such as dichloromethane, chloroform, carbon tetrachloride, tetrahydrofuran, 1,2-dimethoxyethane, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidin-2-one, dimethyl sulfoxide or acetone, and at a temperature in the range, for example, from -78 ° C to 150 ° C, suitably at or near room temperature.

Methods for the preparation of both said intermediates as well as compound 1 are described in PCT / GB97 / 03033.

Compound 1 or a compound of the invention may be administered in therapy, either as the sole active ingredient, or in combination with other pharmaceutically active agents, such as tissue plasminogen activator or derivatives thereof or streptokinase. For example, the compounds of the invention may be co-administered with a known inhibitor of platelet aggregation (such as aspirin, a thromboxane antagonist or a thromboxane synthase inhibitor), a known hypolipidemic agent, or a known antihypertensive agent.

Dissolution rates were determined by methods analogous to those described in British Pharmacopoeia 1998, Annex XIID, A189-A191.

In the following, the invention will be further elucidated by means of specific examples thereof, and are not intended to limit the scope of the invention in any way.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Preparation of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hydrochloride from the free base

1- (6-Chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine free base (54.8 g) was dissolved in dichloromethane (800 mL) and a solution of hydrogen chloride was added with stirring. in ethyl acetate (50 mL 3.1 M, 1.1 eq). The resulting mixture was stirred for 1 hour to give a bulky precipitate. The solvent is removed in vacuo and the colorless solid obtained is dried under high vacuum. Methanol (2.5 L) was added to the dried solid and the resulting suspension was heated to reflux (complete dissolution was achieved), filtered and the solution was concentrated in a water bath until the solution began to crystallize. . The solution is then removed from the water bath and crystallized to yield

46.6 g of 1- (6-chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hydrochloride hemihydrate as a colorless crystalline product.

Melting point: 250 DEG C. @ 1 H-nuclear magnetic resonance spectrum (DMSO-d6):

2.9-3.2 (w S, 4H), 3.3-3.8 (W, 4H), 7.4 (D, 2H), 7.7 (M, 3H), 7.8 (m, 3H), 8.2 (d, 1 H), 8.3 (m, 2H), 8.5 (with, 1H), 8.7 (D, 2H); microanalysis for C ₂₆ H ₂ 3 N ₃ O ₃ C1S. 1.0 HCl . 0.5 H ₁ O C (%) H (%) N (%) WITH (% ) Cl (%) found 57.9 4.5 7.7 6.2 13.0 calculated 58.0 4.7 7.8 6.0 13.2;

mass spectrum (positive ESP): m / z 492/494 (M + H < + >).

Example 2

Preparation of reduced particle size mold of Example 1

The hydrochloride salt hemihydrate of Compound 1 (Example 1) is introduced at a controlled rate into a fluid mill (micronizer), in which it is subjected to auto-disintegration caused by high energy gas streams. The particles thus obtained are continuously sorted and collected by means of a filter.

The solids obtained were measured as a superfine powder (British Pharmacopoeia classification 1993, vol. 2, Annex XVIIB, A193).

Example 3

Illustrative pharmaceutical dosage forms suitable for use of a compound of the invention for therapeutic or prophylactic purposes include the following tablet and capsule formulations, which may be obtained by conventional procedures well known in the pharmaceutical industry and suitable for therapeutic use in human therapy.

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 Tablet II mg / tablet Compound Z * 50 Lactose Ph. Eur. 223.7 croscarmellose sodium 6.0 Maize starch 15.0 polyvinylpyrrolidone [5% (w / v) aqueous paste] 2.25 Magnesium stearate 3.0 Tablet III mg / tablet Compound Z * 100 Lactose Ph. Eur. 182.7! croscarmellose sodium 12.0 Corn starch paste [5% (w / v) aqueous paste] 2.25 Magnesium stearate 3.0

d) Capsule_mg / capsule

Compound Z * 10 Lactose Ph. Eur. 488.5 Magnesium stearate 1.0

*) The active compound Z is a compound of the invention described. Tablet compositions a) to c) can be enteric coated in a conventional manner, for example with a cellulose acetate phthalate coating.

Claims (9)

PATENT CLAIMS A form 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 solvates thereof with reduced particle size. 2. 1- (6-Chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hydrochloride or solvate thereof. 3. 1- (6-Chloronaphth-2-ylsulfonyl) -4- [4- (4-pyridyl) benzoyl] piperazine hydrochloride hemihydrate. 4. Superfine powder 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 solvates thereof. Microfine powder 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 solvates thereof. 6. Very fine powder 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 solvates thereof. The use of any of the substances defined in any one of claims 1 to 7 in therapeutic therapy. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 7 in combination with a pharmaceutically acceptable diluent or carrier. Use of a compound as defined in any one of claims 1 to 7 in the manufacture of a medicament for use in the treatment of a factor Xa mediated disease or condition.