MX2008010379A - Salt of cd 80 antagonist - Google Patents

Abstract

The choline salt of the CD80 antagonist compound 4-(6-fluoro-3-oxo-1,3- dihydro-pyrazolo[4,3-c]cinnolin-2-yl)-N-(2,2-difluoro-ethyl)-benzamide (I) has good aqueous solubility and is therefore convenient for pharmaceutical use.

Description

CD80 ANTAGONIST SALT FIELD OF THE INVENTION The present invention relates to the choline salt of the compound 4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] cinolin-2-yl) -N- (2, 2-difluoro-ethyl) -benzamide of the CD80 antagonist. BACKGROUND OF THE INVENTION International patent application No. WO 2004/08101 relates to a class of compounds that include (among other things) the compound 4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4 , 3-c] cinolin-2-yl) -N- (2, 2-difluoro-ethyl) -benzamide, having the structural formula (A): The compounds described in WO 2004/08101 are CD80 antagonists, capable of inhibiting the interactions between CD80 and CD28, and therefore useful for immuno-inhibition, for example in the treatment of rheumatoid arthritis. The compound (A), in the form of free acid, is poorly Ref.:195037 soluble in water. In general, good solubility in water is a desirable feature in a compound intended for oral, or parenteral, or topical administration in a water-based carrier, such as a pharmaceutical product. WO 2004/08101 also refers to the salts of the class of the compound of which the compound (A) is a member. However, not all salts of the compound have sufficiently improved aqueous solubility over the free acid to be conveniently orally administrable, or forms of the compound based on aqueous solution. BRIEF DESCRIPTION OF THE INVENTION This invention is based on the discovery that the choline salt of compound (A) has good desired aqueous solubility. DETAILED DESCRIPTION OF THE INVENTION According to the present invention, the choline salt of 4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] cinolin-2-yl) is provided) -N- (2, 2-difluoro-ethyl) -benzamide of the formula (A) above. Orally administrable pharmaceutical compositions comprising the choline salt and at least one pharmaceutically acceptable carrier also form an aspect of the invention. The injectable aqueous solutions of the choline salt, and the aqueous compositions of liquid or creamy base Topically applicable salts containing the choline salt form another aspect of the invention. Orally administrable compositions may be in the form of tablets, capsules, pellets, powders, granules, lozenges, liquid or gel preparations. Tablets and capsules for oral administration may be in the form of a unit dose presentation, and may contain conventional excipients such as binding agents, for example syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinyl-pyrrolidone; fillers for example lactose, sugar, corn starch, calcium phosphate, sorbitol or glycine; tablet lubricant, for example magnesium stearate, talc, polyethylene glycol or silica; disintegrant for example potato starch, or acceptable wetting agents such as sodium laurel sulfate. The tablets can be coated according to methods known in normal pharmaceutical practice. The oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product for reconstitution with water or other suitable carrier before use. Such liquid preparations may contain conventional additives such as suspending agents, for example sorbitol, syrup, methyl cellulose, glucose syrup, hydrogenated gelatin edible fats; emulsifying agents, for example lecithin, sorbitan monooleate, or acacia; non-aqueous carriers (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters such as glycerin, propylene glycol, or ethyl alcohol; preservatives, for example methyl or propyl p-hydroxybenzoate or sorbic acid, and if desired conventional flavoring or coloring agents. For topical application to the skin, the drug can be min a cream, a lotion or an ointment. Formulations of the cream or ointment that can be used for conventional formulations of the drug are known in the art, for example as described in standard pharmaceutical textbooks such as the British Pharmacopoeia. The active ingredient can also be administered parenterally in a sterile medium, by injection or infusion. Depending on the carrier and the concentration used, the drug can be suspended or dissolved in the carrier. Advantageously, adjuvants such as a local anesthetic, preservative and buffering agents can be dissolved in the carrier. The preparation of, and aqueous solubility of, the choline salt are further described in the following example.

Example: 4- (6-Fluoro-3-oxo-1,3-dihydro-pyrazolo [4, 3-c] cinolin-2-yl) -N- (2, 2-difluoro-ethyl) -benzamide was prepared and its formed choline salt (i.e. (2-hydroxy-ethyl) -trimethyl-ammonium), as follows: Preparation of N- (2,2-Difluoro-ethyl) -4- (6-fluoro-3-yl-1,3-dihydro-pyrazolo [4, 3-c] cinolin-2-yl) -benzamide. In a round bottom flask equipped with a magnetic stirrer, reflux condenser and gas sparger was charged with 4- (6-Fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] cinoline-2 -yl) -benzoic acid (12.9 g) prepared as in example 5 of WO 2004/08101. Thionyl chloride (65 ml) was added slowly. A nitrogen atmosphere was applied and the mixture was heated to reflux. Upon heating the release of the gas was observed, the gas was trapped in a scrubber. When the gas evolution had ceased (after about 2 h) the mixture changed color from an orange-red suspension to a dark red suspension and was cooled to room temperature. The excess thionyl chloride was removed under vacuum and the red solid obtained was azeotroped with toluene (50 ml). A dark red solid was obtained and placed in anhydrous DMA (65 ml) to give a dark red solution. Diisopropyl ethyl amine (12.9 g, 17.4) was mixed with 2,2-difluoroaminoethane (3.24 g, 2.76 g. mi) and added dropwise to the solution for 4 to 5 minutes. An exothermic was observed. The mixture was stirred at room temperature. The reaction mixture was quenched with 0.5 M HC1 (150 ml) to give a dark red suspension. The solids were collected by filtration and washed with a little water. The solid was triturated with methanol (250 ml) for approximately 1 hour at room temperature, filtered and washed with methanol. The solid was then triturated with acetone (250 ml) for approximately 1 hour at room temperature, filtered and washed with acetone. The solid was finally triturated with acetone (250 ml) for approximately 45 minutes, filtered and washed with acetone. The product (approximately 8 g) was taken in approximately 10 ml of DMA to give a thick dark red solution. Methanol (150 ml) and acetone (150 ml) were added and the precipitate was collected by filtration. LC-MS: A peak of product required. The QC analysis of this material showed a purity of 91.6%.

Preparation of 2- [4- (2, 2-Difluoro-ethylcarbamoyl) -phenyl] -6-fluoro-2H-pyrazolo [4, 3-c] cinoline-3-metho (2-hydroxy-ethyl) -trimethyl-ammonium In a round-bottomed flask equipped with a magnetic stirrer was charged with N- (2,2-difluoro-ethyl) -4- (6-fluoro-3 - oxo-1, 3-dihydro-pyrazolo [4, 3-c] cinolin-2-yl) -benzamide (2.50 g). The solid was suspended in methanol (25 ml) and choline hydroxide (782 mg, 1.74 ml 45% w / w methanol) was added dropwise. After the addition a dark clear brown solution was formed. The solution was stirred for 2 hours at room temperature. The reaction mixture was concentrated under vacuum to give a dark brown oil. Ethyl acetate (100 ml) was added and a two-phase system was obtained. After sonication the brown oil became thick and began to solidify. The solid was broken and isopropyl alcohol (30 ml) was added and the mixture was heated from 65 to 70 ° C. A suspension was obtained. The mixture was cooled to room temperature and diluted with acetate (approximately 100 ml). The solids were collected by filtration and washed with acetate (50 ml). The solid was dried under vacuum. LC-MS: isolated solid; a main peak [M + H] +388, purity 95% The solid salt was a coarse brown powder, 2.26 g, 4.61 mmol, 71% Melting point: 172 to 1802C, decomposition. The product was further purified by recrystallization, as follows: The salt was mixed with ethanol and heated to reflux, stirred for 20 minutes, and filtered hot. The filtered ethanol solution was heated to reflux, then cooled around 5SC and stirred for one hour. The solution was then filtered, washed with ethanol and heptane, and dried at constant weight. The solubility of the choline salt of N- (2, 2-Di-fluoro-ethyl) -4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] cinoline-2- ilo) -benzamide in water and ethanol was tested in the trial below. The solubilities of the non-salt form (free acid) N- (2, 2-Difluoro-ethyl) -4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] cinnoline -2-yl) -benzamide and a range of different salts thereof were also tested in the same assay: Solubility test 10 mg of the test compound were weighed into a vial, and 1 ml of the solvent was added. If the sample dissolves immediately, as evidenced by a formation of a clear solution, more of the test material is added and the vial was sonicated for 15 minutes. This procedure was repeated until no more test compound could be dissolved, as evidenced by the formation of a suspension. The vial containing the suspension was then sonicated for 15 minutes, and placed on a shaker at 25 degrees C / 60% relative humidity for 24 hours. In the elimination of the agitator, the sample was centrifuged and the supernatant analyzed by CLAR. The results are given in Table I.

It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Claims (4)

1. CLAIMS Having described the invention as above, the content of the following claims is claimed as property: 1. The choline salt of 4- (6-fluoro-3-oxo-l, 3-dihydro-pyrazolo [4, 3-c] ] cinolin-2-yl) -N- (2, 2-difluoro-ethyl) -benzamide, characterized in that it has the formula (A):
2. 2. An orally administrable pharmaceutical composition characterized in that it comprises the choline salt according to claim 1 and at least one pharmaceutically acceptable carrier.
3. 3. An aqueous injectable solution, characterized in that it contains the choline salt according to claim 1.
4. 4. A topically applicable liquid or creamy base aqueous composition characterized in that it contains the choline salt according to claim 1.