| Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl) piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride -> Monitor Keywords |
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  Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl) piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochlorideRelated Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of One Nitrogen And Five Carbon Atoms, Piperidines, Additional Ring Containing, The Additional Ring Is A Six-membered Hetero Ring Consisting Of One Nitrogen And Five Carbon AtomsCrystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl) piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20070270465, Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl) piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride. Brief Patent Description - Full Patent Description - Patent Application Claims
BACKGROUND OF THE INVENTION [0001] Compounds of formula I: and pharmaceutically acceptable salts thereof, useful as protein kinase C inhibitors, were disclosed by Heath, et al., in European Patent Publication No. 817,627 (Heath). [0002] Example #49 of Heath disclosed a free base compound of formula FB: [0003] While FB is undoubtedly a very effective pharmaceutical agent, unexpected difficulties were encountered in its large-scale production. Thus, unpredictable formation of solvates complicated the commercial synthesis to such an extent that it became necessary to develop an alternative form for large-scale commercialization. [0004] In this context, WO 02/02094 and WO 02/02116 specifically describe the use of the dihydrochloride salt of FB (FB-2HCl) to treat cancer and to inhibit tumor growth as a mono-therapy or in conjunction with an anti-neoplastic agent or radiation therapy. Unfortunately, it has now been determined that FB-2HCl is hygroscopic. In addition, although FB-2HCl appears to be crystalline by optical light microscopy, more detailed study by X-ray powder diffraction (XRD) has revealed that this material is in fact only poorly crystalline. [0005] Surprisingly, in accordance with the invention, it has now been discovered that the monohydrochloride salt of FB is capable of being reproducibly produced on a commercial scale, is not significantly hygroscopic, is sufficiently stable for use in oral formulations, and can be produced in a highly crystalline state. BRIEF SUMMARY OF THE INVENTION [0006] The present invention relates to crystalline 2,5-dione-3-(1-methyl-1H-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin4-- yl]-1H-indol-3-yl)-1H-pyrrole mono-hydrochloride, a hydrate thereof; or mixtures thereof. [0007] The present invention further relates to crystalline 2,5-dione-3-(1-methyl-1H-indol-3-yl)-4-[1-(pyridin-2-ylmethyl)piperidin-4- -yl]-1H-indol-3-yl)-1H-pyrrole mono-hydrochloride, a hydrate thereof, or mixtures thereof, having an X-ray diffraction pattern which comprises the following peaks: 6.8.+-.0.1, 10.9.+-.0.1, 14.2.+-.0.1 and 16.6.+-.0.1.degree.in 2.theta.; when the pattern is obtained from a copper radiation source (CuK.alpha.; .lamda.=1.54056 .ANG.). This crystalline material is hereafter referred to as "F-I". [0008] The present invention also relates to a pharmaceutical composition containing F-I and a pharmaceutical carrier. In another embodiment, the pharmaceutical formulation of the present invention may be adapted for use in treating cancer and for use in inhibiting tumor growth. [0009] Moreover, the present invention relates to methods for treating cancer and to methods for inhibiting tumor growth which comprise administering to a mammal in need thereof an effective amount of F-I. [0010] In addition, the present invention is related to F-I for treating cancer and for inhibiting tumor growth. [0011] Another embodiment of the invention provides for the use of F-I for the manufacture of a medicament for the treatment of cancer and for the manufacture of a medicament for inhibiting tumor growth. BRIEF DESCRIPTION OF THE FIGURES [0012] FIG. 1 is a representative XRD pattern for F-I. DETAILED DESCRIPTION OF THE INVENTION [0013] Prior to discovering the problems associated with the large-scale manufacturability of FB, due to a concern that FB may not possess optimal bioavailability properties, an in situ salt screen was performed to identify salts for FB possessing improved properties. This screen evaluates the solubility of salts formed in situ in aqueous media. The solubility obtained in situ for a given salt is not directly predictive of the equilibrium solubility of the crystalline form(s) of the same salt. However, the in situ screen can be used to prioritize the salts for synthesis and characterization during salt selection. From these data, five out of seventeen mono-acid salts were chosen for synthesis and characterization. These salts were the citrate, methanesulfonate (mesylate), phosphate, tartrate and mono-hydrochloride (FB-HCl). In addition, FB-2HCl was also synthesized, characterized and analyzed. Some of these salts' properties as wet as those of FB are discussed below. Citrate, Mesylate, Phosphate and Tartrate [0014] The citrate salt generated from methanol is insoluble in water. The mesylate salt is hygroscopic, exhibiting up to 2% weight gain at 70% RH and over 15% weight gain at 95% RH. Although the phosphate salt exhibits rapid dissolution and high solubility at early time points, the solubility of the phosphate drops to 71 .mu.g/mL upon prolonged incubation. The phosphate salt is also somewhat hygroscopic and exhibited hysteresis in water desorption, indicating possible hydrate formation. [0015] The tartrate is only slightly hygroscopic, exhibiting .about.1% weight gain at RH's up to 70%. Based on this and other promising initial results, the tartrate was subjected to a brief polymorph/solvate screen to determine its suitability for bulk manufacturing and use as a pharmaceutical. [0016] The tartrate salt was initially isolated (by titration of the free base with tartaric acid) as a crystalline hydrate. The hydrated material was then recrystallized to determine if other pharmaceutically relevant crystal forms of the tartrate salt could be prepared. The number of solvents suitable for recrystallization was limited by the relatively poor solubility of this salt in many solvents, including polar, protic solvents (H.sub.2O, methanol, ethanol and isopropyl alcohol) and many non-protic solvents (acetone, ethyl acetate, methyl ethyl ketone and tetrahydrofuran). Sufficient solubility was observed only in dimethylformamide, dimethylsulfoxide and organic (and organic/aqueous) mixtures. Elevated temperatures were often required to achieve dissolution. [0017] The tartrate salt was typically not generated from the recrystallization experiments that were carried out. Instead, a crystal form of FB was obtained most often. A non-solvated form of the tartrate was not found. These results suggest that isolation of a tartrate salt of FB could be difficult, presumably due to the low solubility of different crystal forms of FB relative to the tartrate salt, and the relatively small difference in pKa between FB and tartaric acid. FB-2HCl [0018] The aqueous solubility of FB-2HCl under various conditions was analyzed and at concentrations up to 10 mg/mL, solutions of FB-2HCl are stable at ambient temperature for up to 10 days. However, solutions held at 50.degree. C. exhibited profound precipitation prior to the first time point (6 days). At concentrations .gtoreq.40 mg/mL, rapid precipitation within minutes was noted at ambient room temperature. XRD analysis and ion chromatography (to determine chloride content) of the precipitated crystals confirmed that this precipitate was FB-HCl. Continue reading about Crystalline 2,5-dione-3-(1-methyl-1h-indol-3-yl)-4-[1-(pyridin-2-ylmethyl) piperidin-4-yl]-1h-indol-3-yl]-1h-pyrrole mono-hydrochloride... 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