CN101228150A - Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide - Google Patents

Abstract

Crystalline forms of 4-methyl-N-[3-(4-methyl-imidazol-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidin-2-ylamino)-benzamide free base and salts thereof are prepared by various processes.

Description

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-crystalline form of benzamide

The application requires the U.S. Provisional Patent Application No.60/701 of submission on July 20th, 2005,405 rights and interests, and its integral body is openly quoted at this as a reference.

Background of invention

Technical field

The present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystalline form or the polymorph of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide, and prepare their method, the method that comprises their pharmaceutical composition and use their treatments.

Related background art

Polymorphy represents that material exists more than a kind of crystalline structure.Chemical substance has profound influence with more than one crystalline modification crystalline abilities to storage period, solubleness, preparation nature and the working properties of medicine.In addition, the effect of medicine can be subjected to the polymorphy influence of drug molecule.Different polymorph has different uptake rates in vivo, causes more required lower or higher biologic activity.Under extreme case, non-required polymorph even can show toxicity.Produce unknown polymorph during the preparation and have tremendous influence.

Therefore, listing has conclusive benefit for new drug for understanding and control polymorphy.At first also the most important thing is, medicament production is predicted that any possible polymorph can be used for reducing at medication preparation or duration of storage by other polymorph contamination of heavy.In some cases, can not control pollution and have life-threatening consequence.A kind of unwanted polymorph of crystallization during preparation means the production shut-down period of several weeks even several months, during scientist find and correct the reason of new crystalline form or carry out another and take turns test to obtain approval to new crystalline form.

Secondly, in some cases, the understanding of possible crystalline texture is made that the investigator can be with the required character optimization of compound, as solubleness, preparation nature, working properties and storage period.These factors of early stage understanding at new drug development mean that the medicine of preparation is more effective, more stable or more cheap.

Following formula: compound 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide

Be described in WO2004/005281A1, for example embodiment 92.This compound has valuable pharmacological character, and therefore, it can be used as for example kinases inhibitor, can be used for the disease that suppresses in response to protein kinase activity.To 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-knowledge of the possible crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide can be used for developing suitable formulation, because the definite formulation that can not utilize single polymorph can cause institute to use or study when clinical or stability study is not had comparability between criticizing and criticizing.Importantly, polymorph can repeat preparation during selection, and remains unchanged in formulation development long-time.Also need a kind of method to be used for prepared in high purity 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide, because the impurity that exists can produce unwanted toxic action.

WO2004/005281A1 does not provide relevant 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl at all]-information of the possible crystal modifications of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide.This compound is recrystallization from the mixture of tetrahydrofuran (THF) and ethyl acetate, should not implement use therein certain heavy crystallization but WO2004/005281A1 gives explanation, and perhaps specified conditions can be adjusted the crystalline form that is obtained to modify.Now have surprisingly been found that: having the different crystalline modifications of feature hereinafter (4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the new polymorph of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide) can prepare by system of selection condition especially, for example selective solvent system, crystallization time length etc.

Brief summary of the invention

The present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali.

The invention still further relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-hydrochloride of benzamide and the pure basically crystalline form of vitriol.

The invention further relates to pharmaceutical composition, it comprises:

(a) 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-the yl)-5-trifluoromethyl-phenyl of treatment significant quantity]-the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt; With

(b) at least a pharmaceutically acceptable carrier, thinner, medium or vehicle.

The invention still further relates to the method for the disease that treatment suppresses in response to protein kinase activity, it comprises to the 4-methyl-N-[3-of the present invention of the treatment target administering therapeutic significant quantity of this treatment of needs (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-step of the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt.

The accompanying drawing summary

Fig. 1 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali and the x-ray powder diffraction pattern (XRPD) of B.

Fig. 2 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern (XRPD) of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Fig. 3 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-Fourier transform infrared (FT-IR) spectrum of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker IFS-55 instrument, in Nujol mull between two KBr sheets record.

Fig. 4 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-fourier transformation Raman (FT-RAMAN) spectrum of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker RFS-100 instrument record.

Fig. 5 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-thermogravimetric analysis and the differential thermal analysis curve of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Fig. 6 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ' the x-ray powder diffraction pattern.

Fig. 7 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt " the x-ray powder diffraction pattern.

Fig. 8 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Fig. 9 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-IR spectrum of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use the BrukerIFS-55 instrument, in Nujol mull between two KBr sheets record.

Figure 10 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-RAMAN spectrum of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker RFS-100 instrument record.

Figure 11 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-thermogravimetric analysis and the differential thermal analysis curve of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Figure 12 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ' the x-ray powder diffraction pattern.

Figure 13 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _BThe x-ray powder diffraction pattern.

Figure 14 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B' the x-ray powder diffraction pattern.

Figure 15 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Figure 16 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-IR spectrum of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use the BrukerIFS-55 instrument, in Nujol mull between two KBr sheets record.

Figure 17 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-RAMAN spectrum of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker RFS-100 instrument record.

Figure 18 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of the crystalline form C ' of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Figure 19 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _CThe x-ray powder diffraction pattern.

Figure 20 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-crystalline form D of benzamide hydrochloride salt and the mixture of crystal form B.

Figure 21 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _EThe x-ray powder diffraction pattern.

Figure 22 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the unbodied x-ray powder diffraction pattern (XRPD) of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Figure 23 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the unbodied FT-IR spectrum of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker IFS-55 instrument, in Nujol mull between two KBr sheets record.

Figure 24 shows 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the unbodied FT-RAMAN spectrum of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, use Bruker RFS-100 instrument record.

Figure 25 shows 4-methyl-N-[3-of the present invention (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of the vitriol of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide and the x-ray powder diffraction pattern of crystal form B.

Detailed Description Of The Invention

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt and 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide sulfate can obtain with different crystalline forms. These " crystalline forms " (or " crystalline modification " or " polymorph " or " polymorphic ", be used interchangeably in this article) with regard to its thermodynamic stability, physical parameter, x-ray structure and preparation method, be different. Polymorphism refers to that typically compound crystallizes into the ability of more than one different crystal kinds (have identical chemical constitution but physicochemical properties fully different), and the false polymorphism of term typically is used for solvate and hydrate crystalline form. Yet with regard to purpose of the present invention, so many crystalline form and false polymorph are that hydrate and solvate crystalline form all are included in " polymorph " scope. In addition, " amorphous " refers to unordered solid state. Should note: the different samples of specific crystalline form will have same main XRPD peak, but the small peak in coatings may change. In addition, when being considered by those skilled in the art, the term " about " with regard to XRPD maximum (maxima value) (with a ° expression) typically refers in 0.3 ° of set-point, more preferably in 0.2 °, most preferably in 0.1 °; Perhaps, term " about " refers to that (in reaching herein in full) is in acceptable mean value error critical field. Term used herein " separation " and/or " basically pure " refer to crystal 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide or its salt be with a kind of existence the in the crystalline form described herein more than 50%, and have a kind of in preferred at least 70%, more preferably at least 80%, most preferably at least 90% the crystalline form described herein.

First embodiment of the invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the basically pure crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali. The slight moisture absorption of the crystal form A of free alkali (25 ℃, be lower than 2% up to the lower maximum water absorption rate of 80% relative humidity (r.h.)), and in aqueous buffer, have quite low solubility, i.e. 2mg/L during pH6.8 is during pH1.0＞200mg/L; The moisture absorption behavior is reversible. The elementary heat character of crystal form A is as follows by thermogravimetry (TGA) and differential scanning calorimetry (DSC) research:

The thermal property of table 1. free alkali crystal form A

Fusing point (starting point)	～232℃
		Decomposition temperature	＞300℃
Loss on drying	＜0.10％(RT-200℃)

The x-ray powder diffraction pattern of free alkali crystal form A show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum: 9.2 °, 13.1 °, 13.9 °, 16.7 °, 17.9 °, 18.4 °, 19.8 °, 24.1 ° and 25.8 ° (2 θ angle). Term " about " is used for this each listed maximum and every other crystalline form involved in the present invention. Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the basically pure crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali, characterize such as the XRPD of Fig. 1.

Second embodiment of the invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the basically pure crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali. The crystal form B of free alkali do not have hygroscopicity (25 ℃, up to 80% relative humidity under maximum water absorption rate be lower than 0.2%), and in aqueous buffer, has quite low solubility, 0.2mg/L when being pH6.8,2.8mg/L during pH2.8,839mg/L during pH1.0; The moisture absorption behavior is reversible. The elementary heat character of crystal form B is as follows by thermogravimetry and differential scanning calorimetry research:

The thermal properties of table 2. free alkali crystal form B

Fusing point (starting point)	～245℃
		Decomposition temperature	＞300℃
Weight loss on drying	＜0.12％(RT-200℃)

The x-ray powder diffraction pattern of free alkali crystal form B show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 4.3 °, 6.8 °, 7.2 °, 13.5 °, 14.5 °, 17.4 °, 19.6 ° and 26.7 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali, characterize as the XRPD of Fig. 1.

In addition, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the various isolating salt form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide also demonstrated polymorphy, promptly tended to the different crystal forms crystallization.For example, hydrochloride all shows multiple different crystalline form with vitriol." salt " used herein is meant the compound by organic acidity or alkaline drug and acceptable inorganic or organic acid of pharmacy or alkali reaction preparation; The acceptable inorganic or organic acid of pharmacy or the alkali that are fit to are listed in Handbook of Pharmaceutical Salts, P.H.Stahl and C.G.Wermuth (eds.), VHCA, Zurich, the table 1-8 in the 334-345 page or leaf (2002).The U.S. Patent application No.60/701 common co-pending that submits to simultaneously in the lump, among 406 (the attorney docket No.4-34385), 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl has been described respectively]-salt of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide and can be used for preparing the method for this salt.The open integral body of this application is quoted at this as a reference.The crystal form A of hydrochloride, A ', A ", B, B ', S _B, S _B', C, C ', S _C, D and S _ECan characterize by the XRPD figure that is shown in Fig. 2,6-8,12-15 and 18-21 respectively.The crystal form A of vitriol and B can characterize by the XRPD figure that is shown in Figure 25.Correspondingly, other embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-each pure basically crystalline form of the described salt of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide.

The crystal form A of hydrochloride is a dihydrate, and it has poor degree of crystallinity.In the presence of methanol steam, crystal form A is transformed into crystal form B (hereinafter describing).The DSC scanning of crystal form A shows: crystal form A dehydration (usually above 77 ℃) is complicated; In of the fusing of about 210 ℃ final heat absorption incident corresponding to DSC, TGA and XRPD demonstration.XRPD under the differing temps demonstrates transition crystalline form between about 105-135 ℃ (crystal form A that hereinafter further describes '), and it is the monohydrate form of response, and anhydrate form (crystal form A that hereinafter further describes ") obtain more than 135 ℃ from about; Be heated to after about 205 ℃ crystal form A " preserve at about 40 ℃ and can keep its crystalline form in about 30 minutes.

The x-ray powder diffraction pattern of the crystal form A of hydrochloride show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 8.5 °, 11.0 °, 11.5 °, 17.2 °, 18.8 °, 19.2 °, 20.8 °, 22.1 ° and 26.0 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide, characterize as the XRPD of Fig. 2.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-IR spectrum of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Fig. 3.Main IR band is for approximately: 3342,2925,2854,1682,1619,1541,1448,1421,1399,1378,1316,1299,1255,1226,1159,1147,1099,1089,930,868,798,749,708 and 693cm-1.In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is characterised in that: FT-IR spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned IR bands most preferably again.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-RAMAN spectrum of the crystal form A of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is shown in Fig. 4.Main RAMAN band is for approximately: 3059,2933,1684,1617,1594,1562,1493,1452,1423,1401,1384,1300,1260,1115,1039,1023,997,970,807,684,627,407,318,258,227,117 and 86cm ^-1In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is characterised in that: FT-RAMAN spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned RAMAN bands most preferably again.The thermogravimetric analysis of the crystal form A of hydrochloride and differential thermal analysis (TG-DTA) curve display is in Fig. 5.

Other crystalline form relevant with the crystal form A of hydrochloride comprises crystal form A ' and crystal form A ", it represents the monohydrate of crystal form A and the anhydride of crystal form A respectively.Crystal form A ' under indoor conditions, in several minutes, be transformed into crystal form A.The crystal form A of this hydrochloride ' the x-ray powder diffraction pattern of (monohydrate) show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 4.3 °, 8.6 °, 11.6 °, 12.1 °, 17.1 °, 20.6 °, 24.5 °, 25.3 °, 25.8 °, 27.3 ° and 31.6 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ', characterize as the XRPD of Fig. 6.The crystal form A of this hydrochloride " the x-ray powder diffraction pattern of (anhydride) show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 4.5 °, 8.8 °, 11.5 °, 11.9 °, 13.0 °, 14.4 °, 14.8 °, 15.3 °, 16.9 °, 17.6 °, 19.2 °, 19.5 °, 19.9 °, 21.3 °, 24.6 °, 25.4 °, 26.4 °, 27.9 ° and 31.5 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ", characterize as the XRPD of Fig. 7.

The crystal form B of hydrochloride is a monohydrate, and it has 3.1% theoretical water capacity, and demonstrates excellent degree of crystallinity and physical stability with regard to the crystal form A of hydrochloride.Crystal form B is transformed into crystal form A in the presence of ethanol.The DSC scanning of crystal form B shows first endotherm(ic)peak at about 100 ℃-120 ℃, and it promptly is transformed into anhydrous crystal forms B ' corresponding to dehydration; DSC also shows second endotherm(ic)peak at about 190 ℃, and it is corresponding to fusing.The XRPD of differing temps shows that anhydrous crystal forms B ' is between about 145 ℃-195 ℃; After about 195 ℃ of fusings, placed crystal form B about 30 minutes at about 40 ℃ ' become amorphous.Crystal form B ' under indoor conditions, in several minutes, be transformed into crystal form B.

The x-ray powder diffraction pattern of the crystal form B of hydrochloride show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 7.2 °, 9.2 °, 11.4 °, 12.0 °, 12.3 °, 14.6 °, 14.8 °, 15.7 °, 17.6 °, 19.2 °, 19.5 °, 20.5 °, 22.0 °, 23.4 °, 23.9 °, 25.0 °, 25.5 °, 25.9 °, 27.0 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, characterize as the XRPD of Fig. 8.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-IR spectrum of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Fig. 9.Main IR band is for approximately: 3211,3058,2925,2854,1676,1614,1587,1454,1411,1378,1343,1304,1279,1263,1230,1197,1181,1120,1089,1046,1033,1005,905,892,874,801,755,706 and 695cm-1.In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is characterised in that: FT-IR spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned IR band most preferably again.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-RAMAN spectrum of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 10.Main RAMAN band is for approximately: 3078,3026,2975,2930,1672,1610,1602,1593,1541,1476,1451,1400,1385,1332,1303,1263,1251,1210,1089,1046,1033,851,802,755,660,483,456,395,355,317,217,243,198,160,148 and 114cm ^-1In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is characterised in that: FT-RAMAN spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned RAMAN band most preferably again.The thermogravimetric analysis of the crystal form B of hydrochloride and differential thermal analysis (TG-DTA) curve display is in Figure 11.

The crystal form B of this hydrochloride ' the x-ray powder diffraction pattern of (anhydride) shows at least one, more preferably at least two, more preferably at least four again, most preferably all be selected from and be about following maximum value: 7.2 °, 9.2 °, 11.5 °, 12.0 °, 13.9 °, 14.3 °, 15.4 °, 17.6 °, 18.6 °, 20.3 °, 21.7 °, 22.5 °, 23.2 °, 24.7 °, 24.9 °, 25.2 °, 26.0 °, 26.6 °, 27.5 °, 28.2 °, 29.2 ° and 30.0 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ', characterize as the XRPD of Figure 12.Be exposed under the moisture, this anhydrous crystal forms B ' restores and is monohydrate.In a word, crystal form B is favourable in the solvent of low water capacity (＜5%), and crystal form A is favourable in the solvent of high water capacity.The crystal form B of hydrochloride can be prepared by methyl alcohol; Yet, show that it is at first with methanol solvate compound crystallization (the crystalline form S that hereinafter further describes _B), when being exposed to air, be transformed into the monohydrate crystal form B then rapidly.Yet this methanol solvate compound can not be transformed into crystal form B during vacuum-drying; Air-dryly be enough to be transformed into crystal form B.

Another embodiment of the present invention relates to the crystalline form S of this hydrochloride _B, it is corresponding to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the dimethanol solvate of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt; Only avoiding envrionment conditions is that this crystalline form of ambient moisture just can be separated, and envrionment conditions can cause and be transformed into crystal form B monohydrate hydrochloride.The crystalline form S of this hydrochloride _BThe x-ray powder diffraction pattern show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 7.5 °, 9.3 °, 11.5 °, 14.8 °, 19.4 °, 21.9 °, 23.0 °, 23.8 °, 24.9 °, 25.6 °, 25.9 °, 26.3 ° and 26.7 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B, characterize as the XRPD of Figure 13.Another relevant crystalline form is crystalline form S _B', it is considered to the list-methanol solvate compound corresponding to crystal form B.The crystalline form S of this hydrochloride _B' the x-ray powder diffraction pattern show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 7.5 °, 9.3 °, 11.6 °, 12.4 °, 13.4 °, 13.8 °, 14.9 °, 19.7 °, 20.2 °, 22.0 °, 23.0 °, 23.9 °, 24.2 °, 25.1 °, 26.0 °, 26.8 °, 29.3 ° and 30.7 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B', characterize as the XRPD of Figure 14.

The crystalline form C of hydrochloride is another kind of monohydrate.In the presence of methanol steam, crystalline form C is transformed into crystal form B.The DSC scanning of crystalline form C shows first endotherm(ic)peak at about 100 ℃-120 ℃, and it promptly is transformed into anhydrous crystal forms C ' corresponding to dehydration; DSC also shows second endotherm(ic)peak at about 180 ℃, and it is corresponding to fusing.The XRPD of differing temps shows that anhydrous crystal forms C ' is between about 155-195 ℃; After about 195 ℃ of fusings, kept about 30 minutes at about 40 ℃, crystalline form C ' becomes amorphous.

The x-ray powder diffraction pattern of the crystalline form C of hydrochloride show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 6.6 °, 7.0 °, 8.9 °, 11.2 °, 11.8 °, 13.3 °, 14.0 °, 17.3 °, 18.4 °, 20.0 °, 22.1 ° and 23.0 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, characterize as the XRPD of Figure 15.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-IR spectrum of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 16.Main IR band is for approximately: 3332,2925,2854,1670,1615,1588,1556,1455,1414,1312,1293,1260,1234,1179,1126,1087,1087,1050,1032,886,797,758 and 696cm-1.In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is characterised in that: FT-IR spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned IR bands most preferably again.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the FT-RAMAN spectrum of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 17.Main RAMAN band is for approximately: 3075,2932,1670,1610,1592,1494,1452,1398,1383,1309,1294,1259,1210,1087,1047,1033,1022,852,799,639,271,244,162,100 and 85cm ^-1In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is characterised in that: FT-RAMAN spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned RAMAN bands most preferably again.

Crystalline form C dehydration produces anhydrous crystal forms C '.Crystalline form C ' was transformed into the mixture of crystal form B and C in several minutes under indoor conditions.The x-ray powder diffraction pattern of the crystalline form C ' of this hydrochloride show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 6.7 °, 6.9 °, 9.1 °, 11.4 °, 12.0 °, 13.8 °, 14.2 °, 24.8 ° and 25.8 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C ' of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, characterize as the XRPD of Figure 18.

Another embodiment of the present invention relates to the crystalline form S of this hydrochloride _C, it is corresponding to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the methanol solvate compound of the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.Crystalline form C shows at first with methanol solvate compound crystallization (crystalline form S _C), when being exposed to air, be transformed into monohydrate crystalline form C then rapidly.Yet this methanol solvate compound can not be transformed into crystalline form C during vacuum-drying; Air-dryly be enough to be transformed into crystalline form C.The crystalline form S of this hydrochloride _CThe x-ray powder diffraction pattern show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 6.5 °, 7.3 °, 9.1 °, 10.8 °, 12.1 °, 13.0 °, 14.5 °, 14.9 °, 18.9 °, 19.4 °, 24.2 °, 25.0 °, 25.4 °, 26.2 °, 27.4 ° and 28.4 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _C, characterize as the XRPD of Figure 19.

Another crystalline form of hydrochloride is crystalline form D.Crystalline form D obtains with the mixture with the crystal form B of hydrochloride.The x-ray powder diffraction pattern of the crystalline form D of hydrochloride show at least one, more preferably at least two, most preferably all be selected from and be about following maximum value: 5.7 °, 8.4 ° and 9.8 ° (2 θ angle); XRPD also has the maximum value of above-mentioned crystal form B, reason be with the mixture of crystalline form D in have crystal form B.The preferred embodiment of the invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form D of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, as shown in figure 20.Preferred embodiment comprises the pure basically crystalline form D of this hydrochloride.

Another crystalline form again of hydrochloride is crystalline form S _E, it is the solvent dimethylformamide compound of this hydrochloride.Crystalline form S _ECan be by obtaining at for example 25 ℃ of crystalline form C or amorphous substances with this hydrochloride of dimethyl formamide steam treatment.The crystalline form S of this hydrochloride _EThe x-ray powder diffraction pattern show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 3.4 °, 4.5 °, 5.1 °, 5.8 °, 7.2 °, 9.3 °, 10.1 °, 12.9 °, 13.3 °, 13.8 °, 14.8 °, 15.7 °, 17.4 °, 19.6 °, 20.8 °, 21.3 °, 22.5 °, 24.4 °, 25.5 °, 26.0 °, 27.4 ° and 27.9 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form SE of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, characterize as the XRPD of Figure 21.

Except 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the whole above-mentioned crystalline form (being polymorph, false polymorph) of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, hydrochloride also exists with amorphous.After under various relative humidity, preserving, this amorphous spontaneous crystal form A hydrochloride that is transformed into.In the presence of methanol steam, the amorphous crystal form B that is transformed into.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the representative XRPD of the anhydrous form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 22.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the unbodied FT-IR spectrum of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 23.Main IR band is for approximately: 1671,1615,1556,1479,1447,1416,1379,1354,1308,1263,1225,1173,1130,1025,1090,802,753,707 and 695cm-1.In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-pure basically unbodied being characterised in that of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt: FT-IR spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned IR bands most preferably again.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the unbodied FT-RAMAN spectrum of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is shown in Figure 24.Main RAMAN band is for approximately: 3059,2931,1672,1614,1591,1485,1445,1400,1383,1298,1261,1206,1091,1041,1024,999,969,807,755,710,614,315 and 109cm ^-1In the preferred embodiment of the invention, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-pure basically unbodied being characterised in that of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt: FT-RAMAN spectrum have at least one, more preferably at least two, more preferably at least four, whole above-mentioned RAMAN bands most preferably again.

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol is another embodiment of the present invention.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of the crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 6.3 °, 7.7 °, 9.5 °, 10.7 °, 17.9 ° and 18.9 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol, characterize as the XRPD of Figure 25.

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol is another embodiment of the present invention.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the x-ray powder diffraction pattern of the crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol show at least one, more preferably at least two, more more preferably at least four, most preferably all be selected from and be about following maximum value: 7.3 °, 17.7 °, 19.0 °, 20.2 ° and 20.8 ° (2 θ angle).Particularly preferred embodiment of the present invention relates to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol, characterize as the XRPD of Figure 25.

Except 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the above-mentioned crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol, this vitriol also exists with amorphous.The preferred embodiment of the invention comprises 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol pure basically amorphous.

Can in all sorts of ways and obtain 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-each crystalline form (crystal form A and B) of the free alkali of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide, each crystalline form of hydrochloride (crystal form A, A ', A ", B, B ', S _B, S _B', C, C ', S _C, D and S _E) and each crystalline form (crystal form A and B) of vitriol.These methods as mentioned above and as below described in the embodiment that provides, be included in crystallizing at room temperature, crystallization and from hot saturated solution by adding solvent deposition.

Another embodiment of the present invention relates to pharmaceutical composition, and it comprises

(a) 4-methyl-N-[3-(4-methyl-imidazoles-1-the yl)-5-trifluoromethyl-phenyl of one of previous embodiments according to the present invention of treatment significant quantity]-the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt; With

(b) at least a pharmaceutically acceptable carrier, thinner, medium or vehicle.

In preferred embodiments, pure basically crystalline form is 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.Preferably, it is above, more preferably at least 70%, more preferably at least 80%, most preferably at least 90% crystalline form is a kind of in the selected crystalline form again to be present in 50% in the said composition.

" treatment significant quantity " means the amount of crystalline form of the present invention, and when being applied to when the treatment target that needs is arranged, this amount is enough to realize the treatment of diseases that alleviates by the arrestin kinase activity.The treatment significant quantity of the given compound of the present invention will change according to the characteristic of the treatment target of multiple factor such as morbid state and severity thereof, needs treatment etc., and this amount can be determined by those of ordinary skills are conventional.

At least a pharmaceutically acceptable carrier, thinner, medium or vehicle can easily be selected by those of ordinary skills, and are determined by the method for application of needs.The illustrative example of the method for application that is fit to comprises: per os, intranasal, parenteral, part, use through skin and per rectum.Pharmaceutical composition of the present invention can take any those of skill in the art to approve suitable medicament forms.The medicament forms that is fit to comprises solid, semisolid, liquid or freeze-dried preparation, as tablet, pulvis, capsule, suppository, suspensoid, liposome and aerosol.

The present invention's another embodiment again relates to the method for the treatment of the disease that suppresses in response to protein kinase activity, and it comprises 4-methyl-N-[3-(4-methyl-imidazoles-1-the yl)-5-trifluoromethyl-phenyl of one of previous embodiments according to the present invention to the treatment target administering therapeutic significant quantity of this treatment of needs]-step of the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt.In preferred embodiments, this pure basically crystalline form is 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.Preferably, used more than 50%, more preferably at least 70%, more preferably at least 80%, most preferably at least 90% crystalline form is a kind of in the crystalline form of the present invention again.As mentioned above, exemplary method of application comprises per os, intranasal, parenteral, part, uses through skin and per rectum.Using of crystalline form can be by using pharmaceutical composition of the present invention or realizing by any other effective means.

Prove specific embodiments of the present invention referring now to following examples.Should be appreciated that the open of these embodiment, should not limit the scope of the invention by any way only in order to explanation the present invention.

Embodiment 1

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in room temperature]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is with seven kinds of different solvents of 2mL (methyl alcohol, ethanol, 2-propyl alcohol, ethyl acetate, acetone, tetrahydrofuran (THF) and acetonitrile) balance at least 48 hours.Crystal phase transition does not take place.

Embodiment 2

In the water-bath of 25 ℃ ± 0.5 (table 3) and 50 ℃ ± 0.5 (table 4), will about 50mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is with the listed solvent balance of 1mL at least 20 hours.Then solution is filtered, air drying 10 minutes.Then by XRPD research solid part.If the difference of observing is carried out other research (DSC, TGA, infrared (IR), scanning electronic microscope (SEM)).In a vacuum after the evaporating solvent, be determined at approximate solubility in the described solvent by gravimetry.

Table 3. is used solvent balance at 25 ℃

Solvent	Solubleness (mg/g)	Crystalline form
			Acetone	0.2	B
Acetonitrile	0.3	B
			Ethanol (96%)	3.9	B
Ethyl acetate	0.3	B
			Methyl alcohol	16.3	B
Propan-2-ol	1.5	B
			Toluene	1.3	B
Tetrahydrofuran (THF)	5.8	B
			Tetrahydrofuran (THF)-water 1: 1	12.2	A
Acetonitrile-water 1: 1	10.3	A
			Water	0.2	B

Table 4. is used solvent balance at 50 ℃

Solvent	Solubleness (mg/g)	Crystalline form
			Acetone	1.0	B
Acetonitrile	2.1	B
			Ethanol (96%)	22.4	B
Ethanol	26.5	B
			Ethyl acetate	3.0	B
Propan-2-ol	4.8	B
			Toluene	5.6	B
Alcohol-water 1: 1	17.2	B
			Methyl alcohol	＞27.5	Solvate (wet cake-be dried to B)
DMSO	＞27.5	--(very easily molten)

Embodiment 3

With 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-crystal form A of benzamide hydrochloride salt and the mixture of B be equilibrated in all kinds of SOLVENTS.

The balance of table 5.A-B mixture

Solvent	Crystalline form	Note
			Ethanol (95%)	B	After 72 hours
Methyl alcohol 2% water	B	24 hours 40 ℃
			Methyl alcohol 0.25% water	B/？	24 hours 40 ℃, be not the extra peak-may be the free alkali polymorph of crystal form A
Methyl alcohol 2% water	B					40 hours 5 ℃
			Methyl alcohol 0.25% water	B			40 hours 5 ℃
Methyl alcohol
	10% water	A/B	Significant enrichment A after 12 hours
Methyl alcohol 2% water				B	By 24 hours 40 ℃ of rapid evaporated filtrates
	Tetrahydrofuran (THF) 15% water	A

=extra peak (whether unclear is new crystalline form or free alkali)

Embodiment 4

Can check its crystalline form from the resistates of embodiment 2 (4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt) through the room temperature evaporation.The results are shown in following table 6.

Table 6. evaporates in room temperature

Solvent	Crystalline form
		Acetone	Amorphous
Acetonitrile	Amorphous
		Ethanol (96%)	A&B
Ethyl acetate	B
		Methyl alcohol	B
Propan-2-ol	B
		Toluene	B

Tetrahydrofuran (THF)	Amorphous
		Tetrahydrofuran (THF)-water (50: 50)	A
Acetonitrile-water (50: 50)	A
		Alcohol-water (50: 50)	A
Methanol-water (50: 50)	A

Embodiment 5

Will about 300mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl at 60 ℃]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is dissolved in the solvent of minimum.Do not see the residue crystallization.Then this solution is cooled off in ice bath, stir.Use the filter collecting precipitation, drying is studied by XRPD.

Table 7. crystallization from hot saturated solution

Solvent	T 1/r 2(℃)	Crystalline form	Note
				Methanol-water (15%)	50-10	B	By displacement peak due to the hydration
Methyl alcohol	40-5	B
				Methanol-water (2%)	40-10	B	Cooling (Crash cool) fast
Tetrahydrofuran (THF)	50-10	No result
				Tetrahydrofuran (THF)	50-10	No result	1% water
Ethanol	50-10	No result	No crystallization
				Ethanol	50-10	A&B	Add after 2% water and the B crystal seed
Ethanol (95%)	50-10	A
				Ethanol (succsinic acid)	50-10	A	Use	100% ethanol
Ethanol (propanedioic acid)	50-10	B	Use						100% ethanol
				Virahol	50-10	A	Degree of crystallinity is poor
Tetrahydrofuran (THF)-water (15%)	50-10	A
				Tetrahydrofuran (THF)-water (15%)	50-10	A	The B crystal seed

Embodiment 6

Two kinds of different solvents combinations have been tested.With 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is dissolved in the high medium of solubleness, adds the highly insoluble therein solvent of salt again.With filter collecting precipitation thing, drying is studied by XRPD.

Table 8. is by adding solvent deposition

Solvent	The solvent that adds	Crystalline form
			Tetrahydrofuran (THF)-water	Ethyl acetate	A
Methanol-water	Acetonitrile	A

Embodiment 7

With 300mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is with water pressure engine (sheet diameter=13mm) with 10 tons of compressions 5 minutes.Crystalline modification no change (XRPD) after room temperature is compressed 5 minutes.Yet the XRPD peak is wideer, shows less degree of crystallinity.

Embodiment 8

Granulation solvent is dropped to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt in, fully wetting until solid.Between each the interpolation with this material vortex.Then this material is dried under vacuum＜2% or lower, estimate crystalline form and degree of crystallinity by XRPD or DSC again.

Table 9.

Granulation solvent	XRPD result
		Water	No change
Ethanol	No change

Embodiment 9

With amorphous 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt crystallization in acetonitrile, the mixture of the crystal form A of formation hydrochloride and the crystal form A of free alkali.With amorphous 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt crystallization in Virahol, the mixture of the crystal form A of formation hydrochloride and the crystal form A of small-amount free alkali.

Embodiment 10

Will about 50-60mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the listed solvent of 0.75mL.Hydrochloric acid with stoichiometric quantity adds in this suspension subsequently, its viscosity after adding.With this mixture envrionment temperature stir about 5 hours.Solid collected by filtration (salt) is analyzed by XRPD and NMR.

Table 10.

Solvent	The result
			Degree of crystallinity *	1H-NMR
	Methyl alcohol	Well; Crystal form B			Solvent-free peak
Ethanol			Well; Jing XingA ﹠B	Solvent-free peak
	The 2-propyl alcohol	Well; Crystal form A			Solvent-free peak
Acetone			Excellent; Crystal form A	Do not carry out
	Ethyl acetate	Well; Jing XingA ﹠B			Do not carry out
Tetrahydrofuran (THF)			Excellent; Crystal form A	Do not carry out
	Acetonitrile	Excellent; Jing XingA ﹠B			Do not carry out

^*Sharp-pointed and the intensity of excellence=main peak is higher than 70 countings

Well=the sharp-pointed and intensity of main peak is between the 30-70 counting

Embodiment 11

Will about 50-60mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the listed solvent of 0.75mL.Subsequently with the H of stoichiometric quantity ₂SO ₄Add in this suspension its viscosity after adding.With this mixture envrionment temperature stir about 5 hours.Solid collected by filtration (salt) is analyzed by XRPD, also analyzes by NMR in some cases.

Table 11.

Solvent	The result
			Degree of crystallinity *	1H-NMR
	Methyl alcohol	Well; Jing XingA ﹠B			Solvent-free peak
Ethanol			Well; Crystal form B	Solvent-free peak
	The 2-propyl alcohol	Difference			Do not carry out
Acetone			Difference	Do not carry out
	Ethyl acetate	Difference			Do not carry out
Tetrahydrofuran (THF)			Difference	Do not carry out
	Acetonitrile	Difference			Do not carry out

^*Well=the sharp-pointed and intensity of main peak is between the 30-70 counting

Wide and the intensity of difference=main peak is lower than 30 countings

Embodiment 12

With about 300 to 310mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the 9mL 2-propyl alcohol.HCl with stoichiometric quantity adds in this suspension subsequently.After the interpolation, slurries become yellow, are canescence then.With this mixture envrionment temperature stir about 5 hours.After placing 4 hours, slurries become pasty state, are difficult to topple over and filter.Solid collected by filtration is analyzed by XRPD and NMR.XRPD shows the good degree of crystallinity and the crystal form A of hydrochloride, and ¹H-NMR shows that displacement changes and solvent-free peak.

Embodiment 13

Will about 300mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the 30mL methyl alcohol.This suspension is heated to 64 ℃ reflux temperature; Slurries become clear under refluxing.To be dissolved in the H of the stoichiometric quantity in the methyl alcohol subsequently ₂SO ₄Add in this suspension.Solution was stirred 5 hours under refluxing, be cooled to envrionment temperature then; Solid precipitation after placing.Solid collected by filtration is analyzed by XRPD.XRPD shows the crystal form B of vitriol.

Embodiment 14

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the 15mL methyl alcohol.Listed acid with stoichiometric quantity subsequently adds in this suspension.This solution 50 ℃ of stir abouts 5 hours, is cooled to envrionment temperature then.Collect solid (salt), analyze by XRPD and NMR.

Table 12.

Acid	Note	The result
				Degree of crystallinity	1H-NMR
		HCl	Slurries become clear and keep this state during heating.Use N slowly 2Stream is with the evaporation section solvent.			Well; Crystal form B	Change in displacement; Solvent-free peak
H 2SO 4	The heating rear slurry becomes clear and keeps this state.Become slurries during cooling.			Well; Jing XingA ﹠amp; B	Change in displacement;＜2% methyl alcohol

Embodiment 15

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is suspended in the 15mL methyl alcohol.Listed acid that subsequently will the amount of listing adds in this suspension.With this solution in envrionment temperature (HCl) or at 50 ℃ of (H ₂SO ₄) stir about 5 hours.By using N slowly ₂Stream to doing, obtains solid (salt) with solvent evaporation, analyzes by XRPD and NMR.

Table 13.

Acid	Note	The result
				Degree of crystallinity	1H-NMR
		1 equivalent HCl	Slurries become clear and keep this state during heating.			Well; The crystal form B of HCl salt	Change in displacement; Solvent-free peak
0.5 equivalent H 2SO 4	Slurries become clear and keep this state during heating.			Well; The Jing XingA ﹠amp of vitriol; The free alkali crystal form B	Change in displacement; Little solvent peak
		1 equivalent H 2SO 4	Adding sour rear slurry becomes clear and keeps this state.			Well; The crystal form A of vitriol	Change in displacement; Solvent-free peak

Embodiment 16

Under nitrogen gas stream, will be equipped with 4-methyl-N-[3-(4-methyl-imidazoles-1-the yl)-5-trifluoromethyl-phenyl of packing into successively among the 1L, 4-neck round-bottomed flask of mechanical stirrer, thermometer, heating/refrigerating unit and application of sample funnel]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali (10g), methyl alcohol (250mL) and 37% hydrochloric acid (1.85g).With this mixture heating up to 42-50 ℃, restir 15 minutes.Gained solution filters through polypropylene pad, and the temperature of keeping this batch of material simultaneously is higher than 40 ℃.Under nitrogen atmosphere, this settled solution is transferred in another 1L that is equipped with mechanical stirrer, thermometer, heating/refrigerating unit, the 4-neck round-bottomed flask.This batch of material is stirred, go through being cooled to 30 ℃ in 30 minutes.Add kind of brilliant (20mg) in this temperature, go through this batch of material was cooled to 23 ℃ in 45 minutes.With this batch of material restir 3 hours, obtain the heavy-gravity white suspension.Go through and this batch of material was cooled to-10 ℃, restir 30 minutes in 1.5 hours.Filter and collect any solid, wash with cold (10 ℃) methyl alcohol (20mL).With this solid under 50-55 ℃/10-20 holder dry 8-16 hour, obtain 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide one hydrochloride monohydrate crystal form B (9.8g), be white solid.

¹H NMR (300MHz, DMSO-d6), δ 10.9 (s, 1H), 9.58 (s, 1H), 9.29 (s, 1H), 9.20 (s, 1H), 8.70 (d, 1H), 8.63 (s, 1H), 8.55 (d, 1H), 8.49 (d, 1H), 8.32 (d, 2H), 8.00 (s, 1H), 7.91 (s, 1H), 7.84 (d, 1H), 7.56-7.44 (m, 3H), 2.50 (s, 3H), 2.35 (s, 3H); X-ray diffraction figure shows that maximum value is 2 θ=7.4 °, 9.4 °, 11.6 °, 12.1 °, 15.8 °, 19.3 °, 19.6 °, 22.1 °, 24.1 °, 25.7 °.

Embodiment 17

In 25 ℃ of water-baths, respectively will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali and crystal form B be with 13 kinds of different solvents of 2mL (acetone, acetonitrile, diethyl ether, dehydrated alcohol, ethyl acetate, methyl alcohol, propan-2-ol, toluene, tetrahydrofuran (THF), water, tetrahydrofuran (THF)/water (1: 1), ethanol/water (1: 1) and methanol (1: 1)) balance 1 day.Filter this solution then, air drying 10 minutes.Solid part is studied by XRPD.Crystal phase transition does not take place except the test of crystal form B in water; In one case, produce free alkali crystal form A and B, but these results fail repetition.

In addition, will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in 25 ℃ of water-baths]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-crystal form A of benzamide free alkali and the mixture of crystal form B be with 7 kinds of different solvents of 2mL (dehydrated alcohol, methyl alcohol, tetrahydrofuran (THF), water, tetrahydrofuran (THF)/water (1: 1), ethanol/water (1: 1) and methanol (1: 1)) balance 1 day.Filter this solution then, air drying 10 minutes.Solid part is studied by XRPD.Crystal phase transition does not take place.

Embodiment 18

The solubleness of the mixture of crystal form A, crystal form B and crystal form A and B free alkali is measured by saturated solution at 25 ℃.The results are shown in following table 14.

Table 14.

Solvent	Crystal form A (mg/mL)	Crystal form B (mg/mL)	Crystal form A/crystal form B (1: 1) (mg/mL)
				Water	0.00	0.00	0.00
Tetrahydrofuran (THF)/water (1: 1)	1.78	1.95	1.93
				Ethanol/water (1: 1)	0.06	0.07	0.07
Methanol (1: 1)	0.01	0.01	0.01

As seen, in different solvent mixtures, compare with the crystal form B of free alkali, the crystal form A of free alkali has lower solubleness at 25 ℃.Solubleness is too low so that the contrast that can not be fit in water.

Embodiment 19

At 52 ℃ with 12g 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is dissolved in 192mL methyl alcohol and the 21ml water.In 10 minutes, solution is heated to 64-66 ℃, left standstill 45 minutes.Then solution was cooled off 3 hours at 0 ℃.Solution spontaneous crystallization before 0 ℃; Therefore, the cooling slope terminates in 20 ℃, under agitation places 2 days.This suspension at 2 hours internal cooling to 0 ℃, is filtered then in a vacuum, obtains 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide.

Embodiment 20

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt crystal form B is to prepare by free alkali is suspended in the ketone room temperature or 50 ℃.Add 1.06 equivalents, 37% aqueous hydrochloric acid, this mixture heating up to refluxing (64 ℃), is obtained solution, make it clarification by filtration.Then this settled solution is cooled to 42 ℃, plants with 0.1% kind of crystalline substance/alkali.This kind crystalline substance is suspended in the mixture of 99% methyl alcohol and 1% water.This suspension was stirred 2.5 hours at 42 ℃, be cooled to-10 ℃ in slow refrigerative mode then.At 20 ℃, interrupt cooling and reach 4 hours, so that make the methanol solvate compound that may form be transformed into required monohydrate.

Filter this suspension, wash with 2 parts of methanol/water mixture (99% methyl alcohol/1% water).With filter cake in baking oven, 70 ℃, be lower than dried overnight under the vacuum of 10mbar.For 50g and above scale, the water content after finding to filter is lower than 3.05% theoretical value.For guaranteeing suitable water content, add second drying stage, wherein water is evaporated in the container that stirs, and makes it to change in the moisture eliminator by vacuum pump.Condition in the moisture eliminator becomes 60 ℃ and 30mbar, to guarantee the felicity condition of desired moisture content.Add water until the capacity of reaching capacity.Use described method,, obtain the water content of 3.5-3.6% with the agitator drier test of two experimental sizes (1L).

Embodiment 21

With 1.2mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt places 120mg methyl alcohol and 12mg water.Obtain settled solution in room temperature.Other adds 12g 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt, this suspension was placed 1 hour in room temperature.The brilliant suspension of this kind was placed in ultrasonic water bath 10 seconds.

With 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt (12g) is suspended in 192mL methyl alcohol and the 14.87mL water.In 10 minutes, this solution is heated to 64-66 ℃, kept 5 minutes at 66 ℃.In 15 minutes, solution is cooled to 42 ℃ then, plants brilliant then.This suspension was kept 2.5 hours at 42 ℃, at 7 hours internal cooling to 20 ℃ ,-10 ℃ of coolings 6 hours.This suspension was kept 79 hours, filtered in a vacuum then.This solid is washed 2 times with cold methanol 66mL/5.26mL mixture (10 ℃), 70 ℃ of dryings 20 hours, obtain 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in a vacuum]-the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

Embodiment 22

With 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt (14g) be dissolved in hot water bath 1, in the 000g methyl alcohol.In Buchi Mini atomizer, about 65 ℃ with the solution spray drying, form 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-amorphous hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide.

Embodiment 23

At 50 ℃ with 4.0g 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali is dissolved in the 60mL methyl alcohol.The 2mL methanol solution that adds 1.05 equivalents (688.7 μ L) hydrochloric acid.Solution was placed 60 minutes at 50 ℃.Solution is cooled to 42 ℃, reaches 15 minutes in this temperature maintenance.Be added in 4mg 4-methyl-N-[3-of 10 seconds of homogenize (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in the ultra sonic bath]-suspension of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt in methyl alcohol (40mg)/water (0.4mg).This suspension was placed 2.5 hours at 42 ℃, then at 20 ℃ in 7 hours internal cooling.This suspension is maintained at 20 ℃ and reaches 56 hours.The suspension filtered is analyzed then.Obtain 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the dimethanol solvate crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B

Embodiment 24

At 52 ℃ with 36.0g 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is dissolved in the solvent mixture of 576mL methyl alcohol and 44.61mL water.In 15 minutes, solution is heated to 64-66 ℃, and maintains 66 ℃ and reach 5 minutes.Solution is cooled off in 15 minutes at 42 ℃ then, with solution kind crystalline substance.Keep this suspension at 42 ℃ and reach 2.5 hours, at 20 ℃ in 7 hours internal cooling, this temperature maintenance 11 hours.Obtain 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the methanol solvate compound crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _C

By 3.6mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt is dissolved in and obtains kind of a brilliant solution in the methanol/water solution (360mg/36mg).In this solution, add 36mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in addition]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide.Keep this suspension in room temperature and reach 1 hour, place ultra sonic bath to reach 10 seconds this suspension again.

Embodiment 25

Respectively will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl in 25 ℃ of water-baths]-crystal form A, crystal form B and the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt be with 10 kinds of different solvents of 2mL (ethanol, methyl alcohol, water, ethanol/water (99: 1), methanol (99: 1), methanol (99.3: 0.7), methyl alcohol/HCl 0.1N, diethyl ether, hexane, tetrahydrofuran (THF)) balance 1 day.Filtering solution then, solid part is studied by XRPD.

In methyl alcohol, crystal form A is transformed into crystal form B, and in methanol (99: 1), crystal form A is transformed into crystalline form C and a spot of crystal form B; In methanol (99.3: 0.7) and in methyl alcohol/HCl 0.1N, crystal form A is transformed into crystal form B and a spot of crystalline form C.Crystal form B changes.In methyl alcohol, crystalline form C is transformed into crystal form B, and in water, crystalline form C is transformed into crystal form A.

Similarly balance studies carries out at 50 ℃, carries out 1 day for crystal form A and C, carries out 2 days for crystal form B.In methyl alcohol, crystal form A is transformed into the mixture of crystal form B and C; In methanol (99: 1), methanol (99.3: 0.7) and methyl alcohol/HCl 0.1N, crystal form A is transformed into crystalline form C respectively.In ethanol, crystal form B is transformed into the mixture of crystal form A and B.In methyl alcohol, crystalline form C is transformed into crystal form B, and in water, crystalline form C is transformed into crystal form A; In ethanol/water (99: 1), crystalline form C is transformed into the mixture of three kinds of crystalline forms equally, and in tetrahydrofuran (THF), crystalline form C is transformed into the mixture of crystal form B and C.

Embodiment 26

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl at 60 ℃]-crystal form B of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is dissolved in the following solvent of about 2mL.Solution is cooled to-10 ℃.Filter this suspension and analyze solid.

Table 15.

Solvent	Modification by the XRPD acquisition
				2 hours	12 hours	24 hours
	Methyl alcohol	/	B				B
Methanol (99.5/0.5)				/	B	B
	Methanol (99.3/0.7)	/	B				B
Methanol (99.0/1.0)				/	B	B
	Methanol (95.0/5)	B	B				B

/=do not see crystallization

Embodiment 27

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl at 60a]-crystal form B of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is dissolved in the following solvent of about 2mL.Solution is cooled to 20 ℃.Centrifugal but the solid of this suspension is dry before analysis.

Table 16.

Solvent	Modification by the XRPD acquisition
				2 hours	12 hours	24 hours
	Methyl alcohol	/	S B				S B
Methanol (99.5/0.5)				/	S B	S B
	Methanol (99.3/0.7)	/	S B				S B
Methanol (99.0/1.0)				/	S B	S B+S C
	Methanol (95.0/5)	/	S C				S C

/=do not see crystallization

Embodiment 28

Will about 100mg 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl at 60 ℃]-crystal form B of the hydrochloride of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide is dissolved in the following solvent of about 2mL.Solution is cooled to 45 ℃.Centrifugal but the solid of this suspension is dry before analysis.

Table 17.

Solvent	Modification by the XRPD acquisition
				2 hours	12 hours	24 hours
	Methyl alcohol	/	/				S B
Methanol (99.5/0.5)				/	/	S B+S C
	Methanol (99.3/0.7)	/	/				Part S B+S C
Methanol (99.0/1.0)				/	/	S C
	Methanol (95.0/5)	/	/				S C

/=do not see crystallization

Embodiment 29

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-solubleness of crystal form A, crystal form B and the crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt measures in the differing temps different solvents by standard gravimetric techniques.The results are shown in following table 18-20.

Table 18. is in the solubleness of differing temps after 24 hours

T (℃)	Solvent	Crystal form A		Crystal form B		Crystalline form C
								Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD
		25	Water	0.35	A	1.28	B							1.47	C+A
0.1N?HCl	1.32							A	2.36	B	2.35	A
			0.01N?HCl	0.43	A	0.69	B						1.37	A
0.001N?HCl	0.92							A	0.70	B	1.29	C+A
			0.0001N?HCl	0.45	A	0.47	B						1.67	C+A
Methyl alcohol	13.79							B	14.37	B	18.20	B
			50	Water	1.03	A	1.40						B	1.31	A
0.1N?HCl	2.46	A						6.62	B+A	8.30	A+

	?0.01N?HCl	0.85	A	1.44	B	1.69	A
								?0.001N?HCl	0.79	A	1.34	B	6.72	A
	?0.0001N?HCl	0.90	A	1.32	B	3.51	A
								Methyl alcohol	52.47	C+B	52.11	B	55.26	B

Table 19. differing temps, in methanol (99.5/0.5, v/v) solubleness in

T (℃)	Time	Crystal form A		Crystal form B		Crystalline form C
								Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD
		-10	10 minutes	24.01	A	7.62	B							11.91	C
1 hour	26.37							A	5.63	B	7.99	C
			24 hours	4.96	B	4.00	B						6.12	A (being B during repetition)
20	10 minutes							33.69	A+B	12.90	B	24.34			C
		1 hour	19.30	A+B	13.78	B	17.70						C+B
	24 hours							12.19	B	12.21	B	12.09		B
		45	10 minutes	52.23	A+B	33.29	B						39.86		C
1 hour	62.49							C+B	39.39	B	46.15	C
			24 hours	41.86	C+B	40.40	B						45.59	C+B

Table 20. differing temps, methanol (95/5, the v/v) solubleness in

?T ?(℃)	Time	Crystal form A		Crystal form B		Crystalline form C
								Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD	Solubleness (mg/mL)	XRPD
		?-10	10 minutes	12.33	A	9.42	B							9.73	C
1 hour	14.40							A	6.65	B	7.74	C
			24 hours	4.74	B	4.85	B						11.00	C
?20	10 minutes							25.69	A	13.64	B	18.88			C
		1 hour	28.18	A	13.43	B	13.03						C
	24 hours							13.07	B	13.01	B	11.76		C
		?45	10 minutes	46.08	A	34.49	B						37.68		C
1 hour	61.15							A+B+C	38.18	B	31.15	C
			24 hours	36.80	C	41.70	B						32.26	C

From last table as seen, after 25 ℃ and 50 ℃ 24 hours, 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-solubleness of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt in aqueous medium such as water, under pH 1,2,3 and 4 (diluting with HCl) has following trend: crystalline form C＞crystal form B＞crystal form A.In the presence of a large amount of methyl alcohol, 10 minutes afterwards solubleness have following trend: crystal form A＞crystalline form C＞crystal form B.

Embodiment 30

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali prepares according to following scheme:

Under room temperature, inertia and anhydrous condition, 14.5g (60.0mmol) B6 and 20.8g (64.8mmol) B5 are dissolved in the 120mL anhydrous tetrahydro furan.This suspension is cooled to 0-5 ℃ of IT (internal temperature), and added 20% solution of 101.0g (180mmol) potassium tert.-butoxide in tetrahydrofuran (THF) in 1 hour, keeping internal temperature is 0-5 ℃.In 1 hour, reaction mixture is heated to gradually 50 ℃ of IT, then this temperature restir 1 hour.Pass through for 50 ℃ to add 50mL water at IT with reaction mixture (yellow suspension) quencher.Stop to stir, biphasic system is separated.Remove (lower floor) phase of anhydrating.The kind crystalline substance (0.2g) of crystal form A is added in the remaining organic phase, should stir 1 hour by rare suspension, begin crystallization during this period at 50 ℃.About 1.0mL acetate is added in the organic phase, until reaching pH～10.Steam solvent (260mL) under 80-100 ℃ (outside temperature), normal pressure, add 260mL 94% ethanol simultaneously, keep constant volume, promptly solvent is exchanged into ethanol from tetrahydrofuran (THF).In 1 hour this suspension is cooled to IT 0-5 ℃, continuously stirring is 1 hour again.Filter to collect 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form A (crystalline solid) of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali, with cold 94% washing with alcohol of 150mL.Desciccate under 50 ℃, vacuum then.

Embodiment 31

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali prepares according to following scheme:

Under room temperature, inertia and anhydrous condition, 14.5g (60.0mmol) B6 and 20.8g (64.8mmol) B5 are dissolved in the 120mL anhydrous tetrahydro furan.This suspension is cooled to IT 0-5 ℃, added 20% solution of 101.0g (180mmol) potassium tert.-butoxide in tetrahydrofuran (THF) in 1 hour, keeping internal temperature is 0-5 ℃.In 1 hour, reaction mixture is heated to gradually 50 ℃ of IT, then this temperature restir 1 hour.Pass through for 50 ℃ to add 50mL water at IT with reaction mixture (yellow suspension) quencher.Stop to stir, biphasic system is separated.Remove (lower floor) phase of anhydrating.About 1.0mL acetate is added in the organic phase, until reaching pH～10.The kind crystalline substance (0.2g) of crystal form B is added in the organic solution.Steam solvent (260mL) under 80-100 ℃ (outside temperature), normal pressure, add 260mL 94% ethanol simultaneously, keep constant volume, promptly solvent is exchanged into ethanol from tetrahydrofuran (THF).In 1 hour this suspension is cooled to IT 0-5 ℃, continuously stirring is 1 hour again.Filter to collect 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B (crystalline solid) of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali, with cold 94% washing with alcohol of 150mL.Desciccate under 50 ℃, vacuum then.

Chemistry, physical chemistry and morphological feature

4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali (crystal form B) and 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the following commentary valency of chemistry, physical chemistry and morphological feature of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide one hydrochloride hydrate (crystal form B).

The mensuration of approximate solubility: the sample of will weigh (20-50mg) adds in the 2mL solvent., filter then gained slurries balance 24 hours in room temperature.Measure DS concentration in the saturated filtrate by UV or HPLC.

Characteristic dissolution rate (IDR): dissolution rate is determined at 37 ℃, uses rotating disk method (VanKell instrument) to carry out.Use single speed of rotation 200rpm.For the IDR among the 0.1N HCl, use the 800mL volume, for the IDR in the water, use the 200mL volume.The continuous pump of this solution is crossed the UV measuring cell, and be recycled in the dissolution vessel.

Table 21. chemistry and physicochemical characteristic

Parameter	The salt type
					The free alkali crystal form B		Hydrochloride monohydrate (crystal form B)
	Ultimate analysis	Calculated value	Measured value	Calculated value					Measured value
％C					63.46	63.58	57.58	57.66
	％H	4.15	3.97	4.29					4.25
％F					10.76	10.22	9.77	9.83
	％N	18.51	18.57	16.80					16.58
％O					3.02	3.56	5.48	5.68
	％Cl	N/A	N/A	6.08					6.00
DSC purity (mol%) (10 ℃/minute)					98.65		N/A is owing to decomposed before fusing
	HPLC purity (area %)	100.00		100.00
The DSC fusing point (℃) (10 ℃/minute)						249.0		N/A is owing to decomposed before fusing
	Fusion enthalpy (J/g)	153.9		N/A is owing to decomposed before fusing
1% the solution in water or the pH of suspension						7.99		2.53

Parameter	The salt type
					The free alkali crystal form B		Hydrochloride monohydrate (crystal form B)
	Ultimate analysis	Calculated value	Measured value	Calculated value					Measured value
Solubleness (about 25 ℃, mg/mL)
					0.1N?HCl	0.60		0.94
0.01N?HCl	0.0014		0.08
					Phosphate buffered saline buffer, pH6.8	0.0002		Be lower than detected value
Water	Be lower than detected value		0.17
					Ethanol	0.63		3.69
Virahol	0.33		1.93
					Thermogravimetry (weightless %) (10 ℃/minute)	(0.026 RT to 200 ℃)		(0.91 RT to 80 ℃)
Residual solvent (%)	0.2		0.0
					Characteristic dissolution rate (mg min -1cm -2)
pH?1(0.1N?HCl)	0.17		0.17
					Water	0.0013		0.0024

Thermogravimetry research is to 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-each crystal form A, B and the C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt carry out.The results are shown in following table 22.

Table 22.

Crystalline form	Weight loss on drying		Stoichiometry	Explain
					A	?5.69％	5.69(200℃)	2 (theoretical values 5.9%)	Dihydrate
B	?4.02％	1.00(30℃-100℃)	/	Residuary water
						3.02(100℃-220℃)	1 (theoretical value 3.1%)	Monohydrate
	C	?3.50％	0.51(30℃-80℃)	/					Residuary water
					2.99(80℃-220℃)	1 (theoretical value 3.1%)	Monohydrate

Also measured 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-each crystal form A, crystal form B, crystalline form C and the amorphous characteristic dissolution rate in different solvents of 3-(4-pyridin-3-yl 2 pyrimidine-2-base hydrogen bases)-benzamide hydrochloride salt.This is determined on the VanKel instrument, uses Cary 100 photometers to carry out.The results are shown in following table 23.

Table 23.

Dissolve medium	Characteristic dissolution rate value (mg/min/cm 2)
					Crystal form A	Crystal form B	Crystalline form C	Amorphous
	HCl?0.1N	0.6778/1.2467	0.1003	0.2323/0.3213					0.2508
HCl?0.01N					0.0178	0.0224	0.0247	/
	HCl?0.001N	0.0089	0.0045	0.0057					/
HCl?0.0001N					0.0003	0.0010	0.0004	/
	PH2 (citrate buffer solution)	0.0076	/	0.0099					0.0250
Water					0.0004	0.0001	0.000	/

Also carried out 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-each crystal form A, crystal form B, crystalline form C and the unbodied stability study of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.Observe crystal form A, B and C amorphism after preserving and change under different relative humidity, the amorphous spontaneous crystallization of hydrochloride becomes crystal form A.In addition, each crystalline form 50 ℃ 1 month, 80 ℃ 1 month and under 80 ℃ and 75% relative humidity, had good chemical stability in 1 month, although crystalline form C and amorphous condition in the end are shown as the mixture with crystal form A.

To 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B and the crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _BCarried out crystallography research.In room temperature, in methyl alcohol, obtain the monocrystalline that is fit to by slow solvent evaporation.The results are shown in following table 24.

Table 24.

	Crystal form B	Crystalline form S B
			Crystallographic system	Rhombic system	Rhombic system
Spacer	P2 12 12 1	P2 12 12 1
			a，	7.6316(4)	7.596(6)
b，	15.322(2)	16.048(9)
			c，	24.140(3)	23.73(2)
V， 3	2822.6(5)	2893(4)
			D calc，gcm -3	1.369	1.447
Z	4	4
			Radiation, 	1.5406	1.5406

	Crystal form B	Crystalline form S B
			The Θ range, °	5.00-60.00	3.32-58.92
Selected variable number (No.variables refined)	37	404
			Selected reflection number (No.reflect.Refined)	511	4147
GOF/R Bragg	3.8	1.020
			Final R 1[l＞2σ(l)]/R P	0.1168	0.0572
Final wR 1[l＞2σ(l)]/R WP	0.1368	0.1147

Although the present invention describes as above with reference to embodiment, obviously, can carry out many changes, modification and change and can not break away from inventive concept disclosed herein.Therefore, should comprise that all fall into change, modification and change in the present invention's spirit and the claims scope.Whole patent applications that this paper quotes, patent and other publication are incorporated herein by reference with its integral body.

Claims (64)

1.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali.

2. the pure basically crystalline form of claim 1, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 9.2 °, 13.1 °, 13.9 °, 16.7 °, 17.9 °, 18.4 °, 19.8 °, 24.1 ° and 25.8 ° (2 θ angle).

3. the pure basically crystalline form of claim 1, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 1.

4.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali.

5. the pure basically crystalline form of claim 4, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 4.3 °, 6.8 °, 7.2 °, 13.5 °, 14.5 °, 17.4 °, 19.6 ° and 26.7 ° (2 θ angle).

6. the pure basically crystalline form of claim 4, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 1.

7.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

8. the pure basically crystalline form of claim 7, wherein crystal form A is a dihydrate.

9. the pure basically crystalline form of claim 7, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 8.5 °, 11.0 °, 11.5 °, 17.2 °, 18.8 °, 19.2 °, 20.8 °, 22.1 ° and 26.0 ° (2 θ angle).

10. the pure basically crystalline form of claim 7, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 2.

11.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt '.

12. the pure basically crystalline form of claim 11, wherein crystal form A ' be monohydrate.

13. the pure basically crystalline form of claim 11, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 4.3 °, 8.6 °, 11.6 °, 12.1 °, 17.1 °, 20.6 °, 24.5 °, 25.3 °, 25.8 °, 27.3 ° and 31.6 ° (2 θ angle).

14. the pure basically crystalline form of claim 11, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 6.

15.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt ".

16. the pure basically crystalline form of claim 15, wherein crystal form A " be anhydride.

17. the pure basically crystalline form of claim 15, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 4.5 °, 8.8 °, 11.5 °, 11.9 °, 13.0 °, 14.4 °, 14.8 °, 15.3 °, 16.9 °, 17.6 °, 19.2 °, 19.5 °, 19.9 °, 21.3 °, 24.6 °, 25.4 °, 26.4 °, 27.9 ° and 31.5 ° (2 θ angle).

18. the pure basically crystalline form of claim 15, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 7.

19.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

20. the pure basically crystalline form of claim 19, wherein crystal form B is a monohydrate.

21. the pure basically crystalline form of claim 19, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 7.2 °, 9.2 °, 11.4 °, 12.0 °, 12.3 °, 14.6 °, 14.8 °, 15.7 °, 17.6 °, 19.2 °, 19.5 °, 20.5 °, 22.0 °, 23.4 °, 23.9 °, 25.0 °, 25.5 °, 25.9 °, 27.0 ° (2 θ angle).

22. the pure basically crystalline form of claim 19, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in Figure 8.

23.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt '.

24. the pure basically crystalline form of claim 23, wherein crystal form B ' be anhydride.

25. the pure basically crystalline form of claim 23, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 7.2 °, 9.2 °, 11.5 °, 12.0 °, 13.9 °, 14.3 °, 15.4 °, 17.6 °, 18.6 °, 20.3 °, 21.7 °, 22.5 °, 23.2 °, 24.7 °, 24.9 °, 25.2 °, 26.0 °, 26.6 °, 27.5 °, 28.2 °, 29.2 ° and 30.0 ° (2 θ angle).

26. the pure basically crystalline form of claim 23, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 12.

27.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B

28. the pure basically crystalline form of claim 27, wherein crystalline form S _BIt is the dimethanol solvate.

29. the pure basically crystalline form of claim 27, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 7.5 °, 9.3 °, 11.5 °, 14.8 °, 19.4 °, 21.9 °, 23.0 °, 23.8 °, 24.9 °, 25.6 °, 25.9 °, 26.3 ° and 26.7 ° (2 θ angle).

30. the pure basically crystalline form of claim 27, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 13.

31.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _B'.

32. the pure basically crystalline form of claim 31, wherein crystalline form S _B' be a methanol solvate compound.

33. the pure basically crystalline form of claim 31, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 7.5 °, 9.3 °, 11.6 °, 12.4 °, 13.4 °, 13.8 °, 14.9 °, 19.7 °, 20.2 °, 22.0 °, 23.0 °, 23.9 °, 24.2 °, 25.1 °, 26.0 °, 26.8 °, 29.3 ° and 30.7 ° (2 θ angle).

34. the pure basically crystalline form of claim 31, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 14.

35.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

36. the pure basically crystalline form of claim 35, wherein crystalline form C is a monohydrate.

37. the pure basically crystalline form of claim 35, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 6.6 °, 7.0 °, 8.9 °, 11.2 °, 11.8 °, 13.3 °, 14.0 °, 17.3 °, 18.4 °, 20.0 °, 22.1 ° and 23.0 ° (2 θ angle).

38. the pure basically crystalline form of claim 35, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 15.

39.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form C ' of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

40. the pure basically crystalline form of claim 39, wherein crystalline form C ' is an anhydride.

41. the pure basically crystalline form of claim 39, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 6.7 °, 6.9 °, 9.1 °, 11.4 °, 12.0 °, 13.8 °, 14.2 °, 24.8 ° and 25.8 ° (2 θ angle).

42. the pure basically crystalline form of claim 39, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 18.

43.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _C

44. the pure basically crystalline form of claim 43, wherein crystalline form S _CIt is the methanol solvate compound.

45. the pure basically crystalline form of claim 43, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 6.5 °, 7.3 °, 9.1 °, 10.8 °, 12.1 °, 13.0 °, 14.5 °, 14.9 °, 18.9 °, 19.4 °, 24.2 °, 25.0 °, 25.4 °, 26.2 °, 27.4 ° and 28.4 ° (2 θ angle).

46. the pure basically crystalline form of claim 43, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 19.

47.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the crystalline form D of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

48. the crystalline form of claim 47, wherein said crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 5.7 °, 8.4 ° and 9.8 ° (2 θ angle).

49. the crystalline form of claim 47, wherein said crystalline form are the crystalline forms shown in the x-ray powder diffraction pattern shown in Figure 20.

50.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystalline form S of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt _E

51. the pure basically crystalline form of claim 50, wherein crystalline form S _EIt is the solvent dimethylformamide compound.

52. the pure basically crystalline form of claim 50, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 3.4 °, 4.5 °, 5.1 °, 5.8 °, 7.2 °, 9.3 °, 10.1 °, 12.9 °, 13.3 °, 13.8 °, 14.8 °, 15.7 °, 17.4 °, 19.6 °, 20.8 °, 21.3 °, 22.5 °, 24.4 °, 25.5 °, 26.0 °, 27.4 ° and 27.9 ° (2 θ angle).

53. the pure basically crystalline form of claim 50, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 21.

54.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt pure basically amorphous.

55.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form A of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol.

56. the pure basically crystalline form of claim 55, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 6.3 °, 7.7 °, 9.5 °, 10.7 °, 17.9 ° and 18.9 ° (2 θ angle).

57. the pure basically crystalline form of claim 55, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 25.

58.4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-the pure basically crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide vitriol.

59. the pure basically crystalline form of claim 58, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern has at least one and is selected from and is about following maximum value: 7.3 °, 17.7 °, 19.0 °, 20.2 ° and 20.8 ° (2 θ angle).

60. the pure basically crystalline form of claim 58, wherein said pure basically crystalline form is characterised in that: the x-ray powder diffraction pattern as shown in figure 25.

61. pharmaceutical composition, it comprises:

(a) 4-methyl-N-[3-(4-methyl-imidazoles-1-the yl)-5-trifluoromethyl-phenyl of treatment significant quantity]-the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt; With

(b) at least a pharmaceutically acceptable carrier, thinner, medium or vehicle.

62. the pharmaceutical composition of claim 61, wherein said pure basically crystalline form are 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

63. the method for the disease that treatment suppresses in response to protein kinase activity, it comprises to the 4-methyl-N-[3-of the treatment target administering therapeutic significant quantity of this treatment of needs (4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-step of the pure basically crystalline form of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide free alkali or its salt.

64. the method for claim 63, wherein said pure basically crystalline form are 4-methyl-N-[3-(4-methyl-imidazoles-1-yl)-5-trifluoromethyl-phenyl]-crystal form B of 3-(4-pyridin-3-yl-pyrimidine-2--amino)-benzamide hydrochloride salt.

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