CN101641328A - Polymorphs of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide - Google Patents

Abstract

Polymorphic forms of N-hydroxy-3-[4-[[[2-(2-methyl-1H-indol-3-yl)ethyl]amino]methyl]phenyl]-2E-2-propenamide free base and salts thereof are prepared by various processes.

Description

N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-polymorphic form of 2E-2-acrylamide

Background of invention

Invention field

The present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-crystalline form or the polymorphic form of 2E-2-acrylamide, and the method for preparing them, comprise their pharmaceutical composition and use the method for their treatments.

Related background art

Heteromorphism represents that material exists more than a kind of crystalline structure.Chemical substance can have profound influence to physico-chemical property, storage period, solubleness, preparation nature and the working properties of medicine to modify the crystalline ability more than a kind of crystal.In addition, the effect of medicine can be subjected to the heteromorphism influence of drug molecule.Different polymorphic forms can have different uptake rates in vivo, causes the lower or higher biologic activity that has than expection.Under extreme case, undesirable polymorphic form even can show toxicity.In preparation process, form unknown polymorphic form and can have tremendous influence.

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

Secondly, in some cases, understand the sort of crystalline structure and be and possible make the investigator compound can be expected the character optimization, described character is solubleness, preparation nature, working properties and storage period for example.These factors of early stage understanding at new drug development can mean that the medicine of preparation is more effective, more stable or more cheap.

Compound N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide (alternatively, N-hydroxyl-3-(4-{[2-(2-Methyl-1H-indole-3-yl)-ethylamino]-methyl-phenyl)-acrylamide) have a formula (I):

As describing among the WO 02/22577.This compound has valuable pharmacological character; Therefore, it can be used for the treatment of the histone deacetylase activity is suppressed to have the disease of response as for example histone deacetylase inhibitors.To N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-knowledge of the potential polymorphic form of 2E-2-acrylamide is used to develop suitable formulation, do not have comparability between criticizing and criticizing because can not use a definite formulation that single polymorphic form may cause that institute uses or studies when clinical or stability study.Importantly, polymorphic form can repeat to prepare and remain unchanged in long-time in the formulation of exploitation during selection.Also wish to have to prepare high purity N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-method of 2E-2-acrylamide, because the existence of impurity may produce undesirable toxicology effect.

WO 02/22577 does not provide relevant N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl at all] amino] methyl] phenyl]-information that the possible crystal of 2E-2-acrylamide is modified.Now have surprisingly been found that the different crystal with feature hereinafter modify (new N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-polymorphic form of 2E-2-acrylamide) can be by the special method condition preparation of selecting, for example selective solvent system, crystallization time length etc.

Summary of the invention

The present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-pure substantially crystalline form and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of 2E-2-acrylamide free alkali] amino] methyl] phenyl]-the pure substantially crystalline form of the salt of 2E-2-acrylamide.

The invention further relates to pharmaceutical composition, this pharmaceutical composition comprises:

(a) N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl of treatment significant quantity] amino] methyl] phenyl]-the pure substantially crystalline form of 2E-2-acrylamide free alkali or its salt; With

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

The invention still further relates to treatment to the active method that suppresses to have the disease of response of histone deacetylase, this method comprises N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl to the individual administering therapeutic significant quantity of this treatment of needs] amino] methyl] phenyl]-the pure substantially crystalline form of 2E-2-acrylamide free alkali or its salt.

The accompanying drawing summary

Fig. 1 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-form A, B, C, the H of 2E-2-acrylamide free alkali _AAnd H _BThe x-ray powder diffraction pattern.

Fig. 2 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A and the H of 2E-2-acrylamide maleate _AThe x-ray powder diffraction pattern.

Fig. 3 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-form A, the B of 2E-2-acrylamide half tartrate and the x-ray powder diffraction pattern of C.

Fig. 4 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide mesylate and the x-ray powder diffraction pattern of B.

Fig. 5 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A and the S of 2E-2-acrylamide acetate _AThe x-ray powder diffraction pattern.

Fig. 6 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-form A, the S of 2E-2-acrylamide benzoate _AAnd S _BThe x-ray powder diffraction pattern.

Fig. 7 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-form A, B and the H of 2E-2-acrylamide hemifumarate _AThe x-ray powder diffraction pattern.

Fig. 8 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A and the S of 2E-2-acrylamide half malate _AThe x-ray powder diffraction pattern.

Fig. 9 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form A of 2E-2-acrylamide, S _A, S _BAnd H _AThe x-ray powder diffraction pattern.

Figure 10 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A and the S of 2E-2-acrylamide propionic salt _AThe x-ray powder diffraction pattern.

Figure 11 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A and the S of 2E-2-acrylamide vitriol _AThe x-ray powder diffraction pattern.

Figure 12 has shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-form A, B, the S of 2E-2-acrylamide hemisuccinic acid salt _AAnd H _AThe x-ray powder diffraction pattern.

Figure 13 A, 13B and 13C have shown N-hydroxyl-3-[4-[[[2-of the present invention (2-Methyl-1H-indole-3-yl) ethyl respectively] amino] methyl] phenyl]-the Lactated form A of 2E-2-acrylamide DL-, H _AAnd S _AThe x-ray powder diffraction pattern.

Figure 13 D and 13E have shown N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl respectively] amino] methyl] phenyl]-the x-ray powder diffraction pattern of the anhydrous L-lactic acid salt of 2E-2-acrylamide and D-lactate.

Detailed Description Of The Invention

N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali can be with new polymorph A, B, C, H_AAnd H_BObtain. These " crystal modifications " (or " polymorph " or " crystalline form " is as in this article interchangeable application of term) is different with regard to its x-ray powder diffraction pattern, physical chemistry and pharmacokinetic property and thermodynamic stability. With regard to purpose of the present invention, multiple hydrate and solvate forms are included in the scope of " polymorph ". N-hydroxyl-the 3-[4-[[[2-that the present invention relates to (2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-crystalline form of 2E-2-acrylamide free alkali is characterised in that the x-ray powder diffraction pattern (XRPD) that Fig. 1 shows.

Term " separation " and/or " substantially pure " that this paper uses refer to crystallization N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide or its salt be to have and exist preferably one of form described herein of at least 70%, more preferably at least 80% and most preferably at least 90% with one of form described herein more than 50%.

First embodiment of the present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph A of 2E-2-acrylamide free alkali. Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum: 7.9,9.2,12.5,15.2,18.4,19.4,19.7,19.8,27.7 and 28.7 (2 θ degree). Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph A of 2E-2-acrylamide free alkali, as shown in Figure 1. Anhydrous form A can be from the ethanol-water solution (EtOH: H of low water content₂O=20: 1) directly separate. Middle water content (EtOH: H₂O=10: 1 and 7.5: 1) produce the mixture of form A and form HB (monohydrate of form A). Form A is soluble in hot ethanol, in about 110 ℃ of fusings that beginning is wide, subsequently in about 130 ℃ of lower decomposition. In 110 ℃ of lower losss on drying (LOD) less than 0.7%.

Second embodiment of the present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph b of 2E-2-acrylamide free alkali. Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum: 10.6,12.1,13.6,14.1,15.7,16.9,19.4,20.3,22.2,23.4,24.4,24.8,25.5 and 27.7 (2 θ degree). Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph b of 2E-2-acrylamide free alkali, as shown in Figure 1. Anhydrous form B is soluble in hot ethanol; Under heating, it decomposes in about 187 ℃ of lower nothing fusings. At 160 ℃ of lower LOD less than 0.15%.

The 3rd embodiment of the present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph C of 2E-2-acrylamide free alkali. Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum: 8.5,9.7,11.6,12.8,13.6,15.1,16.1,17.1,18.2,19.4,20.4,21.5,22.9,23.4,24.5,25.5,29.9 and 30.5 (2 θ degree). Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the substantially pure polymorph C of 2E-2-acrylamide free alkali, as shown in Figure 1. Can be with form H_ADehydration is converted into anhydrous form C, the back-shaped formula H of rehydration when it is stored under environmental condition fully_A Anhydrous form C is solvable in hot ethanol; Under heating, it is in about 149 ℃ of lower fusings and decomposition. At 140 ℃ of lower LOD less than 0.9%.

The 4th embodiment of the present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide free alkali _AIts x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.7,13.0,13.4,14.4,16.7,17.5,17.8,18.5,19.8,20.1,21.7,22.0,22.3,22.7,23.3,24.2,24.4,25.6,27.0,28.1 and 29.5 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide free alkali _A, as shown in Figure 1.Form H _AIt is the monohydrate of form A.Higher water (EtOH: H ₂O=5: 1 or 3: 1) produce form H _AForm H _AUnder vacuum even dewater fully at ambient temperature and be converted into form A.To naturally when form A is stored under envrionment conditions, rehydration is form H _AForm H _AHaving high relatively decomposition temperature, is 150 ℃.It has slight water absorbability, poor solubility in water, and about 0.004mg/mL, and in ordinary organic solvents, have better solubleness (about 1.5mg/mL in ethanol, about 2.3mg/mL in methyl alcohol, about 5.6mg/mL in ethyl acetate).The LOD of corresponding monohydrate is 4.8%.

The 5th embodiment of the present invention relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide free alkali _BIts x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 8.0,9.5,10.2,14.3,16.9,17.7,18.4,18.7,19.1,19.4,21.2,21.4 and 27.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide free alkali _B, as shown in Figure 1.Form H _BIt is the monohydrate of form A.Under heating, it begins to decompose under about 115 ℃.The LOD of corresponding monohydrate is about 5.0%.

In addition, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the multiple isolating salt form of 2E-2-acrylamide also demonstrated heteromorphism.For example, each in maleate, half-tartrate, mesylate, acetate, benzoate, half-fumarate, half-malate, phosphoric acid salt, propionic salt, vitriol, half-succinate and the lactic acid salt all shows polymorphic form." salt " that this paper uses is meant the compound for preparing by organic acid or alkali medicine and pharmaceutically acceptable inorganic or organic acid or alkali reaction; The pharmaceutically acceptable inorganic or organic acid or the alkali that are fit to are listed in Handbook of Pharmaceutical Salts (pharmaceutical salts handbook), P.H.Stahl and C.G.Wermuth (volume), and VHCA, Zurich 2002, the table 1-8 in the 334-345 page or leaf.

The form A of maleate and H _ACan see XRPD figure shown in Figure 2.Form A, the B of half-tartrate and C can see XRPD figure shown in Figure 3.The form A of mesylate and B can see XRPD figure shown in Figure 4.The form A of acetate and S _ACan see XRPD figure shown in Figure 5.The form A of benzoate, S _AAnd S _BCan see XRPD figure shown in Figure 6.Form A, B and the H of half-fumarate _ACan see XRPD figure shown in Figure 7.The form A and the S of half-malate _ACan see XRPD figure shown in Figure 8.Phosphatic form A, S _A, S _BAnd H _ACan see XRPD figure shown in Figure 9.The form A of propionic salt and S _ACan see XRPD figure shown in Figure 10.The form A of vitriol and S _ACan see XRPD figure shown in Figure 11.Half-form A, the B of succinate, H _AAnd S _ACan see XRPD figure shown in Figure 12.The Lactated form A of DL-, H _AAnd S _ACan see the XRPD figure shown in Figure 13 A-13C.Therefore, other embodiments of the present invention relate to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-each pure substantially polymorphic form of the described salt of 2E-2-acrylamide.

The crystal form A of maleate (it forms in the reagent at dicarboxylate only is 1: 1 salt) does not have fusing down at about 177 ℃ and decomposes under heating.Down its LOD are less than 0.2% at 150 ℃, and it does not have a water absorbability.Maleate has well water-soluble (2.6mg/mL) and has good intrinsic dissolution rate.It demonstrates high solubleness and demonstrate suitable solubleness in other ordinary organic solvents in methyl alcohol and ethanol.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 6.9,8.9,9.3,10.3,13.7,16.8,17.8,19.6,20.7,24.7,25.4 and 27.7 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide maleate, as shown in Figure 2.

The form H of maleate _A(hydrate of form A) do not have fusing down at about 150 ℃ and decomposes under heating.At 100 ℃ of following LOD about 6.0%.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.0,8.5,9.4,11.0,11.7,12.4,13.7,23.1,24.2,24.9,28.5 and 30.2 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide maleate _A, as shown in Figure 2.

The form A of L-tartrate (anhydrous half tartrate) does not have fusing down at about 209 ℃ and decomposes under heating.Less than 0.3%, and form A has slight water absorbability (when relative humidity 85% less than 0.5%) at 150 ℃ of following LOD.The L-tartrate has well water-soluble (3.5mg/mL) and has good intrinsic dissolution rate.It demonstrates good solubleness and demonstrate limited solubleness in alcohols in acetone, ethyl acetate and other ordinary organic solvents.In balance, form A is converted into form A in methyl alcohol, is converted into hydrochloride and is converted into free alkali in 0.1N HCl in phosphate buffered saline buffer (pH=6.8).Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.8,11.9,14.2,15.8,16.8,20.2,21.1,21.7 and 25.0 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide tartrate, as shown in Figure 3.

The crystal form B of tartrate (yet being anhydrous half tartrate) does not have fusing down at about 160 ℃ and decomposes under heating.Less than 2.0%, this shows that it has water absorbability at 150 ℃ of following LOD.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.7,11.9,13.7,14.2,15.8,17.8,18.8,21.2,21.7,24.9,25.9 and 27.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorph b of 2E-2-acrylamide tartrate, as shown in Figure 3.

The form A of tartrate is to be obtained by form A balance in acetone at ambient temperature.The maximum value that its x-ray powder diffraction pattern shows: 10.2,11.5,13.3,16.1,16.9,17.2,19.8 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form C of 2E-2-acrylamide tartrate, as shown in Figure 3.

The form A of mesylate does not have fusing down at about 192 ℃ and decomposes under heating.Down its LOD are less than 0.2% at 150 ℃, and form A has very slight water absorbability (when relative humidity 85% less than 0.35%).Mesylate has fabulous water-soluble (12.9mg/mL) and has very high intrinsic dissolution rate.It has high solubleness and have tangible solubleness in other organic solvent in methyl alcohol and ethanol.In balance, form A is converted into form B in water, is converted into hydrochloride in 0.1N HCl, and is converted into free alkali in phosphate buffered saline buffer (pH=6.8).Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 4.1,8.2,14.5,18.1,18.4,19.8,23.5 and 24.6 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide mesylate, as shown in Figure 4.

The form B of mesylate can by at ambient temperature, reaction and suspension is heated to 50 ℃ subsequently in ethyl acetate, perhaps obtain by the conversion of form A in water.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.6,11.5,13.8,15.1,17.3,18.9,20.4,21.7,23.7 and 24.0 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorph b of 2E-2-acrylamide mesylate, as shown in Figure 4.

The form A of acetate is not having fusing decomposition rapidly more than 60 ℃ under heating.It has the water solubility of about 2mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.1,8.2,8.1,12.6,16.3,21.8 and 23.2 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide acetate, as shown in Figure 5.

The form SA of acetate is an acetone solvate, is 13.5% at about 140 ℃ of following LOD.This solvate is stable being lower than 90 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.9,8.4,9.0,16.5,20.3,22.6,23.4 and 24.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide acetate _A, as shown in Figure 5.

The form A of the benzoate of the Reaction Separation from acetone has fabulous degree of crystallinity and very high decomposition temperature (being higher than 160 ℃).Its LOD is less than 0.6% under 140 ℃.It has the water solubility of about 0.7mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 6.6,7.9,13.2,16.4,16.8,19.1,23.6 and 24.1 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide benzoate, as shown in Figure 6.

The form S of benzoate _ABeing alcohol solvent compound, is 5.2% being higher than 110 ℃ of LOD before decomposing.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.2,9.6,11.5,12.6,18.5,19.4,23.1 and 23.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide benzoate _A, as shown in Figure 6.

The form S of benzoate _BBeing 2-propyl alcohol solvate, is 6.3% being higher than 100 ℃ of LOD before decomposing.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.3,11.6,12.2,17.9,21.0,23.3,24.1 and 24.6 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide benzoate _B, as shown in Figure 6.

The form A of half-fumarate of the Reaction Separation from second alcohol and water (1: 0.05) has fabulous degree of crystallinity and very high decomposition temperature, 217 ℃.Its LOD is less than 0.7% under 200 ℃.It has the water solubility of about 0.4mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 11.5,12.5,15.8,17.2,18.8,22.9,24.5 and 25.0 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide half-fumarate, as shown in Figure 7.

The form B of half-fumarate of the Reaction Separation from ethanol has good degree of crystallinity and is higher than 160 ℃ decomposition temperature.It demonstrates the LOD in two steps: up to 150 ℃ down about 1.1% and be 1.7% subsequently between 150 ℃ and 200 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 11.6,11.9,12.5,14.1,15.8,22.9,24.2 and 27.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorph b of 2E-2-acrylamide half-fumarate, as shown in Figure 7.It demonstrates the LOD in two steps: up to 75 ℃ down about 3.5% and be 6% subsequently between 75 ℃ and 150 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.0,10.1,11.2,15.1,22.1 and 22.8 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide half-fumarate _A, as shown in Figure 7

The form A of half-malate of the Reaction Separation from second alcohol and water (1: 0.05) or straight alcohol and 2-propyl alcohol has fabulous degree of crystallinity and very high decomposition temperature, 206 ℃.Descending its LOD up to 175 ℃ is 2%.It has the water solubility of about 1.4mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.7,12.0,14.2,15.9,16.9,20.3,21.4 and 21.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide half-malate, as shown in Figure 8.

The form S of half-malate _ASalt formation reaction from acetone obtains.It has fabulous degree of crystallinity, but progressively begins to decompose under about 80 ℃.In following its LOD total 0.6% up to 75 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 6.6,7.2,9.4,16.1,18.4,19.0,21.9 and 22.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide half-malate _A, as shown in Figure 8.

The phosphatic form A of the Reaction Separation from acetone has fabulous degree of crystallinity and very high decomposition temperature, 187 ℃.Descending its LOD up to 165 ℃ is 1%.It has the water solubility of about 6mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.3,9.4,16.7,17.7,18.4,21.5,24.3 and 26.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic pure substantially polymorphic form A of 2E-2-acrylamide, as shown in Figure 9.

The phosphatic form S of the Reaction Separation from ethanol _AHave good degree of crystallinity and demonstrate gradually weight loss on heating.Descending its LOD up to 150 ℃ is 6.6%.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 8.4,16.5,20.2,21.8,23.6,25.4 and 31.0 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic pure substantially polymorphic form S of 2E-2-acrylamide _A, as shown in Figure 9.

The phosphatic form S of the Reaction Separation from the 2-propyl alcohol _BHave fabulous degree of crystallinity and demonstrate gradually weight loss on heating.Descending its LOD up to 150 ℃ is 7%.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 6.2,7.5,8.2,17.9,22.1,22.6,23.7 and 25.5 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic pure substantially polymorphic form S of 2E-2-acrylamide _B, as shown in Figure 9.

The phosphatic form H of the Reaction Separation from second alcohol and water (1: 0.05) _A(hydrate) has fabulous degree of crystallinity and very high decomposition temperature, about 180 ℃.Descending its LOD up to 150 ℃ is 7%.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.4,7.6,8.3,16.2,17.4,18.1 and 24.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic pure substantially polymorphic form H of 2E-2-acrylamide _A, as shown in Figure 9.

The form A of the propionic salt of the Reaction Separation from acetone has fabulous degree of crystallinity; About 99 ℃ of its decomposition temperature.Descending its LOD to be about 7% up to 140 ℃.It has the water solubility of about 4mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.0,8.2,9.5,12.6,14.1,14.5,18.4,22.0,23.9 and 25.5 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide propionic salt, as shown in figure 10.

The form S of the propionic salt of the Reaction Separation from the 2-propyl alcohol _ABe 2-propyl alcohol solvate, have fabulous degree of crystallinity.It demonstrates weight loss on heating gradually, is being about 15% up to 140 ℃ of following LOD.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.0,8.1,8.7,11.2,12.0,12.5,16.1,19.8 and 22.3 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide propionic salt _A, as shown in figure 10.

The form A of the vitriol of the Reaction Separation from ethyl acetate has poor degree of crystallinity as yellow hygroscopic powder, very high decomposition temperature, and about 160 ℃, and be about 7% up to 150 ℃ of following LOD.It has tangible water absorbability under envrionment conditions.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 8.9,10.2,13.4,16.1,18.5,22.0,22.7 and 23.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide vitriol, as shown in figure 11.

The form S of the vitriol of the Reaction Separation from the 2-propyl alcohol _ABe 2-propyl alcohol solvate, have fabulous degree of crystallinity and very high decomposition temperature, about 162 ℃.Descending its LOD to be about 9-12% up to 150 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 4.6,9.1,13.7,15.2,18.4,20.2,22.5 and 22.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide vitriol _A, as shown in figure 11.

The form A of half-succinate of the reaction repeated isolation from second alcohol and water (1: 0.05) or straight alcohol has fabulous degree of crystallinity and very high decomposition temperature, about 204 ℃.Descending its LOD to be about 1.1% up to 200 ℃.It has the water solubility of about 0.4mg/mL.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 11.6,12.5,15.6,17.3,18.8,23.1 and 24.7 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form A of 2E-2-acrylamide half-succinate, as shown in figure 12.

The form B of half-succinate of the Reaction Separation from acetone or ethyl acetate has good degree of crystallinity and very high decomposition temperature, is higher than 150 ℃.It demonstrates two step LOD: be about under up to 125 ℃ 1.5% and another be 1.3-2.9% down up to 150 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.2,7.7,9.7,11.5,13.1,15.1,16.1 and 19.1 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorph b of 2E-2-acrylamide half-succinate, as shown in figure 12.

The form S of half-succinate of the Reaction Separation from the 2-propyl alcohol _ABe 2-propyl alcohol solvate, have good degree of crystallinity and very high decomposition temperature, about 155 ℃.It demonstrates two step LOD: be about under up to 70 ℃ 3% and another under up to 140 ℃, be 4.6%.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.0,10.2,10.6,11.1,18.1 and 19.9 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form S of 2E-2-acrylamide half-succinate _A, as shown in figure 12.

The form H of half-succinate monohydrate of the Reaction Separation from 2-third alcohol and water (1: 0.05) _AHave fabulous degree of crystallinity and very high decomposition temperature, about 180 ℃.Descending its LOD to be about 4.6% corresponding to monohydrate up to 160 ℃.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 7.5,11.6,12.5,14.1,17.4,23.0,24.3 and 28.4 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially polymorphic form H of 2E-2-acrylamide half-succinate _A, as shown in figure 12.

The form A of DL-lactic acid salt (anhydrous DL-lactic acid salt) melts down and decomposes at about 183-186 ℃, and has slight water absorbability, is 0.2% until 120 ℃ of following LOD.In water and in most of organic solvents, form A is more stable than Lactated other form of DL-.In most of the cases, form A is not converted into any other form, although in the balance under pH 1 and 2, forms hydrochloride, under 0 ℃ and 10 ℃ and in acetone, and form A and form H _AObserve together.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.9,11.4,13.8,15.7,18.2,19.7,20.3,21.5,25.3,27.4 and 30.0 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially polymorphic form A of 2E-2-acrylamide DL-, as shown in FIG. 13A.

The form H of DL-lactic acid salt (DL-lactic acid salt monohydrate) _AIn about 120 ℃ of fusing and decomposition down, and having slight water absorbability, is 0.4% until 110 ℃ of following LOD, until being 3.0% under 130 ℃ and being 4.4% (degraded) under 155 ℃.In most of the cases, form H _ASlowly be converted into form A,, form hydrochloride although in the balance under pH 1 and 2.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 5.8,8.5,9.0,11.7,13.7,14.5,15.1,17.1,17.4,17.7,18.5,20.5 and 21.2 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially polymorphic form H of 2E-2-acrylamide DL- _A, shown in Figure 13 B.

Balance in methyl alcohol, the Lactated form A of DL-is converted into form S _A(the Lactated methanol solvate thing of DL-).Form S _AIn about 123 ℃ of fusing and decomposition down, be 5.9% (degraded) until 140 ℃ of following LOD.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.9,17.2,17.7,18.1,19.5,20.5,21.4,21.7,22.5,23.6,24.6 and 26.1 (2 θ degree).Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially polymorphic form S of 2E-2-acrylamide DL- _A, shown in Figure 13 C.

Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide L-(+)-Lactated pure substantially polymorphic form S _AMore preferably, lactic acid salt is N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous L-of 2E-2-acrylamide (+)-lactic acid salt.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide L-(+)-Lactated XRPD figure is shown in Figure 13 D.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2 and 29.9 (2 θ degree).N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide L-(+)-Lactated anhydrous form generation fusing simultaneously and decomposition under about 184.7 ℃.

Particularly preferred embodiment relates to N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide D-(-)-Lactated pure substantially polymorphic form S _AMore preferably, lactic acid salt is N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the anhydrous D-of 2E-2-acrylamide (-)-lactic acid salt.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide D-(-)-Lactated XRPD figure is shown in Figure 13 E.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following maximum value: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6 and 25.2 (2 θ degree).N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide D-(-)-Lactated anhydrous form generation fusing simultaneously and decomposition under about 184.1 ℃.

Can use several different methods and obtain N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-every kind of free alkali of 2E-2-acrylamide and the polymorphic form of above-mentioned salt.These methods as mentioned above and as below described in the embodiment that provides.

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

(a) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of one of previous embodiments according to the present invention of treatment significant quantity] amino] methyl] phenyl]-the pure substantially crystalline form of 2E-2-acrylamide free alkali or its salt; With

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

Preferably, be present in the composition more than 50%, more preferably at least 70%, still more preferably at least 80% and most preferably at least 90% crystalline form is one of form of the present invention.

" treatment significant quantity " is intended to represent the amount of polymorphic form of the present invention, and when being applied to need individual, this amount is enough to realize the disease treatment of conditions that alleviates by inhibition of histone deacetylation enzymic activity.The treatment significant quantity of the given compound of the present invention will depend on following factor and difference: the characteristic of the individuality of disease illness and severity thereof, needs etc. for example, 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 and determined by the method for application of expection by those of ordinary skills.That the illustrative example of the method for application that is fit to comprises is oral, intranasal, non-enteron aisle, part, through skin and rectal administration.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, for example tablet, powder, capsule, suppository, suspensoid, liposome and aerosol.

Another embodiment of the invention relates to treats the active method that suppresses to have the disease of response of histone deacetylase, and this method comprises N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl of one of previous embodiments according to the present invention to the individual administering therapeutic significant quantity of this treatment of needs] amino] methyl] phenyl]-step of the pure substantially crystalline form of 2E-2-acrylamide.Preferably, used more than 50%, more preferably at least 70%, still more preferably at least 80% and most preferably at least 90% crystalline form is one of form of the present invention.As mentioned above, illustrative method of application comprise oral, intranasal, non-enteron aisle, part, through skin and rectal administration.Using of crystalline form can be by using pharmaceutical composition of the present invention or realizing by any other effective means.

Prove special embodiment of the present invention referring now to following examples.Should be understood that these embodiment are the scope to illustrate that mode of the present invention is open and do not limit the present invention in any way only.

In following examples, about degree of crystallinity, " fabulous " refers to has the sharp-pointed and intensity material greater than the XRPD main peaks of 70 countings; " fine " refers to has material sharp-pointed and the XRPD main peak of intensity in the 30-70 counting; And " poor " refers to has the wide and intensity material less than the XRPD main peaks of 30 countings.In addition, LOD refers to the weightlessness of measuring between environment and decomposition temperature.The latter is near the starting point of the first order derivative of thermogravimetric curve (to temperature).This is not real starting point, because for all salt, weightlessness can not take place with the phase same rate.Therefore, Shi Ji decomposition temperature may be lower than described.The existence of salt formation, stoichiometry and solvent or do not exist by observing corresponding salt formation reagent and reaction solvent ¹(table comprises the characterization displacement study of salt formation reagent or solvent) that H-NMR chemical potential in-migration is determined.Water content can not be obtained by the NMR data, because the water peak is wide.The protonated degree of free alkali is by benzylic (H _Bz) variation of proton chemical shifts estimates.In addition, salt of the present invention is precipitated as free-pouring powder (FFP), viscosity amorphous substance (SAM) (it has and is easy to coalescent gluey denseness, form single spherical agglomerate or adhere on the wall of reaction vessel) or amorphous gel (AG).At last, "-" is not meant and measures.

Embodiment 1

The preparation of acetate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 1.Acetate with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 1

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	LOD, % T decomposes (T desolvation)	?? 1H-NMR
						Acetone	Environment	??FFP	Fabulous S A	??13.5(107.9) ??147.9	1.89 (acetate, 3H) 2.08 (acetone, 6H) 3.74 (H bz)
??IPA	??60	??FFP	Fine A	??～10.5(72.5) ??148.7	??-
						??AcOEt	??60	??FFP	Fine A	??9.3(105.1) ??147.9	1.89 (acetate, 3H) 3.73 (H bz)

The reaction of salt formation in the acetone produces high crystal salt, N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-ratio of 2E-2-acrylamide and acetate is 1: 1, is accredited as stoichiometric acetone solvate S _ASalt formation reaction in Virahol and ethyl acetate, under 60 ℃ produces identical crystallization, the acetate of non-solventization (form A).Be higher than the weightlessness followed under 105 ℃ by or water is lost or acetate is lost or the both loses and causes.

Embodiment 2

The preparation of benzoate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 2.Phenylformic acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred at ambient temperature (form settled solution, continue to stir down) at 4 ℃.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 2

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH∶H 2O ??(1∶0.05)	Environment	??FFP	Fabulous S A	1.5 before decomposing under 110 ℃	??-
??IPA∶H 2O ??(1∶0.05)	Environment	??FFP	Fabulous S B	(6.3* at 120 ℃ of following isothermals)	??1.02(IPA，6H) ??3.83(H bz)
						??EtOH	Environment	??FFP	Fabulous S A	(5.2* at 120 ℃ of following isothermals)	1.04 (EtOH, 5H) 3.43 (EtOH, 1H) 7.93 (benzoate, 2H) 3.85 (H bz)
??IPA	Environment	??FFP	Fabulous S B	1.5% before decomposing under 100 ℃	??-
						Acetone	Environment	??FFP	Fabulous A	??0.5％ ??160.2	7.93 (benzoate, 2H) 3.84 (H bz)

* keep isothermal to reach 10 minutes down at 120 ℃

Salt formation reaction in independent ethanol and aqueous ethanol produces identical alcohol solvent compound S _AProtonated alkali: benzoate: the alcoholic acid stoichiometry was determined as 1: 1: 0.5 by NMR.Solvent is lost and decomposed under 10 ℃/minute of heating rate is very near at interval incident, and ethanol content can not be measured at first.At last, it is by keeping down measuring in 10 minutes at 120 ℃.5.2% LOD is corresponding to the 0.5 mole of ethanol in every chemical formula unit.Independent Virahol produces identical Virahol (IPA) solvate S with aqueous Virahol _BProtonated alkali: the stoichiometry of benzoate was determined as 1: 1 by NMR.Solvent is lost and is decomposed 10 ℃/minute of heating rate and descend the interval very near, and isopropanol content can not be measured at first.At last, it is by keeping down measuring in 10 minutes at 120 ℃.6.3% LOD is corresponding to the 0.5 mole of IPA in every chemical formula unit.Based on solvent and XRPD figure, two kinds of solvate S _AAnd S _BSeemingly isostructural.The reaction of salt formation in acetone produces the benzoate that does not contain any solvent or water, has 1: 1 stoichiometry salt (form A) of fabulous degree of crystallinity and high decomposition temperature.

Embodiment 3

The formation of half-fumarate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 3.Fumaric acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 3

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH	Environment	FFP to SAM is to FFP	Fabulous B	(1.1+1.7 2 step) 213.2	??3.93(H bz) 6.50 (1H, fumarates)
??IPA	Environment	??FFP	Comprise a strong peak H A	(3.4+6.0 2 step) 159.8	??3.91(H bz) the only a small amount of IPA of 6.50 (1H, fumarates)
						??EtOH∶H 2O ??(1∶0.05)	Environment	FFP to SAM is to FFP	Fabulous A	??0.7 ??217.4	??3.90(H bz) 6.49 (1H, fumarates)

??IPA∶H 2O ??(1∶0.05)	Environment	??FFP	Fabulous A	??1.5 ??208.2	??-
						??IPA∶H 2O ??(1∶0.05)	Environment	??FFP	Fabulous A	??-	??-
??EtOH∶H 2O ??(1∶0.025)	Environment	FFP to SAM is to FFP	Difference A	??0.7 ??154.8	??-
						??EtOH∶H 2O ??(1∶0.05)	Environment	FFP to SAM is to FFP	Fabulous A	??0.9 ??217.1	??3.90(H bz) 6.49 (1H, fumarates)

At ambient temperature, 2: 1 (protonated alkali: fumarate fumarate), i.e. half-fumarate of salt formation reaction generation stoichiometry in Virahol and acetone.Although they are not solvates, they have poor degree of crystallinity and low decomposition temperature.Most possibly lose relevant (most likely H for Virahol LOD at ambient temperature with water _AForm).All under envrionment temperature or 60 ℃, the salt formation reaction in ethanol, second alcohol and water and Virahol and water produced stoichiometry 2: 1 (protonated alkali: fumarate fumarate), i.e. half-fumarate.Under envrionment temperature or 60 ℃, produce identical XRPD spectrogram (anhydrous form A) with salt formation reaction in the water (1: 0.05) at second alcohol and water and Virahol.At ambient temperature, although the spectrogram of the salt that is formed by ethanol is similar, demonstrate unique, half-fumarate polymorphic form (form B) that some little difference and its may be represented similar structures.

Embodiment 4

The formation of maleate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 4.Toxilic acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 4

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	??1H-NMR
						??EtOH	Room temperature to 4	Settled solution is to FFP	Fabulous H A？	(6.2 room temperature) 150	??4.22(H bz) 6.01 (2H, maleate)
??IPA	??60	SAM to FFP	Fabulous A	??0.2 ??178.1	??4.22(H bz) 6.01 (2H, maleate)
						Acetone	??60	SAM to FFP	Fabulous A	??0.2 ??176.1	??4.22(H bz) 6.01 (2H, maleate)

Under 60 ℃, the salt formation reaction in Virahol and acetone produces high-crystallinity, anhydrous solid, and it is being higher than～180 ℃ of decomposition down.Toxilic acid is only dicarboxylic acid, itself and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide produces 1: 1 salt.Its ¹The H-NMR spectrogram is presented at the 6.01ppm place resonance, and corresponding to two olefinic protons, and the resonance at the 10.79ppm place is because a unprotonated carboxylic acid.Toxilic acid also forms the salt of high water content, and it is lost under the heating condition of gentleness.The salt formation of (room temperature to 4 ℃) reaction may produce hydrate (form H in ethanol _A).

Embodiment 5

The formation of half-malate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 5.Oxysuccinic acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 5

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH∶H 2O ??(1∶0.05)	?60	SAM to FFP	Fabulous A	??1.9 ??206.0	??3.96(H bz) 3.83 (0.5H, malates)

??EtOH	??60	SAM to FFP	Fabulous A	??0.4 ??199.3	??-
						??IPA	??60	SAM to FFP	Fabulous A	??-	??-
Acetone	??60	SAM to FFP	Fabulous S A	??0.6 ??95	??3.97(H bz) 3.84 (0.5H, malates)
						??EtOH∶H 2O ??(1∶0.05)	Environment	SAM to FFP	Fabulous A	??-	??-

Salt formation reaction in second alcohol and water, ethanol and Virahol produces identical crystallization and anhydrous half-malate.The difference of LOD between second alcohol and water (1: 0.05) and ethanol can reflect the amorphous substance of different amounts in two samples.Salt formation reaction in acetone obtains half different-malates, and it is being higher than～95 ℃ of continuous down weightlessness.This salt is acetone solvate (form S _A).Solvent is lost and decomposed is very near at interval incident heat.

Embodiment 6

The formation of mesylate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 6.Methylsulfonic acid with stoichiometric quantity adds in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 6

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						Acetone	??60	SAM to FFP	Fabulous A+B?	??1.6 ??172.8	??4.22(H bz) 2.33 (～5H, mesylates)
??AcOEt	Environment	??FFP	Fabulous A	(1.3+1.3 2 step) 170.9	??4.22(H bz) 2.36 (～5H, mesylates)

Salt formation reaction, stirring at room temperature in ethyl acetate obtain yellow salt.This salt (form A) is crystalline, demonstrates 2 step weightlessness, and by NMR mensuration, but it does not contain any solvent shows the mesylate that has more than a molecule.After heating under 60 ℃, the salt formation Reaction Separation in acetone obtains white powder.It demonstrates fabulous degree of crystallinity, but may be the combination more than a kind of polymorphic form (form A and B).Measure by NMR, it does not contain any solvent, but shows the mesylate that contains more than a molecule.Another salt formation reaction (wherein reaction begins at ambient temperature, then the pale yellow powder suspension that obtains is heated to 50 ℃) separation in ethyl acetate obtains new form B, as shown in Figure 4.

Embodiment 7

Phosphatic formation

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 7.Phosphoric acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 7

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH∶H 2O ??(1∶0.05)	??60	??FFP	Fabulous H A	??7.0 ??179.6	??3.94(H bz)
??EtOH	Environment	??FFP	Fine S A	??～6.6	??1.1(～1.5H，EtOH) ??4.00(H bz)
						??IPA	Environment	??FFP	Fabulous S B	??～7.0	??1.02(3-4H，IPA) ??4.00(H bz)
Acetone	Room temperature to 60	SAM to FFP	Fabulous A	??1.0 ??187.4	??4.00(H bz)
						??AcOEt	Room temperature to 60	SAM to FFP	Fine A	??1.2 ??175.5	??-

Salt formation reaction in ethanol and Virahol obtains ethanol and Virahol half-solvate (is respectively form S _AAnd S _B).In the second alcohol and water, only the ethanol of trace detects by NMR, although very big LOD.Material or hygroscopic or hydrate (form H _A), it is losing water (water of being measured by TGA is lost under 10 ℃/minute, finishes) under～60 ℃ under mild heat and the vacuum condition.Salt formation reaction in acetoneand ethyl acetate produces identical crystallization and anhydrous phosphoric acid salt (form A).Stoichiometry most likely 1: 1.Salt demonstrates high decomposition temperature.

Embodiment 8

The formation of propionic salt

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 8.Propionic acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 8

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??IPA	??60	??FFP	Fabulous S A	??15.1	(0.97 3H, propionic salt) 1.02 (～4H, IPA) 3.73 (H bz)
Acetone	??60	??FFP	Fabulous A	??7.0 ??98.9	(0.97 3H, propionic salt) 3.73 (Hbz)
						??AcOEt	??60	??FFP	Fabulous A	??6.3 ??～100	??-

The reaction of salt formation in ethanol obtains unreacted free alkali (most likely form H _B).Virahol produces IPA solvate (the form S of propionic salt _A).Based on NMR, IPA content～0.5.Salt demonstrates 15% weightlessness, and it adds corresponding to IPA does not identify losing of composition.The reaction of salt formation in acetoneand ethyl acetate produces identical crystallization and the salt of solvation (form A) not.The weightlessness of 6.3-7% (beginning under～100 ℃) is because water, propionic acid or degradation production.When finishing weightlessness (～140 ℃), salt decomposes.Should be pointed out that when material being dissolved in when being used for NMR among the DMSO and measuring, detect the free propionic acid and the propionic salt of trace only.

Embodiment 9

The formation of vitriol

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 9.Sulfuric acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 9

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						?IPA	??60	SAM to FFP	Fabulous S A	8.9 to 12 162	??1.02(6H，IPA) ??1.10(3H，IPA +) ??4.22(H bz)
?AcOEt	Environment	??FFP	Difference A	??～6.7 ??～160	??4.22(H bz)

Salt formation Reaction Separation in Virahol obtains white crystals salt.It is accredited as isopropanol solvate (form S _A), every chemical formula unit comprises 1.5 moles of IPA.In DMSO, 0.5 mole of IPA is by protonated.Salt formation Reaction Separation in ethyl acetate obtains yellow hygroscopic powder (form A).In filtering process, the obvious moisture absorption of sample, and the degree of crystallinity of its difference acts on owing to this.

Embodiment 10

The formation of half-succinate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 10.Succsinic acid with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 10

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH∶H 2O ??(1∶0.05)	?60	SAM to FFP	Fabulous A	??1.1 ??203.7	(2.31 2H, succinate) 3.86 (H bz)

??IPA∶H 2O ??(1∶0.05)	??60	SAM to FFP	Fabulous H A	??4.6	(2.31 2H, succinate) 3.85 (H bz)
						??EtOH	Environment	FFP to SAM is to FFP	Fabulous A	??1.1 ??194.6	(2.31 2H, succinate) 3.85 (H bz)
??IPA	Environment	??FFP	Fine S A	2.8+4.6 (90.6) (2 step) 155.8	1.02 (～3H, IPA) 2.32 (2H, succinates), 3.88 (H bz)
						Acetone	Environment	??FFP	Fine B	(1.5+1.3 2 step) 162.3	(2.31 2H, succinate) 3.86 (H bz)
??AcOEt	Environment	??FFP	Fine B	??1.3+2.9 ??154.5	??-
						??EtOH	??60	SAM to FFP	Fabulous A	??-	??-
??EtOH∶H 2O ??(1∶0.025)	??60	SAM to FFP	Fabulous A	??1.0 ??197.3	(2.31 2H, succinate) 3.85 (H bz)
						??EtOH∶H 2O ??(1∶0.05)	??60	SAM to FFP	Fabulous A	??-	??-

Four visibly different half-succinates are separated: half-solvate (form S of monohydrate (form A) (ethanol is under environment), Virahol _A) (Virahol) and two not the form A and the B of solvation.Form A demonstrates higher degree of crystallinity, the following minimum weightless and higher decomposition temperature up to 200 ℃.In addition,, illustrate in ethanol and second alcohol and water that it can repeat to synthesize as under 60 ℃.

Embodiment 11

The formation of half-L-tartrate

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 11.Tartrate with stoichiometric quantity joins in the suspension subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration collected and by XRPD, TGA and pass through in some cases ¹H-NMR analyzes.

Table 11

Solvent	??T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??EtOH∶H 2O ??(1∶0.05)	Room temperature to 60	FFP to SAM is to FFP	Fabulous A	??0.5 ??206.9	(3.86 1H, tartrate) 3.95 (H bz)
??EtOH∶H 2O ??(1∶0.025)	??60	SAM to FFP	Fabulous A	??-	??-
						??EtOH∶H 2O ??(1∶0.05)	??60	SAM to FFP	Fabulous A	??0.5 ??207.6	(3.86 1H, tartrate) 3.95 (H bz)
??EtOH	??60	SAM to FFP	Fabulous A	??-	??-
						??IPA∶H 2O ??(1∶0.05)	??60	SAM to FFP	Fine B	1.9 and 3.4＞160 ℃	(3.90 1H, tartrate) 3.96 (H bz)

Free alkali and tartaric salt formation reaction needed are heated to the temperature of rising.High crystallization, the anhydrous salt that will be higher than 200 ℃ of decomposition are separated into half-tartrate and are labeled as form A.In case in Virahol and water, under 60 ℃, form B is separated, although structurally closely similar with A, visible significant difference on its XRPD figure.

Embodiment 12

The formation of L-tartrate

With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and the 50mL dehydrated alcohol pack in the 250mL 3-neck flask that magnetic stirring apparatus and application of sample funnel are installed.With mixture heating up to 60 ℃, and drip the L-tartrate that is dissolved in the 0.83g (5.5mmol, 10% is excessive) in the 15mL dehydrated alcohol in the suspension of thermotropism.Beginning forms big yellow agglomerate, and it has hindered enough stirrings, but exceeds schedule time the yellow powder that these agglomerates are converted into unrestricted flow and can stir.Continue down to stir 2 hours at 60 ℃.Subsequently mixture is cooled to room temperature and in ice bath, placed about 30 minutes.Yellow powder is washed once by filtered and recycled and with cold dehydrated alcohol (10mL).With its dried overnight under vacuum, obtain 4.1g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the L-tartrate of 2E-2-acrylamide (half-tartrate) (96.6%).

Embodiment 13

The formation of mesylate

With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and the 75mL ethyl acetate pack in the 250mL 3-neck flask that mechanical stirrer and application of sample funnel are installed.In the suspension that stirs, drip 0.65mL (10mmol) methylsulfonic acid that is dissolved in the 20mL ethyl acetate, obtain the suspension that stirs of free-pouring yellow powder.With mixture heating up to 50 ℃ and keep spending the night, and yellow powder is converted into white solid in the meantime.Suspension is cooled to room temperature and white solid is passed through filtered and recycled.It with cold ethyl acetate (15mL) washing dried overnight once and under vacuum, is obtained 4.38g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-mesylate (98.3%) of 2E-2-acrylamide.

It is pointed out that the yellow powder that begins to form is the mesylate form, it comprises the methylsulfonic acid more than equimolar amount.Therefore, this solid has very high water absorbability.Mild heat to 40 ℃ or 50 ℃ and in 2-4 hour, yellow powder is converted into white crystalline solid, it comprises the methylsulfonic acid of equimolar amount.This salt is non-hygroscopic.Also be pointed out that, add methylsulfonic acid and carry out at ambient temperature, then temperature is raise.Can observe under higher temperature to add and obtain sedimentary immediately salt, it be softness and gelationus material.

Embodiment 14

The formation of maleate

With 3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and 75mL acetone pack in the 250mL 3-neck flask that mechanical stirrer and application of sample funnel are installed.With mixture heating up to 45 ℃, and drip the toxilic acid that is dissolved in the 1.16g (10mmol) in the 25mL acetone in the suspension of thermotropism.Although slowly add, the salt that is settled out is soft, colloidal solid, and it has hindered stirring.45 ℃ continue down to stir spend the night and in the meantime solid be converted into white free-pouring powder.Mixture is cooled to room temperature and in ice bath, placed about 30 minutes.White solid is passed through filtered and recycled, with cold acetone (15mL) washing dried overnight once and under vacuum, obtain 4.21g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-maleate (90.5%) of 2E-2-acrylamide.

It is pointed out that the preferred solvent that is used to analyze is the 2-propyl alcohol.But, in optimizing process, can observe except required form, the polymorphic form that another kind has low decomposition temperature (118.9 ℃) can separate from the 2-propyl alcohol, and it is a yellow powder.

Embodiment 15

The Lactated formation of anhydrous DL-

With DL-lactic acid (4.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 3.4g) water (27.2g) dilution, and solution is heated to 90 ℃ (internal temperatures) reaches 15 hours.Solution is cooled to room temperature and is used for following salt formation step as lactic acid solution.

With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali form H _A(10.0g) pack in the 4-neck reaction flask that mechanical stirrer is installed.Add softening water (110.5g), and in 30 minutes, suspension is heated to 65 ℃ (internal temperatures).Under 65 ℃, go through the DL-lactic acid solution joined in this suspension in 30 minutes.In the process that adds lactate solution, suspension is converted into solution.With the application of sample funnel with softening water (9.1g) flushing, and with solution 65 ℃ of following restir 30 minutes.Solution is cooled to 45 ℃ (internal temperatures) and under this temperature, add crystal seed (10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt monohydrate).With suspension be cooled to 33 ℃ and under this temperature restir 20 hours.With suspension reheat to 65 ℃, stirring 1 hour under this temperature and in 1 hour, it is being cooled to 33 ℃.After 3 hours, product is passed through filtering separation at 33 ℃ of following restir, and (2 * 20g) wash with softening water with filter cake.Wet filter cake 50 ℃ of following vacuum-dryings, is obtained anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt, be crystallized product.This product HPLC and ¹Among the H-NMR with monohydrate salt (form H _A) identical, except ¹The integration of water signal in the H-NMR spectrogram.There is anhydrous form in the XRPD demonstration.

In the other salt formation test of carrying out according to above-mentioned method, product solution is filtered down at 65 ℃, be cooled to 45 ℃ then, put into crystal seed and crystallization.In all cases, obtain product form A (anhydrous form).

Embodiment 16

The Lactated formation of anhydrous DL-

With DL-lactic acid (2.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 1.7g) water (13.6g) dilution, and solution is heated to 90 ℃ (internal temperatures) reaches 15 hours.Solution is cooled to room temperature and is used for following salt formation step as lactic acid solution.

With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali form HA (5.0g) packs in the 4-neck reaction flask that mechanical stirrer is installed.Add softening water (54.85g), and in 30 minutes, suspension is heated to 48 ℃ (internal temperatures).Under 48 ℃, go through the DL-lactic acid solution joined in this suspension in 30 minutes.The adding crystal seed (it is 5mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt, anhydrous form A, suspension in 0.25g water), continue again and under 48 ℃ to stir 2 hours.In 30 minutes, temperature is elevated to 65 ℃ (internal temperatures), and with suspension restir 2.5 hours under this temperature.In 2 hours, temperature is cooled to 48 ℃ then, and under this temperature, continues again to stir 22 hours.(2 * 10g) wash with softening water by filtering separation and with filter cake with product.Wet filter cake 50 ℃ of following vacuum-dryings, is obtained anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt (form A), it is a crystallized product.Fusing point and decomposition take place under 183.3 ℃ simultaneously.

Embodiment 17

DL-lactic acid salt monohydrate is converted into DL-lactic acid salt anhydride

With DL-lactic acid (0.59g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 0.5g) water (4.1g) dilution, and solution is heated to 90 ℃ (internal temperatures) reaches 15 hours.Solution is cooled to room temperature and is used for following salt formation step as lactic acid solution.

With 10g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt monohydrate form H _APack in the 4-neck reaction flask.Add entry (110.9g), add lactic acid solution subsequently.Application of sample funnel water (15.65g) flushing with lactic acid.Suspension is heated to 82 ℃ (internal temperatures), obtains solution.With solution 82 ℃ stirred 15 minutes down and heat filtering in other reaction flask, obtain settled solution.Temperature is cooled to 50 ℃, and the adding crystal seed (it is 10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt, anhydrous form, the suspension in 0.5g water).Temperature is cooled to 33 ℃ and continue to stir 19 hours again under this temperature.In 45 minutes,, stirred 1 hour down and at 1 hour internal cooling to 33 ℃ at 65 ℃ with the suspension reheat to 65 ℃ (internal temperature) that forms.After 3 hours, product is passed through filtering separation at 33 ℃ of following restir, and with wet filter cake water (50g) washing.Product 50 ℃ of following vacuum-dryings, is obtained crystal anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt (form A).

Embodiment 18

The Lactated formation of anhydrous DL-

With DL-lactic acid (8.0g, 85% aqueous solution is corresponding to the pure DL-lactic acid of 6.8g) water (54.4g) dilution, and solution is heated to 90 ℃ (internal temperatures) reaches 15 hours.Solution is cooled to room temperature and is used for following salt formation step as lactic acid solution.

With N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali form H _A(20g) pack in the 1L glass reactor, add ethanol/water (1 of 209.4g: the 1w/w mixture).In 30 minutes, faint yellow suspension is heated to 60 ℃ (internal temperatures), and under this temperature, goes through and added lactic acid solution in 30 minutes.Application of sample funnel water (10g) is washed.In 2 hours, solution is heated to 38 ℃, and under 38 ℃, add crystal seed (20mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt, anhydrous form).After 2 hours, in 6 hours, mixture is cooled to 25 ℃ at 38 ℃ of following restir.In 5 hours, continue to be cooled to 10 ℃, in 4 hours, be cooled to 5 ℃ from 10 ℃, in 1 hour, be cooled to 2 ℃ from 5 ℃ from 25 ℃.Suspension 2 ℃ of following restir 2 hours, and is passed through filtering separation with product.With wet filter cake water (2 * 30g) washings, and with product 45 ℃ of following vacuum-dryings, obtain crystal anhydrous N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide DL-lactic acid salt (form A).

Embodiment 19

The formation of DL-lactic acid salt monohydrate salt

Free alkali form H with 3.67g (10mmol) _A(N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the 2E-2-acrylamide) and 75mL acetone pack in the 250mL 3-neck flask that magnetic stirring apparatus and application of sample funnel are installed.In the suspension that stirs, drip the 1M lactic acid (in water (10mmol)) that is dissolved in the 10mL in the 20mL acetone, obtain settled solution.Under environment, continue to stir and after about 1 hour white solid be settled out.Mixture cooled off in ice bath and restir 1 hour.White solid is washed once by filtered and recycled and with cold acetone (15mL).With its vacuum-drying, obtain 3.94g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl subsequently] amino] methyl] phenyl]-the DL-lactic acid salt monohydrate salt (86.2%) of 2E-2-acrylamide.

Embodiment 20

The Lactated formation of monohydrate DL-

Will about 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free form H _ABe suspended in the solvent of listing in the 1mL table 12.Lactic acid with stoichiometric quantity joins in the suspension subsequently.Mixture stirred at ambient temperature and when forming settled solution, continue to stir down at 4 ℃.Solid by filtration collected and by XRPD, TGA and ¹H-NMR analyzes.

Table 12

Solvent	?T，℃	Physical properties	Degree of crystallinity and form	??LOD，％ ??T Decompose	?? 1H-NMR
						??IPA	??4	??FFP	Fabulous H A	??4.3(79.3) ??156.3	??-
Acetone	??4	??FFP	Fabulous H A	??4.5(77.8) ??149.5	??4.18(H bz)

Under 4 ℃, the salt formation reaction in Virahol and acetone produces the DL-lactic acid salt of stoichiometry (1: 1), monohydrate.This salt is crystalline, is higher than to begin dehydration under 77 ℃ and be higher than 150 ℃ to decompose down.

Embodiment 21

Anhydrous L-(+)-Lactated formation

According to the method for describing among the embodiment 19, with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali (20.0g) L-(+)-lactic acid (6.8g) processing, obtain crystalline N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide L-(+)-lactic acid salt, anhydrous form.Fusing point and decomposition take place under 184.7 ℃ simultaneously.XRPD figure is (2 θ=9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2,29.9) shown in Figure 13 D.

Embodiment 22

Anhydrous D-(-)-Lactated formation

According to the method for describing among the embodiment 19, with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide free alkali (20.0g) D-(-)-lactic acid (6.8g) processing, obtain crystalline N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylamide D-(-)-lactic acid salt, anhydrous form.Fusing point and decomposition take place under 184.1 ℃ simultaneously.XRPD figure is (2 θ=9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2) shown in Figure 13 E.

Morphological character

The attached thermoisopleth of absorption-desorption is equaled a record by VTI humidity sky.At first with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-salt of 2E-2-acrylamide carries out (25 ℃ of drying step, relative humidity is less than 2%, 2 hours), carry out then absorption-desorption attached-absorption order, each RH% step kept 3 hours.Free alkali is kept a few hours in relative humidity less than 2% time, and therefore dehydration fully after drying step.Only provided the data of first sorption cycle in the table, therefore, in all cases, two sorption cycle are very similar.

The present invention describes as above with reference to its special embodiment, it is evident that, can carry out many changes, modification and variation and can not break away from inventive concept disclosed herein.Therefore, be intended to comprise all spirit and the change in the wide region, modification and variations in claims.All patent applications that this paper quotes, patent and other publication are incorporated this paper into as a reference with its integral body.

Claims (56)

1.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form A of 2E-2-acrylamide.

2. the pure substantially crystalline form of claim 1, wherein pure substantially crystalline form is characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.9,9.2,12.5,15.2,18.4,19.4,19.7,19.8,27.7 and 28.7 (2 θ degree).

3. the pure substantially crystalline form of claim 2, wherein the x-ray powder diffraction pattern as shown in Figure 1.

4.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form B of 2E-2-acrylamide.

5. the pure substantially crystalline form of claim 4, wherein pure substantially crystalline form is characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 10.6,12.1,13.6,14.1,15.7,16.9,19.4,20.3,22.2,23.4,24.4,24.8,25.5 and 27.7 (2 θ degree).

6. the pure substantially crystalline form of claim 5, wherein the x-ray powder diffraction pattern as shown in Figure 1.

7.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystalline form C of 2E-2-acrylamide.

8. the pure substantially crystalline form of claim 7, wherein pure substantially crystalline form is characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 8.5,9.7,11.6,12.8,13.6,15.1,16.1,17.1,18.2,19.4,20.4,21.5,22.9,23.4,24.5,25.5,29.9 and 30.5 (2 θ degree).

9. the pure substantially crystalline form of claim 8, wherein the x-ray powder diffraction pattern as shown in Figure 1.

10.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially form H of 2E-2-acrylamide _A

11. the pure substantially crystalline form of claim 10, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.7,13.0,13.4,14.4,16.7,17.5,17.8,18.5,19.8,20.1,21.7,22.0,22.3,22.7,23.3,24.2,24.4,25.6,27.0,28.1 and 29.5 (2 θ degree).

12. the pure substantially crystalline form of claim 11, wherein the x-ray powder diffraction pattern as shown in Figure 1.

13.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially form H of 2E-2-acrylamide _B

14. the pure substantially crystalline form of claim 13, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 8.0,9.5,10.2,14.3,16.9,17.7,18.4,18.7,19.1,19.4,21.2,21.4 and 27.4 (2 θ degree).

15. the pure substantially crystalline form of claim 14, wherein the x-ray powder diffraction pattern as shown in Figure 1.

16.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form A of 2E-2-acrylamide maleate.

17. the pure substantially crystalline form of claim 16, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 6.9,8.9,9.3,10.3,13.7,16.8,17.8,19.6,20.7,24.7,25.4 and 27.7 (2 θ degree).

18. the pure substantially crystalline form of claim 17, wherein the x-ray powder diffraction pattern as shown in Figure 2.

19.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially form H of 2E-2-acrylamide maleate _A

20. the pure substantially crystalline form of claim 19, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.0,8.5,9.4,11.0,11.7,12.4,13.7,23.1,24.2,24.9,28.5 and 30.2 (2 θ degree).

21. the pure substantially crystalline form of claim 20, wherein the x-ray powder diffraction pattern as shown in Figure 2.

22.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form A of 2E-2-acrylamide half-tartrate.

23. the pure substantially crystalline form of claim 22, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.8,11.9,14.2,15.8,16.8,20.2,21.1,21.7 and 25.0 (2 θ degree).

24. the pure substantially crystalline form of claim 23, wherein the x-ray powder diffraction pattern as shown in Figure 3.

25.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form B of 2E-2-acrylamide half-tartrate.

26. the pure substantially crystalline form of claim 25, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.7,11.9,13.7,14.2,15.8,17.8,18.8,21.2,21.7,24.9,25.9 and 27.9 (2 θ degree).

27. the pure substantially crystalline form of claim 26, wherein the x-ray powder diffraction pattern as shown in Figure 3.

28.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystalline form C of 2E-2-acrylamide half-tartrate.

29. the pure substantially crystalline form of claim 28, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 10.2,11.5,13.3,16.1,16.9,17.2 and 19.8 (2 θ degree).

30. the pure substantially crystalline form of claim 29, wherein the x-ray powder diffraction pattern as shown in Figure 3.

31.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form A of 2E-2-acrylamide mesylate.

32. the pure substantially crystalline form of claim 31, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 4.1,8.2,14.5,18.1,18.4,19.8,23.5 and 24.6 (2 θ degree).

33. the pure substantially crystalline form of claim 32, wherein the x-ray powder diffraction pattern as shown in Figure 4.

34.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form B of 2E-2-acrylamide mesylate.

35. the pure substantially crystalline form of claim 34, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.6,11.5,13.8,15.1,17.3,18.9,20.4,21.7,23.7 and 24.0 (2 θ degree).

36. the pure substantially crystalline form of claim 35, wherein the x-ray powder diffraction pattern as shown in Figure 4.

37.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystalline form of 2E-2-acrylamide salts, it is selected from:

(a) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide acetate;

(b) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide acetate _A

(c) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide benzoate;

(d) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _A

(e) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _B

(f) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-fumarate;

(g) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-fumarate;

(h) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-fumarate _A

(i) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-malate;

(j) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-malate _A

(k) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form A of 2E-2-acrylamide;

(l) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _A

(m) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _B

(n) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form H of 2E-2-acrylamide _A

(o) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide propionic salt;

(p) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide propionic salt _A

(r) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide vitriol;

(s) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide vitriol _A

(t) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-succinate;

(u) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-succinate;

(v) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-succinate _AWith

(w) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-succinate _A

38. the pure substantially crystalline form of claim 37, wherein pure substantially crystalline form is selected from:

(a) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide acetate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.1,8.2,8.1,12.6,16.3,21.8 and 23.2 (2 θ degree);

(b) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide acetate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.9,8.4,9.0,16.5,20.3,22.6,23.4 and 24.4 (2 θ degree);

(c) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide benzoate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 6.6,7.9,13.2,16.4,16.8,19.1,23.6 and 24.1 (2 θ degree);

(d) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.2,9.6,11.5,12.6,18.5,19.4,23.1 and 23.4 (2 θ degree);

(e) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _B, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.3,11.6,12.2,17.9,21.0,23.3,24.1 and 24.6 (2 θ degree);

(f) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-fumarate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 11.5,12.5,15.8,17.2,18.8,22.9,24.5 and 25.0 (2 θ degree);

(g) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-fumarate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 11.6,11.9,12.5,14.1,15.8,22.9,24.2 and 27.9 (2 θ degree);

(h) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-fumarate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.0,10.1,11.2,15.1,22.1 and 22.8 (2 θ degree);

(i) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-malate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.7,12.0,14.2,15.9,16.9,20.3,21.4 and 21.9 (2 θ degree);

(j) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-malate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 6.6,7.2,9.4,16.1,18.4,19.0,21.9 and 22.4 (2 θ degree);

(k) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form A of 2E-2-acrylamide, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.3,9.4,16.7,17.7,18.4,21.5,24.3 and 26.9 (2 θ degree);

(l) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 8.4,16.5,20.2,21.8,23.6,25.4 and 31.0 (2 θ degree);

(m) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _B, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 6.2,7.5,8.2,17.9,22.1,22.6,23.7 and 25.5 (2 θ degree);

(n) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form H of 2E-2-acrylamide _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.4,7.6,8.3,16.2,17.4,18.1 and 24.4 (2 θ degree);

(o) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide propionic salt, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.0,8.2,9.5,12.6,14.1,14.5,18.4,22.0,23.9 and 25.5 (2 θ degree);

(p) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide propionic salt _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.0,8.1,8.7,11.2,12.0,12.5,16.1,19.8 and 22.3 (2 θ degree);

(r) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide vitriol, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 8.9,10.2,13.4,16.1,18.5,22.0,22.7 and 23.4 (2 θ degree);

(s) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide vitriol _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 4.6,9.1,13.7,15.2,18.4,20.2,22.5 and 22.9 (2 θ degree);

(t) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-succinate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 11.6,12.5,15.6,17.3,18.8,23.1 and 24.7 (2 θ degree);

(u) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-succinate, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.2,7.7,9.7,11.5,13.1,15.1,16.1 and 19.1 (2 θ degree);

(v) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-succinate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.0,10.2,10.6,11.1,18.1 and 19.9 (2 θ degree); With

(w) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-succinate _A, it is characterized in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 7.5,11.6,12.5,14.1,17.4,23.0,24.3 and 28.4 (2 θ degree).

39. the pure substantially crystalline form of claim 38, wherein pure substantially crystalline form is selected from:

(a) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide acetate, wherein the x-ray powder diffraction pattern is as shown in Figure 5;

(b) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide acetate _A, wherein the x-ray powder diffraction pattern as shown in Figure 5;

(c) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide benzoate, wherein the x-ray powder diffraction pattern is as shown in Figure 6;

(d) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _A, wherein the x-ray powder diffraction pattern as shown in Figure 6;

(e) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide benzoate _B, wherein the x-ray powder diffraction pattern as shown in Figure 6;

(f) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-fumarate, wherein the x-ray powder diffraction pattern is as shown in Figure 7;

(g) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-fumarate, wherein the x-ray powder diffraction pattern is as shown in Figure 7;

(h) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-fumarate _A, wherein the x-ray powder diffraction pattern as shown in Figure 7;

(i) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-malate, wherein the x-ray powder diffraction pattern is as shown in Figure 8;

(j) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-malate _A, wherein the x-ray powder diffraction pattern as shown in Figure 8;

(k) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form A of 2E-2-acrylamide, wherein the x-ray powder diffraction pattern is as shown in Figure 9;

(l) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _A, wherein the x-ray powder diffraction pattern as shown in Figure 9;

(m) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form S of 2E-2-acrylamide _B, wherein the x-ray powder diffraction pattern as shown in Figure 9;

(n) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the phosphatic form H of 2E-2-acrylamide _A, wherein the x-ray powder diffraction pattern as shown in Figure 9;

(o) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide propionic salt, wherein the x-ray powder diffraction pattern is as shown in figure 10;

(p) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide propionic salt _A, wherein the x-ray powder diffraction pattern as shown in figure 10;

(r) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide vitriol, wherein the x-ray powder diffraction pattern is as shown in figure 11;

(s) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide vitriol _A, wherein the x-ray powder diffraction pattern as shown in figure 11;

(t) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form A of 2E-2-acrylamide half-succinate, wherein the x-ray powder diffraction pattern is as shown in figure 12;

(u) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form B of 2E-2-acrylamide half-succinate, wherein the x-ray powder diffraction pattern is as shown in figure 12;

(v) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form S of 2E-2-acrylamide half-succinate _A, wherein the x-ray powder diffraction pattern as shown in figure 12; With

(w) N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the form H of 2E-2-acrylamide half-succinate _A, wherein the x-ray powder diffraction pattern as shown in figure 12.

40.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially crystal form A of 2E-2-acrylamide DL-.

41. the pure substantially crystalline form of claim 40, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.9,11.4,13.8,15.7,18.2,19.7,20.3,21.5,25.3,27.4 and 30.0 (2 θ degree).

42. the pure substantially crystalline form of claim 41, wherein the x-ray powder diffraction pattern as shown in FIG. 13A.

43.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially form H of 2E-2-acrylamide DL- _A

44. the pure substantially crystalline form of claim 43, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 8,8.5,9.0,11.7,13.7,14.5,15.1,17.1,17.4,17.7,18.5,20.5 and 21.2 (2 θ degree).

45. the pure substantially crystalline form of claim 44, wherein the x-ray powder diffraction pattern is shown in Figure 13 B.

46.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially crystalline form S of 2E-2-acrylamide DL- _A

47. the pure substantially crystalline form of claim 46, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.9,17.2,17.7,18.1,19.5,20.5,21.4,21.7,22.5,23.6,24.6 and 26.1 (2 θ degree).

48. the pure substantially crystalline form of claim 47, wherein the x-ray powder diffraction pattern is shown in Figure 13 C.

49.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the Lactated pure substantially crystal form A of 2E-2-acrylamide L-.

50. the pure substantially crystalline form of claim 49, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2 and 29.9 (2 θ degree).

51. the pure substantially crystalline form of claim 50, wherein the x-ray powder diffraction pattern is shown in Figure 13 D.

52.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-the pure substantially crystal form A of 2E-2-acrylamide D-lactate.

53. the pure substantially crystalline form of claim 52, wherein pure substantially crystalline form are characterised in that the x-ray powder diffraction pattern has at least two and is selected from following maximum value: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6 and 25.2 (2 θ degree).

54. the pure substantially crystalline form of claim 53, wherein the x-ray powder diffraction pattern is shown in Figure 13 E.

55. pharmaceutical composition, this pharmaceutical composition comprises:

(a) any one pure substantially crystalline form among the claim 1-54 of treatment significant quantity; With

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

56. treatment suppresses to have the method for the disease of response to protein kinase activity, this method comprises the step of pure substantially crystalline form any among the claim 1-54 to the individual administering therapeutic significant quantity of this treatment of needs.

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