CN101641328B - Polymorphs of n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide - Google Patents

Polymorphs of n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide Download PDF

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CN101641328B
CN101641328B CN2007800216589A CN200780021658A CN101641328B CN 101641328 B CN101641328 B CN 101641328B CN 2007800216589 A CN2007800216589 A CN 2007800216589A CN 200780021658 A CN200780021658 A CN 200780021658A CN 101641328 B CN101641328 B CN 101641328B
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methyl
ethyl
phenyl
amino
indole
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CN101641328A (en
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M·阿克莫格鲁
J·S·鲍伊瓦
P·卡普因斯基
D·帕保克沙基斯
J·斯莱德
F·施托瓦塞尔
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Sekula Biology Co Ltd
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Novartis AG
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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

The polymorphic form of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide
Background of invention
Invention field
The present invention relates to the crystalline form or the polymorphic form of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide; And the method for preparing them, comprise their pharmaceutical composition and use the method for their treatments.
Related background art
Heteromorphism representes 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 receive the heteromorphism influence of drug molecule.Different polymorphic forms can have differing absorption speed in vivo, causes the lower or higher BA that has than expection.Under extreme case, undesirable polymorphic form even can show toxicity.In the 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 prodn 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 the preparation process, and scientist finds and corrects the reason of new crystalline form or carries 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 can compound be expected the character optimization, described character is solubleness, preparation nature, working properties and storage period for example.The medicine that can mean preparation in these factors of early stage understanding of new drug development more effectively, more stable or more cheap.
Compound N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide (alternatively, N-hydroxyl-3-(4-{ [2-(2-Methyl-1H-indole-3-yl)-ethylamino]-methyl }-phenyl)-acrylic amide) has formula (I):
Like what describe among the WO 02/22577.This compound has valuable pharmacological character; Therefore, it can be used to treat the histone deacetylase activity is suppressed to have the disease of response as for example histone deacetylase inhibitors.Knowledge to the potential polymorphic form of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide is used to develop suitable formulation, does not have comparability between criticizing and criticizing because when clinical or stability study, can not use a definite formulation that single polymorphic form possibly cause that institute uses or studies.Importantly, polymorphic form can repeat to prepare and in the formulation of exploitation, remain unchanged in long-time during selection.Also hope to have the method for preparing high purity N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide, because the existence of impurity possibly produce undesirable toxicology effect.
The information that WO 02/22577 does not provide the possible crystal of relevant N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide to modify at all.Have surprisingly been found that at present the different crystal modification (polymorphic form of new N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide) with hereinafter characteristic can be through 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 the pure basically crystalline form of salt of pure basically crystalline form and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-2E-2-acrylic amide of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali.
The invention further relates to pharmaceutical composition, this pharmaceutical composition comprises:
(a) N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-2E-2-acrylic amide free alkali of treatment significant quantity or the pure basically crystalline form of 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-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali or the pure basically crystalline form of its salt to the individual administering therapeutic significant quantity of this treatment of needs.
The accompanying drawing summary
Fig. 1 has shown form A, B, C, the H of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali AAnd H BThe x-ray powder diffraction pattern.
Fig. 2 has shown the form A and the H of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide PHENRAMINE MALEATE AThe x-ray powder diffraction pattern.
Fig. 3 has shown the x-ray powder diffraction pattern of form A, B and the C of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half tartrate.
Fig. 4 has shown N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-form A of 2E-2-acrylic amide mesylate and x-ray powder diffraction pattern of B.
Fig. 5 has shown the form A and the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide acetate AThe x-ray powder diffraction pattern.
Fig. 6 has shown form A, the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide benzoate AAnd S BThe x-ray powder diffraction pattern.
Fig. 7 has shown form A, B and the H of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide hemifumarate AThe x-ray powder diffraction pattern.
Fig. 8 has shown the form A and the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half malate AThe x-ray powder diffraction pattern.
Fig. 9 has shown N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-phosphatic form A of 2E-2-acrylic amide, S A, S BAnd H AThe x-ray powder diffraction pattern.
Figure 10 has shown the form A and the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide propionic salt AThe x-ray powder diffraction pattern.
Figure 11 has shown the form A and the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide vitriol AThe x-ray powder diffraction pattern.
Figure 12 has shown form A, B, the S of N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide hemisuccinic acid salt AAnd H AThe x-ray powder diffraction pattern.
Figure 13 A, 13B and 13C have shown N-hydroxyl-3-of the present invention [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-Lactated form A of 2E-2-acrylic amide DL-, H respectively AAnd S AThe x-ray powder diffraction pattern.
Figure 13 D and 13E have shown the x-ray powder diffraction pattern of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-anhydrous L-lactic acid salt of 2E-2-acrylic amide and D-lactate respectively.
Detailed Description Of The Invention
[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali can be with new polymorphic form A, B, C, H for N-hydroxyl-3- AAnd H BObtain.These " crystal modifications " (or " polymorphic form " or " crystalline form " is as the interchangeable in this article 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 the object of the invention, multiple hydrate and solvate forms are included in the scope of " polymorphic form ".The crystalline form of the N-hydroxyl-3-that the present invention relates to [4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali is characterised in that the x-ray powder diffraction pattern (XRPD) that Fig. 1 shows.
What the term " isolating " that this paper uses and/or " pure basically " were meant crystallization N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide or its salt is to have and exist one of form described herein of preferred 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali, and is as shown in Figure 1.Anhydrous form A can be from the ethanol-water solution (EtOH:H of low water content 2O=20:1) direct separation.Middle water cut (EtOH:H 2O=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, decomposes down at about 130 ℃ subsequently.In 110 ℃ of following weight loss on drying (LOD) less than 0.7%.
Second embodiment of the present invention relates to the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 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 the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali, and is as shown in Figure 1.Anhydrous form B is soluble in hot ethanol; Under heating, it does not have fusing down at about 187 ℃ and decomposes.At 160 ℃ of following LOD less than 0.15%.
The 3rd embodiment of the present invention relates to the pure basically polymorphic form C of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 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 the pure basically polymorphic form C of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali, and is 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 envrionment conditions fully AAnhydrous form C is solvable in hot ethanol; Under heating, it is in about 149 ℃ of fusing and decomposition down.At 140 ℃ of following LOD less than 0.9%.
The 4th embodiment of the present invention relates to the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 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 the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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) generation 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 OOS, have better solubleness (about 1.5mg/mL in ethanol, about 2.3mg/mL in methyl alcohol, about 5.6mg/mL in ETHYLE ACETATE).The LOD of corresponding monohydrate is 4.8%.
The 5th embodiment of the present invention relates to the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 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 the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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, the multiple isolating salt form of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide has also demonstrated heteromorphism.For example, each in PHENRAMINE MALEATE, half-tartrate, mesylate, acetate, benzoate, half-fumarate, half-malate, phosphoric acid salt, propionic salt, vitriol, half-SUMATRIPTAN SUCCINATE and the lactic acid salt all shows polymorphic form." salt " that this paper uses is meant the compound for preparing through 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 PHENRAMINE MALEATE and H ACan be shown in XRPD figure shown in Figure 2.Form A, B and the C of half-tartrate can be shown in XRPD figure shown in Figure 3.The form A of mesylate and B can be shown in XRPD figure shown in Figure 4.The form A of acetate and S ACan be shown in XRPD figure shown in Figure 5.The form A of benzoate, S AAnd S BCan be shown in XRPD figure shown in Figure 6.Form A, B and the H of half-fumarate ACan be shown in XRPD figure shown in Figure 7.The form A and the S of half-malate ACan be shown in XRPD figure shown in Figure 8.Phosphatic form A, S A, S BAnd H ACan be shown in XRPD figure shown in Figure 9.The form A of propionic salt and S ACan be shown in XRPD figure shown in Figure 10.The form A of vitriol and S ACan be shown in XRPD figure shown in Figure 11.Half-form the A of SUMATRIPTAN SUCCINATE, B, H AAnd S ACan be shown in XRPD figure shown in Figure 12.The Lactated form A of DL-, H AAnd S ACan be shown in the XRPD figure shown in Figure 13 A-13C.Therefore, other embodiment of the present invention relates to each pure basically polymorphic form of the said salt of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide.
The crystal form A of PHENRAMINE 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.PHENRAMINE MALEATE has well water-soluble (2.6mg/mL) and has good intrinsic dissulution.It demonstrates high solubleness and in other OOS, demonstrates suitable solubleness 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide PHENRAMINE MALEATE, and is as shown in Figure 2.
The form H of PHENRAMINE 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 peak: 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 the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide PHENRAMINE 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 dissulution.It demonstrates good solubleness and in alcohols, demonstrates limited solubleness in acetone, ETHYLE ACETATE and other OOS.In balance, form A is converted into form A in methyl alcohol, in 0.1N HCl, is converted into hydrochloride and in phosphate buffered saline buffer (pH=6.8), is converted into 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide tartrate, and is 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 peak: 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 the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide tartrate, and is as shown in Figure 3.
The form A of tartrate is to be obtained by form A balance in acetone at ambient temperature.The peak 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 the pure basically polymorphic form C of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide tartrate, and is 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 in other organic solvent, has tangible solubleness in methyl alcohol and ethanol.In balance, form A is converted into form B in water, in 0.1N HCl, is converted into hydrochloride, and in phosphate buffered saline buffer (pH=6.8), is converted into 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide mesylate, and is as shown in Figure 4.
The form B of mesylate can through at ambient temperature, reaction and subsequently suspension-s is heated to 50 ℃ in ETHYLE ACETATE, perhaps obtain through 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 peak: 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 the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide mesylate, and is 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 peak: 7.1,8.2,8.1,12.6,16.3,21.8 and 23.2 (2 θ degree).Particularly preferred embodiment relates to the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide acetate, and is as shown in Figure 5.
The form S of acetate ABeing acetone solvate, is 13.5% at about 140 ℃ of following LOD.This solvolyte 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 peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide acetate A, as shown in Figure 5.
The form A of the benzoate of the Reaction Separation from acetone has fabulous percent 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide benzoate, and is as shown in Figure 6.
The form S of benzoate ABeing alcohol solvent compound, is 5.2% being higher than 110 ℃ of LOD before the generation decomposition.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide benzoate A, as shown in Figure 6.
The form S of benzoate BBeing 2-propyl alcohol solvolyte, is 6.3% being higher than 100 ℃ of LOD before the generation decomposition.Its x-ray powder diffraction pattern shows at least two, more preferably at least four and most preferably all be selected from following peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 percent 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-fumarate, and is as shown in Figure 7.
The form B of half-fumarate of the Reaction Separation from ethanol has good percent 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 peak: 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 the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-fumarate, and is 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 peak: 7.0,10.1,11.2,15.1,22.1 and 22.8 (2 θ degree).Particularly preferred embodiment relates to the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 percent 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-malate, and is as shown in Figure 8.
The form S of half-malate ASalt formation reaction from acetone obtains.It has fabulous percent crystallinity, but under about 80 ℃, progressively begins to decompose.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 peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-malate A, as shown in Figure 8.
The phosphatic form A of the Reaction Separation from acetone has fabulous percent 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 peak: 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]-phosphatic pure basically polymorphic form A of 2E-2-acrylic amide, and is as shown in Figure 9.
The phosphatic form S of the Reaction Separation from ethanol AHave good percent crystallinity and demonstrate weight loss on heating gradually.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 peak: 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]-phosphatic pure basically polymorphic form S of 2E-2-acrylic amide A, as shown in Figure 9.
The phosphatic form S of the Reaction Separation from the 2-propyl alcohol BHave fabulous percent crystallinity and demonstrate weight loss on heating gradually.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 peak: 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]-phosphatic pure basically polymorphic form S of 2E-2-acrylic amide 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 percent 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 peak: 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]-phosphatic pure basically polymorphic form H of 2E-2-acrylic amide A, as shown in Figure 9.
The form A of the propionic salt of the Reaction Separation from acetone has fabulous percent 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide propionic salt, and is shown in figure 10.
The form S of the propionic salt of the Reaction Separation from the 2-propyl alcohol ABe 2-propyl alcohol solvolyte, have fabulous percent 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 peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide propionic salt A, shown in figure 10.
The form A of the vitriol of the Reaction Separation from ETHYLE ACETATE has poor percent 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 peak: 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 the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide vitriol, and is shown in figure 11.
The form S of the vitriol of the Reaction Separation from the 2-propyl alcohol ABe 2-propyl alcohol solvolyte, have fabulous percent 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 peak: 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 the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide vitriol A, shown in figure 11.
The form A of half-SUMATRIPTAN SUCCINATE of the reaction repeated isolation from second alcohol and water (1:0.05) or straight alcohol has fabulous percent 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 peak: 11.6,12.5,15.6,17.3,18.8,23.1 and 24.7 (2 θ degree).Particularly preferred embodiment relates to the pure basically polymorphic form A of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-SUMATRIPTAN SUCCINATE, and is shown in figure 12.
The form B of half-SUMATRIPTAN SUCCINATE of the Reaction Separation from acetone or ETHYLE ACETATE has good percent 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 peak: 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 the pure basically polymorph b of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-SUMATRIPTAN SUCCINATE, and is shown in figure 12.
The form S of half-SUMATRIPTAN SUCCINATE of the Reaction Separation from the 2-propyl alcohol ABe 2-propyl alcohol solvolyte, have good percent 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 peak: 7.0,10.2,10.6,11.1,18.1 and 19.9 (2 θ degree).Particularly preferred embodiment relates to the pure basically polymorphic form S of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-SUMATRIPTAN SUCCINATE A, shown in figure 12.
The form H of half-SUMATRIPTAN SUCCINATE monohydrate of the Reaction Separation from 2-third alcohol and water (1:0.05) AHave fabulous percent 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 peak: 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 the pure basically polymorphic form H of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide half-SUMATRIPTAN SUCCINATE A, 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 peak: 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]-Lactated pure basically polymorphic form A of 2E-2-acrylic amide DL-, shown in Figure 13 A.
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 pH1 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 peak: 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]-Lactated pure basically polymorphic form H of 2E-2-acrylic amide 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 peak: 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]-Lactated pure basically polymorphic form S of 2E-2-acrylic amide 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-acrylic amide L-(+)-Lactated pure basically polymorphic form S AMore preferably, lactic acid salt is N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-anhydrous L-of 2E-2-acrylic amide (+)-lactic acid salt.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2 and 29.9 (2 θ degree).Fusing takes place and decomposes in N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide L-(+)-Lactated anhydrous form simultaneously 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-acrylic amide D-(-)-Lactated pure basically polymorphic form S AMore preferably, lactic acid salt is N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-anhydrous D-of 2E-2-acrylic amide (-)-lactic acid salt.N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide 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 peak: 9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6 and 25.2 (2 θ degree).Fusing takes place and decomposes in N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide D-(-)-Lactated anhydrous form simultaneously under about 184.1 ℃.
Several different methods be can use and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-every kind of free alkali of 2E-2-acrylic amide and the polymorphic form of above-mentioned salt obtained.These methods as stated 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] amino] methyl] the phenyl]-2E-2-acrylic amide free alkali of one of previous embodiments according to the present invention of treatment significant quantity or the pure basically crystalline form of its salt; With
(b) at least a pharmaceutically acceptable carrier, thinner, medium or vehicle.
Preferably, be present in the compsn 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 through 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 confirmed by those of ordinary skills are conventional.
At least a pharmaceutically acceptable carrier, thinner, medium or vehicle can easily be selected and confirmed 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 prepn, 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 the step of the pure basically crystalline form of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] the phenyl]-2E-2-acrylic amide of one of previous embodiments according to the present invention to the individual administering therapeutic significant quantity of this treatment of needs.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 stated, illustrative method of application comprise oral, intranasal, non-enteron aisle, part, through skin and rectal administration.Using of crystalline form can be through using pharmaceutical composition of the present invention or realizing through any other effective means.
Prove special embodiment of the present invention with reference to following examples at present.Should be understood that these embodiment are the scope to explain that mode of the present invention is open and do not limit the present invention in any way only.
In following examples, about percent crystallinity, " fabulous " refers to has the sharp-pointed and intensity material greater than the XRPD main peak 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 peak of 30 countings.In addition, LOD refers to the weightlessness of between environment and decomposition temperature, measuring.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, actual decomposition temperature possibly be lower than described.The existence of salt formation, stoichiometry and solvent or do not exist through 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 confirmed.Water cut can not be obtained by the NMR data, because the water peak is wide.The protonated degree of free alkali is through 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 the gluey denseness of the coalescence of being easy to, 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
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 1.Acetate with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 1
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose(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)
Salt formation reaction in the acetone produces high crystal salt, and the ratio of N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide and acetate is 1:1, is accredited as stoichiometric acetone solvate S ASalt formation reaction in Virahol and ETHYLE 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
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 2.Phenylformic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred at ambient temperature (form settled solution, continue to stir down) at 4 ℃.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 2
Solvent T,℃ Physical properties Percent 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 is 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 through 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) solvolyte S with aqueous Virahol BProtonated alkali: the stoichiometry of benzoate is 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 through 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 solvolyte S AAnd S BSeemingly isostructural.The reaction of salt formation in acetone produces the benzoate that does not contain any solvent or water, has the 1:1 stoichiometry salt (form A) of fabulous percent crystallinity and high decomposition temperature.
Embodiment 3
The formation of half-fumarate
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 3.Fumaric acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 3
Solvent T,℃ Physical properties Percent 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 0.7217.4 3.90(H bz) 6.49 (1H, fumarates)
IPA:H 2O(1:0.05) Environment FFP Fabulous A 1.5208.2
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 0.7154.8
EtOH:H 2O(1:0.05) Environment FFP to SAM is to FFP Fabulous A 0.9217.1 3.90(H bz) 6.49 (1H, fumarates)
At ambient temperature, the salt formation reaction in Virahol and acetone produces stoichiometry 2:1 (protonated alkali: fumarate fumarate), i.e. half-fumarate.Although they are not solvolytes, they have poor percent 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 produces 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 possibly represented similar structures.
Embodiment 4
The formation of PHENRAMINE MALEATE
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 4.Toxilic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 4
Solvent T,℃ Physical properties Percent 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, PHENRAMINE MALEATEs)
IPA 60 SAM to FFP Fabulous A 0.2178.1 4.22(H bz) 6.01 (2H, PHENRAMINE MALEATEs)
Acetone 60 SAM to FFP Fabulous A 0.2176.1 4.22(H bz) 6.01 (2H, PHENRAMINE MALEATEs)
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 dicarboxylicacid, and itself and N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide produce 1:1 salt.Its 1The H-NMR spectrogram is presented at the 6.01ppm place has 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 possibly produce hydrate (form H in ethanol A).
Embodiment 5
The formation of half-malate
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 5.Oxysuccinic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 5
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose 1H-NMR
EtOH:H 2O(1:0.05) 60 SAM to FFP Fabulous A 1.9206.0 3.96(H bz) 3.83 (0.5H, malates)
EtOH 60 SAM to FFP Fabulous A 0.4199.3
IPA 60 SAM to FFP Fabulous A
Acetone 60 SAM to FFP Fabulous S A 0.695 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
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 6.Methylsulfonic acid with stoichiometric quantity adds in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 6
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose 1H-NMR
Acetone 60 SAM to FFP Fabulous A+B? 1.6172.8 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 ETHYLE ACETATE obtain yellow salt.This salt (form A) is crystalline, demonstrates 2 step weightlessness, and through NMR mensuration, it does not contain any solvent and still shows to have the mesylate more than a molecule.After heating under 60 ℃, the salt formation Reaction Separation in acetone obtains white powder.It demonstrates fabulous percent crystallinity, but possibly be the combination more than a kind of polymorphic form (form A and B).Measure through NMR, it does not contain any solvent, but demonstration contains the mesylate more than a molecule.Another salt formation reaction (wherein reaction begins at ambient temperature, then the pale yellow powder suspension-s that obtains is heated to 50 ℃) separation in ETHYLE ACETATE obtains new form B, and is as shown in Figure 4.
Embodiment 7
Phosphatic formation
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 7.Phosphoric acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 7
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose 1H-NMR
EtOH:H 2O(1:0.05) 60 FFP Fabulous H A 7.0179.6 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 1.0187.4 4.00(H bz)
AcOEt Room temperature to 60 SAM to FFP Fine A 1.2175.5
Salt formation reaction in ethanol and Virahol obtains ethanol and Virahol half-solvolyte (is respectively form S AAnd S B).In the second alcohol and water, only the ethanol of trace detects through 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, accomplishes down at~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 is 1:1 most likely.Salt demonstrates high decomposition temperature.
Embodiment 8
The formation of propionic salt
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 8.Propionic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 8
Solvent T,℃ Physical properties Percent 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 7.098.9 (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 solvolyte (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% (under~100 ℃, beginning) is because water, propionic acid or degradation production.When accomplishing 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
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 9.Sulfuric acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 9
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose 1H-NMR
IPA 60 SAM to FFP Fabulous S A 8.9 to 12162 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 ETHYLE ACETATE obtains yellow hygroscopic powder (form A).In filtering process, the obvious moisture absorption of sample, and the percent crystallinity of its difference acts on owing to this.
Embodiment 10
The formation of half-SUMATRIPTAN SUCCINATE
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 10.Succsinic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 10
Solvent T,℃ Physical properties Percent crystallinity and form LOD,%T Decompose 1H-NMR
EtOH:H 2O(1:0.05) 60 SAM to FFP Fabulous A 1.1203.7 (2.31 2H, SUMATRIPTAN SUCCINATE) 3.86 (H bz)
IPA:H 2O(1:0.05) 60 SAM to FFP Fabulous H A 4.6 (2.31 2H, SUMATRIPTAN SUCCINATE) 3.85 (H bz)
EtOH Environment FFP to SAM is to FFP Fabulous A 1.1194.6 (2.31 2H, SUMATRIPTAN 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, SUMATRIPTAN SUCCINATEs), 3.88 (H bz)
Acetone Environment FFP Fine B (1.5+1.3 2 step) 162.3 (2.31 2H, SUMATRIPTAN SUCCINATE) 3.86 (H bz)
AcOEt Environment FFP Fine B 1.3+2.9154.5
EtOH 60 SAM to FFP Fabulous A
EtOH:H 2O(1:0.025) 60 SAM to FFP Fabulous A 1.0197.3 (2.31 2H, SUMATRIPTAN SUCCINATE) 3.85 (H bz)
EtOH:H 2O(1:0.05) 60 SAM to FFP Fabulous A
Four visibly different half-SUMATRIPTAN SUCCINATEs are separated: half-solvolyte (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 percent crystallinity, the following minimum weightless and higher decomposition temperature up to 200 ℃.In addition,, explain in ethanol and second alcohol and water that it can repeat to synthesize as under 60 ℃.
Embodiment 11
The formation of half-L-tartrate
About 40-50mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali monohydrate is suspended in the solvent of listing in the 1mL table 11.Tartrate with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred (form settled solution, continue down to stir) at 4 ℃ under 60 ℃ or envrionment temperature.Solid by filtration is collected and through XRPD, TGA and pass through in some cases 1H-NMR analyzes.
Table 11
Solvent T,℃ Physical properties Percent 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 0.5206.9 (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 0.5207.6 (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 with 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
3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide) and 50mL absolute ethyl alcohol are packed in the 250mL3-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 absolute ethyl alcohol in the suspension-s 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 through filtered and recycled and with cold absolute ethyl alcohol (10mL).With its dried overnight under vacuum, obtain the L-tartrate (half-tartrate) (96.6%) of 4.1g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide.
Embodiment 13
The formation of mesylate
3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide) and 75mL ETHYLE ACETATE are packed in the 250mL 3-neck flask that mechanical stirrer and application of sample funnel are installed.Dropping is dissolved in 0.65mL (10mmol) methylsulfonic acid in the 20mL ETHYLE ACETATE in the suspension-s that stirs, and obtains the suspension-s 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-s is cooled to room temperature and white solid is passed through filtered and recycled.It with cold ETHYLE ACETATE (15mL) washing dried overnight once and under vacuum, is obtained the mesylate (98.3%) of 4.38g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide.
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 PHENRAMINE MALEATE
3.67g (10mmol) free alkali monohydrate (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide) and 75mL acetone are packed 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-s of thermotropism.Although slowly add, the salt that is settled out is soft, colloidal solid, and it has hindered stirring.45 ℃ continue down stirred overnight 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 the PHENRAMINE MALEATE (90.5%) of 4.21g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide.
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-acrylic amide 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-s is heated to 65 ℃ (internal temperatures).Under 65 ℃, go through the DL-lactic acid solution joined in this suspension-s in 30 minutes.In the process that adds lactate solution, suspension-s 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, adds crystal seed (10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide DL-lactic acid salt monohydrate).With suspension-s be cooled to 33 ℃ and under this temperature restir 20 hours.With suspension-s 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-acrylic amide DL-lactic acid salt, be crystallized product.This product HPLC with 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-acrylic amide free alkali form H A(5.0g) pack in the 4-neck reaction flask that mechanical stirrer is installed.Add softening water (54.85g), and in 30 minutes, suspension-s is heated to 48 ℃ (internal temperatures).Under 48 ℃, go through the DL-lactic acid solution joined in this suspension-s in 30 minutes.Add crystal seed (it is 5mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide DL-lactic acid salt, anhydrous form A, the suspension-s in 0.25g water), and under 48 ℃, continue again to stir 2 hours.In 30 minutes, temperature is elevated to 65 ℃ (internal temperatures), and with suspension-s 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 through 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-acrylic amide DL-lactic acid salt (form A), and it is a crystallized product.Fusing point takes place with decomposing 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-acrylic amide 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-s 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 adds crystal seed (it is 10mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide DL-lactic acid salt, anhydrous form, the suspension-s in 0.5g water).Temperature is cooled to 33 ℃ and under this temperature, continue to stir 19 hours again.In 45 minutes,, stirred 1 hour down and at 1 hour internal cooling to 33 ℃ at 65 ℃ with the suspension-s 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-acrylic amide 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-acrylic amide free alkali form H A(20g) pack in the 1L glass reactor, add ethanol/water (the 1:1w/w mixture of 209.4g).In 30 minutes, faint yellow suspension-s is heated to 60 ℃ (internal temperatures), and under this temperature, goes through 30 minutes adding lactic acid solutions.Application of sample funnel water (10g) is washed.In 2 hours, solution is heated to 38 ℃, and adds crystal seed (20mg N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide DL-lactic acid salt, anhydrous form) down at 38 ℃.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-s 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-acrylic amide DL-lactic acid salt (form A).
Embodiment 19
The formation of DL-lactic acid salt monohydrate salt
The free alkali form HA (N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide) of 3.67g (10mmol) and 75mL acetone are packed in the 250mL 3-neck flask that magnetic stirring apparatus and application of sample funnel are installed.In the suspension-s 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 is cooled off in ice bath and restir 1 hour.White solid is washed once through filtered and recycled and with cold acetone (15mL).With its vacuum-drying, obtain the DL-lactic acid salt monohydrate salt (86.2%) of 3.94g N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide subsequently.
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-acrylic amide free form H ABe suspended in the solvent of listing in the 1mL table 12.Lactic acid with stoichiometric quantity joins in the suspension-s subsequently.Mixture is stirred at ambient temperature and when forming settled solution, continues to stir down at 4 ℃.With solid by filtration collect and through XRPD, TGA and 1H-NMR analyzes.
Table 12
Solvent T,℃ Physical properties Percent 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; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali (20.0g) is handled with L-(+)-lactic acid (6.8g); Obtain crystalline N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide L-(+)-lactic acid salt, anhydrous form.Fusing point takes place with decomposing under 184.7 ℃ simultaneously.XRPD figure is shown in Figure 13 D (2 θ=9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2,29.9).
Embodiment 22
Anhydrous D-(-)-Lactated formation
According to the method for describing among the embodiment 19; N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide free alkali (20.0g) is handled with D-(-)-lactic acid (6.8g); Obtain crystalline N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide D-(-)-lactic acid salt, anhydrous form.Fusing point takes place with decomposing under 184.1 ℃ simultaneously.XRPD figure is shown in Figure 13 E (2 θ=9.9,11.4,13.8,18.1,18.5,19.7,20.2,21.6,25.2).
Morphological character
Absorption-desorption attaches thermo-isopleth and equals a record through VTI humidity sky.At first the salt with N-hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide carries out (25 ℃ of drying step; Relative humidity is less than 2%; 2 hours), to carry out absorption-desorption then and attach-the absorption order, each RH% step kept 3 hours.Free alkali was kept several hours less than 2% time in relative humidity, 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, and it is obvious that, can carry out many changes, modification and variation and can not break away from this paper invention disclosed notion.Therefore, be intended to comprise all spirit and the change in the wide region, modification and variations in accompanying claims.All patented claims that this paper quotes, patent and other publication are incorporated this paper into as a reference with its integral body.

Claims (2)

1.N-the Lactated crystalline, anhydrous form of DL-of hydroxyl-3-[4-[[[2-(2-Methyl-1H-indole-3-yl) ethyl] amino] methyl] phenyl]-2E-2-acrylic amide,
Wherein the x-ray powder diffraction pattern 2 θ degree of crystalline, anhydrous form have peak 9.9,11.4,13.8,15.7,18.2,19.7,20.3,21.5,25.3,27.4 and 30.0.
2. the Lactated crystalline, anhydrous form of the DL-of claim 1, wherein the x-ray powder diffraction pattern is shown in Figure 13 A.
CN2007800216589A 2006-06-12 2007-06-07 Polymorphs of n-hydroxy-3-[4-[[[2-(2-methyl-1h-indol-3-yl)ethyl]amino]methyl]phenyl]-2e-2-propenamide Active CN101641328B (en)

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