WO2016206634A1 - 吗啡啉苯基氨基嘧啶化合物或其盐的多晶型物 - Google Patents

吗啡啉苯基氨基嘧啶化合物或其盐的多晶型物 Download PDF

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WO2016206634A1
WO2016206634A1 PCT/CN2016/087093 CN2016087093W WO2016206634A1 WO 2016206634 A1 WO2016206634 A1 WO 2016206634A1 CN 2016087093 W CN2016087093 W CN 2016087093W WO 2016206634 A1 WO2016206634 A1 WO 2016206634A1
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polymorph
compound
formula
ray powder
powder diffraction
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PCT/CN2016/087093
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French (fr)
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吕彬华
李成伟
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苏州泽璟生物制药有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/42—One nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

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  • the present invention belongs to the field of medicine, and in particular to a polymorph of a morpholine phenylaminopyrimidine compound or a salt thereof, and more particularly, to N-(cyanomethyl)-4-(2-(4- A polymorph of (morpholine phenylamino)pyrimidin-4-yl)benzamide, or a pharmaceutically acceptable salt thereof.
  • N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzamide N-(cyanomethyl)-4-(2-((4-morpholino) )phenyl)amino)pyrimidin-4-yl)benzamide
  • the compound of formula I has the formula C 23 H 22 N 6 O 2 and has a molecular weight of 414.46.
  • the compound is a class of non-receptor tyrosine kinases such as inhibitors of JAK kinase, and is suitable for the preparation of a medicament for the treatment/prevention of cancer and myeloproliferative diseases. , inflammation and other related diseases.
  • a first aspect of the invention provides a polymorph, which is a polymorph of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a solvate thereof,
  • the pharmaceutically acceptable salt is a hydrochloride salt.
  • the molar ratio of the compound of formula I to hydrochloric acid in the hydrochloride salt of the compound of formula I is about 1:1 or 1:2.
  • the solvate is a monohydrate of the hydrochloride salt of the compound of formula I.
  • the polymorph is a polymorph I of the hydrochloride salt of the compound of formula I, wherein the polymorph I has 3 or more selected from the group consisting of X-ray powder diffraction characteristic peaks: 5.427 ⁇ 0.2 °, 9.968 ⁇ 0.2 °, 13.437 ⁇ 0.2 °, 14.726 ⁇ 0.2 °, 23.921 ⁇ 0.2 °, 25.068 ⁇ 0.2 °, 26.470 ⁇ 0.2 ° and 29.452 ⁇ 0.2 °.
  • the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 8.824 ⁇ 0.2°, 15.574 ⁇ 0.2°, 17.173 ⁇ 0.2°, 19.247 ⁇ 0.2°, 20.784 ⁇ 0.2°, 27.063 ⁇ 0.2° and 30.220 ⁇ 0.2°.
  • the polymorph I has an X-ray powder diffraction characteristic peak substantially as shown in Figure 1a.
  • the differential scanning calorimetry pattern of the polymorph I has a maximum peak at 219.7 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 1b.
  • the molar ratio of the compound of formula I to hydrochloric acid in the polymorph I is about 1:2.
  • the polymorph is a polymorph II of the hydrochloride salt solvate of the compound of formula I, wherein the polymorph II has 3 or more selected from the group consisting of X-ray powder diffraction characteristic peaks of the lower group: 17.310 ⁇ 0.2 °, 18.553 ⁇ 0.2 °, 19.227 ⁇ 0.2 °, 22.643 ⁇ 0.2 °, 23.964 ⁇ 0.2 ° and 29.511 ⁇ 0.2 °.
  • the polymorph II has an X-ray powder diffraction characteristic peak selected from the group consisting of 15.278 ⁇ 0.2°, 16.699 ⁇ 0.2°, 24.617 ⁇ 0.2°, 25.600 ⁇ 0.2°, 27.119 ⁇ 0.2° and 30.282 ⁇ 0.2°.
  • the polymorph II has an X-ray powder diffraction characteristic peak substantially as shown in Figure 2a.
  • the differential scanning calorimetry pattern of the polymorph II is at 140.87 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C), 182.2 ° C ⁇ 2 ° C (or ⁇ 1 ° C , or ⁇ 0.5 ° C) and 234.34 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C) have the largest peak.
  • the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.
  • the molar ratio of the compound of formula I, hydrochloric acid and water in the polymorph II is about 1:2:1.
  • the polymorph II is a monohydrate of the compound dihydrochloride salt of formula I.
  • the polymorph is a polymorph III of the hydrochloride salt of the compound of formula I, wherein the polymorph III has 3 or more selected from the group consisting of X-ray powder diffraction characteristic peaks: 15.217 ⁇ 0.2 °, 18.847 ⁇ 0.2 °, 20.724 ⁇ 0.2 °, 26.372 ⁇ 0.2 ° and 28.107 ⁇ 0.2 °.
  • the polymorph III further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.404 ⁇ 0.2°, 13.362 ⁇ 0.2°, 16.225 ⁇ 0.2°, 16.976 ⁇ 0.2°, 20.055 ⁇ 0.2°, 22.956 ⁇ 0.2°, 25.996 ⁇ 0.2° and 31.783 ⁇ 0.2°.
  • the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a.
  • the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 231.1 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph III has a differential scanning calorimetry (DSC) substantially as shown in Figure 3b.
  • the molar ratio of the compound of formula I to hydrochloric acid in the polymorph III is about 1:1.
  • the polymorph is a polymorph IV of the hydrochloride salt of the compound of formula I, wherein the polymorph IV has 3 or more selected from the group consisting of X-ray powder diffraction characteristic peaks: 4.422 ⁇ 0.2 °, 12.474 ⁇ 0.2 °, 14.429 ⁇ 0.2 °, 17.627 ⁇ 0.2 °, 19.501 ⁇ 0.2 °, 23.213 ⁇ 0.2 °, 23.803 ⁇ 0.2 ° and 24.794 ⁇ 0.2 °.
  • the polymorph IV further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.949 ⁇ 0.2°, 13.778 ⁇ 0.2°, 16.600 ⁇ 0.2°, 17.018 ⁇ 0.2°, 20.625 ⁇ 0.2°, 21.003 ⁇ 0.2°, 21.891 ⁇ 0.2°, 24.377 ⁇ 0.2°, 28.718 ⁇ 0.2°, 29.550 ⁇ 0.2° and 31.739 ⁇ 0.2°.
  • the polymorph IV has an X-ray powder diffraction pattern substantially as shown in Figure 4a.
  • the differential scanning calorimetry pattern of the polymorph IV has a maximum peak at 245.24 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C).
  • the polymorph IV has a differential scanning calorimetry (DSC) substantially as shown in Figure 4b.
  • the molar ratio of the compound of formula I to hydrochloric acid in the polymorph IV is about 1:1.
  • the polymorph is a polymorph V of a compound of formula I, wherein the polymorph V has 3 or more X-rays selected from the group consisting of Powder diffraction characteristic peaks: 4.342 ⁇ 0.2 °, 12.753 ⁇ 0.2 °, 18.161 ⁇ 0.2 ° and 23.193 ⁇ 0.2 °.
  • the polymorph V further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.981 ⁇ 0.2°, 9.495 ⁇ 0.2°, 14.014 ⁇ 0.2°, 19.680 ⁇ 0.2°, 21.280 ⁇ 0.2°, 24.319 ⁇ 0.2°, 25.326 ⁇ 0.2° and 30.143 ⁇ 0.2°.
  • the polymorph V has an X-ray powder diffraction pattern substantially as shown in Figure 5a.
  • the differential scanning calorimetry pattern of the polymorph V has a maximum peak at 256.79 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph V has a differential scanning calorimetry (DSC) substantially as shown in Figure 5b.
  • a second aspect of the invention provides the use of a polymorph according to the first aspect of the invention for the preparation of a pharmaceutical composition of a non-receptor tyrosine kinase such as JAK kinase.
  • the pharmaceutical composition is for the treatment and prevention of cancer, myeloproliferative and inflammatory diseases.
  • a third aspect of the invention provides a pharmaceutical composition comprising:
  • a fourth aspect of the present invention provides a process for the preparation of a polymorph according to the first aspect of the present invention, which comprises the steps of: salt-forming a compound of the formula I and an acid in an inert solvent, or formula I
  • the compound or a pharmaceutically acceptable salt thereof, or a solvate thereof, is recrystallized in an inert solvent to obtain the polymorph described in the first aspect of the invention.
  • the recrystallization is carried out with or without seeding.
  • the acid is hydrochloric acid.
  • the process for preparing the polymorph I comprises the steps of: salt-crystallizing a compound of the formula I and hydrochloric acid in an inert solvent to obtain the polymorph I of the present invention.
  • the inert solvent is selected from the group consisting of ethanol, methanol, isopropanol, acetic acid, A Acid or a combination thereof.
  • the process for preparing the polymorph I comprises the steps of: crystallizing a compound of the formula I and hydrochloric acid in ethanol and/or methanol to obtain the polymorph I of the present invention. .
  • the process for preparing the polymorph I comprises the steps of: salt-crystallizing a compound of the formula I and hydrochloric acid in a mixed solvent of acetic acid and ethanol to obtain the polymorph I of the present invention.
  • the molar ratio of the compound of formula I to hydrochloric acid is from about 1:2 to 1:5.
  • the volume ratio of ethanol to methanol is from 1:50 to 50:1.
  • the volume ratio of acetic acid to ethanol is from 1:5 to 5:1, preferably from 1:2 to 2:1.
  • the process for preparing the polymorph II comprises the steps of: forming a salt of the compound of the formula I in a mixed solvent of hydrochloric acid in dimethyl sulfoxide and ethanol or a mixed solvent of dimethyl sulfoxide and acetone. Crystallization, thereby obtaining the polymorph II of the present invention.
  • the volume ratio of the dimethyl sulfoxide to the ethanol is 1:5 to 5:1; and the volume ratio of the dimethyl sulfoxide to the acetone is 1:5 to 5:1.
  • the method for preparing the polymorph II comprises the steps of: placing the prepared polymorph I in a high humidity (for example, humidity of 90%) environment for a period of time, thereby obtaining the present invention.
  • a high humidity for example, humidity of 90%
  • the process for preparing the polymorph II comprises the steps of: crystallizing the obtained polymorph I in a mixed solvent of acetone and water to obtain the polymorph of the present invention. II.
  • the weight ratio of acetone to water is from 8:1 to 50:1, preferably from 10:1 to 30:1, more preferably from 12:1 to 18:1.
  • the method of preparing the polymorph II comprises the steps of:
  • the concentration of the hydrochloric acid is from 0.5 to 3 M, preferably from 0.7 to 2 M, more preferably from 0.8 to 1.2 M.
  • the crystallization is carried out under stirring.
  • the agitation condition is from 4 to 48 h, preferably from 6 to 30 h, more preferably from 10 to 24 h.
  • the molar ratio of the polymorph I to hydrochloric acid is about 10:1 to 1:1, preferably 8:1 to 2:1, more preferably 6 :1-3:1.
  • the methanol comprises anhydrous methanol.
  • the method for preparing the polymorph III comprises the steps of: salt-crystallizing a compound of the formula I and hydrochloric acid in a mixed solvent of N-methylpyrrolidone and ethanol to obtain the polycrystal of the present invention.
  • Form III comprises the steps of: salt-crystallizing a compound of the formula I and hydrochloric acid in a mixed solvent of N-methylpyrrolidone and ethanol to obtain the polycrystal of the present invention.
  • the volume ratio of the N-methylpyrrolidone to ethanol is from 3:1 to 1:3, preferably from 2:1 to 1:2, more preferably from 1:1.
  • the process for preparing the polymorph III comprises the steps of: crystallizing the obtained polymorph II in methanol to obtain the polymorph III of the present invention.
  • the process for preparing the polymorph III includes the steps of: stirring and crystallization of a mixture of the compound of the formula I, hydrochloric acid and methanol to obtain the polymorph III.
  • the concentration of the hydrochloric acid is from 6 M to a saturated concentration of concentrated hydrochloric acid, preferably from 8 to 12 M.
  • the molar ratio of the compound of formula I to hydrochloric acid is from about 1:0.9 to 1:1.2.
  • the method of preparing the polymorph IV comprises the steps of: preparing the polymorph I Recrystallization from water or aqueous hydrochloric acid gives the polymorph IV of the present invention.
  • the process for preparing the polymorph IV includes the steps of: suspending the obtained polymorph II in a mixed solvent of methanol and water to obtain the polymorph IV. .
  • the volume ratio of methanol to water is from 5:1 to 1:10.
  • the process for preparing the polymorph V comprises the steps of: recrystallizing a compound of the formula I in a mixed solvent of acetic acid and water or a mixed solvent of dimethyl sulfoxide and water to obtain the present invention.
  • Polymorph V is described.
  • the volume ratio of acetic acid to water is 1:3 to 3:1; and the volume ratio of dimethyl sulfoxide to water is 1:3 to 3:1.
  • a fifth aspect of the invention provides a method for preparing a polymorph II, comprising the steps of:
  • the concentration of hydrochloric acid is from 6 M to a saturated concentration of concentrated hydrochloric acid, preferably from 8 to 12 M.
  • the molar ratio of the compound of the formula I to hydrochloric acid is from 1:1.8 to 1:3, preferably from 1:1.9 to 1:2.5, preferably from 1:2.0 to 1:2.4.
  • Figure 1a shows an X-ray powder diffraction pattern of polymorph I.
  • Figure 1b shows a differential scanning calorimetry plot of polymorph I.
  • Figure 1c shows a 1 H NMR chart of polymorph I.
  • Figure 2a shows an X-ray powder diffraction pattern of polymorph II.
  • Figure 2b shows a differential scanning calorimetry plot of polymorph II.
  • Figure 2c shows the 1 H NMR spectrum of polymorph II.
  • Figure 3a shows an X-ray powder diffraction pattern of polymorph III.
  • Figure 3b shows a differential scanning calorimetry plot of polymorph III.
  • Figure 3c shows a 1 H NMR chart of polymorph III.
  • Figure 4a shows an X-ray powder diffraction pattern of polymorph IV.
  • Figure 4b shows a differential scanning calorimetry plot of polymorph IV.
  • Figure 4c shows a 1 H NMR chart of polymorph IV.
  • Figure 5a shows an X-ray powder diffraction pattern of polymorph V.
  • Figure 5b shows a differential scanning calorimetry plot of polymorph V.
  • Figure 5c shows a 1 H NMR plot of polymorph V.
  • onset represents an initial (initial value)
  • peak represents a peak (peak).
  • the present inventors have unexpectedly discovered, through long-term and intensive research, various polymorphs of a compound of the formula I or a pharmaceutically acceptable salt thereof, or a solvate thereof, which has a better drug Bioavailability, and the polymorph is high in purity and very stable, and is suitable for preparing a pharmaceutical composition for inhibiting non-receptor tyrosine kinases (such as JAK kinase), thereby being more beneficial for treating cancer and bone marrow multiplication. And diseases such as inflammation.
  • the polymorph of the present invention is difficult to lift during the manufacturing process of the drug such as dispensing, is easy to collect, is not easy to cause waste, and helps protect the health of the operator. On this basis, the inventors completed the present invention.
  • a compound of formula I refers to N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzene as shown in formula I. Amide.
  • inert solvent means methanol, ethanol, isopropanol, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, acetone, acetonitrile, acetic acid, formic acid, n-hexane, N-heptane, toluene, tetrahydrofuran, ethyl acetate, 1,4-dioxane, methyl tert-butyl ether, water or a mixture of the above solvents.
  • the N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzamide hydrochloride of the present invention comprises various hydrochloric acids of the compound of formula I Salt form.
  • N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzamide dihydrochloride refers to the molar ratio of the compound of formula I to hydrochloric acid a salt of 1:2; or
  • N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzamide dihydrochloride monohydrate refers to the compound of formula I with hydrochloric acid, water The molar ratio is 1:2:1 salt.
  • N-(cyanomethyl)-4-(2-(4-(morpholinephenylamino)pyrimidin-4-yl)benzamide monohydrochloride refers to a molar ratio of the compound of formula I to hydrochloric acid of 1: 1 salt.
  • the solid does not exist in an amorphous form or in a crystalline form.
  • the molecules are positioned within the three-dimensional lattice lattice.
  • polymorphism When a compound crystallizes out of a solution or slurry, it can crystallize in different spatial lattices (this property is called "polymorphism"), forming crystals with different crystalline forms, and these various crystalline forms are It is called "polymorph”.
  • Different polymorphs of a given substance may differ from one another in one or more physical properties such as solubility and dissolution rate, true specific gravity, crystalline form, bulk mode, flowability, and/or solid state stability.
  • the solubility limit of the compound of interest can be exceeded by operating the solution to complete production-scale crystallization. This can be done in a number of ways, for example, at relatively high temperatures. The compound is then cooled to below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. The solubility of the compound of interest can be lowered by adding an antisolvent or a solvent having a low solubility in the compound or a mixture of such a solvent. Another alternative is to adjust the pH to reduce solubility. For a detailed description of crystallization, see Crystallization, Third Edition, J W Mullens, Butterworth-Heineman Ltd., 1993, ISBN 0750611294.
  • salt formation is desired to occur simultaneously with crystallization, if the salt is less soluble than the starting material in the reaction medium, the addition of a suitable acid or base can result in direct crystallization of the desired salt. Similarly, in the final desired form of the medium having less solubility than the reactants, the completion of the synthesis reaction allows the final product to crystallize directly.
  • optimization of crystallization can include seeding the crystal in a desired form with the crystal as a seed.
  • many crystallization methods use a combination of the above strategies.
  • One embodiment is to dissolve the compound of interest in a solvent at elevated temperatures, followed by controlled addition of an appropriate volume of anti-solvent to bring the system just below the level of saturation. At this point, seed crystals of the desired form can be added (and the integrity of the seed crystals maintained) and the system cooled to complete crystallization.
  • room temperature generally refers to 4-30 ° C, preferably 20 ⁇ 5 ° C.
  • polymorph of the invention includes a compound of formula I, or a pharmaceutically acceptable salt thereof (such as a hydrochloride salt), or a polymorph of its various solvates, and includes the same Different polymorphs of the hydrochloride or solvate.
  • Preferred polymorphs of the invention include, but are not limited to:
  • the molar ratio of the compound of the formula I to hydrochloric acid is 1:2; in the polymorph II, the molar ratio of the compound of the formula I, hydrochloric acid and water is 1:2:1; In the polymorphs III and IV, the molar ratio of the compound of the formula I to hydrochloric acid is 1:1.
  • X-ray powder diffraction of crystalline forms are known in the art.
  • a copper radiation target is used to acquire a spectrum using a Rigaku D/max 2550VB/PC model X-ray powder diffractometer at a scan speed of 2° per minute.
  • the polymorph of the compound of formula I of the present invention has a specific crystalline form and has a specific characteristic peak in an X-ray powder diffraction (XRPD) pattern.
  • XRPD X-ray powder diffraction
  • the polymorph I has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of 5.427 ⁇ 0.2°, 9.968 ⁇ 0.2°, 13.437 ⁇ 0.2°, 14.726 ⁇ 0.2°, 23.921 ⁇ 0.2 °, 25.068 ⁇ 0.2 °, 26.470 ⁇ 0.2 ° and 29.452 ⁇ 0.2 °.
  • the polymorph I has an X-group selected from the group consisting of Ray powder diffraction characteristic peaks: 8.824 ⁇ 0.2°, 15.574 ⁇ 0.2°, 17.173 ⁇ 0.2°, 19.247 ⁇ 0.2°, 20.784 ⁇ 0.2°, 27.063 ⁇ 0.2° and 30.220 ⁇ 0.2°.
  • the polymorph I has an X-ray powder diffraction pattern substantially as shown in Figure 1a.
  • the polymorph II has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of 17.310 ⁇ 0.2°, 18.553 ⁇ 0.2°, 19.227 ⁇ 0.2°, 22.643 ⁇ 0.2°, 23.964 ⁇ 0.2 ° and 29.511 ⁇ 0.2 °.
  • the polymorph II has an X-ray powder diffraction characteristic peak selected from the group consisting of 15.278 ⁇ 0.2°, 16.699 ⁇ 0.2°, 24.617 ⁇ 0.2°, 25.600 ⁇ 0.2°, 27.119 ⁇ 0.2° and 30.282 ⁇ 0.2°.
  • the polymorph II has an X-ray powder diffraction pattern substantially as shown in Figure 2a.
  • the polymorph III has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of 15.217 ⁇ 0.2°, 18.847 ⁇ 0.2°, 20.724 ⁇ 0.2°, 26.372 ⁇ 0.2° and 28.107 ⁇ 0.2. °.
  • the polymorph III further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.404 ⁇ 0.2°, 13.362 ⁇ 0.2°, 16.225 ⁇ 0.2°, 16.976 ⁇ 0.2°, 20.055 ⁇ 0.2°, 22.956 ⁇ 0.2°, 25.996 ⁇ 0.2° and 31.783 ⁇ 0.2°.
  • the polymorph III has an X-ray powder diffraction pattern substantially as shown in Figure 3a.
  • the polymorph IV has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.422 ⁇ 0.2°, 12.474 ⁇ 0.2°, 14.429 ⁇ 0.2°, 17.627 ⁇ 0.2°, 19.501 ⁇ 0.2 °, 23.213 ⁇ 0.2 °, 23.803 ⁇ 0.2 ° and 24.794 ⁇ 0.2 °.
  • the polymorph IV further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 12.949 ⁇ 0.2°, 13.778 ⁇ 0.2°, 16.600 ⁇ 0.2°, 17.018 ⁇ 0.2°, 20.625 ⁇ 0.2°, 21.003 ⁇ 0.2°, 21.891 ⁇ 0.2°, 24.377 ⁇ 0.2°, 28.718 ⁇ 0.2°, 29.550 ⁇ 0.2° and 31.739 ⁇ 0.2°.
  • the polymorph IV has an X-ray powder diffraction pattern substantially as shown in Figure 4a.
  • the polymorph V has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of 4.342 ⁇ 0.2°, 12.753 ⁇ 0.2°, 18.161 ⁇ 0.2°, and 23.193 ⁇ 0.2°. In another preferred embodiment, the polymorph V further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 5.981 ⁇ 0.2°, 9.495 ⁇ 0.2°, 14.014 ⁇ 0.2°, 19.680 ⁇ 0.2°, 21.280 ⁇ 0.2°, 24.319 ⁇ 0.2°, 25.326 ⁇ 0.2° and 30.143 ⁇ 0.2°. In another preferred embodiment, the polymorph V has an X-ray powder diffraction pattern substantially as shown in Figure 5a.
  • DSC differential calorimetric scanning analysis
  • a DSC scan of the crystal form can be obtained by using a NETZSCH DSC 204F1 differential scanning calorimeter at a temperature increase rate of 10 ° C per minute from 25 ° C to 300 ° C.
  • the polymorph of the compound of formula I of the present invention has a specific characteristic peak in a differential calorimetric analysis (DSC) chart.
  • the differential scanning calorimetry spectrum of the polymorph I has a maximum peak at 219.7 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph I has a differential scanning calorimetry (DSC) substantially as shown in Figure 1b.
  • the differential scanning calorimetry spectrum of the polymorph II is at 140.87 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C), 182.2 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C) And 234.34 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C) has the largest peak.
  • the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.
  • the differential scanning calorimetry pattern of the polymorph III has a maximum peak at 231.1 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph III has a differential scanning calorimetry pattern substantially as shown in Figure 3b.
  • the differential scanning calorimetry pattern of the polymorph IV has a maximum peak at 245.24 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C).
  • the polymorph IV has a differential scanning calorimetry pattern substantially as shown in Figure 4b.
  • the differential scanning calorimetry spectrum of the polymorph V has a maximum peak at 256.79 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph V has a differential scanning calorimetry pattern substantially as shown in Figure 5b.
  • Nuclear magnetic resonance can also be employed to aid in the determination of crystal structure, the method of which is known in the art.
  • the invention preferably employs Bruker Avance III plus-400 MHz.
  • active ingredient refers to a polymorph of the invention, ie, a polymorph of a compound of Formula I, or a pharmaceutically acceptable salt thereof (eg, a hydrochloride thereof), or a solvate thereof Shape.
  • the polymorph of the present invention has excellent inhibitory activity against a non-receptor tyrosine kinase such as JAK kinase
  • the polymorph of the present invention and a pharmaceutical composition containing the polymorph of the present invention as a main active ingredient Therapies can be used to treat, prevent, and alleviate diseases mediated by non-receptor tyrosine kinases such as JAK kinase.
  • the polymorphs of the invention can be used to treat diseases such as cancer, myeloproliferative and inflammatory, and the like.
  • compositions of the present invention comprise a polymorph of the invention in a safe and effective amount and a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutical compositions will contain from 1 to 2000 mg of the polymorph/agent of the invention, more preferably from 10 to 200 mg of the polymorph/agent of the invention.
  • the "one dose” is a capsule or tablet.
  • “Pharmaceutically acceptable carrier” means: one or more compatible solid or liquid fillers or gel materials which are suitable for human use and which must be of sufficient purity and of sufficiently low toxicity.
  • “compatibility” it is meant herein that the components of the composition are capable of intermingling with the active ingredients of the present invention and with respect to each other without significantly reducing the efficacy of the active ingredients.
  • pharmaceutically acceptable carriers are cellulose and its derivatives (such as sodium carboxymethylcellulose, sodium ethylcellulose, cellulose acetate, etc.), gelatin, talc, solid lubricants (such as stearic acid).
  • magnesium stearate magnesium stearate
  • calcium sulfate vegetable oil (such as soybean oil, sesame oil, peanut oil, olive oil, etc.), polyol (such as propylene glycol, glycerin, mannitol, sorbitol, etc.), emulsifier Wetting agents (such as sodium lauryl sulfate), colorants, flavoring agents, stabilizers, antioxidants, preservatives, pyrogen-free water, and the like.
  • the mode of administration of the polymorph or pharmaceutical composition of the present invention is not particularly limited, and representative modes of administration include, but are not limited to, oral, intratumoral, rectal, parenteral (intravenous, intramuscular or subcutaneous), And topical administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active ingredient is mixed with at least one conventional inert excipient (or carrier), such as sodium citrate or dicalcium phosphate, or mixed with: (a) a filler or compatibilizer, for example, Microcrystalline cellulose, starch, lactose, sucrose, glucose, mannitol, and silicic acid; (b) binders, for example, hydroxymethylcellulose, alginate, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) a humectant, for example, glycerin; (d) a disintegrant such as agar, calcium carbonate, potato starch or tapioca starch, alginic acid, certain complex silicates, sodium carbonate, crospovidone, cross-linking Sodium carboxymethylcellulose; (e) a slow solvent such as paraffin; (f) an absorption accelerator, for
  • Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other materials known in the art. They may contain opacifying agents and the release of the active ingredient in such compositions may be released in a portion of the digestive tract in a delayed manner. Examples of embedding components that can be employed are polymeric and waxy materials. If necessary, the active ingredient may also be in microencapsulated form with one or more of the above-mentioned excipients.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups or elixirs.
  • the liquid dosage form may contain inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethylformamide and oils, especially cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil and sesame oil or a mixture of these substances.
  • inert diluents conventionally employed in the art, such as water or other solvents, solubilizers and emulsifiers, for example, ethanol, isopropanol, ethyl carbonate, ethyl acetate, propylene glycol, 1 , 3-butanediol, dimethyl
  • compositions may contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening agents, flavoring agents and perfumes.
  • the suspension may contain suspending agents, for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • suspending agents for example, ethoxylated isostearyl alcohol, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum methoxide and agar or mixtures of these and the like.
  • compositions for parenteral injection may comprise a physiologically acceptable sterile aqueous or nonaqueous solution, dispersion, suspension or emulsion, and a sterile powder for reconstitution into a sterile injectable solution or dispersion.
  • Suitable aqueous and nonaqueous vehicles, diluents, solvents or vehicles include water, ethanol, polyols, and suitable mixtures thereof.
  • Dosage forms of the polymorphs of the invention for topical administration include ointments, powders, patches, propellants, and inhalants.
  • the active ingredient is admixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers, or, if necessary, propellants.
  • polymorphs of the invention may be administered alone or in combination with other pharmaceutically acceptable compounds.
  • a safe and effective amount of the polymorph of the present invention is suitable for use in a mammal (e.g., a human) in need of treatment wherein the dosage is a pharmaceutically effective effective dosage for a 60 kg body weight.
  • the daily dose is usually from 1 to 2000 mg, preferably from 10 to 500 mg.
  • specific doses should also consider factors such as the route of administration, the health of the patient, etc., which are within the skill of the skilled physician.
  • polymorph of the invention comprises polymorphs I to V.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 870 mg, yield: 74%.
  • the X-ray powder diffraction pattern is shown in Figure 1a, the parameters of each peak are shown in Table 1, the differential scanning calorimetry (DSC) is shown in Figure 1b, and the 1 H NMR spectrum is shown in Figure 1c.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 579 mg, yield: 95%.
  • Fig. 2a The X-ray powder diffraction pattern is shown in Fig. 2a, the parameters of each peak are shown in Table 2, the differential scanning calorimetry (DSC) is shown in Fig. 2b, and the 1 H NMR spectrum is shown in Fig. 2c.
  • DSC differential scanning calorimetry
  • N-(cyanomethyl))-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide (4.0 g, 9.6 mmol)
  • Sulfate (14.0ml)
  • stir to room temperature at room temperature add 1.7ml of 37% concentrated hydrochloric acid to the mixture once, stir evenly, add acetone (16ml), clarify the mixture, continue stirring for 3h at room temperature, filter, filter cake
  • acetone (16ml)
  • clarify the mixture continue stirring for 3h at room temperature, filter, filter cake
  • the mixture was washed with acetone, and dried under high vacuum at 45 ⁇ 5 ° C for 3 h to give the title compound as a title compound.
  • Its X-ray powder diffraction pattern is the same as in Figure 2a.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 836 mg, yield: 77%.
  • Fig. 3a The X-ray powder diffraction pattern is shown in Fig. 3a, the parameters of each peak are shown in Table 3, the differential scanning calorimetry (DSC) is shown in Fig. 3b, and the 1 H NMR spectrum is shown in Fig. 3c.
  • DSC differential scanning calorimetry
  • Fig. 4a The X-ray powder diffraction pattern is shown in Fig. 4a, the parameters of each peak are shown in Table 4, the differential scanning calorimetry (DSC) is shown in Fig. 4b, and the 1 H NMR spectrum is shown in Fig. 4c.
  • DSC differential scanning calorimetry
  • Fig. 5a The X-ray powder diffraction pattern is shown in Fig. 5a, the parameters of each peak are shown in Table 5, the differential scanning calorimetry (DSC) is shown in Fig. 5b, and the 1 H NMR spectrum is shown in Fig. 5c.
  • DSC differential scanning calorimetry
  • N-(Cyanomethyl)-4-(2-(4-(morpholine)phenylamino)pyrimidin-4-yl)benzamide dihydrochloride (23.0 g) was added, and dimethyl sulfoxide was added ( 105 ml), the solution was dissolved under stirring at room temperature; the mixture was slowly added dropwise to a saturated sodium hydrogencarbonate solution (1.1 L), and the solid was precipitated, stirring was continued for 4 h; filtered, and the solid was washed with purified water (100 ml x 3). Drying at a high vacuum of about 65 ° C for 8 h gave 18.8 g of a yellow solid. Its X-ray powder diffraction pattern is the same as in Figure 5a.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • Example 32 The operation of Example 32 was repeated except that the polymorphs I, III to V of the present invention were used instead of the polymorph II, and it was found that the various polymorphs described in the present invention were very stable and basic. There is no hygroscopicity, and only polymorph I is slightly hygroscopic.
  • the polymorphs described herein are highly suitable for use in pharmaceutical compositions.
  • the polymorph of the present invention is difficult to lift during the manufacturing process of the drug such as dispensing, is easy to collect, is not easy to cause waste, and helps protect the health of the operator.

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Abstract

本发明涉及吗啡啉苯基氨基嘧啶化合物或其盐的多晶型物，更具体地，涉及N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺、或其药学上可接受的盐，或其溶剂合物的多晶型物。所述多晶型物适合用于制备抑制非受体酪氨酸激酶(如JAK激酶)的药物组合物。

Description

吗啡啉苯基氨基嘧啶化合物或其盐的多晶型物 技术领域
本发明属于医药领域，具体地，涉及一种吗啡啉苯基氨基嘧啶化合物或其盐的多晶型物，更具体地，涉及N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺、或其药学上可接受的盐的多晶型物。
背景技术
N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺(N-(cyanomethyl)-4-(2-((4-morpholino)phenyl)amino)pyrimidin-4-yl)benzamide),结构如式I所示：
Figure PCTCN2016087093-appb-000001
式I化合物的分子式为C23H22N6O2，分子量为414.46，该化合物是一类非受体酪氨酸激酶如JAK激酶的抑制剂，适用于制备治疗/预防癌症、骨髓增殖性疾病、炎症以及其它相关疾病的药物。
由于药物的不同晶型和盐型可能会影响其在体内的溶出、吸收，进而可能在一定程度上影响药物的临床疗效和安全性，特别是一些难溶性口服固体或半固体制剂，晶型的影响会更大。目前没有对式I化合物多晶型进行研究，尚没有开发出式I化合物的多晶型物。
因此，研发式I化合物的多晶型物是十分必要的。
发明内容
本发明的目的是提供一种式I化合物或其药学上可接受的盐、或其溶剂合物的多晶型物。
本发明的第一方面提供了一种多晶型物，所述多晶型物为式I所示化合物或其药学上可接受的盐或其溶剂合物的多晶型物，
Figure PCTCN2016087093-appb-000002
在另一优选例中，所述药学上可接受的盐为盐酸盐。
在另一优选例中，所述式I所示化合物的盐酸盐中，式I所示化合物和盐酸的摩尔比约为1：1或1：2。
在另一优选例中，所述溶剂合物为式I所示化合物盐酸盐的一水合物。
在另一优选例中，所述多晶型物为式I所示化合物盐酸盐的多晶型物I，其中，所述多晶型物I具有3个或3个以上选自下组的X-射线粉末衍射特征峰：5.427±0.2°，9.968±0.2°，13.437±0.2°，14.726±0.2°，23.921±0.2°，25.068±0.2°，26.470±0.2°和29.452±0.2°。
在另一优选例中，所述多晶型物I具有选自下组的X-射线粉末衍射特征峰：8.824±0.2°，15.574±0.2°，17.173±0.2°，19.247±0.2°，20.784±0.2°，27.063±0.2°和30.220±0.2°。
在另一优选例中，所述多晶型物I具有基本如图1a所示的X-射线粉末衍射特征峰。
在另一优选例中，所述多晶型物I的差示扫描量热法图谱在219.7℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物I具有基本如图1b所示的差示扫描量热法图谱(DSC)。
在另一优选例中，所述多晶型物I中，式I化合物和盐酸的摩尔比约为1：2。
在另一优选例中，所述多晶型物为式I所示化合物盐酸盐溶剂合物的多晶型物II，其中，所述多晶型物II具有3个或3个以上选自下组的X-射线粉末衍射特征峰：17.310±0.2°，18.553±0.2°，19.227±0.2°，22.643±0.2°，23.964±0.2°和29.511±0.2°。
在另一优选例中，所述多晶型物II具有选自下组的X-射线粉末衍射特征峰：15.278±0.2°，16.699±0.2°，24.617±0.2°，25.600±0.2°，27.119±0.2°和30.282±0.2°。
在另一优选例中，所述多晶型物II具有基本如图2a所示的X-射线粉末衍射特征峰。
在另一优选例中，所述多晶型物II的差示扫描量热法图谱在140.87℃±2℃(或±1℃，或±0.5℃)、182.2℃±2℃(或±1℃，或±0.5℃)和234.34℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物II具有基本如图2b所示的差示扫描量热法图谱(DSC)。
在另一优选例中，所述多晶型物II中，式I化合物、盐酸和水的摩尔比约为1：2：1。
在另一优选例中，所述多晶型物II为式I化合物二盐酸盐的一水合物。
在另一优选例中，所述多晶型物为式I所示化合物盐酸盐的多晶型物III，其中，所述多晶型物III具有3个或3个以上选自下组的X-射线粉末衍射特征峰：15.217±0.2°，18.847±0.2°，20.724±0.2°，26.372±0.2°和28.107±0.2°。
在另一优选例中，所述多晶型物III还具有1个或多个选自下组的X-射线粉末衍射特征峰：4.404±0.2°，13.362±0.2°，16.225±0.2°，16.976±0.2°，20.055±0.2°，22.956±0.2°，25.996±0.2°和31.783±0.2°。
在另一优选例中，所述多晶型物III具有基本如图3a所示的X-射线粉末衍射谱图。
在另一优选例中，所述多晶型物III的差示扫描量热法图谱在231.1℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物III具有基本如图3b所示的差示扫描量热法图谱(DSC)。
在另一优选例中，所述多晶型物III中，式I化合物和盐酸的摩尔比约为1：1。
在另一优选例中，所述多晶型物为式I所示化合物盐酸盐的多晶型物IV，其中，所述多晶型物IV具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.422±0.2°，12.474±0.2°，14.429±0.2°，17.627±0.2°，19.501±0.2°，23.213±0.2°，23.803±0.2°和24.794±0.2°。
在另一优选例中，所述多晶型物IV还具有1个或多个选自下组的X-射线粉末衍射特征峰：12.949±0.2°，13.778±0.2°，16.600±0.2°，17.018±0.2°，20.625±0.2°，21.003±0.2°，21.891±0.2°，24.377±0.2°，28.718±0.2°，29.550±0.2°和31.739±0.2°。
在另一优选例中，所述多晶型物IV具有基本如图4a所示的X-射线粉末衍射谱图。
在另一优选例中，所述多晶型物IV的差示扫描量热法图谱在245.24℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物IV具有基本如图4b所示的差示扫描量热法图谱(DSC)。
在另一优选例中，所述多晶型物IV中，式I化合物和盐酸的摩尔比约为1：1。
在另一优选例中，所述多晶型物为式I所示化合物的多晶型物V，其中，所述多晶型物V具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.342±0.2°，12.753±0.2°，18.161±0.2°和23.193±0.2°。
在另一优选例中，所述多晶型物V还具有1个或多个选自下组的X-射线粉末衍射特征峰：5.981±0.2°，9.495±0.2°，14.014±0.2°，19.680±0.2°，21.280±0.2°，24.319±0.2°，25.326±0.2°和30.143±0.2°。
在另一优选例中，所述多晶型物V具有基本如图5a所示的X-射线粉末衍射谱图。
在另一优选例中，所述多晶型物V的差示扫描量热法图谱在256.79℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物V具有基本如图5b所示的差示扫描量热法图谱(DSC)。
本发明第二方面提供了一种本发明第一方面所述的多晶型物的用途，用于制备非受体酪氨酸激酶(如JAK激酶)的药物组合物。
在另一优选例中，所述的药物组合物用于治疗和预防癌症、骨髓增殖性和炎症疾病。
本发明第三方面提供了一种药物组合物，包含：
(a)本发明第一方面所述的多晶型物；和
(b)药学上可接受的载体。
本发明第四方面提供了一种本发明第一方面所述的多晶型物的制备方法，包括步骤：将式I所示化合物和酸在惰性溶剂中成盐结晶，或将式I所示化合物或其药学上可接受的盐、或其溶剂合物在惰性溶剂中重结晶，从而得到本发明第一方面所述的多晶型物。
在另一优选例中，所述重结晶在添加晶种或不添加晶种的条件下进行。
在另一优选例中，所述的酸为盐酸。
在另一优选例中，所述多晶型物I的制法，包括步骤：将式I化合物和盐酸在惰性溶剂中成盐结晶，从而得到本发明所述的多晶型物I。
在另一优选例中，所述惰性溶剂选自下组：乙醇、甲醇、异丙醇、醋酸、甲 酸或其组合。
在另一优选例中，所述多晶型物I的制法，包括步骤：将式I化合物和盐酸在乙醇和/或甲醇中成盐结晶，从而得到本发明所述的多晶型物I。
在另一优选例中，所述多晶型物I的制法，包括步骤：将式I化合物和盐酸在醋酸和乙醇混合溶剂中成盐结晶，从而得到本发明所述的多晶型物I。
在另一优选例中，所述式I化合物与盐酸的摩尔比约为1:2－1:5。
在另一优选例中，所述乙醇和甲醇的体积比为1:50－50:1。
在另一优选例中，所述醋酸和乙醇的体积比为1:5－5:1，较佳地，1:2－2:1。
在另一优选例中，所述多晶型物II的制法，包括步骤：将式I化合物在和盐酸在二甲亚砜和乙醇混合溶剂、或二甲亚砜和丙酮混合溶剂中成盐结晶，从而得到本发明所述多晶型物II。
在另一优选例中，所述二甲亚砜和乙醇的体积比为1:5－5:1；所述二甲亚枫和丙酮的体积比为1:5－5:1。
在另一优选例中，所述多晶型物II的制法，包括步骤：将制得的多晶型物I放置于高湿度(如湿度90％)环境中一段时间，从而得到本发明所述多晶型物II。
在另一优选例中，所述多晶型物II的制法，包括步骤：将制得的多晶型物I在丙酮和水的混合溶剂中结晶，从而得到本发明所述多晶型物II。
在另一优选例中，所述丙酮和水的重量比为8:1－50:1，较佳地，10:1－30:1，更佳地，12:1-18:1。
在另一优选例中，所述多晶型物II的制法，包括步骤：
(i)将制得的多晶型物I悬浮在甲醇中，形成混合物A1；和
(ii)向所述混合物A1中，加入盐酸，进行析晶，从而得到所述的多晶型物II。
在另一优选例中，步骤(i)中，所述盐酸的浓度为0.5-3M，较佳地0.7-2M，更佳地0.8-1.2M。
在另一优选例中，所述析晶在搅拌条件下进行。
在另一优选例中，所述搅拌条件的时间为4-48h，较佳地，6-30h，更佳地，10-24h。
在另一优选例中，步骤(ii)中，所述多晶型物I与盐酸的摩尔比约为10:1-1:1，较佳地8:1-2:1，更佳地6:1-3:1。
在另一优选例中，所述甲醇包括无水甲醇。
在另一优选例中，所述多晶型物III的制法，包括步骤：将式I化合物和盐酸在N-甲基吡咯烷酮和乙醇混合溶剂中成盐结晶，从而得到本发明所述多晶型物III。
在另一优选例中，所述N-甲基吡咯烷酮和乙醇的体积比为3:1-1:3，较佳地，2:1-1:2，更佳地，1:1。
在另一优选例中，所述多晶型物III的制法，包括步骤：将制得的多晶型物II在甲醇中结晶，从而得到本发明所述多晶型物III。
在另一优选例中，所述多晶型物III的制法，包括步骤：将式I化合物、盐酸和甲醇形成的混合物进行搅拌、析晶，从而得到所述多晶型物III。
在另一优选例中，所述盐酸的浓度为6M至饱和浓度的浓盐酸，较佳地为8-12M。
在另一优选例中，所述式I化合物与盐酸的摩尔比约为1：0.9－1：1.2。
在另一优选例中，所述多晶型物IV的制法，包括步骤：将制得的多晶型物I 在水或盐酸水溶液中重结晶，从而得到本发明所述多晶型物IV。
在另一优选例中，所述多晶型物IV的制法，包括步骤：将制得的多晶型物II悬浮在甲醇和水的混合溶剂中搅拌，从而得到所述多晶型物IV。
在另一优选例中，所述甲醇和水的体积比为5：1－1：10。
在另一优选例中，所述多晶型物V的制法，包括步骤：将式I化合物在醋酸和水混合溶剂或二甲亚砜和水的混合溶剂中重结晶，从而得到本发明所述多晶型物V。
在另一优选例中，所述醋酸与水的体积比为1:3－3:1；所述二甲亚枫与水的体积比为1:3－3:1。
本发明第五方面提供了一种多晶型物II的制备方法，包括步骤：
(i)将式I化合物悬浮在甲醇中，形成混合物A2，
(ii)向所述混合物A2中，加入盐酸，搅拌溶清后，立即加入晶种和水，从而形成所述的多晶型物II。
在另一优选例中，所述步骤(ii)中，盐酸的浓度为6M至饱和浓度的浓盐酸，较佳地为8-12M。
在另一优选例中，所述式I化合物与盐酸的摩尔比为1:1.8-1:3，较佳地1:1.9-1:2.5，较佳地，1:2.0-1:2.4。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图说明
图1a显示了多晶型物I的X-射线粉末衍射图。
图1b显示了多晶型物I的差示扫描量热法图。
图1c显示了多晶型物I的1HNMR图。
图2a显示了多晶型物II的X-射线粉末衍射图。
图2b显示了多晶型物II的差示扫描量热法图。
图2c显示了多晶型物II的1H NMR图。
图3a显示了多晶型物III的X-射线粉末衍射图。
图3b显示了多晶型物III的差示扫描量热法图。
图3c显示了多晶型物III的1HNMR图。
图4a显示了多晶型物IV的X-射线粉末衍射图。
图4b显示了多晶型物IV的差示扫描量热法图。
图4c显示了多晶型物IV的1HNMR图。
图5a显示了多晶型物V的X-射线粉末衍射图。
图5b显示了多晶型物V的差示扫描量热法图。
图5c显示了多晶型物V的1HNMR图。
其中，在上述各图中，onset表示初始(初始值)，peak表示峰(峰值)。
具体实施方式
本发明人通过长期而深入的研究，意外地发现了式I化合物或其药学上可接受的盐，或其溶剂合物的多种多晶型物，所述多晶型物具有更佳的药物生物利用度，且所述多晶型物纯度高，且非常稳定，适合用于制备抑制非受体酪氨酸激酶(如JAK激酶)的药物组合物，从而更有利于治疗癌症、骨髓增殖性和炎症等疾病。此外，本发明的多晶型物在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，且有助于保护操作人员的身体健康。在此基础上，发明人完成了本发明。
如本文所用，“式I化合物”是指结构式如式I所示的N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺。
如本文所用，“惰性溶剂”是指甲醇、乙醇、异丙醇、二甲亚砜、N-甲基吡咯烷酮、N、N-二甲基甲酰胺、丙酮、乙腈、醋酸、甲酸、正己烷、正庚烷、甲苯、四氢呋喃、乙酸乙酯、1，4-二氧六环、甲基叔丁基醚、水或上述溶剂的混合物。
N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐
本发明所述的N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐包括式I化合物的各种盐酸盐形式。
优选地，N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐，是指式I化合物与盐酸摩尔比为1：2的盐；或
N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物，是指式I化合物与盐酸、水的摩尔比为1：2：1的盐。
N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺单盐酸盐，是指式I化合物与盐酸摩尔比为1：1的盐。
多晶型物
固体不是以无定形的形式就是以结晶的形式存在。在结晶形式的情况下，分子定位于三维晶格格位内。当化合物从溶液或浆液中结晶出来时，它可以不同的空间点阵排列结晶(这种性质被称作“多晶型现象”)，形成具有不同的结晶形式的晶体，这各种结晶形式被称作“多晶型物”。给定物质的不同多晶型物可在一个或多个物理属性方面(如溶解度和溶解速率、真比重、晶形、堆积方式、流动性和/或固态稳定性)彼此不同。
结晶
可以通过操作溶液，使得感兴趣化合物的溶解度极限被超过，从而完成生产规模的结晶。这可以通过多种方法来完成，例如，在相对高的温度下溶解化 合物，然后冷却溶液至饱和极限以下。或者通过沸腾、常压蒸发、真空干燥或通过其它的一些方法来减小液体体积。可通过加入抗溶剂或化合物在其中具有低的溶解度的溶剂或这样的溶剂的混合物，来降低感兴趣化合物的溶解度。另一种可选方法是调节pH值以降低溶解度。有关结晶方面的详细描述请参见Crystallization,第三版,J W Mullens,Butterworth-Heineman Ltd.，1993,ISBN0750611294。
假如期望盐的形成与结晶同时发生，如果盐在反应介质中比原料溶解度小，那么加入适当的酸或碱可导致所需盐的直接结晶。同样，在最终想要的形式比反应物溶解度小的介质中，合成反应的完成可使最终产物直接结晶。
结晶的优化可包括用所需形式的晶体作为晶种接种于结晶介质中。另外，许多结晶方法使用上述策略的组合。一个实施例是在高温下将感兴趣的化合物溶解在溶剂中，随后通过受控方式加入适当体积的抗溶剂，以使体系正好在饱和水平之下。此时，可加入所需形式的晶种(并保持晶种的完整性)，将体系冷却以完成结晶。
如本文所用，术语“室温”一般指4-30℃，较佳地指20±5℃。
本发明的多晶型物
如本文所用，术语“本发明的多晶型物”包括式I化合物或其药学上可接受的盐(如盐酸盐)，或其各种溶剂合物的多晶型物，还包括相同的盐酸盐或溶剂合物的不同多晶型物。
优选的本发明多晶型物包括(但并不限于)：
式I化合物的二盐酸盐的多晶型物I；
式I化合物的二盐酸盐一水合物的多晶型物II；
式I化合物的单盐酸酸盐的多晶型物III和IV；
式I化合物的多晶型物V；
其中，所述多晶型物I中，式I化合物和盐酸的摩尔比为1：2；所述多晶型物II中，式I化合物、盐酸和水的摩尔比为1：2：1；所述多晶型物III和IV中，式I化合物和盐酸的摩尔比为1：1。
多晶型物的鉴定和性质
本发明在制备式I化合物的多晶型物后，采用如下多种方式和仪器对其性质进行了研究。
X射线粉末衍射
测定晶型的X射线粉末衍射的方法在本领域中是已知的。例如使用Rigaku D/max 2550VB/PC型号的X射线粉末衍射仪，以2°每分钟的扫描速度，采用铜辐射靶获取图谱。
本发明的式I化合物的多晶型物，具有特定的晶型形态，在X-射线粉末衍射(XRPD)图中具有特定的特征峰。优选如下：
(1)多晶型物I
所述多晶型物I具有3个或3个以上选自下组的X-射线粉末衍射特征峰：5.427±0.2°，9.968±0.2°，13.437±0.2°，14.726±0.2°，23.921±0.2°，25.068±0.2°，26.470±0.2°和29.452±0.2°。在另一优选例中，所述多晶型物I具有选自下组的X- 射线粉末衍射特征峰：8.824±0.2°，15.574±0.2°，17.173±0.2°，19.247±0.2°，20.784±0.2°，27.063±0.2°和30.220±0.2°。在另一优选例中，所述多晶型物I具有基本如图1a所示的X-射线粉末衍射谱图。
(2)多晶型物II
所述多晶型物II具有3个或3个以上选自下组的X-射线粉末衍射特征峰：17.310±0.2°，18.553±0.2°，19.227±0.2°，22.643±0.2°，23.964±0.2°和29.511±0.2°。在另一优选例中，所述多晶型物II具有选自下组的X-射线粉末衍射特征峰：15.278±0.2°，16.699±0.2°，24.617±0.2°，25.600±0.2°，27.119±0.2°和30.282±0.2°。在另一优选例中，所述多晶型物II具有基本如图2a所示的X-射线粉末衍射谱图。
(3)多晶型物III
所述多晶型物III具有3个或3个以上选自下组的X-射线粉末衍射特征峰：15.217±0.2°，18.847±0.2°，20.724±0.2°，26.372±0.2°和28.107±0.2°。在另一优选例中，所述多晶型物III还具有1个或多个选自下组的X-射线粉末衍射特征峰：4.404±0.2°，13.362±0.2°，16.225±0.2°，16.976±0.2°，20.055±0.2°，22.956±0.2°，25.996±0.2°和31.783±0.2°。在另一优选例中，所述多晶型物III具有基本如图3a所示的X-射线粉末衍射谱图。
(4)多晶型物IV
所述多晶型物IV具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.422±0.2°，12.474±0.2°，14.429±0.2°，17.627±0.2°，19.501±0.2°，23.213±0.2°，23.803±0.2°和24.794±0.2°。在另一优选例中，所述多晶型物IV还具有1个或多个选自下组的X-射线粉末衍射特征峰：12.949±0.2°，13.778±0.2°，16.600±0.2°，17.018±0.2°，20.625±0.2°，21.003±0.2°，21.891±0.2°，24.377±0.2°，28.718±0.2°，29.550±0.2°和31.739±0.2°。在另一优选例中，所述多晶型物IV具有基本如图4a所示的X-射线粉末衍射谱图。
(5)多晶型物V
所述多晶型物V具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.342±0.2°，12.753±0.2°，18.161±0.2°和23.193±0.2°。在另一优选例中，所述多晶型物V还具有1个或多个选自下组的X-射线粉末衍射特征峰：5.981±0.2°，9.495±0.2°，14.014±0.2°，19.680±0.2°，21.280±0.2°，24.319±0.2°，25.326±0.2°和30.143±0.2°。在另一优选例中，所述多晶型物V具有基本如图5a所示的X-射线粉末衍射谱图。
示差扫描量热分析
又称“差示量热扫描分析”(DSC)，是在加热过程中，测量被测物质与参比物之间的能量差与温度之间关系的一种技术。DSC图谱上的峰位置、形状和峰数目与物质的性质有关，故可以定性地用来鉴定物质。本领域常用该方法来检测物质的相变温度、玻璃化转变温度、反应热等多种参数。
DSC测定方法在本领域中是已知的。例如可使用NETZSCH DSC 204F1差示扫描量热计，以10℃每分钟的升温速率，从25℃升温至300℃，获得晶型的DSC扫描图谱。
本发明的式I化合物的多晶型物，在差示量热扫描分析(DSC)图中具有特定的特征峰。
(1)多晶型物I
所述多晶型物I的差示扫描量热法图谱在219.7℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物I具有基本如图1b所示的差示扫描量热法图谱(DSC)。
(2)多晶型物II
所述多晶型物II的差示扫描量热法图谱在在140.87℃±2℃(或±1℃，或±0.5℃)、182.2℃±2℃(或±1℃，或±0.5℃)和234.34℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物II具有基本如图2b所示的差示扫描量热法图谱(DSC)。
(3)多晶型物III
所述多晶型物III的差示扫描量热法图谱在231.1℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物III具有基本如图3b所示的差示扫描量热法图谱。
(4)多晶型物IV
所述多晶型物IV的差示扫描量热法图谱在245.24℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物IV具有基本如图4b所示的差示扫描量热法图谱。
(5)多晶型物V
所述多晶型物V的差示扫描量热法图谱在256.79℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物V具有基本如图5b所示的差示扫描量热法图谱。
也可采用核磁共振(NMR)来辅助确定晶型结构，其测定方法在本领域中是已知的。本发明优选地采用Bruker Avance III plus-400MHz。
活性成分
如本文所用，术语“活性成分”或“活性化合物”指本发明的多晶型物，即式I化合物或其药学上可接受的盐(如其盐酸盐)，或其溶剂合物的多晶型物。
药物组合物和施用方法
由于本发明的多晶型物具有优异的对非受体酪氨酸激酶例如JAK激酶的抑制活性，因此本发明的多晶型物以及含有本发明的多晶型物为主要活性成分的药物组合物可用于治疗、预防以及缓解由对非受体酪氨酸激酶例如JAK激酶介导的疾病。根据现有技术，本发明所述的多晶型物可用于治疗以下疾病：癌症，骨髓增殖性和炎症等等。
本发明的药物组合物包含安全有效量范围内的本发明的多晶型物及药学上可以接受的赋形剂或载体。
其中，“安全有效量”指的是：化合物(或多晶型物)的量足以明显改善病情，而不至于产生严重的副作用。通常，药物组合物含有1-2000mg本发明的多晶型物/剂，更佳地，含有10-200mg本发明的多晶型物/剂。较佳地，所述的“一剂”为一个胶囊或药片。
“药学上可以接受的载体”指的是：一种或多种相容性固体或液体填料或凝胶物质，它们适合于人使用，而且必须有足够的纯度和足够低的毒性。“相容性”在此指的是组合物中各组份能和本发明的活性成分以及它们之间相互掺和，而不明显降低活性成分的药效。药学上可以接受的载体部分例子有纤维素及其衍生物(如羧甲基纤维素钠、乙基纤维素钠、纤维素乙酸酯等)、明胶、滑石、固体润滑剂(如硬脂酸、硬脂酸镁)、硫酸钙、植物油(如豆油、芝麻油、花生油、橄榄油等)、多元醇(如丙二醇、甘油、甘露醇、山梨醇等)、乳化剂
Figure PCTCN2016087093-appb-000004
润湿剂(如十二烷基硫酸钠)、着色剂、调味剂、稳定剂、抗氧化剂、防腐剂、无热原水等。
本发明的多晶型物或药物组合物的施用方式没有特别限制，代表性的施用方式包括(但并不限于)：口服、瘤内、直肠、肠胃外(静脉内、肌肉内或皮下)、和局部给药。
用于口服给药的固体剂型包括胶囊剂、片剂、丸剂、散剂和颗粒剂。在这些固体剂型中，活性成分与至少一种常规惰性赋形剂(或载体)混合，如柠檬酸钠或磷酸二钙，或与下述成分混合：(a)填料或增容剂，例如，微晶纤维素、淀粉、乳糖、蔗糖、葡萄糖、甘露醇和硅酸；(b)粘合剂，例如，羟甲基纤维素、藻酸盐、明胶、聚乙烯基吡咯烷酮、蔗糖和阿拉伯胶；(c)保湿剂，例如，甘油；(d)崩解剂，例如，琼脂、碳酸钙、马铃薯淀粉或木薯淀粉、藻酸、某些复合硅酸盐、碳酸钠、交联聚维酮、交联羧甲基纤维素钠；(e)缓溶剂，例如石蜡；(f)吸收加速剂，例如，季胺化合物；(g)润湿剂，例如鲸蜡醇和单硬脂酸甘油酯；(h)吸附剂，例如，高岭土；和(i)润滑剂，例如，滑石、硬脂酸钙、硬脂酸镁、固体聚乙二醇、十二烷基硫酸钠，或其混合物。胶囊剂、片剂和丸剂中，剂型也可包含缓冲剂。
固体剂型如片剂、糖丸、胶囊剂、丸剂和颗粒剂可采用包衣和壳材制备，如肠衣和其它本领域公知的材料。它们可包含不透明剂，并且，这种组合物中活性成分的释放可以延迟的方式在消化道内的某一部分中释放。可采用的包埋组分的实例是聚合物质和蜡类物质。必要时，活性成分也可与上述赋形剂中的一种或多种形成微胶囊形式。
用于口服给药的液体剂型包括药学上可接受的乳液、溶液、悬浮液、糖浆或酊剂。除了活性成分外，液体剂型可包含本领域中常规采用的惰性稀释剂，如水或其它溶剂，增溶剂和乳化剂，例知，乙醇、异丙醇、碳酸乙酯、乙酸乙酯、丙二醇、1,3-丁二醇、二甲基甲酰胺以及油，特别是棉籽油、花生油、玉米胚油、橄榄油、蓖麻油和芝麻油或这些物质的混合物等。
除了这些惰性稀释剂外，组合物也可包含助剂，如润湿剂、乳化剂和悬浮剂、甜味剂、矫味剂和香料。
除了活性成分外，悬浮液可包含悬浮剂，例如，乙氧基化异十八烷醇、聚氧乙烯山梨醇和脱水山梨醇酯、微晶纤维素、甲醇铝和琼脂或这些物质的混合物等。
用于肠胃外注射的组合物可包含生理上可接受的无菌含水或无水溶液、分散液、悬浮液或乳液，和用于重新溶解成无菌的可注射溶液或分散液的无菌粉末。适宜的含水和非水载体、稀释剂、溶剂或赋形剂包括水、乙醇、多元醇及其适宜的混合物。
用于局部给药的本发明的多晶型物的剂型包括软膏剂、散剂、贴剂、喷射剂和吸入剂。活性成分在无菌条件下与生理上可接受的载体及任何防腐剂、缓冲剂，或必要时可能需要的推进剂一起混合。
本发明的多晶型物可以单独给药，或者与其他药学上可接受的化合物联合给药。
使用药物组合物时，是将安全有效量的本发明的多晶型物适用于需要治疗的哺乳动物(如人)，其中施用时剂量为药学上认为的有效给药剂量，对于60kg体重的人而言，日给药剂量通常为1～2000mg，优选10～500mg。当然，具体剂量还应考虑给药途径、病人健康状况等因素，这些都是熟练医师技能范围之内的。
本发明的主要优点包括：
1.提供了一系列新颖的N-(氰基甲基)-4-(2-(4-(吗啡啉苯基氨基)嘧啶-4-基)苯甲酰胺或其药学上可接受的盐，或其溶剂合物的多晶型物。本发明所述多晶型物包括多晶型物I～V。
2.还提供了多种多晶型物的用途，可用于制备抑制非受体酪氨酸激酶(如JAK激酶)的药物组合物，从而用于治疗癌症、骨髓增殖性和炎症等疾病。
下面结合具体实施，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。除非另外指明，所有包括数量、百分比、分数和比例的量被理解为由词“约”所修饰，并且量并不旨在表示有效数字。
实施例1制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I
取1.0g N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入40ml无水甲醇，室温搅拌，室温下，滴入新制备的盐酸乙醇溶液4.8ml(氯化氢浓度为40mg/ml)，滴完后，过滤，滤液在室温继续搅拌2h，析出固体，过滤，无水甲醇淋洗，固体55±5℃高真空干燥6h，得黄色固体。
取样经1H NMR、X-射线粉末衍射、DSC等检测证明为标题晶型化合物，称重870mg,收率：74％。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.56(t,J＝4.0Hz,1H),8.65(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.09(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,2H),7.81(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),4.36(d,J＝4.0Hz,2H),4.10(s,4H),3.57(s,4H)。
元素分析：C：56.33％，H：5.33％，N：17.05％。
其X-射线粉末衍射图见图1a，各个峰的参数如表1所示，差示扫描量热法 图(DSC)见图1b，1H NMR的图谱见1c。
表1
峰号 2θ(°) 峰高 相对强度(I％) 峰号 2θ(°) 峰高 相对强度(I％)
1 5.427 1232 36.7 19 25.068 3354 100.0
2 7.601 394 11.7 20 26.470 1964 58.6
3 8.824 587 17.5 21 27.063 1182 35.2
4 9.968 1914 57.1 22 28.129 737 22.0
5 12.757 463 13.8 23 28.938 565 16.8
6 13.437 985 29.4 24 29.452 1250 37.3
7 14.726 1604 47.8 25 30.220 1099 32.8
8 15.574 944 28.1 26 31.105 463 13.8
9 16.364 790 23.6 27 32.073 423 12.6
10 17.173 1036 30.9 28 32.572 422 12.6
11 17.943 862 25.7 29 34.171 448 13.4
12 18.569 537 16.0 30 36.258 375 11.2
13 19.247 1068 31.8 31 37.680 353 10.5
14 19.945 368 11.0 32 39.027 396 11.8
15 20.784 734 21.9 33 39.578 377 11.2
16 22.309 511 15.2 34 40.796 369 11.0
17 22.916 732 21.8 35 41.769 353 10.5
18 23.921 1635 48.7        
实施例2制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入10ml无水甲醇，室温搅拌，室温滴入新制备的盐酸甲醇溶液2.6ml(氯化氢浓度为40mg/ml)，滴完后，加入多晶型物I晶种，搅拌过夜，过滤，无水甲醇洗涤，固体55±5℃高真空干燥6h，得黄色固体即为标题晶型化合物，称重488mg,收率：83％。其X-射线粉末衍射图与图1a相同。
实施例3制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I
取1.0g N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入10ml无水乙醇，室温搅拌，室温滴入新制备的盐酸乙醇溶液4.8ml(氯化氢浓度为40mg/ml)，滴完后，继续搅拌2h，过滤，无水乙醇洗涤，固体55±5℃高真空干燥6h，得黄色固体即为标题晶型化合物，称重1.11g,收率：94％。其X-射线粉末衍射图与图1a相同。
实施例4制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入2.0ml冰醋酸，室温搅拌至溶清，室温滴入新制备的盐酸乙醇溶液2.6ml(氯化氢浓度为40mg/ml)，滴完后继续搅拌2h，固体析出，过滤，无水乙醇洗涤，固体55±5℃高真空干燥6h，得黄色固体即为标题晶型化合物，称重543mg,收 率：92％。其X-射线粉末衍射图与图1a相同。
实施例5制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
取500mg N-(氰基甲基))-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入N-甲基吡咯烷酮1.0ml，室温搅拌至溶清，室温下滴入新制备的盐酸乙醇溶液2.6ml(氯化氢浓度为40mg/ml)，滴完后室温下继续搅拌2h，过滤，无水乙醇快速淋洗，55±5℃高真空干燥6h，得黄色固体。
取样经1H NMR、X-射线粉末衍射、DSC等检测证明为标题晶型化合物，称重579mg,收率：95％。
1H NMR(400MHz,DMSO-d6)δ10.13(s,1H),9.57(t,J＝8.0Hz,1H),8.65(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.09(d,J＝8.0Hz,2H),7.98(d,J＝8.0Hz,2H),7.82(d,J＝8.0Hz,2H),7.58(d,J＝8.0Hz,1H),6.78(brs,2H)，4.36(d,J＝8.0Hz,2H),4.11(s,4H),3.58(s,4H)。
元素分析：C：55.06％，H：5.52％，N：16.34％；
其X-射线粉末衍射图见图2a，各个峰的参数如表2所示，差示扫描量热法图(DSC)见图2b，1H NMR的图谱见2c。
表2
Figure PCTCN2016087093-appb-000005
实施例6制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
向四口烧瓶中加入化合物N-(氰基甲基))-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(87.0g,0.21mol)、二甲亚砜(260ml)，室温搅拌至溶清，室温下向其缓慢滴入新制备的盐酸乙醇溶液400ml(氯化氢浓度为40mg/ml)，约30min滴完，滴完后继续搅拌3h，过滤，滤饼用无水乙醇快速淋洗，55±5℃高真空干 燥6h，得黄色固体即为标题晶型化合物，称重86.1g,收率：81％。其X-射线粉末衍射图与图2a相同。
实施例7制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
向四口烧瓶中加入N-(氰基甲基))-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(4.0g,9.6mmol)、二甲亚砜(14.0ml)，室温搅拌至溶清，向其一次性加入1.7ml 37％浓盐酸，搅拌均匀后再加入丙酮(16ml)，混合液澄清，室温下继续搅拌3h，过滤，滤饼用丙酮洗涤，45±5℃高真空干燥3h，得黄色固体即为标题晶型化合物，称重3.3g，收率：68％。其X-射线粉末衍射图与图2a相同。
实施例8制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
向四口烧瓶中加入N-(氰基甲基))-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(1.0g)、二甲亚砜(2.5ml)，室温搅拌至溶清，室温下向其缓慢滴入新制备的盐酸甲醇溶液5ml(氯化氢浓度为40mg/ml)，滴完后继续搅拌3h，过滤，滤饼用无水甲醇快速淋洗，55±5℃高真空干燥6h，得黄色固体即为标题晶型化合物，称重0.91g,收率：75％。其X-射线粉末衍射图与图2a相同。
实施例9制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
取230.0g N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐(多晶型物I)样品，研钵研细后置于湿度大于90％环境中，密闭保存4天，得到黄色固体即为标题晶型化合物，称重237g，收率：99％。X-射线粉末衍射图基本与图2a相同。
实施例10制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐(多晶型物I)样品，加入丙酮3.16g，纯化水0.25g，室温下打浆搅拌16h，过滤，丙酮洗涤，40度真空干燥6h，得到固体即为标题晶型化合物，称重437mg，收率：84％。X-射线粉末衍射图基本与图2a相同。
实施例11制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐(多晶型物I)样品悬浮搅拌于3.0ml无水甲醇中，缓慢滴入0.25ml 1M稀盐酸溶液，室温搅拌过夜，过滤，无水甲醇洗涤，干燥，得到固体即为标题晶型化合物，称重422mg，收率：81％。X-射线粉末衍射图基本与图2a相同。
实施例12制备N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰 胺二盐酸盐一水合物的多晶型物II
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺样品悬浮搅拌于5.0ml无水甲醇中，加入略过2当量的浓盐酸，搅拌溶清后立即加入25mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物(多晶型物II)晶种，再加入50mg纯化水，室温搅拌过夜，过滤，无水甲醇洗涤，干燥，得到固体即为标题晶型化合物，称重389mg，收率：64％。X-射线粉末衍射图基本与图2a相同。
实施例13N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物III
取1.0g N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺悬浮于N-甲基吡咯烷酮和无水乙醇的混合液中(10ml,v：v＝1:1)，室温下滴入新制备的盐酸乙醇溶液2.6ml(氯化氢浓度为40mg/ml)，滴完后继续搅拌3h，过滤，无水乙醇洗涤，固体55±5℃高真空干燥6h，得灰白固体。
取样经1H NMR、X-射线粉末衍射、DSC等检测证明为标题晶型化合物，称重836mg,收率：77％。
1H NMR(400MHz,DMSO-d6)δ9.93(s,1H),9.45(t,J＝4.0Hz,1H),8.62(d,J＝8.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.06(d,J＝8.0Hz,2H),7.89(d,J＝8.0Hz,2H),7.54-7.53(m,3H),4.36(d,J＝8.0Hz,2H),3.98(s,4H),3.43(s,4H)。
元素分析：C:61.15％H:5.54％N:18.28％。
其X-射线粉末衍射图见图3a，各个峰的参数如表3所示，差示扫描量热法图(DSC)见图3b，1H NMR的图谱见3c。
表3
峰号 2θ(°) 峰高 相对强度(I％) 峰号 2θ(°) 峰高 相对强度(I％)
1 4.404 743 11.0 17 23.964 1222 18.0
2 9.238 742 11.0 18 25.342 1065 15.7
3 10.282 578 8.5 19 25.996 1696 25.0
4 12.546 730 10.8 20 26.372 2559 37.8
5 13.362 1384 20.4 21 27.084 1010 14.9
6 14.035 742 11.0 22 28.107 2131 31.5
7 15.217 4747 70.1 23 29.012 743 11.0
8 16.225 1831 27.0 24 30.241 872 12.9
9 16.976 1575 23.3 25 31.227 846 12.5
10 17.982 1018 15.0 26 31.783 958 14.1
11 18.847 1974 29.1 27 32.846 806 11.9
12 20.055 1845 27.2 28 34.660 607 9.0
13 20.724 6774 100.0 29 37.390 486 7.2
14 21.751 1092 16.1 30 38.136 473 7.0
15 22.188 1167 17.2 31 41.885 469 6.9
16 22.956 1961 28.9        
实施例14N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐 酸盐的多晶型物III
取150mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物(多晶型物II)悬浮于6ml无水甲醇中，室温搅拌24h，过滤，无水甲醇洗涤，固体55±5℃高真空干燥6h，得灰白固体即为标题晶型化合物，称重130mg,收率：97％。其X-射线粉末衍射图与图3a相同。
实施例15N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物III
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺悬浮于5ml无水甲醇中，加入1当量的浓盐酸，室温搅拌16h，过滤，无水甲醇洗涤，干燥，得到固体即为标题晶型化合物，称重408mg，收率：75％。其X-射线粉末衍射图与图3a相同。
实施例16(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺,滴入新制备的盐酸乙醇溶液2.3ml(氯化氢浓度为40mg/ml)，补加2ml纯化水，室温搅拌3h，过滤，四氢呋喃洗涤，高真空室温干燥3h，得白色固体，取样经1H NMR、X-射线粉末衍射、DSC等检测证明为标题晶型化合物，称重425mg，收率：78％。
1H NMR(400MHz,DMSO-d6)δ9.96(s,1H),9.47(t,J＝4.0Hz,1H),8.62(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.07(d,J＝8.0Hz,2H),7.90(d,J＝8.0Hz,2H),7.55-7.54(m,3H),4.37(d,J＝4.0Hz,2H),4.00(s,4H),3.45(s,4H)。
元素分析：C:61.33％，H:5.36％，N:18.54％。
其X-射线粉末衍射图见图4a，各个峰的参数如表4所示，差示扫描量热法图(DSC)见图4b，1H NMR的图谱见4c。
表4
峰号 2θ(°) 峰高 相对强度(I％) 峰号 2θ(°) 峰高 相对强度(I％)
1 4.422 1816 60.9 20 26.517 961 32.2
2 8.921 416 13.9 21 27.082 688 23.1
3 12.474 2117 71.0 22 27.596 789 26.4
4 12.949 793 26.6 23 28.130 681 22.8
5 13.778 650 21.8 24 28.718 790 26.5
6 14.429 2623 87.9 25 29.550 998 33.5
7 16.600 710 23.8 26 30.180 1045 35.0
8 17.018 973 32.6 27 30.768 658 22.1
9 17.627 2633 88.3 28 31.739 660 22.1
10 19.501 2983 100.0 29 33.458 1328 44.5
11 20.625 662 22.2 30 35.018 591 19.8
12 21.003 644 21.6 31 35.747 636 21.3
13 21.891 625 21.0 32 37.419 569 19.1
14 22.404 1214 40.7 33 39.102 409 13.7
15 23.213 2023 67.8 34 39.775 391 13.1
16 23.803 1852 62.1 35 40.208 488 16.4
17 24.377 804 27.0 36 41.174 462 15.5
18 24.794 1797 60.2 37 41.869 536 18.0
19 25.797 961 32.2 38 42.756 526 17.6
实施例17(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV
取300mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物(多晶型物II)样品，加入12.0ml纯化水，搅拌下样品溶清，室温搅拌3h，白色固体析出，过滤，四氢呋喃洗涤，室温干燥3h，得白色固体即为标题晶型化合物，称重185mg,收率：69％。其X-射线粉末衍射图与图4a相同。
实施例18氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV
取1.0g N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入5.0ml 1M盐酸，室温搅拌过夜，白色固体析出，过滤，四氢呋喃洗涤，室温高真空干燥3h，得白色固体即为标题晶型化合物，称重为785mg,收率：72％。其X-射线粉末衍射图与图4a相同。
实施例19(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV
取500mg N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物(多晶型物II)样品，在甲醇/水(3.5ml/1.5ml)混合液中悬浮搅拌16h，过滤，四干燥，得到固体即为标题晶型化合物，称重327mg，收率：73％。其X-射线粉末衍射图与图4a相同。
实施例20(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物V
向反应瓶中加入N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(80.0g)和醋酸(270mL)，搅拌溶解。将上述溶液缓慢滴加到纯水(540mL)中，室温搅拌4h后过滤，滤饼用纯水(0.2L x 3)淋洗，尽量抽干。固体70℃下高真空干燥6h，得黄色固体，取样经1H NMR、X-射线粉末衍射、DSC等检测证明，即为标题晶型化合物，称重58.0g，收率：72.5％。
1H NMR(400MHz,DMSO-d6)δ9.51(s,1H),9.36(t,J＝4.0Hz,1H),8.55(d,J＝4.0Hz,1H),8.28(d,J＝8.0Hz,2H),8.04(d,J＝8.0Hz,2H),7.68(d,J＝8.0Hz,2H),7.41(d,J＝8.0Hz,1H),6.94(d,J＝8.0Hz,2H),4.37(d,J＝8.0Hz,2H),3.75(t,J＝4.0Hz,4H),3.05(t,J＝4.0Hz,4H)。
元素分析：C:66.50％H:5.18％N:20.01％
其X-射线粉末衍射图见图5a，各个峰的参数如表5所示，差示扫描量热法图(DSC)见图5b，1H NMR的图谱见5c。
表5
峰号 2θ(°) 峰高 相对强度(I％) 峰号 2θ(°) 峰高 相对强度(I％)
1 4.342 5318 45.8 17 19.680 2987 25.7
2 5.981 2484 21.4 18 20.407 1063 9.2
3 6.373 649 5.6 19 21.280 1951 16.8
4 9.495 1991 17.1 20 21.729 1478 12.7
5 10.046 1072 9.2 21 23.193 5429 46.7
6 12.042 997 8.6 22 23.748 1496 12.9
7 12.753 11617 100.0 23 24.319 3051 26.3
8 13.462 1041 9.0 24 24.826 1626 14.0
9 14.014 2597 22.4 25 25.326 2885 24.8
10 14.309 1580 13.6 26 26.057 1868 16.1
11 15.476 604 5.2 27 27.387 922 7.9
12 16.362 1233 10.6 28 28.125 1306 11.2
13 17.705 1723 14.8 29 29.352 894 7.7
14 18.161 5373 46.3 30 30.143 1340 11.5
15 18.575 1462 12.6 31 38.238 501 4.3
16 19.285 1308 11.3        
实施例21N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物V
取N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐(23.0g)，加入二甲亚砜(105ml)，室温搅拌下溶清；搅拌下将上述混合液缓缓滴入饱和碳酸氢钠溶液(1.1L)中，固体析出，持续搅拌4h；过滤，固体用纯化水(100ml x 3)洗涤，65℃左右高真空干燥8h，得黄色固体18.8g，即为标题晶型化合物，收率：96％。其X-射线粉末衍射图与图5a相同。
实施例22N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I的稳定性
在经过6个月的加速试验(试验条件40±2℃、75％±5％RH)后，结果表明：多晶型物I的晶型十分稳定，且相比较新制备的(0月)多晶型物I而言，多晶型物I的纯度基本没有变化，始终在99％以上，未见明显降解杂质。
实施例23N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II的稳定性
在经过6个月的加速试验(试验条件40±2℃、75％±5％RH)后，结果表明：多晶型物II的晶型十分稳定，且相比较新制备的(0月)多晶型物II而言，多晶型物II的纯度基本没有变化，始终在99％以上，未见明显降解杂质。
实施例24N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物III的稳定性
在经过6个月的加速试验(试验条件40±2℃、75％±5％RH)后，结果表明：多晶型物III的晶型十分稳定，且相比较新制备的(0月)多晶型物III而言，多晶型物III的纯度基本没有变化，始终在99％以上，未见明显降解杂质。
实施例25(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV的稳定性
在经过6个月的加速试验(试验条件40±2℃、75％±5％RH)后，结果表明：多晶型物IV的晶型十分稳定，且相比较新制备的(0月)多晶型物IV而言，多晶型物IV的纯度基本没有变化，始终在99％以上，未见明显降解杂质。
实施例26(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物V的稳定性
在经过6个月的加速试验(试验条件40±2℃、75％±5％RH)后，结果表明：多晶型物V的晶型十分稳定，且相比较新制备的(0月)多晶型物V而言，多晶型物V的纯度基本没有变化，始终在99％以上，未见明显降解杂质。
实施例27药物组合物
N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物I(实施例1-4)      200g
淀粉               180g
微晶纤维素         40g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
实施例28药物组合物
N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物的多晶型物II(实施例5-12)   200g
淀粉               180g
微晶纤维素         40g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
实施例29药物组合物
N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物III(实施例13-15)       200g
淀粉               180g
微晶纤维素         40g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
实施例30药物组合物
N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺盐酸盐的多晶型物IV(实施例16-19)       200g
淀粉               180g
微晶纤维素         40g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
实施例31药物组合物
N-(氰基甲基)-4-(2-(4-(吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物V(实施例20-21)         200g
淀粉               180g
微晶纤维素         40g
按常规方法，将上述物质混合均匀后，装入普通明胶胶囊，得到1000颗胶囊。
实施例32多晶型物引湿性实验
按照药物引湿性试验指导原则(中国药典2010年版二部附录XIX J)进行。
1.取4只干燥的带盖的玻璃称量瓶(外径为60mm，高为30mm)，于试验前一天置于25℃±1℃的恒温恒湿箱内的下部放置硫酸铵饱和溶液的玻璃干燥器(“恒温恒湿干燥器”)中。
2.各空的称量瓶连同盖在“恒温恒湿干燥器”内放置24小时后，以套(称量瓶+盖)为单位精密稳定各自重量，计为m1。
3.取多晶型物II样品适量，平铺置于已称重的玻璃称量瓶内(样品厚度约1mm)，盖好盖，精密称定此时各称量瓶(称量瓶+盖+样品)重量，计为m2。
3.各样品在“恒温恒湿干燥器”内放置24小时后精密称定此时的各称量瓶的(称量瓶+盖+样品)重量，计为m3。
4.计算各样品的引湿增重百分率(计算公式如下)，当引湿增重百分率小于0.2％，界定为无或几乎无引湿性。引湿增重百分率大于等于0.2％，但小于2.0％时，界定为略有引湿性。
增重百分率＝[(m3-m2)/(m2-m1)]×100％
按上述步骤，测定本发明所述多晶型物II的引湿性，结果表明：多晶型物II的增重百分率[(35.2607-35.2566)/(35.2566-34.1458)]×100％＝0.37％。可见，多晶型物II略有引湿性。
重复实施例32操作，不同的是采用本发明所述的多晶型物I、III～V代替多晶型物II，结果发现，本发明所述的多种多晶型物均非常稳定，基本上无引湿性，仅多晶型I略有引湿性。
因此，本发明所述的多晶型物非常适合用于药物组合物。而且本发明的多晶型物在分装等药品制造过程中，不易扬起，易收集，不易造成浪费，有助于保护操作人员的身体健康。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (12)

  1. 一种多晶型物，其特征在于，所述多晶型物为式I所示化合物或其药学上可接受的盐或其溶剂合物的多晶型物，
    Figure PCTCN2016087093-appb-100001
  2. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为式I所示化合物盐酸盐的多晶型物I，其中，所述多晶型物I具有3个或3个以上选自下组的X-射线粉末衍射特征峰：5.427±0.2°，9.968±0.2°，13.437±0.2°，14.726±0.2°，23.921±0.2°，25.068±0.2°，26.470±0.2°和29.452±0.2°。
  3. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为式I所示化合物盐酸盐溶剂合物的多晶型物II，其中，所述多晶型物II具有3个或3个以上选自下组的X-射线粉末衍射特征峰：17.310±0.2°，18.553±0.2°，19.227±0.2°，22.643±0.2°，23.964±0.2°和29.511±0.2°。
  4. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为式I所示化合物盐酸盐的多晶型物III，其中，所述多晶型物III具有3个或3个以上选自下组的X-射线粉末衍射特征峰：15.217±0.2°，18.847±0.2°，20.724±0.2°，26.372±0.2°和28.107±0.2°。
  5. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为式I所示化合物盐酸盐的多晶型物IV，其中，所述多晶型物IV具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.422±0.2°，12.474±0.2°，14.429±0.2°，17.627±0.2°，19.501±0.2°，23.213±0.2°，23.803±0.2°和24.794±0.2°。
  6. 如权利要求1所述的多晶型物，其特征在于，所述多晶型物为式I所示化合物的多晶型物V，其中，所述多晶型物V具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.342±0.2°，12.753±0.2°，18.161±0.2°和23.193±0.2°。
  7. 一种如权利要求1－6任一项所述的多晶型物的用途，其特征在于，用于制备非受体酪氨酸激酶(如JAK激酶)的药物组合物。
  8. 一种药物组合物，其特征在于，包含：
    (a)权利要求1－6任一项所述的多晶型物；和
    (b)药学上可接受的载体。
  9. 一种如权利要求1－6任一项所述的多晶型物的制备方法，其特征在于，包括步骤：将式I所示化合物和酸在惰性溶剂中成盐结晶，或将式I所示化合物或其药学上可接受的盐、或其溶剂合物在惰性溶剂中重结晶，从而得到权利要求1-6任一项所述的多晶型物。
  10. 一种多晶型物II的制备方法，其特征在于，包括步骤：
    (i)将式I化合物悬浮在甲醇中，形成混合物A2，
    Figure PCTCN2016087093-appb-100002
    (ii)向所述混合物A2中，加入盐酸，搅拌溶清后，立即加入晶种和水，从而形成所述的多晶型物II。
  11. 如权利要求10所述的方法，其特征在于，所述步骤(ii)中，所述盐酸的浓度为6M至饱和浓度的浓盐酸，较佳地为8-12M。
  12. 如权利要求10所述的方法，其特征在于，所述式I化合物与盐酸的摩尔比为1:1.8-1:3，较佳地1:1.9-1:2.5，较佳地，1:2.0-1:2.4。
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