WO2016206633A1 - 苯基氨基嘧啶化合物或其盐的多晶型物 - Google Patents

苯基氨基嘧啶化合物或其盐的多晶型物 Download PDF

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WO2016206633A1
WO2016206633A1 PCT/CN2016/087092 CN2016087092W WO2016206633A1 WO 2016206633 A1 WO2016206633 A1 WO 2016206633A1 CN 2016087092 W CN2016087092 W CN 2016087092W WO 2016206633 A1 WO2016206633 A1 WO 2016206633A1
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polymorph
compound
formula
powder diffraction
ray powder
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PCT/CN2016/087092
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English (en)
French (fr)
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吕彬华
李成伟
肖丹
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苏州泽璟生物制药有限公司
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Priority to CA2990747A priority Critical patent/CA2990747C/en
Priority to RU2018102761A priority patent/RU2712226C2/ru
Priority to EP22170063.6A priority patent/EP4056559A1/en
Priority to BR112017027841-3A priority patent/BR112017027841A2/zh
Priority to KR1020207010203A priority patent/KR20200039838A/ko
Priority to EP16813749.5A priority patent/EP3315493B1/en
Priority to CN201680037404.5A priority patent/CN107709304B/zh
Priority to KR1020187002393A priority patent/KR20180080711A/ko
Priority to US15/739,254 priority patent/US10377725B2/en
Priority to JP2017567076A priority patent/JP7139116B2/ja
Publication of WO2016206633A1 publication Critical patent/WO2016206633A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/28—1,4-Oxazines; Hydrogenated 1,4-oxazines
    • C07D265/30—1,4-Oxazines; Hydrogenated 1,4-oxazines not condensed with other rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • 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

Definitions

  • the present invention belongs to the field of medicine, and in particular to a polymorph of a phenylaminopyrimidine compound or a salt thereof, and more particularly to N-(cyanomethyl)-4-(2-(4-(2) A polymorph of ',2',6',6'-d 4 -morpholine)phenylamino)pyrimidin-4-yl)benzamide, or a pharmaceutically acceptable salt thereof.
  • N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 -morpholine)phenylamino)pyrimidin-4-yl)benzamide N-(cyanomethyl)-4-(2-((4-(2',2',6',6'-d 4 -morpholino)phenyl)amino)pyrimidin-4-yl)benzamide
  • structure as in Formula I Shown as follows:
  • the compound of formula I has the formula C 23 H 18 D 4 N 6 O 2 and has a molecular weight of 418.49.
  • the compound is a class of non-receptor tyrosine kinases such as inhibitors of JAK kinase, which are suitable for the preparation of a medicament for the treatment/prevention of cancer and bone marrow proliferation. Drugs for sexually transmitted 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: 5.426 ⁇ 0.2 °, 9.985 ⁇ 0.2 °, 13.424 ⁇ 0.2 °, 14.765 ⁇ 0.2 °, 25.148 ⁇ 0.2 ° and 26.566 ⁇ 0.2 °.
  • the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 8.827 ⁇ 0.2°, 15.537 ⁇ 0.2°, 17.193 ⁇ 0.2°, 19.268 ⁇ 0.2°, 20.862 ⁇ 0.2° and 30.282 ⁇ 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 233.19 °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 The X-ray powder diffraction characteristic peaks of the lower group: 17.249 ⁇ 0.2 °, 19.224 ⁇ 0.2 °, 23.885 ⁇ 0.2 ° and 29.488 ⁇ 0.2 °.
  • the polymorph II has an X-ray powder diffraction characteristic peak selected from the group consisting of 7.579 ⁇ 0.2°, 15.181 ⁇ 0.2°, 18.515 ⁇ 0.2°, 22.603 ⁇ 0.2°, 25.581 ⁇ 0.2° and 27.003 ⁇ 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 166.66 ° C ⁇ 2 ° C (or ⁇ 1 ° C, or ⁇ 0.5 ° C), 207.84 ° C ⁇ 2 ° C (or ⁇ 1 ° C , or ⁇ 0.5 ° C) and 240.84 ° 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: 15.178 ⁇ 0.2 °, 20.705 ⁇ 0.2 °, 26.390 ⁇ 0.2 ° and 28.088 ⁇ 0.2 °.
  • the polymorph III further has an X-ray powder diffraction characteristic peak selected from the group consisting of 13.305 ⁇ 0.2°, 16.204 ⁇ 0.2°, 16.953 ⁇ 0.2°, 18.809 ⁇ 0.2°, 20.073. ⁇ 0.2°, 22.937 ⁇ 0.2°, 25.958 ⁇ 0.2° and 31.837 ⁇ 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 249.49 °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: 12.493 ⁇ 0.2°, 14.447 ⁇ 0.2°, 17.627 ⁇ 0.2°, 19.519 ⁇ 0.2°, 23.231 ⁇ 0.2°, 23.805 ⁇ 0.2° and 24.831 ⁇ 0.2°.
  • the polymorph IV further has an X-ray powder diffraction characteristic peak selected from the group consisting of 4.422 ⁇ 0.2°, 12.986 ⁇ 0.2°, 17.074 ⁇ 0.2°, 22.344 ⁇ 0.2°, 24.396. ⁇ 0.2°, 25.778 ⁇ 0.2°, 28.166 ⁇ 0.2°, 28.738 ⁇ 0.2°, 29.607 ⁇ 0.2° and 31.741 ⁇ 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 242.73 °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: 13.621 ⁇ 0.2 °, 18.634 ⁇ 0.2 °, 20.331 ⁇ 0.2 °, 21.675 ⁇ 0.2 °, 22.621 ⁇ 0.2 ° and 28.048 ⁇ 0.2 °.
  • the polymorph V further has an X-ray powder diffraction characteristic peak selected from the group consisting of 7.263 ⁇ 0.2°, 17.647 ⁇ 0.2°, 21.179 ⁇ 0.2°, 23.509 ⁇ 0.2°, 24.852. ⁇ 0.2°, 25.148 ⁇ 0.2°, 27.179 ⁇ 0.2°, and 30.181 ⁇ 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 258.31 ° 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.
  • the polymorph is a polymorph VI of a compound of formula I, wherein the polymorph VI has 3 or more X-rays selected from the group consisting of Powder diffraction characteristic peaks: 4.084 ⁇ 0.2 °, 18.832 ⁇ 0.2 °, 19.542 ⁇ 0.2 °, 20.529 ⁇ 0.2 °, and 26.468 ⁇ 0.2 °.
  • the polymorph VI further has one or more X-ray powder diffraction characteristic peaks selected from the group consisting of 12.277 ⁇ 0.2°, 17.589 ⁇ 0.2°, 20.032 ⁇ 0.2°, 21.003. ⁇ 0.2°, 24.870 ⁇ 0.2° and 27.597 ⁇ 0.2°.
  • the polymorph VI has an X-ray powder diffraction pattern substantially as shown in Figure 6a.
  • the differential scanning calorimetry pattern of the polymorph VI has a maximum peak at 259.38 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph VI has a differential scanning calorimetry (DSC) substantially as shown in Figure 6b.
  • 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, formic acid, water, or a combination thereof.
  • the molar ratio of the compound of formula I to hydrochloric acid is from about 1:2 to 1:5.
  • 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 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: mixing a compound of the formula I with a mixture of hydrochloric acid in dimethyl sulfoxide and ethanol, a mixed solvent of dimethyl sulfoxide and methanol, or dimethyl
  • the salt is crystallized in a mixed solvent of sulfoxide and acetone to obtain the polymorph II of the present invention.
  • the volume ratio of the dimethyl sulfoxide to the ethanol is 1:5-5:1; the volume ratio of the dimethyl sulfoxide to the methanol is 1:5-5:1; The volume ratio of yam and acetone is 1:5-5:1.
  • the method for preparing the polymorph II comprises the steps of: suspending the obtained polymorph I in a mixed solvent of acetone and water to obtain a polymorph of the present invention. II.
  • the volume ratio of acetone to water is from 10:1 to 50:1, preferably 20:1.
  • 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 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 method of preparing the polymorph II comprises 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 formula I to hydrochloric acid is from about 1:1.8 to 1:3, preferably from 1:1.9 to 1:2.5, preferably from 1:2.0 to 1:2.4.
  • 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 1:1 to 1:10.
  • the process for preparing the polymorph III comprises the steps of: recrystallizing the obtained polymorph II in anhydrous methanol to obtain the polymorph III of the present invention.
  • the process for preparing the polymorph III comprises the steps of: stirring a mixture of a 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 methanol comprises anhydrous methanol.
  • the process for preparing the polymorph IV comprises the steps of recrystallizing the obtained polymorph I in water to obtain the polymorph IV of the present invention.
  • the process for the preparation of the polymorph IV comprises the steps of: salt-crystallizing a compound of the formula I in aqueous hydrochloric acid to obtain the polymorph IV of the 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 N, N-dimethylformamide (or DMSO) and water to obtain the present invention.
  • the polymorph V is invented.
  • the N, N-dimethylformamide or DMSO and water are present in a volume ratio of 1:2-1:10, preferably 1:3.
  • the method for preparing the polymorph VI comprises the steps of: stirring the prepared polymorph II in a pH 6.8 phosphate buffer to obtain the polymorph of the present invention.
  • a fifth aspect of the invention provides a method for preparing a polymorph II, comprising the steps of:
  • the molar ratio of the compound of formula I to hydrochloric acid in the first mixture is from about 1:1.8 to 1:3, preferably from 1:1.9 to 1:2.5, preferably, 1:2.0-1:2.4.
  • the acetone/water mixed solvent has a volume ratio of acetone to water of from 8:1 to 50:1, preferably from 10:1 to 30:1, more preferably 12:1. 25:1.
  • the first solvent is selected from the group consisting of dimethyl sulfoxide, N, N-dimethylformamide, N-methylpyrrolidone, acetic acid, or a combination thereof.
  • the method has one or more characteristics selected from the group consisting of:
  • the temperature is 4 to 35 ° C, preferably 5 to 30 ° C, more preferably 10 to 25 ° C;
  • the temperature is 4 to 35 ° C, preferably 5 to 30 ° C, more preferably 10 to 25 ° C;
  • the temperature is 4 to 35 ° C, preferably 5 to 30 ° C, more preferably 10 to 25 ° C;
  • step (2) hydrochloric acid and acetone are added in the form of an acetone solution of hydrochloric acid; preferably, the HCl content of the hydrochloric acid in acetone solution is 0.1 to 20% by weight; preferably 0.5 to 15% by weight. More preferably from 1 to 10% by weight (e.g., 4% by weight or 5% by weight).
  • 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.
  • Figure 6a shows an X-ray powder diffraction pattern of polymorph VI.
  • Figure 6b shows a differential scanning calorimetry plot of polymorph VI.
  • Figure 6c shows a 1 H NMR chart of polymorph VI.
  • Figure 7 shows the crystalline form N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 -morpholine)phenylamino)pyrimidine-4- Molecular structure of benzamide.
  • 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.
  • compound of formula I refers to N-(cyanomethyl)-4-(2-(4-(2',2',6',6'-d 4 ) of formula I as shown in formula I. - morpholine)phenylamino)pyrimidin-4-yl)benzamide.
  • 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.
  • benzamide hydrochloride salt comprises various hydrochloride forms of the compound of formula I.
  • Formamide dihydrochloride refers to a salt having a molar ratio of the compound of the formula I to hydrochloric acid of 1:2;
  • hydrochloride monohydrate refers to a salt of a compound of the formula I in a molar ratio of hydrochloric acid to water of 1:2:1.
  • hydrochloride salt refers to a salt having a molar ratio of the compound of the formula I to hydrochloric acid of 1:1.
  • 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 by dissolving the compound at relatively high temperatures and then cooling the solution below the saturation limit. Alternatively, the volume of liquid can be reduced by boiling, atmospheric evaporation, vacuum drying, or by other methods. By adding an anti-solvent or a solvent in which the compound has low solubility or such A mixture of solvents to reduce the solubility of the compound of interest. 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 scanning 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 5.426 ⁇ 0.2°, 9.985 ⁇ 0.2°, 13.424 ⁇ 0.2°, 14.765 ⁇ 0.2°, 25.148 ⁇ 0.2 ° and 26.566 ⁇ 0.2 °.
  • the polymorph I has an X-ray powder diffraction characteristic peak selected from the group consisting of: 8.827 ⁇ 0.2°, 15.537 ⁇ 0.2°, 17.193 ⁇ 0.2°, 19.268 ⁇ 0.2°, 20.862 ⁇ 0.2° and 30.282 ⁇ 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 17.249 ⁇ 0.2°, 19.224 ⁇ 0.2°, 23.885 ⁇ 0.2° and 29.488 ⁇ 0.2°.
  • the polymorph II has a bottom selected from The X-ray powder diffraction characteristic peaks of the group were: 7.778 ⁇ 0.2 °, 15.181 ⁇ 0.2 °, 18.515 ⁇ 0.2 °, 22.603 ⁇ 0.2 °, 25.581 ⁇ 0.2 ° and 27.003 ⁇ 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 15.178 ⁇ 0.2°, 20.705 ⁇ 0.2°, 26.390 ⁇ 0.2° and 28.088 ⁇ 0.2°.
  • the polymorph III has an X-ray powder diffraction characteristic peak selected from the group consisting of 13.305 ⁇ 0.2°, 16.204 ⁇ 0.2°, 16.953 ⁇ 0.2°, 18.809 ⁇ 0.2°, 20.073 ⁇ 0.2°, 22.937 ⁇ 0.2°, 25.958 ⁇ 0.2° and 31.837 ⁇ 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 12.493 ⁇ 0.2°, 14.447 ⁇ 0.2°, 17.627 ⁇ 0.2°, 19.519 ⁇ 0.2°, 23.231 ⁇ 0.2 °, 23.805 ⁇ 0.2 ° and 24.831 ⁇ 0.2 °.
  • the polymorph IV has an X-ray powder diffraction characteristic peak selected from the group consisting of: 4.422 ⁇ 0.2°, 12.986 ⁇ 0.2°, 17.074 ⁇ 0.2°, 22.344 ⁇ 0.2°, 24.396 ⁇ 0.2°, 25.778 ⁇ 0.2°, 28.166 ⁇ 0.2°, 28.738 ⁇ 0.2°, 29.607 ⁇ 0.2° and 31.741 ⁇ 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 13.621 ⁇ 0.2°, 18.634 ⁇ 0.2°, 20.331 ⁇ 0.2°, 21.675 ⁇ 0.2°, 22.621 ⁇ 0.2 ° and 28.048 ⁇ 0.2 °.
  • the polymorph V has an X-ray powder diffraction characteristic peak selected from the group consisting of 7.263 ⁇ 0.2°, 17.647 ⁇ 0.2°, 21.179 ⁇ 0.2°, 23.509 ⁇ 0.2°, 24.852 ⁇ 0.2°, 25.148 ⁇ 0.2°, 27.179 ⁇ 0.2°, and 30.181 ⁇ 0.2°.
  • the polymorph V has an X-ray powder diffraction pattern substantially as shown in Figure 5a.
  • the polymorph VI has 3 or more X-ray powder diffraction characteristic peaks selected from the group consisting of: 4.084 ⁇ 0.2°, 18.832 ⁇ 0.2°, 19.542 ⁇ 0.2°, 20.529 ⁇ 0.2°, and 26.468 ⁇ 0.2°.
  • the polymorph VI has an X-ray powder diffraction characteristic peak selected from the group consisting of 12.277 ⁇ 0.2°, 17.589 ⁇ 0.2°, 20.032 ⁇ 0.2°, 21.003 ⁇ 0.2°, 24.870 ⁇ 0.2° and 27.597 ⁇ 0.2°.
  • the polymorph VI has an X-ray powder diffraction pattern substantially as shown in Figure 6a.
  • 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 pattern of the polymorph I has a maximum peak at 233.19 °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 pattern of the polymorph II has a maximum peak at 166.66 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph II has a differential scanning calorimetry (DSC) substantially as shown in Figure 2b.
  • the differential scanning calorimetry spectrum of the polymorph III has a maximum peak at 249.49 °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 242.73 °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 pattern of the polymorph V has a maximum peak at 258.31 ° 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.
  • the differential scanning calorimetry spectrum of the polymorph VI has a maximum peak at 259.38 °C ⁇ 2 °C (or ⁇ 1 °C, or ⁇ 0.5 °C).
  • the polymorph VI has a differential scanning calorimetry pattern substantially as shown in Figure 6b.
  • 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 (such as ), a wetting agent (such as sodium lauryl sulfate), a coloring agent, a flavoring agent, a stabilizer, an antioxidant, a preservative, a 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.
  • the polymorphs of the present invention include polymorphs I to VI.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 512 mg, yield: 87%.
  • 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 38.1 g, yield: 92%.
  • 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
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., and weighed 312 g, yield: 99.7%. Its X-ray powder diffraction pattern is consistent with Figure 2a.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 885.0 g, yield: 82%. Its X-ray powder diffraction pattern is consistent with Figure 2a.
  • the sample was confirmed to be the title crystal form compound by 1 H NMR, X-ray powder diffraction, DSC or the like. Its X-ray powder diffraction pattern is consistent with Figure 2a.
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 285 mg, yield: 87%.
  • 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
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., weighing 156 mg, yield: 84%.
  • 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
  • the sample was confirmed by 1 H NMR, X-ray powder diffraction, DSC, and the like to be the title crystal compound, weighing 45.0 g, yield: 90%.
  • 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
  • the sample was confirmed to be the title crystalline compound by 1 H NMR, X-ray powder diffraction, DSC, etc., yield: 89%.
  • Fig. 6a The X-ray powder diffraction pattern is shown in Fig. 6a, the parameters of each peak are shown in Table 6, the differential scanning calorimetry (DSC) is shown in Fig. 6b, and the 1 H NMR spectrum is shown in Fig. 6c.
  • DSC differential scanning calorimetry
  • 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.
  • the above materials were uniformly mixed according to a conventional method, and then filled into ordinary gelatin capsules to obtain 1000 capsules.
  • Example 34 The operation of Example 34 was repeated except that the polymorphs I, III to VI of the present invention were used instead of the polymorph II, and as a result, it was found that the various polymorphs of the present invention were very stable and basic. There is no hygroscopicity, and only the 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

本发明涉及苯基氨基嘧啶化合物或其盐的多晶型物，具体地，涉及N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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，即式I所示化合物或其盐、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

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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(N-(cyanomethyl)-4-(2-((4-(2',2',6',6'-d4-morpholino)phenyl)amino)pyrimidin-4-yl)benzamide),结构如式I所示：
Figure PCTCN2016087092-appb-000001
式I化合物的分子式为C23H18D4N6O2，分子量为418.49，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，所述多晶型物是式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 PCTCN2016087092-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：5.426±0.2°，9.985±0.2°，13.424±0.2°，14.765±0.2°，25.148±0.2°和26.566±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：8.827±0.2°，15.537±0.2°，17.193±0.2°，19.268±0.2°，20.862±0.2°和30.282±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233.19℃±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:17.249±0.2°，19.224±0.2°，23.885±0.2°和29.488±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：7.578±0.2°，15.181±0.2°，18.515±0.2°，22.603±0.2°，25.581±0.2°和27.003±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166.66℃±2℃(或±1℃，或±0.5℃)、207.84℃±2℃(或±1℃，或±0.5℃)和240.84℃±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:15.178±0.2°，20.705±0.2°，26.390±0.2°和28.088±0.2°。
在另一优选例中，所述多晶型物III还具有选自下组的X-射线粉末衍射特征峰:13.305±0.2°，16.204±0.2°，16.953±0.2°，18.809±0.2°，20.073±0.2°，22.937±0.2°，25.958±0.2°和31.837±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249.49℃±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:12.493±0.2°，14.447±0.2°，17.627±0.2°，19.519±0.2°，23.231±0.2°，23.805±0.2°和24.831±0.2°。
在另一优选例中，所述多晶型物IV还具有选自下组的X-射线粉末衍射特征峰：4.422±0.2°，12.986±0.2°，17.074±0.2°，22.344±0.2°，24.396±0.2°，25.778±0.2°，28.166±0.2°，28.738±0.2°，29.607±0.2°和31.741±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242.73℃±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:13.621±0.2°，18.634±0.2°，20.331±0.2°，21.675±0.2°，22.621±0.2°和28.048±0.2°。
在另一优选例中，所述多晶型物V还具有选自下组的X-射线粉末衍射特征峰：7.263±0.2°，17.647±0.2°，21.179±0.2°，23.509±0.2°，24.852±0.2°，25.148±0.2°，27.179±0.2°，和30.181±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258.31℃±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)。
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VI，其中，所述多晶型物VI具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.084±0.2°，18.832±0.2°，19.542±0.2°，20.529±0.2°，和26.468±0.2°。
在另一优选例中，所述多晶型物VI还具有1个或多个选自下组的X-射线粉末衍射特征峰:12.277±0.2°，17.589±0.2°，20.032±0.2°，21.003±0.2°，24.870±0.2°和27.597±0.2°。
在另一优选例中，所述多晶型物VI具有基本如图6a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VI的差示扫描量热法图谱在259.38℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物VI具有基本如图6b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、水、或其组合。
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、二甲亚砜和甲醇混合溶剂、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；所述二甲亚枫和甲醇的体积比为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悬浮在丙酮和水混合溶剂中搅拌，从而得到本发明所述多晶型物II。
在另一优选例中，所述丙酮和水的体积比为10:1-50:1，较佳地，20:1。
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：
(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，所述多晶型物II的制法，包括步骤：
(i)将式I化合物悬浮在甲醇中，形成混合物A2；和
(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约为1:1.8-1:3，较佳地1:1.9-1:2.5，较佳地，1:2.0-1:2.4。
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1:1-1:10。
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在无水甲醇中重结晶，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，所述甲醇包括无水甲醇。
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：将式I化合物在盐酸水溶液中成盐结晶，从而得到本发明所述的多晶型物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N、N-二甲基甲酰胺(或DMSO)和水混合溶剂中重结晶，从而得到本发明所述多晶型物V。
在另一优选例中，所述N、N-二甲基甲酰胺或DMSO和水的体积比为1:2-1:10，较佳地，1:3。
在另一优选例中，所述多晶型物VI的制法，包括步骤：将制得的多晶型物II在pH6.8磷酸缓冲液中搅拌，从而得到本发明所述的多晶型物VI。
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：
(1)将式I化合物与第一溶剂混合，形成含式I化合物的第一溶液；
Figure PCTCN2016087092-appb-000003
(2)向所述第一溶液中，加入盐酸和丙酮，形成第一混合物；
(3)对所述第一混合物进行搅拌，从而析出固体；
(4)分离获得上一步骤中析出的固体；
(5)将所述经分离的固体与丙酮/水混合溶剂进行混合，形成第二混合物；和
(6)从所述第二混合物中分离出析出的多晶型物II。
在另一优选例中，在所述第一混合物中，所述式I化合物与盐酸的摩尔比约为1:1.8-1:3，较佳地1:1.9-1:2.5，较佳地，1:2.0-1:2.4。
在另一优选例中，所述丙酮/水混合溶剂中，丙酮和水的体积比为8:1-50:1，较佳地，10:1-30:1，更佳地12:1-25:1。
在另一优选例中，所述第一溶剂选自下组：二甲亚砜、N、N-二甲基甲酰胺、N-甲基吡咯烷酮、醋酸、或其组合。
在另一优选例中，所述方法具有选自下组的一个或多个特征：
(a)步骤(3)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
(b)步骤(5)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
(c)步骤(6)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
(d)步骤(2)中，以盐酸的丙酮溶液形式，加入盐酸和丙酮；较佳地，所述盐酸的丙酮溶液中，HCl的含量为0.1-20wt％；较佳地0.5-15wt％，更佳地1-10wt％(如4wt％或5wt％)。
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。
图6a显示了多晶型物VI的X-射线粉末衍射图。
图6b显示了多晶型物VI的差示扫描量热法图。
图6c显示了多晶型物VI的1HNMR图。
图7显示了晶型N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的分子结构。
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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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,ISBN 0750611294。
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化合物的多晶型物V
式I化合物的多晶型物VI；
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；
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。
其中，式I化合物晶型的分子结构式如图7所示。
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：5.426±0.2°，9.985±0.2°，13.424±0.2°，14.765±0.2°，25.148±0.2°和26.566±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：8.827±0.2°，15.537±0.2°，17.193±0.2°，19.268±0.2°，20.862±0.2°和30.282±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:17.249±0.2°，19.224±0.2°，23.885±0.2°和29.488±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：7.578±0.2°，15.181±0.2°，18.515±0.2°，22.603±0.2°，25.581±0.2°和27.003±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:15.178±0.2°，20.705±0.2°，26.390±0.2°和28.088±0.2°。在另一优选例中，所述多晶型物III具有选自下组的X-射线粉末衍射特征峰:13.305±0.2°，16.204±0.2°，16.953±0.2°，18.809±0.2°，20.073±0.2°，22.937±0.2°，25.958±0.2°和31.837±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:12.493±0.2°，14.447±0.2°，17.627±0.2°，19.519±0.2°，23.231±0.2°，23.805±0.2°和24.831±0.2°。在另一优选例中，所述多晶型物IV具有选自下组的X-射线粉末衍射特征峰：4.422±0.2°，12.986±0.2°，17.074±0.2°，22.344±0.2°，24.396±0.2°，25.778±0.2°，28.166±0.2°，28.738±0.2°，29.607±0.2°和31.741±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:13.621±0.2°，18.634±0.2°，20.331±0.2°，21.675±0.2°，22.621±0.2°和28.048±0.2°。
在另一优选例中，所述多晶型物V具有选自下组的X-射线粉末衍射特征峰：7.263±0.2°，17.647±0.2°，21.179±0.2°，23.509±0.2°，24.852±0.2°，25.148±0.2°，27.179±0.2°，和30.181±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。
(6)多晶型物VI
所述多晶型物VI具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.084±0.2°，18.832±0.2°，19.542±0.2°，20.529±0.2°，和26.468±0.2°。在另一优选例中，所述多晶型物VI具有选自下组的X-射线粉末衍射特征峰:12.277±0.2°，17.589±0.2°，20.032±0.2°，21.003±0.2°，24.870±0.2°和27.597±0.2°。在另一优选例中，所述多晶型物VI具有基本如图6a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233.19℃±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166.66℃±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249.49℃±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242.73℃±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258.31℃±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。
(6)多晶型物VI
所述多晶型物VI的差示扫描量热法图谱在259.38℃±2℃(或±1℃，或±0.5℃)有最大峰值。
在另一优选例中，所述多晶型物VI具有基本如图6b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(如
Figure PCTCN2016087092-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-(2',2',6',6'-d4-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～VI。
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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入无水乙醇5.0ml，室温悬浮搅拌。室温下滴入新制备的盐酸乙醇溶液2.3ml(氯化氢浓度为40mg/ml)，滴完后悬浮混合液室温下继续搅拌2.5h。过滤，无水乙醇洗涤，固体40±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512mg,收率：87％。
1H NMR(400MHz,DMSO-d6)δ10.15(s,1H),9.59(t,J＝4.0Hz,1H),8.66(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),7.85(d,J＝8.0Hz,2H),7.59(d,J＝4.0Hz,1H),4.36(d,J＝4.0Hz,2H),4.10(s,4H)。
元素分析：C：55.89％H：5.79％N:16.74％，
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 5.426 1014 51.3 19 26.217 753 38.1
2 8.827 518 26.2 20 26.566 1358 68.8
3 9.985 1835 92.9 21 27.098 762 38.6
4 12.870 408 20.7 22 28.094 568 28.8
5 13.424 939 47.5 23 28.485 527 26.7
6 14.765 1417 71.7 24 28.940 476 24.1
7 15.537 815 41.3 25 29.529 642 32.5
8 16.462 644 32.6 26 29.745 615 31.1
9 17.193 854 43.2 27 30.282 794 40.2
10 17.923 722 36.6 28 31.206 435 22.0
11 18.122 731 37.0 29 31.925 399 20.2
12 19.268 848 42.9 30 34.184 397 20.1
13 20.862 755 38.2 31 37.841 277 14.0
14 21.127 647 32.8 32 39.225 280 14.2
15 22.019 495 25.1 33 40.784 329 16.7
16 22.896 730 37.0 34 41.111 297 15.0
17 23.253 522 26.4 35 41.111 297 15.0
18 25.148 1975 100.0        
实施例2制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰 胺，加入4.0ml冰醋酸，室温搅拌至溶清，室温滴入新制备的盐酸乙醇溶液5.2ml(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1.1g,收率：94％。其X-射线粉末衍射图与图1a相同。
实施例3N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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，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，即为标题晶型化合物，称重0.88g,收率：75％。其X-射线粉末衍射图与图1a相同。
实施例4N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，悬浮搅拌在5.0ml无水甲醇中，加入略过2当量的浓盐酸，搅拌下慢慢溶解，不久固体析出，补加50mg纯化水，继续搅拌16小时，过滤，干燥得到黄色固体即为标题晶型化合物，称重420mg，收率：72％。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-(2',2',6',6'-d4-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34.0g N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入二甲亚砜109ml，室温搅拌至溶清。室温下滴入新制备的盐酸乙醇溶液177ml(氯化氢浓度为40mg/ml)，滴完后，室温下继续搅拌2h，固体析出。过滤，无水乙醇洗涤，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38.1g,收率：92％。
1H NMR(400MHz,DMSO-d6)δ10.12(s,1H),9.55(t,J＝4.0Hz,1H),8.66(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),7.0(brs,3H),4.36(d,J＝8.0Hz,2H),4.09(s,4H)。
元素分析：C：54.77％H：4.64％N:16.35％
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 PCTCN2016087092-appb-000005
Figure PCTCN2016087092-appb-000006
实施例6制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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302.0g N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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％环境中保存4天，得到黄色固体。
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312g，收率：99.7％。其X-射线粉末衍射图与图2a一致。
实施例7制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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880g N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入二甲亚砜3.15L，35℃搅拌至溶清。室温下加入新制备的盐酸丙酮溶液4.14L(氯化氢浓度为40mg/ml)，然后加入25g多晶型物II晶种，室温下继续搅拌2h，固体析出。过滤，丙酮淋洗，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885.0g,收率：82％。其X-射线粉末衍射图与图2a一致。
实施例8制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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1.0g N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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10ml丙酮和0.5ml纯化水，室温搅拌3h，过滤，丙酮淋洗，室温高真空干燥3h，得黄色固体，即为标题晶型化合物，称重950mg，收率：92％。
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。其X-射线粉末衍射图与图2a一致。
实施例9制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(2.0g)、二甲亚砜(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10ml(氯化氢浓度为40mg/ml)，滴完后继续搅拌5h，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1.92g,收率：79％。其X-射线粉末衍射图与图2a相同。
实施例10制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐固体(多晶型物I)，悬浮搅拌在3.0ml无水甲醇中，缓缓加入0.25ml 1M稀盐酸，室温下搅拌过夜，过滤，固体用无水甲醇(0.5ml x2)和1M稀盐酸(0.5ml)洗涤，55±5℃高真空干燥8h，得到固体即为标题晶型化合物，称重326mg，收率：63％。其X-射线粉末衍射图与图2a相同。
实施例11制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺固体，悬浮搅拌在5.0ml无水甲醇中，加入略过2当量的浓盐酸(0.21ml)，搅拌溶清后立即加入20mg N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐一水合物晶种(多晶型物II)，再补加50mg纯化水，室温搅拌4h，过滤，固体用无水甲醇和1M稀盐酸(0.5ml)洗涤，干燥，得到固体即为标题晶型化合物，称重462mg，收率：76％。其X-射线粉末衍射图与图2a相同。
实施例12制备N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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20L反应釜中加入1.465kg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，二甲亚砜5.640kg，控温40度左右搅拌至溶清，过滤，母液转入反应釜，随即一次性加入新制的盐酸丙酮溶液5.515kg(0.765kg盐酸加入到4.750kg丙酮中)，室温下搅拌4.5h，过滤，丙酮淋洗，抽干，固体打碎后再转入反应釜，加入丙酮(9.240kg)和水(0.735kg)。室温下继续搅拌2.5h，过滤，丙酮淋洗，55±5℃高真空干燥，得黄色固体，称重1.470kg，收率：82％。其X-射线粉末衍射图与图2a一致。
实施例13N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺单盐酸盐的多晶型物III
取300mg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺，加入1ml N-甲基吡咯烷酮，溶清，加入4.0ml无水乙醇，搅拌，室温下滴入新制备的盐酸乙醇溶液1.0ml(氯化氢浓度为40mg/ml)，滴完后搅拌2分钟，溶清，室温继续搅拌3h，固体析出，过滤，无水乙醇淋洗，室温高真空干燥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285mg,收率：87％。
1H NMR(400MHz,DMSO-d6)δ10.05(s,1H),9.54(t,J＝4.0Hz,1H),8.64(d,J＝4.0Hz,1H),8.29(d,J＝8.0Hz,2H),8.08(d,J＝8.0Hz,2H),7.95(d,J＝8.0Hz,2H),7.72-7.55(m,3H),4.37(d,J＝4.0Hz,2H),4.05(s,4H)。
元素分析：C:60.42％H:6.23％N:17.90％。
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
Figure PCTCN2016087092-appb-000007
实施例14N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺单盐酸盐的多晶型物III
取150mg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺单盐酸盐的多晶型物III
取500mg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺固体悬浮于5ml无水甲醇中，加入1当量浓盐酸(100ul)，室温搅拌14h，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412mg，收率：76％。其X-射线粉末衍射图与图3a相同。
实施例16N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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200mg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐(多晶型物I)，加入2ml纯化水，室温搅拌12h，晶体析出，过滤，丙酮淋洗，固体室温高真空干燥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156mg,收率：84％。
1H NMR(400MHz,DMSO-d6)δ10.0(s,1H),9.49(t,J＝4.0Hz,1H),8.64(d,J＝4.0Hz,1H),8.30(d,J＝8.0Hz,2H),8.07(d,J＝8.0Hz,2H),7.92(d,J＝8.0Hz,2H),7.63-7.54(m,3H),4.37(d,J＝4.0Hz,2H),4.01(s,4H)。
元素分析：C:60.96％H:6.04％N:18.36％。
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 1275 25.8 22 27.040 951 19.3
2 8.902 360 7.3 23 27.556 925 18.7
3 12.493 3984 80.7 24 28.166 1251 25.3
4 12.986 1815 36.8 25 28.738 1668 33.8
5 13.779 839 17.0 26 29.607 1295 26.2
6 14.447 4040 81.9 27 30.180 954 19.3
7 16.582 989 20.0 28 30.747 638 12.9
8 17.074 1937 39.3 29 31.741 1160 23.5
9 17.627 3970 80.4 30 33.534 567 11.5
10 18.366 547 11.1 31 34.251 444 9.0
11 19.519 2907 58.9 32 35.017 964 19.5
12 20.586 584 11.8 33 35.727 857 17.4
13 20.984 642 13.0 34 37.366 557 11.3
14 21.906 860 17.4 35 39.124 509 10.3
15 22.344 1559 31.6 36 39.811 656 13.3
16 23.231 4935 100.0 37 41.176 474 9.6
17 23.805 4724 95.7 38 41.984 569 11.5
18 24.396 1260 25.5 39 42.814 446 9.0
19 24.831 4251 86.1 40 43.526 411 8.3
20 25.778 1213 24.6 41 44.691 468 9.5
21 26.569 1073 21.7        
实施例17N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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600mg N-(氰基甲基))-4-(2-(4-(2',2',6',6'-d4-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24.0ml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478mg,收率：89％。其X-射线粉末衍射图与图4a相同。
实施例18N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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0.8g,收率：74％。其X-射线粉末衍射图与图4a相同。
实施例19N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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14h，过滤，无水甲醇洗涤，40±5℃高真空干燥，得到固体即为标题晶型化合物，称重375mg，收率：84％。其X-射线粉末衍射图与图4a相同。
实施例20N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺(50.0g)和二甲亚砜(150mL)，搅拌溶解。将上述溶液缓慢滴加到纯水(500mL)中，室温搅拌2h后过滤，滤饼用纯水(0.5L 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45.0g，收率：90％。
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.34(t,J＝4.0Hz,1H),8.54(d,J＝4.0Hz,1H),8.27(d,J＝8.0Hz,2H),8.03(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,2H),4.36(d,J＝8.0Hz,2H),3.73(s,4H)。
元素分析：C:66.08％H:5.40％N:19.91％
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
Figure PCTCN2016087092-appb-000008
实施例21N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物VI
取1.5g N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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)，加入到150ml pH 6.8的磷酸缓冲液中(按药典方法配制)，磁力搅拌16h；过滤，用pH 6.8磷酸缓冲液(5.0ml x 2)洗涤固体，50℃下真空干燥8h,得黄色固体1.1g。
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，收率：89％。
1H NMR(400MHz,DMSO-d6)δ9.50(s,1H),9.35(t,J＝4.0Hz,1H),8.53(d,J＝4.0Hz,1H),8.26(d,J＝8.0Hz,2H),8.02(d,J＝8.0Hz,2H),7.66(d,J＝8.0Hz,2H),7.40(d,J＝8.0Hz,1H),6.92(d,J＝8.0Hz,2H),4.35(d,J＝8.0Hz,2H),3.72(s,4H)。
元素分析：C：65.63％H：5.59％N：20.05％
其X-射线粉末衍射图见图6a，各个峰的参数如表6所示，差示扫描量热法图(DSC)见图6b，1H NMR的图谱见6c。
表6
峰号 2θ(°) 峰高 相对强度(I％) 峰号 2θ(°) 峰高 相对强度(I％)
1 4.084 5319 33.6 23 25.937 1161 7.3
2 8.170 453 2.9 24 26.468 3162 20.0
3 12.035 1578 10.0 25 27.597 2320 14.7
4 12.277 1805 11.4 26 28.503 999 6.3
5 12.831 952 6.0 27 29.349 766 4.8
6 13.286 1500 9.5 28 29.846 980 6.2
7 13.679 699 4.4 29 30.237 898 5.7
8 14.922 1653 10.5 30 31.224 710 4.5
9 16.403 490 3.1 31 32.366 600 3.8
10 17.589 1772 11.2 32 33.289 594 3.8
11 18.257 1546 9.8 33 34.202 678 4.3
12 18.832 2951 18.7 34 35.294 535 3.4
13 19.542 3342 21.1 35 35.885 546 3.5
14 20.032 1818 11.5 36 37.015 631 4.0
15 20.529 15807 100.0 37 37.426 744 4.7
16 21.003 2332 14.8 38 38.633 669 4.2
17 21.475 1619 10.2 39 39.786 430 2.7
18 21.856 1406 8.9 40 40.704 449 2.8
19 23.231 829 5.2 41 42.378 713 4.5
20 23.644 784 5.0 42 42.931 740 4.7
21 24.200 961 6.1 43 43.744 434 2.7
22 24.870 1975 12.5        
实施例22N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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-(2',2',6',6'-d4-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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺单盐酸盐的多晶型物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25N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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26N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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27N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物VI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VI的晶型十分稳定，且相比较新制备的(0月)多晶型物VI而言，多晶型物VI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28药物组合物
N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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)   120g
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-(2',2',6',6'-d4-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)120g
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-(2',2',6',6'-d4-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)120g
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-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺二盐酸盐的多晶型物IV(实施例16-19)120g
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药物组合物
N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-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)120g
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33药物组合物
N-(氰基甲基)-4-(2-(4-(2',2',6',6'-d4-吗啡啉)苯基氨基)嘧啶-4-基)苯甲酰胺的多晶型物VI(实施例21)120g
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34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[(35.2826-35.2801)/(35.2801-34.2546)]×100％＝0.24％。可见，多晶型物II略有引湿性。
重复实施例34操作，不同的是采用本发明所述的多晶型物I、III～VI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，仅多晶型物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 (15)

  1. 一种多晶型物，其特征在于，所述多晶型物是式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 PCTCN2016087092-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：5.426±0.2°，9.985±0.2°，13.424±0.2°，14.765±0.2°，25.148±0.2°和26.566±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:17.249±0.2°，19.224±0.2°，23.885±0.2°和29.488±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:15.178±0.2°，20.705±0.2°，26.390±0.2°和28.088±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:12.493±0.2°，14.447±0.2°，17.627±0.2°，19.519±0.2°，23.231±0.2°，23.805±0.2°和24.831±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:13.621±0.2°，18.634±0.2°，20.331±0.2°，21.675±0.2°，22.621±0.2°和28.048±0.2°。
  7. 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VI，其中，所述多晶型物VI具有3个或3个以上选自下组的X-射线粉末衍射特征峰：4.084±0.2°，18.832±0.2°，19.542±0.2°，20.529±0.2°，和26.468±0.2°。
  8. 一种如权利要求1-7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。
  9. 一种药物组合物，其特征在于，包含：
    (a)权利要求1-7任一项所述的多晶型物；和
    (b)药学上可接受的载体。
  10. 一种如权利要求1-7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1-7任一项所述的多晶型物。
  11. 一种多晶型物II的制备方法，其特征在于，包括步骤：
    (1)将式I化合物与第一溶剂混合，形成含式I化合物的第一溶液；
    Figure PCTCN2016087092-appb-100002
    (2)向所述第一溶液中，加入盐酸和丙酮，形成第一混合物；
    (3)对所述第一混合物进行搅拌，从而析出固体；
    (4)分离获得上一步骤中析出的固体；
    (5)将所述经分离的固体与丙酮/水混合溶剂进行混合，形成第二混合物；
    (6)从所述第二混合物中分离出析出的多晶型物II。
  12. 如权利要求11所述的方法，其特征在于，在所述第一混合物中，所述式I化合物与盐酸的摩尔比约为1:1.8-1:3，较佳地1:1.9-1:2.5，较佳地，1:2.0-1:2.4。
  13. 如权利要求11所述的方法，其特征在于，所述丙酮/水混合溶剂中，丙酮和水的体积比为8:1-50:1，较佳地，10:1-30:1，更佳地12:1-25:1。
  14. 如权利要求11所述的方法，其特征在于，所述第一溶剂选自下组：二甲亚砜、N、N-二甲基甲酰胺、N-甲基吡咯烷酮、醋酸、或其组合。
  15. 如权利要求11所述的方法，其特征在于，所述方法具有选自下组的一个或多个特征：
    (a)步骤(3)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
    (b)步骤(5)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
    (c)步骤(6)中，温度为4-35℃，较佳地5-30℃，更佳地10-25℃；
    (d)步骤(2)中，以盐酸的丙酮溶液形式，加入盐酸和丙酮；较佳地，所述盐酸的丙酮溶液中，HCl的含量为0.1-20wt％；较佳地0.5-15wt％，更佳地1-10wt％(如4wt％或5wt％)。
PCT/CN2016/087092 2015-06-26 2016-06-24 苯基氨基嘧啶化合物或其盐的多晶型物 WO2016206633A1 (zh)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246807A1 (zh) * 2022-06-21 2023-12-28 苏州泽璟生物制药股份有限公司 杰克替尼二盐酸盐一水合物的制备工艺

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008109943A1 (en) * 2007-03-12 2008-09-18 Cytopia Research Pty Ltd Phenyl amino pyrimidine compounds and uses thereof
WO2014110189A1 (en) * 2013-01-09 2014-07-17 Concert Pharmaceuticals Inc. Deuterated momelotinib
WO2014114274A1 (zh) * 2013-01-28 2014-07-31 苏州泽璟生物制药有限公司 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009029998A1 (en) * 2007-09-06 2009-03-12 Cytopia Research Pty Ltd Retrometabolic compounds
NZ611654A (en) * 2010-12-03 2015-08-28 Ym Biosciences Australia Pty Treatment of jak2-mediated conditions
CA2931615A1 (en) * 2013-11-26 2015-06-04 Gilead Sciences, Inc. Therapies for treating myeloproliferative disorders
TWI729644B (zh) * 2014-06-12 2021-06-01 美商西爾拉癌症醫學公司 N-(氰基甲基)-4-(2-(4-𠰌啉基苯基胺基)嘧啶-4-基)苯甲醯胺

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008109943A1 (en) * 2007-03-12 2008-09-18 Cytopia Research Pty Ltd Phenyl amino pyrimidine compounds and uses thereof
WO2014110189A1 (en) * 2013-01-09 2014-07-17 Concert Pharmaceuticals Inc. Deuterated momelotinib
WO2014114274A1 (zh) * 2013-01-28 2014-07-31 苏州泽璟生物制药有限公司 氘代的苯基氨基嘧啶化合物以及包含该化合物的药物组合物

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP3315493A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023246807A1 (zh) * 2022-06-21 2023-12-28 苏州泽璟生物制药股份有限公司 杰克替尼二盐酸盐一水合物的制备工艺

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