WO2018133823A1 - 一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法 - Google Patents

一种jak激酶抑制剂的硫酸氢盐的晶型及其制备方法 Download PDF

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WO2018133823A1
WO2018133823A1 PCT/CN2018/073310 CN2018073310W WO2018133823A1 WO 2018133823 A1 WO2018133823 A1 WO 2018133823A1 CN 2018073310 W CN2018073310 W CN 2018073310W WO 2018133823 A1 WO2018133823 A1 WO 2018133823A1
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iii
crystal form
solvent
formula
compound
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PCT/CN2018/073310
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French (fr)
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张全良
刘兵
高晓晖
边林
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江苏恒瑞医药股份有限公司
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Priority to CN201880001322.4A priority Critical patent/CN108779122B/zh
Publication of WO2018133823A1 publication Critical patent/WO2018133823A1/zh

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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to (3aR,5s,6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3- Form III of d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogensulfate and preparation method thereof, and application thereof in pharmaceutical composition and the III Use of a crystalline form, a composition, for the manufacture of a medicament for the treatment and/or prevention of arthritic diseases.
  • Tofacitinib (CP-690550) is a new oral JAK pathway inhibitor developed by Pfizer Inc. Tofacitinib is a first-in-class drug for the treatment of rheumatoid arthritis. Based on the structure of Tofacitinib, WO2013091539 discloses a series of JAK kinase inhibitor compounds having in vivo and exogenous activity and high absorption.
  • Patent applications WO2016054959 and WO2016070697 disclose Form I and Form II of the compound of formula (I), respectively.
  • all of the above crystal forms have defects of poor solubility, and it is necessary to dig deeper to find a crystal form with better solubility.
  • the technical problem to be solved by the present invention is to provide a (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl (7H) -III-crystal of pyrrolo[2,3-d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogensulfate (as shown in formula (I)) Type, the crystal form has good stability and solubility.
  • the present invention provides a crystal form of a compound of the formula (I), characterized in that an X-ray powder diffraction pattern represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation at 7.43, 9.60, 11.19, There are characteristic peaks at 18.18, 19.31, 19.64, 21.25, 22.80 and 25.63, where the error range of each characteristic peak 2 ⁇ is ⁇ 0.2.
  • the present invention provides a crystal form of III of the compound of the formula (I), characterized in that an X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained using Cu-K ⁇ radiation. Diffraction pattern, the III crystal form has characteristic peaks at 7.43, 9.09, 9.60, 11.19, 13.13, 14.90, 16.35, 18.18, 19.31, 19.64, 21.25, 22.80, 25.63 and 28.10, wherein the error of each characteristic peak 2 ⁇ The range is ⁇ 0.2.
  • the present invention provides a crystal form of a compound of the formula (I), characterized in that X-ray powder represented by a diffraction angle 2 ⁇ angle is obtained by Cu-K ⁇ radiation. Diffraction pattern, the III crystal form is 7.43, 9.09, 9.60, 11.19, 12.27, 13.13, 13.95, 14.90, 16.35, 17.76, 18.18, 19.31, 19.64, 21.25, 21.82, 22.45, 22.80, 23.43, 24.42, 25.63, 26.37 There are characteristic peaks at 27.49, 28.10, 29.07, 30.07, 31.32, 32.13, 32.90, 33.50, 34.64, 35.73, 36.69, 37.70 and 38.48, wherein the error range of each characteristic peak 2 ⁇ is ⁇ 0.2.
  • the invention further provides a method of preparing a crystalline form of Compound III of formula (I), the method comprising:
  • the method of adding the anti-solvent of the invention is:
  • the multiple additions are preferably added in ten portions (10 min each) or in three portions (20 min each).
  • the anti-solvent of the present invention is selected from the group consisting of esters, ketones, ethers, nitriles or alcohol solvents, the ester solvent is preferably ethyl acetate, and the ketone solvent is preferably acetone or methyl isobutyl ketone.
  • the ether solvent is preferably tetrahydrofuran or 1,4-dioxane, the nitrile solvent is preferably acetonitrile, and the alcohol solvent is preferably methanol.
  • the DSC endothermic peak of the III crystal form of the present invention is from 209.5 ° C to 228 ° C, preferably from 209.8 ° C to 218 ° C, more preferably 177.04 ° C.
  • the invention further relates to a pharmaceutical composition of Form III of the compound of formula (I) consisting of Form III and a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to a process for the preparation of a pharmaceutical composition as described above, characterized in that it comprises the step of mixing a crystalline form of III with a pharmaceutically acceptable carrier, diluent or excipient.
  • the invention further relates to the use of a pharmaceutical composition of Form III or Form III of a compound of formula (I) for the manufacture of a medicament for the treatment of a disease associated with JAK kinase selected from the group consisting of rheumatoid and rheumatoid arthritis.
  • the crystal form of the III crystal form of the obtained compound of the formula (I) was examined by X-ray powder diffraction pattern (XRPD) and differential scanning calorimetry (DSC).
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound of the formula (I) can be dissolved in an organic solvent and then added to an anti-solvent to crystallize. After the crystallization is completed, it can be dried by filtration to obtain a desired crystal.
  • the method for crystallization of the present invention includes room temperature crystallization, cooling crystallization, and the like.
  • the starting material used in the method for preparing a crystal form of the present invention may be any compound of the formula (I), and the specific forms include, but are not limited to, amorphous, arbitrary crystal forms and the like.
  • the "ketone solvent” as used in the present invention means a compound in which a carbonyl group (-C(O)-) is bonded to two hydrocarbon groups, and the ketone can be classified into an aliphatic ketone, an alicyclic ketone, an aromatic ketone according to a hydrocarbon group in the molecule.
  • Saturated ketones and unsaturated ketones specific examples include, but are not limited to, acetone, methyl butanone or methyl isobutyl ketone.
  • ester solvent means a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms, and specific examples include, but are not limited to, acetic acid. Ethyl ester, isopropyl acetate or butyl acetate.
  • ether solvent as used in the present invention means a chain compound or a cyclic compound having an ether bond -O- and having 1 to 10 carbon atoms, and specific examples include, but are not limited to, propylene glycol methyl ether, tetrahydrofuran or , 4-dioxane.
  • the "alcohol solvent” as used in the present invention means a group derived from one or more "hydroxyl groups” substituted with one or more hydrogen atoms on the "C 1-6 alkyl group", said "hydroxyl group” and “C” 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, methanol, ethanol, propanol or 2-propanol.
  • nitrile solvent as used in the present invention means a group derived from one or more hydrogen atoms on one or more "cyano" substituted “C 1-6 alkyl", said “cyano” and “C 1-6 alkyl” is as defined above, and specific examples include, but are not limited to, acetonitrile or propionitrile.
  • the "differential scanning calorimetry or DSC” as used in the present invention refers to measuring the temperature difference and heat flow difference between a sample and a reference during temperature rise or constant temperature of the sample to characterize all physical changes and chemistry related to thermal effects. Change to get the phase change information of the sample.
  • the "2 ⁇ or 2 ⁇ angle" as used in the present invention means a diffraction angle, ⁇ is a Bragg angle, and the unit is ° or degree, and the error range of 2 ⁇ is ⁇ 0.1 to ⁇ 0.5, preferably ⁇ 0.1 to ⁇ 0.3, more preferably ⁇ 0.2.
  • the "plane spacing or interplanar spacing (d value)" means that the spatial lattice selects three unit vectors a, b, c which are not parallel to each other and adjacent two lattice points, and they point the points.
  • the parallelepiped unit which is divided into juxtapositions, is called the interplanar spacing.
  • the spatial lattice is divided according to the determined parallelepiped unit lines, and a set of linear grids is obtained, which is called a space lattice or a lattice.
  • the lattice and the lattice reflect the periodicity of the crystal structure by geometric points and lines, respectively, and the interplanar spacing (ie, the distance between two adjacent parallel crystal planes) is different; Or ang.
  • the invention further relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a crystalline form of the compound of formula (I), and optionally one or more pharmaceutically acceptable carriers and/or diluents.
  • the pharmaceutical composition can be formulated into any of the pharmaceutically acceptable dosage forms.
  • the III crystalline form or pharmaceutical preparation of the present invention can be formulated into tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injection and concentrated injections). Solution), suppository, inhalant or spray.
  • the pharmaceutical composition of the present invention can also be administered to a patient or subject in need of such treatment by any suitable mode of administration, such as oral, parenteral, rectal, pulmonary or topical administration.
  • the pharmaceutical composition can be formulated into an oral preparation, such as an oral solid preparation such as a tablet, a capsule, a pill, a granule, or the like; or an oral liquid preparation such as an oral solution or an oral mixture. Suspension, syrup, and the like.
  • the pharmaceutical preparation may further contain a suitable filler, binder, disintegrant, lubricant, and the like.
  • the pharmaceutical preparation When used for parenteral administration, the pharmaceutical preparation can be prepared as an injection, including an injection, a sterile powder for injection, and a concentrated solution for injection.
  • the pharmaceutical composition When formulated as an injection, the pharmaceutical composition can be produced by a conventional method in the existing pharmaceutical field.
  • an additional agent may be added to the pharmaceutical preparation, and a suitable additional agent may be added depending on the nature of the drug.
  • the pharmaceutical preparation When used for rectal administration, can be formulated into a suppository or the like.
  • the pharmaceutical preparation For pulmonary administration, the pharmaceutical preparation can be formulated as an inhalant or a spray.
  • the Form III of the invention is present in a pharmaceutical composition or medicament in a therapeutically and/or prophylactically effective amount.
  • the Form III of the invention is present in a pharmaceutical composition or medicament in unit dosage form.
  • the crystalline form III of the compound of the formula (I) of the present invention can be used for the preparation of a medicament for treating a disease associated with JAK kinase. Accordingly, the present application also relates to the use of the crystalline form III of the compound of the formula (I) of the present invention for the preparation of a medicament for use in a medicament for the treatment of a disease associated with JAK kinase. Furthermore, the present application relates to a method of inhibiting a disease associated with JAK kinase comprising administering to a subject in need thereof a therapeutically and/or prophylactically effective amount of a crystalline form III of a compound of formula (I) of the present invention, Or a pharmaceutical composition of the invention.
  • the disease is a disease associated with JAK kinase selected from the group consisting of rheumatoid and rheumatoid arthritis.
  • the III crystal form of the compound of the formula (I) prepared by the invention has excellent solubility and high purity, and the crystal form is not changed by XRPD under the conditions of illumination, high temperature and high humidity, and the crystal form is stable. Good in purity; small change in HPLC purity and high chemical stability; the crystal form of the compound of the formula (I) obtained by the technical scheme of the present invention can meet the pharmaceutical requirements for production, transportation and storage, and the production process is stable, reproducible and controllable, and capable of Adapted to industrial production.
  • Figure 1 is an XRPD pattern of the crystalline form of Compound III of formula (I).
  • Figure 2 is a DSC chart of the crystalline form of Compound III of formula (I).
  • Figure 3 is an amorphous XRPD pattern of the compound of formula (I).
  • Figure 4 is an amorphous DSC spectrum of the compound of formula (I).
  • Example 1 (3aR, 5s, 6aS)-N-(3-methoxy-1,2,4-thiadiazol-5-yl)-5-(methyl(7H-pyrrolo[2,3] -d]pyrimidin-4-yl)amino)hexahydrocyclopenta[c]pyrrole-2(1H)-carboxamide hydrogensulfate (prepared according to the method of patent application WO2014194741)
  • the insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure and dried to give the desired product (168 g, yield: 90%).
  • the X-ray diffraction spectrum of the sample is shown in Fig. 3, showing the characteristic peak of the amorphous form.
  • the DSC spectrum is shown in Fig. 4. No melting characteristic absorption peak was observed below 300 ° C, and the product was determined to be an amorphous solid.
  • a sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was added to a reaction flask, DMSO (150 ⁇ L) was added thereto, and the mixture was stirred and dissolved at 25 ° C, and ethyl acetate (1 mL) was gradually added thereto, and 100 ⁇ L each was added. The middle interval is about 10 min. After the addition, the heating is turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate is vacuum dried to obtain a solid sample. The diffraction angle 2 ⁇ is detected by XRPD at 7.44 (11.87), 9.10 (9.72), 9.61 (9.20).
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and acetone (1 mL) was gradually added thereto, and 100 ⁇ L each was added. The interval was about 10 min; after the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and acetone (1 mL) was gradually added thereto, and added in three portions, respectively. 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, with an interval of about 20 min. After the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, acetone (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating was turned off, stirring was carried out for about 40 hours, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, and DMSO (150 ⁇ L) was added thereto, and the mixture was stirred and dissolved at 25 ° C, and tetrahydrofuran (1 mL) was gradually added thereto, and 100 ⁇ L each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and tetrahydrofuran (1 mL) was gradually added thereto, and added in three portions, respectively. 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid.
  • the XRPD pattern and DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was gradually added. Add 100 ⁇ L each time, the interval is about 10 min, add up, heat off after 1.5 h, stir for about 40 h, filter, and the precipitate is vacuum dried to obtain a solid.
  • the XRPD pattern and DSC spectrum of the crystal sample are compared by study to confirm that the product is Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was gradually added. Add three times, respectively, 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, with an interval of about 20min. After the addition, 1.5h, turn off the heating, stir for about 40h, filter, and the precipitate is vacuum dried to obtain a solid. The XRPD pattern and DSC spectrum of the crystal sample are The study was compared to confirm that the product was a crystalline form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and 1,4-dioxane (1 mL) was added in one portion. After the addition, the heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and acetonitrile (1 mL) was gradually added thereto, and 100 ⁇ L each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and acetonitrile (1 mL) was gradually added thereto, and added in three portions, respectively. 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid.
  • the XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and methyl isobutyl ketone (1 mL) was gradually added thereto. Add 100 ⁇ L, the interval is about 10 min, add up, heat off after 1.5 h, stir for about 40 h, filter, and the precipitate is vacuum dried to obtain a solid. The XRPD pattern and the DSC spectrum of the crystal sample are compared by study to confirm that the product is a crystal form III. .
  • a sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was gradually added thereto, and 100 ⁇ L each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was gradually added thereto, and added in three portions, respectively. 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, intermediate interval of about 20 min, after adding, heating was turned off after 1.5 h, stirred for about 40 h, filtered, and the precipitate was vacuum dried to obtain a solid.
  • the XRPD pattern and DSC pattern of the crystal sample were compared by study to confirm that the product was Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 25 ° C, and methanol (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating was turned off, stirring was carried out for about 40 hours, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 50 ° C, and acetone (1 mL) was gradually added thereto, and 100 ⁇ L each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 20 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of the formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, and DMSO (150 ⁇ L) was added thereto, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was gradually added thereto, and 100 ⁇ L each was added. After the interval was about 10 min, the heating was turned off after 1.5 h, the mixture was stirred for about 20 h, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was gradually added thereto, and added in three portions, respectively. 300 ⁇ L, 300 ⁇ L, 400 ⁇ L, the interval is about 20min, after adding, after 1.5h, the heating is turned off, stirred for about 20h, filtered, and the precipitate is vacuum dried to obtain a solid.
  • the XRPD pattern and DSC spectrum of the crystal sample are compared by study to confirm that the product is Form III.
  • a sample of the compound of formula (I) (prepared according to the method of Example 1) (50 mg) was placed in a reaction flask, DMSO (150 ⁇ L) was added, and the mixture was stirred and dissolved at 50 ° C, and methanol (1 mL) was added in one portion, and the addition was completed for 1.5 h. After heating, the heating was turned off, stirred for about 20 hours, filtered, and the precipitate was vacuum dried to obtain a solid. The XRPD pattern and the DSC pattern of the crystal sample were compared by study to confirm that the product was a crystal form of III.
  • Example 1 The amorphous product sample obtained in Example 1 and the III crystal product sample obtained in Example 3 were placed in an open position, and examined under illumination (4,500 Lux), heating (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90). The stability of the sample under the condition of %) was investigated for 5 days and 10 days, and the purity of the HPLC was shown in Table 1.
  • Test sample Form III (prepared according to the method of Example 3), Form I (which can be prepared according to the method of WO2016054959), Form II (which can be prepared according to the method of WO2016070697).
  • Solvent water, 0.1 N HCl.

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Abstract

本发明涉及一种JAK激酶抑制剂的硫酸氢盐的晶型及其制备方法。具体地，本发明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的III晶型及其制备方法。本发明式(I)化合物的III晶型具备良好的晶型稳定性，并且所用结晶溶剂低毒低残留，可更好地用于临床治疗。

Description

一种JAK激酶抑制剂的硫酸氢盐的晶型及其制备方法 技术领域
本发明涉及(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐的III晶型及其制备方法，其在药物组合物中的应用以及该III晶型、组合物在制备治疗和/或预防关节炎疾病药物中的用途。
背景技术
关节炎是全世界最常见的慢性疾病，导致关节炎的原因很多，引起关节损伤的原因也各有不同。目前，Tofacitinib(CP-690550)是辉瑞公司研发的一种新型口服JAK通路抑制剂，Tofacitinib是用于类风湿性关节炎(rheumatoid arthritis)治疗的首创药物(first-in-class drug)。基于Tofacitinib的结构，WO2013091539公开了一系列具有体内、外活性，高吸收的JAK激酶抑制剂化合物。
专利申请WO2014194741中公开了式(I)所示的(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐。
Figure PCTCN2018073310-appb-000001
专利申请WO2016054959、WO2016070697分别公开了式(I)所示化合物的I晶型、II晶型。但上述晶型均存在溶解度较差的缺陷，需要深入摸索找到溶解度更好的晶型。
发明内容
本发明要解决的技术问题是提供一种(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐(如式(I)所示)的III晶型，该晶型具备良好的稳定性和溶解性。
本发明的技术方案如下：
本发明提供一种式(I)所示化合物的III晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在7.43，9.60，11.19，18.18，19.31，19.64，21.25，22.80和25.63处有特征峰，其中，每个特征峰2θ的 误差范围为±0.2，
Figure PCTCN2018073310-appb-000002
在本发明的一个优选实施例方案中，本发明提供一种式(I)所示化合物的III晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，所述III晶型在7.43，9.09，9.60，11.19，13.13，14.90，16.35，18.18，19.31，19.64，21.25，22.80，25.63和28.10处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
在本发明的一个优选实施例方案中，本发明提供一种式(I)所示化合物的III晶型，其特征在于，使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，所述III晶型在7.43，9.09，9.60，11.19，12.27，13.13，13.95，14.90，16.35，17.76，18.18，19.31，19.64，21.25，21.82，22.45，22.80，23.43，24.42，25.63，26.37，27.49，28.10，29.07，30.07，31.32，32.13，32.90，33.50，34.64，35.73，36.69，37.70和38.48处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
在本发明的一个优选实施例方案中，本发明进一步提供一种制备式(I)所示化合物III晶型的方法，所述方法包括：
(1)将式(I)所示化合物溶解于二甲基亚砜中，加入反溶剂，搅拌析晶；
(2)过滤，固体干燥后即得目标III晶型。
本发明所述反溶剂的加入方式为：
多次加入或一次性加入；
所述多次加入优选分十次加入(每次间隔10min)或分三次加入(每次间隔20min)。
本发明所述反溶剂选自酯类、酮类、醚类、腈类或醇类溶剂，所述酯类溶剂优选乙酸乙酯，所述酮类溶剂优选丙酮或甲基异丁酮，所述醚类溶剂优选四氢呋喃或1,4-二氧六环，所述腈类溶剂优选乙腈，所述醇类溶剂优选甲醇。
本发明III晶型的DSC吸热峰值为209.5℃～228℃，优选为209.8℃～218℃，更优选为217.04℃。
本发明进一步涉及式(I)所示化合物的III晶型的药物组合物，所述药物组合物由III晶型与药学上可接受的载体、稀释剂或赋形剂组成。
本发明还涉及一种制备上述药物组合物的方法，其特征在于，所述方法包括 由III晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
本发明进一步涉及式(I)所示化合物的III晶型或III晶型的药物组合物在制备治疗与JAK激酶有关疾病药物中的用途，所述疾病选自风湿及类风湿性关节炎。
通过X-射线粉末衍射图谱(XRPD)、差示扫描量热分析(DSC)对所得到式(I)所示化合物的III晶型进行结构测定、晶型研究。
重结晶的方法没有特别限定，可以用通常的重结晶操作方法进行。例如，可以用原料式(I)所示化合物在有机溶剂中溶解后加入反溶剂析晶，结晶完成后，经过滤干燥，即可得到所需要的结晶。
本发明析晶的方法有室温析晶、冷却析晶等。
本发明晶型制备方法中所用的起始原料可以是任意形式的式(I)所示化合物，具体形式包括但不限于：无定形、任意晶型等。
发明详述
在本申请的说明书和权利要求书中，除非另有说明，否则本文中使用的科学和技术名词具有本领域技术人员所通常理解的含义。然而，为了更好地理解本发明，下面提供了部分相关术语的定义和解释。另外，当本申请所提供的术语的定义和解释与本领域技术人员所通常理解的含义不一致时，以本申请所提供的术语的定义和解释为准。
本发明所述的“酮类溶剂”是指羰基(-C(O)-)与两个烃基相连的化合物，根据分子中烃基的不同，酮可分为脂肪酮、脂环酮、芳香酮、饱和酮和不饱和酮，具体实例包括但不限于：丙酮、甲基丁酮或甲基异丁酮。
本发明所述的“酯类溶剂”是指含碳原子数为1至4个的低级有机酸与含碳原子数为1至6个的低级醇的结合物，具体实例包括但不限于：乙酸乙酯、乙酸异丙酯或乙酸丁酯。
本发明所述的“醚类溶剂”是指含有醚键-O-且碳原子数为1至10个的链状化合物或环状化合物，具体实例包括但不限于：丙二醇甲醚、四氢呋喃或1,4-二氧六环。
本发明所述的“醇类溶剂”是指一个或多个“羟基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“羟基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：甲醇、乙醇、丙醇或2-丙醇。
本发明所述的“腈类溶剂”是指一个或多个“氰基”取代“C 1-6烷基”上的一个或多个氢原子所衍生的基团，所述“氰基”和“C 1-6烷基”如前文所定义，具体实例包括但不限于：乙腈或丙腈。
本发明所述的“X-射线粉末衍射图谱或XRPD”是指根据布拉格公式2d sinθ＝nλ(式中，λ为X射线的波长，
Figure PCTCN2018073310-appb-000003
，衍射的级数n为任何正整数，一般取一级衍射峰，n＝1)，当X射线以掠角θ(入射角的余角，又称为布拉格角)入射到晶体或部分晶体样品的某一具有d点阵平面间距的原子面上时，就能满足布拉格方 程，从而测得了这组X射线粉末衍射图。
本发明所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
本发明所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度，2θ的误差范围为±0.1～±0.5，优选±0.1～±0.3，更优选±0.2。
本发明所述的“晶面间距或晶面间距(d值)”是指空间点阵选择3个不相平行的连结相邻两个点阵点的单位矢量a，b，c，它们将点阵划分成并置的平行六面体单位，称为晶面间距。空间点阵按照确定的平行六面体单位连线划分，获得一套直线网格，称为空间格子或晶格。点阵和晶格是分别用几何的点和线反映晶体结构的周期性，不同的晶面，其面间距(即相邻的两个平行晶面之间的距离)各不相同；单位为
Figure PCTCN2018073310-appb-000004
或埃。
本发明还涉及，包括式(I)所示的化合物的III晶型，以及任选的一种或多种药用载体和/或稀释剂的药物组合物。所述药物组合物可以制成药学上可接受的任一剂型。例如，本发明的III晶型或药物制剂可以配制为片剂、胶囊剂、丸剂、颗粒剂、溶液剂、混悬剂、糖浆剂、注射剂(包括注射液、注射用无菌粉末与注射用浓溶液)、栓剂、吸入剂或喷雾剂。
此外，本发明的所述药物组合物还可以以任何合适的给药方式，例如口服、肠胃外、直肠、经肺或局部给药等方式施用于需要这种治疗的患者或受试者。当用于口服给药时，所述药物组合物可制成口服制剂，例如口服固体制剂，如片剂、胶囊剂、丸剂、颗粒剂等；或，口服液体制剂，如口服溶液剂、口服混悬剂、糖浆剂等。当制成口服制剂时，所述药物制剂还可包含适宜的填充剂、粘合剂、崩解剂、润滑剂等。当用于肠胃外给药时，所述药物制剂可制成注射剂，包括注射液、注射用无菌粉末与注射用浓溶液。当制成注射剂时，所述药物组合物可采用现有制药领域中的常规方法来进行生产。当配制注射剂时，所述药物制剂中可以不加入附加剂，也可根据药物的性质加入适宜的附加剂。当用于直肠给药时，所述药物制剂可制成栓剂等。用于经肺给药时，所述药物制剂可制成吸入剂或喷雾剂等。在某些优选的实施方案中，本发明的III晶型以治疗和/或预防有效量存在于药物组合物或药物中。在某些优选的实施方案中，本发明的III晶型以单位剂量的形式存在于药物组合物或药物中。
本发明式(I)化合物的III晶型可用于制备治疗与JAK激酶有关疾病药物中的用途。因此，本申请还涉及，本发明式(I)化合物的III晶型用于制备药物的用途，所述药物用于治疗与JAK激酶有关的疾病的药物中的用途。此外，本申请还涉及，一种抑制与JAK激酶有关的疾病的方法，其包括给有此需要的受试者施用治疗和/或预防有效量的本发明式(I)化合物的III晶型，或者本发明的药物组合物。
在某些优选的实施方案中，所述疾病为与JAK激酶有关的疾病，选自风湿及 类风湿性关节炎。
发明的有益效果
与现有技术相比，本发明的技术方案具有以下优点：
经研究表明，本发明制备的式(I)所示化合物的III晶型溶解性优、纯度较高，在光照、高温、高湿的条件下晶型经XRPD检测均未发生改变、晶型稳定性良好；HPLC纯度变化小、化学稳定性高；本发明技术方案得到的式(I)所示化合物的III晶型能够满足生产运输储存的药用要求，生产工艺稳定、可重复可控，能够适应于工业化生产。
附图说明
图1为式(I)所示化合物III晶型的XRPD图谱。
图2为式(I)所示化合物III晶型的DSC图谱。
图3为式(I)所示化合物无定形的XRPD图谱。
图4为式(I)所示化合物无定形的DSC图谱。
具体实施方式
以下将结合实施例更详细地解释本发明，本发明的实施例仅用于说明本发明的技术方案，并非限定本发明的实质和范围。
实验所用仪器的测试条件：
1、差示扫描量热仪(Differential Scanning Calorimeter,DSC)
仪器型号：Mettler Toledo DSC 1STAR e System
吹扫气：氮气
升温速率：10.0℃/min
温度范围：40-300℃
2、X-射线粉末衍射谱(X-ray Powder Diffraction,XRPD)
仪器型号：Bruker D8Focus X-射线粉末衍射仪
射线：单色Cu-Kα射线(λ＝1.5406)
扫描方式：θ/2θ，扫描范围：2-40 o
电压：40kV，电流：40mA
实施例1：(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺硫酸氢盐(可按专利申请WO2014194741中的方法制备)
将(3aR,5s,6aS)-N-(3-甲氧基-1,2,4-噻二唑-5-基)-5-(甲基(7H-吡咯并[2,3-d]嘧啶-4-基)氨基)六氢环戊并[c]吡咯-2(1H)-甲酰胺(140g，0.34mol)加入反应瓶中，加入无水甲醇(350g)、二氯甲烷(2.0kg)，悬浮搅拌，室温下缓慢滴加硫酸(34.8g，0.36mol)， 反应液澄清，搅拌反应30min。过滤除去不溶物，滤液减压浓缩，干燥，得目标产物(168g，产率90％)。该样品的X-射线衍射谱图见图3，显示无晶型特征吸收峰，DSC谱图见图4，在300℃以下未见熔融特征吸收峰，据此确定产物为无定形固体。
实施例2
将式(I)化合物(按实施例1的方法制备)样品(50mg)加入反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入乙酸乙酯(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥后得固体样品，经XRPD检测衍射角2θ在7.44(11.87)，9.10(9.72)，9.61(9.20)，11.20(7.89)，12.28(7.20)，13.14(6.73)，13.96(6.34)，14.91(5.94)，16.35(5.42)，17.76(4.99)，18.19(4.87)，19.31(4.59)，19.66(4.51)，21.27(4.17)，21.82(4.07)，22.47(3.95)，22.80(3.90)，23.44(3.79)，24.44(3.64)，25.65(3.47)，26.38(3.38)，27.49(3.24)，28.13(3.17)，29.10(3.07)，30.08(2.97)，31.34(2.85)，32.15(2.78)，32.91(2.72)，33.50(2.07)，34.63(2.59)，35.73(2.51)，36.73(2.45)，37.64(2.39)和38.47(2.34)处有特征峰，将此晶型定义为III晶型。
实施例3
将式(I)化合物(按实施例1的方法制备)样品(500mg)置于反应瓶中，加入DMSO(1.5mL)，60℃下搅拌溶解，加入甲醇(10mL)，关闭加热，搅拌析晶，过滤，真空干燥得固体样品393mg，收率78.6％。将此晶型定义为III晶型，该结晶样品的XRPD图谱见图1，其DSC谱图见图2，熔点在217.04附近，起始熔化温度为209.82℃，其特征峰位置如下表所示：
表1、III晶型特征峰
Figure PCTCN2018073310-appb-000005
Figure PCTCN2018073310-appb-000006
实施例4
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入丙酮(1mL)，每次加入100μL，中间间隔约10min；加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例5
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入丙酮(1mL)，分三次加入，分别为300μL、300μL、400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例6
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，一次性加入丙酮(1mL)，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例7
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入四氢呋喃(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例8
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入四氢呋喃(1mL)，分三次加入，分别为300μL，300μL，400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例9
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入1,4-二氧六环(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例10
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入1,4-二氧六环(1mL)，分三次加入，分别为300μL，300μL，400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例11
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，一次性加入1,4-二氧六环(1mL)，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例12
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入乙腈(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例13
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入乙腈(1mL)，分三次加入，分别为300μL，300μL，400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约40h，过滤， 沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例14
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入甲基异丁酮(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例15
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入甲醇(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例16
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，逐步加入甲醇(1mL)，分三次加入，分别为300μL，300μL，400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例17
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，25℃下搅拌溶解，一次性加入甲醇(1mL)，加毕，1.5h后关闭加热，搅拌约40h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例18
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，50℃下搅拌溶解，逐步加入丙酮(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约20h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例19
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，50℃下搅拌溶解，逐步加入甲醇(1mL)，每次加入100μL，中间间隔约10min，加毕，1.5h后关闭加热，搅拌约20h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例20
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，50℃下搅拌溶解，逐步加入甲醇(1mL)，分三次加入，分别为300μL、 300μL、400μL，中间间隔约20min，加毕，1.5h后关闭加热，搅拌约20h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例21
将式(I)化合物(按实施例1的方法制备)样品(50mg)置于反应瓶中，加入DMSO(150μL)，50℃下搅拌溶解，一次性加入甲醇(1mL)，加毕，1.5h后关闭加热，搅拌约20h，过滤，沉淀物真空干燥得固体，该结晶样品的XRPD图谱和DSC图谱经研究比对，确定产物为III晶型。
实施例22
将实施例1所得的无定形产物样品和实施例3所得的III晶型产物样品敞口平摊放置，考察在光照(4500Lux)、加热(40℃、60℃)、高湿(RH75％、RH90％)条件下样品的稳定性，考察取样时间为5天和10天，HPLC检测纯度结果见表1。
试验结果：
表2、本发明式(I)所示化合物III晶型与无定形稳定性比较
Figure PCTCN2018073310-appb-000007
试验结论
由表2的稳定性考察结果显示：
在光照、高湿、高温敞口放置条件下，高湿对两者的影响不大，但是在光照、高温的条件下，III晶型的稳定性显著优于无定形样品，经XRPD检测晶型均未发生改变，说明本发明的III晶型稳定性显著优于无定形。
实施例23、本发明晶型III与现有技术公开的晶型I、晶型II溶解性比较
供试品：晶型III(按照实施例3方法制备)、晶型I(可按照WO2016054959方法制备)、晶型II(可按照WO2016070697方法制备)。
溶剂：水、0.1N HCl。
试验结果：
表3、式(I)所示化合物的III晶型与I晶型、II晶型的饱和溶解度比较
Figure PCTCN2018073310-appb-000008
Figure PCTCN2018073310-appb-000009
试验结论
由表3实验结果显示：本发明晶型III在水或0.1N HCl中的饱和溶解度均大于晶型I或晶型II，本发明晶型III的溶解性更优。

Claims (9)

  1. 式(I)所示化合物的III晶型，其特征在于：使用Cu-Kα辐射，得到以衍射角2θ角度表示的X-射线粉末衍射图谱，其在7.43，9.60，11.19，18.18，19.31，19.64，21.25，22.80和25.63处有特征峰，其中，每个特征峰2θ的误差范围为±0.2，
    Figure PCTCN2018073310-appb-100001
  2. 根据权利要求1所述的III晶型，其特征在于，所述III晶型在7.43，9.09，9.60，11.19，13.13，14.90，16.35，18.18，19.31，19.64，21.25，22.80，25.63和28.10处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
  3. 根据权利要求2所述的III晶型，其特征在于，所述III晶型在7.43，9.09，9.60，11.19，12.27，13.13，13.95，14.90，16.35，17.76，18.18，19.31，19.64，21.25，21.82，22.45，22.80，23.43，24.42，25.63，26.37，27.49，28.10，29.07，30.07，31.32，32.13，32.90，33.50，34.64，35.73，36.69，37.70和38.48处有特征峰，其中，每个特征峰2θ的误差范围为±0.2。
  4. 一种制备如权利要求1-3中任一项所述III晶型的方法，其特征在于，所述方法包括：
    1)将式(I)所示化合物溶解于二甲基亚砜中，加入反溶剂，搅拌析晶；
    2)过滤，固体干燥后即得目标III晶型。
  5. 如权利要求4所述的方法，其特征在于，所述反溶剂的加入方式为：多次加入或一次性加入。
  6. 如权利要求4所述的方法，其特征在于，所述反溶剂选自酯类、酮类、醚类、腈类或醇类溶剂，所述酯类溶剂优选乙酸乙酯，所述酮类溶剂优选丙酮或甲基异丁酮，所述醚类溶剂优选四氢呋喃或1,4-二氧六环，所述腈类溶剂优选乙腈，所述醇类溶剂优选甲醇。
  7. 一种药物组合物，所述药物组合物由权利要求1-3中任一项所述的III晶型与药学上可接受的载体、稀释剂或赋形剂组成。
  8. 一种制备药物组合物的方法，其特征在于，所述方法包括由权利要求1-3中任一项所述的III晶型与药学上可接受的载体、稀释剂或赋形剂混合的步骤。
  9. 含有权利要求1-3任一项所述式(I)化合物的III晶型、权利要求7所述III晶型的药物组合物在制备治疗与JAK激酶有关疾病药物中的用途，所述疾病选自风湿及类风湿性关节炎。
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