WO2016141891A1 - Jak抑制剂的晶型及其制备方法 - Google Patents

Jak抑制剂的晶型及其制备方法 Download PDF

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WO2016141891A1
WO2016141891A1 PCT/CN2016/076141 CN2016076141W WO2016141891A1 WO 2016141891 A1 WO2016141891 A1 WO 2016141891A1 CN 2016076141 W CN2016076141 W CN 2016076141W WO 2016141891 A1 WO2016141891 A1 WO 2016141891A1
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crystal form
ray powder
powder diffraction
diffraction pattern
solvent
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PCT/CN2016/076141
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English (en)
French (fr)
Inventor
陈敏华
张炎锋
刁小娟
夏楠
张晓宇
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苏州晶云药物科技有限公司
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Priority to EP16761118.5A priority Critical patent/EP3269719B1/en
Priority to US15/557,119 priority patent/US10377757B2/en
Publication of WO2016141891A1 publication Critical patent/WO2016141891A1/zh

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    • 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
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • 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 relates to the field of chemical medicine, in particular to ⁇ 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazole-1 a crystalline form of -yl]azetidin-3-yl ⁇ acetonitrile and a process for the preparation thereof.
  • JAK Junus kinase
  • JAK-dependent cytokines are involved in the pathogenesis of a variety of inflammatory and autoimmune diseases, and JAK inhibitors may be widely used to treat various inflammatory diseases.
  • Baricitinib is a selective JAK1 and JAK2 inhibitor developed by Lilly Pharmaceuticals and Incyte. In the kinase assay, Baricitinib exhibits a higher inhibitory intensity against JAK1 and JAK2 than JAK3. 100 times. Baricitinib is currently in clinical trials in the United States for the treatment of rheumatoid arthritis.
  • the chemical name of the drug is: ⁇ 1-(ethylsulfonyl)-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl] Azetidin-3-yl ⁇ acetonitrile having the structural formula shown in formula (I).
  • the specific medicinal activity is an essential prerequisite for the pharmaceutically active substance to be approved for marketing.
  • requirements are based on various parameters relating to the nature of the active substance itself. Without limitation, examples of such parameters are chemical and solid state stability and storage stability of the active ingredient under various environmental conditions, stability during manufacture of the pharmaceutical composition, and stability of the active ingredient in the final pharmaceutical composition, and the like. .
  • the pharmaceutically active substance used for the preparation of the pharmaceutical composition should be as pure as possible and must have a long-term preservation stability under various environmental conditions. It is essential to avoid the use of a pharmaceutical composition containing, for example, a decomposition product thereof in addition to the actual active substance, in which case the active substance content of the drug may be less than the indicated content.
  • the pharmaceutically active substance is non-hygroscopic, stable to degradation and subsequent changes in its solid form, if the pharmaceutically active substance is hygroscopic in the sense that it absorbs water (slowly or over time), It is not possible to reliably make a pharmaceutically active substance into a drug because the amount of the substance to be added to provide the same dose varies greatly depending on the degree of hydration, and in addition, changes in hydration or solid form can cause physical and chemical properties (such as solubility or dissolution rate). Changes in physical and chemical properties can in turn lead to inconsistent absorption by patients. Therefore, preferably, the pharmaceutically active substance should have only slight hygroscopicity.
  • the chemical stability, solid state stability, "shelf life” and material handling properties of the pharmaceutically active substance are very important factors.
  • the pharmaceutically active substance and any pharmaceutical composition comprising the same should be capable of being effectively stored for a substantial period of time without exhibiting the physicochemical properties of the active substance (eg, its activity, moisture content, solubility properties, solid form, etc.) Significant changes.
  • the drug will typically require treatment to achieve a particle size suitable for inhalation and any crystalline form must be stabilized during this treatment to make the properties of the final product predictable and reliable.
  • Different crystal forms of the same drug may have significant differences in appearance, solubility, melting point, dissolution, bioavailability, etc., and may also have different effects on drug stability, bioavailability, and efficacy. Therefore, the development of new crystal forms that are more suitable for application is of great significance for drug development.
  • the inventors of the present invention surprisingly discovered two crystal forms of the compound of formula (I) and three phosphate crystal forms during the course of the research. Moreover, the crystal form of the invention has good stability, solubility and wettability meet the requirements of medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the present invention provides novel crystalline forms of the compounds of formula (I), novel crystalline forms of the salts, and processes for their preparation and use.
  • the crystal form I provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 15.33 ° ⁇ 0.20 °, 16.66 ° ⁇ 0.20 °, 19.06 ° ⁇ 0.20 °.
  • the crystal form I provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 14.91° ⁇ 0.20°, 16.25° ⁇ 0.20°, 15.74° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form I provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 14.91 ° ⁇ 0.20 °, 16.25 ° ⁇ 0.20 °, 15.74 ° ⁇ There is a characteristic peak at 0.20°.
  • the crystal form I provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 25.51° ⁇ 0.20°, 12.40° ⁇ 0.20°, 17.39° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystalline form I provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 25.51° ⁇ 0.20°, 12.40° ⁇ 0.20°, 17.39 ° ⁇ at 2theta. There is a characteristic peak at 0.20°.
  • the crystalline form I provided by the present invention has an X-ray powder diffraction pattern comprising a value of 15.33 ° ⁇ 0.20 at 2theta. °, 16.66 ° ⁇ 0.20 °, 19.06 ° ⁇ 0.20 °, 14.91 ° ⁇ 0.20 °, 16.25 ° ⁇ 0.20 °, 15.74 ° ⁇ 0.20 °, 25.51 ° ⁇ 0.20 °, 12.40 ° ⁇ 0.20 °, 17.39 ° ⁇ 0.20 ° A characteristic peak at one or more locations in the location.
  • crystal form I provided by the present invention is further characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form I provided by the present invention is characterized in that when differential scanning calorimetry is performed, an endothermic peak begins to appear near the temperature of 212 ° C, and the differential scanning calorimetry diagram is substantially as shown in FIG. 2 .
  • the crystal form I provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, when heated to 200 ° C, it has a weight loss gradient of about 0.8%, and the thermogravimetric analysis chart is basically as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of Form I, characterized in that a compound of the formula (I) is added to one or more solvent systems selected from the group consisting of water, alcohols, ketones, esters A single or mixed system of aromatic hydrocarbons, halogenated hydrocarbons, nitriles, nitroalkanes, cyclic ethers or aliphatic hydrocarbons, obtained by anti-solvent addition, suspension stirring, heat-cooling crystallization or volatile crystallization.
  • solvent systems selected from the group consisting of water, alcohols, ketones, esters
  • the alcohol solvent is preferably methanol; the ketone solvent is preferably acetone; and the halogenated hydrocarbon is preferably dichloromethane.
  • Another object of the invention is to provide a crystalline form of the compound of formula (I), designated as Form II.
  • the crystal form II provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 18.00 ° ⁇ 0.20 °, 10.80 ° ⁇ 0.20 °, 7.26 ° ⁇ 0.20 °.
  • the crystal form II provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 14.60° ⁇ 0.20°, 12.14° ⁇ 0.20°, and 11.21° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form II provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 14.60° ⁇ 0.20°, 12.14° ⁇ 0.20°, and 11.21 ° ⁇ at 2theta. There is a characteristic peak at 0.20°.
  • the crystal form II provided by the present invention is further characterized in that the X-ray powder diffraction pattern is one or two of 2theta values of 22.59° ⁇ 0.20°, 22.03° ⁇ 0.20°, 19.64° ⁇ 0.20°. There are characteristic peaks at or at three locations; preferred crystal form II provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 22.59 ° ⁇ 0.20 °, 22.03 ° ⁇ 0.20 °, 19.64 ° ⁇ 0.20 °. There are characteristic peaks.
  • the crystal form II provided by the present invention has an X-ray powder diffraction pattern including a value of 18.00 ° ⁇ 0.20 °, 10.80 ° ⁇ 0.20 °, 7.26 ° ⁇ 0.20 °, 14.60 ° ⁇ 0.20 °, 12.14 ° ⁇ 0.20.
  • crystal form II provided by the present invention is further characterized in that the X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form II provided by the present invention is characterized in that, when performing differential scanning calorimetry, the first endothermic peak starts to be heated to around 144 ° C, and the second endothermic peak begins to be heated until the vicinity of 213 ° C.
  • the differential scanning calorimetry chart is basically as shown in FIG. 6.
  • the crystal form II provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, when heated to 200 ° C, it has a weight loss gradient of about 16.5%, and the thermogravimetric analysis chart is basically as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of Form II comprising adding a solid of the compound (I) to ice vinegar In the mixed system of acid or glacial acetic acid and other solvents, it is obtained by adding anti-solvent, volatilization, heating, cooling or suspension stirring.
  • the other organic solvents include, but are not limited to, water, alcohols, ketones, esters, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, nitroalkanes, cyclic ethers, aliphatic hydrocarbon solvents.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of Form I or Form II or a mixture of both and a pharmaceutically acceptable carrier, diluent or excipient.
  • a therapeutically effective amount of Form I or Form II or a mixture of the two is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical composition or formulation which is pharmaceutical Prepared in a manner well known in the art.
  • the crystalline form I or the crystalline form II of the compound of the formula (I) provided by the present invention or a mixture of the two can be used for the preparation of a medicament for the treatment of an autoimmune disease, in particular for the treatment of a rheumatoid arthritis pharmaceutical preparation.
  • Another object of the present invention is to provide a phosphate crystal form of the compound of formula (I), designated as Form A.
  • the crystal form A provided by the present invention is characterized in that its X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 17.22 ° ⁇ 0.20 °, 8.37 ° ⁇ 0.20 °, and 3.59 ° ⁇ 0.20 °.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 23.96° ⁇ 0.20°, 19.40° ⁇ 0.20°, 18.55° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form I provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a 2theta value of 23.96 ° ⁇ 0.20 °, 19.40 ° ⁇ 0.20 °, 18.55 ° ⁇ There is a characteristic peak at 0.20°.
  • the crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 7.78° ⁇ 0.20°, 18.00° ⁇ 0.20°, 25.40° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form A provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 7.78° ⁇ 0.20°, 18.00° ⁇ 0.20°, 25.40° ⁇ at 2theta. There is a characteristic peak at 0.20°.
  • the crystal form A of the present invention has an X-ray powder diffraction pattern including 2theta values of 17.22° ⁇ 0.20°, 8.37° ⁇ 0.20°, 3.59° ⁇ 0.20°, 23.96° ⁇ 0.20°, 19.40° ⁇ 0.20.
  • crystal form A provided by the present invention is further characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form A provided by the present invention is characterized in that when differential scanning calorimetry is performed, an endothermic peak begins to appear near 187 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG.
  • the crystal form A provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, when heated to 175 ° C, it has a weight loss gradient of about 1.3%, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of a phosphate crystal form A, which comprises adding a compound of the formula (I) and phosphoric acid to a solvent, a suitable mixed crystallizing solvent, and stirring.
  • the suitable mixed crystallization solvent includes, but is not limited to, a mixed system of alcohols, ketones, nitriles, cyclic ethers, and aliphatic hydrocarbon solvents.
  • the mixed solvent system is preferably mixed with acetonitrile and ethanol, and the preferred volume ratio of the acetonitrile to ethanol is about 4:1 to 2:1, more preferably about 3:1 by volume.
  • Another object of the present invention is to provide a phosphate crystal form of the compound of formula (I), designated as Form B.
  • the crystal form B provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 19.62 ° ⁇ 0.20 °, 16.73 ° ⁇ 0.20 °, 3.20 ° ⁇ 0.20 °.
  • the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 16.21° ⁇ 0.20°, 22.67° ⁇ 0.20°, 25.85° ⁇ 0.20°. Or two or three having characteristic peaks; preferred form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 16.21 ° ⁇ 0.20 °, 22.67 ° ⁇ 0.20 °, 25.85 ° ⁇ in the 2theta. There is a characteristic peak at 0.20°.
  • the crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 20.90° ⁇ 0.20°, 17.53° ⁇ 0.20°, 26.67° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 20.90° ⁇ 0.20°, 17.53° ⁇ 0.20°, 26.67° ⁇ at 2theta. There is a characteristic peak at 0.20°.
  • the crystal form B of the present invention has an X-ray powder diffraction pattern including 2theta values of 19.62° ⁇ 0.20°, 16.73° ⁇ 0.20°, 3.20° ⁇ 0.20°, 16.21° ⁇ 0.20°, 22.67° ⁇ 0.20.
  • crystal form B provided by the present invention is further characterized in that the X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form B provided by the present invention is characterized in that when differential scanning calorimetry is performed, an endothermic peak begins to appear near 169 ° C, and the differential scanning calorimetry diagram is substantially as shown in FIG.
  • the crystal form B provided by the present invention is characterized in that, when subjected to thermogravimetric analysis, when heated to 160 ° C, it has a weight loss gradient of about 1.2%, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of a phosphate form B, which comprises adding a compound of the formula (I) and phosphoric acid to a suitable crystallization solvent and stirring.
  • the suitable crystallization solvent includes, but is not limited to, anhydrous alcohols, ketones, esters, aromatic hydrocarbons, halogenated hydrocarbons, nitriles, nitroalkanes, cyclic ether solvent systems.
  • the ketone crystallization solvent is preferably methyl isobutyl ketone; and the ester crystallization solvent is preferably isopropyl acetate.
  • Another object of the present invention is to provide a phosphate crystal form of the compound of formula (I), designated as Form C.
  • the crystal form C provided by the present invention is characterized in that the X-ray powder diffraction pattern has a characteristic peak at a 2theta value of 20.90 ° ⁇ 0.20 °, 18.01 ° ⁇ 0.20 °, 24.10 ° ⁇ 0.20 °.
  • the crystal form C provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes a place where the 2theta value is 15.30° ⁇ 0.20°, 21.46° ⁇ 0.20°, 14.62° ⁇ 0.20°. Or two or three having characteristic peaks; preferred crystal form C provided by the present invention is further characterized in that the X-ray powder diffraction pattern has a value of 15.30° ⁇ 0.20°, 21.46° ⁇ 0.20°, 14.62 ° ⁇ at 2theta. There is a characteristic peak at 0.20°.
  • the crystal form C provided by the present invention is further characterized in that the X-ray powder diffraction pattern further includes one of 2theta values of 4.46° ⁇ 0.20°, 22.83° ⁇ 0.20°, 18.94 ⁇ 0.20° or Two or three have characteristic peaks; preferred crystalline form C provided by the present invention is further characterized by an X-ray powder diffraction pattern having a value of 4.46° ⁇ 0.20°, 22.83° ⁇ 0.20°, 18.94 ⁇ 0.20° at 2theta. There are characteristic peaks.
  • the crystal form C provided by the present invention has an X-ray powder diffraction pattern including a 2theta value of 20.90° ⁇ 0.20. °, 18.01 ° ⁇ 0.20 °, 24.10 ° ⁇ 0.20 °, 15.30 ° ⁇ 0.20 °, 21.46 ° ⁇ 0.20 °, 14.62 ° ⁇ 0.20 °, 4.46 ° ⁇ 0.20 °, 22.83 ° ⁇ 0.20 °, 18.94 ⁇ 0.20 ° position
  • One or more characteristic peaks in the middle One or more characteristic peaks in the middle.
  • crystal form C provided by the present invention is further characterized in that its X-ray powder diffraction pattern is substantially as shown in FIG.
  • the crystal form C provided by the present invention is characterized in that when performing differential scanning calorimetry, a small endothermic peak starts to be heated to around 157 ° C, and has a sharp endothermic near 178 ° C (peak temperature).
  • the peak, the differential scanning calorimetry chart is basically as shown in FIG. 21.
  • the crystal form C provided by the present invention is characterized in that when subjected to thermogravimetric analysis, when heated to 162 ° C, it has a weight loss gradient of about 2.4%, and the thermogravimetric analysis chart is substantially as shown in FIG.
  • Another object of the present invention is to provide a process for the preparation of a phosphate crystal form C, which is obtained by adding a phosphate powder of the compound of the formula (I) to a single solvent or a mixture of a plurality of solvents.
  • the solvent includes, but is not limited to, a single or mixed system of a nitrile, water, an alcohol, a ketone, an ester, an aromatic hydrocarbon, a halogenated hydrocarbon, a nitroalkane, a cyclic ether solvent.
  • the solvent is preferably water or a mixed solvent of water and a nitrile solvent.
  • a mixed solvent of the water and the nitrile solvent is preferably a mixed solvent of water and acetonitrile.
  • the phosphate powder comprises the phosphate crystal form B.
  • the phosphate crystal form B of the compound of the formula (I) is obtained by adding a compound of the formula (I) and phosphoric acid to a solvent system of an alcohol, a ketone, a nitrile, a cyclic ether or an aliphatic hydrocarbon.
  • the X-ray powder diffraction pattern of the phosphate form B of the compound of the formula (I) is included in the 2theta value of 19.62 ° ⁇ 0.20 °, 16.73 ° ⁇ 0.20 °, 3.20 ° ⁇ 0.20 °, 16.21 ° ⁇ 0.20 °, 22.67 ° ⁇
  • Another object of the present invention is to provide a process for the preparation of a phosphate crystal form C, which is obtained by adding a compound of the formula (I) and concentrated phosphoric acid (14.6 mol/L) to an aqueous solvent and stirring.
  • the aqueous solvent comprises a mixed solvent of water and a nitrile, an alcohol, a ketone, an ester, an aromatic hydrocarbon, a halogenated hydrocarbon, a nitroalkane or a cyclic ether solvent.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising an effective amount of a phosphate crystal form A, a phosphate crystal form B, a phosphate form C, or a mixture of two or three thereof, and a pharmaceutically acceptable Accepted carrier, diluent or excipient.
  • a therapeutically effective amount of a phosphate crystal form A, a phosphate form B, a phosphate form C, or a mixture of two or three thereof is mixed or contacted with one or more pharmaceutical excipients to form a pharmaceutical combination.
  • the pharmaceutical composition or formulation is prepared in a manner well known in the pharmaceutical art.
  • the phosphate crystal form A, the phosphate crystal form B, the phosphate crystal form C of the compound of the formula (I) or a mixture of two or three thereof can be used for the preparation.
  • the above pharmaceutical composition can be formulated into a certain dosage form and administered by a suitable route.
  • Dosage forms suitable for oral administration include tablets Agent, capsule, granule, powder, pill, powder, lozenge, solution, syrup or suspension, if necessary, can be suitable for rapid release, delayed release or regulated release of pharmaceutically active ingredients; suitable for parenteral administration
  • Dosage forms include aqueous or non-aqueous sterile injectable solutions, emulsions or suspensions; formulations suitable for rectal administration include suppositories or enemas; suitable formulations for transdermal administration include ointments, creams, patches;
  • Dosage forms for administration include aerosols, sprays, nasal drops; dosage forms suitable for vaginal administration include suppositories, stoppers, gels, pastes or sprays.
  • a pharmaceutically acceptable excipient in the above pharmaceutical composition, in the case of a solid oral dosage form including but not limited to: a diluent such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, Calcium hydrogen phosphate, tricalcium phosphate, mannitol, sorbitol, sugar, etc.; binders such as acacia, guar gum, gelatin, polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, poly Ethylene glycol or the like; a disintegrating agent such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silica, etc.; a lubricant such as stearic acid , magnesium stearate, zinc stearate, sodium benzoate, sodium acetate, etc.; glidants, such as colloidal silica; complex forming agents, such as
  • the coating is applied to the tablet, for example to provide a shellac barrier coating, a sugar coating or a polymeric coating, a polymer in the coating layer such as hydroxypropyl methylcellulose, polyvinyl alcohol, ethyl Cellulose, methacrylic polymer, hydroxypropyl cellulose or starch may also include anti-adherents such as silica, talc, opacifiers such as titanium dioxide, colorants such as iron oxide-based colorants.
  • suitable excipients include water, oils, alcohols, glycols, flavoring agents, preservatives, stabilizers, coloring agents, and the like; aqueous or nonaqueous sterile suspensions may be employed Containing suspending agents and thickeners; excipients suitable for aqueous suspensions include synthetic or natural gums such as gum arabic, arborvitae, alginate, dextran, sodium carboxymethylcellulose, methylcellulose , polyvinylpyrrolidone or gelatin.
  • the excipient of the aqueous or non-aqueous sterile injectable solution is usually sterile water, physiological saline or aqueous dextrose, may contain buffers, antioxidants, bacteriostatic agents and enable The pharmaceutical composition is isotonic with a blood solute.
  • Each excipient must be acceptable, compatible with the other ingredients in the formulation, and not deleterious to the patient.
  • the pharmaceutically acceptable carrier in the above pharmaceutical composition includes, but is not limited to, a mono-, di- or polysaccharide, a sugar alcohol or an additional polyhydroxy compound.
  • Suitable carriers include sugars and starches, such as lactose, sucrose, sorbitol, Mannitol, starch such as potato starch, corn starch or amylopectin, cellulose derivatives and the like.
  • the pharmaceutical composition can be prepared using methods well known to those skilled in the art in the art. In preparing a pharmaceutical composition, the crystalline form of the invention is admixed with one or more pharmaceutically acceptable excipients, optionally with one or more additional pharmaceutically active ingredients.
  • tablets, capsules, granules can be prepared by a process such as mixing, granulating, tableting or filling capsules; powders are prepared by mixing finely divided pharmaceutically active ingredients and excipients; solution and syrup
  • the agent can be prepared by dissolving the pharmaceutically active ingredient in a suitably flavored water or aqueous solution; the suspension can be prepared by dispersing the pharmaceutically active ingredient in a pharmaceutically acceptable carrier.
  • the crystalline form of the compound of formula (I) and its phosphate crystal form provided by the present invention can be used as an inhibitor of one or more JAKs,
  • the crystal form of the present invention can regulate the activity of JAK by the amount administered.
  • the crystalline form of the compound of formula (I) and its phosphate crystal form-adjustable JAK include any member of the JAK family, JAK can be JAK1, JAK2, JAK3 or TYK2, preferably, JAK is JAK1 or JAK2.
  • the crystalline form of the compound of formula (I) and its phosphate crystalline form provided herein can be used to treat a JAK-associated disease or condition in an individual (e.g., a patient) by administering a therapeutically effective amount or a therapeutically effective amount of a crystalline form of the compound of the present invention. Or a phosphate crystal form thereof or a pharmaceutical composition thereof is administered to an individual in need of such treatment.
  • a JAK-associated disease can include any disease, disorder, or condition that is directly or indirectly associated with the expression or activity of JAK, including levels of overexpression and/or abnormal activity.
  • JAK-associated diseases can also include any disease, disorder, or condition that can be prevented, ameliorated, or cured by modulating JAK activity.
  • JAK-related diseases include autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, juvenile arthritis, psoriatic arthritis, type I diabetes, lupus, psoriasis, inflammatory bowel disease, ulcerative colitis, Crohn Disease, myasthenia gravis, immunoglobulin nephropathy, autoimmune thyroid disease, etc.
  • the JAK-related disease is cancer, including cancer characterized by solid tumors (eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer) , malignant glioma, Kaposi's sarcoma, Castleman's disease, melanoma, etc., hematological cancer (eg, lymphoma, leukemia such as acute lymphoblastic leukemia, acute myeloid leukemia (AML) ) or multiple myeloma), as well as skin cancers such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma.
  • solid tumors eg, prostate cancer, kidney cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer
  • malignant glioma e.g., Kaposi's sarcoma, Castleman's disease, melanoma
  • hematological cancer
  • Examples of cutaneous T-cell lymphoma include Sezary syndrome and mycosis fungoides.
  • Other JAK-related diseases include inflammation and inflammatory diseases.
  • Exemplary inflammatory diseases include inflammatory diseases of the eye (eg, ulceris, uveitis, scleritis, conjunctivitis, or related diseases), inflammatory diseases of the respiratory tract (eg, the upper respiratory tract including the nose and sinuses, such as rhinitis or Sinusitis, or lower respiratory tract, including bronchitis, chronic obstructive pulmonary disease, etc.), inflammatory myopathy such as myocarditis, and other inflammatory diseases.
  • inflammatory diseases of the eye eg, ulceritis, scleritis, conjunctivitis, or related diseases
  • inflammatory diseases of the respiratory tract eg, the upper respiratory tract including the nose and sinuses, such as rhinitis or Sinusitis, or lower respiratory tract, including bronchitis, chronic obstructive pulmonary disease
  • phrases "effective therapeutic amount” or “therapeutically effective amount” as used herein refers to a biological response or drug response that is caused by a researcher, veterinarian, doctor or other clinician in a tissue, system, animal, individual or human. The amount of active compound or agent.
  • treating refers to one or more of the following: (1) preventing a disease; for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease. Preventing the disease, condition or disorder in the individual; (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or showing a disease or condition of the disease, condition or disorder; and (3) improving the disease A disease; for example, ameliorating the disease, condition or disorder (i.e., reversing the disease and/or condition) in an individual suffering from or showing a disease or condition of the disease, condition or disorder, e.g., reducing the severity of the disease.
  • a disease for example, a disease or condition that may be predisposed to a disease, disorder, or disorder, but has not yet suffered or manifested the disease.
  • Preventing the disease, condition or disorder in the individual (2) inhibiting the disease; for example, inhibiting the disease, condition or disorder in an individual who is suffering from or
  • polymorphic compound refers to different crystalline forms of the same compound and includes, but is not limited to, other solid molecular forms comprising hydrates and solvates of the same compound.
  • the phenomenon that a plurality of crystal forms are formed by the same drug molecule is called a drug polymorph, and a drug polymorph is a phenomenon commonly found in solid drugs.
  • X-ray powder diffraction pattern refers to an experimentally observed diffraction pattern or parameters derived therefrom.
  • the X-ray powder diffraction pattern was characterized by peak position and peak intensity.
  • the crystal form provided by the invention has good stability and remarkable process purification effect. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has low wettability, meets the requirements of bioavailability and efficacy, does not require special drying conditions in the preparation process, simplifies the preparation process and post-treatment process of the drug, and is not easily affected by humidity, and the storage condition The requirements are not harsh, and it is convenient for long-term storage, which greatly reduces the cost of material storage and quality control, and has strong economic value.
  • Figure 1 is an XRPD pattern of Form I
  • Figure 2 is a DSC diagram of Form I
  • Figure 3 is a TGA diagram of Form I
  • Figure 4 is a DVS diagram of Form I
  • Figure 5 is an XRPD pattern of Form II
  • Figure 6 is a DSC diagram of Form II
  • Figure 7 is a TGA diagram of Form II
  • Figure 8 is a 1 H NMR chart of Form II
  • Figure 9 is a comparison of XRPD before and after 90 days of Form I placed at 5 °C (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 10 is a comparison of XRPD of Form I placed at 25 °C / 60% (relative humidity) for 90 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 11 is a comparison of XRPD of Form I placed at 40 °C / 75% (relative humidity) for 90 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 12 is a comparison of XRPD of Form II placed at 5 °C for 90 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 13 is a comparison of XRPD of Form II placed at 25 °C / 60% (relative humidity) for 30 days (the above figure shows the XRPD pattern before placement, and the figure below shows the XRPD pattern after placement)
  • Figure 14 is an XRPD pattern of phosphate crystal form A
  • Figure 15 is a DSC chart of phosphate crystal form A
  • Figure 16 is a TGA diagram of phosphate crystal form A
  • Figure 17 is an XRPD pattern of phosphate form B
  • Figure 18 is a DSC chart of phosphate crystal form B
  • Figure 19 is a TGA diagram of phosphate form B
  • Figure 20 is an XRPD pattern of phosphate crystal form C
  • Figure 21 is a DSC chart of phosphate crystal form C
  • Figure 22 is a TGA diagram of the phosphate crystal form C
  • Figure 23 is a DVS diagram of phosphate crystal form A
  • Figure 24 is a DVS diagram of the phosphate crystal form C
  • Figure 25 is a comparison of XRPD of phosphate crystal form C before and after being placed at 25 ° C / 60% relative humidity for 30 days (the above figure is an XRPD pattern of pre-placement phosphate crystal form C, and the lower figure shows the phosphate crystal form after standing C's XRPD diagram)
  • Figure 26 is a comparison of XRPD of phosphate crystal form C before and after being placed at 40 ° C / 75% relative humidity for 30 days (the upper figure shows the XRPD pattern of the pre-placement phosphate crystal form C, and the lower figure shows the phosphate crystal form after standing. C's XRPD diagram)
  • test methods described are generally carried out under conventional conditions or conditions recommended by the manufacturer.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 1. Its XRPD diagram is shown in Figure 1, its DSC diagram is shown in Figure 2, and its TGA diagram is shown in Figure 3.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 3.
  • the XRPD pattern is shown in Fig. 5.
  • the DSC chart is shown in Fig. 6.
  • the TGA chart is shown in Fig. 7.
  • the 1 H-NMR chart is shown in Fig. 8.
  • the 1 H-NMR data is as follows:
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the crystal form I prepared by the present invention was allowed to stand under conditions of 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity for 90 days, and its XRPD was measured.
  • the experimental results are shown in Table 6.
  • the XRPD of crystal form I placed under the above three conditions for 90 days is shown in Fig. 9, Fig. 10, Fig. 11 respectively (Fig. 9 upper view, Fig. 10 upper view, Fig. 11 upper view, crystal form I before placement) XRPD map).
  • the crystal form II prepared by the present invention was placed under conditions of 5 ° C and 25 ° C / 60% relative humidity, respectively, and its XRPD was measured.
  • the experimental results are shown in Table 7.
  • the XRPD of Form II before and after being placed under the above conditions is shown in Fig. 12 and Fig. 13 (Fig. 12, Fig. 13 and Fig. 13 is the XRPD pattern of Form II before placement).
  • the results show that the crystalline form II of the compound of the formula (I) is left at 5 ° C for 90 days, and the crystal form remains unchanged at 25 ° C / 60% relative humidity for 30 days.
  • the crystalline form II of the compound of the formula (I) provided by the present invention has good stability. Sex.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 8. Its XRPD diagram is shown in Figure 14, its DSC diagram is shown in Figure 15, and its TGA diagram is shown in Figure 16.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 10. Its XRPD diagram is shown in Figure 17, its DSC diagram is shown in Figure 18, and its TGA diagram is shown in Figure 19.
  • the X-ray powder diffraction data of the crystal form obtained in this example is shown in Table 12. Its XRPD diagram is shown in Figure 20, its DSC diagram is shown in Figure 21, and its TGA diagram is shown in Figure 22.
  • the wetting weight gain is not less than 15%
  • Humidity Wet weight gain is less than 15% but not less than 2%
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%
  • the phosphate crystal form A prepared by the present invention was allowed to stand under conditions of 5 ° C, 25 ° C / 60% relative humidity, and 40 ° C / 75% relative humidity for 90 days, and its XRPD was measured.
  • the experimental results are shown in Table 16.

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Abstract

本发明涉及JAK抑制剂的新晶型及其制备方法。本发明提供的新晶型可用于治疗自身免疫疾病，特别是类风湿性关节炎。本发明提供的新晶型稳定性好，工艺提纯效果显著，且溶解度、引湿性符合药用要求。新晶型的制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。

Description

JAK抑制剂的晶型及其制备方法 技术领域
本发明涉及化学医药领域，特别是涉及{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈的晶型及其制备方法。
背景技术
JAK(Janus kinase)激酶是一个细胞内非受体酪氨酸激酶家族，介导细胞因子产生的信号，并通过JAK-STAT信号通路传递下去。目前有四种已知的JAK家族成员：JAK激酶1(JAK1)、JAK激酶2(JAK2)、JAK激酶3(JAK3)和酪氨酸激酶2(Tyrosine Kinase,TYK2)。JAK-依赖性细胞因子参与多种炎症和自身免疫性疾病的发病过程，JAK抑制剂或可广泛用于治疗各种炎性疾病。
Baricitinib是由礼来(Lilly)制药和因塞特(Incyte)公司共同研发的一种选择性的JAK1和JAK2抑制剂，在激酶检测中，Baricitinib针对JAK1和JAK2表现出的抑制强度要比JAK3高100倍。目前Baricitinib在美国处于临床试验，用于类风湿性关节炎的治疗。该药物的化学名称为：{1-(乙基磺酰基)-3-[4-(7H-吡咯并[2，3-d]嘧啶-4-基)-1H-吡唑-1-基]氮杂环丁烷-3-基}乙腈，其结构式如式(I)所示。
Figure PCTCN2016076141-appb-000001
具体的药用活性是药物活性物质被批准上市必需满足的基本先决条件。然而，有多种其他的要求也是药物活性物质必须遵循的条件。这些要求以各种与其本身活性物质的性质有关的参数为基础。在没有限制下，这些参数的实例为活性成分在各种环境条件下的化学和固态稳定性及储存稳定、在药物组合物制造期间的稳定性，以及活性成分在最终药物组合物的稳定性等。
用于制备药物组合物的药物活性物质应尽可能纯且必须保证在各种环境情况下具有长期保存的稳定性。避免使用含有除了含有确实活性物质外还含有例如其分解产物的药物组合物是最基本的，在这些情形下，药物中的活性物质含量可能少于标示的含量。此外，药学活性物质为非吸湿性、对降解和随后其固体形式的变化均稳定是重要的，如果药学活性物质在其吸收水(缓慢地或随时间)的意义上为吸湿性的，则几乎不可能可靠地将药学活性物质制成药物，原因是待添加以提供相同剂量的物质的量会根据水合程度大幅变化，另外，水合或固体形式的改变可以引起理化性质(例如溶解度或溶解速率)的变化，理化性质的变化可以进而引起患者的不一致的吸收。因此优选地，药物活性物质应只具有轻微吸湿性。
因此，药学活性物质的化学稳定性、固态稳定性、“保存期”和材料处理性质(例如使化合物溶解的容易度)是非常重要的因素。在理想的情况下，药学活性物质和包含其的任何药物组合物应当能够有效储存相当长的时期，而不表现出活性物质的理化性质(例如其活性、水分含量、溶解度性质、固体形式等)的显著变化。此外，药品将通常需要处理以达到适于吸入的粒径且任何结晶型在此处理期间必须稳定以使最终产品的性质可预测并可靠。简言之，在生产商业上可行并且药学上可接受的药用组合物时，无论哪种可能，以一种充分结晶和稳定的形态提供药物都是理想的。
同一药物的不同晶型在外观、溶解度、熔点、溶出度、生物有效性等方面可能会有显著不同，也会对药物的稳定性、生物利用度及疗效产生不同的影响。因此，研发新的更适合应用的晶型对于药物开发具有非常重要的意义。
如本领域技术人员所知，已知化学物质的新的固体多晶型形式的存在是不可预见的。多晶型化合物的存在或多晶型形式的数量均不可预见。另外，在什么条件下发生结晶并得到特定的形式，以及所述多晶型形式的特性如何，也都是不可预测的。由于多晶型化合物的每种多晶型的特性(例如溶解度、稳定性)以及因此引起的应用与储存的适用性不同，因此研究药物物质的所有固态形式，包括所有的多晶型形式，对于提供具有改善的储存稳定性或可预测的溶解度特性的药物是必要的。
固体化学药物晶型不同，可造成其溶解度和稳定性不同，从而影响药物的吸收和生物利用度，并且会导致临床药效的差异。然而，目前尚无式(I)化合物的晶型的相关报导，因此，有必要对式(I)化合物进行全面系统的多晶型筛选，选择最适合开发的晶型。
本发明的发明人在研究过程中惊奇的发现了式(I)化合物的两种晶型及三种磷酸盐晶型。并且本发明的晶型稳定性好，溶解度、引湿性符合药用要求，且制备方法简单，成本低廉，对未来该药物的优化和开发具有重要价值。
发明内容
本发明提供了式(I)化合物的新晶型，盐的新晶型及其制备方法和用途。
本发明的一个目的是提供一种式(I)化合物的晶型，命名为晶型I。
本发明提供的晶型I，其特征在于，其X射线粉末衍射图在2theta值为15.33°±0.20°、16.66°±0.20°、19.06°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图还包括在2theta值为14.91°±0.20°、16.25°±0.20°、15.74°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为14.91°±0.20°、16.25°±0.20°、15.74°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图还包括在2theta值为25.51°±0.20°、12.40°±0.20°、17.39°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为25.51°±0.20°、12.40°±0.20°、17.39°±0.20°处具有特征峰。
优选的，本发明提供的晶型I，其X射线粉末衍射图包括在2theta值为15.33°±0.20 °、16.66°±0.20°、19.06°±0.20°、14.91°±0.20°、16.25°±0.20°、15.74°±0.20°、25.51°±0.20°、12.40°±0.20°、17.39°±0.20°的位置中的一处或多处的特征峰。
更进一步的，本发明提供的晶型I，其特征还在于，其X射线粉末衍射图基本如图1所示。
本发明提供的晶型I，其特征在于，当进行差示扫描量热分析时，加热至212℃附近开始出现吸热峰，其差示扫描量热分析图基本如图2所示。
本发明提供的晶型I，其特征在于，当进行热重分析时，加热至200℃时，具有约0.8％的重量损失梯度，其热重分析图基本如图3所示。
本发明的另一个目的是提供晶型I的制备方法，其特征在于，将式(I)化合物加入到一种或多种选自以下的溶剂体系中：水，醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚或脂肪烃类的单一或它们的混合体系，通过反溶剂添加、悬浮搅拌、加热降温结晶或挥发结晶制得。
更进一步的，所述醇类溶剂优选甲醇；所述酮类溶剂优选丙酮；所述卤代烃优选二氯甲烷。
本发明的另一个目的是提供一种式(I)化合物的晶型，命名为晶型II。
本发明提供的晶型II，其特征在于，其X射线粉末衍射图在2theta值为18.00°±0.20°、10.80°±0.20°、7.26°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型II，其特征还在于，其X射线粉末衍射图还包括在2theta值为14.60°±0.20°、12.14°±0.20°、11.21°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为14.60°±0.20°、12.14°±0.20°、11.21°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为22.59°±0.20°、22.03°±0.20°、19.64°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为22.59°±0.20°、22.03°±0.20°、19.64°±0.20°处具有特征峰。
优选的，本发明提供的晶型II，其X射线粉末衍射图包括在2theta值为18.00°±0.20°、10.80°±0.20°、7.26°±0.20°、14.60°±0.20°、12.14°±0.20°、11.21°±0.20°、22.59°±0.20°、22.03°±0.20°、19.64°±0.20°的位置中的一处或多处的特征峰。
更进一步的，本发明提供的晶型II，其特征还在于，其X射线粉末衍射图基本如图5所示。
本发明提供的晶型II，其特征在于，当进行差示扫描量热分析时，加热至144℃附近开始出现第一个吸热峰，继续加热至213℃附近开始出现第二个吸热峰，其差示扫描量热分析图基本如图6所示。
本发明提供的晶型II，其特征在于，当进行热重分析时，加热至200℃时，具有约16.5％的重量损失梯度，其热重分析图基本如图7所示。
本发明的另一个目的是提供晶型II的制备方法，包括将(I)化合物的固体加入到冰醋 酸或冰醋酸与其他溶剂的混合体系中，通过反溶剂添加、挥发、加热降温或悬浮搅拌制得。
更进一步的，所述其他有机溶剂包括但不限于水，醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚，脂肪烃类溶剂。
本发明的另一个目的是提供一种药用组合物，包含有效治疗量的晶型I或晶型II或二者的混合物以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的晶型I或晶型II或二者的混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
本发明提供的式(I)化合物的晶型I或晶型II或二者的混合物可用于治疗自身免疫疾病的药物的制备，特别是用于治疗类风湿性关节炎药物制剂的用途。
本发明的另一个目的是提供一种式(I)化合物的磷酸盐晶型，命名为晶型A。
本发明提供的晶型A，其特征在于，其X射线粉末衍射图在2theta值为17.22°±0.20°、8.37°±0.20°、3.59°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图还包括在2theta值为23.96°±0.20°、19.40°±0.20°、18.55°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为23.96°±0.20°、19.40°±0.20°、18.55°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图还包括在2theta值为7.78°±0.20°、18.00°±0.20°、25.40°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为7.78°±0.20°、18.00°±0.20°、25.40°±0.20°处具有特征峰。
优选的，本发明供的晶型A，其X射线粉末衍射图包括在2theta值为17.22°±0.20°、8.37°±0.20°、3.59°±0.20°、23.96°±0.20°、19.40°±0.20°、18.55°±0.20°、7.78°±0.20°、18.00°±0.20°、25.40°±0.20°的位置中的一处或多处的特征峰。
更进一步的，本发明提供的晶型A，其特征还在于，其X射线粉末衍射图基本如图14所示。
本发明提供的晶型A，其特征在于，当进行差示扫描量热分析时，加热至187℃附近开始出现吸热峰，其差示扫描量热分析图基本如图15所示。
本发明提供的晶型A，其特征在于，当进行热重分析时，加热至175℃时，具有约1.3％的重量损失梯度，其热重分析图基本如图16所示。
本发明的另一个目的是提供磷酸盐晶型A的制备方法，其特征在于，将式(I)化合物与磷酸加入到多种溶剂适当的混合析晶溶剂中，通过搅拌制得。
更进一步的，所述适当的混合析晶溶剂包括但不限于醇类，酮类，腈类，环醚，脂肪烃类溶剂的混合体系。
更进一步的，所述混合溶剂体系优选乙腈和乙醇混合，所述乙腈和乙醇的优选体积比约为4:1至2:1，更优选体积比约为3:1。
本发明的另一个目的是提供一种式(I)化合物的磷酸盐晶型，命名为晶型B。
本发明提供的晶型B，其特征在于，其X射线粉末衍射图在2theta值为19.62°±0.20°、16.73°±0.20°、3.20°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图还包括在2theta值为16.21°±0.20°、22.67°±0.20°、25.85°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为16.21°±0.20°、22.67°±0.20°、25.85°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图还包括在2theta值为20.90°±0.20°、17.53°±0.20°、26.67°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型B，其特征还在于，其X射线粉末衍射图在2theta值为20.90°±0.20°、17.53°±0.20°、26.67°±0.20°处具有特征峰。
优选的，本发明供的晶型B，其X射线粉末衍射图包括在2theta值为19.62°±0.20°、16.73°±0.20°、3.20°±0.20°、16.21°±0.20°、22.67°±0.20°、25.85°±0.20°、20.90°±0.20°、17.53°±0.20°、26.67°±0.20°的位置中的一处或多处的特征峰。
更进一步的，本发明提供的晶型B，其特征还在于，其X射线粉末衍射图基本如图17所示。
本发明提供的晶型B，其特征在于，当进行差示扫描量热分析时，加热至169℃附近开始出现吸热峰，其差示扫描量热分析图基本如图18所示。
本发明提供的晶型B，其特征在于，当进行热重分析时，加热至160℃时，具有约1.2％的重量损失梯度，其热重分析图基本如图19所示。
本发明的另一个目的是提供磷酸盐晶型B的制备方法，其特征在于，将式(I)化合物与磷酸加入到适当的析晶溶剂中，通过搅拌制得。
更进一步的，所述适当的析晶溶剂包括但不限于无水醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚类溶剂体系。
更进一步的，所述酮类析晶溶剂优选甲基异丁酮；所述酯类析晶溶剂优选醋酸异丙酯。
本发明的另一个目的是提供一种式(I)化合物的磷酸盐晶型，命名为晶型C。
本发明提供的晶型C，其特征在于，其X射线粉末衍射图在2theta值为20.90°±0.20°、18.01°±0.20°、24.10°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型C，其特征还在于，其X射线粉末衍射图还包括在2theta值为15.30°±0.20°、21.46°±0.20°、14.62°±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型C，其特征还在于，其X射线粉末衍射图在2theta值为15.30°±0.20°、21.46°±0.20°、14.62°±0.20°处具有特征峰。
更进一步的，本发明提供的晶型C，其特征还在于，其X射线粉末衍射图还包括在2theta值为4.46°±0.20°、22.83°±0.20°、18.94±0.20°中的一处或两处或三处具有特征峰；优选的本发明提供的晶型C，其特征还在于，其X射线粉末衍射图在2theta值为4.46°±0.20°、22.83°±0.20°、18.94±0.20°处具有特征峰。
优选的，本发明提供的晶型C，其X射线粉末衍射图包括在2theta值为20.90°±0.20 °、18.01°±0.20°、24.10°±0.20°、15.30°±0.20°、21.46°±0.20°、14.62°±0.20°、4.46°±0.20°、22.83°±0.20°、18.94±0.20°的位置中的一处或多处的特征峰。
更进一步的，本发明提供的晶型C，其特征还在于，其X射线粉末衍射图基本如图20所示。
本发明提供的晶型C，其特征在于，当进行差示扫描量热分析时，加热至157℃附近开始出现一个小吸热峰，并在178℃(峰值温度)附近具有一个尖锐的吸热峰，其差示扫描量热分析图基本如图21所示。
本发明提供的晶型C，其特征在于，当进行热重分析时，加热至162℃时，具有约2.4％的重量损失梯度，其热重分析图基本如图22所示。
本发明的另一个目的是提供磷酸盐晶型C的制备方法，其特征在于，将式(I)化合物的磷酸盐粉末加入到单一溶剂或多种溶剂的混合体系内搅拌即可得到。
更进一步的，所述溶剂包括但不局限于腈类，水，醇类，酮类，酯类，芳香烃类，卤代烃类，硝基烷烃类，环醚类溶剂的单一或者混合体系。
更进一步的，所述溶剂优选水或水与腈类溶剂的混合溶剂。
更进一步的，所述水与腈类溶剂的混合溶剂优选水与乙腈的混合溶剂。
更进一步的，所述磷酸盐粉末包含所述的磷酸盐晶型B。
其中所述式(I)化合物的磷酸盐晶型B是通过将式(I)化合物与磷酸加入到醇类、酮类、腈类、环醚类、脂肪烃类溶剂体系中搅拌得到。
其中式(I)化合物的磷酸盐晶型B的X射线粉末衍射图包括在2theta值为19.62°±0.20°、16.73°±0.20°、3.20°±0.20°、16.21°±0.20°、22.67°±0.20°、25.85°±0.20°、20.90°±0.20°、17.53°±0.20°、26.67°±0.20°的位置中的一处或多处的特征峰。
本发明的另一个目的是提供磷酸盐晶型C的制备方法，其特征在于，将式(I)化合物与浓磷酸(14.6mol/L)加入到含水溶剂中搅拌即可得到。
更进一步的，所述含水溶剂包含水和腈类，醇类，酮类，酯类，芳香烃类，卤代烃类，硝基烷烃类或环醚类溶剂的混合溶剂。
本发明的另一个目的是提供一种药用组合物，包含有效量的磷酸盐晶型A、磷酸盐晶型B、磷酸盐晶型C或其中二者或三者的混合物，以及药学上可接受的载体、稀释剂或赋形剂。一般是将治疗有效量的磷酸盐晶型A、磷酸盐晶型B、磷酸盐晶型C或其中二者或三者的混合物与一种或多种药用辅料混合或接触制成药用组合物或制剂，该药用组合物或制剂是以制药领域中熟知的方式进行制备的。
更进一步的，本发明所述的药用组合物中，式(I)化合物的磷酸盐晶型A、磷酸盐晶型B、磷酸盐晶型C或其中二者或三者的混合物可用于制备治疗自身免疫疾病的药物，特别是类风湿关节炎药物制剂中的用途。
上述药物组合物可制成一定的剂型，通过适合的途径给药。例如口服、肠胃外(包括皮下、肌肉、静脉或皮内)、直肠、透皮、经鼻、阴道等途径。适合口服给药的剂型包括片 剂、胶囊剂、颗粒剂、散剂、丸剂、粉剂、锭剂、溶液、糖浆剂或混悬剂，根据需要，可适于药物活性成分的快速释放、延迟释放或调节释放；适合肠胃外给药的剂型包括水性或非水性的无菌注射溶液、乳液或混悬液；适合直肠给药的剂型包括栓剂或灌肠剂；适合透皮给药的剂型包括软膏、霜剂、贴剂；适合经鼻给药的剂型包括气雾剂、喷剂、滴鼻剂；适合阴道给药的剂型包括栓剂、塞剂、凝胶、糊剂或喷剂。优选地，本发明的晶型尤其适合制备成片剂、混悬剂、胶囊剂、崩解片、即释、缓释和控释片剂；进一步优选为片剂、混悬剂和胶囊剂。
上述药物组合物中药学上可接受的赋形剂，在固体口服剂型的情况下，包括但不限于：稀释剂，例如淀粉、预胶化淀粉、乳糖、粉状纤维素、微晶纤维素、磷酸氢钙、磷酸三钙、甘露醇、山梨醇、糖等；粘合剂，例如阿拉伯胶、瓜尔胶、明胶、聚乙烯吡咯烷酮、羟丙基纤维素、羟丙基甲基纤维素、聚乙二醇等；崩解剂，例如淀粉、羟基乙酸淀粉钠、预胶化淀粉、交联聚维酮、交联羧甲基纤维素钠、胶体二氧化硅等；润滑剂，例如硬脂酸、硬脂酸镁、硬脂酸锌、苯甲酸钠、乙酸钠等；助流剂，例如胶体二氧化硅等；复合物形成剂，例如各种级别的环糊精和树脂；释放速度控制剂，例如羟丙基纤维素、羟甲基纤维素、羟丙基甲基纤维素、乙基纤维素、甲基纤维素、甲基丙烯酸甲酯、蜡等。可用的其他药学上可接受的赋形剂包括但不限于成膜剂、增塑剂、着色剂、调味剂、粘度调节剂、防腐剂、抗氧化剂等。任选地，对片剂涂覆包衣层，例如提供虫胶隔离包衣、糖衣或聚合物包衣，包衣层中的聚合物例如羟丙基甲基纤维素、聚乙烯醇、乙基纤维素、甲基丙烯酸类聚合物、羟丙基纤维素或淀粉，还可以包括抗粘着剂如二氧化硅、滑石粉，乳浊剂如二氧化钛，着色剂如氧化铁类着色剂。在液体口服剂型的情况下，合适的赋形剂包括水、油类、醇类、二醇类、调味剂、防腐剂、稳定剂、着色剂等；水或非水的无菌混悬剂可含有悬浮剂和增稠剂；适用于水性混悬剂的赋形剂包括合成胶或天然胶例如阿拉伯树胶、苍耳树胶、藻酸盐、葡聚糖、羧甲基纤维素钠、甲基纤维素、聚乙烯吡咯烷酮或明胶。在胃肠外给药剂型的情况下，水或非水的无菌注射溶液的赋形剂通常为无菌水、生理盐水或葡萄糖水溶液，可以含有缓冲剂、抗氧化剂、抑菌剂和能够使该药物组合物与血液等渗的溶质。每一种赋形剂必须是可接受的，能与配方中的其他成分兼容并且对于患者无害。
上述药物组合物中药学上可接受的载体包括但不限于：单，双或多糖，糖醇或另外的多羟基化合物混合，适宜的载体包括糖和淀粉等，如乳糖，蔗糖，山梨醇糖，甘露醇，淀粉如马铃薯淀粉，玉米淀粉或支链淀粉，纤维素衍生物等。所述药物组合物可以使用现有技术中本领域技术人员公知的方法来制备。制备药物组合物时，将本发明的晶型与一种或多种药学上可接受的赋形剂相混合，任选地与一种或多种其他的药物活性成分相混合。例如，片剂、胶囊剂、颗粒剂可以通过混合、制粒、压片或填充胶囊等工艺来制备；粉剂通过将研细到合适大小的药物活性成分及赋形剂混合来制备；溶液和糖浆剂可通过将药物活性成分溶解于适当调味的水或水性溶液中来制备；混悬剂可通过将药物活性成分分散于药学上可接受的载体中来制备。
本发明提供的式(I)化合物晶型及其磷酸盐晶型可以用作一种或多种JAK的抑制剂， 本发明的晶型可通过给药量来调节JAK的活性。式(I)化合物晶型及其磷酸盐晶型可调节的JAK包括JAK家族的任何成员，JAK可以是JAK1、JAK2、JAK3或TYK2，优选的，JAK是JAK1或JAK2。
本发明提供的式(I)化合物晶型及其磷酸盐晶型可用于治疗个体(例如患者)的JAK相关性疾病或病症，其通过将治疗有效量或治疗有效剂量的本发明的化合物晶型或其磷酸盐晶型或其药物组合物给药于需要这种治疗的个体而进行。JAK相关性疾病可以包括与JAK的表达或活性、包括过表达和/或异常活性水平直接或间接关联的任何疾病、障碍或病症。JAK相关性疾病还可以包括能够通过调节JAK活性来预防、改善或治愈的任何疾病、障碍或病症。JAK相关性疾病包括自身免疫病如多发性硬化，类风湿性关节炎，少年关节炎，牛皮癣关节炎，I型糖尿病，狼疮，银屑病，炎症性肠病，溃疡性结肠炎，克罗恩氏病，重症肌无力，免疫球蛋白肾病，自身免疫甲状腺疾病等。
在其他实施方案中，该JAK相关性疾病是癌症，包括以实性肿瘤为特征的癌症(例如前列腺癌，肾癌，肝癌，胰腺癌，胃癌，乳腺癌，肺癌，头颈部癌，甲状腺癌，恶性胶质瘤，卡波济氏肉瘤，巨大淋巴结增生症(Castleman’s disease)，黑色素瘤等)，血液系统癌症(例如，淋巴瘤，白血病如急性淋巴母细胞性白血病，急性髓性白血病(AML)或多发性骨髓瘤)，以及皮肤癌如皮肤T细胞淋巴瘤(CTCL)和皮肤B细胞淋巴瘤。皮肤T细胞淋巴瘤的实例包括塞扎里综合征和蕈样肉芽肿病。其他JAK相关性疾病包括炎症和炎性疾病。示例性炎性疾病包括眼睛的炎性疾病(例如，虹膜炎，眼色素层炎，巩膜炎，结膜炎或相关疾病)，呼吸道的炎性疾病(例如包括鼻子和鼻窦的上呼吸道，如鼻炎或鼻窦炎，或下呼吸道，包括支气管炎、慢性阻塞性肺病等)，炎症性肌病如心肌炎，和其他炎性疾病。
本文所使用的短语“有效治疗量”或“治疗有效量”是指引起由研究人员、兽医、医生或其他临床医师在组织、系统、动物、个体或人中所要寻求的生物反应或药物反应的活性化合物或药剂的量。
本文所使用的术语“治疗”是指下列中的一种或多种：(1)预防疾病；例如在可能倾向于罹患疾病、病症或障碍、但还没有遭受或显示该疾病的病变或症状的个体中预防该疾病、病症或障碍；(2)抑制该疾病；例如在正遭受或显示该疾病、病症或障碍的病变或症状的个体中抑制该疾病、病症或障碍；以及(3)改善该疾病；例如，在遭受或显示该疾病、病症或障碍的病变或症状的个体中改善该疾病、病症或障碍(即逆转病变和/或症状)，例如减低疾病的严重度。
本文所使用的术语“多晶型化合物”是指相同化合物的不同晶型且包括但不限于包含相同化合物的水合物及溶剂合物的其它固态分子形式。同一种药物分子形成多种晶型的现象称为药物多晶型，药物多晶型是固体药物中普遍存在的现象。
本文所使用的术语“X射线粉末衍射图”是指实验观测到的衍射图或源自其的参数。通过峰位置及峰强度表征X射线粉末衍射图。
本发明的有益效果为：
目前尚无专利或文献报导式(I)化合物的晶型，本发明的发明人经过研究，突破了这 一难题，找到了适合开发的几种新晶型。
本发明提供的晶型稳定性好，工艺提纯效果显著。能很好地避免药物储存以及开发过程中发生转晶，从而避免生物利用度以及药效的改变。
本发明提供的晶型引湿性较低，满足生物利用度和药效要求，在制备工艺中无需特殊的干燥条件，简化了药物的制备工艺和后处理工艺，且不易受湿度影响，对储存条件要求不苛刻，便于长期贮存，大大降低了物料储存以及质量控制方面的成本，具有很强的经济价值。
附图说明
图1为晶型I的XRPD图
图2为晶型I的DSC图
图3为晶型I的TGA图
图4为晶型I的DVS图
图5为晶型II的XRPD图
图6为晶型II的DSC图
图7为晶型II的TGA图
图8为晶型II的1H NMR图
图9为晶型I放置在5℃条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图10为晶型I放置在25℃/60％(相对湿度)条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图11为晶型I放置在40℃/75％(相对湿度)条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图12为晶型II放置在5℃条件下90天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图13为晶型II放置在25℃/60％(相对湿度)条件下30天前后的XRPD对比图(上图为放置前的XRPD图，下图为放置后的XRPD图)
图14为磷酸盐晶型A的XRPD图
图15为磷酸盐晶型A的DSC图
图16为磷酸盐晶型A的TGA图
图17为磷酸盐晶型B的XRPD图
图18为磷酸盐晶型B的DSC图
图19为磷酸盐晶型B的TGA图
图20为磷酸盐晶型C的XRPD图
图21为磷酸盐晶型C的DSC图
图22为磷酸盐晶型C的TGA图
图23为磷酸盐晶型A的DVS图
图24为磷酸盐晶型C的DVS图
图25为磷酸盐晶型C在25℃/60％相对湿度条件下放置30天前后的XRPD对比图(上图为放置前磷酸盐晶型C的XRPD图，下图为放置后磷酸盐晶型C的XRPD图)
图26为磷酸盐晶型C在40℃/75％相对湿度条件下放置30天前后的XRPD对比图(上图为放置前磷酸盐晶型C的XRPD图，下图为放置后磷酸盐晶型C的XRPD图)
具体实施方式
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。
下述实施例中，所述的试验方法通常按照常规条件或制造厂商建议的条件实施。
本发明中所用到的缩写的解释如下：
XRPD：X射线粉末衍射
DSC：差示扫描量热分析
TGA：热重分析
DVS：动态水分吸附
1H NMR：液态核磁氢谱
本发明所述的X射线粉末衍射图在Panalytical Empyrean X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下：
X射线反射参数：Cu,Kα
Kα1
Figure PCTCN2016076141-appb-000002
1.540598；Kα2
Figure PCTCN2016076141-appb-000003
1.544426
Kα2/Kα1强度比例：0.50
电压：45仟伏特(kV)
电流：40毫安培(mA)
扫描范围：自3.0至40.0度
本发明所述的差示扫描量热分析(DSC)图在TA Q2000上采集。本发明所述的差示扫描量热分析(DSC)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
本发明所述的热重分析(TGA)图在TA Q5000上采集。本发明所述的热重分析(TGA)的方法参数如下：
扫描速率：10℃/min
保护气体：氮气
实施例1
式(I)化合物晶型I的制备方法：
将39.5mg式(I)化合物加到1.5mL丙酮中得悬浊液，将该悬浊液置于50℃恒温培养箱中搅拌100分钟，趁热过滤得澄清溶液，以0.1℃每分钟的速度缓慢降温至5℃，有固体析出，离心取下层固体，置于25℃恒温干燥过夜，经检测，所得固体为晶型I。
本实施例得到的晶型的X射线粉末衍射数据如表1所示。其XRPD图如图1，其DSC图如图2，其TGA图如图3。
表1
2theta d间隔 强度％
4.14 21.35 3.97
12.46 7.10 28.61
13.96 6.35 13.61
14.58 6.08 14.56
14.97 5.92 59.98
15.39 5.76 100.00
15.68 5.65 34.24
16.27 5.45 38.33
16.66 5.32 94.55
16.88 5.25 38.62
17.39 5.10 28.27
19.06 4.66 64.93
19.20 4.62 51.06
19.60 4.53 16.15
19.87 4.47 14.94
20.37 4.36 16.94
20.69 4.29 10.35
22.03 4.03 15.63
22.43 3.96 15.50
24.14 3.69 7.46
25.16 3.54 23.41
25.51 3.49 33.04
26.23 3.40 10.01
26.56 3.36 6.90
27.47 3.25 8.05
28.45 3.14 6.62
29.18 3.06 9.44
29.39 3.04 9.93
29.81 3.00 10.45
30.76 2.91 5.05
31.36 2.85 3.06
31.69 2.82 2.04
32.40 2.76 4.13
33.20 2.70 2.80
33.62 2.67 4.66
33.99 2.64 5.61
35.24 2.55 8.54
35.85 2.50 1.86
37.12 2.42 3.93
实施例2
式(I)化合物晶型I的制备方法：
将5.16mg的式(I)化合物溶解于1.80mL二氯甲烷中，室温下挥发，所得固体经检测为晶型I。
本实施例得到的晶型的X射线粉末衍射数据如表2所示。
表2
2theta d间隔 强度％
3.92 22.52 36.56
12.39 7.14 62.10
13.95 6.35 64.03
14.55 6.09 16.66
14.93 5.93 63.18
15.39 5.76 80.22
15.66 5.66 48.17
16.25 5.45 64.90
16.60 5.34 100.00
17.37 5.10 5.25
19.06 4.66 56.99
19.89 4.46 25.90
20.37 4.36 13.73
20.71 4.29 12.40
22.05 4.03 8.24
24.17 3.68 8.96
25.25 3.53 55.47
25.46 3.50 52.40
26.34 3.38 9.04
26.60 3.35 6.65
28.51 3.13 2.56
29.49 3.03 6.70
29.89 2.99 8.73
30.87 2.90 25.90
31.80 2.81 5.47
33.27 2.69 4.75
34.10 2.63 3.58
35.37 2.54 7.36
36.02 2.49 5.63
37.09 2.42 4.65
实施例3
式(I)化合物晶型II的制备方法：
将106.3mg的式(I)化合物溶解于1.0mL冰醋酸中，室温下缓慢挥发，所得固体经检测为晶型II。
本实施例得到的晶型的X射线粉末衍射数据如表3所示。其XRPD图如图5，其DSC图如图6，其TGA图如图7，其1H-NMR图如图8，1H-NMR数据如下：
1H-NMR(400MHz,DMSO-d6)δ12.13(s,1H),8.92(s,1H),8.71(s,1H),8.47(s,1H),7.62(dd,J1＝2.4Hz,J2＝3.2Hz,1H),7.08(dd,J1＝1.2Hz,J2＝3.2Hz,1H),4.60(d,J＝9.2Hz,2H),4.24(d,J＝9.2Hz,2H),3.69(s,2H),3.23(q,J＝7.2Hz,2H),1.90(s,3H),1.25(t,J＝7.2Hz,3H)。
表3
2theta d间隔 强度％
7.26 12.18 80.22
9.31 9.50 16.60
10.87 8.14 94.25
11.21 7.89 29.44
12.14 7.29 59.63
14.60 6.07 68.00
15.10 5.87 4.89
16.96 5.23 4.01
17.52 5.06 18.17
18.00 4.93 100.00
19.33 4.59 5.61
19.64 4.52 18.18
19.96 4.45 4.49
20.73 4.29 0.89
21.27 4.18 3.69
22.03 4.03 19.86
22.42 3.96 13.33
22.59 3.94 24.49
23.60 3.77 5.99
24.18 3.68 1.69
25.67 3.47 6.76
26.70 3.34 3.41
27.30 3.27 3.07
27.53 3.24 5.43
28.28 3.16 2.93
28.84 3.10 5.32
29.51 3.03 17.10
29.92 2.99 4.03
30.55 2.93 1.16
31.07 2.88 1.20
31.78 2.82 4.30
34.22 2.62 5.60
35.54 2.53 1.72
37.42 2.40 1.93
38.49 2.34 1.02
实施例4
式(I)化合物晶型II的制备方法：
将5.22mg式(I)化合物的固体溶解于0.1mL冰醋酸中，室温下挥发，所得固体经检测为晶型II。
本实施例得到的晶型的X射线粉末衍射数据如表4所示。
表4
2theta d间隔 强度％
7.27 12.16 64.39
9.31 9.50 63.85
10.87 8.14 99.37
11.21 7.89 26.31
12.14 7.29 49.51
14.61 6.06 57.03
15.08 5.88 4.74
17.51 5.07 22.95
18.00 4.93 100.00
19.63 4.52 15.32
19.96 4.45 11.72
22.01 4.04 18.45
22.29 3.99 11.02
22.57 3.94 17.52
23.60 3.77 6.34
25.64 3.47 6.00
26.70 3.34 5.23
27.51 3.24 5.33
28.29 3.15 7.97
28.83 3.10 6.43
29.52 3.03 17.04
31.79 2.82 4.23
34.22 2.62 4.17
35.53 2.53 2.34
实施例5
式(I)化合物晶型I的引湿性实验：
取本发明的式(I)化合物晶型I约10mg采用动态水分吸附(DVS)仪测试其引湿性。实验结果如表5所示。晶型I的引湿性实验的DVS图如图4所示。
表5
Figure PCTCN2016076141-appb-000004
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的式(I)化合物晶型I在80％湿度下平衡后增重0.44％，根据引湿 性增重的界定标准，属于略有引湿性。
实施例6
式(I)化合物晶型I的稳定性实验：
将本发明制备得到的晶型I分别在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下放置90天，测定其XRPD。实验结果见表6。晶型I放置在上述三个条件下90天前后的XRPD分别如图9、图10、图11所示(图9上图、图10上图、图11上图为晶型I在放置前的XRPD图)。
表6
Figure PCTCN2016076141-appb-000005
结果表明，式(Ⅰ)化合物晶型I在5℃、25℃/60％相对湿度和40℃/75％相对湿度条件下，放置90天晶型保持不变，本发明提供的式(Ⅰ)化合物晶型I具有良好的稳定性。
实施例7
式(I)化合物晶型II的稳定性实验：
将本发明制备得到的晶型II分别在5℃、25℃/60％相对湿度的条件下放置，测定其XRPD。实验结果见表7。晶型II在上述条件下放置前后的XRPD分别如图12、图13所示(图12上图、图13上图为晶型II在放置前的XRPD图)。
表7
Figure PCTCN2016076141-appb-000006
结果表明，式(Ⅰ)化合物晶型II在5℃放置90天，25℃/60％相对湿度放置30天晶型保持不变，本发明提供的式(Ⅰ)化合物晶型II具有良好的稳定性。
实施例8
式(I)化合物磷酸盐晶型A的制备方法：
将502.6mg式(I)化合物悬浮于12.5mL乙腈和4.0mL乙醇的混合溶剂中，将90μL浓磷酸(14.6mol/L)溶于1mL乙醇中后滴加到该悬浮液中，置于70℃烘箱中搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为磷酸盐晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表8所示。其XRPD图如图14，其DSC图如图15，其TGA图如图16。
表8
2theta d间隔 强度％
3.59 24.63 47.91
4.02 22.01 1.79
7.78 11.36 86.50
8.00 11.05 37.44
8.38 10.55 49.77
10.65 8.31 2.31
11.51 7.69 4.68
12.20 7.25 3.22
13.07 6.78 3.32
14.14 6.26 1.98
15.72 5.64 38.58
16.48 5.38 22.57
17.22 5.15 100.00
17.99 4.93 50.58
18.55 4.78 25.56
19.40 4.58 36.35
20.00 4.44 3.83
20.59 4.31 2.57
21.62 4.11 9.41
23.03 3.86 7.56
23.62 3.77 35.97
23.96 3.71 43.13
24.47 3.64 21.25
24.83 3.59 19.98
25.40 3.51 68.63
26.27 3.39 20.98
27.09 3.29 9.50
27.79 3.21 8.59
29.34 3.04 6.23
30.90 2.89 2.07
31.73 2.82 6.85
32.75 2.73 2.71
35.15 2.55 0.90
36.51 2.46 2.17
实施例9
式(I)化合物磷酸盐晶型A的制备方法：
将100.4mg式(I)化合物悬浮于2.5mL乙腈和0.79mL乙醇的混合溶剂中，将17.7μL浓磷酸(14.6mol/L)溶于390μL乙醇中后滴加到该悬浮液中，置于70℃烘箱中搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为磷酸盐晶型A。
本实施例得到的晶型的X射线粉末衍射数据如表9所示。
表9
2theta d间隔 强度％
3.56 24.79 77.29
7.78 11.36 73.30
8.37 10.57 61.12
11.52 7.68 4.20
14.77 6.00 5.34
15.72 5.64 23.84
17.20 5.15 100.00
18.00 4.93 48.24
18.55 4.78 45.75
19.42 4.57 49.05
20.56 4.32 6.53
21.63 4.11 8.99
23.96 3.71 37.14
25.38 3.51 52.10
26.24 3.40 21.72
27.67 3.22 9.74
29.36 3.04 5.10
31.74 2.82 4.01
35.18 2.55 2.21
36.89 2.44 1.16
实施例10
式(I)化合物磷酸盐晶型B的制备方法：
将503.4mg式(I)化合物悬浮于15.0mL甲基异丁酮中，加入0.14mL浓磷酸(14.6mol/L)后室温搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为磷酸盐晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表10所示。其XRPD图如图17，其DSC图如图18，其TGA图如图19。
表10
2theta d间隔 强度％
3.19 27.66 32.85
12.92 6.85 16.82
13.93 6.36 4.49
15.02 5.90 9.60
15.94 5.56 18.35
16.21 5.47 27.78
16.71 5.30 73.18
17.47 5.08 22.00
18.94 4.69 16.40
19.62 4.52 100.00
20.88 4.25 24.03
22.28 3.99 15.79
22.67 3.92 27.33
24.25 3.67 16.12
24.87 3.58 15.91
25.82 3.45 24.63
26.67 3.34 18.05
27.59 3.23 12.70
29.98 2.98 3.28
32.23 2.78 2.89
35.53 2.53 3.80
实施例11
式(I)化合物磷酸盐晶型B的制备方法：
将10.6mg式(I)化合物悬浮于0.8mL醋酸异丙酯中，加入17mL磷酸乙醇溶液(2mol/L)后置于50℃恒温培养箱中搅拌24小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体经检测为磷酸盐晶型B。
本实施例得到的晶型的X射线粉末衍射数据如表11所示。
表11
2theta d间隔 强度％
3.24 27.28 100.00
8.32 10.63 5.04
8.82 10.02 6.26
10.39 8.52 1.92
12.93 6.85 10.87
15.04 5.89 15.51
16.00 5.54 18.40
16.23 5.46 23.52
16.76 5.29 85.35
17.60 5.04 9.37
19.10 4.65 9.10
19.62 4.52 30.64
19.90 4.46 10.74
20.95 4.24 15.77
22.23 4.00 6.65
22.68 3.92 5.50
25.13 3.54 18.70
25.87 3.44 26.35
26.36 3.38 18.62
26.69 3.34 24.91
27.54 3.24 9.69
30.12 2.97 1.69
35.73 2.51 1.14
实施例12
式(I)化合物磷酸盐晶型C的制备方法：
将10.2mg式(I)化合物的磷酸盐晶型B悬浮于0.97mL乙腈和0.03mL水的混合溶剂中，将该混悬液置于25℃搅拌12小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体为磷酸盐晶型C。
本实施例得到的晶型的X射线粉末衍射数据如表12所示。其XRPD图如图20，其DSC图如图21，其TGA图如图22。
表12
2theta d间隔 强度％
4.47 19.77 13.51
6.25 14.15 5.34
9.04 9.78 1.84
12.54 7.06 7.86
12.94 6.84 9.99
13.43 6.59 8.85
14.62 6.06 14.06
15.29 5.79 31.90
16.01 5.54 3.92
18.01 4.93 67.14
18.23 4.87 20.45
18.49 4.80 11.46
18.91 4.69 11.53
19.25 4.61 7.95
20.07 4.42 9.37
20.90 4.25 100.00
21.44 4.14 17.65
22.12 4.02 3.14
22.83 3.89 13.11
23.62 3.77 7.02
24.05 3.70 38.78
24.57 3.62 6.29
25.29 3.52 6.28
26.31 3.39 9.73
29.56 3.02 9.41
30.65 2.92 3.22
33.62 2.67 2.35
实施例13
式(I)化合物磷酸盐晶型C的制备方法：
将9.6mg式(I)化合物的磷酸盐晶型B悬浮于0.95mL乙腈和0.05mL水的混合溶剂中，将该混悬液置于25℃搅拌12小时，离心取下层固体，置于25℃烘箱干燥过夜，所得固体为磷酸盐晶型C。
本实施例得到的晶型的X射线粉末衍射数据如表13所示。
表13
2theta d间隔 强度％
4.46 19.82 5.24
6.22 14.20 2.24
7.43 11.90 0.94
9.07 9.75 0.69
12.59 7.03 3.64
12.97 6.82 1.55
13.45 6.58 7.05
14.63 6.05 10.26
15.33 5.78 4.93
15.91 5.57 0.86
16.58 5.35 1.99
17.64 5.03 7.13
18.01 4.93 31.58
18.49 4.80 3.21
18.94 4.69 4.87
19.29 4.60 2.19
20.09 4.42 3.55
20.90 4.25 100.00
21.45 4.14 6.89
22.84 3.89 5.46
24.13 3.69 5.67
24.64 3.61 1.51
25.33 3.52 4.97
25.91 3.44 3.13
26.24 3.40 2.17
27.20 3.28 2.52
29.27 3.05 3.37
29.58 3.02 3.35
30.60 2.92 0.85
31.89 2.81 1.26
33.63 2.67 1.73
35.00 2.56 0.75
实施例14
式(I)化合物磷酸盐晶型C的制备方法：
将8.0mg式(I)化合物的磷酸盐晶型B悬浮于0.97mL乙腈和0.03mL水的混合溶剂中，将该混悬液置于40℃搅拌12小时，离心取下层固体，置于25℃恒温干燥过夜，所得固体为磷酸盐晶型C。
本实施例得到的晶型的X射线粉末衍射数据如表14所示。
表14
2theta d间隔 强度％
3.29 26.83 37.61
4.45 19.85 33.84
6.23 14.18 13.30
12.54 7.06 6.59
12.96 6.83 9.58
13.47 6.57 12.44
14.18 6.24 4.38
14.62 6.06 14.36
15.32 5.78 18.20
17.64 5.03 8.32
18.02 4.92 50.92
18.27 4.86 10.99
18.48 4.80 8.86
18.94 4.69 9.36
19.26 4.61 5.60
20.05 4.43 5.38
20.90 4.25 100.00
21.45 4.14 10.37
22.83 3.89 5.93
24.09 3.69 15.36
24.57 3.62 4.42
25.34 3.52 4.34
25.89 3.44 5.23
26.24 3.40 5.98
29.40 3.04 1.24
实施例15
式(I)化合物磷酸盐晶型A和晶型C的引湿性试验：
分别取本发明的式(I)化合物晶型A和式(I)化合物磷酸盐晶型C约10mg采用动态水分吸附(DVS)仪测试各自的引湿性。实验结果如表15所示。晶型A的引湿性实验的DVS图如图23所示，晶型C的引湿性实验的DVS图如图24所示。
表15
Figure PCTCN2016076141-appb-000007
关于引湿性特征描述与引湿性增重的界定(中国药典2010年版附录XIX J药物引湿性试验指导原则，实验条件：25℃±1℃，80％相对湿度)：
潮解：吸收足量水分形成液体
极具引湿性：引湿增重不小于15％
有引湿性：引湿增重小于15％但不小于2％
略有引湿性：引湿增重小于2％但不小于0.2％
无或几乎无引湿性：引湿增重小于0.2％
结果表明，本发明的式(I)化合物磷酸盐晶型A和晶型C在80％湿度下平衡后分别增重0.99％和2.85％。
实施例16
式(I)化合物磷酸盐晶型A的稳定性实验：
将本发明制备得到的磷酸盐晶型A分别在5℃、25℃/60％相对湿度、40℃/75％相对湿度的条件下放置90天，测定其XRPD。实验结果见表16。
表16
Figure PCTCN2016076141-appb-000008
结果表明，式(Ⅰ)化合物磷酸盐晶型A在5℃、25℃/60％相对湿度和40℃/75％相对湿度条件下，放置90天晶型保持不变，本发明提供的式(Ⅰ)化合物磷酸盐晶型A具有良好的稳定性。
实施例17
式(I)化合物磷酸盐晶型C的稳定性试验：
取2份磷酸盐晶型C各约10mg分别敞口放置于25℃/60％相对湿度和40℃/75％相对湿度的恒温恒湿箱中，放置30天后分别检测样品的晶型XRPD变化和纯度。结果如表17所示，其稳定性试验前后XRPD对比图分别如图25和图26(图25：上图为放置前磷酸盐晶型C的XRPD图，下图为放置在25℃/60％相对湿度条件30天后磷酸盐晶型C的XRPD图；图26：上图为放置前磷酸盐晶型C的XRPD图，下图为放置在40℃/75％相对湿度条件30天后磷酸盐晶型C的XRPD图)。
表17
Figure PCTCN2016076141-appb-000009

Claims (55)

  1. 一种式(I)化合物的晶型I，
    Figure PCTCN2016076141-appb-100001
    其特征在于，其X射线粉末衍射图在2theta值为15.33°±0.20°、16.66°±0.20°、19.06°±0.20°处具有特征峰。
  2. 根据权利要求1所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为14.91°±0.20°、16.25°±0.20°、15.74°±0.20°中的一处或两处或三处具有特征峰。
  3. 根据权利要求2所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为14.91°±0.20°、16.25°±0.20°、15.74°±0.20°处具有特征峰。
  4. 根据权利要求1-3任一项所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为25.51°±0.20°、12.40°±0.20°、17.39°±0.20°中的一处或两处或三处具有特征峰。
  5. 根据权利要求4所述的晶型I，其特征还在于，其X射线粉末衍射图在2theta值为25.51°±0.20°、12.40°±0.20°、17.39°±0.20°处具有特征峰。
  6. 根据权利要求1所述的晶型I，其特征在于，其X射线粉末衍射图基本上与图1一致。
  7. 一种权利要求1-6中任一项所述的晶型I的制备方法，其特征在于，将式(I)化合物加入到一种或多种选自以下的溶剂体系中：水，醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚或脂肪烃类的单一或它们的混合体系，通过反溶剂添加、悬浮搅拌、加热降温结晶或挥发结晶制得。
  8. 根据权利要求7所述的制备方法，所述醇类溶剂为甲醇；所述酮类溶剂为丙酮；所述卤代烃溶剂为二氯甲烷。
  9. 一种式(I)化合物的晶型II，其特征在于，其X射线粉末衍射图在2theta值为18.00°±0.20°、10.80°±0.20°、7.26°±0.20°处具有特征峰。
  10. 根据权利要求9所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为14.60°±0.20°、12.14°±0.20°、11.21°±0.20°中的一处或两处或三处具有特征峰。
  11. 根据权利要求10所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为14.60°±0.20°、12.14°±0.20°、11.21°±0.20°处具有特征峰。
  12. 根据权利要求9-11任一项所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为22.59°±0.20°、22.03°±0.20°、19.64°±0.20°中的一处或两处或三处具有特征峰。
  13. 根据权利要求12所述的晶型II，其特征还在于，其X射线粉末衍射图在2theta值为22.59°±0.20°、22.03°±0.20°、19.64°±0.20°处具有特征峰。
  14. 根据权利要求9所述的晶型II，其特征在于，其X射线粉末衍射图基本上与图5一致。
  15. 一种权利要求9-14中任一项所述的晶型II的制备方法，其特征在于，将式(I)化合物加入到冰醋酸或冰醋酸与其他溶剂的混合体系中，通过反溶剂添加、挥发结晶、加热降温或悬浮搅拌制得。
  16. 根据权利要求15所述的制备方法，所述其他溶剂包括水，醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃，环醚或脂肪烃类溶剂。
  17. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求1-6中任意一项所述的晶型I或权利要求9-14中任意一项所述的晶型II或二者的混合物及药学上可接受的载体、稀释剂或赋形剂。
  18. 权利要求1-6中任一项的晶型I或权利要求9-14中任一项所述的晶型II或二者的混合物在生产用于JAK激酶抑制剂的药物中的用途。
  19. 权利要求1-6中任一项的晶型I或权利要求9-14中任一项所述的晶型II或二者的混合物在生产用于制备治疗自身免疫疾病的药物中的用途。
  20. 权利要求1-6中任一项的晶型I或权利要求9-14中任一项所述的晶型II或二者的混合物在生产用于治疗类风湿性关节炎药物制剂的用途。
  21. 一种式(Ⅰ)化合物的磷酸盐晶型A，其特征在于，其X射线粉末衍射图在2theta值为17.22°±0.20°、8.37°±0.20°、3.59°±0.20°处具有特征峰。
  22. 根据权利要求21所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.96°±0.20°、19.40°±0.20°、18.55°±0.20°中的一处或两处或三处具有特征峰。
  23. 根据权利要求22所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为23.96°±0.20°、19.40°±0.20°、18.55°±0.20°处具有特征峰。
  24. 根据权利要求21-23任一项所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为7.78°±0.20°、18.00°±0.20°、25.40°±0.20°中的一处或两处或三处具有特征峰。
  25. 根据权利要求24所述的晶型A，其特征还在于，其X射线粉末衍射图在2theta值为7.78°±0.20°、18.00°±0.20°、25.40°±0.20°处具有特征峰。
  26. 根据权利要求21所述的晶型A，其特征在于，其X射线粉末衍射图基本上与图14一致。
  27. 一种权利要求21-26中任一项所述的磷酸盐晶型A的制备方法，其特征在于，将式(I)化合物与磷酸加入到多种溶剂的混合溶剂体系中，通过搅拌制得。
  28. 根据权利要求27所述磷酸盐晶型A的制备方法，所述混合溶剂体系包括醇类，酮类，腈类，环醚或脂肪烃类溶剂的混合。
  29. 根据权利要求28所述的磷酸盐晶型A制备方法，所述混合溶剂体系为乙腈和乙醇混合。
  30. 根据权利要求29所述的磷酸盐晶型A制备方法，所述乙腈和乙醇的体积比约为4:1至2:1。
  31. 根据权利要求30所述的磷酸盐晶型A制备方法，所述乙腈和乙醇的体积比约为3:1。
  32. 一种式(Ⅰ)化合物的磷酸盐晶型B，其特征在于，其X射线粉末衍射图在2theta值为19.62°±0.20°、16.73°±0.20°、3.20°±0.20°处具有特征峰。
  33. 根据权利要求32所述的磷酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为16.21°±0.20°、22.67°±0.20°、25.85°±0.20°中的一处或两处或三处具有特征峰。
  34. 根据权利要求33所述的磷酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为16.21°±0.20°、22.67°±0.20°、25.85°±0.20°处具有特征峰。
  35. 根据权利要求32-34任一项所述的磷酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为20.90°±0.20°、17.53°±0.20°、26.67°±0.20°中的一处或两处或三处具有特征峰。
  36. 根据权利要求35所述的磷酸盐晶型B，其特征还在于，其X射线粉末衍射图在2theta值为20.90°±0.20°、17.53°±0.20°、26.67°±0.20°处具有特征峰。
  37. 根据权利要求32所述的磷酸盐晶型B，其特征在于，其X射线粉末衍射图基本上与图17一致。
  38. 一种权利要求32-37中任一项所述的磷酸盐晶型B的制备方法，其特征在于，将式(I)化合物与磷酸加入到无水醇类，酮类，酯类，芳香烃，卤代烃，腈类，硝基烷烃或环醚类析晶溶剂中，通过搅拌制得。
  39. 根据权利要求38所述的磷酸盐晶型B的制备方法，所述酮类析晶溶剂为甲基异丁酮；所述酯类析晶溶剂为醋酸异丙酯。
  40. 一种式(Ⅰ)化合物的磷酸盐晶型C，其特征在于，其X射线粉末衍射图在2theta值为20.90°±0.20°、18.01°±0.20°、24.10°±0.20°处具有特征峰。
  41. 根据权利要求40所述的磷酸盐晶型C，其特征还在于，其X射线粉末衍射图在2theta值为15.30°±0.20°、21.46°±0.20°、14.62°±0.20°中的一处或两处或三处具有特征峰。
  42. 根据权利要求41所述的磷酸盐晶型C，其特征还在于，其X射线粉末衍射图在2theta值为15.30°±0.20°、21.46°±0.20°、14.62°±0.20°处具有特征峰。
  43. 根据权利要求40-42任一项所述的磷酸盐晶型C，其特征还在于，其X射线粉末衍射图在2theta值为4.46°±0.20°、22.83°±0.20°、18.94±0.20°中的一处或两处或三处具有特征峰。
  44. 根据权利要求43所述的磷酸盐晶型C，其特征还在于，其X射线粉末衍射图在2theta值为4.46°±0.20°、22.83°±0.20°、18.94±0.20°处具有特征峰。
  45. 根据权利要求40所述的磷酸盐晶型C，其特征在于，其X射线粉末衍射图基本上与图20一致。
  46. 一种权利要求40-45中任一项所述的磷酸盐晶型C的制备方法，其特征在于，将式(I)化合物的磷酸盐粉末加入到单一溶剂或多种溶剂的混合体系内搅拌即可得到。
  47. 根据权利要求46所述的磷酸盐晶型C的制备方法，其特征在于，所述单一溶剂或多种溶剂的混合体系包括腈类，水，醇类，酮类，酯类，芳香烃类，卤代烃类，硝基烷烃类，环醚类溶剂的单一或者混合体系。
  48. 根据权利要求47所述的磷酸盐晶型C的制备方法，其特征在于，所述单一溶剂为水。
  49. 根据权利要求48所述的磷酸盐晶型C的制备方法，其特征在于，所述多种溶剂的混合体系为水和腈类溶剂的混合体系。
  50. 根据权利要求49所述的磷酸盐晶型C的制备方法，其特征在于，所述水和腈类溶剂的混合体系为水和乙腈的混合溶剂。
  51. 根据权利要求46-50任一项所述的磷酸盐晶型C的制备方法，所述式(I)化合物的磷酸盐粉末包括磷酸盐晶型B。
  52. 一种药用组合物，所述药用组合物包含有效治疗量的权利要求21-26中任一项的晶型A或权利要求32-37中任一项所述的晶型B或权利要求40-45中任一项所述的晶型C或其中二者或三者的混合物及药学上可接受的载体、稀释剂或赋形剂。
  53. 权利要求21-26中任一项的晶型A或权利要求32-37中任一项所述的晶型B或权利要求40-45中任一项所述的晶型C或其中二者或三者的混合物在生产用于JAK激酶抑制剂的药物中的用途。
  54. 权利要求21-26中任一项的晶型A或权利要求32-37中任一项所述的晶型B或权利要求40-45中任一项所述的晶型C或其中二者或三者的混合物在生产用于制备治疗自身免疫疾病的药物中的用途。
  55. 权利要求21-26中任一项的晶型A或权利要求32-37中任一项所述的晶型B或权利要求40-45中任一项所述的晶型C或其中二者或三者的混合物在生产用于治疗类风湿性关节炎药物制剂的用途。
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EP3771715A1 (en) 2019-08-02 2021-02-03 Zaklady Farmaceutyczne "Polpharma" S.A. Crystalline forms of baricitinib
EP3771716A1 (en) 2019-08-02 2021-02-03 Zaklady Farmaceutyczne "Polpharma" S.A. Low hygroscopic amorphous form of baricitinib
TWI781345B (zh) * 2019-09-06 2022-10-21 台耀化學股份有限公司 Ｂａｒｉｃｉｔｉｎｉｂ的結晶型與其製備方法

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