WO2022033551A1 - Jak抑制剂的盐型、晶型及其制备方法和应用 - Google Patents

Jak抑制剂的盐型、晶型及其制备方法和应用 Download PDF

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WO2022033551A1
WO2022033551A1 PCT/CN2021/112278 CN2021112278W WO2022033551A1 WO 2022033551 A1 WO2022033551 A1 WO 2022033551A1 CN 2021112278 W CN2021112278 W CN 2021112278W WO 2022033551 A1 WO2022033551 A1 WO 2022033551A1
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formula
crystal form
compound represented
compound
hydrochloride
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PCT/CN2021/112278
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English (en)
French (fr)
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成明
曹雅琪
孙军恩
浦宇
蒋剑平
张文伯
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上海复旦张江生物医药股份有限公司
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Priority to AU2021324240A priority Critical patent/AU2021324240A1/en
Priority to EP21855601.7A priority patent/EP4198035A1/en
Priority to CN202180061258.0A priority patent/CN116322678A/zh
Priority to CA3189275A priority patent/CA3189275A1/en
Priority to JP2023507518A priority patent/JP2023536893A/ja
Priority to US18/021,032 priority patent/US20230295160A1/en
Priority to KR1020237007522A priority patent/KR20230051207A/ko
Publication of WO2022033551A1 publication Critical patent/WO2022033551A1/zh

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D471/00Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04Ortho-condensed systems
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/54Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/541Non-condensed thiazines containing further heterocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00Drugs for disorders of the respiratory system
    • A61P11/06Antiasthmatics
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00Drugs for immunological or allergic disorders
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07BGENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to salt forms and crystal forms of JAK inhibitors, as well as preparation methods and applications thereof.
  • the Janus kinase (JAK) signaling pathway found in interferon-induced receptor-mediated gene expression has been shown to be a common signaling pathway used by many cytokines and growth factors.
  • the mammalian JAK family of intracellular tyrosine kinases has four members: Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), Janus kinase 3 (JAK3), and tyrosine kinase 2 (TYK2). JAKs range in size from 120 to 140 kDa and contain seven conserved JAK homology (JH) domains that define this kinase superfamily.
  • JH JAK homology
  • JAKs can be used by multiple cytokine pathways, and even the biological activity of many cytokines can be modulated by inhibition of single or multiple JAKs.
  • Inhibition of JAKs can be used to prevent, inhibit or treat the progression or onset of various diseases and disorders, including hyperproliferative diseases and cancers such as leukemias and lymphomas, immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease , allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis and multiple sclerosis.
  • hyperproliferative diseases and cancers such as leukemias and lymphomas
  • immune and inflammatory disorders such as transplant rejection, asthma, chronic obstructive pulmonary disease , allergies, rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amy
  • the compound of formula I is an effective JAK inhibitor for preventing or treating one or more symptoms of Janus kinase-mediated diseases
  • the solubility of the free base form of the compound represented by formula I in water is too low, which will affect its dissolution and absorption in the body, resulting in too low bioavailability, making it unsuitable for further drug development.
  • the water solubility is too low, it is not easy to be purified in the production process, which brings certain difficulties to industrial production.
  • the present invention provides salt forms and crystal forms of JAK inhibitors, as well as preparation methods and applications thereof.
  • Said salt form and crystal form have good JAK kinase inhibitory activity, solubility, stability and bioavailability, which enhances the developability of the oral preparation of the compound represented by formula I.
  • the present invention provides the crystalline form A of the hydrochloride hydrate of the compound represented by formula I, and its X-ray powder diffraction (XRPD) pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.9° ⁇ 0.2°, 7.4° ⁇ 0.2° , 11.6° ⁇ 0.2°, 21.7° ⁇ 0.2° and 23.8° ⁇ 0.2°;
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.9° ⁇ 0.2°, 7.4° ⁇ 0.2°, 11.6° ⁇ 0.2°, 17.7 ° ⁇ 0.2°, 17.8° ⁇ 0.2°, 21.7° ⁇ 0.2°, 23.6° ⁇ 0.2°, 23.8° ⁇ 0.2°, 29.0° ⁇ 0.2°, 30.4° ⁇ 0.2° and 34.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.9° ⁇ 0.2°, 7.4° ⁇ 0.2°, 8.9° ⁇ 0.2°, 11.6 ° ⁇ 0.2°, 14.6° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.7° ⁇ 0.2°, 21.9° ⁇ 0.2°, 22.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, 23.8° ⁇ 0.2°, 29.0° ⁇ 0.2°, 30.4° ⁇ 0.2°, 33.3° ⁇ 0.2°, 34.9° ⁇ 0.2° and 37.7° ⁇ 0.2° .
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.9° ⁇ 0.2°, 6.6° ⁇ 0.2°, 7.4° ⁇ 0.2°, 8.9 ° ⁇ 0.2°, 10.5° ⁇ 0.2°, 11.6° ⁇ 0.2°, 12.3° ⁇ 0.2°, 13.9° ⁇ 0.2°, 14.2° ⁇ 0.2°, 14.6° ⁇ 0.2°, 17.1° ⁇ 0.2°, 17.7° ⁇ 0.2°, 17.8° ⁇ 0.2°, 18.7° ⁇ 0.2°, 19.5° ⁇ 0.2°, 20.4° ⁇ 0.2°, 21.0° ⁇ 0.2°, 21.2° ⁇ 0.2°, 21.7° ⁇ 0.2°, 21.9° ⁇ 0.2° , 22.6° ⁇ 0.2°, 23.6° ⁇ 0.2°, 23.8° ⁇ 0.2°, 24.9° ⁇ 0.2°, 26.6° ⁇ 0.2°, 26.8° ⁇ 0.2°, 28.3° ⁇ 0.2°, 29.0° ⁇ 0.2°, 30.4 ° ⁇ 0.2°, 31.2° ⁇ 0.2°, 31.2° ⁇ 0.2°
  • the X-ray powder diffraction pattern of the crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 5.9°, 6.6°, 7.4°, 8.9°, 10.5°, 11.6°, 12.3° °, 13.9°, 14.2°, 14.6°, 17.1°, 17.7°, 17.8°, 18.7°, 19.5°, 20.4°, 21.0°, 21.2°, 21.7°, 21.9°, 22.6°, 23.6°, 23.8°, 24.9°, 26.6°, 26.8°, 28.3°, 29.0°, 30.4°, 31.2°, 32.3°, 33.3°, 34.2°, 34.9°, 35.6°, 35.9°, 36.4°, 36.9°, 37.7°, 39.3° and 39.8°.
  • the XRPD pattern analysis data of the crystal form A is shown in Table 1:
  • the XRPD pattern of the crystal form A is shown in FIG. 1 .
  • thermogravimetric analysis curve of the crystal form A has a weight loss of 8.31 ⁇ 0.50% before 148°C; and a weight loss of 4.76 ⁇ 0.50% at 148°C-228°C.
  • thermogravimetric analysis curve of the crystal form A has 8.31% weight loss before 148°C; and 4.76% weight loss at 148°C-228°C.
  • thermogravimetric analysis curve of the crystal form A has 8.3143% weight loss before 148°C; and 4.7637% weight loss at 148°C-228°C.
  • thermogravimetric analysis curve of the crystal form A is shown in FIG. 3 .
  • thermogravimetric analysis curve is detected under the condition that the temperature rising interval is 10°C-300°C and the temperature rising rate is 10°C/min.
  • the differential scanning calorimetry (DSC) analysis pattern of the crystal form A has absorption peaks at 165°C ⁇ 3°C and 198°C ⁇ 3°C, respectively.
  • the differential scanning thermogram of the crystal form A has absorption peaks at 165.14°C and 197.70°C, respectively.
  • the differential scanning thermogram of the crystal form A has absorption peaks with onset temperatures of 141°C ⁇ 3°C and 179°C ⁇ 3°C, respectively.
  • the differential scanning thermogram of the crystal form A has absorption peaks with onset temperatures of 140.82°C and 179.20°C, respectively.
  • the differential scanning thermogram of the crystal form A is shown in FIG. 2 .
  • the differential scanning thermogram is detected under the condition that the temperature rising interval is 25°C-300°C and the temperature rising rate is 10°C/min.
  • the Form A is a single crystal.
  • the single crystal of Form A belongs to the monoclinic system, space group P21/c.
  • the unit cell volume of the crystal form A is
  • the unit cell parameters and/or unit cell volume of the single crystal of the crystal form A can be obtained by X-ray single crystal diffraction detection.
  • the X-ray wavelength ⁇ of the X-ray single crystal diffraction can be
  • the molar ratio of the compound of formula I, HCl and water is 1:x:y, wherein x is greater than 0 but not greater than 3, and y is greater than 0 not more than 3.
  • the molar ratio of the compound of formula I, HCl and water is 1:2:2.
  • the present invention also provides a method for preparing the crystal form A of the hydrochloride hydrate of the compound represented by the formula I, which comprises the following steps: precipitating crystals from the hydrochloride solution of the compound represented by the formula I, and the crystals It is crystal form A; wherein, the hydrochloride solution of the compound shown in the formula I contains the hydrochloride of the compound shown in the formula I, an organic solvent and water, and the organic solvent is selected from methanol, ethanol, normal One or more mixtures of propanol, n-butanol, isopropanol, isobutanol and tert-butanol. Two or more here should be understood to include two. It should be clear to those skilled in the art that the hydrochloride solution of the compound represented by the formula I does not contain other organic solvents, unless it is inevitable impurities or solvent residues.
  • the molar ratio of the compound of formula I and HCl is 1:x, and x is greater than 0 but not greater than 3, such as 1:2.
  • the organic solvent is ethanol.
  • the volume ratio of the organic solvent and water is 5-15:0.5-1.5, such as 10:1 to 6:1, another example is 10:1 to 8:1, another example is 9 :1.
  • the temperature of the hydrochloride solution of the compound represented by formula I is 30-70°C.
  • the step of precipitating crystals from the hydrochloride solution of the compound shown in formula I comprises: cooling the hydrochloride solution of the compound shown in formula I, for example, the cooling is cooling to 20 °C to 30 °C.
  • the step of precipitating crystals from the hydrochloride salt solution of the compound represented by formula I comprises: stirring the hydrochloride salt solution of the compound represented by formula I at 20°C to 30°C to separate out crystals;
  • the stirring time is, for example, 48-96 hours, and another example is 48 hours.
  • the preparation method further comprises: after precipitating crystals from the hydrochloride solution of the compound represented by formula I, filtering, washing and drying the obtained filter cake to obtain crystal form A.
  • the preparation method further comprises: cooling the solution of the crystal form A of the hydrochloride hydrate of the compound shown in formula I to crystallize to obtain the crystal form A of the hydrochloride hydrate of the compound shown in the formula I
  • the single crystal wherein, the solvent of the solution of the solution of the hydrochloride hydrate of the compound shown in formula I is a mixture of ethanol and water; for example, the crystal of the hydrochloride hydrate of the compound shown in formula I
  • the temperature of the solution of type A is 55-75°C, another example is 60-70°C, another example is 64-66°C; for example, the volume ratio of ethanol and water in the mixture of ethanol and water is 5-15: 0.5-1.5, another example is 10:1 to 6:1, another example is 10:1 to 8:1, another example is 9:1; for example, the cooling is cooling to 20°C to 30°C.
  • the hydrochloride solution of the compound represented by the formula I is obtained by mixing raw materials including the hydrochloride hydrate of the compound represented by the formula I, an organic solvent and water; for example, the compound represented by the formula I
  • the hydrochloride solution is a mixture of the hydrochloride hydrate of the compound represented by formula I, an organic solvent and water.
  • the volume ratio of the organic solvent to water is 5-15:0.5-1.5, another example is 10:1 to 6:1, another example is 10:1 to 8:1, another example is 9:1; for example , the dosage ratio of the hydrochloride hydrate of the compound represented by formula I to water is 250-450mg:1mL, another example is 300-400mg:1mL, another example is 350mg:1mL.
  • the hydrochloride solution of the compound represented by the formula I is obtained by mixing raw materials comprising the compound represented by the formula I, an organic solvent, water and a concentrated hydrochloric acid solution.
  • the hydrochloride solution of the compound represented by the formula I is a mixture of the compound represented by the formula I, an organic solvent, water and a concentrated hydrochloric acid solution.
  • the preparation method further comprises: mixing the compound shown in formula I, an organic solvent and water, heating the obtained mixture to 30-70° C., adding concentrated hydrochloric acid solution to obtain the hydrochloride of the compound shown in formula I solution.
  • the ratio of the concentrated hydrochloric acid solution to the compound shown in formula I can be, for example, 0.38mL-0.57mL: 1g, such as 0.4mL-0.5mL: 1g, or 0.38mL-0.40mL: 1g, 0.40mL- 0.42mL: 1g, 0.42mL-0.44mL: 1g, 0.44mL-0.46mL: 1g, 0.46mL-0.48mL: 1g, 0.48mL-0.50mL: 1g, 0.50mL-0.52mL: 1g, 0.52mL-0.54mL : 1g or 0.54mL-0.57mL: 1g.
  • the ratio of the organic solvent and the compound shown in formula I can be, for example, 5mL-15mL: 1g, such as 8mL-12mL: 1g, and for example 5mL-6mL: 1g, 6mL-7mL: 1g, 7mL-8mL: 1g, 8mL-9mL: 1g, 9mL-10mL: 1g, 10mL-11mL: 1g, 11mL-12mL: 1g, 12mL-13mL: 1g, 13mL-14mL: 1g or 14mL-15mL: 1g.
  • the volume ratio of the organic solvent and water may be, for example, 5-15:0.5-1.5, another example is 10:1 to 6:1, another example is 10:1 to 8:1, another example is 9:1 .
  • the ratio of the water and the compound represented by formula I can be, for example, 0.5mL-1.5mL: 1g; : 1g, 0.7mL-0.8mL: 1g, 0.8mL-0.9mL: 1g, 0.9mL-1.0mL: 1g, 1.0mL-1.1mL: 1g, 1.1mL-1.2mL: 1g, 1.2mL-1.3mL: 1g , 1.3mL-1.4mL: 1g or 1.4mL-1.5mL: 1g.
  • the ratio of the organic solvent, water and the compound shown in formula I can be, for example, 5mL-15mL: 0.5mL-1.5mL: 1g, another example is 8mL-12mL: 0.8mL-1.2mL: 1g, another example is 9mL : 1mL: 1g.
  • the ratio of the organic solvent, water, concentrated hydrochloric acid solution and the compound shown in formula I can be, for example, 5mL-15mL: 0.5mL-1.5mL: 0.38mL-0.57mL: 1g, and, for example, 8mL-12mL: 0.8mL -1.2mL: 0.38mL-0.48mL: 1g, another example is 9mL: 1mL: 0.41mL: 1g.
  • the concentration of the concentrated hydrochloric acid solution can be, for example, 8mol/L-12mol/L, another example is 10mol/L-12mol/L, and another example is 12mol/L.
  • the molar ratio of HCl and the compound shown in the formula I can be, for example, 2:1 to 3:1, or 2.0:1 to 2.5:1, for example, Another example is 2.1:1 to 2.3:1.
  • the hydrochloride solution of the compound represented by the formula I is obtained by mixing the solution comprising the compound represented by the formula I with the raw materials of concentrated hydrochloric acid solution; for example, the hydrochloride solution of the compound represented by the formula I It is a mixture of raw materials composed of a solution of the compound represented by formula I and a concentrated hydrochloric acid solution.
  • the solvent of the solution of the compound represented by the formula I is a mixture of an organic solvent and water; for another example, the solution of the compound represented by the formula I is a mixture of the compound represented by the formula I, an organic solvent and water.
  • the volume ratio of the organic solvent to water is 5-15:0.5-1.5, another example is 10:1 to 6:1, another example is 10:1 to 8:1, another example is 9:1.
  • the solution of the compound represented by the formula I is obtained by mixing the compound represented by the formula I and the solvent at a temperature of 30-70°C, and the temperature is, for example, 40-60°C, or, for example, 45- 55°C.
  • the present invention also provides a method for preparing the crystal form A of the hydrochloride hydrate of the compound represented by the formula I, which comprises the following steps: precipitating crystals from the hydrochloride solution of the compound represented by the formula I, and the crystals It is crystal form A; wherein, the hydrochloride solution of the compound shown in the formula I contains the compound shown in the formula I, organic solvent, water and concentrated hydrochloric acid solution, and the organic solvent is selected from methanol, ethanol , one or more mixtures of n-propanol, n-butanol, isopropanol, isobutanol and tert-butanol. Two or more here should be understood to include two. It should be clear to those skilled in the art that the hydrochloride solution of the compound represented by the formula I does not contain other organic solvents, unless it is inevitable impurities or solvent residues.
  • the organic solvent is ethanol.
  • the hydrochloride salt solution of the compound of formula I is a mixture of the compound of formula I, an organic solvent, water and concentrated hydrochloric acid solution.
  • the ratio of the concentrated hydrochloric acid solution to the compound represented by formula I is 0.38mL-0.57mL:1g, for example, 0.4mL-0.5mL:1g, another example is 0.38mL-0.40mL:1g, 0.40 mL-0.42mL: 1g, 0.42mL-0.44mL: 1g, 0.44mL-0.46mL: 1g, 0.46mL-0.48mL: 1g, 0.48mL-0.50mL: 1g, 0.50mL-0.52mL: 1g, 0.52mL- 0.54mL: 1g or 0.54mL-0.57mL: 1g.
  • the ratio of the organic solvent to the compound shown in formula I is 5mL-15mL:1g, such as 8mL-12mL:1g, another example is 5mL-6mL:1g, 6mL-7mL:1g, 7mL- 8mL: 1g, 8mL-9mL: 1g, 9mL-10mL: 1g, 10mL-11mL: 1g, 11mL-12mL: 1g, 12mL-13mL: 1g, 13mL-14mL: 1g or 14mL-15mL: 1g.
  • the ratio of the water and the compound represented by formula I is 0.5mL-1.5mL:1g; 0.7mL: 1g, 0.7mL-0.8mL: 1g, 0.8mL-0.9mL: 1g, 0.9mL-1.0mL: 1g, 1.0mL-1.1mL: 1g, 1.1mL-1.2mL: 1g, 1.2mL-1.3mL : 1g, 1.3mL-1.4mL: 1g or 1.4mL-1.5mL: 1g.
  • the volume ratio of the organic solvent to water is 5-15:0.5-1.5, preferably 10:1 to 6:1, more preferably 10:1 to 8:1, more preferably 9:1 1.
  • the ratio of the organic solvent, water and the compound shown in formula I is 5mL-15mL:0.5mL-1.5mL:1g, preferably 8mL-12mL:0.8mL-1.2mL:1g, more preferably 9mL: 1mL: 1g.
  • the ratio of the organic solvent, water, concentrated hydrochloric acid solution and the compound shown in formula I is 5mL-15mL: 0.5mL-1.5mL: 0.38mL-0.57mL: 1g, preferably 8mL-12mL: 0.8 mL to 1.2 mL: 0.38 mL to 0.48 mL: 1 g, more preferably 9 mL: 1 mL: 0.41 mL: 1 g.
  • the concentration of the concentrated hydrochloric acid solution is 8mol/L-12mol/L, preferably 10mol/L-12mol/L, more preferably 12mol/L.
  • the molar ratio of HCl to the compound represented by formula I is 2:1 to 3:1, preferably 2.0:1 to 2.5:1 , more preferably 2.1:1 to 2.3:1.
  • the hydrochloride salt solution of the compound of formula I is a mixture of a solution of the compound of formula I and a concentrated hydrochloric acid solution.
  • the hydrochloride salt solution of the compound of formula I is obtained by adding (eg, dropwise) a concentrated hydrochloric acid solution to the solution of the compound of formula I.
  • the solvent of the solution of the compound represented by formula I is a mixture of organic solvent and water.
  • the solution of the compound represented by the formula I is obtained by mixing the compound represented by the formula I and the solvent at a temperature of 30-70°C, the temperature is preferably 40-60°C, more preferably 45-55°C.
  • the solution of the compound of formula I is a mixture of the compound of formula I, an organic solvent and water.
  • the volume ratio of the organic solvent to water is 10:1 to 6:1, preferably 10:1 to 8:1, more preferably 9:1.
  • the preparation method further comprises: mixing the compound shown in formula I, an organic solvent and water, and heating the obtained mixture to 30-70° C. (preferably 40-60° C., more preferably 45-55° C. °C), adding (for example, by dropwise addition) a concentrated hydrochloric acid solution to obtain the hydrochloride solution of the compound represented by the formula I.
  • the preparation method further comprises: stirring the hydrochloride solution of the compound represented by formula I at 30-70°C.
  • the step of stirring the hydrochloride solution of the compound represented by formula I at 30-70° C. is performed before the step of precipitating crystals from the hydrochloride solution of the compound represented by formula I.
  • the stirring time is, for example, 1-5 hours, and another example is 1 hour.
  • the step of precipitating crystals from the hydrochloride solution of the compound shown in formula I comprises: cooling the hydrochloride solution of the compound shown in formula I, preferably, the cooling is cooling to 20°C to 30°C.
  • the step of precipitating crystals from the hydrochloride salt solution of the compound represented by formula I comprises: stirring the hydrochloride salt solution of the compound represented by formula I at 20°C to 30°C to separate out crystals .
  • the stirring time is, for example, 48-96 hours, and another example is 48 hours.
  • the preparation method further comprises: after precipitating crystals from the hydrochloride solution of the compound represented by formula I, filtering, washing and drying the obtained filter cake to obtain crystal form A.
  • the raw materials of the preparation method only include the compound shown in formula I, absolute ethanol, water and concentrated hydrochloric acid solution.
  • the preparation method of the crystal form A of the hydrochloride hydrate of the compound represented by the formula I further comprises: cooling the solution of the crystal form A of the hydrochloride hydrate of the compound represented by the formula I to crystallize to obtain A single crystal of the crystal form A of the hydrochloride hydrate of the compound represented by the formula I, wherein the solvent of the solution of the crystal form A of the hydrochloride hydrate of the compound represented by the formula I is a mixture of ethanol and water.
  • the temperature of the mixture of ethanol and water may be 55-75°C, more preferably 60-70°C, further preferably 64-66°C.
  • the volume ratio of ethanol and water in the mixture of ethanol and water may be 10:1 to 6:1, preferably 10:1 to 8:1, more preferably 9:1.
  • the cooling can be cooled to 20°C to 30°C.
  • the present invention also provides the hydrochloride hydrate of the compound represented by formula I.
  • the molar ratio of the compound of formula I, HCl and water is 1:x:y, and x is greater than 0 but not greater than 3 , y is greater than 0 but not greater than 3.
  • the molar ratio of the compound of formula I, HCl and water is 1:2:2.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the hydrochloride hydrate of the compound represented by formula I described in any of the above schemes and a crystal of the hydrochloride hydrate of the compound represented by formula I described in any of the above schemes at least one of Form A, and at least one pharmaceutically acceptable carrier.
  • the carrier is at least one of an excipient, a diluent, and a vehicle.
  • the present invention also provides the hydrochloride hydrate, crystal form A or pharmaceutical composition of the compound represented by formula I described in any of the above schemes in the preparation of a medicament for preventing or treating Janus kinase-mediated disorders, diseases or conditions use in.
  • the present invention also provides a method of preventing or treating a Janus kinase-mediated disorder, disease or condition in a subject in need thereof, comprising administering to the subject a prophylactically or therapeutically effective amount of any of the above regimens
  • the present invention also provides the hydrochloride hydrate, crystal form A or pharmaceutical composition of the compound of formula I described in any of the above schemes for preventing or treating disorders, diseases or conditions mediated by Janus kinase.
  • the Janus kinase is at least one of JAK1, JAK2, JAK3, and TyK2.
  • the Janus kinase-mediated disease is hyperproliferative disease, cancer (eg, leukemia and lymphoma), immune and inflammatory disorders (eg, transplant rejection, asthma, chronic obstructive pulmonary disease, allergy, at least one of rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, and multiple sclerosis).
  • cancer eg, leukemia and lymphoma
  • immune and inflammatory disorders eg, transplant rejection, asthma, chronic obstructive pulmonary disease, allergy, at least one of rheumatoid arthritis, psoriasis, atopic dermatitis, Crohn's disease, ulcerative colitis, amyotrophic lateral sclerosis, and multiple sclerosis.
  • the Janus kinase-mediated disease is leukemia, lymphoma, transplant rejection, asthma, chronic obstructive pulmonary disease, allergy, rheumatoid arthritis, psoriasis, atopic dermatitis, At least one of Roan's disease, ulcerative colitis, amyotrophic lateral sclerosis, and multiple sclerosis.
  • the reagents and raw materials used in the present invention are all commercially available.
  • the positive improvement effect of the present invention is that the salt form and crystal form of the present invention have good JAK kinase inhibitory activity, solubility, stability and bioavailability, which enhances the developability of oral preparations of the compound represented by formula I.
  • pharmaceutically acceptable carrier refers to pharmaceutical excipients, which refer to all substances contained in pharmaceutical preparations except active ingredients, such as those specified in Part IV of the Pharmacopoeia of the People's Republic of China (2015 Edition or 2020 Edition) medical supplements.
  • composition refers to a composition containing the specified active ingredients and which can be prepared in the same dosage form.
  • the term "subject” refers to any animal, preferably a mammal, and most preferably a human, to whom the compound or composition is or has been administered according to embodiments of the present invention.
  • the term “mammal” includes any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans, etc., with humans being the most preferred.
  • prophylactically or therapeutically effective amount refers to an amount of a compound that, when administered to a subject, is sufficient to prevent or treat the disorder, disease or condition described herein.
  • the amount of compound that constitutes a “prophylactically or therapeutically effective amount” will vary depending on the compound, the type and severity of the disorder, disease or condition, and the age of the subject, but can be adjusted as needed by those skilled in the art.
  • treatment refers to therapeutic therapy.
  • treating means at least one of: (1) alleviating one or more biological manifestations of the disorder, disease or condition, (2) interfering with the disorder, disease or condition One or more biological manifestations, (3) amelioration or elimination of one or more symptoms, effects or side effects associated with the disorder, disease or condition, or one or more of the treatment associated with the disorder, disease or condition symptoms, effects, or side effects; and (4) slowing the progression of one or more biological manifestations of the disorder, disease, or condition.
  • the present invention adopts the following abbreviations:
  • each XRPD data described in the present invention is determined using the following conditions:
  • Sample preparation Take an appropriate amount of the sample to be tested and evenly distribute it in the sample holder, and flatten it with a clean glass plate so that the surface of the sample is flush with the surface of the sample holder.
  • the instrument used is Bruker D2Phaser X-ray powder diffractometer, wherein the detector: PSD LynxEye detector
  • Diffractometer parameter settings goniometer diameter, 282.2mm; divergence slit, 1.0mm; main cable slit, 2.5 degrees; secondary cable slit, 2.5 degrees; anti-air scattering component, 1.0mm; light pipe element, Copper; light tube parameters, voltage 30kV, current 10mA;
  • Scanning parameter settings scan type, Locked coupled; scan mode, Continuous PSD fast mode; rotation speed, 20 degrees/min; scan range, 3 degrees to 40 degrees (2 ⁇ ); scan step size, 0.02 degrees (2 ⁇ ); scan speed , 0.2 sec/step; detector opening, 4.5 degrees.
  • DSC data described in the present invention are measured using the following conditions:
  • the heating interval is 25°C-300°C, and the heating rate is 10°C/min;
  • TGA data of the present invention are determined using the following conditions:
  • Sample tray type default open aluminum tray
  • Heating interval 10°C-300°C, and the heating rate is 10°C/min.
  • Fig. 1 is the XRPD spectrum of crystal form A
  • Fig. 2 is the DSC spectrum of crystal form A
  • Fig. 3 is the TGA spectrum of crystal form A
  • Fig. 4 is the XRPD spectrum of crystal form C
  • Fig. 5 is the XRPD spectrum of crystal form D
  • Fig. 6 is the XRPD pattern of crystal form E
  • Fig. 7 is the XRPD pattern of crystal form F
  • Figure 8 is the XRPD pattern of Form A after being placed in a stable chamber at 40°C/60%-RH for 30 days;
  • Figure 9 is the XRPD pattern of Form A after being placed in a stable chamber at 25°C/75%-RH for 30 days;
  • Figure 10 is the XRPD spectrum of the solid precipitated after adding crystal form A to the saturated solution system in Example 5;
  • Figure 11 is the XRPD spectrum of the solid precipitated after adding crystal form E to the saturated solution system in Example 5;
  • Figure 12 is the XRPD spectrum of the solid precipitated after adding crystal form F to the saturated solution system in Example 5;
  • Figure 13 is the single crystal shape of crystal form A obtained in Example 8.
  • Figure 14 is the XRPD pattern of the crystal form A single crystal obtained in Example 8.
  • FIG. 15 is a schematic diagram of the asymmetric structural unit of the crystal form A single crystal obtained in Example 8.
  • FIG. 15 is a schematic diagram of the asymmetric structural unit of the crystal form A single crystal obtained in Example 8.
  • mass spectrometry was detected by Waters Acquity Xevo G2-XS QTof UPLC/MS ultra-high performance liquid chromatography high-resolution mass spectrometry system, and 1 H-NMR was detected by Bruker AVANCE III 400MHz nuclear magnetic resonance instrument or Bruker AVANCE III HD 300MHz nuclear magnetic resonance instrument was used for detection, and HPLC was detected by Agilent 1260 high performance liquid chromatograph.
  • the concentrated hydrochloric acid solution described in the present invention refers to an aqueous solution of hydrogen chloride (HCl), the concentration of which is not less than 8 mol/L.
  • the room temperature in the present invention refers to 20-30°C.
  • Embodiment 1 the synthesis of compound shown in formula I
  • the compound represented by formula I (1.5 g, 3.4 mmol) was added to a round-bottomed flask, followed by 13.5 mL of absolute ethanol and 1.5 mL of purified water, and the resulting mixture was heated to 50°C with stirring. Then 0.62mL concentrated hydrochloric acid solution (12mol/L, 7.4mmol) was added dropwise, after the dropwise addition, the hydrochloride solution of the compound shown in the obtained formula I was incubated at 50°C and stirred for 1 hour and then naturally cooled to 25°C at room temperature, Then, the temperature was kept at 25° C. and stirred for 48 hours to precipitate crystals, and the stirring was stopped. After filtration, the obtained filter cake was washed with a small amount of ethanol, collected, and dried under vacuum at 40° C. for 6 hours. The obtained crystal was crystal form A.
  • the XRPD pattern of the crystal form A is shown in FIG. 1 , wherein the X-ray powder diffraction peaks represented by the 2 ⁇ angle are shown in Table 1.
  • the DSC results of Form A are shown in Figure 2.
  • the DSC shows the first endothermic peak at 165.14 °C, the enthalpy value is 180.63 J/g, and the onset temperature is 140.82 °C; the other endothermic peak is at 197.70 °C , the enthalpy value is 23.689J/g, and the initial temperature is 179.20°C.
  • the crystal form A is the hydrochloride hydrate of the compound of formula I, and in the hydrochloride hydrate, the molar ratio of the compound of formula I, HCl and water is 1:2:2.
  • the compound represented by formula I (1.0 g, 2.3 mmol) was added to a round-bottomed flask, followed by 9 mL of THF and 1 mL of pure water, and the resulting mixture was heated to 60° C. with stirring. Then, 0.41 mL of concentrated hydrochloric acid solution (12 mol/L, 4.9 mmol) was added dropwise. After the dropwise addition, the obtained hydrochloride solution of the compound represented by formula I was kept at 60 °C and stirred for 1 hour, and then cooled to 25 °C naturally at room temperature. , and then kept at 25 °C and stirred for 48 hours to precipitate crystals, and stopped stirring. Filtration, the obtained filter cake is washed with a small amount of THF and then dried, and the obtained solid is crystal form C, and its XRPD spectrum is shown in Figure 4, and it can be seen that the obtained crystal form C is different from crystal form A.
  • the compound of formula I (0.5 g, 1.1 mmol) was added to a round bottom flask, followed by 10 mL of DCM and 10 mL of MeOH, and the resulting mixture was heated to 40°C with stirring. Then 4M hydrochloric acid solution (0.6 mL, 2.4 mmol) was added dropwise, after the dropwise addition, the obtained hydrochloric acid salt solution of the compound represented by formula I was kept at 40 °C and stirred for 1 hour, and then cooled to 25 °C naturally at room temperature, and then Keep stirring at 25°C for 48 hours to precipitate crystals, and stop stirring. After filtration, the obtained filter cake was washed with a small amount of DCM and then dried. The obtained solid was crystal form D, and its XRPD pattern was shown in FIG. 5 . It can be seen that the obtained crystal form D is different from the crystal form A.
  • crystal form A of the hydrochloride hydrate of the compound represented by formula I was added to 0.3 mL of acetonitrile, stirred at room temperature for 3 days, and filtered to obtain crystal form E. Its crystal form XRPD pattern is shown in Figure 6.
  • the detection instrument used for the XRPD pattern shown in FIG. 6 of the present invention is a Bruker D8 Advance X-ray diffractometer, wherein the X-ray tube parameters are set: X-ray wavelength, Cu:K-Alpha Voltage, 40 kV; Current, 40 mA; Sample rotation speed: 15 rpm; Scanning range: 3 to 40 degrees (2 ⁇ ); Scanning speed: 10 degrees/min.
  • the detection instrument used for the XRPD pattern shown in FIG. 7 of the present invention is a Bruker D8 Advance X-ray diffractometer, wherein the X-ray tube parameter settings are: X-ray wavelength, Cu:K-Alpha Voltage, 40 kV; Current, 40 mA; Sample rotation speed: 15 rpm; Scanning range: 3 to 40 degrees (2 ⁇ ); Scanning speed: 10 degrees/min.
  • Cisbio Homogeneous Time-Resolved Fluorescence
  • HTRF kinEASE-TK kit catalog number: 62TKOPEC
  • HTRF kinEASE-TK kit catalog number: 62TKOPEC
  • Liquid, allophycocyanin modified (XL-665)-labeled streptavidin, europium (EU)-labeled specific phosphorylated antibody and SEB are all provided with the kit.
  • JAK1 used in the assay was purchased from Invitrogen (Cat. No. PV4774), JAK2, JAK3 and TYK2 were all purchased from Carna Biosciences, Inc. (Cat. Nos.: 08-045, 08-046, 08-147, respectively), DTT was purchased from Sigma (catalog number 43816).
  • the compound (the hydrochloride hydrate crystal form A or Tofacitinib citrate (Shanghai Haoyuan Chemical Technology Co., Ltd., HY-40354A) of the compound of formula I prepared according to the method of Example 2) was serially diluted 3 times in DMSO 10 times, the concentration of the resulting compound dilution was 100 times the final test concentration. Then, the concentration of the compound diluent is further diluted to 2.5 times the final test concentration with kinase reaction buffer to obtain a solution of the compound to be tested.
  • Enzymatic reactions were performed in white 384-well polypropylene plates (Greniner, catalog number: 784075 ) in a total reaction volume of 10 uL containing 500 ng/mL JAK1, 6 ng/mL JAK2, 37 ng/mL JAK3, 100 ng/mL TYK2, 1 uM Substrate and 1 mM ATP (Sigma-Aldrich, catalog number: A7699).
  • the enzymatic reaction was initiated by adding a mixture of 2uL of substrate and 2uL of ATP prepared in kinase reaction buffer. After a 30-minute reaction at room temperature, 5uL of allophycocyanin modified (XL-665)-labeled streptavidin prepared in detection buffer and 5uL of europium-labeled specific phosphorylated antibody prepared in detection buffer were added to stop the reaction. Enzymatically react and generate a signal. After 1 hour incubation at room temperature, the plate was read in a Molecular Devices SpectraMAX Paradigm multi-plate reader with the following settings: Excitation 340 nm/Emission 1 616 nm/Emission 2 665 nm.
  • Embodiment 4 The solubility test of compound shown in formula I and crystal form A
  • “Easyly soluble” means that 1g (mL) of solute can be dissolved in a solvent with a volume of 1mL ⁇ V ⁇ 10mL; “dissolved” means that 1g (mL) of solute can be dissolved in a solvent with a volume of 10mL ⁇ V ⁇ 30mL; “Slightly soluble” It means that 1g (mL) of solute can be dissolved in a solvent with a volume of 30mL ⁇ V ⁇ 100mL; “slightly soluble” means that 1g (mL) of solute can be dissolved in a solvent with a volume of 100mL ⁇ V ⁇ 1000mL; “Very slightly soluble” means 1g ( mL) the solute can be dissolved in a solvent with a volume of 1000mL ⁇ V ⁇ 10000mL; “barely insoluble” or “insoluble” means that 1 g (mL) of the solute cannot be completely dissolved in a solvent with a volume of 10000mL.
  • Form A was placed in a stabilization chamber, and the temperature and humidity were controlled at 40°C/60%-RH and 25°C/75%-RH, respectively. After 30 days, the obtained solid was compared with its initial crystal form A: no obvious change in its appearance, no obvious change in the content of the compound represented by formula I (as shown in Table 4) measured by HPLC, XRPD (40°C/60%-RH) The XRPD patterns obtained after treatment at 25°C/75%-RH (see Figure 8 and Figure 9, respectively) also have no obvious change, indicating that the crystal form A has good stability.
  • the obtained XRPD pattern and the XRPD pattern of crystal form A as shown in Figure 1 are compared and analyzed, and it is found that the crystals precipitated from the system adding crystal form A are still crystal form A, while crystal form E and crystal form F are transformed into crystal form A. , indicating that Form A has better thermodynamic stability than Form E and Form F.
  • Instrument model AB SCIEX TRIPLE QUAD 6500 mass spectrometer; ion source, electrospray (ESI); ionization mode, positive ion scan; multiple ion (MRM) transition pairs are shown in Table 6; instrument parameters are shown in Table 7.
  • Example 7 Study on the hygroscopicity of crystal form A, crystal form C, crystal form D, crystal form E and crystal form F
  • FIG. 15 is a schematic diagram of the asymmetric structural unit of the crystal, and the asymmetric unit contains one cation of the compound represented by formula I, two chloride ions and two crystal waters.
  • the solid samples obtained from the experiments were analyzed with an X-ray powder diffractometer Bruker D8 Advance (Bruker, GER).
  • the 2 ⁇ scan angle was from 3° to 45°, the scan step was 0.02°, and the exposure time was 0.12s.
  • the phototube voltage and current of the test samples were 40kV and 40mA, respectively, and the sample pan was zero background sample pan.
  • a single crystal with suitable shape and size is selected from the single crystal samples obtained by cultivation, the single crystal is glued on the Loop ring, and then the single crystal sample is placed on the crystal stage.
  • Pre-experiments of single crystal samples and single crystal diffraction data were collected using a SuperNova (Rigaku, JPN) single crystal diffractometer (Cu target light source, ) in a temperature environment of 253.0K, and the diffraction data were analyzed and processed using the CrysAlisPro software package.
  • the angle range of diffraction data collected at 253.0K is 4.4340° ⁇ 73.8890°, and 8128 diffraction points were collected from this angle range, which were analyzed by CrysAlisPro program and refined by least squares method to obtain the crystal
  • the CrysAlisPro 1.171.39.46 (Rigaku Oxford Diffraction, 2018) program was used to restore and integrate each frame of diffraction images collected by the detector, and a total of 16159 diffraction points were collected, including 4275 independent diffraction points. Diffraction data were corrected for absorption using the SCALE3ABSPACK scaling algorithm.
  • the crystal sample has a wavelength
  • the linear absorption coefficient of the X-ray is 3.404 mm -1
  • the minimum transmission coefficient (Tmin) is 0.586
  • the maximum transmission coefficient (Tmax) is 1.000.
  • the intensities of all equivalent diffraction spots are substantially equal within experimental error, with a Rint of 4.30%.
  • the single crystal structure was analyzed using OLEX2 software, and the XS (Sheldrick, 2008) initial solution program was used to perform the initial structural solution of the diffraction data, and the space group to which the crystal belonged was determined to be P21/c. Structural refinement was subsequently performed using the XH (Sheldrick, 2008) program.
  • the coordinates of all non-hydrogen atoms are determined by several rounds of difference Fourier synthesis, followed by anisotropic refinement of all non-hydrogen atoms by full-matrix least squares method. All hydrogen atoms were calculated using theoretical hydrogenation.
  • the schematic diagram of the crystal structure and the atomic thermal vibration ellipsoid were drawn using Diamond software.

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Abstract

本发明提供了一种JAK抑制剂的盐型、晶型及其制备方法和应用。所述式I所示化合物的晶型A,其X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,21.7°±0.2°,和23.8°±0.2°;

Description

JAK抑制剂的盐型、晶型及其制备方法和应用
本申请要求申请日为2020年8月14日的PCT专利申请PCT/CN2020/109279以及申请日为2021年2月3日的PCT专利申请PCT/CN2021/075086的优先权。本申请引用上述专利申请的全文。
技术领域
本发明涉及JAK抑制剂的盐型、晶型及其制备方法和应用。
背景技术
在干扰素诱导的受体介导的基因表达中发现的Janus激酶(JAK)信号传导通路已经表明是许多细胞因子和生长因子使用的共同信号传导通路。细胞内的酪氨酸激酶的哺乳类JAK家族有4种成员:Janus激酶1(JAK1)、Janus激酶2(JAK2)、Janus激酶3(JAK3)和酪氨酸激酶2(TYK2)。JAK的大小范围在120至140kDa并且包含7种保守的JAK同源性(JH)结构域,其定义该激酶超家族。
各个JAK同种型可以被多种细胞因子通路使用,乃至许多细胞因子的生物活性可以通过单种或多种JAK进行抑制调节。JAK的抑制可用于预防、抑制或治疗各种疾病和失调的演变或发作,包括过度增生性疾病和癌症,例如白血病和淋巴瘤,免疫和炎性病症,例如移植排斥、哮喘、慢性阻塞性肺病、过敏症、类风湿性关节炎、银屑病、特应性皮炎、克罗恩病、溃疡性结肠炎、肌萎缩性侧索硬化和多发性硬化。
在WO2016119700A1中公开了式I所示化合物是一种有效的JAK抑制剂,用于预防或治疗Janus激酶介导的疾病的一种或多种症状;
Figure PCTCN2021112278-appb-000001
式I所示化合物的游离碱形式在水中的溶解度过低,会影响其在体内的溶解吸收,导致生物利用度过低,使其不适用于进一步的药物开发。同时由于水溶解度过低,其在生产过程中不易被纯化,给工业化生产带来一定困难。
发明内容
本发明提供了JAK抑制剂的盐型、晶型及其制备方法和应用。所述的盐型和晶型具有良好的JAK激酶抑制活性、溶解性、稳定性和生物利用度,增强了式I所示化合物口服制剂的可开发性。
本发明提供了式I所示化合物的盐酸盐水合物的晶型A,其X-射线粉末衍射(XRPD)图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,21.7°±0.2°和23.8°±0.2°;
Figure PCTCN2021112278-appb-000002
在本发明的一些实施方案中,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,17.7°±0.2°,17.8°±0.2°,21.7°±0.2°,23.6°±0.2°,23.8°±0.2°,29.0°±0.2°,30.4°±0.2°和34.9°±0.2°。
在本发明的一些实施方案中,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,8.9°±0.2°,11.6°±0.2°,14.6°±0.2°,17.7°±0.2°,17.8°±0.2°,18.7°±0.2°,19.5°±0.2°,21.0°±0.2°,21.7°±0.2°,21.9°±0.2°,22.6°±0.2°,23.6°±0.2°,23.8°±0.2°,29.0°±0.2°,30.4°±0.2°,33.3°±0.2°,34.9°±0.2°和37.7°±0.2°。
在本发明的一些实施方案中,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,6.6°±0.2°,7.4°±0.2°,8.9°±0.2°,10.5°±0.2°,11.6°±0.2°,12.3°±0.2°,13.9°±0.2°,14.2°±0.2°,14.6°±0.2°,17.1°±0.2°,17.7°±0.2°,17.8°±0.2°,18.7°±0.2°,19.5°±0.2°,20.4°±0.2°,21.0°±0.2°,21.2°±0.2°,21.7°±0.2°,21.9°±0.2°,22.6°±0.2°,23.6°±0.2°,23.8°±0.2°,24.9°±0.2°,26.6°±0.2°,26.8°±0.2°,28.3°±0.2°,29.0°±0.2°,30.4°±0.2°,31.2°±0.2°,32.3°±0.2°,33.3°±0.2°,34.2°±0.2°,34.9°±0.2°,35.6°±0.2°,35.9°±0.2°,36.4°±0.2°,36.9°±0.2°,37.7°±0.2°,39.3°±0.2°和39.8°±0.2°。
在本发明的一些实施方案中,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°,6.6°,7.4°,8.9°,10.5°,11.6°,12.3°,13.9°,14.2°,14.6°,17.1°,17.7°,17.8°,18.7°,19.5°,20.4°,21.0°,21.2°,21.7°,21.9°,22.6°,23.6°,23.8°,24.9°,26.6°,26.8°,28.3°,29.0°,30.4°,31.2°,32.3°,33.3°,34.2°,34.9°,35.6°,35.9°,36.4 °,36.9°,37.7°,39.3°和39.8°。
在本发明的一些实施方案中,所述晶型A的XRPD图谱解析数据如表1所示:
表1.晶型A的X-射线粉末衍射图谱解析数据
衍射角(°2θ) 相对强度[%] 衍射角(°2θ) 相对强度[%]
5.9 20.7 23.6 15.3
6.6 0.9 23.8 29.8
7.4 55.4 24.9 14.3
8.9 7.8 26.6 1.2
10.5 1.3 26.8 3.9
11.6 100 28.3 4.2
12.3 0.7 29.0 19.0
13.9 3.6 30.4 19.7
14.2 2.0 31.2 0.8
14.6 6.2 32.3 1.2
17.1 3.9 33.3 8.0
17.7 17.0 34.2 1.7
17.8 18.8 34.9 15.6
18.7 5.0 35.6 3.1
19.5 14.8 35.9 2.3
20.4 1.7 36.4 0.8
21.0 9.4 36.9 0.9
21.2 2.6 37.7 5.7
21.7 33.6 39.3 1.0
21.9 11.8 39.8 2.5
22.6 5.3    
在本发明的一些实施方案中,所述晶型A的XRPD图谱如图1所示。
在本发明的一些实施方案中,所述晶型A的热重分析曲线在148℃前,有8.31±0.50%的失重;在148℃-228℃,有4.76±0.50%的失重。
在本发明的一些实施方案中,所述晶型A的热重分析曲线在148℃前,有8.31%的失重;在148℃-228℃,有4.76%的失重。
在本发明的一些实施方案中,所述晶型A的热重分析曲线在148℃前,有8.3143%的失重;在148℃-228℃,有4.7637%的失重。
在本发明的一些实施方案中,所述晶型A的热重分析曲线如图3所示。
在本发明的一些实施方案中,所述热重分析曲线是在升温区间为10℃-300℃且升温速率为10℃/min的条件下检测得到。
在本发明的一些实施方案中,所述晶型A的差示扫描热(DSC)分析图在165℃±3℃和198℃±3℃分别具有吸收峰。
在本发明的一些实施方案中,所述晶型A的差示扫描热分析图在165.14℃和197.70℃分别具有吸收峰。
在本发明的一些实施方案中,所述晶型A的差示扫描热分析图具有起始温度分别为141℃±3℃和179℃±3℃的吸收峰。
在本发明的一些实施方案中,所述晶型A的差示扫描热分析图具有起始温度分别为140.82℃和179.20℃的吸收峰。
在本发明的一些实施方案中,所述晶型A的差示扫描热分析图如图2所示。
在本发明的一些实施方案中,所述差示扫描热分析图是在升温区间为25℃-300℃且升温速度为10℃/min的条件下检测得到。
在本发明的一些实施方案中,所述晶型A为单晶。
在本发明的一些实施方案中,所述晶型A的单晶属于单斜晶系,P21/c空间群。
在本发明的一些实施方案中,所述晶型A的晶胞参数为
Figure PCTCN2021112278-appb-000003
Figure PCTCN2021112278-appb-000004
α=90°,β=101.262(3)°,γ=90°。
在本发明的一些实施方案中,所述晶型A的晶胞体积为
Figure PCTCN2021112278-appb-000005
所述的晶型A的单晶的晶胞参数和/或晶胞体积可通过X射线单晶衍射检测得到。所述的X射线单晶衍射的X射线波长λ可为
Figure PCTCN2021112278-appb-000006
在本发明的一些实施方案中,所述的晶型A中,所述式I化合物、HCl和水的摩尔比为1:x:y,其中,x大于0而不大于3,且y大于0而不大于3。
在本发明的一些实施方案中,所述的晶型A中,所述式I化合物、HCl和水的摩尔比为1:2:2。
本发明还提供了一种所述式I所示化合物的盐酸盐水合物的晶型A的制备方法,其包括以下步骤:从式I所示化合物的盐酸盐溶液中析出晶体,所述晶体即为晶型A;其中,所述式I所示化合物的盐酸盐溶液中含有式I所示化合物的盐酸盐、有机溶剂和水,所述的有机溶剂为选自甲醇、乙醇、正丙醇、正丁醇、异丙醇、异丁醇和叔丁醇中的一种或两种以上的混合物。 此处的两种以上应理解为包含两种。本领域技术人员应当清楚,所述式I所示化合物的盐酸盐溶液中不含有其它有机溶剂,除非是不可避免的杂质或溶剂残留。
其中,所述的式I所示化合物的盐酸盐中,所述式I化合物和HCl的摩尔比为1:x,x大于0而不大于3,例如1:2。
在一些实施方案中,所述的有机溶剂为乙醇。
在一些实施方案中,所述的有机溶剂和水的体积比例为5-15:0.5-1.5,例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1。
在一些实施方案中,所述的式I所示化合物的盐酸盐溶液的温度为30-70℃。
在一些实施方案中,所述从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液降温,例如,所述降温为降温到20℃至30℃。
在一些实施方案中,所述从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液在20℃至30℃搅拌以析出晶体;所述的搅拌时间例如为48-96小时,又例如为48小时。
在一些实施方案中,所述的制备方法还包括:在从式I所示化合物的盐酸盐溶液中析出晶体后,过滤,将所得滤饼洗涤、干燥,得到晶型A。
在一些实施方案中,所述的制备方法还包括:将式I所示化合物的盐酸盐水合物的晶型A的溶液冷却进行结晶,得到式I所示化合物的盐酸盐水合物的晶型A的单晶,其中,所述式I所示化合物的盐酸盐水合物的晶型A的溶液的溶剂为乙醇和水的混合物;例如,所述的式I所示化合物的盐酸盐水合物的晶型A的溶液的温度为55-75℃,又例如为60-70℃,又例如为64-66℃;例如,所述的乙醇和水的混合物中乙醇和水的体积比为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1;例如,所述的冷却为冷却到20℃至30℃。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液由包括式I所示化合物的盐酸盐水合物、有机溶剂和水的原料混合得到;例如,所述式I所示化合物的盐酸盐溶液为式I所示化合物的盐酸盐水合物、有机溶剂和水的混合物。例如,所述有机溶剂和水的体积比为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1;例如,所述的式I所示化合物的盐酸盐水合物和水的用量比为250-450mg:1mL,又例如为300-400mg:1mL,又例如为350mg:1mL。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液由包括所述式I所示化合物、有机溶剂、水和浓盐酸溶液的原料混合得到。例如,所述式I所示化合物的盐酸盐溶液为式I所示化合物、有机溶剂、水和浓盐酸溶液的混合物。例如,所述的制备方法还包括:将式I所示化合物、有机溶剂和水混合,将所得混合物加热至30-70℃,加入浓盐酸溶液,得到所述式I所 示化合物的盐酸盐溶液。
其中,所述浓盐酸溶液和式I所示化合物的比例例如可为0.38mL-0.57mL:1g,例如为0.4mL-0.5mL:1g,又例如为0.38mL-0.40mL:1g、0.40mL-0.42mL:1g、0.42mL-0.44mL:1g、0.44mL-0.46mL:1g、0.46mL-0.48mL:1g、0.48mL-0.50mL:1g、0.50mL-0.52mL:1g、0.52mL-0.54mL:1g或0.54mL-0.57mL:1g。
其中,所述有机溶剂和式I所示化合物的比例例如可为5mL-15mL:1g,例如为8mL-12mL:1g,又例如为5mL-6mL:1g、6mL-7mL:1g、7mL-8mL:1g、8mL-9mL:1g、9mL-10mL:1g、10mL-11mL:1g、11mL-12mL:1g、12mL-13mL:1g、13mL-14mL:1g或14mL-15mL:1g。
其中,所述有机溶剂和水的体积比例例如可为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1。
其中,所述水和式I所示化合物的比例例如可为0.5mL-1.5mL:1g;例如为0.8mL-1.2mL:1g,又例如为0.5mL-0.6mL:1g、0.6mL-0.7mL:1g、0.7mL-0.8mL:1g、0.8mL-0.9mL:1g、0.9mL-1.0mL:1g、1.0mL-1.1mL:1g、1.1mL-1.2mL:1g、1.2mL-1.3mL:1g、1.3mL-1.4mL:1g或1.4mL-1.5mL:1g。
其中,所述有机溶剂、水和式I所示化合物的比例例如可为5mL-15mL:0.5mL-1.5mL:1g,又例如为8mL-12mL:0.8mL-1.2mL:1g,又例如为9mL:1mL:1g。
其中,所述有机溶剂、水、浓盐酸溶液和式I所示化合物的比例例如可为5mL-15mL:0.5mL-1.5mL:0.38mL-0.57mL:1g,又例如为8mL-12mL:0.8mL-1.2mL:0.38mL-0.48mL:1g,又例如为9mL:1mL:0.41mL:1g。
其中,所述的浓盐酸溶液的浓度例如可为8mol/L-12mol/L,又例如为10mol/L-12mol/L,又例如为12mol/L。
其中,所述式I所示化合物的盐酸盐溶液中,HCl和所述式I所示化合物的摩尔比例如可为2:1至3:1,又例如为2.0:1至2.5:1,又例如为2.1:1至2.3:1。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液由包括式I所示化合物的溶液与浓盐酸溶液的原料混合得到;例如,所述式I所示化合物的盐酸盐溶液为式I所示化合物的溶液与浓盐酸溶液组成的原料的混合物。
例如,所述的式I所示化合物的溶液的溶剂是有机溶剂和水的混合物;又例如,所述式I所示化合物的溶液为式I所示化合物、有机溶剂和水的混合物。
例如,所述有机溶剂和水的体积比为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1。
例如,所述式I所示化合物的溶液通过将式I所示化合物和所述溶剂在30-70℃的温度下混合得到,所述的温度又例如为40-60℃,又例如为45-55℃。
本发明还提供了一种所述式I所示化合物的盐酸盐水合物的晶型A的制备方法,其包括以下步骤:从式I所示化合物的盐酸盐溶液中析出晶体,所述晶体即为晶型A;其中,所述式I所示化合物的盐酸盐溶液中含有所述式I所示化合物、有机溶剂、水和浓盐酸溶液,所述的有机溶剂为选自甲醇、乙醇、正丙醇、正丁醇、异丙醇、异丁醇和叔丁醇中的一种或两种以上的混合物。此处的两种以上应理解为包含两种。本领域技术人员应当清楚,所述式I所示化合物的盐酸盐溶液中不含有其它有机溶剂,除非是不可避免的杂质或溶剂残留。
在一些实施方案中,所述的有机溶剂为乙醇。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液为所述式I所示化合物、有机溶剂、水和浓盐酸溶液的混合物。
在一些实施方案中,所述浓盐酸溶液和式I所示化合物的比例为0.38mL-0.57mL:1g,例如为0.4mL-0.5mL:1g,又例如为0.38mL-0.40mL:1g、0.40mL-0.42mL:1g、0.42mL-0.44mL:1g、0.44mL-0.46mL:1g、0.46mL-0.48mL:1g、0.48mL-0.50mL:1g、0.50mL-0.52mL:1g、0.52mL-0.54mL:1g或0.54mL-0.57mL:1g。
在一些实施方案中,所述有机溶剂和式I所示化合物的比例为5mL-15mL:1g,例如为8mL-12mL:1g,又例如为5mL-6mL:1g、6mL-7mL:1g、7mL-8mL:1g、8mL-9mL:1g、9mL-10mL:1g、10mL-11mL:1g、11mL-12mL:1g、12mL-13mL:1g、13mL-14mL:1g或14mL-15mL:1g。
在一些实施方案中,所述水和式I所示化合物的比例为0.5mL-1.5mL:1g;例如为0.8mL-1.2mL:1g,又例如为0.5mL-0.6mL:1g、0.6mL-0.7mL:1g、0.7mL-0.8mL:1g、0.8mL-0.9mL:1g、0.9mL-1.0mL:1g、1.0mL-1.1mL:1g、1.1mL-1.2mL:1g、1.2mL-1.3mL:1g、1.3mL-1.4mL:1g或1.4mL-1.5mL:1g。
在一些实施方案中,所述有机溶剂和水的体积比例为5-15:0.5-1.5,优选为10:1至6:1,更优选为10:1至8:1,更优选为9:1。
在一些实施方案中,所述有机溶剂、水和式I所示化合物的比例为5mL-15mL:0.5mL-1.5mL:1g,优选为8mL-12mL:0.8mL-1.2mL:1g,进一步优选为9mL:1mL:1g。
在一些实施方案中,所述有机溶剂、水、浓盐酸溶液和式I所示化合物的比例为5mL-15mL:0.5mL-1.5mL:0.38mL-0.57mL:1g,优选为8mL-12mL:0.8mL-1.2mL:0.38mL-0.48mL:1g,进一步优选为9mL:1mL:0.41mL:1g。
在一些实施方案中,所述的浓盐酸溶液的浓度为8mol/L-12mol/L,优选为10mol/L-12mol/L, 更优选为12mol/L。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液中,HCl和所述式I所示化合物的摩尔比为2:1至3:1,优选为2.0:1至2.5:1,进一步优选为2.1:1至2.3:1。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液是式I所示化合物的溶液与浓盐酸溶液的混合物。
在一些实施方案中,所述式I所示化合物的盐酸盐溶液通过向式I所示化合物的溶液中加入(例如通过滴加的方式)浓盐酸溶液得到。
在一些实施方案中,所述的式I所示化合物的溶液的溶剂是有机溶剂和水的混合物。
在一些实施方案中,所述式I所示化合物的溶液通过将式I所示化合物和所述溶剂在30-70℃的温度下混合得到,所述的温度优选为40-60℃,进一步优选为45-55℃。
在一些实施方案中,所述式I所示化合物的溶液为式I所示化合物、有机溶剂和水的混合物。
在一些实施方案中,所述的式I所示化合物的溶液的溶剂中,所述有机溶剂和水的体积比为10:1至6:1,优选为10:1至8:1,更优选为9:1。
在一些实施方案中,所述的制备方法还包括:将式I所示化合物、有机溶剂和水混合,将所得混合物加热至30-70℃(优选为40-60℃,进一步优选为45-55℃),加入(例如通过滴加的方式)浓盐酸溶液,得到所述式I所示化合物的盐酸盐溶液。
在一些实施方案中,所述的制备方法还包括:将所述的式I所示化合物的盐酸盐溶液在30-70℃进行搅拌。所述将所述的式I所示化合物的盐酸盐溶液在30-70℃进行搅拌的步骤在所述从式I所示化合物的盐酸盐溶液中析出晶体的步骤之前进行。所述的搅拌时间例如为1-5小时,又例如为1小时。
在一些实施方案中,所述从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液降温,优选地,所述降温为降温到20℃至30℃。
在一些实施方案中,所述的从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液在20℃至30℃搅拌以析出晶体。所述的搅拌时间例如为48-96小时,又例如为48小时。
在一些实施方案中,所述的制备方法还包括:在从式I所示化合物的盐酸盐溶液中析出晶体后,过滤,将所得滤饼洗涤、干燥,得到晶型A。
在一些实施方案中,所述的制备方法的原料仅包括式I所示化合物、无水乙醇、水和浓盐酸溶液。
在一些实施方案中,所述式I所示化合物的盐酸盐水合物的晶型A的制备方法还包括:将 式I所示化合物的盐酸盐水合物的晶型A的溶液冷却进行结晶,得到式I所示化合物的盐酸盐水合物的晶型A的单晶,其中,所述式I所示化合物的盐酸盐水合物的晶型A的溶液的溶剂为乙醇和水的混合物。
其中,所述的乙醇和水的混合物的温度可为55-75℃,进一步优选为60-70℃,进一步优选为64-66℃。
其中,所述的乙醇和水的混合物中乙醇和水的体积比可为10:1至6:1,优选为10:1至8:1,更优选为9:1。
其中,所述的冷却可为冷却到20℃至30℃。
本发明还提供了式I所示化合物的盐酸盐水合物,所述盐酸盐水合物中,所述式I化合物、HCl和水的摩尔比为1:x:y,x大于0而不大于3,y大于0而不大于3。
在一些实施方案中,所述盐酸盐水合物中,所述式I化合物、HCl和水的摩尔比为1:2:2。
本发明还提供了一种药物组合物,其包含以上任一方案所述的式I所示化合物的盐酸盐水合物和以上任一方案所述的式I所示化合物的盐酸盐水合物的晶型A中的至少一种,以及至少一种药学上可接受的载体。
在一些实施方案中,所述载体为赋形剂、稀释剂和溶媒中的至少一种。
本发明还提供了以上任一方案所述的式I所示化合物的盐酸盐水合物、晶型A或药物组合物在制备用于预防或治疗对Janus激酶介导的失调、疾病或病症的药物中的用途。
本发明还提供了一种预防或治疗有此需要的受试者的对Janus激酶介导的失调、疾病或病症的方法,其包括向此受试者给予预防或治疗有效量的以上任一方案所述的式I所示化合物的盐酸盐水合物、晶型A或药物组合物。
本发明还提供了以上任一方案所述的式I所示化合物的盐酸盐水合物、晶型A或药物组合物用于预防或治疗对Janus激酶介导的失调、疾病或病症。
在一些实施方案中,所述的Janus激酶为JAK1、JAK2、JAK3以及TyK2中的至少一个。
在一些实施方案中,所述的Janus激酶介导的疾病为过度增生性疾病、癌症(例如白血病和淋巴瘤)、免疫和炎性病症(例如移植排斥、哮喘、慢性阻塞性肺病、过敏症、类风湿性关节炎、银屑病、特应性皮炎、克罗恩病、溃疡性结肠炎、肌萎缩性侧索硬化和多发性硬化)中的至少一种。
在一些实施方案中,所述的Janus激酶介导的疾病为白血病、淋巴瘤、移植排斥、哮喘、慢性阻塞性肺病、过敏症、类风湿性关节炎、银屑病、特应性皮炎、克罗恩病、溃疡性结肠炎、肌萎缩性侧索硬化和多发性硬化中的至少一种。
在不违背本领域常识的基础上,上述各优选条件,可任意组合,即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
本发明的积极进步效果在于:本发明的盐型和晶型具有良好的JAK激酶抑制活性、溶解性、稳定性和生物利用度,增强了式I所示化合物口服制剂的可开发性。
定义和说明
除非另有说明,本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的,而应该按照普通的含义去理解。当本文中出现商品名时,意在指代其对应的商品或其活性成分。
本文所采用的术语“药学可接受的载体”即为药用辅料,是指除活性成分以外,包含在药物制剂中的所有物质,例如中华人民共和国药典(2015年版或2020年版)四部中规定的药用辅料。
本文所用术语“药物组合物”是指含有指定的活性成分,且可被制备成同一剂型的组合物。
本文所用术语“受试者”是指根据本发明的实施例,即将或已经接受了该化合物或组合物给药的任何动物,哺乳动物为优,人类最优。如本文所用,术语“哺乳动物”包括任何哺乳动物。哺乳动物的实例包括但不限于牛、马、羊、猪、猫、狗、小鼠、大鼠、家兔、豚鼠、猴、人等,以人类为最优。
本文所用术语“预防或治疗有效量”是指在给予受试者时足以有效预防或治疗本文所述的失调、疾病或病症的化合物的量。构成“预防或治疗有效量”的化合物的量将根据化合物,失调、疾病或病症的种类及其严重度,以及受试者的年龄而变化,但可由本领域技术人员根据需要进行调整。
本文所用术语“治疗”指治疗性疗法。涉及具体疾病或病症时,“治疗”是指下列各项中的至少一种:(1)缓解失调、疾病或病症的一种或多种生物学表现,(2)干扰失调、疾病或病症的一种或多种生物学表现,(3)改善或消除与失调、疾病或病症相关的一种或多种症状、影响或副作用,或者与失调、疾病或病症的治疗相关的一种或多种症状、影响或副作用;以及(4)减缓失调、疾病或病症的一种或多种生物学表现发展。
本发明采用下述缩略词:
XRPD      X-射线粉末衍射
DSC       示差扫描量热法
TGA       热重分析
rpm       每分钟转速
ATP       三磷酸腺苷
DTT        DL-二硫代苏糖醇
SEB        Supplier of Enzymatic Buffer,酶反应缓冲液添加物
AUClast    血药浓度-时间曲线下面积
Cmax       峰浓度
min        分钟
-RH        相对湿度
XRPD表征方法
如无特殊说明,本发明所述的各XRPD数据(包括但不限于附图1、4-5、8-12所示的XRPD图谱)采用如下条件测定:
样品制备:取适量待测样品均匀分布在样品架里,并用干净的玻璃板压平实,使样品表面与样品架表面平齐。
所用的仪器为布鲁克D2Phaser X射线粉末衍射仪,其中,检测器:PSD LynxEye检测器
衍射仪参数设置:测角仪直径,282.2mm;发散狭缝,1.0mm;主索拉狭缝,2.5度;副索拉狭缝,2.5度;防空气散射组件,1.0mm;光管元素,铜;光管参数,电压30kV,电流10mA;
扫描参数设置:扫描类型,Locked coupled;扫描模式,Continuous PSD fast模式;旋转速度,20度/分;扫描范围,3度~40度(2θ);扫描步长,0.02度(2θ);扫描速度,0.2秒/步;检测器开口,4.5度。
DSC表征方法
如无特殊说明,本发明所述的DSC数据采用如下条件测定:
仪器:Discovery DSC250差示扫描量热仪,样品盘类型为扎孔;
升温区间为25℃-300℃,升温速度为10℃/min;
TGA表征方法
如无特殊说明,本发明所述的TGA数据采用如下条件测定:
仪器:Discovery 55热重分析仪
样品盘类型:默认开口铝盘;
升温区间:10℃-300℃,升温速度为10℃/min。
附图说明
图1为晶型A的XRPD图谱;
图2为晶型A的DSC图谱;
图3为晶型A的TGA图谱;
图4为晶型C的的XRPD图谱;
图5为晶型D的的XRPD图谱;
图6为晶型E的XRPD图谱;
图7为晶型F的XRPD图谱;
图8为晶型A在40℃/60%-RH的稳定室中放置30天后的XRPD图谱;
图9为晶型A在25℃/75%-RH的稳定室中放置30天后的XRPD图谱;
图10为实施例5中向饱和溶液体系中加入晶型A后析出固体的XRPD图谱;
图11为实施例5中向饱和溶液体系中加入晶型E后析出固体的XRPD图谱;
图12为实施例5中向饱和溶液体系中加入晶型F后析出固体的XRPD图谱;
图13为实施例8所得晶型A的单晶形状;
图14为实施例8所得晶型A单晶的XRPD图谱;
图15为实施例8所得晶型A单晶的不对称结构单元示意图。
图1、4-5、8-12、14中,纵坐标强度的单位为计数(counts),横坐标2θ角度单位为度(°),图6-7中横坐标2θ角度单位为度(°)。
具体实施方式
下面通过实施例的方式进一步说明本发明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
以下实施例中,如无特别注明,质谱采用Waters Acquity Xevo G2-XS QTof UPLC/MS超高效液相色谱高分辨质谱联用系统检测, 1H-NMR采用Bruker AVANCE III 400MHz核磁共振仪或Bruker AVANCE III HD 300MHz核磁共振仪检测,HPLC采用Agilent 1260高效液相色谱仪检测。
如无特别注明,本发明中所述的浓盐酸溶液是指氯化氢(HCl)的水溶液,其浓度不低于8mol/L。
如无特别说明,本发明中的室温是指20-30℃。
实施例1.式I所示化合物的合成
化合物4的合成
Figure PCTCN2021112278-appb-000007
在3L的圆底烧瓶中加入SM1-1(54.60g,175.0mmol)和二氯甲烷(1L),冷却至0℃后,缓慢滴加三氟乙酸(200mL)。滴毕室温搅拌10小时。HPLC显示反应完全,真空除去三氟乙酸,然后用二氯甲烷(500mL)稀释。所得溶液用NaHCO 3水溶液洗涤后干燥浓缩,硅胶柱层析纯化,得到白色固体化合物4(23.00g,收率62.0%)。
化合物4的核磁数据: 1H NMR(400MHz,DMSO-d 6)δppm:7.24(d,J=8.4Hz,1H),7.05(dd,J=1.1Hz,6.8Hz,1H),6.97-7.01(m,2H),5.31(br,2H)。
化合物5的合成
Figure PCTCN2021112278-appb-000008
向2L圆底烧瓶中加入化合物4(23.00g,108.5mmol)、三乙胺(39.46g,390.0mmol)和乙腈(400mL)。冷却至0℃后,缓慢滴加环丙基酰氯(40.23g,384.9mmol)。滴毕室温搅拌8小时,HPLC显示反应完全。将所得反应液浓缩至干,然后加入水洗涤,过滤得固体,所得固体经柱层析得到白色固体化合物5(29.46g,收率97.0%)。
化合物5的核磁数据: 1H NMR(400MHz,DMSO-d 6)δppm:11.14(br,1H),8.05(s,1H),7.50-7.52(m,1H),7.19-7.28(m,2H),1.92-1.99(m,1H),0.82-0.84(m,4H)。
式I所示化合物的合成
Figure PCTCN2021112278-appb-000009
向2L圆底烧瓶中加入化合物5(29.46g,105.2mmol)、SM2-1(41.88g,113.4mmol)、K 2CO 3(26.12g,189.0mmol)、Pd(dppf)Cl 2.CH 2Cl 2(6.91g,8.5mmol)、H 2O(120mL)和1,4-二氧 六环(600mL)。N 2保护下加热回流10小时。HPLC显示反应完全,加入冰水淬灭反应,过滤得固体。所得固体经柱层析得到式I所示化合物(27.42g,收率58.9%),其为白色固体。
式I所示化合物的表征数据: 1H(400Hz,DMSO-d 6)δppm:8.08(1H,dd,J=9.2,7.3Hz),8.03(1H,dd,J=9.3,1.6Hz),7.84-7.78(3H,m),7.60(1H,dd,J=7.1,1.6Hz),4.66(2H,s),3.90-3.89,(4H,m),3.70-3.68(4H,m),1.97-1.94(1H,m),1.08-1.04(4H,m)。LC/MS m/z:443.2(M+H)。
实施例2.式I所示化合物的盐酸盐水合物的晶型A的制备
在圆底烧瓶中加入式I所示化合物(1.5g,3.4mmol),接着加入13.5mL无水乙醇和1.5mL纯净水,将所得混合物搅拌加热至50℃。然后滴加0.62mL浓盐酸溶液(12mol/L,7.4mmol),滴加完毕后,将所得的式I所示化合物的盐酸盐溶液保温50℃搅拌1小时后室温下自然冷却至25℃,然后保温25℃搅拌48小时以析出晶体,停止搅拌。过滤,所得滤饼用少量乙醇洗涤后收集,于40℃下真空干燥6小时,所得晶体即为晶型A。
晶型A的XRPD图谱如图1所示,其中以2θ角度表示的X-射线粉末衍射峰如表1所示。
晶型A的DSC结果如图2所示,DSC在165.14℃处显示第一处吸热峰,热焓值为180.63J/g,起始温度为140.82℃;另一处吸热峰在197.70℃,热焓值为23.689J/g,起始温度为179.20℃。
晶型A的TGA结果如图3所示,显示该样品在148.00℃前,有8.3143%的失重;在148-228℃,有4.7637%的失重。
使用梅特勒-托利多T5电位滴定仪进行氯离子含量测定,结果显示样品中氯离子含量为12.3%,与样品含有两个氯离子基本相符(样品含有两个盐酸盐的氯离子理论值为12.9%)。使用梅特勒-托利多KF滴定仪V30S进行水分含量测定,结果显示样品中水含量为8.0%,与样品含有两个结晶水基本相符(样品含有两个结晶水的水分理论值为6.5%)。由此可以确定,所述的晶型A为式I化合物的盐酸盐水合物,该盐酸盐水合物中,式I化合物、HCl和水的摩尔比为1:2:2。
对比例1.用其他溶剂体系制备晶型A的尝试
(1)THF/水体系中结晶
在圆底烧瓶中加入式I所示化合物(1.0g,2.3mmol),接着加入9mL THF和1mL纯水,所得混合物搅拌加热至60℃。然后滴加0.41mL浓盐酸溶液(12mol/L,4.9mmol),滴加完毕后,将所得的式I所示化合物的盐酸盐溶液保温60℃搅拌1小时后,室温下自然冷却至25℃,然后保温25℃搅拌48小时析出晶体,停止搅拌。过滤,所得滤饼用少量THF洗涤后干燥,所得 固体即为晶型C,其XRPD图谱如图4所示,可见所得晶型C与晶型A不同。
(2)DCM/MeOH体系中结晶
在圆底烧瓶中加入式I所示化合物(0.5g,1.1mmol),接着加入10mL DCM和10mLMeOH,所得混合物搅拌加热至40℃。然后滴加4M的盐酸溶液(0.6mL,2.4mmol),滴加完毕后,将所得的式I所示化合物的盐酸盐溶液保温40℃搅拌1小时后,室温下自然冷却至25℃,然后保温25℃搅拌48小时析出晶体,停止搅拌。过滤,所得滤饼用少量DCM洗涤后干燥,所得固体即为晶型D,其XRPD图谱如图5所示。可见所得晶型D与晶型A不同。
对比例2.式I所示化合物的盐酸盐晶型E的制备
取10mg式I所示化合物的盐酸盐水合物的晶型A加入至0.3mL乙腈中,室温下搅拌3天,过滤得到晶型E。其晶型XRPD图谱如图6所示。
本发明附图6所示的XRPD图谱所用的检测仪器为Bruker D8 Advance X射线衍射仪,其中,X-射线管参数设定:X-射线波长,Cu:K-Alpha
Figure PCTCN2021112278-appb-000010
电压,40kV;电流,40mA;样品旋转速度:15rpm;扫描范围:3到40度(2θ);扫描速度:10度/分。
对比例3.式I所示化合物的盐酸盐晶型F的制备
将10mg式I所示化合物的盐酸盐水合物的晶型A加入至4mL小瓶中,加入至0.5mL的DMSO中,搅拌溶清。另取40mL圆底烧瓶,加入4mL乙腈。将小瓶置于圆底烧瓶中,圆底烧瓶加盖,室温下放置缓慢结晶。3天后过滤得到晶型F,其XRPD如图7所示。
本发明附图7所示的XRPD图谱所用的检测仪器为Bruker D8 Advance X射线衍射仪,其中,X-射线管参数设定:X-射线波长,Cu:K-Alpha
Figure PCTCN2021112278-appb-000011
电压,40kV;电流,40mA;样品旋转速度:15rpm;扫描范围:3到40度(2θ);扫描速度:10度/分。
实施例3.式I所示化合物的盐酸盐水合物的晶型A的JAK激酶抑制活性测试
采用Cisbio的
Figure PCTCN2021112278-appb-000012
(均相时间分辨荧光,Homogeneous Time-Resolved Fluorescence)试剂盒(HTRF kinEASE-TK kit,目录号:62TKOPEC)进行化合物的体外酶活生化测定,测试中所用的底物、激酶反应缓冲液、检测缓冲液、别藻蓝蛋白修饰物(XL-665)标记的链和亲和素、铕(EU)标记的特异性磷酸化抗体和SEB都是试剂盒自带的。测定中使用的JAK1购自Invitrogen(目录号为PV4774),JAK2、JAK3和TYK2均购自Carna Biosciences,Inc.(目录号分别为:08-045,08-046,08-147),DTT购自Sigma(目录号为43816)。
将化合物(按照实施例2方法制备所得式I所示化合物的盐酸盐水合物晶型A或Tofacitinib 柠檬酸盐(上海皓元化学科技有限公司,HY-40354A))在DMSO中以3倍连续稀释10次,所得化合物稀释液的浓度为最终试验浓度的100倍。然后用激酶反应缓冲液将所述化合物稀释液的浓度进一步稀释至最终试验浓度的2.5倍,得到化合物待测溶液。
酶促反应在白色的384孔聚丙烯板(Greniner,目录号:784075)中进行,总反应体积为10uL,含有500ng/mL JAK1,6ng/mL JAK2,37ng/mL JAK3,100ng/mL TYK2,1uM底物和1mM ATP(Sigma-Aldrich,目录号:A7699)。
将4uL化合物待测溶液加到384孔聚丙烯板孔中,然后加入2uL在激酶反应缓冲液中稀释的JAK1(另外加入缓冲添加物MgCl 2、MnCl 2和DTT,各自的最终浓度分别为5mM、1mM和1mM),JAK2(另外加入缓冲添加物MgCl 2和DTT,各自的最终浓度分别为5mM和1mM),JAK3(另外加入缓冲添加物MgCl 2和DTT,各自的最终浓度分别为5mM和1mM),TYK2(另外加入缓冲添加物MgCl 2、MnCl 2、DTT和SEB,各自的最终浓度分别为5mM、1mM、1mM和12.5nM),在室温下孵育15分钟进行预处理。通过加入在激酶反应缓冲液中制备的2uL底物和2uL ATP的混合物来引发酶促反应。30分钟室温反应后,加入5uL用检测缓冲液配制的别藻蓝蛋白修饰物(XL-665)标记的链和亲和素和5uL用检测缓冲液配制的铕标记的特异性磷酸化抗体,以停止酶促反应并产生信号。室温下温育1小时后,在具有以下设置的Molecular Devices SpectraMAX Paradigm多功能酶标仪中读取板:激发为340nm/发射1为616nm/发射2为665nm。按下式计算每个孔的受体和供体的发射光信号的比率(Ratio):Ratio=signal665nm/signal 616nm*10000,其中,signal 665nm为665nm的信号,signal 616nm为616nm的信号。按下式计算抑制百分数:抑制百分数=100%-处理的化合物ratio值/处理的DMSO运载体ratio值的百分比(DMSO运载体是不含药物的空白对照组)。
生成剂量-反应曲线,并使用GraphPad Prism软件通过非线性S形曲线拟合计算IC 50。所得结果如下:
表2.式I所示化合物的盐酸盐水合物的晶型A的IC 50数据
Figure PCTCN2021112278-appb-000013
实施例4.式I所示化合物及晶型A的溶解性测试
称取研成细粉的样品分别加入一定体积的溶剂中(环境温度:25℃±5℃),每隔5分钟强力振摇30秒钟,观察30分钟内的溶解情况,如无目视可见的溶质颗粒或液滴时,即视为完全 溶解。按照该方法观察式I所示化合物的盐酸盐水合物的晶型A和式I所示化合物的游离碱形式在常见溶剂中的溶解情况,结果见表3。其中“易溶”指1g(mL)溶质能在体积1mL≤V<10mL的溶剂中溶解;“溶解”指1g(mL)溶质能在体积10mL≤V<30mL的溶剂中溶解;“略溶”指1g(mL)溶质能在体积30mL≤V<100mL的溶剂中溶解;“微溶”指1g(mL)溶质能在体积100mL≤V<1000mL的溶剂中溶解;“极微溶”指1g(mL)溶质能在体积1000mL≤V<10000mL的溶剂中溶解;“几乎不溶”或“不溶”指1g(mL)溶质在体积为10000mL的溶剂中不能完全溶解。
表3.式I所示化合物游离碱和其盐酸盐水合物的晶型A的溶解度
溶剂 式I所示化合物游离碱 晶型A
甲醇 微溶 易溶
乙醇 微溶 溶解
极微溶 溶解
模拟胃液 不溶 略溶
实施例5.不同晶型的稳定性测试
测试温度和湿度对式I所示化合物的盐酸盐水合物的晶型A的稳定性是否有影响:
将晶型A置于稳定室中,温度和湿度分别控制在40℃/60%-RH和25℃/75%-RH。30天后,将所得固体与其初始晶型A进行比较:其外观无明显变化,HPLC测得式I所示化合物的含量(如表4所示)无明显变化,XRPD(40℃/60%-RH和25℃/75%-RH处理后所得的XRPD图谱分别见图8和图9)也无明显变化,显示晶型A具有很好的稳定性。
表4.晶型A放置前后式I所示化合物的含量
样品 式I所示化合物含量
初始晶体A 99.901%
晶体A于40℃/75%‐RH条件下放置30天后 99.905%
晶体A于25℃/75%‐RH条件下放置30天后 99.899%
晶型A、晶型E和晶型F的热力学稳定性比较:
将晶型A、晶型E和晶型F分别溶于乙醇/水(体积比=9:1)的混合溶剂中制成饱和溶液。加热至50℃,搅拌下分别加入10mg晶型A,晶型E和晶型F。保温50℃下搅拌24小时后过滤,分别测定所得晶体的XRPD(加入晶型A、E和F析出的晶体的XRPD图谱分别如图 10、11和12所示)。将所得XRPD图谱和如图1所示的晶型A的XRPD图谱比较分析,发现加入晶型A的体系析出的晶体仍是晶型A,而晶型E和晶型F均转化为晶型A,说明晶型A比晶型E和晶型F具有更好的热力学稳定性。
实施例6.单剂量PK研究
2组SD大鼠(每组3只雌性),分别施用单次口服剂量3mg/kg式I所示化合物游离碱和单次口服剂量3mg/kg式I所示化合物的盐酸盐水合物的晶型A。药物以0.5%CMC-Na混悬液形式施用。在不同时间取样直到24小时,采用LC-MS/MS法分析血浆中的式I所示化合物的药物浓度,并最终计算所得结果见表8。
式I所示化合物LC-MS/MS法的色谱条件:
仪器型号,SHIMADZU LC-30AD液相系统;色谱柱,ACQUITY
Figure PCTCN2021112278-appb-000014
BEH C18(2.1×50mm,1.7μm);柱温,40℃;进样量,1μL;流速0.6mL/min;运行时间6min;流动相梯度设置见表5。
表5.
Figure PCTCN2021112278-appb-000015
质谱条件:
仪器型号,AB SCIEX TRIPLE QUAD 6500质谱仪;离子源,电喷雾(ESI);离子化模式,正离子扫描;多离子(MRM)离子对见表6;仪器参数见表7。
表6.
分析物 Q1质荷比(m/Z) Q3质荷比(m/Z) 扫描间隔(毫秒)
式I所示化合物 443.2 375.3 100
GLPG0634* 426.1 291.2 100
*:为内标化合物,购自MedChemExpress公司(目录号:HY-18300),表7中同。
表7.
参数 式I所示化合物 GLPG0634
喷雾电压(v) 5000 5000
离子源温度(℃) 550 550
碰撞气(psi) 10 10
气帘气(psi) 40 40
雾化气(psi) 50 50
辅助气(psi) 40 40
去簇电压(v) 110 110
入口电压(v) 12 12
碰撞电压(v) 47 39
碰撞室出口电压(v) 10 10
表8.式I所示化合物的盐酸盐水合物的晶型A与式I所示化合物游离碱的PK数据
固体形式 AUClast Cmax
游离碱 987h*ng/mL 352ng/mL
晶型A 1390h*ng/mL 456ng/mL
实施例7.晶型A、晶型C、晶型D、晶型E和晶型F的吸湿性研究
取晶型A、晶型C、晶型D、晶型E和晶型F各500mg左右,精确称重后置于恒湿密闭容器中,25℃/75%-RH条件下放置5天,然后取出测定其吸湿增重,结果见表9,说明晶型A的吸湿性最低。
表9:各晶型的吸湿性数据
晶型 晶型A 晶型C 晶型D 晶型E 晶型F
吸湿增重 2.4% 6.1% 8.1% 5.3% 4.9%
实施例8.晶型A的单晶测试与结构解析
称取35mg实施例2所制备的式I所示化合物的盐酸盐水合物的晶型A样品,在65℃下溶解于1mL乙醇/水(9:1,v/v)中,冷却至室温进行降温结晶,得到长棒状晶体(图13)。然后选取部分晶体进行XRPD衍射研究(图14),图14中,在如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,21.7°±0.2°和23.8°±0.2°有特征峰,与图1吻合,证明其为晶型A。选取该晶体进行单晶测试及结构解析。单晶结构解析结果显示,晶型A属于单斜晶系,P21/c空间群,其晶胞参数为
Figure PCTCN2021112278-appb-000016
α=90°,β=101.262(3)°,γ=90°,
Figure PCTCN2021112278-appb-000017
图15为该晶体的不对称结构单元示意图,该不对称单元中含有1个式I所示化合物的阳离子,2个氯离子和2个结晶水。
实验所用仪器、软件及方法:
X射线粉末衍射(XRPD)
实验所得固体样品用X射线粉末衍射仪Bruker D8 Advance(Bruker,GER)进行分析。2θ扫描角度从3°到45°,扫描步长为0.02°,曝光时间为0.12s。测试样品时光管电压和电流分别为40kV和40mA,样品盘为零背景样品盘。
X射线单晶衍射(SCXRD)
从培养得到的单晶样品中挑选一颗形貌及大小合适的单晶,将该单晶粘在Loop环上,再将单晶样品安置在载晶台上。单晶样品的预实验以及单晶衍射数据收集使用SuperNova(Rigaku,JPN)单晶衍射仪(Cu靶光源,
Figure PCTCN2021112278-appb-000018
)在253.0K温度环境下进行,衍射数据使用CrysAlisPro软件包进行分析处理。
在253.0K温度下衍射数据收集的角度范围为4.4340°<θ<73.8890°,从该角度范围内收集到8128个衍射点,采用CrysAlisPro程序对其进行分析并以最小二乘法精修后获得该晶体的晶胞参数和取向矩阵。对应于最高θ角(θ=66.97°)的数据收集完整度为99.94%。
数据还原
采用CrysAlisPro 1.171.39.46(Rigaku Oxford Diffraction,2018)程序对探测器所采集得到的每一帧衍射图像进行还原整合,共收集得到16159个衍射点,其中独立衍射点4275个。使用SCALE3ABSPACK scaling algorithm对衍射数据进行吸收矫正。该晶体样品对波长
Figure PCTCN2021112278-appb-000019
Figure PCTCN2021112278-appb-000020
的X射线的线性吸收系数为3.404mm -1,最小透过系数(Tmin)为0.586,最大透过系数(Tmax)为1.000。所有等效衍射点的强度在实验误差范围内基本相等,其Rint为4.30%。
结构解析及精修
单晶结构解析采用OLEX2软件,以XS(Sheldrick,2008)初解程序对衍射数据进行结构初解并确定晶体所属空间群为P21/c。随后采用XH(Sheldrick,2008)程序进行结构精修。以 数轮差值Fourier合成确定全部非氢原子的坐标,继而以全矩阵最小二乘法对所有非氢原子进行各向异性精修。所有氢原子均采用理论加氢的方式计算得到。
晶体结构图
晶体结构示意图及原子热振动椭球图采用Diamond软件绘制。
虽然以上描述了本发明的具体实施方式,但是本领域的技术人员应当理解,这仅是举例说明,本发明的保护范围是由所附权利要求书限定的。本领域的技术人员在不背离本发明的原理和实质的前提下,可以对这些实施方式做出多种变更或修改,但这些变更和修改均落入本发明的保护范围。

Claims (20)

  1. 式I所示化合物的盐酸盐水合物的晶型A,其特征在于,其X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,21.7°±0.2°和23.8°±0.2°;
    Figure PCTCN2021112278-appb-100001
  2. 如权利要求1所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,11.6°±0.2°,17.7°±0.2°,17.8°±0.2°,21.7°±0.2°,23.6°±0.2°,23.8°±0.2°,29.0°±0.2°,30.4°±0.2°和34.9°±0.2°。
  3. 如权利要求1或2所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,7.4°±0.2°,8.9°±0.2°,11.6°±0.2°,14.6°±0.2°,17.7°±0.2°,17.8°±0.2°,18.7°±0.2°,19.5°±0.2°,21.0°±0.2°,21.7°±0.2°,21.9°±0.2°,22.6°±0.2°,23.6°±0.2°,23.8°±0.2°,29.0°±0.2°,30.4°±0.2°,33.3°±0.2°,34.9°±0.2°和37.7°±0.2°;例如,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°±0.2°,6.6°±0.2°,7.4°±0.2°,8.9°±0.2°,10.5°±0.2°,11.6°±0.2°,12.3°±0.2°,13.9°±0.2°,14.2°±0.2°,14.6°±0.2°,17.1°±0.2°,17.7°±0.2°,17.8°±0.2°,18.7°±0.2°,19.5°±0.2°,20.4°±0.2°,21.0°±0.2°,21.2°±0.2°,21.7°±0.2°,21.9°±0.2°,22.6°±0.2°,23.6°±0.2°,23.8°±0.2°,24.9°±0.2°,26.6°±0.2°,26.8°±0.2°,28.3°±0.2°,29.0°±0.2°,30.4°±0.2°,31.2°±0.2°,32.3°±0.2°,33.3°±0.2°,34.2°±0.2°,34.9°±0.2°,35.6°±0.2°,35.9°±0.2°,36.4°±0.2°,36.9°±0.2°,37.7°±0.2°,39.3°±0.2°和39.8°±0.2°;又例如,所述晶型A的X-射线粉末衍射图谱于如下2θ角度处具有特征衍射峰:5.9°,6.6°,7.4°,8.9°,10.5°,11.6°,12.3°,13.9°,14.2°,14.6°,17.1°,17.7°,17.8°,18.7°,19.5°,20.4°,21.0°,21.2°,21.7°,21.9°,22.6°,23.6°,23.8°,24.9°,26.6°,26.8°,28.3°,29.0°,30.4°,31.2°,32.3°,33.3°,34.2°,34.9°,35.6°,35.9°,36.4°,36.9°,37.7°,39.3°和39.8°。
  4. 如权利要求1-3中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的XRPD图谱解析数据如下表所示:
    衍射角(°2θ) 相对强度[%] 衍射角(°2θ) 相对强度[%] 5.9 20.7 23.6 15.3 6.6 0.9 23.8 29.8 7.4 55.4 24.9 14.3 8.9 7.8 26.6 1.2 10.5 1.3 26.8 3.9 11.6 100 28.3 4.2 12.3 0.7 29.0 19.0 13.9 3.6 30.4 19.7 14.2 2.0 31.2 0.8 14.6 6.2 32.3 1.2 17.1 3.9 33.3 8.0 17.7 17.0 34.2 1.7 17.8 18.8 34.9 15.6 18.7 5.0 35.6 3.1 19.5 14.8 35.9 2.3 20.4 1.7 36.4 0.8 21.0 9.4 36.9 0.9 21.2 2.6 37.7 5.7 21.7 33.6 39.3 1.0 21.9 11.8 39.8 2.5 22.6 5.3    
    ;例如,所述晶型A的XRPD图谱如图1所示。
  5. 如权利要求1-4中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的热重分析曲线在148℃前,有8.31±0.50%的失重;且在148℃-228℃,有4.76±0.50%的失重。
  6. 如权利要求1-5中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的热重分析曲线在148℃前,有8.31%的失重,且在148℃-228℃,有4.76%的失重;例如,所述晶型A的热重分析曲线在148℃前,有8.3143%的失重,且在148℃-228℃,有4.7637%的失重;又例如,所述晶型A的热重分析曲线如图3所示。
  7. 如权利要求1-6中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在 于,所述晶型A的差示扫描热分析图在165℃±3℃和198℃±3℃分别具有吸收峰;例如,所述晶型A的差示扫描热分析图在165.14℃和197.70℃分别具有吸收峰;
    和/或,所述晶型A的差示扫描热分析图具有起始温度分别为141℃±3℃和179℃±3℃的吸收峰;例如,所述晶型A的差示扫描热分析图具有起始温度分别为140.82℃和179.20℃的吸收峰。
  8. 如权利要求1-7中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A的差示扫描热分析图如图2所示。
  9. 如权利要求1-8中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述晶型A为单晶,其属于单斜晶系,P21/c空间群,晶胞参数为
    Figure PCTCN2021112278-appb-100002
    Figure PCTCN2021112278-appb-100003
    α=90°,β=101.262(3)°,γ=90°,晶胞体积为
    Figure PCTCN2021112278-appb-100004
    Figure PCTCN2021112278-appb-100005
  10. 如权利要求1-9中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A,其特征在于,所述的晶型A中,所述式I化合物、HCl和水的摩尔比为1:x:y,其中,x大于0而不大于3,且y大于0而不大于3;优选地,所述的晶型A中,所述式I化合物、盐酸和水的摩尔比为1:2:2。
  11. 权利要求1-10中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,包括以下步骤:从式I所示化合物的盐酸盐溶液中析出晶体,所述晶体即为晶型A;其中,所述式I所示化合物的盐酸盐溶液中含有式I所示化合物的盐酸盐、有机溶剂和水,所述的有机溶剂为选自甲醇、乙醇、正丙醇、正丁醇、异丙醇、异丁醇和叔丁醇中的一种或两种以上的混合物;例如,所述的有机溶剂为乙醇。
  12. 如权利要求11所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,所述的式I所示化合物的盐酸盐中,所述式I化合物和HCl的摩尔比为1:x,x大于0而不大于3,例如,所述式I化合物和HCl的摩尔比为1:2;
    和/或,所述有机溶剂和水的体积比例为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1;
    和/或,所述的式I所示化合物的盐酸盐溶液的温度为30-70℃;
    和/或,所述从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液降温,例如,所述降温为降温到20℃至30℃;
    和/或,所述的从式I所示化合物的盐酸盐溶液中析出晶体的步骤包括:将所述式I所示化合物的盐酸盐溶液在20℃至30℃搅拌以析出晶体;所述的搅拌时间例如为48-96小时;
    和/或,所述的制备方法还包括:在从式I所示化合物的盐酸盐溶液中析出晶体后,过滤, 将所得滤饼洗涤、干燥,得到晶型A;
    和/或,所述的制备方法还包括:将式I所示化合物的盐酸盐水合物的晶型A的溶液冷却进行结晶,得到式I所示化合物的盐酸盐水合物的晶型A的单晶,其中,所述式I所示化合物的盐酸盐水合物的晶型A的溶液的溶剂为乙醇和水的混合物;例如,所述的式I所示化合物的盐酸盐水合物的晶型A的溶液的温度为55-75℃,又例如为60-70℃,又例如为64-66℃;例如,所述的乙醇和水的混合物中乙醇和水的体积比为5-15:0.5-1.5,又例如为10:1至6:1,又例如为10:1至8:1,又例如为9:1;例如,所述的冷却为冷却到20℃至30℃。
  13. 如权利要求11或12所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,所述式I所示化合物的盐酸盐溶液由包括式I所示化合物的盐酸盐水合物、有机溶剂和水的原料混合得到;例如,所述的式I所示化合物的盐酸盐水合物和水的用量比为250-450mg:1mL,又例如为300-400mg:1mL。
  14. 如权利要求11或12所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,所述式I所示化合物的盐酸盐溶液由包括所述式I所示化合物、有机溶剂、水和浓盐酸溶液的原料混合得到;例如,所述的制备方法还包括:将式I所示化合物、有机溶剂和水混合,将所得混合物加热至30-70℃,加入浓盐酸溶液,得到所述式I所示化合物的盐酸盐溶液。
  15. 如权利要求14所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,所述浓盐酸溶液和式I所示化合物的比例为0.38mL-0.57mL:1g,例如为0.4mL-0.5mL:1g,又例如为0.38mL-0.40mL:1g、0.40mL-0.42mL:1g、0.42mL-0.44mL:1g、0.44mL-0.46mL:1g、0.46mL-0.48mL:1g、0.48mL-0.50mL:1g、0.50mL-0.52mL:1g、0.52mL-0.54mL:1g或0.54mL-0.57mL:1g;
    和/或,所述有机溶剂和式I所示化合物的比例为5mL-15mL:1g,例如为8mL-12mL:1g,又例如为5mL-6mL:1g、6mL-7mL:1g、7mL-8mL:1g、8mL-9mL:1g、9mL-10mL:1g、10mL-11mL:1g、11mL-12mL:1g、12mL-13mL:1g、13mL-14mL:1g或14mL-15mL:1g;
    和/或,所述的浓盐酸溶液的浓度为8mol/L-12mol/L,例如为10mol/L-12mol/L,又例如为12mol/L。
  16. 如权利要求11或12所述的式I所示化合物的盐酸盐水合物的晶型A的制备方法,其特征在于,所述式I所示化合物的盐酸盐溶液由包括式I所示化合物的溶液与浓盐酸溶液的原料混合得到;例如,所述的式I所示化合物的溶液的溶剂是有机溶剂和水的混合物;例如,所述式I所示化合物的溶液通过将式I所示化合物和所述溶剂在30-70℃的温度下混合得到,所 述的温度又例如为40-60℃,又例如为45-55℃。
  17. 式I所示化合物的盐酸盐水合物,其特征在于,所述盐酸盐水合物中,所述式I化合物、HCl和水的摩尔比为1:x:y,x大于0而不大于3,y大于0而不大于3;优选地,所述盐酸盐水合物中,所述式I化合物、HCl和水的摩尔比为1:2:2;
    Figure PCTCN2021112278-appb-100006
  18. 一种药物组合物,其包含权利要求17所述的式I所示化合物的盐酸盐水合物和权利要求1-10中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A中的至少一种,以及至少一种药学上可接受的载体;优选地,所述载体为赋形剂、稀释剂和溶媒中的至少一种。
  19. 权利要求17所述的式I所示化合物的盐酸盐水合物、权利要求1-10中至少一项所述的式I所示化合物的盐酸盐水合物的晶型A或权利要求18所述的药物组合物在制备用于预防或治疗对Janus激酶介导的失调、疾病或病症的药物中的用途;优选地,所述的Janus激酶为JAK1、JAK2、JAK3以及TyK2中的至少一个。
  20. 如权利要求19所述的用途,其特征在于,所述的Janus激酶介导的疾病为过度增生性疾病、癌症、免疫和炎性病症中的至少一种;优选地,所述的Janus激酶介导的疾病为白血病、淋巴瘤、移植排斥、哮喘、慢性阻塞性肺病、过敏症、类风湿性关节炎、银屑病、特应性皮炎、克罗恩病、溃疡性结肠炎、肌萎缩性侧索硬化和多发性硬化中的至少一种。
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