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 PDFInfo
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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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- YNZAONSQDDODAC-UHFFFAOYSA-N O=C(C1CC1)Nc1c[n]2c(-c3ccc(CN(CC4)CCS4(=O)=O)cc3F)cccc2n1 Chemical compound O=C(C1CC1)Nc1c[n]2c(-c3ccc(CN(CC4)CCS4(=O)=O)cc3F)cccc2n1 YNZAONSQDDODAC-UHFFFAOYSA-N 0.000 description 2
- LNTNLAXZWWWAIF-UHFFFAOYSA-N C=[Br]c1cccc2nc(NC(C3CC3)=O)c[n]12 Chemical compound C=[Br]c1cccc2nc(NC(C3CC3)=O)c[n]12 LNTNLAXZWWWAIF-UHFFFAOYSA-N 0.000 description 1
- YETVWHXKIRPRJC-UHFFFAOYSA-N CC(C)(C)OC(Nc1c[n]2c(Br)cccc2n1)=O Chemical compound CC(C)(C)OC(Nc1c[n]2c(Br)cccc2n1)=O YETVWHXKIRPRJC-UHFFFAOYSA-N 0.000 description 1
- OGTBAZGVNKAHSD-UHFFFAOYSA-N CC1(C)OB(c2ccc(CN(CC3)CCS3(=O)=O)cc2F)OC1(C)C Chemical compound CC1(C)OB(c2ccc(CN(CC3)CCS3(=O)=O)cc2F)OC1(C)C OGTBAZGVNKAHSD-UHFFFAOYSA-N 0.000 description 1
- LGEYLALWDKSHHR-UHFFFAOYSA-N Nc1c[n]2c(Br)cccc2n1 Chemical compound Nc1c[n]2c(Br)cccc2n1 LGEYLALWDKSHHR-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic 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
- C07D471/02—Heterocyclic 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
- C07D471/04—Ortho-condensed systems
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/541—Non-condensed thiazines containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- 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 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
Description
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 |
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 |
水 | 极微溶 | 溶解 |
模拟胃液 | 不溶 | 略溶 |
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% |
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 |
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 |
固体形式 | AUClast | Cmax |
游离碱 | 987h*ng/mL | 352ng/mL |
晶型A | 1390h*ng/mL | 456ng/mL |
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% |
Claims (20)
- 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°。
- 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°。
- 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。 - 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。
- 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。
- 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。
- 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。
- 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。
- 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。
- 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℃。
- 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。
- 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。
- 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。
- 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℃。
- 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。
- 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。
- 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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AU2021324240A AU2021324240A1 (en) | 2020-08-14 | 2021-08-12 | Salt form and crystal form of JAK inhibitor, preparation method therefor, and use thereof |
EP21855601.7A EP4198035A1 (en) | 2020-08-14 | 2021-08-12 | Salt form and crystal form of jak inhibitor, preparation method therefor, and use thereof |
CN202180061258.0A CN116322678A (zh) | 2020-08-14 | 2021-08-12 | Jak抑制剂的盐型、晶型及其制备方法和应用 |
CA3189275A CA3189275A1 (en) | 2020-08-14 | 2021-08-12 | Salt form and crystal form of jak inhibitor, preparation method therefor, and use thereof |
JP2023507518A JP2023536893A (ja) | 2020-08-14 | 2021-08-12 | Jak阻害剤の塩形、結晶及びその製造方法と使用 |
US18/021,032 US20230295160A1 (en) | 2020-08-14 | 2021-08-12 | Salt form and crystal form of jak inhibitor, preparation method therefor, and use thereof |
KR1020237007522A KR20230051207A (ko) | 2020-08-14 | 2021-08-12 | Jak 억제제의 염 형태, 결정형, 이의 제조방법 및 이의 용도 |
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WO2014164409A1 (en) * | 2013-03-13 | 2014-10-09 | Bristol-Myers Squibb Company | Inhibitors of human immunodeficiency virus replication |
WO2016119700A1 (en) | 2015-01-28 | 2016-08-04 | Jn Therapeutics | Substituted imidazo [1, 2-a] pyridin-2-ylamine compounds, and pharmaceutical compositions and methods of use thereof |
CN107428749A (zh) * | 2015-01-28 | 2017-12-01 | 南京泽宁医药研发有限公司 | 取代的咪唑并[1,2‑α]吡啶‑2‑基胺化合物及其药物组合物和使用方法 |
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