WO2022089620A1 - Nouvelles formes cristallines de composé d'indole carboxamide et procédé de préparation associé - Google Patents

Nouvelles formes cristallines de composé d'indole carboxamide et procédé de préparation associé Download PDF

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WO2022089620A1
WO2022089620A1 PCT/CN2021/127741 CN2021127741W WO2022089620A1 WO 2022089620 A1 WO2022089620 A1 WO 2022089620A1 CN 2021127741 W CN2021127741 W CN 2021127741W WO 2022089620 A1 WO2022089620 A1 WO 2022089620A1
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crystal form
formula
compound
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solvent
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鲁霞
陈智雄
张晓宇
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苏州晶云药物科技股份有限公司
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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/10—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the invention relates to the field of chemical medicine, in particular to a new crystal form of an indolylcarboxamide compound and a preparation method thereof.
  • B cells can secrete various antibodies to resist the invasion of foreign viruses or bacteria.
  • Bruton's nomine kinase (BTK) is mainly expressed in B cells and myeloid cells, and is widely distributed in the blood and lymphatic systems. It is a key kinase in the B cell antigen receptor (BCR) signaling pathway and can regulate the proliferation, differentiation and apoptosis of normal B cells.
  • BCR B cell antigen receptor
  • Malignant B cells require continuous activation of BTK to ensure rapid cancer cell growth. Therefore, inhibiting the activity of BTK can achieve the therapeutic effect of malignant tumors.
  • Formula (I) can selectively combine with BTK, reduce the degree of BTK activation, can effectively control the growth of malignant B cells, and has potential anti-tumor activity.
  • Formula (I) has certain therapeutic potential in chronic lymphocytic leukemia, mantle cell lymphoma and Waldenstrom's macroglobulinemia
  • Patent US20160115126A1 discloses the preparation method of the free base of formula (I) for the first time, the washing and purification process is complicated, and its solid form is not described. Therefore, it is necessary to carry out a complete polymorphic screening in order to obtain a simpler preparation and purification method.
  • Polymorphic forms of the same drug may change its physicochemical properties, such as solubility, dissolution rate, melting point and stability, which in turn may affect the effect of the drug in the human body. Therefore, it is necessary to carry out a comprehensive and systematic crystal form screening of formula (I) to develop a crystal form with good solubility and high stability, so as to provide more and better choices for the subsequent development of the drug.
  • the present invention provides preparation methods and uses of six crystal forms C, A, Y, V, AE and AA of the compound of formula (I).
  • the substances are polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, polycaprolactone, polyethylene glycol, polymethyl methacrylate, A single component or mixture of sodium alginate and hydroxyethyl cellulose; volatilize the above solution at 20°C to 30°C, and the solid is precipitated to obtain crystal form A; or
  • the compound of formula (I) is dissolved in an alcohol solvent, and the dissolution equilibrium is reached at 40° C. to 60° C., and the solution is cooled to solid precipitation to obtain crystal form AA.
  • a pharmaceutical composition comprising the crystal of any one of the above 1, 3, 5, 7, 9, 11 and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having BTK inhibitory activity comprising the crystal according to any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient.
  • a preventive or therapeutic drug for chronic lymphocytic leukemia, mantle cell lymphoma and Waldenström's macroglobulinemia which contains the crystal described in any one of the above 1, 3, 5, 7, 9, and 11 as an active ingredient .
  • the crystalline form C, crystalline form A, crystalline form Y, crystalline form V, crystalline form AE and crystalline form AA of the compound of formula (I) provided by the invention are in solubility, melting point, stability, and dissolution rate.
  • hygroscopicity, adhesion, fluidity, bioavailability, and processing performance, purification, preparation production, safety, etc. have advantages in at least one aspect, providing for the preparation of this new type of BTK inhibitor pharmaceutical preparation. It is of great significance for drug development to develop new and better options.
  • Figure 32 Dynamic moisture adsorption and desorption of crystal form A
  • Figure 33 Dynamic moisture adsorption and desorption of crystal form C
  • Figure 36 Dynamic moisture adsorption and desorption of crystal form Y
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the C-type crystal of 7-formamide that is, crystal form C
  • the X-ray powder diffraction of the crystal form C has a 2 ⁇ value of 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, There is a characteristic peak at 17.5° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form C is at one or two or three places in the 2 ⁇ value of 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 14.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, and 14.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has one or two or three 2 ⁇ values of 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has characteristic peaks at 2 ⁇ values of 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.2° ⁇ 0.2°, 14.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, 7.2° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form C has 2 ⁇ values of 6.6° ⁇ 0.2°, 13.2° ⁇ 0.2°, 17.5° ⁇ 0.2°, 23.2° ⁇ 0.2°, 24.2° ⁇ There are characteristic peaks at 0.2°, 14.7° ⁇ 0.2°, 18.9° ⁇ 0.2°, 21.9° ⁇ 0.2°, and 7.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form C is shown in FIG. 1 .
  • the alcoholic solvent includes methanol, ethanol, and isopropanol.
  • the hetero-nitrogen-based solvent is dimethyl sulfoxide.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the A-type crystal of 7-formamide that is, the crystal form A
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, There is a characteristic peak at 8.3° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A is at one or two or three places in the 2 ⁇ value of 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, 11.4° ⁇ 0.2°, 16.6° ⁇ 0.2°, 18.4° ⁇ 0.2° any 4 places, or 5 places, or 6 places have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has 2 ⁇ values of 7.1° ⁇ 0.2°, 14.3° ⁇ 0.2°, 8.3° ⁇ 0.2°, 11.4° ⁇ 0.2°, 16.6° ⁇ There are characteristic peaks at 0.2° and 18.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form A is shown in FIG. 2 .
  • the compound of formula (I) is dissolved in an organic solvent, the solution is added to a glass bottle containing a high polymer to volatilize, and a solid is precipitated to obtain crystal form A.
  • the organic solvent is selected from alcohols, ketones, ethers, halogenated hydrocarbons.
  • the high polymer is selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose, methylcellulose, and polycaproic acid. At least one of ester, polyethylene glycol, polymethyl methacrylate, sodium alginate or hydroxyethyl cellulose.
  • the mass of the high polymer is 0.5% to 15% of the mass of the compound of formula (I).
  • the alcohols are ethanol
  • the ketones are acetone
  • the ethers are tetrahydrofuran
  • the halogenated hydrocarbons are dichloromethane, dibromomethane, and chloroform.
  • the dissolution and precipitation temperature is 20°C to 30°C.
  • the positive solvent includes alcohols, ketones, cyclic ethers, and esters
  • the anti-solvent includes pure water, linear ethers, and alkanes.
  • the dissolution and precipitation temperature is 20°C to 30°C.
  • the alcohols include ethanol and methanol
  • the ketones are acetone
  • the cyclic ethers include 1,4-dioxane and tetrahydrofuran
  • the esters are isopropyl acetate.
  • the linear ethers include methyl tert-butyl ether and cyclopentyl methyl ether, and the alkanes are n-heptane, n-hexane, and n-pentane.
  • the penetration time is 1 to 4 weeks, eg 2 weeks.
  • the organic solvent includes alcohols, ketones, ethers, esters, halogenated hydrocarbons, aromatic hydrocarbons, alkanes and mixtures thereof.
  • the alcohols are ethanol, isopropanol, methanol, the ketones are acetone, and the ethers are 2-methyltetrahydrofuran, tetrahydrofuran, 1,4-dioxane , methyl tert-butyl ether, cyclopentyl methyl ether, the esters are ethyl acetate, the halogenated hydrocarbons are chloroform, methylene chloride, the aromatic hydrocarbons are toluene, and the alkanes are n-heptyl alkyl.
  • the positive solvent includes alcohols, ketones, cyclic ethers, and esters.
  • the anti-solvents include ethers, aromatic hydrocarbons, and alkanes.
  • alcohols are ethanol
  • ketones are acetone
  • cyclic ethers include tetrahydrofuran and 2-methyltetrahydrofuran
  • esters are ethyl acetate
  • halogenated hydrocarbons are chloroform .
  • the ethers are methyl tert-butyl ether
  • the aromatic hydrocarbons are toluene
  • the alkanes are n-heptane.
  • the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
  • the alcohol is isopropanol
  • the ester is isopropyl acetate
  • the alkanes are n-heptane.
  • the temperature of dissolving, adding and stirring is 5°C to 50°C, preferably 20°C to 30°C.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the Y-type crystal of 7-formamide that is, the crystal form Y
  • the Y-type crystal of 7-formamide is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form Y has a 2 ⁇ value of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, There is a characteristic peak at 17.5° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form Y is at one or two or three locations in the 2 ⁇ value of 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 21.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2 ⁇ values of 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, and 21.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form Y is at one or two or three locations in the 2 ⁇ value of 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 22.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form Y has characteristic peaks at 2 ⁇ values of 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 25.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form Y has 2 ⁇ values of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 24.6° ⁇ 0.2°, 24.0° ⁇ 0.2°, 21.7° ⁇ 0.2°, 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 22.5° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form Y has 2 ⁇ values of 14.0° ⁇ 0.2°, 7.0° ⁇ 0.2°, 17.5° ⁇ 0.2°, 24.6° ⁇ 0.2°, 24.0° ⁇ There are characteristic peaks at 0.2°, 21.7° ⁇ 0.2°, 27.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, and 22.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form Y is shown in FIG. 3 .
  • the alcoholic solvent is isopropanol.
  • the alcoholic solvent is isopropanol.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the V-type crystal of 7-formamide that is, the crystal form V
  • the X-ray powder diffraction of the crystal form V has a 2 ⁇ value of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, There is a characteristic peak at 13.0° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form V has one or two or three 2 ⁇ values of 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.1° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has characteristic peaks at 2 ⁇ values of 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, and 17.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form V has one or two or three 2 ⁇ values of 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has characteristic peaks at 2 ⁇ values of 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form V has 2 ⁇ values of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 24.4° ⁇ 0.2°, 17.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, 22.9° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form V has 2 ⁇ values of 6.5° ⁇ 0.2°, 15.0° ⁇ 0.2°, 13.0° ⁇ 0.2°, 16.3° ⁇ 0.2°, 24.4° ⁇ There are characteristic peaks at 0.2°, 17.1° ⁇ 0.2°, 23.6° ⁇ 0.2°, 28.8° ⁇ 0.2°, and 22.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form V is shown in FIG. 4 .
  • the preparation method of described crystal form V is characterized in that,
  • the cyclic ether solvent is tetrahydrofuran.
  • the mass of the high polymer is 0.5% to 15% of the mass of the formula (I).
  • the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
  • the precipitation temperature is 20°C to 30°C.
  • the alcohol solvent is methanol.
  • the high temperature is 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C.
  • the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
  • the cooling is rapid cooling.
  • the alkyl nitrile solvent is acetonitrile.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the AE-type crystal of 7-formamide that is, the crystalline form AE, is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystalline form AE has a 2 ⁇ value of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, There is a characteristic peak at 12.8° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form AE has one or two or three 2 ⁇ values of 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 21.0° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2 ⁇ values of 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, and 21.0° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AE has one or two or three 2 ⁇ values of 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AE has characteristic peaks at 2 ⁇ values of 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystalline form AE has 2 ⁇ values of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 20.0° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, 16.4° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystalline form AE has 2 ⁇ values of 6.4° ⁇ 0.2°, 15.5° ⁇ 0.2°, 12.8° ⁇ 0.2°, 16.0° ⁇ 0.2°, 20.0° ⁇ There are characteristic peaks at 0.2°, 21.0° ⁇ 0.2°, 24.2° ⁇ 0.2°, 21.4° ⁇ 0.2°, and 16.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form AE is shown in FIG. 5 .
  • the hetero-nitrogen solvent is N,N-dimethylacetamide.
  • the mass of the high polymer is 0.5% to 5% of the mass of the formula (I).
  • the high polymer is selected from at least one of polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl chloride, polyvinyl acetate, hydroxypropyl methylcellulose or methylcellulose .
  • the alcoholic solvent is n-propanol.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling is rapid cooling.
  • the alcoholic solvent is n-propanol.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the cooling rate is 0.05°C/min to 0.5°C/min, eg 0.1°C/min.
  • the alcoholic solvent is n-propanol.
  • the compound represented by formula (I) (S)-4-(3-(butyn-2-ylamide)piperidin-1-yl)-5-fluoro-2,3-dimethyl-1H-indole-
  • the AA-type crystal of 7-formamide that is, the crystal form AA
  • the AA-type crystal of 7-formamide is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form AA has a 2 ⁇ value of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, There is a characteristic peak at 16.7° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form AA has one or two or three 2 ⁇ values of 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 8.9° ⁇ 0.2°. There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 8.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has characteristic peaks at 2 ⁇ values of 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form AA has 2 ⁇ values of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 8.2° ⁇ 0.2°, 8.9° ⁇ 0.2°, 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, 23.4° ⁇ 0.2° any 4, or 5, or 6, or 7, or 8, or 9 There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form AA has 2 ⁇ values of 11.7° ⁇ 0.2°, 16.1° ⁇ 0.2°, 16.7° ⁇ 0.2°, 17.9° ⁇ 0.2°, 8.2° ⁇ There are characteristic peaks at 0.2°, 8.9° ⁇ 0.2°, 20.0° ⁇ 0.2°, 18.3° ⁇ 0.2°, and 23.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of crystal form AA is shown in FIG. 6 .
  • the preparation method of the crystal form AA is characterized in that,
  • the compound of formula (I) is dissolved in an alcoholic solvent at a high temperature, the solution is cooled down, and a solid is precipitated to obtain crystal form AA.
  • the dissolution conditions are 40°C to 60°C, for example 50°C.
  • the crystallization temperature is -20°C to 5°C, eg -20°C.
  • the cooling is rapid cooling.
  • the alcoholic solvent is isopropanol.
  • said formula (I) and/or its salts as raw materials refer to its solid (crystalline or amorphous), semi-solid, wax or oil form.
  • the compounds and/or their salts as raw materials are in the form of solid powders.
  • the "stirring" is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rev/min, wherein the magnetic stirring is preferably 300-1000 rev/min, and the mechanical stirring is preferably 100-100 300 rpm.
  • crystalline or “polymorphic form” means as evidenced by the characterization of the X-ray diffraction pattern shown.
  • X-ray diffraction patterns generally vary with the conditions of the instrument.
  • the relative intensities of X-ray diffraction patterns may also vary with experimental conditions, so the order of peak intensities cannot be used as the sole or decisive factor.
  • the relative intensities of the diffraction peaks in the XRPD pattern are related to the preferred orientation of the crystals, and the peak intensities shown here are illustrative rather than absolute comparisons.
  • the experimental error of the peak angle is usually 5% or less, and the error of these angles should also be taken into account, and an error of ⁇ 0.2° is usually allowed.
  • the overall shift of the peak angle will be caused, and a certain shift is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not necessarily have to be exactly the same as the X-ray diffraction pattern in the examples mentioned here, and the "same XRPD pattern" mentioned herein does not mean absolutely the same , the same peak position can differ by ⁇ 0.2° and the peak intensity allows some variability. Any crystalline form having the same or similar pattern as the characteristic peaks in these patterns is within the scope of the present invention. Those skilled in the art can compare the patterns listed in the present invention with a pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • Form C, Form A, Form Y, Form V, Form AE, Form AA of the present invention are pure, single, and substantially not mixed with any other crystalline form.
  • substantially free when used to refer to a new crystal form means that the crystal form contains less than 20% by weight of other crystal forms, especially less than 10% by weight of other crystal forms, and even less More than 5% (weight) of other crystal forms, more than 1% (weight) of other crystal forms.
  • the crystal form C, crystal form A, crystal form Y, crystal form V, crystal form AE, crystal form AA of the formula (I) provided by the present invention are in solubility, melting point, stability, dissolution, wettability, adhesion, fluidity
  • Drug development is very important.
  • the new crystal form of the compound of formula (I) provided by the invention has the advantages of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, bioavailability, processability, purification, There are advantages in at least one aspect of preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations of BTK inhibitors, and are of great significance for drug development.
  • room temperature generally refers to 22°C to 28°C unless otherwise specified.
  • the X-ray powder diffraction patterns of the present invention were collected on Empyrean and X'Pert3 ray powder diffractometers of PANalytacal.
  • the method parameters of X-ray powder diffraction of the present invention are as follows:
  • the differential scanning calorimetry analysis curve of the present invention is collected on the Q2000 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameters of the differential scanning calorimetry analysis of the present invention are as follows:
  • thermogravimetric analysis curve of the present invention is collected on the Discovery TGA 5500 type and Q5000 type thermogravimetric analyzer of TA company.
  • the method parameters of the thermogravimetric analysis of the present invention are as follows:
  • UPLC high performance liquid chromatography
  • PDA diode array detector
  • Chromatographic column Waters Xbridge C18, 150 ⁇ 4.6mm, 5 ⁇ m
  • the elution gradient is as follows:
  • ion chromatography (IC) data is collected from ThermoFisher ICS-1100, and the IC method parameters of the test chloride ion content of the present invention are as follows:
  • Chromatographic column IonPac AS18Analytical Column (4 ⁇ 250mm)
  • the dynamic moisture adsorption diagram of the present invention is collected on the Intrinsic type and Intrinsic Plus type dynamic moisture adsorption instrument of SMS company.
  • the method parameters of the dynamic moisture adsorption test of the present invention are as follows:
  • Relative humidity gradient 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test adopts the wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameters of the laser particle size analyzer are as follows:
  • the intrinsic dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company. Described inherent dissolution test conditions are as follows:
  • the polarized light microscope photos described in the present invention were collected at room temperature by a Zeiss microscope Axio Scope.A1 equipped with an Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • the starting material of compound (I) used in the following examples can be prepared according to the prior art, for example, according to the method described in US20160115126A1, but the starting crystal form is not a limitation for preparing the crystal form of the present invention.
  • Example 1 At room temperature, 15.2 mg of the solid compound of formula (I) was weighed and placed in a 3 mL glass vial, and the open mouth was placed in a 20 mL glass vial prefilled with 4 mL of ethanol. After sealing, it was placed at room temperature for gas-solid permeation for about 12 days, and the sample was dissolved and clear, and then the sample was transferred to room temperature for volatilization until a solid was precipitated, and crystal form C was obtained.
  • the X-ray powder diffraction data are shown in Table 1, and the diffraction pattern is shown in Figure 1.
  • the TGA data is shown in FIG. 7
  • the DSC data is shown in FIG. 8
  • the 1 H NMR data is shown in FIG. 9 .
  • Example 2 At room temperature, weigh 15.3 mg of the solid compound of formula (I) into a 3-mL glass vial, add 0.6 mL of isopropanol to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene filter to filter the sample. The solution was filtered into a new 3 ml glass vial, and the open mouth was placed in a fume hood to evaporate at room temperature, and a solid was precipitated to obtain crystal form C. Its X-ray powder diffraction data are shown in Table 2.
  • Examples 3-4 Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent at 50°C to dissolve the solid, and use a 0.45-micron pore size polytetrafluoroethylene. The sample solution was filtered through a filter membrane, and then quickly placed at -20 °C to stand, the sample was clarified, and evaporated at room temperature until a solid was precipitated, and crystal form C was obtained. The detailed test conditions involved in this example are shown in Table 3.
  • Table 4 The detailed test conditions involved in this example are shown in Table 4, the X-ray powder diffraction data of the sample of Example 11 is shown in Table 5, and the diffraction pattern is shown in FIG. 2 .
  • the TGA data is shown in FIG. 10
  • the DSC data is shown in FIG. 11
  • the 1 H NMR data is shown in FIG. 12 .
  • Hybrid Polymer A Polyvinylpyrrolidone, Polyvinyl Alcohol, Polyvinyl Chloride, Polyvinyl Acetate, Hydroxypropyl Methyl Cellulose and Methyl Cellulose (mixed in equal mass)
  • Mixed polymer B polycaprolactone, polyethylene glycol, polymethyl methacrylate, sodium alginate and hydroxyethyl cellulose (mixed in equal mass)
  • Examples 19-29 Under room temperature conditions, weigh an appropriate amount of the solid of the compound of formula (I) and place it in a 1.5-ml glass vial, add a corresponding volume of solvent to dissolve the solid, and place the sample at 50 °C for 2 hours. The sample solution was filtered through a 0.45-micron pore size polytetrafluoroethylene filter into a new 1.5-ml glass vial, and the opening was placed in a fume hood to evaporate at room temperature, and a solid was precipitated. Form A was obtained. The detailed test conditions involved in this example are shown in Table 8, and the X-ray powder diffraction data of the sample of Example 19 is shown in Table 9.
  • Examples 30-31 Under room temperature conditions, place an appropriate amount of the solid of the compound of formula (I) in a 3 ml glass vial, add a corresponding volume of solvent to dissolve the solid, and filter through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, then The solution was placed in an atmosphere containing 4 ml of different solvents, and gas-liquid infiltration was carried out. After about 14 days, no solid was precipitated, and the solution was transferred to room temperature for volatilization, and a solid was precipitated to obtain crystal form A.
  • Table 10 The detailed test conditions involved in this example are shown in Table 10.
  • Examples 32 to 37 under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 1.5 ml glass vial, add a corresponding volume of solvent to dissolve the solid, place it at 50°C to dissolve it, and use The sample solution was filtered through a polytetrafluoroethylene filter membrane with a pore size of 0.45 microns, and then the filtrate was quickly placed at -20°C for standing, and no solid was precipitated for about 1 to 3 days.
  • Table 11 The detailed test conditions involved in this example are shown in Table 11.
  • Examples 38-40 Under room temperature conditions, place an appropriate amount of the solid compound of formula (I) in a 5-mL glass vial, add a corresponding volume of positive solvent to obtain a clear solution, and place a 20-mL glass bottle containing an anti-solvent in advance. Equilibrate at -20°C for about 0.5 to 2 hours. The positive solvent solution containing the compound was filtered through a 0.45-micron polytetrafluoroethylene membrane to obtain a clear solution, and the filtrate was rapidly added to the pre-cooled anti-solvent. After the dropwise addition, there is no solid precipitation. Transfer the sample to 5 °C and stir for about 1 to 2 days. If there is still no solid, transfer it to -20 °C and stir for about 1 to 2 days. There is still no solid precipitation. Finally, it was placed in a fume hood to volatilize, and a solid was precipitated to obtain crystal form A. The detailed test conditions involved in this example are shown in Table 12.
  • the X-ray powder diffraction data of its samples are shown in Table 21.
  • the TGA data is shown in FIG. 20
  • the DSC data is shown in FIG. 21
  • the 1 H NMR data is shown in FIG. 22 .
  • Example 60 Preparation of crystal form AA (rapid cooling method)
  • Example 61 Preparation of crystal form G (rapid evaporation method)
  • Example 62 Preparation of crystal form G (rapid evaporation method)
  • Example 26 The detailed test conditions involved in this example are shown in Table 26, and the X-ray powder diffraction data of the sample of Example 63 are shown in Table 27.
  • the sample is at about 7.2° ⁇ 0.2°, about 6.4° ⁇ 0.2°, about 14.5° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 10.2° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 21.8° ⁇ 0.2
  • Example 66 Preparation of crystal form M (rapid evaporation method)
  • the sample is at about 7.1° ⁇ 0.2°, about 6.5° ⁇ 0.2°, about 14.3° ⁇ 0.2°, about 19.6° ⁇ 0.2°, about 10.2° ⁇ 0.2°, about 21.6° ⁇ 0.2°, about 13.0° ⁇ 0.2
  • the sample is at about 6.4° ⁇ 0.2°, about 19.4° ⁇ 0.2°, about 12.9° ⁇ 0.2°, about 7.2° ⁇ 0.2°, about 22.6° ⁇ 0.2°, about 17.1° ⁇ 0.2°, about 10.1° ⁇ 0.2
  • the sample is at about 7.0° ⁇ 0.2°, about 14.2° ⁇ 0.2°, about 6.5° ⁇ 0.2°, about 21.3° ⁇ 0.2°, about 19.7° ⁇ 0.2°, about 13.1° ⁇ 0.2°, about 10.2° ⁇ 0.2
  • the crystal form C/Y/A/V/AE of the present invention is respectively prepared into a suspension with SGF (simulated artificial gastric fluid), FaSSIF (artificial intestinal fluid in fasting state), FeSSIF (artificial intestinal fluid in satiation state) and pure water, After equilibration at room temperature for 1 hour, 2 hours, 4 hours and 24 hours, a saturated solution was obtained by filtration. The content of the sample in the saturated solution was determined by high performance liquid chromatography (HPLC). The experimental results are shown in Table 31, and the solubility curves are shown in Figures 23 to 26, respectively. The experimental results show that the crystal form C/Y/A/V/AE of the present invention has good solubility in SGF, FaSSIF, FeSSIF and pure water.
  • Example 70 Compressibility of crystal forms
  • the DVS of Form C is shown in Figure 33
  • the XRPD comparison chart of Form C before and after the DVS test is shown in Figure 34
  • the DVS of Form V is shown in Figure 35
  • the DVS of Form Y is shown in Figure 36
  • the XRPD comparison diagram of the crystal form Y before and after the DVS test is shown in Figure 37
  • the DVS of the crystal form AE is shown in Figure 38
  • the XRPD comparison diagram of the crystal form AE before and after the DVS test is shown in Figure 39.
  • the test results show that the crystalline form C/Y/A/V/AE of the present invention has lower hygroscopicity.
  • Moisture gain is less than 15% but not less than 2%
  • wet weight gain is less than 2% but not less than 0.2%
  • wet weight gain is less than 0.2%
  • the adhesion of the crystal form of the present invention is better than that of the solid S1 disclosed in the prior art.

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Abstract

L'invention concerne de nouvelles formes cristallines d'un composé d'indole carboxamide et un procédé de préparation associé. L'invention concerne des procédés de préparation et des utilisations de la forme cristalline C, de la forme cristalline A, de la forme cristalline Y, de la forme cristalline V, de la forme cristalline AE et de la forme cristalline AA de formule (I), les formes cristalline C, forme cristalline A, forme cristalline Y, forme cristalline V, forme cristalline AE et forme cristalline AA fournies d'un composé de formule (I) sont avantageuses dans au moins un aspect parmi la solubilité, le point de fusion, la stabilité, la dissolution, l'hygroscopicité, l'adhésivité, l'aptitude à l'écoulement, la biodisponibilité, ainsi que l'aptitude au traitement, un effet de purification, la production d'une formulation, la sécurité, etc., fournissant de nouveaux choix meilleurs pour la préparation d'une formulation pharmaceutique contenant un composé de formule (I), et ayant une grande importance pour le développement pharmaceutique.
PCT/CN2021/127741 2020-10-30 2021-10-30 Nouvelles formes cristallines de composé d'indole carboxamide et procédé de préparation associé WO2022089620A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065226A1 (fr) * 2014-10-24 2016-04-28 Bristol-Myers Squibb Company Composés indolecarboxamides utiles comme inhibiteurs de kinase
WO2018045157A1 (fr) * 2016-09-02 2018-03-08 Bristol-Myers Squibb Company Procédé de préparation de composés d'indole carboxamide

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016065226A1 (fr) * 2014-10-24 2016-04-28 Bristol-Myers Squibb Company Composés indolecarboxamides utiles comme inhibiteurs de kinase
WO2018045157A1 (fr) * 2016-09-02 2018-03-08 Bristol-Myers Squibb Company Procédé de préparation de composés d'indole carboxamide

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
WATTERSON SCOTT H., LIU QINGJIE, BEAUDOIN BERTRAND MYRA, BATT DOUGLAS G., LI LING, PATTOLI MARK A., SKALA STACEY, CHENG LIHONG, OB: "Discovery of Branebrutinib (BMS-986195): A Strategy for Identifying a Highly Potent and Selective Covalent Inhibitor Providing Rapid in Vivo Inactivation of Bruton’s Tyrosine Kinase (BTK)", JOURNAL OF MEDICINAL CHEMISTRY, AMERICAN CHEMICAL SOCIETY, US, vol. 62, no. 7, 11 April 2019 (2019-04-11), US , pages 3228 - 3250, XP055781288, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.9b00167 *

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