WO2024017299A1 - Cristal de dérivé d'acide benzoïque substitué par un hétérocycle ponté ou sel de celui-ci et procédé de préparation associé - Google Patents

Cristal de dérivé d'acide benzoïque substitué par un hétérocycle ponté ou sel de celui-ci et procédé de préparation associé Download PDF

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WO2024017299A1
WO2024017299A1 PCT/CN2023/108171 CN2023108171W WO2024017299A1 WO 2024017299 A1 WO2024017299 A1 WO 2024017299A1 CN 2023108171 W CN2023108171 W CN 2023108171W WO 2024017299 A1 WO2024017299 A1 WO 2024017299A1
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compound
formula
crystal form
crystal
radiation
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Chinese (zh)
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丁照中
颜小兵
孙翔
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正大天晴药业集团股份有限公司
南京明德新药研发有限公司
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Publication of WO2024017299A1 publication Critical patent/WO2024017299A1/fr

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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • 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

Definitions

  • the invention belongs to the field of medical technology and relates to the crystallization of a bridged heterocyclic substituted benzoic acid derivative or its salt and its preparation method, specifically to the crystallization of the compound of formula (II), the hydrochloride of the compound of formula (II) and its crystallization , and preparation method thereof.
  • the complement system is an important component of the body's innate immunity against infections such as foreign pathogens, bacteria, and parasites.
  • the complement system is also an important component of the connection between innate immunity and adaptive immunity.
  • Complement consists of plasma proteins, including soluble proteins, membrane-bound proteins and complement receptors. It is mainly produced by membrane proteins expressed in the liver or cell surface and plays a role in plasma, tissues or cells.
  • the complement system is mainly activated through three pathways: the classical pathway (CP), the lectin pathway (LP), and the alternative pathway (AP).
  • the AP pathway always maintains a low-level activation state to monitor the invasion status of foreign pathogens at any time.
  • Complement proteins are distributed on the surface of apoptotic cells, and complement activation is strictly regulated and is only used to clear apoptotic cells without further activating other innate or adaptive immune responses.
  • the complement system In the case of infection by foreign pathogens, the complement system is fully activated, producing inflammatory responses, opsonization or phagocytosis, etc., destroying the pathogens and ultimately activating the adaptive immune response.
  • Both complement inefficiency and overstimulation can be harmful and are associated with increased susceptibility to infections or non-communicable diseases, such as autoimmune diseases, chronic inflammation, thrombotic microangiopathies, transplant rejection and tumors.
  • Complement factor B acts on the AP pathway. Inhibiting Factor B activity can prevent the activation of the API pathway without interfering with the CP and LP pathways, and can avoid increasing the risk of infection due to complement system inhibition.
  • Factor B inhibitors There are currently no small molecule Factor B inhibitors on the market.
  • Novartis' factor B inhibitor LNP023 is in the clinical phase III research stage and is used for the treatment of PNH, IgAN, C3G and other diseases. Therefore, it is necessary to develop new small molecule inhibitors of the complement system Factor B, increase clinical research and verification, and use them in the treatment of various diseases caused by complement abnormalities to provide new treatment methods for unmet clinical needs.
  • the invention provides crystallization of a compound of formula (II),
  • the crystallization of the compound of formula (II) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
  • the crystal of the compound of formula (II) is crystal form A
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the crystal form A has a characteristic diffraction peak at the following 2 ⁇ angle: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20° and 14.31 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has at least 3 or 4 characteristic diffraction peaks at the following 2 ⁇ angles: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20°, 14.31 ⁇ 0.20°, 19.52 ⁇ 0.20° and 21.77 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.15 ⁇ 0.20°, 9.28 ⁇ 0.20°, 14.31 ⁇ 0.20°, 19.52 ⁇ 0.20 ° and 21.77 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned A crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.15°, 9.28°, 14.31°, 19.52° and 21.77°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned crystal form A is shown in Figure 1.
  • the peak position and relative intensity of the diffraction peak are as shown in Table 1-1:
  • the peak position and relative intensity of the diffraction peak are as shown in Table 1:
  • the present invention also provides the hydrochloride salt of the compound of formula (II),
  • the invention provides crystallization of the hydrochloride salt of the compound of formula (II).
  • the crystallization of the hydrochloride of the compound of formula (II) according to the present invention may be in the form of a non-solvate or in the form of a solvate, such as a hydrate.
  • the invention provides compounds of formula (II-1),
  • n is selected from 0 to 2.5;
  • n is selected from 0 to 2.5.
  • the above m is selected from 0, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3 or 2.0.
  • the above m is selected from 1.0 or 2.0.
  • the above m is selected from 1.0.
  • n is selected from 0, 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5.
  • n is selected from 0, 1.0 or 2.0.
  • n is selected from 0.
  • the above-mentioned compound of formula (II-1) is selected from the group consisting of compounds of formula (I),
  • the present invention also provides crystallization of the compound of formula (I),
  • the crystallization of the compound of formula (I) according to the present invention may be in the form of a non-solvate or a solvate, such as a hydrate.
  • the crystal of the compound of formula (I) is crystal form B, and the X-ray powder diffraction pattern of Cu K ⁇ radiation of the crystal form B has a characteristic diffraction peak at the following 2 ⁇ angle: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20° and 10.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 18.55 ⁇ 0.20 ° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 16.74 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.95 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 16.74 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.95 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20° , 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has at least 11, 12, 13, 14 or 15 characteristic diffraction peaks at the following 2 ⁇ angle: 6.16 ⁇ 0.20 °, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20 °, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20°, 22.17 ⁇ 0.20°, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, 12.30 ⁇ 0.20 °, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20°, 22.17 ⁇ 0.20 °, 22.75 ⁇ 0.20° and 24.62 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.16 ⁇ 0.20°, 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20 °, 12.30 ⁇ 0.20°, 13.19 ⁇ 0.20°, 14.74 ⁇ 0.20°, 16.74 ⁇ 0.20°, 17.39 ⁇ 0.20°, 17.90 ⁇ 0.20°, 18.55 ⁇ 0.20°, 19.49 ⁇ 0.20°, 19.95 ⁇ 0.20°, 21.55 ⁇ 0.20
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16 ⁇ 0.20°, 8.96 ⁇ 0.20°, 10.53 ⁇ 0.20°, and/or 3.16 ⁇ 0.20°, and/or 10.79 ⁇ 0.20°, and/or 12.30 ⁇ 0.20°, and/or 13.19 ⁇ 0.20°, and/or 14.74 ⁇ 0.20°, and/or 16.74 ⁇ 0.20°, and/or 17.39 ⁇ 0.20°, and/or 17.90 ⁇ 0.20°, and/or 18.55 ⁇ 0.20°, and/or 19.49 ⁇ 0.20°, and/or 19.95 ⁇ 0.20°, and/or 21.55 ⁇ 0.20°, and/or 22.17 ⁇ 0.20° , and/or 22.75 ⁇ 0.20°, and/or 24.62 ⁇ 0.20°, and/or 27.29 ⁇ 0.20°, and/or 28.05 ⁇ 0.20°, and/or 29.03 ⁇
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 3.16°, 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05°, 29.03°, 32.55° and 34.15° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned B crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 6.16°, 8.96°, 10.53°, 10.79°, 12.30°, 13.19°, 14.74°, 16.74°, 17.39°, 17.90°, 18.55°, 19.49°, 19.95°, 21.55°, 22.17°, 22.75°, 24.62°, 27.29°, 28.05° and 29.03°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned B crystal form is shown in Figure 2.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned Form B shows an exothermic peak at 221.2°C ⁇ 3°C.
  • the DSC spectrum of the above crystal form B is shown in Figure 3.
  • thermogravimetric analysis (TGA) curve of the above-mentioned B crystal form has a weight loss of 3.85% at 150°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form B is shown in Figure 4.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I), which includes mixing the hydrochloride of the compound of formula (II) in solvents S1, S2 and S3, and then separating the solid.
  • the hydrochloride salt of the compound of formula (II) is amorphous. In one embodiment of the present invention, the hydrochloride salt of the compound of formula (II) is a compound of formula (I).
  • the method for preparing the crystal form of compound (I) B includes first mixing the hydrochloride of the compound of formula (II) in solvents S1 and S2, and then adding solvent S3.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
  • the preparation method of the B crystal form includes the following steps:
  • the solvent S1 is selected from one or two mixture solvents of acetonitrile or acetone.
  • the solvent S2 is selected from water.
  • the solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane.
  • the volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
  • the present invention also provides a method for preparing the crystal form B of the compound of formula (I),
  • the preparation method of the B crystal form includes the following steps:
  • Solvent S1 is selected from one or two mixtures of acetonitrile or acetone;
  • Solvent S2 is selected from water;
  • Solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, acetonitrile or 1,4-dioxane;
  • the volume ratio of solvent S1 to solvent S2 is 5:1 to 1:5.
  • the volume ratio of the above solvent S1 to solvent S2 is 5:1 to 1:1; preferably, the volume ratio of solvent S1 to solvent S2 is 5:1, 4:1, 3:1, 2:1 or 1:1; further preferably, the volume ratio of solvent S1 and solvent S2 is 5:1.
  • the above-mentioned solvent S1 is selected from acetone
  • the solvent S2 is selected from water
  • the volume ratio of acetone and water is 5:1, 4:1, 3:1, 2:1 or 1:1;
  • the volume ratio of acetone and water is 5:1.
  • the above-mentioned solvent S3 is selected from a mixed solvent of acetone and ethyl acetate, and the volume ratio of acetone and ethyl acetate is 1:1 to 1:3; preferably, acetone and ethyl acetate The volume ratio of acetone and ethyl acetate is 1:1, 1:1.5, 1:2 or 1:3; further preferably, the volume ratio of acetone and ethyl acetate is 1:1.5.
  • the above-mentioned solvent S1 is selected from acetone
  • solvent S2 is selected from water
  • solvent S3 is selected from a mixed solvent of acetone and ethyl acetate
  • the acetone water: a mixed solvent of acetone and ethyl acetate.
  • the volume ratios are 1 to 5:1:5 to 15 respectively
  • the preferred volume ratios of the mixed solvents of acetone:water:acetone and ethyl acetate are 5:1:5, 5:1:10, and 5:1:15 respectively.
  • the volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:5, 5:1: 10 or 5:1:15; the further preferred volume ratio of the mixed solvent of acetone and ethyl acetate is 5:1:15 respectively.
  • the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1 is 100 mg: 0.5 ⁇ 1 mL; preferably, the mass volume ratio of the hydrochloride of the compound of formula (II) to the solvent S1
  • the volume ratio is 100mg:0.5mL, 100mg:0.6mL, 100mg:0.7mL, 100mg:0.8mL, 100mg:0.9mL or 100mg:1mL; further preferably, the mass of the hydrochloride of the compound of formula (II) and the solvent S1
  • the volume ratio is 100mg:0.6mL.
  • the stirring temperature of step (b) is 15°C to 35°C; the stirring time is 5 minutes to 1 hour; preferably, the stirring temperature of step (b) is 15°C to 25°C; stirring The time is 5 to 10 minutes; further preferably, the stirring temperature of step (b) is 15°C ⁇ 25°C; stirring time is 5 minutes.
  • the stirring temperature of step (d) is 15°C to 35°C; the stirring time is 5 to 15 hours; preferably, the stirring temperature of step (d) is 15°C to 25°C; the stirring time for 12 hours.
  • the crystal of the compound of formula (I) is C crystal form
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the C crystal form has a characteristic diffraction peak at the following 2 ⁇ angle: 7.72 ⁇ 0.20°, 15.31 ⁇ 0.20° and 19.53 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20° and 24.28 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20 °, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20° and 24.28 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has at least 9, 10 or 11 characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 10.75 ⁇ 0.20° , 13.80 ⁇ 0.20°, 14.67 ⁇ 0.20°, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20°, 24.28 ⁇ 0.20°, 25.95 ⁇ 0.20° and 26.65 ⁇ 0.20° .
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 10.75 ⁇ 0.20°, 13.80 ⁇ 0.20°, 14.67 ⁇ 0.20 °, 15.31 ⁇ 0.20°, 16.66 ⁇ 0.20°, 18.76 ⁇ 0.20°, 19.53 ⁇ 0.20°, 22.67 ⁇ 0.20°, 24.28 ⁇ 0.20°, 25.95 ⁇ 0.20° and 26.65 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72 ⁇ 0.20°, 15.31 ⁇ 0.20°, 19.53 ⁇ 0.20°, and/or 10.75 ⁇ 0.20°, and/or 13.80 ⁇ 0.20°, and/or 14.67 ⁇ 0.20°, and/or 16.66 ⁇ 0.20°, and/or 18.76 ⁇ 0.20°, and/or 22.67 ⁇ 0.20°, and/or 24.28 ⁇
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 7.72°, 10.75°, 13.80°, 14.67°, 15.31°, 16.66°, 18.76°, 19.53°, 22.67°, 24.28°, 25.95° and 26.65°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned C crystal form is shown in Figure 5.
  • the differential scanning calorimetry (DSC) curve of the above-mentioned C crystal form shows an exothermic peak at 227.5°C ⁇ 3°C.
  • thermogravimetric analysis (TGA) curve of the above-mentioned C crystal form loses 2.88% weight at 150.0°C ⁇ 3°C.
  • the TGA spectrum of the above crystal form C is shown in Figure 7.
  • the crystal of the compound of formula (I) is the D crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.93 ⁇ 0.20° and 11.82 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned D crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.93° and 11.82°.
  • the crystal of the compound of formula (I) is the E crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the E crystal form has at least 3 characteristic diffraction peaks at the following 2 ⁇ angle: 5.98 ⁇ 0.20°, 7.83 ⁇ 0.20°, 8.87 ⁇ 0.20° and 10.76 ⁇ 0.20°.
  • the E crystalline form of the compound of formula (I) is in the form of a hydrate.
  • the crystal of the compound of formula (I) is in the form of a hydrate
  • the hydrate is the E crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the E crystal form has at the following 2 ⁇ angle Characteristic diffraction peaks: 5.98 ⁇ 0.20°, 7.83 ⁇ 0.20°, 8.87 ⁇ 0.20° and 10.76 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned E crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.98°, 7.83°, 8.87° and 10.76°.
  • the X-ray powder diffraction pattern of the above-mentioned E crystal form is shown in Figure 9.
  • the crystal of the compound of formula (I) is the F crystal form
  • the X-ray powder diffraction pattern of the Cu K ⁇ radiation of the F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20° and 24.04 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has at least 6 or 7 characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.82 ⁇ 0.20°, 13.32 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20°, 24.04 ⁇ 0.20° and 24.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.82 ⁇ 0.20°, 13.32 ⁇ 0.20 °, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20°, 24.04 ⁇ 0.20° and 24.74 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 10.66 ⁇ 0.20°, 10.82 ⁇ 0.20 °, 11.94 ⁇ 0.20°, 13.32 ⁇ 0.20°, 14.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 17.96 ⁇ 0.20°, 18.72 ⁇ 0.20°, 19.52 ⁇ 0.20°, 21.66 ⁇ 0.20°, 24.04 ⁇ 0.20°, 24.74 ⁇ 0.20° and 26.56 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96 ⁇ 0.20°, 8.86 ⁇ 0.20°, 17.40 ⁇ 0.20°, 19.52 ⁇ 0.20 °, 24.04 ⁇ 0.20°, and/or 10.66 ⁇ 0.20°, and/or 10.82 ⁇ 0.20°, and/or 11.06 ⁇ 0.20°, and/or 11.54 ⁇ 0.20°, and/or 11.94 ⁇ 0.20°, and/or 13.32 ⁇ 0.20°, and/or 14.86 ⁇ 0.20°, and/or 17.96 ⁇ 0.20°, and/or 18.72 ⁇ 0.20°, and/or 21.66 ⁇ 0.20°, and/or 23.68 ⁇ 0.20°, and/or 24.74 ⁇ 0.20°, and/or 26.56 ⁇ 0.20°, and/or 27.42 ⁇ 0.20°, and/or 30.78 ⁇ 0.20°.
  • the X-ray powder diffraction pattern of Cu K ⁇ radiation of the above-mentioned F crystal form has characteristic diffraction peaks at the following 2 ⁇ angles: 5.96°, 8.86°, 10.66°, 10.82°, 11.06°, 11.54°, 11.94°, 13.32°, 14.86°, 17.40°, 17.96°, 18.72°, 19.52°, 21.66°, 23.68°, 24.04°, 24.74°, 26.56°, 27.42° and 30.78°.
  • the XRPD pattern of Cu K ⁇ radiation of the above-mentioned F crystal form is shown in Figure 11.
  • the peak position and relative intensity of the diffraction peak are shown in Table 16.
  • the present invention provides a crystalline composition
  • a crystalline composition comprising crystals of the compound of formula (II), wherein the crystals of the compound of formula (II) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%.
  • Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (II).
  • the present invention provides a crystalline composition
  • a crystalline composition comprising crystals of the compound of formula (I), wherein the crystals of the compound of formula (I) account for more than 50%, preferably more than 75%, by weight of the crystalline composition, More preferably, it is more than 90%, and even better, it is more than 95%.
  • Each of the crystalline compositions may also contain small amounts of other crystalline or non-crystalline forms of the compound of formula (I).
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient.
  • the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
  • the present invention provides a pharmaceutical composition, which contains a therapeutically effective amount of the above-mentioned compound of formula (I) or its crystal, or a crystal composition of its crystal; the pharmaceutical composition may contain at least one pharmaceutically acceptable Acceptable carrier or other excipient.
  • the pharmaceutical compositions of the present application may further include one or more other therapeutic agents.
  • the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the preparation of treatment or prevention of diseases related to complement factor B. Applications in medicine.
  • the present invention provides the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. application.
  • the present invention provides a method for treating or preventing diseases related to complement factor B, which includes administering to a mammal in need a therapeutically effective amount of the above-mentioned compound of formula (II) or its crystal, the above-mentioned compound of formula (I) or Its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition.
  • the present invention provides the above-mentioned compound of formula (II) or crystal thereof, the above-mentioned compound of formula (I) or its crystal, the above-mentioned crystal composition, or the above-mentioned pharmaceutical composition for the treatment or prevention of diseases related to complement factor B. .
  • the mammal is a human.
  • the complement factor B-related disease is selected from the group consisting of inflammatory disorders and autoimmune diseases.
  • the compound of the present invention has obvious inhibitory activity on the activation of the human serum bypass pathway, and also has significant binding activity on human complement Factor B protein.
  • the crystal form and salt form of the compound of the present invention have simple preparation process, stable physical and chemical properties, good hygroscopicity, good pharmacokinetic properties (such as AUC, C max , T 1/2 ), easy preparation, and good use in prevention. And/or it has broad application prospects in the treatment of complement factor B-related drugs.
  • the intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents and preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • room temperature in the present invention means 15°C to 35°C.
  • mammals include humans and domestic animals, such as laboratory mammals and household pets (such as cats, dogs, pigs, sheep, cattle, sheep, goats, horses, rabbits), and non-domesticated mammals, such as wild mammals.
  • composition refers to a formulation of a compound of the present application with a vehicle generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable carriers for their use. Pharmaceutical compositions facilitate the administration of compounds to an organism.
  • terapéuticaally effective amount refers to a non-toxic amount of a drug or agent sufficient to achieve the desired effect.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • treating means administering a compound or formulation described herein to ameliorate or eliminate a disease or one or more symptoms associated with the disease, and includes:
  • prevention means the administration of a compound or formulation described herein to prevent a disease or one or more symptoms associated with said disease, and includes preventing the occurrence of a disease or disease state in a mammal, in particular when Such mammals are susceptible to the disease state but have not yet been diagnosed as having the disease state.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • pharmaceutically acceptable carriers refer to those carriers that are administered together with the active ingredients, have no obvious irritating effect on the organism, and do not impair the biological activity and performance of the active compound.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction uses a Bruker D8 venture diffractometer to collect diffraction intensity data on the cultured single crystal.
  • the light source is CuK ⁇ radiation.
  • the scanning method is: After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure, and the absolute configuration can be confirmed.
  • ACN represents acetonitrile
  • DMSO represents dimethyl sulfoxide.
  • N 2 nitrogen; RH: relative humidity; mL: milliliter; L: liter; min: minutes; °C: degrees Celsius; ⁇ m: micrometers; mm: millimeters; ⁇ L: microliters; moL/L: moles per liter; mg: milligrams ;s: seconds; nm: nanometers; MPa: megapascals; lux: lux; ⁇ w/cm 2 : microwatts per square centimeter; h: hours; Kg: kilograms; nM: nanomoles, rpm: rotational speed; XRPD represents X-rays Powder diffraction; DSC stands for differential scanning calorimetry; TGA stands for thermogravimetric analysis; 1 H NMR stands for hydrogen nuclear magnetic resonance spectroscopy.
  • the compounds of the present invention are named according to the conventional naming principles in this field or used Software nomenclature, commercially available compounds using supplier catalog names, all solvents used in this invention are commercially available.
  • Instrument model PANalytical X'Pert 3 type X-ray diffractometer.
  • Test method About 10mg sample is used for XRPD detection.
  • Step size 0.0263 degrees.
  • the acid-base molar ratio test in the experiment was performed by Agilent H-Class high performance liquid chromatography and ion chromatography.
  • the analysis conditions are shown in Tables 7 and 8.
  • RH gradient 10% (0%RH-90%RH, 90%RH-0%RH); 5% (90%RH-95%RH, 95%RH-90%RH).
  • Hygroscopicity evaluation classification absorb enough water to form liquid: deliquescence; ⁇ W% ⁇ 15%: extremely hygroscopic; 15% > ⁇ W% ⁇ 2%: yes Hygroscopicity; 2%> ⁇ W% ⁇ 0.2%: slightly hygroscopic; ⁇ W% ⁇ 0.2%: no or almost no hygroscopicity.
  • ⁇ W% represents the moisture absorption weight gain of the test product at 25 ⁇ 1°C and 80 ⁇ 2%RH.
  • Figure 1 is the XRPD pattern of the crystal form A of the compound of formula (II).
  • Figure 2 is the XRPD pattern of the crystal form B of the compound of formula (I).
  • Figure 3 is a DSC spectrum of compound B crystal form of formula (I).
  • Figure 4 is a TGA spectrum of the crystal form B of compound (I).
  • Figure 5 is the XRPD pattern of crystal form C of compound of formula (I).
  • Figure 6 is a DSC spectrum of crystal form C of compound of formula (I).
  • Figure 7 is a TGA spectrum of crystal form C of compound of formula (I).
  • Figure 8 is the XRPD pattern of the crystal form D of the compound of formula (I).
  • Figure 9 is the XRPD pattern of the hydrate crystal form E of the compound of formula (I).
  • Figure 10 is an ellipsoid diagram of the three-dimensional structure of a single crystal of the compound of formula (I).
  • Figure 11 is an XRPD simulation diagram of a single crystal of the compound of formula (I).
  • Benzylamine (194.62g) was slowly added to water (850mL) dissolved in acetic acid (103.88mL). The reaction system was cooled to 0-10°C, then 1,3-acetone dicarboxylic acid (265.36g) was slowly added in batches, and the reaction solution was allowed to react at 0°C for 0.5 hours. A solution of compound 10 (170 g) dissolved in dioxane (850 mL) was slowly added to the reaction system, the reaction solution was slowly returned to room temperature, and then reacted at 45°C for 12 hours.
  • Dissolve compound 11 (220g, 1eq) in acetonitrile (1700mL), then raise the temperature to 70°C and stir for 2 hours.
  • L-type dibenzoyl tartaric acid 200g, 0.8eq
  • the reaction solution is continued Stir at 70°C for 2 hours, then slowly return to 25°C and stir for 12 hours.
  • Add the filtered solid to 1000 mL of water, add 1 M NaOH aqueous solution with stirring to adjust the pH to 8, and then add ethyl acetate for extraction (2000 mL*2).
  • the organic phases were combined and washed with saturated brine (2000 mL*2).
  • N,N-dimethylformamide dimethyl acetal (59.81g) was added to a solution of compound 15 (99g) in methanol (1000mL), and the reaction solution was heated to 40°C and stirred for 16 hours. The reaction solution was directly concentrated under reduced pressure to obtain the residue. Ethyl acetate (1000 mL) was added to the residue, and then washed with water (500 mL) and saturated brine (500 mL) in sequence, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16, which was used directly in the next step.
  • the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 (0.4g) was dissolved in a mixed solvent of deionized water (1mL) and acetonitrile (3mL), and then a saturated sodium bicarbonate aqueous solution (70 ⁇ L) was slowly added , a solid precipitated, and the reaction system continued to stir at 20°C for 5 minutes. The solid is filtered and collected, and after drying, the crystal form A of the compound of formula (II) is obtained.
  • the amorphous form of the hydrochloride of the compound of formula (II) prepared in Example 1 was replaced with the crystal form of the compound of formula (I) B, the crystal form of the compound of formula (I) C, and the crystal form of the compound of formula (I) D. or the crystal form of compound E of formula (I) to obtain the crystal form of compound A of formula (II).
  • Method 1 Dissolve 100 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 in a mixed solution of acetone (0.5 mL) and water (0.1 mL), stir for 5 minutes, and add acetone dropwise to the mixed solution. (0.6 mL) and ethyl acetate (0.9 mL), the reaction solution was stirred at room temperature for 12 hours, a solid precipitated, filtered, and the filter cake was dried to obtain the crystal form B of the compound of formula (I).
  • Method 2 Weigh approximately 20 mg of the amorphous hydrochloride of the compound of formula (II) prepared in Example 1 into a 20 ml glass vial, and add 1.0 mL of the corresponding solvent to completely dissolve the solid. Add anti-solvent dropwise to the clear solution while stirring until solid precipitates or the volume of anti-solvent added reaches 10 mL. Centrifuge and collect the solid for XRPD testing. The experimental results are shown in Table 9.
  • the three-dimensional structure ellipsoid diagram of the single crystal of the compound of formula (I) is shown in Figure 10, and the XRPD simulation diagram is shown in Figure 11.
  • the crystal structure data and parameters of the compound of formula (I) are shown in Tables 10 to 15, and the diffraction data of the XRPD simulation pattern are shown in Table 16.
  • ICH conditions the total visible light illumination reached 1,200,000 Lux ⁇ hrs, the total ultraviolet light When the illumination reaches 200W ⁇ hrs/m 2 ), place it in the open under visible light and ultraviolet light (samples in the shading control group are placed at the same time and wrapped in tin foil), and placed 1, 2 and 3 under 40°C/75%RH (open) conditions. months, placed at 25°C/60%RH (exposure) for 3 months. XRPD testing was performed on all stability samples to detect changes in crystal form.
  • the complement system alternative pathway kit is used to determine the inhibitory activity of the test compound against the complement alternative pathway in human serum.
  • the TR-FRET method was used to determine the binding activity of the test compound against human complement Factor B protein.
  • the binding activity of the test compounds to human complement Factor B protein is shown in Table 18.
  • hydrochloride salt of the compound of formula (II) in Example 1 has significant binding activity to human complement Factor B protein.
  • the compound of the present invention was prepared into a suspension with an aqueous solution of 0.5% MC (4000cP)/0.5% Tween 80. Rats were fasted overnight and then administered orally by gavage. The dosages were: 10mpk, 30mpk and 50mpk. Collect blood before and 0.25, 0.5, 1, 2, 4, 7, and 24 hours after administration, place it in a heparinized anticoagulant test tube, centrifuge at 7000 rpm (5204g), 4°C, separate plasma, and store at -80°C save. Eat 4 hours after dosing. The LC/MS/MS method was used to determine the content of the test compound in rat plasma after oral administration. Plasma samples were analyzed after pretreatment with precipitated proteins. Conclusion: Both the compounds and crystals of the present invention have good oral exposure, long half-life, and excellent pharmacokinetic properties.

Abstract

La présente invention concerne un cristal d'un dérivé d'acide benzoïque substitué par un hétérocycle ponté ou un sel de celui-ci et procédé de préparation associé. L'invention concerne en particulier un cristal d'un composé de formule (II), un chlorhydrate d'un composé de formule (II), un cristal de celui-ci et un procédé de préparation associé.
PCT/CN2023/108171 2022-07-20 2023-07-19 Cristal de dérivé d'acide benzoïque substitué par un hétérocycle ponté ou sel de celui-ci et procédé de préparation associé WO2024017299A1 (fr)

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
WO2022028527A1 (fr) * 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Inhibiteur du facteur b du complément et composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée
WO2022143845A1 (fr) * 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Composé hétérocyclique ponté contenant de l'azote, son procédé de préparation et son utilisation médicale

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109414441A (zh) * 2016-06-27 2019-03-01 艾其林医药公司 治疗医学障碍的喹唑啉和吲哚化合物
WO2022028527A1 (fr) * 2020-08-07 2022-02-10 上海美悦生物科技发展有限公司 Inhibiteur du facteur b du complément et composition pharmaceutique de celui-ci, procédé de préparation correspondant et utilisation associée
WO2022143845A1 (fr) * 2020-12-30 2022-07-07 江苏恒瑞医药股份有限公司 Composé hétérocyclique ponté contenant de l'azote, son procédé de préparation et son utilisation médicale

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