WO2023025268A1 - Crystal forms of pyridazine carboxamide compound and preparation method thereof - Google Patents

Crystal forms of pyridazine carboxamide compound and preparation method thereof Download PDF

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WO2023025268A1
WO2023025268A1 PCT/CN2022/114984 CN2022114984W WO2023025268A1 WO 2023025268 A1 WO2023025268 A1 WO 2023025268A1 CN 2022114984 W CN2022114984 W CN 2022114984W WO 2023025268 A1 WO2023025268 A1 WO 2023025268A1
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crystal form
crystal
formula
compound
present
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PCT/CN2022/114984
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French (fr)
Chinese (zh)
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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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07D401/14—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 three or more hetero rings

Definitions

  • the invention relates to the field of chemistry and medicine, in particular to the crystal form of pyridazine carboxamide compounds and a preparation method thereof.
  • the androgen receptor belongs to the nuclear hormone receptor family. When androgens bind AR, its conformation changes, enabling AR to translocate into the nucleus where it acts as a transcription factor to promote the expression of genes responsible for male sexual characteristics. Meanwhile, studies have shown that AR is also a well-documented oncogene in some forms of cancer, including prostate cancer.
  • prostate cancer treatment typically employs two regimens that utilize androgen suppression. The first approach relies on reducing androgen, while the second strategy aims to inhibit AR function.
  • effective targeted therapies have been developed, most patients develop resistance as the disease progresses. Considering that AR is a key driver of tumorigenesis in many forms of prostate cancer, eliminating AR could represent a novel and effective therapeutic option.
  • Hexyl]pyridazine-3-carboxamide is a novel and efficient AR degradation accelerator, clinically used for the treatment of prostate cancer, its structural formula is as follows:
  • Patent WO2018071606A1 discloses the compound of formula (I) and its synthesis. The disclosed synthesis method needs to be purified by a preparation column. The preparation method is cumbersome and will produce toxic and harmful waste liquid. A simpler and safer preparation method needs to be developed. Patent WO2021231174A1 discloses Form 2 of compound (I) and Form 4 of an ethanol solvate.
  • the present invention provides crystal forms B, M, P, S, E, A of the compound of formula (I) and a preparation method thereof.
  • the solid compound of formula (I) was heated to 250° C., and the temperature was lowered to obtain Form B.
  • the crystal form M is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form M is at 2 ⁇ There are characteristic peaks at 15.4° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.2° ⁇ 0.2°,
  • a pharmaceutical composition comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above and a pharmaceutically acceptable carrier.
  • a pharmaceutical composition having AR degradation promoting activity comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above as an active ingredient.
  • a therapeutic agent for prostate cancer comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above as an active ingredient.
  • the crystal forms B, M, P, S, E, and A of the compound of formula (I) provided by the present invention have better solubility, melting point, stability, dissolution rate, hygroscopicity, adhesion, fluidity,
  • bioavailability and processing performance purification, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing compounds of formula (I), for drug development is of great significance.
  • crystal form A is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of There are characteristic peaks at 14.1° ⁇ 0.2°, 16.0° ⁇ 0.2°, 21.7° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 7.8° ⁇ 0.2°, 9.4° ⁇ 0.2°, 18.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 7.8° ⁇ 0.2°, 9.4° ⁇ 0.2°, and 18.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has one or two or three 2 ⁇ values of 10.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, 20.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has characteristic peaks at 2 ⁇ values of 10.7° ⁇ 0.2°, 17.0° ⁇ 0.2°, and 20.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 7.8° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.0° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 17.0° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.7° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form A has a 2 ⁇ value of 7.8° ⁇ 0.2°, 9.4° ⁇ 0.2°, 10.7° ⁇ 0.2°, 14.1° ⁇ 0.2°, 16.0° ⁇ 0.2° There are characteristic peaks at 0.2°, 17.0° ⁇ 0.2°, 18.7° ⁇ 0.2°, 20.7° ⁇ 0.2°, 21.7° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1 or Figure 5 .
  • the preparation method of the crystal form A is characterized in that,
  • the solid of the compound of formula (I) is added to dissolve in the positive solvent, and the anti-solvent is added dropwise thereto under stirring until a solid is precipitated to obtain the crystal form A.
  • the positive solvent is a halogenated hydrocarbon solvent
  • the anti-solvent is an alkane solvent.
  • the halogenated hydrocarbon solvent is dichloromethane or chloroform
  • the alkane solvent is n-heptane or cyclohexane
  • the temperature of dissolution, dropping, stirring and precipitation is 10°C to 50°C, for example, 20°C to 30°C.
  • crystal form B is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form B has a 2 ⁇ value of There are characteristic peaks at 16.1° ⁇ 0.2°, 18.4° ⁇ 0.2°, 22.9° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form B has one or two or three 2 ⁇ values of 17.2° ⁇ 0.2°, 19.8° ⁇ 0.2°, 21.1° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has characteristic peaks at 2 ⁇ values of 17.2° ⁇ 0.2°, 19.8° ⁇ 0.2°, and 21.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form B has one or two or three 2 ⁇ values of 7.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 26.8° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has characteristic peaks at 2 ⁇ values of 7.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, and 26.8° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form B has a 2 ⁇ value of 7.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.4° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 19.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 22.9° ⁇ 0.2°, 26.8° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form B has a 2 ⁇ value of 7.3° ⁇ 0.2°, 13.5° ⁇ 0.2°, 16.1° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.4° ⁇ 0.2° There are characteristic peaks at 0.2°, 19.8° ⁇ 0.2°, 21.1° ⁇ 0.2°, 22.9° ⁇ 0.2°, 26.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 6 .
  • the preparation method of the crystal form B is characterized in that,
  • the solid compound of formula (I) was heated to 250°C, and then cooled to obtain Form B.
  • the solid compound of formula (I) is Form A.
  • the heating rate is 10 ⁇ 30° C./minute, for example, 10° C./minute.
  • the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
  • the crystal form M is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form M has a 2 ⁇ value of There are characteristic peaks at 15.4° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.2° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form M has one or two or three 2 ⁇ values of 7.5° ⁇ 0.2°, 14.4° ⁇ 0.2°, 17.7° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form M has characteristic peaks at 2 ⁇ values of 7.5° ⁇ 0.2°, 14.4° ⁇ 0.2°, and 17.7° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form M has a 2 ⁇ value of 10.8 ⁇ 0.2°, 15.9° ⁇ 0.2°, 27.1° ⁇ 0.2° at one or two or three places Characteristic peaks.
  • the X-ray powder diffraction of the crystal form M has characteristic peaks at 2 ⁇ values of 10.8 ⁇ 0.2°, 15.9° ⁇ 0.2°, and 27.1° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form M has a 2 ⁇ value of 7.5° ⁇ 0.2°, 10.8° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.9° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 17.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.2° ⁇ 0.2°, 27.1° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form M has a 2 ⁇ value of 7.5° ⁇ 0.2°, 10.8° ⁇ 0.2°, 14.4° ⁇ 0.2°, 15.4° ⁇ 0.2°, 15.9° ⁇ 0.2° There are characteristic peaks at 0.2°, 17.7° ⁇ 0.2°, 20.2° ⁇ 0.2°, 21.2° ⁇ 0.2°, 27.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form M is shown in FIG. 11 .
  • the preparation method of the crystal form M is characterized in that,
  • the solid compound of formula (I) is Form A.
  • the temperature of the suspension stirring is 10-50°C, for example, 20-30°C.
  • the heating rate is 10 ⁇ 40° C./minute, for example, 10° C./minute.
  • the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
  • the suspension stirring time is 8-30 days, such as 25 days.
  • the crystal form P is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form P is at 2 ⁇ There are characteristic peaks at 11.0° ⁇ 0.2°, 18.6° ⁇ 0.2°, 20.1° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form P has a 2 ⁇ value of 7.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, 22.2° ⁇ 0.2° at one or two or three places have characteristic peaks.
  • the X-ray powder diffraction of the crystal form P has characteristic peaks at 2 ⁇ values of 7.3° ⁇ 0.2°, 13.8° ⁇ 0.2°, and 22.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form P has one or two or three 2 ⁇ values of 17.2° ⁇ 0.2°, 25.3° ⁇ 0.2°, and 25.9° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form P has characteristic peaks at 2 ⁇ values of 17.2° ⁇ 0.2°, 25.3° ⁇ 0.2°, and 25.9° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form P has a 2 ⁇ value of 7.3° ⁇ 0.2°, 11.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.6° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.1° ⁇ 0.2°, 22.2° ⁇ 0.2°, 25.3° ⁇ 0.2°, 25.9° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form P has a 2 ⁇ value of 7.3° ⁇ 0.2°, 11.0° ⁇ 0.2°, 13.8° ⁇ 0.2°, 17.2° ⁇ 0.2°, 18.6° ⁇ 0.2° There are characteristic peaks at 0.2°, 20.1° ⁇ 0.2°, 22.2° ⁇ 0.2°, 25.3° ⁇ 0.2°, 25.9° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form P is shown in Figure 15 or Figure 19 .
  • the preparation method of the crystal form P is characterized in that,
  • the solid compound of formula (I) is dissolved in a halogenated hydrocarbon solvent, and an alkyl nitrile solvent is added dropwise thereto under stirring until a jelly-like substance is produced; the solution is volatilized to obtain Form P.
  • the halogenated hydrocarbon solvent is chloroform
  • the alkyl nitrile solvent is acetonitrile
  • the dissolution and volatilization temperature is 10-50°C, for example, 20-30°C.
  • crystal form S is characterized in that, using Cu-K ⁇ radiation, the X-ray powder diffraction of the crystal form S has a 2 ⁇ value of There are characteristic peaks at 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 22.7° ⁇ 0.2°,
  • the X-ray powder diffraction of the crystal form S has one or two or three 2 ⁇ values of 11.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, 23.3° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form S has characteristic peaks at 2 ⁇ values of 11.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, and 23.3° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form S has a 2 ⁇ value of 18.6 ⁇ 0.2°, 20.2° ⁇ 0.2°, 25.6° ⁇ 0.2° at one or two or three places Characteristic peaks.
  • the X-ray powder diffraction of the crystal form S has characteristic peaks at 2 ⁇ values of 18.6 ⁇ 0.2°, 20.2° ⁇ 0.2°, and 25.6° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form S has a 2 ⁇ value of 11.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.6° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 25.6° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form S has a 2 ⁇ value of 11.6° ⁇ 0.2°, 15.7° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.6° ⁇ 0.2°, 18.6° ⁇ 0.2° There are characteristic peaks at 0.2°, 20.2° ⁇ 0.2°, 22.7° ⁇ 0.2°, 23.3° ⁇ 0.2°, 25.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form S is shown in FIG. 20 .
  • the preparation method of the crystal form S is characterized in that,
  • the solid compound of formula (I) was added to nitromethane, suspended and stirred for a certain period of time, and the solid was collected; the aforementioned solid was heated to 150° C., and then cooled to obtain the crystal form S.
  • the solid compound of formula (I) is Form A.
  • the temperature of the suspension stirring is 10-50°C, for example, 20-30°C.
  • the heating rate is 10 ⁇ 40° C./minute, for example, 10° C./minute.
  • the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
  • the suspension stirring time is 8-30 days, such as 25 days.
  • the X-ray powder diffraction of the crystal form E has one or two or three 2 ⁇ values of 5.6° ⁇ 0.2°, 12.5° ⁇ 0.2°, 19.2° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form E has characteristic peaks at 2 ⁇ values of 5.6° ⁇ 0.2°, 12.5° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form E has one or two or three 2 ⁇ values of 9.0° ⁇ 0.2°, 17.8° ⁇ 0.2°, 24.5° ⁇ 0.2° have characteristic peaks.
  • the X-ray powder diffraction of the crystal form E has characteristic peaks at 2 ⁇ values of 9.0° ⁇ 0.2°, 17.8° ⁇ 0.2°, and 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction of the crystal form E has a 2 ⁇ value of 5.6° ⁇ 0.2°, 9.0° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.5° ⁇ 0.2°, 17.8° ⁇ 0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 18.5° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.5° ⁇ 0.2° There are characteristic peaks.
  • the X-ray powder diffraction of the crystal form E has a 2 ⁇ value of 5.6° ⁇ 0.2°, 9.0° ⁇ 0.2°, 11.1° ⁇ 0.2°, 12.5° ⁇ 0.2°, 17.8° ⁇ 0.2° There are characteristic peaks at 0.2°, 18.5° ⁇ 0.2°, 19.2° ⁇ 0.2°, 21.0° ⁇ 0.2°, 24.5° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystal form E is shown in FIG. 23 .
  • the preparation method of the crystal form E is characterized in that,
  • the solvent is a single or mixed solvent of pure water, alcohols, and aromatic hydrocarbons.
  • the solid compound of formula (I) is crystal form A or amorphous.
  • the alcohol solvent includes methanol and ethanol
  • the aromatic hydrocarbon solvent includes toluene and m-xylene
  • the mixed solvent includes methanol/pure water, ethanol/pure water.
  • the volume ratio of methanol/pure water is 0.5-4:1, such as 1:1; the volume ratio of ethanol/pure water is 80-100:8, such as 92:8 .
  • the temperature of the suspension stirring is -5-50°C, such as 20-30°C, or 5°C.
  • the suspension stirring time is 3-15 days, for example, 8 days.
  • the aromatic hydrocarbon solvent is toluene.
  • the gas-solid diffusion temperature is 10-50°C, for example, 20-30°C.
  • the solid compound of formula (I) is amorphous.
  • the gas-solid diffusion time is 5-14 days, for example, 7 days.
  • the positive solvent includes halogenated hydrocarbons and cyclic ether solvents
  • the anti-solvent includes aromatic hydrocarbons and alcohol solvents.
  • the halogenated hydrocarbon solvent is chloroform, and the cyclic ether solvent is tetrahydrofuran; in the anti-solvent, the aromatic hydrocarbon solvent is toluene, and the alcohol solvent is methanol.
  • the temperature of dissolution, dropping, stirring and precipitation is 10°C to 50°C, for example, 20°C to 30°C.
  • said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, waxy or oily form.
  • the compound of formula (I) as starting material is in the form of a solid powder.
  • the "stirring" is accomplished by conventional methods in this field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is 200-1500 rpm, preferably 300-1000 rpm , The mechanical stirring is preferably 100 to 300 rpm.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition, which contains the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier.
  • the above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition having AR degradation promoting activity, which comprises the above-mentioned crystals of the present invention as an active ingredient.
  • the above-mentioned crystals of the present invention can be used in the preparation of prophylactic or therapeutic drugs for prostate cancer, which contain the above-mentioned crystals of the present invention as active ingredients.
  • the present invention also provides a pharmaceutical composition comprising the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
  • the present invention also provides a pharmaceutical composition having AR degradation-promoting activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • the present invention provides a prophylactic or therapeutic drug for prostate cancer, which contains the above-mentioned crystal of the present invention as an active ingredient.
  • crystal or “polymorph” refers to what is characterized by the shown X-ray diffraction pattern.
  • X-ray diffraction patterns often vary with the conditions of the instrument.
  • the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor.
  • the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal, and the peak intensities shown here are illustrative rather than for absolute comparison.
  • 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 the error of ⁇ 0.2° is usually allowed.
  • due to the influence of experimental factors such as sample thickness it will cause the overall deviation of the peak angle, and a certain deviation is usually allowed.
  • the X-ray diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here, and the "same X-ray diffraction pattern" mentioned herein does not mean absolutely identical, identical peak positions may differ by ⁇ 0.2° and peak intensities allow for some variability. Any crystal form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of spectrum reflect the same or different crystal forms.
  • the crystalline form of the invention is pure, single, substantially free of any other crystalline forms.
  • substantially free when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms.
  • the numerical values and numerical ranges mentioned in the present invention should not be narrowly interpreted as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can vary according to the specific technical environment without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles, and in the present invention, such fluctuation ranges that are foreseeable by those skilled in the art are often expressed by the term "about”.
  • Root temperature in the present invention usually refers to 22°C to 28°C unless otherwise specified.
  • the X-ray powder diffraction patterns described in the present invention were collected on Empyrean type and X'Pert 3 type X-ray powder diffractometers of Panalytical (Panalytical) Company.
  • the method parameter of X-ray powder diffraction of the present invention is as follows:
  • the differential scanning calorimetry chart of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company.
  • the method parameter of differential scanning calorimetry analysis of the present invention is as follows:
  • thermogravimetric analysis figure of the present invention is collected on the Discovery TGA 5500 type of TA company and Q5000 type thermogravimetric analyzer.
  • the method parameter of thermogravimetric analysis of the present invention is as follows:
  • the proton nuclear magnetic resonance spectrum data ( 1 H NMR) described in the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5mg sample, dissolve it with 0.5mL deuterated dimethyl sulfoxide, and prepare a 2-10mg/mL solution for testing.
  • the dynamic moisture adsorption figure 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)
  • the particle size distribution results described in the present invention are collected on the S3500 laser particle size analyzer of Microtrac Company.
  • Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system.
  • SDC Sample Delivery Controller
  • This test adopts wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin).
  • the method parameter of described laser particle size analyzer is as follows:
  • the inherent dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company.
  • the inherent dissolution test conditions described are as follows:
  • the polarizing microscope photos described in the present invention were collected at room temperature by Zeiss microscope Axio Scope.A1, and the microscope was equipped with Axiocam 305 color camera and 5 ⁇ , 10 ⁇ , 20 ⁇ and 50 ⁇ objective lenses.
  • Embodiment 1 ⁇ 2 the preparation of crystal form A
  • Example 1 The detailed test conditions involved in this example are shown in Table 1, and the X-ray powder diffraction data of the sample in Example 1 are shown in Table 2. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 1 to 4, respectively.
  • Embodiment 3 the preparation of crystal form A
  • the sample is at about 7.8° ⁇ 0.2°, about 9.4° ⁇ 0.2°, about 10.7° ⁇ 0.2°, about 11.9° ⁇ 0.2°, about 14.1° ⁇ 0.2°, about 16.0° ⁇ 0.2°, about 17.0° ⁇ 0.2 °, about 18.7° ⁇ 0.2°, about 19.1° ⁇ 0.2°, about 20.7° ⁇ 0.2°, and about 21.7° ⁇ 0.2° have characteristic peaks. Its XRPD is shown in FIG. 5 .
  • Embodiment 4 the preparation of crystal form B
  • Example 3 Weigh an appropriate amount of the compound of formula (I) in Example 3 at room temperature and place it in a DSC crucible, heat it to 250°C at a rate of 10°C/min, keep it warm for 3 minutes, and then cool it down to 30°C at a rate of 30°C/min. °C, the crystal form B was obtained. Its X-ray powder diffraction data are shown in Table 4.
  • the sample is at about 7.3° ⁇ 0.2°, about 13.5° ⁇ 0.2°, about 16.1° ⁇ 0.2°, about 17.2° ⁇ 0.2°, about 17.7° ⁇ 0.2°, about 18.4° ⁇ 0.2°, about 19.8° ⁇ 0.2 °, about 21.1° ⁇ 0.2°, about 21.6° ⁇ 0.2°, about 22.9° ⁇ 0.2°, and about 26.8° ⁇ 0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 6-9, respectively.
  • Embodiment 5 the preparation of amorphous
  • Embodiment 6 Preparation of crystal form M
  • Example 3 At room temperature, 98.8 mg of solid compound of formula (I) in Example 3 was weighed and placed in a 3.0 ml glass vial, and 2.0 ml of nitromethane was added to obtain a suspension. The samples were suspended and stirred (500 rpm) at room temperature for about 25 days. The solid was collected by suction filtration.
  • Embodiment 7 the preparation of crystal form P
  • the sample is at about 3.1° ⁇ 0.2°, about 7.3° ⁇ 0.2°, about 11.0° ⁇ 0.2°, about 13.8° ⁇ 0.2°, about 17.2° ⁇ 0.2°, about 18.6° ⁇ 0.2°, about 20.1° ⁇ 0.2 °, about 21.9° ⁇ 0.2°, about 22.2° ⁇ 0.2°, about 25.3° ⁇ 0.2°, and about 25.9° ⁇ 0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 15-18, respectively.
  • Embodiment 8 Preparation of crystal form P
  • Diffraction angle 2 ⁇ d value strength% 18.57 4.78 100.00 18.84 4.71 16.03 20.08 4.42 26.68 20.42 4.35 9.46 21.96 4.05 20.50 22.19 4.01 42.97 23.89 3.72 3.30 24.53 3.63 12.81 25.35 3.51 11.54 25.93 3.44 16.60 26.47 3.37 8.30 26.82 3.32 5.54 27.58 3.23 3.34 28.63 3.12 3.95 29.06 3.07 8.23 29.84 2.99 2.50 30.99 2.89 4.48 33.37 2.68 1.32 35.47 2.53 1.98 36.60 2.45 1.56 38.40 2.34 3.16 38.89 2.32 1.85
  • Embodiment 9 Preparation of crystal form S
  • Example 3 At room temperature, 98.8 mg of solid compound of formula (I) in Example 3 was weighed and placed in a 3.0 ml glass vial, and 2.0 ml of nitromethane was added to obtain a suspension. The samples were suspended and stirred (500 rpm) at room temperature for about 25 days. The solid was collected by suction filtration.
  • Example 3 At room temperature, an appropriate amount of solid compound of formula (I) of Example 3 or Example 5 was weighed and placed in a 1.5-5.0 ml glass vial, and a corresponding solvent was added to obtain a suspension. The sample was suspended and stirred (500 rpm) at room temperature or 5°C to obtain Form E.
  • Example 10 The detailed test conditions involved in this example are shown in Table 9, and the X-ray powder diffraction data of the sample in Example 10 are shown in Table 10.
  • the sample is at about 5.6° ⁇ 0.2°, about 8.4° ⁇ 0.2°, about 9.0° ⁇ 0.2°, about 11.1° ⁇ 0.2°, about 12.5° ⁇ 0.2°, about 17.8° ⁇ 0.2°, about 18.5° ⁇ 0.2° °, about 19.2° ⁇ 0.2°, about 21.0° ⁇ 0.2°, about 22.9° ⁇ 0.2°, and about 24.5° ⁇ 0.2° have characteristic peaks.
  • Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 23-26, respectively.
  • Example 5 At room temperature, 15.9 mg of solid compound of formula (I) in Example 5 was weighed and placed in a 3 ml glass vial, and then opened and placed in a 20 ml glass vial filled with 4 ml of toluene. After sealing, place it at room temperature for about 7 days to obtain Form E. Its X-ray powder diffraction data are shown in Table 11.
  • Example 12 The detailed test conditions involved in this example are shown in Table 12, and the X-ray powder diffraction data of the sample in Example 16 are shown in Table 13.
  • Diffraction angle 2 ⁇ d value strength% 18.49 4.80 75.08 19.23 4.62 27.29 21.05 4.22 100.00 21.71 4.09 23.50 22.40 3.97 16.40 22.87 3.89 25.06 23.21 3.83 20.14 23.81 3.74 13.58 24.45 3.64 23.70 26.38 3.38 7.60 27.13 3.29 5.82 29.36 3.04 5.23 31.63 2.83 3.16 33.11 2.71 2.62 36.08 2.49 1.89
  • Form E of the present invention and Form 2 of WO2021231174A1 were prepared into suspensions with FaSSIF (artificial intestinal fluid in fasting state), and filtered after equilibrating for 1 hour and 4 hours to obtain a saturated solution.
  • the content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • Table 14 The test results are shown in Table 14, and the solubility curve is shown in Figure 27. The test results show that the solubility of Form E of the present invention in FaSSIF within 4 hours is higher than that of Form 2.
  • the crystal form A, crystal form M and Form 2 of WO2021231174A1 of the present invention were respectively prepared into suspensions with FeSSIF (artificial intestinal fluid in a fed state), and filtered after equilibrating for 1 hour, 4 hours and 24 hours to obtain a saturated solution.
  • the content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC).
  • HPLC high performance liquid chromatography
  • the test results are shown in Table 15, and the solubility curve is shown in Figure 28.
  • the test results show that the solubility of Form A and Form M of the present invention in FeSSIF is higher than that of Form 2.
  • a manual tablet press is used for tablet compression.
  • a circular flat punch that can be compressed into a cylindrical tablet is selected, and a certain amount of crystal form A, crystal form E, crystal form M, crystal form P and
  • the crystal form S was pressed into round tablets with a pressure of 10kN, and the radial crushing force (hardness, H) was tested with a tablet hardness tester.
  • Use a vernier caliper to measure the diameter (D) and thickness (L) of the tablet, and use the formula T 2H/ ⁇ DL to calculate the tensile strength of the powder at different hardnesses.
  • the test results are shown in Table 16, and the XRPD comparison charts before and after tablet compression are shown in Figures 29-33 respectively.
  • Embodiment 19 Stability comparative study
  • Form A initial purity 99.19%), Form B (initial purity 99.00%), Form E (initial purity 98.79%) and Form M (initial purity 99.08%) of the present invention , placed in a stable box under the conditions of 25°C/60%RH and 40°C/75%RH respectively, and samples were taken to measure the purity by XRPD and HPLC after 1 week, 2 weeks, 4 weeks and 8 weeks.
  • the test results are shown in Table 17.
  • the stability of Form A is shown in Figures 34-35
  • the stability of Form B is shown in Figures 36-37
  • the stability of Form E is shown in Figures 38-39.
  • the stability of crystal form M is shown in Figures 40-41.
  • the test results show that the crystal forms A, B, E and M of the present invention have better physical and chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH.
  • Embodiment 20 Contrastive research on moisture absorption
  • Moisture-absorbing the weight gain of moisture-absorbing is less than 15% but not less than 2%
  • Embodiment 21 Comparative study on crystal habit
  • Embodiment 22 comparative study of particle size distribution
  • the test results show that the crystal form A of the present invention has a unimodal distribution with an average particle size of 17.39 microns, and the particle size distribution is uniform; Form 2 has a bimodal distribution with an average particle size of 224.6 microns. It shows that the crystal form A of the present invention has a more uniform particle size distribution.

Abstract

Crystal forms B, M, P, S, E and A of a compound of formula (I), a preparation method therefor and a use thereof. The crystal forms have advantages in at least one of solubility, melting point, stability, dissolution, hygroscopicity, adhesion, fluidity, biological availability and processing performance, purification, preparation production, safety, etc., provide better options for the preparation of pharmaceutical preparations containing the compound of formula (I), and have significance for drug development.

Description

哒嗪甲酰胺类化合物的晶型及其制备方法Crystal form of pyridazine carboxamide compound and preparation method thereof 技术领域technical field
本发明涉及化学医药领域，特别是涉及哒嗪甲酰胺类化合物的晶型及其制备方法。The invention relates to the field of chemistry and medicine, in particular to the crystal form of pyridazine carboxamide compounds and a preparation method thereof.
背景技术Background technique
雄激素受体(AR)属于核激素受体家族。当雄激素结合AR时，其构型发生变化，使得AR能够易位到细胞核中，充当转录因子以促进负责雄性性特征的基因表达。同时，有研究表明，AR在某些形式的癌症(包括前列腺癌)中也是有明确记录的致癌基因。目前，前列腺癌的治疗通常采用两种利用抑制雄激素的方案。第一种方法依赖于减少雄激素，而第二种策略旨在抑制AR功能。尽管已经开发了有效的靶向疗法，但大多数患者随着病情发展会产生抗药性。考虑到AR在许多形式的前列腺癌中是肿瘤发生的关键驱动因子，因此消除AR可以成为一种新型有效的治疗方案。The androgen receptor (AR) belongs to the nuclear hormone receptor family. When androgens bind AR, its conformation changes, enabling AR to translocate into the nucleus where it acts as a transcription factor to promote the expression of genes responsible for male sexual characteristics. Meanwhile, studies have shown that AR is also a well-documented oncogene in some forms of cancer, including prostate cancer. Currently, prostate cancer treatment typically employs two regimens that utilize androgen suppression. The first approach relies on reducing androgen, while the second strategy aims to inhibit AR function. Although effective targeted therapies have been developed, most patients develop resistance as the disease progresses. Considering that AR is a key driver of tumorigenesis in many forms of prostate cancer, eliminating AR could represent a novel and effective therapeutic option.
6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺是一种新型、高效的AR降解促进剂，临床上用于前列腺癌的治疗，其结构式如下所示：6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3-dihydro-1H-iso Indol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4-cyanophenoxy)ring Hexyl]pyridazine-3-carboxamide is a novel and efficient AR degradation accelerator, clinically used for the treatment of prostate cancer, its structural formula is as follows:
Figure PCTCN2022114984-appb-000001
Figure PCTCN2022114984-appb-000001
专利WO2018071606A1公开了式(I)化合物及其合成，公开的合成方法需利用制备柱进行提纯，制备方法过程繁琐且会产生有毒有害的废液，需开发更为简单、安全的制备方法。专利WO2021231174A1公开了(I)化合物的Form 2和一个乙醇溶剂合物Form 4。Patent WO2018071606A1 discloses the compound of formula (I) and its synthesis. The disclosed synthesis method needs to be purified by a preparation column. The preparation method is cumbersome and will produce toxic and harmful waste liquid. A simpler and safer preparation method needs to be developed. Patent WO2021231174A1 discloses Form 2 of compound (I) and Form 4 of an ethanol solvate.
此外，同一药物的不同晶型在溶解度、熔点、密度、稳定性等方面有显著的差异，从而不同程度地影响药物的稳定性、均一性、生物利用度、疗效和安全性。因此，药物研发中进行全面系统的多晶型筛选，选择最适合开发的晶型，是不可忽视的重要研究内容之一。基于此，有必要对化合物(I)进行多晶型筛选，为药物的后续开发提供更多更好的选择。In addition, different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, uniformity, bioavailability, efficacy, and safety of the drug to varying degrees. Therefore, comprehensive and systematic polymorph screening in drug development and selection of the most suitable crystal form for development is one of the important research contents that cannot be ignored. Based on this, it is necessary to screen polymorphs of compound (I) to provide more and better choices for the subsequent development of drugs.
发明内容Contents of the invention
本发明提供了式(I)化合物的晶型B、M、P、S、E、A及其制备方法。The present invention provides crystal forms B, M, P, S, E, A of the compound of formula (I) and a preparation method thereof.
1.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在2θ值为16.1°±0.2°、18.4°±0.2°、22.9°±0.2°处有特征峰，1. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 shown in formula (I) ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide type B crystal, i.e. crystal form B, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form B is at 2θ There are characteristic peaks at 16.1°±0.2°, 18.4°±0.2°, 22.9°±0.2°,
Figure PCTCN2022114984-appb-000002
Figure PCTCN2022114984-appb-000002
2.上述1所述的晶型B的制备方法，其特征在于，2. The preparation method of the crystal form B described in 1 above, characterized in that,
将式(I)化合物固体加热至250℃，降温得到晶型B。The solid compound of formula (I) was heated to 250° C., and the temperature was lowered to obtain Form B.
3.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的M型晶体、即晶型M，其特征在于，使用Cu-Kα辐射，所述晶型M的X射线粉末衍射在2θ值为15.4°±0.2°、20.2°±0.2°、21.2°±0.2°处有特征峰，3. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 shown in formula (I) ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- The M-type crystal of 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. the crystal form M, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form M is at 2θ There are characteristic peaks at 15.4°±0.2°, 20.2°±0.2°, 21.2°±0.2°,
Figure PCTCN2022114984-appb-000003
Figure PCTCN2022114984-appb-000003
4.上述3所述的晶型M的制备方法，其特征在于，4. The preparation method of the crystal form M described in the above 3, characterized in that,
在10～50℃下，将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至230℃，降温得到晶型M。Add the solid compound of formula (I) into nitromethane at 10-50°C, suspend and stir for a certain period of time, and collect the solid; heat the aforementioned solid to 230°C, and cool down to obtain Form M.
5.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的P型晶体、即晶型P，其特征在于，使用Cu-Kα辐射，所述晶型P的X射线粉末衍射在2θ值为11.0°±0.2°、18.6±0.2°、20.1°±0.2°处有特征峰，5. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 represented by formula (I) ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- The P-type crystal of 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. the crystal form P, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form P is at 2θ There are characteristic peaks at 11.0°±0.2°, 18.6±0.2°, 20.1°±0.2°,
Figure PCTCN2022114984-appb-000004
Figure PCTCN2022114984-appb-000004
6.上述5所述的晶型P的制备方法，其特征在于，6. The preparation method of the crystal form P described in the above 5, characterized in that,
在10～50℃下，将式(I)化合物固体溶解于卤代烃类溶剂中，加入烷基腈类溶剂，搅拌至产生胶状物；将溶液挥发，得到晶型P。Dissolve the solid compound of formula (I) in a halogenated hydrocarbon solvent at 10-50°C, add an alkylnitrile solvent, and stir until a jelly is produced; volatilize the solution to obtain Form P.
7.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的S型晶体、即晶型S，其特征在于，使用Cu-Kα辐射，所述晶型S的X射线粉末衍射在2θ值为15.7°±0.2°、16.6±0.2°、22.7°±0.2°处有特征峰，7. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- The S-type crystal of 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form S, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form S is at 2θ There are characteristic peaks at 15.7°±0.2°, 16.6±0.2°, 22.7°±0.2°,
Figure PCTCN2022114984-appb-000005
Figure PCTCN2022114984-appb-000005
8.上述7所述的晶型S的制备方法，其特征在于，8. The preparation method of the crystal form S described in the above 7, characterized in that,
在10～50℃下，将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至150℃，降温得到晶型S。Add the solid compound of formula (I) into nitromethane at 10-50°C, suspend and stir for a certain period of time, and collect the solid; heat the aforementioned solid to 150°C, and cool down to obtain Form S.
9.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的E型晶体、即晶型E，其特征在于，使用Cu-Kα辐射，所述晶型E的X射线粉末衍射在2θ值为11.1°±0.2°、18.5°±0.2°、21.0°±0.2°处有特征峰，9. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide type E crystal, i.e. crystal form E, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form E is at 2θ There are characteristic peaks at 11.1°±0.2°, 18.5°±0.2°, 21.0°±0.2°,
Figure PCTCN2022114984-appb-000006
Figure PCTCN2022114984-appb-000006
10.上述9所述的晶型E的制备方法，其特征在于，10. The preparation method of the crystal form E described in the above 9, characterized in that,
(1)在-5～50℃下，将式(I)化合物固体加入至纯水、醇类、芳香烃类的单一或混合溶剂中，悬浮搅拌，得到晶型E；或(1) Add the solid compound of formula (I) to pure water, alcohols, aromatic hydrocarbons or a mixed solvent at -5 to 50°C, suspend and stir to obtain crystal form E; or
(2)在10～50℃下，将式(I)化合物固体置于芳香烃类溶剂氛围下进行气固扩散，得到晶型E；或or
(3)在10～50℃下，将式(I)化合物溶解于卤代烃、环醚类溶剂中，向其中加入芳香烃类、醇类溶剂，搅拌至有固体析出，得到晶型E。(3) Dissolve the compound of formula (I) in halogenated hydrocarbons and cyclic ether solvents at 10-50°C, add aromatic hydrocarbons and alcohol solvents therein, and stir until solids are precipitated to obtain crystal form E.
11.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.1°±0.2°、16.0°±0.2°、21.7°±0.2°处有特征峰，11. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide type A crystal, i.e. crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A is at 2θ There are characteristic peaks at 14.1°±0.2°, 16.0°±0.2°, 21.7°±0.2°,
Figure PCTCN2022114984-appb-000007
Figure PCTCN2022114984-appb-000007
12.上述11所述的晶型A的制备方法，其特征在于，12. The preparation method of the crystal form A described in the above 11, characterized in that,
在10～50℃下，将式(I)化合物固体溶解于卤代烃类溶剂中，向其中加入烷烃类溶剂，搅拌至有固体析出，得到晶型A。Dissolve the solid compound of formula (I) in a halogenated hydrocarbon solvent at 10-50°C, add an alkane solvent therein, and stir until a solid precipitates out to obtain Form A.
13.药物组合物，其包含上述1，3，5，7，9和11中任一项所述的晶体和制药学可接受的载体。13. A pharmaceutical composition comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above and a pharmaceutically acceptable carrier.
14.具有AR降解促进活性的药物组合物，其含有上述1，3，5，7，9和11中任一项所述的晶体作为有效成分。14. A pharmaceutical composition having AR degradation promoting activity, comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above as an active ingredient.
15.前列腺癌的治疗药，其含有上述1，3，5，7，9和11中任一项所述的晶体作为有效成分。15. A therapeutic agent for prostate cancer, comprising the crystal described in any one of 1, 3, 5, 7, 9 and 11 above as an active ingredient.
与现有技术相比，本发明提供的式(I)化合物晶型B、M、P、S、E、A，在溶解度、熔点、稳定性、溶出度、引湿性、黏附性、流动性、生物有效性以及加工性能、提纯作用、制剂生产、安全性等方面中的至少一方面上存在优势，为含式(I)化合物的药物制剂的制备提供了新的更好的选择，对于药物开发具有非常重要的意义。Compared with the prior art, the crystal forms B, M, P, S, E, and A of the compound of formula (I) provided by the present invention have better solubility, melting point, stability, dissolution rate, hygroscopicity, adhesion, fluidity, There are advantages in at least one aspect of bioavailability and processing performance, purification, preparation production, safety, etc., which provide a new and better choice for the preparation of pharmaceutical preparations containing compounds of formula (I), for drug development is of great significance.
附图说明Description of drawings
图1实施例1晶型A的XRPD图The XRPD figure of Fig. 1 embodiment 1 crystal form A
图2实施例1晶型A的TGA图The TGA figure of Fig. 2 embodiment 1 crystal form A
图3实施例1晶型A的DSC图The DSC figure of Fig. 3 embodiment 1 crystal form A
图4实施例1晶型A的 1H NMR图 The 1 H NMR figure of the crystal form A of Fig. 4 embodiment 1
图5实施例3晶型A的XRPD图The XRPD figure of Fig. 5 embodiment 3 crystal form A
图6晶型B的XRPD图Figure 6 XRPD pattern of crystal form B
图7晶型B的TGA图Figure 7 TGA diagram of crystal form B
图8晶型B的DSC图Figure 8 DSC diagram of crystal form B
图9晶型B的 1H NMR图 The 1 H NMR figure of Fig. 9 crystal form B
图10无定形的XRPD图Figure 10 XRPD pattern of amorphous
图11晶型M的XRPD图Figure 11 XRPD pattern of Form M
图12晶型M的TGA图Figure 12 TGA diagram of Form M
图13晶型M的DSC图Figure 13 DSC chart of Form M
图14晶型M的 1H NMR图 Figure 14 1 H NMR chart of Form M
图15实施例7晶型P的XRPD图The XRPD figure of Fig. 15 embodiment 7 crystal form P
图16实施例7晶型P的TGA图The TGA figure of Fig. 16 embodiment 7 crystal form P
图17实施例7晶型P的DSC图The DSC figure of Fig. 17 embodiment 7 crystal form P
图18实施例7晶型P的 1H NMR图 The 1 H NMR figure of the crystal form P of Fig. 18 embodiment 7
图19实施例8晶型P的XRPD图The XRPD figure of Fig. 19 embodiment 8 crystal form P
图20晶型S的XRPD图Figure 20 XRPD pattern of Form S
图21晶型S的TGA图Figure 21 TGA diagram of Form S
图22晶型S的DSC图Figure 22 DSC chart of Form S
图23晶型E的XRPD图Figure 23 XRPD pattern of Form E
图24晶型E的TGA图Figure 24 TGA diagram of Form E
图25晶型E的DSC图Figure 25 DSC diagram of Form E
图26晶型E的 1H NMR图 Figure 26 1 H NMR chart of Form E
图27不同晶型在FaSSIF中的溶解度对比图Figure 27 Solubility comparison chart of different crystal forms in FaSSIF
图28不同晶型在FeSSIF中的溶解度对比图Figure 28 Comparison of solubility of different crystal forms in FeSSIF
图29晶型A压片前后的XRPD对比图Figure 29 XRPD comparison chart of Form A before and after tablet compression
图30晶型E压片前后的XRPD对比图Figure 30 XRPD comparison chart of Form E before and after tablet compression
图31晶型M压片前后的XRPD对比图Figure 31 XRPD comparison chart of crystal form M before and after tablet compression
图32晶型P压片前后的XRPD对比图Figure 32 XRPD comparison chart of crystal form P before and after compression
图33晶型S压片前后的XRPD对比图Figure 33 XRPD comparison chart of crystal form S before and after compression
图34晶型A在25℃/60％相对湿度下稳定性测试的XRPD对比图Figure 34 XRPD comparison chart of crystal form A stability test at 25°C/60% relative humidity
图35晶型A在40℃/75％相对湿度下稳定性测试的XRPD对比图Figure 35 XRPD comparison chart of crystal form A stability test at 40°C/75% relative humidity
图36晶型B在25℃/60％相对湿度下稳定性测试的XRPD对比图Figure 36 XRPD comparison chart of crystal form B stability test at 25°C/60% relative humidity
图37晶型B在40℃/75％相对湿度下稳定性测试的XRPD对比图Figure 37 XRPD comparison chart of crystal form B stability test at 40°C/75% relative humidity
图38晶型E在25℃/60％相对湿度下稳定性测试的XRPD对比图Figure 38 XRPD comparison chart of crystal form E stability test at 25°C/60% relative humidity
图39晶型E在40℃/75％相对湿度下稳定性测试的XRPD对比图Figure 39 XRPD comparison chart of stability test of Form E at 40°C/75% relative humidity
图40晶型M在25℃/60％相对湿度下稳定性测试的XRPD对比图Figure 40 XRPD comparison chart of crystal form M stability test at 25°C/60% relative humidity
图41晶型M在40℃/75％相对湿度下稳定性测试的XRPD对比图Figure 41 XRPD comparison chart of crystal form M stability test at 40°C/75% relative humidity
图42晶型B的动态水分吸附图Figure 42 Dynamic moisture adsorption diagram of Form B
图43晶型B测试DVS前后的XRPD对比图Figure 43 XRPD comparison chart of Form B before and after DVS test
图44晶型M的动态水分吸附图Figure 44 Dynamic water adsorption diagram of crystal form M
图45晶型M测试DVS前后的XRPD对比图Figure 45 XRPD comparison chart of Form M test before and after DVS
图46 Form 2的动态水分吸附图Figure 46 Dynamic moisture adsorption diagram of Form 2
图47 Form 2测试DVS前后的XRPD对比图Figure 47 XRPD comparison chart of Form 2 before and after DVS test
图48晶型A的粒径分布图Figure 48 Particle size distribution of Form A
图49 Form 2的粒径分布图Figure 49 Particle size distribution of Form 2
具体实施方式Detailed ways
晶型AForm A
式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.1°±0.2°、16.0°±0.2°、21.7°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The type A crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has a 2θ value of There are characteristic peaks at 14.1°±0.2°, 16.0°±0.2°, 21.7°±0.2°,
Figure PCTCN2022114984-appb-000008
Figure PCTCN2022114984-appb-000008
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为7.8°±0.2°、9.4°±0.2°、18.7°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has one or two or three 2θ values of 7.8°±0.2°, 9.4°±0.2°, 18.7°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为7.8°±0.2°、9.4°±0.2°、18.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 7.8°±0.2°, 9.4°±0.2°, and 18.7°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为10.7°±0.2°、17.0°±0.2°、20.7°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has one or two or three 2θ values of 10.7°±0.2°, 17.0°±0.2°, 20.7°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为10.7°±0.2°、17.0°±0.2°、20.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has characteristic peaks at 2θ values of 10.7°±0.2°, 17.0°±0.2°, and 20.7°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为7.8°±0.2°、9.4°±0.2°、10.7°±0.2°、14.1°±0.2°、16.0°±0.2°、17.0°±0.2°、18.7°±0.2°、20.7°±0.2°、21.7°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 7.8°±0.2°, 9.4°±0.2°, 10.7°±0.2°, 14.1°±0.2°, 16.0°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.7°±0.2°, 21.7°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射在2θ值为7.8°±0.2°、9.4°±0.2°、10.7°±0.2°、14.1°±0.2°、16.0°±0.2°、17.0°±0.2°、18.7°±0.2°、20.7°±0.2°、21.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form A has a 2θ value of 7.8°±0.2°, 9.4°±0.2°, 10.7°±0.2°, 14.1°±0.2°, 16.0°±0.2° There are characteristic peaks at 0.2°, 17.0°±0.2°, 18.7°±0.2°, 20.7°±0.2°, 21.7°±0.2°.
在本发明的一个实施方式中，所述晶型A的X射线粉末衍射图如图1或图5所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form A is shown in Figure 1 or Figure 5 .
所述的晶型A的制备方法，其特征在于，The preparation method of the crystal form A is characterized in that,
将式(I)化合物固体加入至溶解于正溶剂中，搅拌状态下向其中逐滴加入反溶剂，直至有固体析出，得到晶型A。所述正溶剂为卤代烃类溶剂，所述反溶剂为烷烃类溶剂。The solid of the compound of formula (I) is added to dissolve in the positive solvent, and the anti-solvent is added dropwise thereto under stirring until a solid is precipitated to obtain the crystal form A. The positive solvent is a halogenated hydrocarbon solvent, and the anti-solvent is an alkane solvent.
在本发明的一个实施方式中，所述卤代烃类溶剂为二氯甲烷或氯仿，所述烷烃类溶剂为正庚烷或环己烷。In one embodiment of the present invention, the halogenated hydrocarbon solvent is dichloromethane or chloroform, and the alkane solvent is n-heptane or cyclohexane.
在本发明的一个实施方式中，所述溶解、滴加、搅拌和析出温度为10℃到50℃，例如20℃到30℃。In one embodiment of the present invention, the temperature of dissolution, dropping, stirring and precipitation is 10°C to 50°C, for example, 20°C to 30°C.
晶型BForm B
式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在2θ值为16.1°±0.2°、18.4°±0.2°、22.9°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The type B crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form B, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form B has a 2θ value of There are characteristic peaks at 16.1°±0.2°, 18.4°±0.2°, 22.9°±0.2°,
Figure PCTCN2022114984-appb-000009
Figure PCTCN2022114984-appb-000009
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为17.2°±0.2°、19.8°±0.2°、21.1°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has one or two or three 2θ values of 17.2°±0.2°, 19.8°±0.2°, 21.1°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为17.2°±0.2°、19.8°±0.2°、21.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has characteristic peaks at 2θ values of 17.2°±0.2°, 19.8°±0.2°, and 21.1°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为7.3°±0.2°、13.5°±0.2°、26.8°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has one or two or three 2θ values of 7.3°±0.2°, 13.5°±0.2°, 26.8°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为7.3°±0.2°、13.5°±0.2°、26.8°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has characteristic peaks at 2θ values of 7.3°±0.2°, 13.5°±0.2°, and 26.8°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为7.3°±0.2°、13.5°±0.2°、16.1°±0.2°、17.2°±0.2°、18.4°±0.2°、19.8°±0.2°、21.1°±0.2°、22.9°±0.2°、26.8°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has a 2θ value of 7.3°±0.2°, 13.5°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 18.4°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 19.8°±0.2°, 21.1°±0.2°, 22.9°±0.2°, 26.8°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射在2θ值为7.3°±0.2°、13.5°±0.2°、16.1°±0.2°、17.2°±0.2°、18.4°±0.2°、19.8°±0.2°、21.1°±0.2°、22.9°±0.2°、26.8°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form B has a 2θ value of 7.3°±0.2°, 13.5°±0.2°, 16.1°±0.2°, 17.2°±0.2°, 18.4°±0.2° There are characteristic peaks at 0.2°, 19.8°±0.2°, 21.1°±0.2°, 22.9°±0.2°, 26.8°±0.2°.
在本发明的一个实施方式中，所述晶型B的X射线粉末衍射图如图6所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form B is shown in FIG. 6 .
所述的晶型B的制备方法，其特征在于，The preparation method of the crystal form B is characterized in that,
将式(I)化合物固体加热至250℃，继而降温，得到晶型B。The solid compound of formula (I) was heated to 250°C, and then cooled to obtain Form B.
在本发明的一个实施方式中，所述式(I)化合物固体为晶型A。In one embodiment of the present invention, the solid compound of formula (I) is Form A.
在本发明的一个实施方式中，所述加热速率为10～30℃/分钟，例如10℃/分钟。In one embodiment of the present invention, the heating rate is 10˜30° C./minute, for example, 10° C./minute.
在本发明的一个实施方式中，所述降温为温度降至20～40℃，例如30℃。In one embodiment of the present invention, the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
晶型MForm M
式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的M型晶体、即晶型M，其特征在于，使用Cu-Kα辐射，所述晶型M的X射线粉末衍射在2θ值为15.4°±0.2°、20.2°±0.2°、21.2°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The M-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. the crystal form M, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form M has a 2θ value of There are characteristic peaks at 15.4°±0.2°, 20.2°±0.2°, 21.2°±0.2°,
Figure PCTCN2022114984-appb-000010
Figure PCTCN2022114984-appb-000010
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为7.5°±0.2°、14.4°±0.2°、17.7°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has one or two or three 2θ values of 7.5°±0.2°, 14.4°±0.2°, 17.7°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为7.5°±0.2°、14.4°±0.2°、17.7°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has characteristic peaks at 2θ values of 7.5°±0.2°, 14.4°±0.2°, and 17.7°±0.2°.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为10.8±0.2°、15.9°±0.2°、27.1°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has a 2θ value of 10.8±0.2°, 15.9°±0.2°, 27.1°±0.2° at one or two or three places Characteristic peaks.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为10.8±0.2°、15.9°±0.2°、27.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has characteristic peaks at 2θ values of 10.8±0.2°, 15.9°±0.2°, and 27.1°±0.2°.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为7.5°±0.2°、10.8°±0.2°、14.4°±0.2°、15.4°±0.2°、15.9°±0.2°、17.7°±0.2°、20.2°±0.2°、21.2°±0.2°、27.1°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has a 2θ value of 7.5°±0.2°, 10.8°±0.2°, 14.4°±0.2°, 15.4°±0.2°, 15.9°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 17.7°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 27.1°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射在2θ值为7.5°±0.2°、10.8°±0.2°、14.4°±0.2°、15.4°±0.2°、15.9°±0.2°、17.7°±0.2°、20.2°±0.2°、21.2°±0.2°、27.1°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form M has a 2θ value of 7.5°±0.2°, 10.8°±0.2°, 14.4°±0.2°, 15.4°±0.2°, 15.9°±0.2° There are characteristic peaks at 0.2°, 17.7°±0.2°, 20.2°±0.2°, 21.2°±0.2°, 27.1°±0.2°.
在本发明的一个实施方式中，所述晶型M的X射线粉末衍射图如图11所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form M is shown in FIG. 11 .
所述的晶型M的制备方法，其特征在于，The preparation method of the crystal form M is characterized in that,
将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至230℃，继而降温，得到晶型M。Add the solid compound of formula (I) into nitromethane, suspend and stir for a certain period of time, and collect the solid; heat the aforementioned solid to 230° C., and then cool down to obtain the crystal form M.
在本发明的一个实施方式中，所述式(I)化合物固体为晶型A。In one embodiment of the present invention, the solid compound of formula (I) is Form A.
在本发明的一个实施方式中，所述悬浮搅拌的温度为10～50℃，例如20～30℃。In one embodiment of the present invention, the temperature of the suspension stirring is 10-50°C, for example, 20-30°C.
在本发明的一个实施方式中，所述加热速率为10～40℃/分钟，例如10℃/分钟。In one embodiment of the present invention, the heating rate is 10˜40° C./minute, for example, 10° C./minute.
在本发明的一个实施方式中，所述降温为温度降至20～40℃，例如30℃。In one embodiment of the present invention, the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
在本发明的一个实施方式中，所述悬浮搅拌的时间为8～30天，例如25天。In one embodiment of the present invention, the suspension stirring time is 8-30 days, such as 25 days.
晶型PForm P
1.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H- 异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的P型晶体、即晶型P，其特征在于，使用Cu-Kα辐射，所述晶型P的X射线粉末衍射在2θ值为11.0°±0.2°、18.6°±0.2°、20.1°±0.2°处有特征峰，1. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 shown in formula (I) ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- The P-type crystal of 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. the crystal form P, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form P is at 2θ There are characteristic peaks at 11.0°±0.2°, 18.6°±0.2°, 20.1°±0.2°,
Figure PCTCN2022114984-appb-000011
Figure PCTCN2022114984-appb-000011
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为7.3°±0.2°、13.8°±0.2°、22.2°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has a 2θ value of 7.3°±0.2°, 13.8°±0.2°, 22.2°±0.2° at one or two or three places have characteristic peaks.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为7.3°±0.2°、13.8°±0.2°、22.2°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has characteristic peaks at 2θ values of 7.3°±0.2°, 13.8°±0.2°, and 22.2°±0.2°.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为17.2°±0.2°、25.3°±0.2°、25.9°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has one or two or three 2θ values of 17.2°±0.2°, 25.3°±0.2°, and 25.9°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为17.2°±0.2°、25.3°±0.2°、25.9°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has characteristic peaks at 2θ values of 17.2°±0.2°, 25.3°±0.2°, and 25.9°±0.2°.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为7.3°±0.2°、11.0°±0.2°、13.8°±0.2°、17.2°±0.2°、18.6°±0.2°、20.1°±0.2°、22.2°±0.2°、25.3°±0.2°、25.9°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has a 2θ value of 7.3°±0.2°, 11.0°±0.2°, 13.8°±0.2°, 17.2°±0.2°, 18.6°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.1°±0.2°, 22.2°±0.2°, 25.3°±0.2°, 25.9°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射在2θ值为7.3°±0.2°、11.0°±0.2°、13.8°±0.2°、17.2°±0.2°、18.6°±0.2°、20.1°±0.2°、22.2°±0.2°、25.3°±0.2°、25.9°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form P has a 2θ value of 7.3°±0.2°, 11.0°±0.2°, 13.8°±0.2°, 17.2°±0.2°, 18.6°±0.2° There are characteristic peaks at 0.2°, 20.1°±0.2°, 22.2°±0.2°, 25.3°±0.2°, 25.9°±0.2°.
在本发明的一个实施方式中，所述晶型P的X射线粉末衍射图如图15或图19所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form P is shown in Figure 15 or Figure 19 .
所述的晶型P的制备方法，其特征在于，The preparation method of the crystal form P is characterized in that,
将式(I)化合物固体溶解于卤代烃类溶剂中，搅拌状态下向其中逐滴加入烷基腈类溶剂，直至产生胶状物；将溶液挥发，得到晶型P。The solid compound of formula (I) is dissolved in a halogenated hydrocarbon solvent, and an alkyl nitrile solvent is added dropwise thereto under stirring until a jelly-like substance is produced; the solution is volatilized to obtain Form P.
在本发明的一个实施方式中，所述卤代烃类溶剂为氯仿，烷基腈类溶剂为乙腈。In one embodiment of the present invention, the halogenated hydrocarbon solvent is chloroform, and the alkyl nitrile solvent is acetonitrile.
在本发明的一个实施方式中，所述溶解、挥发的温度为10～50℃，例如20～30℃。In one embodiment of the present invention, the dissolution and volatilization temperature is 10-50°C, for example, 20-30°C.
晶型SForm S
式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的S型晶体、即晶型S，其特征在于，使用Cu-Kα辐射，所述晶型S的X射线粉末衍射在2θ值为15.7°±0.2°、16.6°±0.2°、22.7°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The S-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form S, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form S has a 2θ value of There are characteristic peaks at 15.7°±0.2°, 16.6°±0.2°, 22.7°±0.2°,
Figure PCTCN2022114984-appb-000012
Figure PCTCN2022114984-appb-000012
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为11.6°±0.2°、17.6°±0.2°、23.3°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has one or two or three 2θ values of 11.6°±0.2°, 17.6°±0.2°, 23.3°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为11.6°±0.2°、17.6°±0.2°、23.3°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has characteristic peaks at 2θ values of 11.6°±0.2°, 17.6°±0.2°, and 23.3°±0.2°.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为18.6±0.2°、20.2°±0.2°、25.6°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has a 2θ value of 18.6±0.2°, 20.2°±0.2°, 25.6°±0.2° at one or two or three places Characteristic peaks.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为18.6±0.2°、20.2°±0.2°、25.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has characteristic peaks at 2θ values of 18.6±0.2°, 20.2°±0.2°, and 25.6°±0.2°.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为11.6°±0.2°、15.7°±0.2°、16.6°±0.2°、17.6°±0.2°、18.6°±0.2°、20.2°±0.2°、22.7°±0.2°、23.3°±0.2°、25.6°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has a 2θ value of 11.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 17.6°±0.2°, 18.6°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 20.2°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 25.6°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射在2θ值为11.6°±0.2°、15.7°±0.2°、16.6°±0.2°、17.6°±0.2°、18.6°±0.2°、20.2°±0.2°、22.7°±0.2°、23.3°±0.2°、25.6°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form S has a 2θ value of 11.6°±0.2°, 15.7°±0.2°, 16.6°±0.2°, 17.6°±0.2°, 18.6°±0.2° There are characteristic peaks at 0.2°, 20.2°±0.2°, 22.7°±0.2°, 23.3°±0.2°, 25.6°±0.2°.
在本发明的一个实施方式中，所述晶型S的X射线粉末衍射图如图20所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form S is shown in FIG. 20 .
所述的晶型S的制备方法，其特征在于，The preparation method of the crystal form S is characterized in that,
将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至150℃，继而降温，得到晶型S。The solid compound of formula (I) was added to nitromethane, suspended and stirred for a certain period of time, and the solid was collected; the aforementioned solid was heated to 150° C., and then cooled to obtain the crystal form S.
在本发明的一个实施方式中，所述式(I)化合物固体为晶型A。In one embodiment of the present invention, the solid compound of formula (I) is Form A.
在本发明的一个实施方式中，所述悬浮搅拌的温度为10～50℃，例如20～30℃。In one embodiment of the present invention, the temperature of the suspension stirring is 10-50°C, for example, 20-30°C.
在本发明的一个实施方式中，所述加热速率为10～40℃/分钟，例如10℃/分钟。In one embodiment of the present invention, the heating rate is 10˜40° C./minute, for example, 10° C./minute.
在本发明的一个实施方式中，所述降温为温度降至20～40℃，例如30℃。In one embodiment of the present invention, the lowering of temperature is lowering the temperature to 20-40°C, such as 30°C.
在本发明的一个实施方式中，所述悬浮搅拌的时间为8～30天，例如25天。In one embodiment of the present invention, the suspension stirring time is 8-30 days, such as 25 days.
晶型EForm E
1.式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的E型晶体、即晶型E，其特征在于，使用Cu-Kα辐射，所述晶型E的X射线粉末衍射在2θ值为11.1°±0.2°、18.5°±0.2°、21.0°±0.2°处有特征峰，1. Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2 shown in formula (I) ,3-Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro- 4-cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide type E crystal, i.e. crystal form E, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form E is at 2θ There are characteristic peaks at 11.1°±0.2°, 18.5°±0.2°, 21.0°±0.2°,
Figure PCTCN2022114984-appb-000013
Figure PCTCN2022114984-appb-000013
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为5.6°±0.2°、12.5°±0.2°、19.2°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has one or two or three 2θ values of 5.6°±0.2°, 12.5°±0.2°, 19.2°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为5.6°±0.2°、12.5°±0.2°、19.2°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has characteristic peaks at 2θ values of 5.6°±0.2°, 12.5°±0.2°, and 19.2°±0.2°.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为9.0°±0.2°、17.8°±0.2°、24.5°±0.2°中的一处或两处或三处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has one or two or three 2θ values of 9.0°±0.2°, 17.8°±0.2°, 24.5°±0.2° have characteristic peaks.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为9.0°±0.2°、17.8°±0.2°、24.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has characteristic peaks at 2θ values of 9.0°±0.2°, 17.8°±0.2°, and 24.5°±0.2°.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为5.6°±0.2°、9.0°±0.2°、11.1°±0.2°、12.5°±0.2°、17.8°±0.2°、18.5°±0.2°、19.2°±0.2°、21.0°±0.2°、24.5°±0.2°中的任意4处、或5处、或6处、或7处、或8处、或9处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has a 2θ value of 5.6°±0.2°, 9.0°±0.2°, 11.1°±0.2°, 12.5°±0.2°, 17.8°±0.2° Any 4, or 5, or 6, or 7, or 8, or 9 of 0.2°, 18.5°±0.2°, 19.2°±0.2°, 21.0°±0.2°, 24.5°±0.2° There are characteristic peaks.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射在2θ值为5.6°±0.2°、9.0°±0.2°、11.1°±0.2°、12.5°±0.2°、17.8°±0.2°、18.5°±0.2°、19.2°±0.2°、21.0°±0.2°、24.5°±0.2°处有特征峰。In one embodiment of the present invention, the X-ray powder diffraction of the crystal form E has a 2θ value of 5.6°±0.2°, 9.0°±0.2°, 11.1°±0.2°, 12.5°±0.2°, 17.8°±0.2° There are characteristic peaks at 0.2°, 18.5°±0.2°, 19.2°±0.2°, 21.0°±0.2°, 24.5°±0.2°.
在本发明的一个实施方式中，所述晶型E的X射线粉末衍射图如图23所示。In one embodiment of the present invention, the X-ray powder diffraction pattern of the crystal form E is shown in FIG. 23 .
所述的晶型E的制备方法，其特征在于，The preparation method of the crystal form E is characterized in that,
(1)将式(I)化合物固体加入至溶剂中，悬浮搅拌，得到晶型E。所述溶剂为纯水、醇类、芳香烃类的单一或混合溶剂。(1) Add the solid compound of formula (I) into the solvent, suspend and stir to obtain the crystal form E. The solvent is a single or mixed solvent of pure water, alcohols, and aromatic hydrocarbons.
在本发明的一个实施方式中，所述式(I)化合物固体为晶型A或无定形。In one embodiment of the present invention, the solid compound of formula (I) is crystal form A or amorphous.
在本发明的一个实施方式中，所述醇类溶剂包括甲醇、乙醇，芳香烃类溶剂包括甲苯、间二甲苯。In one embodiment of the present invention, the alcohol solvent includes methanol and ethanol, and the aromatic hydrocarbon solvent includes toluene and m-xylene.
在本发明的一个实施方式中，所述混合溶剂包括甲醇/纯水、乙醇/纯水。In one embodiment of the present invention, the mixed solvent includes methanol/pure water, ethanol/pure water.
在本发明的一个实施方式中，所述甲醇/纯水的体积比为0.5～4:1，例如1:1；所述乙醇/纯水的体积比为80～100:8，例如92:8。In one embodiment of the present invention, the volume ratio of methanol/pure water is 0.5-4:1, such as 1:1; the volume ratio of ethanol/pure water is 80-100:8, such as 92:8 .
在本发明的一个实施方式中，所述悬浮搅拌的温度为-5～50℃，例如20～30℃，或5℃。In one embodiment of the present invention, the temperature of the suspension stirring is -5-50°C, such as 20-30°C, or 5°C.
在本发明的一个实施方式中，所述悬浮搅拌的时间为3～15天，例如8天。In one embodiment of the present invention, the suspension stirring time is 3-15 days, for example, 8 days.
(2)将式(I)化合物固体置于芳香烃类溶剂氛围下进行气固扩散，得到晶型E。(2) The solid compound of formula (I) is placed in an aromatic hydrocarbon solvent atmosphere for gas-solid diffusion to obtain crystal form E.
在本发明的一个实施方式中，所述芳香烃类溶剂为甲苯。In one embodiment of the present invention, the aromatic hydrocarbon solvent is toluene.
在本发明的一个实施方式中，所述气固扩散温度为10～50℃，例如20～30℃。In one embodiment of the present invention, the gas-solid diffusion temperature is 10-50°C, for example, 20-30°C.
在本发明的一个实施方式中，所述式(I)化合物固体为无定形。In one embodiment of the present invention, the solid compound of formula (I) is amorphous.
在本发明的一个实施方式中，所述气固扩散的时间为5～14天，例如7天。In one embodiment of the present invention, the gas-solid diffusion time is 5-14 days, for example, 7 days.
(3)将式(I)化合物固体溶解于正溶剂中，搅拌状态下向其中逐滴加入反溶剂，直至有固体析出，得到晶型E。所述正溶剂包括卤代烃类、环醚类溶剂，所述反溶剂包括芳香烃类、醇类溶剂。(3) Dissolving the solid compound of formula (I) in a positive solvent, and adding an anti-solvent dropwise thereto under stirring until a solid precipitates out to obtain crystal form E. The positive solvent includes halogenated hydrocarbons and cyclic ether solvents, and the anti-solvent includes aromatic hydrocarbons and alcohol solvents.
在本发明的一个实施方式中，所述正溶剂中，卤代烃类溶剂为氯仿，环醚类溶剂为四氢呋喃；所述反溶剂中，芳香烃类溶剂为甲苯，醇类溶剂为甲醇。In one embodiment of the present invention, in the positive solvent, the halogenated hydrocarbon solvent is chloroform, and the cyclic ether solvent is tetrahydrofuran; in the anti-solvent, the aromatic hydrocarbon solvent is toluene, and the alcohol solvent is methanol.
在本发明的一个实施方式中，所述溶解、滴加、搅拌和析出温度为10℃到50℃，例如20℃到30℃。In one embodiment of the present invention, the temperature of dissolution, dropping, stirring and precipitation is 10°C to 50°C, for example, 20°C to 30°C.
根据本发明，作为原料的所述式(I)化合物指其固体(晶体或无定形)、半固体、蜡或油形式。优选地，作为原料的式(I)化合物为固体粉末形式。所述“搅拌”，采用本领域的常规方法完成，例如磁力搅拌或机械搅拌，搅拌速度为50～1800转/分钟，其中，磁力搅拌 200～1500转/分钟，优选为300～1000转/分钟，机械搅拌优选为100～300转/分钟。According to the present invention, said compound of formula (I) as starting material refers to its solid (crystalline or amorphous), semi-solid, waxy or oily form. Preferably, the compound of formula (I) as starting material is in the form of a solid powder. The "stirring" is accomplished by conventional methods in this field, such as magnetic stirring or mechanical stirring, and the stirring speed is 50-1800 rpm, wherein the magnetic stirring is 200-1500 rpm, preferably 300-1000 rpm , The mechanical stirring is preferably 100 to 300 rpm.
上述本发明的晶体可以用于制备药物组合物，在制备药物组合物时含有上述本发明的晶体和制药学可接受的载体。上述本发明的晶体可以用于制备具有AR降解促进活性的药物组合物，其包含上述本发明的晶体作为有效成分。上述本发明的晶体可以用于制备前列腺癌的预防药或治疗药，其包含上述本发明的晶体作为有效成分。The above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition, which contains the above-mentioned crystals of the present invention and a pharmaceutically acceptable carrier. The above-mentioned crystals of the present invention can be used to prepare a pharmaceutical composition having AR degradation promoting activity, which comprises the above-mentioned crystals of the present invention as an active ingredient. The above-mentioned crystals of the present invention can be used in the preparation of prophylactic or therapeutic drugs for prostate cancer, which contain the above-mentioned crystals of the present invention as active ingredients.
本发明还提供药物组合物，其包含上述本发明的晶体和制药学可接受的载体。The present invention also provides a pharmaceutical composition comprising the above-mentioned crystal of the present invention and a pharmaceutically acceptable carrier.
本发明还提供具有AR降解促进活性的药物组合物，其含有上述本发明的晶体作为有效成分。The present invention also provides a pharmaceutical composition having AR degradation-promoting activity, which contains the above-mentioned crystal of the present invention as an active ingredient.
本发明提供前列腺癌的预防药或治疗药，其含有上述本发明的晶体作为有效成分。The present invention provides a prophylactic or therapeutic drug for prostate cancer, which contains the above-mentioned crystal of the present invention as an active ingredient.
本发明中，“晶体”或“多晶型”指的是被所示的X射线衍射图表征所证实的。本领域技术人员能够理解，这里所讨论的理化性质可以被表征，其中的实验误差取决于仪器的条件、样品的准备和样品的纯度。特别是，本领域技术人员公知，X射线衍射图通常会随着仪器的条件而有所改变。特别需要指出的是，X射线衍射图的相对强度也可能随着实验条件的变化而变化，所以峰强度的顺序不能作为唯一或决定性因素。事实上，X射线衍射图中衍射峰的相对强度与晶体的择优取向有关，本文所示的峰强度为说明性而非用于绝对比较。另外，峰角度的实验误差通常在5％或更少，这些角度的误差也应该被考虑进去，通常允许有±0.2°的误差。另外，由于样品厚度等实验因素的影响，会造成峰角度的整体偏移，通常允许一定的偏移。因而，本领域技术人员可以理解的是，本发明中一个晶型的X射线衍射图不必和这里所指的例子中的X射线衍射图完全一致，本文所述“X射线衍射图相同”并非指绝对相同，相同峰位置可相差±0.2°且峰强度允许一定可变性。任何具有和这些图谱中的特征峰相同或相似的图的晶型均属于本发明的范畴之内。本领域技术人员能够将本发明所列的图谱和一个未知晶型的图谱相比较，以证实这两组图谱反映的是相同还是不同的晶型。In the present invention, "crystal" or "polymorph" refers to what is characterized by the shown X-ray diffraction pattern. Those skilled in the art will appreciate that the physicochemical properties discussed herein can be characterized with experimental error depending on instrument conditions, sample preparation, and sample purity. In particular, it is well known to those skilled in the art that X-ray diffraction patterns often vary with the conditions of the instrument. In particular, it should be pointed out that the relative intensity of the X-ray diffraction pattern may also vary with the experimental conditions, so the order of peak intensities cannot be used as the only or decisive factor. In fact, the relative intensity of the diffraction peaks in the X-ray diffraction pattern is related to the preferred orientation of the crystal, and the peak intensities shown here are illustrative rather than for absolute comparison. In addition, 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 the error of ±0.2° is usually allowed. In addition, due to the influence of experimental factors such as sample thickness, it will cause the overall deviation of the peak angle, and a certain deviation is usually allowed. Therefore, those skilled in the art can understand that the X-ray diffraction pattern of a crystal form in the present invention does not have to be completely consistent with the X-ray diffraction pattern in the example referred to here, and the "same X-ray diffraction pattern" mentioned herein does not mean Absolutely identical, identical peak positions may differ by ±0.2° and peak intensities allow for some variability. Any crystal form having the same or similar pattern as the characteristic peaks in these patterns falls within the scope of the present invention. Those skilled in the art can compare the spectrum listed in the present invention with the spectrum of an unknown crystal form to confirm whether the two sets of spectrum reflect the same or different crystal forms.
在一些实施方案中，本发明的晶型是纯的、单一的，基本没有混合任何其他晶型。本发明中，“基本没有”当用来指新晶型时指这个晶型含有少于20％(重量)的其他晶型，尤其指少于10％(重量)的其他晶型，更指少于5％(重量)的其他晶型，更指少于1％(重量)的其他晶型。需要说明的是，本发明中提及的数值及数值范围不应被狭隘地理解为数值或数值范围本身，本领域技术人员应当理解其可以根据具体技术环境的不同，在不背离本发明精神和原则的基础上围绕具体数值有所浮动，本发明中，这种本领域技术人员可预见的浮动范围多以术语“约”来表示。In some embodiments, the crystalline form of the invention is pure, single, substantially free of any other crystalline forms. In the present invention, "substantially free" when used to refer to a new crystal form means that this crystal form contains less than 20% (weight) of other crystal forms, especially refers to less than 10% (weight) of other crystal forms, and even less More than 5% (weight) of other crystal forms, more refers to less than 1% (weight) of other crystal forms. It should be noted that the numerical values and numerical ranges mentioned in the present invention should not be narrowly interpreted as numerical values or numerical ranges themselves, and those skilled in the art should understand that they can vary according to the specific technical environment without departing from the spirit and scope of the present invention. There are fluctuations around specific numerical values on the basis of principles, and in the present invention, such fluctuation ranges that are foreseeable by those skilled in the art are often expressed by the term "about".
本发明说明书中记载的数值范围的上限值和下限值可以任意地组合。The upper limit and lower limit of the numerical range described in the specification of the present invention can be combined arbitrarily.
实施例Example
以下将通过具体实施例进一步阐述本发明，但并不用于限制本发明的保护范围。本领域技术人员可在权利要求范围内对制备方法和使用仪器作出改进，这些改进也应视为本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。The following will further illustrate the present invention through specific examples, but it is not intended to limit the protection scope of the present invention. Those skilled in the art can make improvements to the preparation method and the equipment used within the scope of the claims, and these improvements should also be considered as the protection scope of the present invention. Therefore, the protection scope of the patent for the present invention should be based on the appended claims.
本发明中“室温”如果没有特别说明，通常是指22℃到28℃。"Room temperature" in the present invention usually refers to 22°C to 28°C unless otherwise specified.
本发明中所用到的缩写的解释如下：The abbreviations used in the present invention are explained as follows:
XRPD：X射线粉末衍射XRPD: X-ray powder diffraction
DSC：差示扫描量热分析DSC: Differential Scanning Calorimetry
TGA：热重分析TGA: Thermal Gravimetric Analysis
1H NMR：核磁共振氢谱 1 H NMR: Proton Magnetic Resonance Spectroscopy
DVS：动态水分吸附DVS: Dynamic Moisture Sorption
PSD：粒径分布PSD: Particle Size Distribution
PLM：偏光显微镜PLM: polarized light microscope
HPLC：高效液相色谱HPLC: High Performance Liquid Chromatography
本发明所述的X射线粉末衍射图在Panalytical(帕纳科)公司的Empyrean型及X'Pert 3型X射线粉末衍射仪上采集。本发明所述的X射线粉末衍射的方法参数如下： The X-ray powder diffraction patterns described in the present invention were collected on Empyrean type and X'Pert 3 type X-ray powder diffractometers of Panalytical (Panalytical) Company. The method parameter of X-ray powder diffraction of the present invention is as follows:
X射线光源：Cu,KαX-ray light source: Cu, Kα
Kα1
Figure PCTCN2022114984-appb-000014
1.54060；Kα2
Figure PCTCN2022114984-appb-000015
1.54443 Kα1
Figure PCTCN2022114984-appb-000014
1.54060; Kα2
Figure PCTCN2022114984-appb-000015
1.54443
Kα2/Kα1强度比例：0.50Kα2/Kα1 intensity ratio: 0.50
电压：45千伏特(kV)Voltage: 45 kilovolts (kV)
电流：40毫安培(mA)Current: 40 milliamps (mA)
扫描范围：自3.0至40.0度(2θ角)Scanning range: from 3.0 to 40.0 degrees (2θ angle)
本发明所述的差示扫描量热分析图在TA公司的Q200型及Discovery DSC 2500型差示扫描量热仪上采集。本发明所述的差示扫描量热分析的方法参数如下：The differential scanning calorimetry chart of the present invention is collected on the Q200 type and Discovery DSC 2500 type differential scanning calorimeter of TA company. The method parameter of differential scanning calorimetry analysis of the present invention is as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
本发明所述的热重分析图在TA公司的Discovery TGA 5500型及Q5000型热重分析仪上采集。本发明所述的热重分析的方法参数如下：The thermogravimetric analysis figure of the present invention is collected on the Discovery TGA 5500 type of TA company and Q5000 type thermogravimetric analyzer. The method parameter of thermogravimetric analysis of the present invention is as follows:
扫描速率：10℃/分钟Scan rate: 10°C/min
保护气体：氮气Protective gas: nitrogen
本发明所述的核磁共振氢谱数据( 1H NMR)采自于Bruker Avance II DMX 400M HZ核磁共振波谱仪。称量1-5mg样品，用0.5mL氘代二甲亚砜溶解，配制成2-10mg/mL的溶液进行测试。 The proton nuclear magnetic resonance spectrum data ( 1 H NMR) described in the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. Weigh 1-5mg sample, dissolve it with 0.5mL deuterated dimethyl sulfoxide, and prepare a 2-10mg/mL solution for testing.
本发明所述的动态水分吸附图在SMS公司的Intrinsic型及Intrinsic Plus型动态水分吸附仪上采集。本发明所述的动态水分吸附测试的方法参数如下：The dynamic moisture adsorption figure 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:
温度：25℃Temperature: 25°C
保护气体及流量：N 2，200毫升/分钟 Protective gas and flow rate: N 2 , 200ml/min
dm/dt：0.002％/分钟dm/dt: 0.002%/min
最小dm/dt平衡时间：10分钟Minimum dm/dt balance time: 10 minutes
最大平衡时间：180分钟Maximum equilibration time: 180 minutes
相对湿度范围：0％RH-95％RH-0％RHRelative humidity range: 0%RH-95%RH-0%RH
相对湿度梯度：10％(0％RH-90％RH-0％RH)、5％(90％RH-95％RH和95％RH-90％RH)Relative humidity gradient: 10% (0%RH-90%RH-0%RH), 5% (90%RH-95%RH and 95%RH-90%RH)
本发明中所述的粒径分布结果是在Microtrac公司的S3500型激光粒度分析仪上采集。Microtrac S3500配备SDC(Sample Delivery Controller)进样系统。本测试采用湿法，测试分散介质为Isopar G(含0.2％卵磷脂)。所述的激光粒度分析仪的方法参数如下：The particle size distribution results described in the present invention are collected on the S3500 laser particle size analyzer of Microtrac Company. Microtrac S3500 is equipped with SDC (Sample Delivery Controller) sampling system. This test adopts wet method, and the test dispersion medium is Isopar G (containing 0.2% lecithin). The method parameter of described laser particle size analyzer is as follows:
粒度分布：体积分布Particle Size Distribution: Volume Distribution 采集时间：10秒Collection time: 10 seconds
分散介质：Isopar GDispersion medium: Isopar G 粒度坐标：标准Grain Coordinates: Standard
采集次数：3次Collection times: 3 times 分散介质折射率：1.42Dispersion medium refractive index: 1.42
透明度：透明Transparency: transparent 残差：启用residuals: enabled
颗粒折射率：1.59Particle Refractive Index: 1.59 流速：60％*Flow Rate: 60%*
颗粒形状：不规则Particle shape: irregular 过滤：启用Filtering: Enabled
超声功率：30瓦Ultrasonic power: 30 watts 超声时间：超声30sUltrasound time: Ultrasound 30s
*：流速60％为65mL/s的60％*: Flow rate 60% is 60% of 65mL/s
本发明中所述的固有溶出速率数据是在Agilent公司的Agilent 708DS型溶出仪上采集。所述的固有溶出测试条件如下：The inherent dissolution rate data described in the present invention is collected on the Agilent 708DS type dissolution apparatus of Agilent Company. The inherent dissolution test conditions described are as follows:
溶出仪Dissolution Apparatus Agilent 708DSAgilent 708DS
方法method 桨法Paddle
介质medium pH 6.8磷酸盐缓冲液pH 6.8 Phosphate Buffer
介质体积Medium volume 900mL900mL
转速Rotating speed 100rpm100rpm
介质温度Medium temperature 37℃37° C
取样点Sampling point 1,2,3,4,5,10,15,20,25,30min1,2,3,4,5,10,15,20,25,30min
补充介质supplementary medium Nono
本发明中所述的偏光显微镜照片是通过蔡司显微镜Axio Scope.A1在室温条件下采集，显微镜配备Axiocam 305彩色相机以及5×、10×、20×和50×物镜。The polarizing microscope photos described in the present invention were collected at room temperature by Zeiss microscope Axio Scope.A1, and the microscope was equipped with Axiocam 305 color camera and 5×, 10×, 20× and 50× objective lenses.
下述实施例中所使用的式(I)化合物可以通过商业渠道购买获得。The compounds of formula (I) used in the following examples can be purchased from commercial sources.
实施例1～2：晶型A的制备 Embodiment 1～2: the preparation of crystal form A
室温条件下称取适量的式(I)化合物固体置于3.0毫升的玻璃小瓶中，加入相应溶剂溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入相应反溶剂，直至固体析出，得到晶型A。Weigh an appropriate amount of formula (I) compound solid in a 3.0 ml glass vial at room temperature, add the corresponding solvent to dissolve the solid, and filter the sample solution into a 20 ml glass vial using a polytetrafluoroethylene filter membrane with a pore size of 0.45 micron to obtain Clear solution. Then, under magnetic stirring (about 500 r/min), the corresponding anti-solvent was added dropwise therein until the solid precipitated to obtain the crystal form A.
本实施例中所涉详细试验条件如表1所示，实施例1样品的X射线粉末衍射数据如表2所示。其XRPD、TGA、DSC和 1H NMR分别如图1～4所示。 The detailed test conditions involved in this example are shown in Table 1, and the X-ray powder diffraction data of the sample in Example 1 are shown in Table 2. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 1 to 4, respectively.
表1Table 1
实施例Example 质量(毫克)Mass (mg) 溶剂solvent 体积(毫升)Volume (ml) 反溶剂Anti-solvent 体积(毫升)Volume (ml)
11 20.420.4 二氯甲烷Dichloromethane 2.02.0 正庚烷n-heptane 2.02.0
22 20.720.7 氯仿Chloroform 1.01.0 环己烷Cyclohexane 1.01.0
表2Table 2
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
4.844.84 18.2418.24 15.9715.97
7.127.12 12.4212.42 24.2324.23
7.807.80 11.3411.34 57.3457.34
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
9.439.43 9.389.38 62.1162.11
9.759.75 9.079.07 23.2923.29
10.7210.72 8.258.25 45.0445.04
12.6912.69 6.986.98 8.178.17
14.1114.11 6.286.28 80.5380.53
16.0116.01 5.545.54 100.00100.00
17.0217.02 5.215.21 23.3923.39
17.8317.83 4.984.98 16.6216.62
18.6718.67 4.754.75 84.8684.86
18.9618.96 4.684.68 63.5063.50
20.0320.03 4.434.43 35.3835.38
20.6820.68 4.304.30 61.5861.58
21.7721.77 4.084.08 84.4684.46
22.8322.83 3.903.90 20.0620.06
23.1523.15 3.843.84 8.748.74
23.5823.58 3.773.77 10.7910.79
24.6724.67 3.613.61 9.229.22
25.8025.80 3.453.45 10.7510.75
28.3428.34 3.153.15 6.986.98
29.5229.52 3.033.03 8.338.33
实施例3：晶型A的制备Embodiment 3: the preparation of crystal form A
室温条件下称取499.7毫克的式(I)化合物固体置于100毫升的玻璃小瓶中，加入50毫升二氯甲烷溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至100毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入60毫升正庚烷，直至固体析出，得到晶型A。其X射线粉末衍射数据如表3所示。该样品在约7.8°±0.2°、约9.4°±0.2°、约10.7°±0.2°、约11.9°±0.2°、约14.1°±0.2°、约16.0°±0.2°、约17.0°±0.2°、约18.7°±0.2°、约19.1°±0.2°、约20.7°±0.2°、约21.7°±0.2°处有特征峰。其XRPD如图5所示。Weigh 499.7 mg of the solid compound of formula (I) at room temperature and place it in a 100 ml glass vial, add 50 ml of dichloromethane to dissolve the solid, and filter the sample solution to 100 ml using a polytetrafluoroethylene filter membrane with a 0.45 micron pore size A clear solution was obtained in a glass vial. Then, under magnetic stirring (about 500 r/min), 60 ml of n-heptane was added dropwise therein until solids were precipitated to obtain Form A. Its X-ray powder diffraction data are shown in Table 3. The sample is at about 7.8°±0.2°, about 9.4°±0.2°, about 10.7°±0.2°, about 11.9°±0.2°, about 14.1°±0.2°, about 16.0°±0.2°, about 17.0°±0.2 °, about 18.7°±0.2°, about 19.1°±0.2°, about 20.7°±0.2°, and about 21.7°±0.2° have characteristic peaks. Its XRPD is shown in FIG. 5 .
表3table 3
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
4.834.83 18.3118.31 12.7712.77
7.137.13 12.4012.40 14.8014.80
7.817.81 11.3311.33 25.3625.36
9.429.42 9.389.38 43.7843.78
9.759.75 9.089.08 17.8517.85
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
10.7510.75 8.238.23 29.8529.85
11.9411.94 7.417.41 9.339.33
12.6012.60 7.037.03 10.0610.06
14.1314.13 6.276.27 70.8370.83
16.0116.01 5.545.54 76.4776.47
17.0317.03 5.215.21 28.3828.38
17.3517.35 5.115.11 20.3620.36
17.7917.79 4.994.99 19.6019.60
18.7618.76 4.734.73 100.00100.00
20.0320.03 4.434.43 42.3842.38
20.6720.67 4.304.30 69.4569.45
21.0021.00 4.234.23 41.7541.75
21.7621.76 4.094.09 94.1494.14
22.8822.88 3.893.89 29.3429.34
23.5423.54 3.783.78 16.3616.36
24.6924.69 3.613.61 13.3713.37
25.7425.74 3.463.46 16.2116.21
26.5926.59 3.353.35 12.1912.19
28.1828.18 3.173.17 14.3714.37
28.5728.57 3.123.12 10.2510.25
29.5829.58 3.023.02 12.4112.41
30.3830.38 2.942.94 10.1210.12
32.3132.31 2.772.77 5.395.39
34.2234.22 2.622.62 4.274.27
35.7235.72 2.512.51 1.361.36
37.7237.72 2.382.38 3.703.70
实施例4：晶型B的制备Embodiment 4: the preparation of crystal form B
室温条件下称取适量的实施例3式(I)化合物固体置于DSC坩埚中，以10℃/分钟的速率加热至250℃，并保温3分钟，继而以30℃/分钟的速率降温至30℃，得到晶型B。其X射线粉末衍射数据如表4所示。该样品在约7.3°±0.2°、约13.5°±0.2°、约16.1°±0.2°、约17.2°±0.2°、约17.7°±0.2°、约18.4°±0.2°、约19.8°±0.2°、约21.1°±0.2°、约21.6°±0.2°、约22.9°±0.2°、约26.8°±0.2°处有特征峰。其XRPD、TGA、DSC和 1H NMR分别如图6～9所示。 Weigh an appropriate amount of the compound of formula (I) in Example 3 at room temperature and place it in a DSC crucible, heat it to 250°C at a rate of 10°C/min, keep it warm for 3 minutes, and then cool it down to 30°C at a rate of 30°C/min. °C, the crystal form B was obtained. Its X-ray powder diffraction data are shown in Table 4. The sample is at about 7.3°±0.2°, about 13.5°±0.2°, about 16.1°±0.2°, about 17.2°±0.2°, about 17.7°±0.2°, about 18.4°±0.2°, about 19.8°±0.2 °, about 21.1°±0.2°, about 21.6°±0.2°, about 22.9°±0.2°, and about 26.8°±0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 6-9, respectively.
表4Table 4
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
6.566.56 13.4613.46 9.829.82
7.297.29 12.1312.13 11.3111.31
7.727.72 11.4511.45 3.203.20
13.5313.53 6.546.54 9.489.48
16.0916.09 5.515.51 38.0838.08
17.1917.19 5.165.16 29.9329.93
17.6817.68 5.025.02 30.3130.31
18.3718.37 4.834.83 100.00100.00
19.8119.81 4.484.48 17.2917.29
21.0721.07 4.224.22 21.8621.86
21.6121.61 4.114.11 24.6324.63
22.8922.89 3.893.89 30.5730.57
23.8323.83 3.733.73 5.655.65
25.5925.59 3.483.48 6.296.29
26.7626.76 3.333.33 11.7311.73
28.0928.09 3.183.18 3.123.12
29.4029.40 3.043.04 2.352.35
31.2131.21 2.872.87 1.971.97
35.3135.31 2.542.54 0.770.77
实施例5：无定形的制备Embodiment 5: the preparation of amorphous
室温条件下称取604.7毫克的式(I)化合物固体置于20毫升玻璃小瓶中，加入12毫升四氢呋喃溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至100毫升圆底烧瓶中得到澄清溶液。使用旋转蒸发仪在45℃水浴下，旋蒸移除溶剂。收集固体，得到无定形。其XRPD如图10所示。Weigh 604.7 mg of the solid compound of formula (I) at room temperature and place it in a 20 ml glass vial, add 12 ml of tetrahydrofuran to dissolve the solid, and filter the sample solution into a 100 ml round bottom flask using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm A clear solution was obtained. Using a rotary evaporator in a water bath at 45°C, the solvent was removed by rotary evaporation. The solid was collected to give an amorphous form. Its XRPD is shown in FIG. 10 .
实施例6：晶型M的制备Embodiment 6: Preparation of crystal form M
室温条件下称取98.8毫克的实施例3式(I)化合物固体置于3.0毫升玻璃小瓶中，加入2.0毫升硝基甲烷得到悬浮液。将样品置于室温条件下悬浮搅拌(500转/分钟)约25天时间。抽滤，收集固体。At room temperature, 98.8 mg of solid compound of formula (I) in Example 3 was weighed and placed in a 3.0 ml glass vial, and 2.0 ml of nitromethane was added to obtain a suspension. The samples were suspended and stirred (500 rpm) at room temperature for about 25 days. The solid was collected by suction filtration.
室温条件下将前述固体置于DSC坩埚中，以10℃/分钟的速率加热至230℃，并保温5分钟，继而以30℃/分钟的速率降温至30℃，得到晶型M。其X射线粉末衍射数据如表5所示。该样品在约7.5°±0.2°、约10.8°±0.2°、约14.4°±0.2°、约15.4°±0.2°、约15.9°±0.2°、约17.7°±0.2°、约18.7°±0.2°、约20.2°±0.2°、约21.2°±0.2°、约21.6°±0.2°、约27.1°±0.2°处有特征峰。其XRPD、TGA、DSC和 1H NMR分别如图11～14所示。 表5 The aforementioned solid was placed in a DSC crucible at room temperature, heated to 230°C at a rate of 10°C/min, kept for 5 minutes, and then cooled to 30°C at a rate of 30°C/min to obtain Form M. Its X-ray powder diffraction data are shown in Table 5. The sample is at about 7.5°±0.2°, about 10.8°±0.2°, about 14.4°±0.2°, about 15.4°±0.2°, about 15.9°±0.2°, about 17.7°±0.2°, about 18.7°±0.2° °, about 20.2°±0.2°, about 21.2°±0.2°, about 21.6°±0.2°, and about 27.1°±0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 11-14, respectively. table 5
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.023.02 29.2129.21 5.895.89
7.467.46 11.8511.85 12.4012.40
9.909.90 8.948.94 8.618.61
10.8010.80 8.208.20 11.3911.39
13.0113.01 6.806.80 5.195.19
14.3614.36 6.176.17 21.0421.04
15.0015.00 5.915.91 3.083.08
15.4415.44 5.745.74 51.5651.56
15.9015.90 5.575.57 30.3730.37
16.1816.18 5.485.48 3.423.42
16.6816.68 5.325.32 3.513.51
17.1717.17 5.165.16 3.483.48
17.6917.69 5.015.01 22.3922.39
18.1518.15 4.894.89 5.715.71
18.7218.72 4.744.74 13.0313.03
19.9419.94 4.454.45 59.0959.09
20.1820.18 4.404.40 100.00100.00
20.6120.61 4.314.31 10.9510.95
21.2521.25 4.184.18 31.0531.05
21.6521.65 4.104.10 31.0631.06
21.9121.91 4.064.06 7.947.94
22.3522.35 3.983.98 9.099.09
22.7022.70 3.923.92 8.148.14
23.0823.08 3.853.85 7.267.26
23.4523.45 3.793.79 1.951.95
24.3124.31 3.663.66 4.564.56
25.0025.00 3.563.56 12.1012.10
25.7425.74 3.463.46 3.193.19
26.2126.21 3.403.40 13.4513.45
27.0927.09 3.293.29 21.7121.71
28.3828.38 3.153.15 1.951.95
28.9828.98 3.083.08 1.681.68
30.5030.50 2.932.93 5.475.47
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
31.2031.20 2.872.87 5.625.62
32.2732.27 2.772.77 2.422.42
33.3933.39 2.682.68 2.342.34
33.7533.75 2.662.66 2.722.72
36.4636.46 2.462.46 1.281.28
37.5537.55 2.402.40 0.510.51
38.4038.40 2.342.34 1.731.73
39.5039.50 2.282.28 0.700.70
实施例7：晶型P的制备Embodiment 7: the preparation of crystal form P
室温条件下称取20.8毫克的式(I)化合物固体置于3.0毫升的玻璃小瓶中，加入1.0毫升氯仿溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入10.0毫升乙腈，得到胶状物。将样品置于室温条件下挥发约16天时间，得到晶型P。其X射线粉末衍射数据如表6所示。该样品在约3.1°±0.2°、约7.3°±0.2°、约11.0°±0.2°、约13.8°±0.2°、约17.2°±0.2°、约18.6°±0.2°、约20.1°±0.2°、约21.9°±0.2°、约22.2°±0.2°、约25.3°±0.2°、约25.9°±0.2°处有特征峰。其XRPD、TGA、DSC和 1H NMR分别如图15～18所示。 Weigh 20.8 mg of the solid compound of formula (I) at room temperature and place it in a 3.0 ml glass vial, add 1.0 ml of chloroform to dissolve the solid, and filter the sample solution into a 20 ml glass vial using a polytetrafluoroethylene filter membrane with a pore size of 0.45 μm A clear solution was obtained. Then, under magnetic stirring (about 500 rpm), 10.0 ml of acetonitrile was added dropwise thereto to obtain a gel. The sample was volatilized at room temperature for about 16 days to obtain Form P. Its X-ray powder diffraction data are shown in Table 6. The sample is at about 3.1°±0.2°, about 7.3°±0.2°, about 11.0°±0.2°, about 13.8°±0.2°, about 17.2°±0.2°, about 18.6°±0.2°, about 20.1°±0.2 °, about 21.9°±0.2°, about 22.2°±0.2°, about 25.3°±0.2°, and about 25.9°±0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 15-18, respectively.
表6Table 6
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.103.10 28.5228.52 7.417.41
6.606.60 13.4013.40 6.896.89
7.347.34 12.0512.05 28.3728.37
7.877.87 11.2311.23 1.931.93
8.618.61 10.2710.27 2.182.18
11.0211.02 8.038.03 12.4212.42
13.8213.82 6.416.41 12.4612.46
14.7714.77 6.006.00 2.432.43
15.8615.86 5.595.59 4.984.98
16.7716.77 5.295.29 5.225.22
17.1617.16 5.175.17 11.6311.63
18.5718.57 4.784.78 100.00100.00
20.0820.08 4.424.42 22.7922.79
20.4120.41 4.354.35 4.714.71
21.9521.95 4.054.05 10.4710.47
22.1822.18 4.014.01 21.9121.91
23.1223.12 3.853.85 1.681.68
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
24.5124.51 3.633.63 6.536.53
25.3325.33 3.523.52 7.557.55
25.9125.91 3.443.44 7.367.36
26.4826.48 3.373.37 4.844.84
27.5827.58 3.233.23 2.092.09
28.6428.64 3.123.12 3.243.24
29.0229.02 3.083.08 6.296.29
29.8529.85 2.992.99 1.781.78
30.9230.92 2.892.89 2.882.88
31.8631.86 2.812.81 1.511.51
33.3633.36 2.692.69 0.760.76
36.8936.89 2.442.44 0.370.37
实施例8：晶型P的制备Embodiment 8: Preparation of crystal form P
室温条件下称取587.6毫克的式(I)化合物固体置于65毫升的玻璃小瓶中，加入20毫升氯仿溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至100毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入40毫升乙腈，得到澄清溶液。随后往澄清溶液中加入少量实施例7固体，将样品置于室温条件下挥发约7天时间。收集固体，室温真空干燥约2小时，得到晶型P。其X射线粉末衍射数据如表7所示。其XRPD如图19所示。Weigh 587.6 mg of the solid compound of formula (I) at room temperature and place it in a 65 ml glass vial, add 20 ml of chloroform to dissolve the solid, and filter the sample solution into a 100 ml glass vial using a polytetrafluoroethylene filter membrane with a 0.45 micron pore size A clear solution was obtained. Then, under magnetic stirring (about 500 rpm), 40 ml of acetonitrile was added dropwise thereto to obtain a clear solution. Subsequently, a small amount of the solid of Example 7 was added to the clear solution, and the sample was left to evaporate at room temperature for about 7 days. The solid was collected and dried under vacuum at room temperature for about 2 hours to obtain Form P. Its X-ray powder diffraction data are shown in Table 7. Its XRPD is shown in FIG. 19 .
表7Table 7
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.545.54 15.9515.95 4.364.36
6.616.61 13.3713.37 9.979.97
7.357.35 12.0312.03 79.4379.43
8.638.63 10.2510.25 3.323.32
11.0311.03 8.028.02 36.5936.59
11.2511.25 7.867.86 14.4514.45
13.8213.82 6.416.41 19.8119.81
14.7914.79 5.995.99 4.894.89
16.1316.13 5.505.50 38.6738.67
16.3816.38 5.415.41 29.6529.65
16.7616.76 5.295.29 15.5415.54
17.1917.19 5.165.16 27.6527.65
17.7017.70 5.015.01 6.926.92
18.1818.18 4.884.88 14.0214.02
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.5718.57 4.784.78 100.00100.00
18.8418.84 4.714.71 16.0316.03
20.0820.08 4.424.42 26.6826.68
20.4220.42 4.354.35 9.469.46
21.9621.96 4.054.05 20.5020.50
22.1922.19 4.014.01 42.9742.97
23.8923.89 3.723.72 3.303.30
24.5324.53 3.633.63 12.8112.81
25.3525.35 3.513.51 11.5411.54
25.9325.93 3.443.44 16.6016.60
26.4726.47 3.373.37 8.308.30
26.8226.82 3.323.32 5.545.54
27.5827.58 3.233.23 3.343.34
28.6328.63 3.123.12 3.953.95
29.0629.06 3.073.07 8.238.23
29.8429.84 2.992.99 2.502.50
30.9930.99 2.892.89 4.484.48
33.3733.37 2.682.68 1.321.32
35.4735.47 2.532.53 1.981.98
36.6036.60 2.452.45 1.561.56
38.4038.40 2.342.34 3.163.16
38.8938.89 2.322.32 1.851.85
实施例9：晶型S的制备Embodiment 9: Preparation of crystal form S
室温条件下称取98.8毫克的实施例3式(I)化合物固体置于3.0毫升玻璃小瓶中，加入2.0毫升硝基甲烷得到悬浮液。将样品置于室温条件下悬浮搅拌(500转/分钟)约25天时间。抽滤，收集固体。At room temperature, 98.8 mg of solid compound of formula (I) in Example 3 was weighed and placed in a 3.0 ml glass vial, and 2.0 ml of nitromethane was added to obtain a suspension. The samples were suspended and stirred (500 rpm) at room temperature for about 25 days. The solid was collected by suction filtration.
室温条件下将前述固体置于DSC坩埚中，以10℃/分钟的速率加热至150℃，并保温2分钟，继而以30℃/分钟的速率降温至30℃，得到晶型S。其X射线粉末衍射数据如表8所示。该样品在约11.6°±0.2°、约14.9°±0.2°、约15.7°±0.2°、约16.6°±0.2°、约17.6°±0.2°、约18.6°±0.2°、约19.3°±0.2°、约20.2°±0.2°、约22.7°±0.2°、约23.3°±0.2°、约25.6°±0.2°处有特征峰。其XRPD、TGA和DSC分别如图20～22所示。The aforementioned solid was placed in a DSC crucible at room temperature, heated to 150°C at a rate of 10°C/min, kept for 2 minutes, and then cooled to 30°C at a rate of 30°C/min to obtain Form S. Its X-ray powder diffraction data are shown in Table 8. The sample is at about 11.6°±0.2°, about 14.9°±0.2°, about 15.7°±0.2°, about 16.6°±0.2°, about 17.6°±0.2°, about 18.6°±0.2°, about 19.3°±0.2 °, about 20.2°±0.2°, about 22.7°±0.2°, about 23.3°±0.2°, and about 25.6°±0.2° have characteristic peaks. Its XRPD, TGA and DSC are shown in Figures 20-22, respectively.
表8Table 8
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.295.29 16.6916.69 1.201.20
7.697.69 11.5011.50 2.872.87
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
8.778.77 10.0910.09 6.526.52
9.259.25 9.569.56 3.213.21
9.879.87 8.968.96 4.674.67
10.1810.18 8.698.69 2.442.44
10.6110.61 8.338.33 6.476.47
11.6411.64 7.607.60 11.5211.52
12.3012.30 7.207.20 6.866.86
12.5512.55 7.057.05 5.785.78
14.4714.47 6.126.12 7.007.00
14.9114.91 5.945.94 10.7710.77
15.6615.66 5.665.66 100.00100.00
15.9815.98 5.555.55 13.0813.08
16.6416.64 5.335.33 33.2433.24
16.9516.95 5.235.23 9.379.37
17.1317.13 5.185.18 6.586.58
17.4117.41 5.095.09 9.289.28
17.6117.61 5.045.04 24.3124.31
18.5718.57 4.784.78 17.4817.48
18.9118.91 4.694.69 7.307.30
19.2719.27 4.614.61 12.0612.06
20.2220.22 4.394.39 14.9514.95
20.9520.95 4.244.24 2.202.20
21.4521.45 4.144.14 3.453.45
22.2822.28 3.993.99 4.504.50
22.7522.75 3.913.91 38.5138.51
23.2723.27 3.823.82 25.9725.97
24.3224.32 3.663.66 7.107.10
24.7724.77 3.593.59 2.512.51
25.6025.60 3.483.48 11.5611.56
26.1026.10 3.413.41 5.465.46
26.4526.45 3.373.37 7.367.36
26.8326.83 3.323.32 10.1710.17
27.9427.94 3.193.19 1.051.05
28.6328.63 3.123.12 5.255.25
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
29.1829.18 3.063.06 2.342.34
30.5330.53 2.932.93 1.581.58
30.9030.90 2.892.89 1.381.38
31.4931.49 2.842.84 1.041.04
32.0832.08 2.792.79 0.770.77
33.2833.28 2.692.69 6.456.45
33.6333.63 2.672.67 3.753.75
34.0934.09 2.632.63 4.074.07
34.6734.67 2.592.59 0.910.91
35.6835.68 2.522.52 0.870.87
36.8736.87 2.442.44 0.660.66
38.9138.91 2.312.31 0.370.37
实施例10～13：晶型E的制备Examples 10-13: Preparation of Form E
室温条件下称取适量的实施例3或实施例5式(I)化合物固体置于1.5-5.0毫升的玻璃小瓶中，加入相应溶剂得到悬浮液。将样品置于室温或5℃条件下悬浮搅拌(500转/分钟)，得到晶型E。At room temperature, an appropriate amount of solid compound of formula (I) of Example 3 or Example 5 was weighed and placed in a 1.5-5.0 ml glass vial, and a corresponding solvent was added to obtain a suspension. The sample was suspended and stirred (500 rpm) at room temperature or 5°C to obtain Form E.
本实施例中所涉详细试验条件如表9所示，实施例10样品的X射线粉末衍射数据如表10所示。该样品在约5.6°±0.2°、约8.4°±0.2°、约9.0°±0.2°、约11.1°±0.2°、约12.5°±0.2°、约17.8°±0.2°、约18.5°±0.2°、约19.2°±0.2°、约21.0°±0.2°、约22.9°±0.2°、约24.5°±0.2°处有特征峰。其XRPD、TGA、DSC和 1H NMR分别如图23～26所示。 The detailed test conditions involved in this example are shown in Table 9, and the X-ray powder diffraction data of the sample in Example 10 are shown in Table 10. The sample is at about 5.6°±0.2°, about 8.4°±0.2°, about 9.0°±0.2°, about 11.1°±0.2°, about 12.5°±0.2°, about 17.8°±0.2°, about 18.5°±0.2° °, about 19.2°±0.2°, about 21.0°±0.2°, about 22.9°±0.2°, and about 24.5°±0.2° have characteristic peaks. Its XRPD, TGA, DSC and 1 H NMR are shown in Figures 23-26, respectively.
表9Table 9
Figure PCTCN2022114984-appb-000016
Figure PCTCN2022114984-appb-000016
表10Table 10
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
3.013.01 29.3229.32 36.1936.19
5.605.60 15.7715.77 37.6937.69
6.416.41 13.7913.79 28.1328.13
8.458.45 10.4710.47 27.4027.40
9.039.03 9.799.79 42.4442.44
11.0911.09 7.987.98 37.9337.93
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
12.5312.53 7.067.06 44.4044.40
13.3013.30 6.656.65 29.4329.43
13.6613.66 6.486.48 29.6129.61
15.5015.50 5.725.72 17.9517.95
15.7815.78 5.625.62 16.1316.13
16.6416.64 5.335.33 17.9017.90
16.9416.94 5.235.23 21.2321.23
17.8317.83 4.984.98 35.0935.09
18.4918.49 4.804.80 84.9084.90
19.2219.22 4.624.62 33.7633.76
21.0421.04 4.224.22 100.00100.00
21.7521.75 4.094.09 26.9026.90
22.9222.92 3.883.88 31.9031.90
23.8023.80 3.743.74 15.8815.88
24.4724.47 3.643.64 23.3823.38
26.4526.45 3.373.37 11.7411.74
29.3229.32 3.053.05 6.436.43
31.6931.69 2.822.82 3.983.98
33.2133.21 2.702.70 2.142.14
36.0736.07 2.492.49 1.461.46
实施例14：晶型E的制备Example 14: Preparation of Form E
室温条件下称取15.9毫克的实施例5式(I)化合物固体置于3毫升的玻璃小瓶中，然后敞口置于预盛有4毫升甲苯的20毫升玻璃瓶中。封口后置于室温条件下约7天，得到晶型E。其X射线粉末衍射数据如表11所示。At room temperature, 15.9 mg of solid compound of formula (I) in Example 5 was weighed and placed in a 3 ml glass vial, and then opened and placed in a 20 ml glass vial filled with 4 ml of toluene. After sealing, place it at room temperature for about 7 days to obtain Form E. Its X-ray powder diffraction data are shown in Table 11.
表11Table 11
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.615.61 15.7515.75 9.599.59
8.398.39 10.5310.53 9.709.70
9.089.08 9.749.74 12.1712.17
11.0711.07 7.997.99 26.8926.89
12.6112.61 7.027.02 22.7222.72
13.2913.29 6.666.66 27.3427.34
15.7215.72 5.645.64 9.849.84
17.0517.05 5.205.20 12.0512.05
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
17.8017.80 4.984.98 38.5938.59
18.4918.49 4.804.80 62.9462.94
19.1319.13 4.644.64 20.7220.72
20.9020.90 4.254.25 100.00100.00
22.9522.95 3.883.88 26.8926.89
23.7323.73 3.753.75 15.1515.15
24.3524.35 3.663.66 13.3613.36
28.9628.96 3.083.08 5.195.19
31.5031.50 2.842.84 4.964.96
实施例15～16：晶型E的制备Examples 15-16: Preparation of Form E
室温条件下称取适量的式(I)化合物固体置于3.0毫升的玻璃小瓶中，加入相应溶剂溶解固体，使用0.45微米孔径的聚四氟乙烯滤膜将样品溶液过滤至20毫升玻璃小瓶中得到澄清溶液。随后在磁力搅拌(转速约为500转/分钟)下，往其中逐滴加入相应反溶剂，得到晶型E。Weigh an appropriate amount of formula (I) compound solid in a 3.0 ml glass vial at room temperature, add the corresponding solvent to dissolve the solid, and filter the sample solution into a 20 ml glass vial using a polytetrafluoroethylene filter membrane with a pore size of 0.45 micron to obtain Clear solution. Then, under magnetic stirring (about 500 rpm), the corresponding anti-solvent was added dropwise therein to obtain the crystal form E.
本实施例中所涉详细试验条件如表12所示，实施例16样品的X射线粉末衍射数据如表13所示。The detailed test conditions involved in this example are shown in Table 12, and the X-ray powder diffraction data of the sample in Example 16 are shown in Table 13.
表12Table 12
实施例Example 质量(毫克)Mass (mg) 溶剂solvent 体积(毫升)Volume (ml) 反溶剂Anti-solvent 体积(毫升)Volume (ml)
1515 17.817.8 氯仿Chloroform 1.01.0 甲苯Toluene 10.010.0
1616 17.517.5 四氢呋喃Tetrahydrofuran 0.50.5 甲醇Methanol 10.010.0
表13Table 13
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
5.605.60 15.7715.77 21.6221.62
6.376.37 13.8713.87 19.8019.80
8.478.47 10.4410.44 20.4720.47
9.009.00 9.829.82 33.2133.21
11.0911.09 7.987.98 31.8131.81
12.1012.10 7.317.31 12.3612.36
12.5412.54 7.067.06 40.7640.76
12.9912.99 6.826.82 18.5818.58
13.3013.30 6.666.66 22.1722.17
13.6613.66 6.486.48 24.5024.50
15.7815.78 5.615.61 9.219.21
16.6316.63 5.335.33 10.6510.65
17.8017.80 4.984.98 31.0331.03
衍射角2θDiffraction angle 2θ d值d value 强度％strength%
18.4918.49 4.804.80 75.0875.08
19.2319.23 4.624.62 27.2927.29
21.0521.05 4.224.22 100.00100.00
21.7121.71 4.094.09 23.5023.50
22.4022.40 3.973.97 16.4016.40
22.8722.87 3.893.89 25.0625.06
23.2123.21 3.833.83 20.1420.14
23.8123.81 3.743.74 13.5813.58
24.4524.45 3.643.64 23.7023.70
26.3826.38 3.383.38 7.607.60
27.1327.13 3.293.29 5.825.82
29.3629.36 3.043.04 5.235.23
31.6331.63 2.832.83 3.163.16
33.1133.11 2.712.71 2.622.62
36.0836.08 2.492.49 1.891.89
实施例17：晶型的溶解度Example 17: Solubility of Crystal Forms
将本发明晶型E和WO2021231174A1的Form 2用FaSSIF(空腹状态下人工肠液)分别配制成悬浊液，在1小时和4小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表14所示，溶解度曲线如图27所示。试验结果显示，本发明晶型E在FaSSIF中4小时内的溶解度高于Form 2。Form E of the present invention and Form 2 of WO2021231174A1 were prepared into suspensions with FaSSIF (artificial intestinal fluid in fasting state), and filtered after equilibrating for 1 hour and 4 hours to obtain a saturated solution. The content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 14, and the solubility curve is shown in Figure 27. The test results show that the solubility of Form E of the present invention in FaSSIF within 4 hours is higher than that of Form 2.
将本发明晶型A、晶型M和WO2021231174A1的Form 2用FeSSIF(饱食状态下人工肠液)分别配制成悬浊液，在1小时、4小时和24小时平衡后过滤，得到饱和溶液。通过高效液相色谱法(HPLC)测定饱和溶液中样品的含量。试验结果如表15所示，溶解度曲线如图28所示。试验结果显示，本发明晶型A和晶型M在FeSSIF中的溶解度高于Form 2。The crystal form A, crystal form M and Form 2 of WO2021231174A1 of the present invention were respectively prepared into suspensions with FeSSIF (artificial intestinal fluid in a fed state), and filtered after equilibrating for 1 hour, 4 hours and 24 hours to obtain a saturated solution. The content of the samples in the saturated solution was determined by high performance liquid chromatography (HPLC). The test results are shown in Table 15, and the solubility curve is shown in Figure 28. The test results show that the solubility of Form A and Form M of the present invention in FeSSIF is higher than that of Form 2.
表14Table 14
Figure PCTCN2022114984-appb-000017
Figure PCTCN2022114984-appb-000017
表15Table 15
Figure PCTCN2022114984-appb-000018
Figure PCTCN2022114984-appb-000018
实施例18：晶型的可压性Example 18: Compressibility of Crystalline Forms
采用手动压片机进行压片，压片时，选择可以压制成圆柱体片剂的圆形平冲，分别加 入一定量的本发明晶型A、晶型E、晶型M、晶型P和晶型S，采用10kN压力压制成圆形片剂，采用片剂硬度测定仪测试其径向破碎力(硬度，H)。采用游标卡尺测量片剂的直径(D)和厚度(L)，利用公式T＝2H/πDL计算出不同硬度下粉体的抗张强度。试验结果如表16所示，压片前后的XRPD对比图分别如图29～33所示。在一定的压力下，抗张强度越大的，表示其可压性越好。试验结果显示，本发明晶型A、晶型E、晶型M、晶型P和晶型S具有较大的抗张强度，说明具有较优的可压性。A manual tablet press is used for tablet compression. During tablet compression, a circular flat punch that can be compressed into a cylindrical tablet is selected, and a certain amount of crystal form A, crystal form E, crystal form M, crystal form P and The crystal form S was pressed into round tablets with a pressure of 10kN, and the radial crushing force (hardness, H) was tested with a tablet hardness tester. Use a vernier caliper to measure the diameter (D) and thickness (L) of the tablet, and use the formula T=2H/πDL to calculate the tensile strength of the powder at different hardnesses. The test results are shown in Table 16, and the XRPD comparison charts before and after tablet compression are shown in Figures 29-33 respectively. Under a certain pressure, the greater the tensile strength, the better its compressibility. The test results show that the crystalline form A, crystalline form E, crystalline form M, crystalline form P and crystalline form S of the present invention have greater tensile strength, indicating better compressibility.
表16Table 16
晶型crystal form 直径(毫米)Diameter (mm) 厚度(毫米)Thickness (mm) 径向破碎力(牛)Radial crushing force (N) 抗张强度(兆帕)Tensile strength (MPa)
晶型AForm A 6.226.22 2.762.76 52.7952.79 1.961.96
晶型EForm E 6.086.08 2.702.70 37.7037.70 1.461.46
晶型MForm M 6.186.18 2.722.72 67.2267.22 2.552.55
晶型PForm P 6.206.20 2.742.74 48.4448.44 1.821.82
晶型SForm S 6.086.08 2.802.80 74.5874.58 2.792.79
实施例19：稳定性对比研究Embodiment 19: Stability comparative study
称取本发明晶型A(起始纯度99.19％)、晶型B(起始纯度99.00％)、晶型E(起始纯度98.79％)和晶型M(起始纯度99.08％)各约15mg，分别敞口放置于25℃/60％RH和40℃/75％RH条件的稳定箱中，在1周、2周、4周和8周后取样测XRPD和HPLC纯度。试验结果如表17所示，晶型A的稳定性如图34～35所示，晶型B的稳定性如图36～37所示，晶型E的稳定性如图38～39所示，晶型M的稳定性如图40～41所示。试验结果显示，本发明晶型A、晶型B、晶型E和晶型M在25℃/60％RH和40℃/75％RH条件下具有较好的物理化学稳定性。Weigh about 15 mg each of Form A (initial purity 99.19%), Form B (initial purity 99.00%), Form E (initial purity 98.79%) and Form M (initial purity 99.08%) of the present invention , placed in a stable box under the conditions of 25°C/60%RH and 40°C/75%RH respectively, and samples were taken to measure the purity by XRPD and HPLC after 1 week, 2 weeks, 4 weeks and 8 weeks. The test results are shown in Table 17. The stability of Form A is shown in Figures 34-35, the stability of Form B is shown in Figures 36-37, and the stability of Form E is shown in Figures 38-39. The stability of crystal form M is shown in Figures 40-41. The test results show that the crystal forms A, B, E and M of the present invention have better physical and chemical stability under the conditions of 25°C/60%RH and 40°C/75%RH.
表17Table 17
Figure PCTCN2022114984-appb-000019
Figure PCTCN2022114984-appb-000019
Figure PCTCN2022114984-appb-000020
Figure PCTCN2022114984-appb-000020
实施例20：引湿性对比研究Embodiment 20: Contrastive research on moisture absorption
称取本发明晶型B、晶型M和WO2021231174A1的Form 2各约10mg进行动态水分吸附(DVS)测试，然后取样测XRPD。试验结果如表18所示，晶型B的DVS如图42所示，晶型B测试DVS前后的XRPD如图43所示；晶型M的DVS如图44所示，晶型M测试DVS前后的XRPD如图45所示；Form 2的DVS如图46所示，Form 2测试DVS前后的XRPD如图47所示。试验结果显示，本发明晶型B和晶型M与Form 2相比具有更低的引湿性。Weigh about 10 mg each of Form B, Form M and Form 2 of WO2021231174A1 of the present invention for dynamic moisture adsorption (DVS) test, and then sample for XRPD. The test results are shown in Table 18, the DVS of Form B is shown in Figure 42, the XRPD of Form B before and after DVS test is shown in Figure 43; the DVS of Form M is shown in Figure 44, and the DVS of Form M before and after DVS test is shown in Figure 43. The XRPD of Form 2 is shown in Figure 45; the DVS of Form 2 is shown in Figure 46, and the XRPD of Form 2 before and after DVS is shown in Figure 47. The test results show that the crystal form B and the crystal form M of the present invention have lower hygroscopicity than Form 2.
表18Table 18
起始晶型starting crystal form 80％相对湿度的增重Weight gain at 80% relative humidity 引湿性Humidity DVS测试后晶型Crystal form after DVS test
晶型BForm B 0.13720.1372 无或几乎无引湿性Little or no hygroscopicity 晶型BForm B
晶型MForm M 0.21100.2110 略有引湿性slightly hygroscopic 晶型M Form M
Form 2Form 2 0.34950.3495 略有引湿性slightly hygroscopic Form 2Form 2
关于引湿性特征描述与引湿性增重的界定(中国药典2020年版四部药物引湿性试验指导原则)：Regarding the description of hygroscopic characteristics and the definition of hygroscopic weight gain (Guidelines for the hygroscopicity test of four medicines in the Chinese Pharmacopoeia 2020 Edition):
潮解：吸收足量水分形成液体Deliquescence: the absorption of sufficient water to form a liquid
极具引湿性：引湿增重不小于15％Extremely hygroscopic: the weight gain of moisture is not less than 15%
有引湿性：引湿增重小于15％但不小于2％Moisture-absorbing: the weight gain of moisture-absorbing is less than 15% but not less than 2%
略有引湿性：引湿增重小于2％但不小于0.2％Slight hygroscopicity: the weight gain of moisture is less than 2% but not less than 0.2%
无或几乎无引湿性：引湿增重小于0.2％No or almost no hygroscopicity: the weight gain of moisture is less than 0.2%
实施例21：晶习对比研究Embodiment 21: Comparative study on crystal habit
称取本发明晶型和WO2021231174A1的Form 2各约10mg，分别置于载玻片上，滴加少许真空硅油分散样品，然后盖上盖玻片，置于偏光显微镜下观察。试验结果显示，本发明晶型比Form 2具有更优的晶习。Weigh about 10 mg each of the crystal form of the present invention and Form 2 of WO2021231174A1, place them on glass slides, add a little vacuum silicone oil dropwise to disperse the samples, cover with a cover glass, and observe under a polarizing microscope. The test results show that the crystal form of the present invention has a better crystal habit than Form 2.
实施例22：粒径分布对比研究Embodiment 22: comparative study of particle size distribution
称取本发明晶型A和WO2021231174A1的Form 2各约10-30mg，然后加入约5mL Isopar G(含有0.2％卵磷脂)，将待测样品充分混合均匀后加入SDC进样系统中，使遮光度达到合适范围，开始实验，超声30秒后进行粒径分布的测试。试验结果如表19所示，晶型A的粒径分布图如图48所示，Form 2的粒径分布图如图49所示。试验结果显示，本发明晶型A呈单峰分布，平均粒径为17.39微米，粒径分布均匀；Form 2呈双峰分布，平均粒径为224.6微米。说明，本发明晶型A具有更加均匀的粒径分布。Weigh about 10-30 mg each of Form A of the present invention and Form 2 of WO2021231174A1, then add about 5 mL of Isopar G (containing 0.2% lecithin), fully mix the sample to be tested and add it to the SDC sampling system to make the shading When the appropriate range is reached, the experiment is started, and the particle size distribution is tested after 30 seconds of ultrasonication. The test results are shown in Table 19, the particle size distribution diagram of Form A is shown in Figure 48, and the particle size distribution diagram of Form 2 is shown in Figure 49. The test results show that the crystal form A of the present invention has a unimodal distribution with an average particle size of 17.39 microns, and the particle size distribution is uniform; Form 2 has a bimodal distribution with an average particle size of 224.6 microns. It shows that the crystal form A of the present invention has a more uniform particle size distribution.
表19Table 19
晶型crystal form 平均粒径(微米)Average particle size (micron) D10(微米)D10 (micron) D50(微米)D50(micron) D90(微米)D90(micron)
晶型AForm A 17.3917.39 3.063.06 12.1112.11 30.8430.84
Form 2 Form 2 224.6224.6 70.7770.77 252.4252.4 316.1316.1
实施例23：黏附性对比研究Example 23: Comparative Adhesion Study
称取本发明晶型A、晶型M、晶型P、晶型S和WO2021231174A1的Form 2各约100mg，然后加入到6mm圆形平冲中，采用10kN的压力进行压片处理，压片后停留约半分钟，记录最后制成片剂的质量，并计算压制过程中的黏附量和黏附百分比，试验结果如表20所示。试验结果显示，本发明晶型A、晶型M、晶型P和晶型S比Form 2更不易粘冲。Weigh about 100 mg each of Form A, Form M, Form P, Form S, and Form 2 of WO2021231174A1 of the present invention, and then add it to a 6mm circular flat punch, and perform tableting treatment with a pressure of 10kN. After tableting, Stay for about half a minute, record the mass of the final tablet, and calculate the adhesion amount and adhesion percentage during the compression process. The test results are shown in Table 20. The test results show that the crystal form A, crystal form M, crystal form P and crystal form S of the present invention are less prone to sticking than Form 2.
表20Table 20
Figure PCTCN2022114984-appb-000021
Figure PCTCN2022114984-appb-000021
上述实施例只为说明本发明的技术构思及特点，其目的在于让熟悉此项技术的人士能够了解本发明的内容并据以实施，并不能以此限制本发明的保护范围。凡根据本发明精神实质所作的等效变化或修饰，都应涵盖在本发明的保护范围之内。The above-mentioned embodiments are only to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly, and not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention shall fall within the protection scope of the present invention.

Claims (15)

  1. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的B型晶体、即晶型B，其特征在于，使用Cu-Kα辐射，所述晶型B的X射线粉末衍射在2θ值为16.1°±0.2°、18.4°±0.2°、22.9°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The type B crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form B, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form B has a 2θ value of There are characteristic peaks at 16.1°±0.2°, 18.4°±0.2°, 22.9°±0.2°,
    Figure PCTCN2022114984-appb-100001
    Figure PCTCN2022114984-appb-100001
  2. 权利要求1所述的晶型B的制备方法，其特征在于，The preparation method of the crystal form B described in claim 1, is characterized in that,
    将式(I)化合物固体加热至250℃，降温得到晶型B。The solid compound of formula (I) was heated to 250° C., and the temperature was lowered to obtain Form B.
  3. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的M型晶体、即晶型M，其特征在于，使用Cu-Kα辐射，所述晶型M的X射线粉末衍射在2θ值为15.4°±0.2°、20.2°±0.2°、21.2°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The M-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. the crystal form M, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form M has a 2θ value of There are characteristic peaks at 15.4°±0.2°, 20.2°±0.2°, 21.2°±0.2°,
    Figure PCTCN2022114984-appb-100002
    Figure PCTCN2022114984-appb-100002
  4. 权利要求3所述的晶型M的制备方法，其特征在于，The preparation method of crystal form M described in claim 3, is characterized in that,
    在10～50℃下，将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至230℃，降温得到晶型M。Add the solid compound of formula (I) into nitromethane at 10-50°C, suspend and stir for a certain period of time, and collect the solid; heat the aforementioned solid to 230°C, and cool down to obtain Form M.
  5. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的P型晶体、即晶型P，其特征在于，使用Cu-Kα辐射，所述晶型P的X射线粉末衍射在2θ值为11.0°±0.2°、18.6±0.2°、20.1°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The P-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form P, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form P has a 2θ value of There are characteristic peaks at 11.0°±0.2°, 18.6±0.2°, 20.1°±0.2°,
    Figure PCTCN2022114984-appb-100003
    Figure PCTCN2022114984-appb-100003
  6. 权利要求5所述的晶型P的制备方法，其特征在于，The preparation method of crystal form P according to claim 5, characterized in that,
    在10～50℃下，将式(I)化合物固体溶解于卤代烃类溶剂中，加入烷基腈类溶剂，搅拌至产生胶状物；将溶液挥发，得到晶型P。Dissolve the solid compound of formula (I) in a halogenated hydrocarbon solvent at 10-50°C, add an alkylnitrile solvent, and stir until a jelly is produced; volatilize the solution to obtain Form P.
  7. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲 酰胺的S型晶体、即晶型S，其特征在于，使用Cu-Kα辐射，所述晶型S的X射线粉末衍射在2θ值为15.7°±0.2°、16.6±0.2°、22.7°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The S-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form S, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form S has a 2θ value of There are characteristic peaks at 15.7°±0.2°, 16.6±0.2°, 22.7°±0.2°,
    Figure PCTCN2022114984-appb-100004
    Figure PCTCN2022114984-appb-100004
  8. 权利要求7所述的晶型S的制备方法，其特征在于，The preparation method of crystal form S according to claim 7, characterized in that,
    在10～50℃下，将式(I)化合物固体加入至硝基甲烷中，悬浮搅拌一定时间，收集固体；将前述固体加热至150℃，降温得到晶型S。Add the solid compound of formula (I) into nitromethane at 10-50°C, suspend and stir for a certain period of time, and collect the solid; heat the aforementioned solid to 150°C, and cool down to obtain Form S.
  9. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的E型晶体、即晶型E，其特征在于，使用Cu-Kα辐射，所述晶型E的X射线粉末衍射在2θ值为11.1°±0.2°、18.5°±0.2°、21.0°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The E-type crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form E, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form E has a 2θ value of There are characteristic peaks at 11.1°±0.2°, 18.5°±0.2°, 21.0°±0.2°,
    Figure PCTCN2022114984-appb-100005
    Figure PCTCN2022114984-appb-100005
  10. 权利要求9所述的晶型E的制备方法，其特征在于，The preparation method of the crystal form E described in claim 9, is characterized in that,
    (1)在-5～50℃下，将式(I)化合物固体加入至纯水、醇类、芳香烃类的单一或混合溶剂中，悬浮搅拌，得到晶型E；或(1) Add the solid compound of formula (I) to pure water, alcohols, aromatic hydrocarbons or a mixed solvent at -5 to 50°C, suspend and stir to obtain crystal form E; or
    (2)在10～50℃下，将式(I)化合物固体置于芳香烃类溶剂氛围下进行气固扩散，得到晶型E；或or
    (3)在10～50℃下，将式(I)化合物溶解于卤代烃、环醚类溶剂中，向其中加入芳香烃类、醇类溶剂，搅拌至有固体析出，得到晶型E。(3) Dissolve the compound of formula (I) in halogenated hydrocarbons and cyclic ether solvents at 10-50°C, add aromatic hydrocarbons and alcohol solvents therein, and stir until solids are precipitated to obtain crystal form E.
  11. 式(I)所示化合物6-[4-([4-[2-(2,6-二氧代哌啶-3-基)-6-氟-1,3-二氧代-2,3-二氢-1H-异吲哚-5-基]哌嗪-1-基]甲基)哌啶-1-基]-N-[(1r,4r)-4-(3-氯-4-氰基苯氧基)环己基]哒嗪-3-甲酰胺的A型晶体、即晶型A，其特征在于，使用Cu-Kα辐射，所述晶型A的X射线粉末衍射在2θ值为14.1°±0.2°、16.0°±0.2°、21.7°±0.2°处有特征峰，Compound 6-[4-([4-[2-(2,6-dioxopiperidin-3-yl)-6-fluoro-1,3-dioxo-2,3 shown in formula (I) -Dihydro-1H-isoindol-5-yl]piperazin-1-yl]methyl)piperidin-1-yl]-N-[(1r,4r)-4-(3-chloro-4- The type A crystal of cyanophenoxy)cyclohexyl]pyridazine-3-carboxamide, i.e. crystal form A, is characterized in that, using Cu-Kα radiation, the X-ray powder diffraction of the crystal form A has a 2θ value of There are characteristic peaks at 14.1°±0.2°, 16.0°±0.2°, 21.7°±0.2°,
    Figure PCTCN2022114984-appb-100006
    Figure PCTCN2022114984-appb-100006
  12. 权利要求11所述的晶型A的制备方法，其特征在于，The preparation method of the crystal form A described in claim 11, characterized in that,
    在10～50℃下，将式(I)化合物固体溶解于卤代烷烃类溶剂中，向其中加入烷烃类溶剂，搅拌至有固体析出，得到晶型A。Dissolve the solid compound of formula (I) in a halogenated alkane solvent at 10-50°C, add the alkane solvent therein, and stir until solids are precipitated to obtain crystal form A.
  13. 药物组合物，其包含权利要求1，3，5，7，9和11中任一项所述的晶体和制药学可接受的载体。A pharmaceutical composition comprising the crystal according to any one of claims 1, 3, 5, 7, 9 and 11 and a pharmaceutically acceptable carrier.
  14. 具有AR降解促进活性的药物组合物，其含有权利要求1，3，5，7，9和11中任一项所述的晶体作为有效成分。A pharmaceutical composition having AR degradation promoting activity, which contains the crystal according to any one of claims 1, 3, 5, 7, 9 and 11 as an active ingredient.
  15. 前列腺癌的治疗药，其含有权利要求1，3，5，7，9和11中任一项所述的晶体作为有效成分。A therapeutic agent for prostate cancer comprising the crystal according to any one of claims 1, 3, 5, 7, 9 and 11 as an active ingredient.
PCT/CN2022/114984 2021-08-27 2022-08-26 Crystal forms of pyridazine carboxamide compound and preparation method thereof WO2023025268A1 (en)

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Publication number Priority date Publication date Assignee Title
CN110506039A (en) * 2016-10-11 2019-11-26 阿尔维纳斯股份有限公司 Compounds and methods for for androgen receptor targeting degradation
WO2021231174A1 (en) * 2020-05-09 2021-11-18 Arvinas Operations, Inc. Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same
WO2022087125A1 (en) * 2020-10-21 2022-04-28 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor protein

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110506039A (en) * 2016-10-11 2019-11-26 阿尔维纳斯股份有限公司 Compounds and methods for for androgen receptor targeting degradation
WO2021231174A1 (en) * 2020-05-09 2021-11-18 Arvinas Operations, Inc. Methods of manufacturing a bifunctional compound, ultrapure forms of the bifunctional compound, and dosage forms comprising the same
WO2022087125A1 (en) * 2020-10-21 2022-04-28 Arvinas Operations, Inc. Compounds and methods for the targeted degradation of androgen receptor protein

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