CN112300076A - Crystal form of androgen receptor inhibitor and preparation method thereof - Google Patents
Crystal form of androgen receptor inhibitor and preparation method thereof Download PDFInfo
- Publication number
- CN112300076A CN112300076A CN202011180867.1A CN202011180867A CN112300076A CN 112300076 A CN112300076 A CN 112300076A CN 202011180867 A CN202011180867 A CN 202011180867A CN 112300076 A CN112300076 A CN 112300076A
- Authority
- CN
- China
- Prior art keywords
- formula
- compound
- crystal form
- radiation
- ray powder
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 102000001307 androgen receptors Human genes 0.000 title claims abstract description 14
- 108010080146 androgen receptors Proteins 0.000 title claims abstract description 14
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- 239000013078 crystal Substances 0.000 title abstract description 96
- 239000003112 inhibitor Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims description 96
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 45
- 230000005855 radiation Effects 0.000 claims description 33
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- 239000002904 solvent Substances 0.000 claims description 14
- 238000001914 filtration Methods 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 11
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 10
- 238000004519 manufacturing process Methods 0.000 claims description 10
- 230000008569 process Effects 0.000 claims description 10
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- 206010060862 Prostate cancer Diseases 0.000 claims description 9
- 208000000236 Prostatic Neoplasms Diseases 0.000 claims description 9
- 239000008194 pharmaceutical composition Substances 0.000 claims description 9
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 8
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 8
- 239000012296 anti-solvent Substances 0.000 claims description 8
- VLKZOEOYAKHREP-UHFFFAOYSA-N hexane Substances CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 6
- 239000003085 diluting agent Substances 0.000 claims description 6
- 239000003937 drug carrier Substances 0.000 claims description 6
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 5
- 239000003208 petroleum Substances 0.000 claims description 5
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 201000010099 disease Diseases 0.000 claims description 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- NTIZESTWPVYFNL-UHFFFAOYSA-N Methyl isobutyl ketone Chemical compound CC(C)CC(C)=O NTIZESTWPVYFNL-UHFFFAOYSA-N 0.000 claims description 2
- UIHCLUNTQKBZGK-UHFFFAOYSA-N Methyl isobutyl ketone Natural products CCC(C)C(C)=O UIHCLUNTQKBZGK-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- 229910002483 Cu Ka Inorganic materials 0.000 claims 3
- 238000000113 differential scanning calorimetry Methods 0.000 description 19
- 238000004090 dissolution Methods 0.000 description 9
- 238000002441 X-ray diffraction Methods 0.000 description 8
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 238000005303 weighing Methods 0.000 description 8
- 238000006243 chemical reaction Methods 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 239000003098 androgen Substances 0.000 description 6
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- 230000008859 change Effects 0.000 description 5
- 238000001816 cooling Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000007924 injection Substances 0.000 description 4
- 238000002347 injection Methods 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 229910017488 Cu K Inorganic materials 0.000 description 3
- 229910017541 Cu-K Inorganic materials 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 102000002812 Heat-Shock Proteins Human genes 0.000 description 2
- 108010004889 Heat-Shock Proteins Proteins 0.000 description 2
- 102000007066 Prostate-Specific Antigen Human genes 0.000 description 2
- 108010072866 Prostate-Specific Antigen Proteins 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 210000002307 prostate Anatomy 0.000 description 2
- 238000004537 pulping Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229940030486 androgens Drugs 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 230000002280 anti-androgenic effect Effects 0.000 description 1
- 239000000051 antiandrogen Substances 0.000 description 1
- 239000008346 aqueous phase Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 229910001873 dinitrogen Inorganic materials 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 238000001471 micro-filtration Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000011474 orchiectomy Methods 0.000 description 1
- 238000009304 pastoral farming Methods 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 210000000064 prostate epithelial cell Anatomy 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 238000010926 purge Methods 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 230000019491 signal transduction Effects 0.000 description 1
- 238000004611 spectroscopical analysis Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 210000001550 testis Anatomy 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 239000013598 vector Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/86—Oxygen and sulfur atoms, e.g. thiohydantoin
-
- 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
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a crystal form of an androgen receptor inhibitor and a preparation method thereof. In particular to a crystal form of an androgen receptor inhibitor shown in a formula (I) and a preparation method thereof. The novel crystal form has good stability and can be better used for clinical treatment.
Description
The application is a divisional application of Chinese patent application with the application number of 201811514940.7, the application date of 2018, 12 months and 12 days, and the invention name of 'a crystal form of an androgen receptor inhibitor and a preparation method thereof'.
Technical Field
The present invention relates to a novel crystalline form of an androgen receptor inhibitor and a process for its preparation.
Background
Prostate cancer (PCa) is a malignant tumor that occurs in the prostate tissue of men and is the result of abnormal, disordered growth of prostate acinar cells. Differentiation and growth of normal prostate epithelial cells and the development of prostate cancer are dependent on androgens, which are mainly synthesized in the testes, accounting for approximately 80-90%. Synthetic androgens bind to the Androgen Receptor (AR) upon entry into the cell, causing dissociation of Heat Shock Proteins (HSP) from the AR and entry of the AR into the nucleus, activating a number of downstream genes, including Prostate Specific Antigen (PSA). Early stage prostate cancer is androgen sensitive and orchiectomy (castration) can significantly inhibit the development of prostate cancer. However, castration has a certain timeliness, many patients undergo a transition from androgen-dependent to androgen-independent for a while after castration, are no longer effective for anti-androgen therapy, and develop androgen-independent prostate cancer (AIPC), while the occurrence of AlPC is still important in connection with the activation of AR signaling pathway in PCa cells.
WO2014036897 discloses a new class of AR antagonists, including compounds of formula (I), which have superior activity and fewer side effects, and thus have broad clinical prospects.
WO2017041622 discloses crystalline form I of a compound of formula (I); CN106518773A discloses a crystal form II of the compound represented by formula (I).
It is well known that compounds may exist in a variety of crystalline forms. The crystal structure of the compound used as a medicinal active ingredient usually affects the chemical and physical stability of the medicament, and the difference of the crystal form, the preparation method and the storage condition may cause the change of the crystal structure of the compound and sometimes cause the generation of other forms of crystal forms. The physicochemical properties of different crystal forms are slightly different, and the drug effect and stability of the final finished medicine are also influenced. Therefore, it is necessary to improve various properties of the compound, and intensive research is needed to find a new crystal form with high purity and good physicochemical stability.
Disclosure of Invention
The invention aims to provide a novel crystal form of a compound shown as a formula (I), which has good crystal form stability and chemical stability and can be better applied to clinic.
The invention provides a B crystal form of a compound shown as a formula (I), which is characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 4.52, 9.215, 13.92, 14.98, 18.62, 23.99 and 32.822.
In a preferred embodiment, the present invention provides a crystalline form B of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 4.52, 9.215, 13.92, 14.98, 18.62, 23.28, 23.99, 28.63, 32.822, and 33.33.
In a preferred embodiment, the present invention provides a crystalline form B of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 4.52, 9.215, 13.92, 14.98, 18.62, 19.47, 23.28, 23.99, 28.63, 32.822, 33.33, 37.825 and 38.31.
In a preferred embodiment, the present invention provides a crystalline form B of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 1.
The present invention further provides a process for preparing form B of a compound of formula (I), said process comprising:
(1) dissolving a compound shown in a formula (I) in a proper amount of solvent, and volatilizing and crystallizing to obtain a target crystal form B, wherein the solvent can be one or more of methanol, ethanol, isopropanol and water; or
(2) Dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding anti-solvent for crystallization, filtering and crystallizing to obtain the target crystal form B, wherein the good solvent can be one or more of acetic acid, ethanol and isopropanol, and the anti-solvent can be one or more of petroleum ether, cyclohexane, n-heptane and n-hexane.
In another aspect, the present invention provides a crystalline form C of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992, and 20.365.
In a preferred embodiment, the present invention provides a crystalline form C of a compound of formula (I) characterized by: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992, 20.365, 22.837, 23.975, 24.433, 27.517, 29.48, and 30.274.
In a preferred embodiment, the present invention provides a crystalline form C of a compound of formula (I) characterized by: using Cu — K α radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ was obtained, which had characteristic peaks at 2 θ angles of 8.735, 9, 15.04, 15.66, 17.79, 18.992, 20.365, 22.145, 22.837, 23.975, 24.433, 27.517, 29.48, 30.274, 30.735, 31.688, 33.19, 35.715, and 44.893.
In a preferred embodiment, the present invention provides a crystalline form C of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 2.
The present invention further provides a process for preparing form C of the compound of formula (I), the process comprising:
dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding anti-solvent for crystallization, filtering and crystallizing to obtain the target C crystal form, wherein the good solvent can be dioxane, and the anti-solvent can be one or more of petroleum ether, cyclohexane, n-heptane and n-hexane.
In another aspect, the present invention provides a crystalline form D of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78 and 16.28.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 20.815, 23.255, and 24.695.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, having characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 16.96, 20.815, 23.255, 24.695, 26.23 and 26.714.
In a preferred embodiment, the present invention provides a crystalline form D of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 3.
The present invention further provides a process for preparing form D of a compound of formula (I), said process comprising:
dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding an anti-solvent for crystallization, filtering and crystallizing to obtain a target D crystal form, wherein the good solvent can be one or more of tetrahydrofuran, dichloromethane, acetone, dioxane, acetonitrile, N-dimethylformamide, acetic acid, methyl isobutyl ketone, ethyl acetate, methanol, ethanol and isopropanol, and the anti-solvent can be one or more of water, petroleum ether, cyclohexane, N-heptane and N-hexane.
In another aspect, the present invention provides a crystalline form E of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 7.29, 10.985, 12.425, 14.765, 15.855, 19.42, and 21.89.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.705, 7.29, 10.985, 12.425, 14.765, 15.855, 18.555, 19.42, 21.89, 22.98 and 26.725.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.705, 7.29, 10.985, 12.425, 14.765, 15.855, 17.76, 18.555, 19.42, 21.89, 22.98, 26.725, 28.48 and 38.12.
In a preferred embodiment, the present invention provides a crystalline form E of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 4.
The present invention further provides a process for preparing form E of the compound of formula (I), comprising:
the target E crystal form is obtained by dissolving the compound shown in the formula (I) in ethanol, cooling and crystallizing, and filtering.
In certain embodiments, the reduced temperature crystallization temperature is less than 10 ℃.
In another aspect, the present invention provides a crystalline form F of a compound of formula (I), characterized in that: using Cu-K alpha radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 theta angles, with characteristic peaks at 2 theta angles of 6.24, 12.52, 15.43, 15.885, 18.44, and 21.59.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized by: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.24, 9.436, 12.52, 13.895, 15.43, 15.885, 18.44, 21, 21.59, and 37.705.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized by: using Cu-K α radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, which had characteristic peaks at 2 θ angles of 6.24, 9.436, 12.52, 13.895, 15.43, 15.885, 16.912, 18.44, 21, 21.59, 22.47, 31.084, 37.705, and 39.28.
In a preferred embodiment, the present invention provides a crystalline form F of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 5.
The present invention further provides a process for preparing crystalline form F of a compound of formula (I), said process comprising:
the target F crystal form is obtained by dissolving the compound shown in the formula (I) in ethyl acetate, cooling and crystallizing, and filtering.
In certain embodiments, the reduced temperature crystallization temperature is less than 10 ℃.
In another aspect, the invention provides a crystal form G of a compound of formula (I), wherein: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834 and 18.865.
In a preferred embodiment, the present invention provides in a further aspect a crystalline form G of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834, 18.865, 20.545, 21.265, 23.005, and 25.156.
In a preferred embodiment, the present invention provides a crystalline form G of a compound of formula (I) characterized by: using Cu — K α radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ was obtained, which had characteristic peaks at 2 θ angles of 7.889, 8.832, 13.375, 14.58, 15.9, 17.834, 18.865, 20.545, 21.265, 23.005, 25.156, 25.975 and 26.784.
In a preferred embodiment, the present invention provides a crystalline form G of a compound of formula (I) characterized by: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 6.
The present invention further provides a process for preparing crystalline form G of a compound of formula (I), said process comprising:
dissolving the compound shown in the formula (I) in dimethyl sulfoxide, and volatilizing and crystallizing to obtain a target G crystal form.
In another aspect, the present invention provides a crystalline form H of a compound of formula (I), characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.48, 13.165, 15.68, 16.535, 18.96, 22.2, and 22.65.
In a preferred embodiment, the present invention provides in a further aspect a crystalline form H of a compound of formula (I) characterized in that: using Cu-ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, with characteristic peaks at 2 θ angles of 6.48, 9.815, 13.165, 15.68, 16.535, 18.96, 19.879, 20.975, 22.2, 22.65, 25.489, and 26.655.
In a preferred embodiment, the present invention provides a crystalline form H of a compound of formula (I) characterized in that: using Cu — K α radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ was obtained, which had characteristic peaks at 2 θ angles of 6.48, 9.815, 13.165, 15.68, 16.535, 18.96, 19.879, 20.975, 22.2, 22.65, 24.454, 25.489, 26.655, 27.982, 28.75 and 31.635.
In a preferred embodiment, the present invention provides a crystalline form H of a compound of formula (I) characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 7.
The present invention further provides a process for preparing the H crystalline form of the compound of formula (I), which process comprises:
the D crystal form of the compound shown in the formula (I) is placed in water for crystal transformation to obtain a target H crystal form.
The invention further relates to a pharmaceutical composition comprising one or more of the B, C, D, E, F, G, H crystal forms of the compound of formula (I), and one or more pharmaceutically acceptable carriers, diluents, or excipients.
The invention further relates to a pharmaceutical composition which is prepared by mixing one or more crystal forms of B, C, D, E, F, G, H crystal forms of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The invention further relates to a preparation method of a pharmaceutical composition containing the compound shown in the formula (I) or pharmaceutically acceptable salts thereof, which comprises mixing one or more of B, C, D, E, F, G, H crystal forms of the compound shown in the formula (I) with one or more pharmaceutically acceptable carriers, diluents or excipients.
The pharmaceutical composition can be prepared into any pharmaceutically acceptable dosage form. For example, the crystalline form or pharmaceutical preparation of the present invention may be formulated as tablets, capsules, pills, granules, solutions, suspensions, syrups, injections (including injections, sterile powders for injections and concentrated solutions for injections), suppositories, inhalants or sprays.
The invention further relates to the application of the B, C, D, E, F, G, H crystal form of the compound shown in the formula (I) or the pharmaceutical composition in the preparation of medicines for treating diseases related to androgen receptors; the disease is preferably prostate cancer.
The crystal form obtained by the invention is subjected to structure determination and crystal form research through X-ray powder diffraction pattern (XRPD) and Differential Scanning Calorimetry (DSC).
The crystallization method of the crystal form in the invention is conventional, such as volatile crystallization, cooling crystallization or room temperature crystallization.
The starting materials used in the preparation method of the crystal form of the invention can be compounds represented by formula (I) in any form, and specific forms include but are not limited to: amorphous, random crystalline, and the like.
In the description and claims of this application, unless otherwise indicated, scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. However, for a better understanding of the present invention, the following provides definitions and explanations of some of the relevant terms. In addition, where the definitions and explanations of terms provided herein are inconsistent with the meanings that would normally be understood by those skilled in the art, the definitions and explanations of terms provided herein shall control.
The 'pulping' of the invention refers to a method for purifying by utilizing the characteristic that a substance has poor solubility in a solvent but impurities have good solubility in the solvent, and the pulping purification can remove color, change crystal forms or remove a small amount of impurities.
The "X-ray powder diffraction pattern or XRPD" as used herein refers to the pattern obtained by dividing the X-ray beam according to bragg formula 2d sin θ ═ n λ (where λ is the wavelength of the X-ray,
the order n of diffraction is any positive integer, a first-order diffraction peak is generally taken, n is 1, when X-rays are incident on an atomic plane with a d-lattice plane spacing of a crystal or a part of a crystal sample at a grazing angle theta (complementary angle of incidence, also called Bragg angle), the Bragg equation can be satisfied, and the set of X-ray powder diffraction patterns can be measured.
The differential scanning calorimetry or DSC in the invention refers to measuring the temperature difference and the heat flow difference between a sample and a reference substance in the process of heating or keeping constant temperature of the sample so as to represent all physical changes and chemical changes related to the heat effect and obtain the phase change information of the sample.
The 2 theta or 2 theta angle refers to a diffraction angle, theta is a Bragg angle and has the unit of DEG or degree, and the error range of 2 theta is +/-0.3 or +/-0.2 or +/-0.1.
The "interplanar spacing or interplanar spacing (d value)" referred to herein means that the spatial lattice selects 3 non-parallel unit vectors a, b, c connecting two adjacent lattice points, which divide the lattice into juxtaposed parallelepiped units, called interplanar spacing. Spatial lattice according to determined parallelepiped unitAnd (4) connecting and dividing to obtain a set of linear grids called space grids or lattices. The lattice and the crystal lattice respectively reflect the periodicity of the crystal structure by using geometrical points and lines, and the surface spacing (namely the distance between two adjacent parallel crystal surfaces) of different crystal surfaces is different; has a unit of
Or angstroms.
Advantageous effects of the invention
The B, C, D, E, F, G, H crystal form of the compound shown in the formula (I) prepared by the invention has higher purity, and the crystal form stability is good under the conditions of illumination, high temperature and high humidity; the HPLC purity change is small, the chemical stability is high, the dissolution rate in a solvent is higher than that of the existing crystal form, and the effect of the medicine is better played; the B, C, D, E, F, G, H crystal form of the compound shown in the formula (I) can meet the medicinal requirements of production, transportation and storage, the production process is stable, can be repeated and controlled, and can be suitable for industrial production.
Drawings
FIG. 1 is an XRPD pattern for form B of compound represented by formula (I);
FIG. 2 is an XRPD pattern for crystalline form C of compound represented by formula (I);
FIG. 3 is an XRPD pattern for form D of compound represented by formula (I);
FIG. 4 is an XRPD pattern for crystalline form E of compound represented by formula (I);
FIG. 5 is an XRPD pattern for crystalline form F of compound represented by formula (I);
FIG. 6 is an XRPD pattern for crystalline form G of compound represented by formula (I);
FIG. 7 is an XRPD pattern for form H of compound represented by formula (I);
FIG. 8 is a DSC of crystalline form B of compound represented by formula (I);
FIG. 9 is a DSC of crystalline form C of compound represented by formula (I);
FIG. 10 is a DSC of crystalline form D of compound represented by formula (I);
FIG. 11 is a DSC of crystalline form E of compound represented by formula (I);
FIG. 12 is a DSC spectrum of crystalline form F of compound represented by formula (I);
FIG. 13 is a DSC of crystalline form G of compound represented by formula (I);
FIG. 14 is a DSC of the crystal form H of the compound of formula (I).
FIG. 15 is B, D, H, I crystal form SGF physiological medium dissolution curve
FIG. 16 is a dissolution curve of physiological medium of B, D, H, I crystal form FESSIF
Detailed Description
The present invention will be explained in more detail with reference to examples, which are provided only for illustrating the technical solutions of the present invention and are not intended to limit the spirit and scope of the present invention.
Test conditions of the apparatus used for the test:
1. differential Scanning Calorimeter (DSC)
The instrument model is as follows: MettlerToledo DSC 3+STARe System
And (3) purging gas: nitrogen gas
The heating rate is as follows: 10.0 ℃/min
Temperature range: 25-300 deg.C
2. X-ray Diffraction Spectroscopy (XRPD)
The instrument model is as follows: bruker D8 Discover A25X-ray powder diffractometer
Ray: monochromatic Cu-ka radiation (λ ═ 1.5406)
The scanning mode is as follows: θ/2 θ, scan range: 4-60 degree
Voltage: 40KV, current: 40mA
Example 1
Weighing 150mg of the I crystal form of the compound shown in the formula (I) (prepared according to the method disclosed in WO 2017041622) and placing the I crystal form into a reaction bottle, adding 6ml of ethanol for dissolving, then adding 30ml of petroleum ether, standing for 30min at room temperature, and filtering to obtain the B crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 1, the DSC pattern is shown in figure 8, and the characteristic peak positions are shown in the following table:
TABLE 1 characteristic peaks of form B
Example 2
Weighing 150mg of the crystal form I of the compound shown in the formula (I), putting the crystal form I into a reaction bottle, adding 0.5ml of dioxane for dissolving, adding 5ml of n-hexane, standing at room temperature for 6 hours, and filtering to obtain the crystal form C of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 2, the DSC pattern is shown in figure 9, and the characteristic peak positions are shown in the following table:
TABLE 2C Crystal form characteristic peaks
Example 3
Weighing 150mg of the crystal form I of the compound shown in the formula (I), putting the crystal form I into a reaction bottle, adding 0.5ml of acetonitrile, dissolving, adding 5ml of water, standing for 1h at room temperature, and filtering to obtain the crystal form D of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 3, the DSC pattern is shown in figure 10, and the characteristic peak positions are shown in the following table:
TABLE 3 characteristic peaks of the D crystal form
Example 4
Weighing 100mg of the crystal form I of the compound shown in the formula (I) and placing the crystal form I into a reaction bottle, adding 3ml of ethanol, stirring and dissolving at room temperature, cooling to-5 ℃ for crystallization, and filtering to obtain the crystal form E of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 4, the DSC pattern is shown in figure 11, and the characteristic peak positions are shown in the following table:
TABLE 4 characteristic peaks of the E crystal form
Example 5
Weighing 180mg of the crystal form I of the compound shown in the formula (I), putting the crystal form I into a reaction bottle, adding 1.1ml of ethyl acetate, stirring and dissolving at room temperature, cooling to-5 ℃ for crystallization, and filtering to obtain the crystal form F of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 5, the DSC pattern is shown in figure 12, and the characteristic peak positions are shown in the following table:
TABLE 5 characteristic peaks of the F crystal form
Example 6
Weighing 100mg of the crystal form I of the compound shown in the formula (I) and placing the crystal form I into a reaction bottle, adding 0.3ml of DMSO, dissolving, and placing the mixture at room temperature until the solvent is completely volatilized, so as to obtain the crystal form G of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 6, the DSC pattern is shown in figure 13, and the characteristic peak positions are shown in the following table:
TABLE 6 characteristic peaks of the G crystal form
Example 7
Weighing 100mg of the D crystal form of the compound shown in the formula (I) obtained in example 3, putting the D crystal form into a reaction bottle, adding 3ml of water, stirring at room temperature overnight, and filtering to obtain the H crystal form of the compound shown in the formula (I). The X-ray diffraction pattern is shown in figure 7, the DSC pattern is shown in figure 14, and the characteristic peak positions are shown in the following table:
TABLE 7 characteristic peaks of the H crystal form
Example 8
The B, C, D, E, F, H crystal form samples were subjected to physical stability tests under different standing conditions. The placing conditions are as follows:
1. opening at 40 ℃ and humidity of 75 percent;
2. opening at 25 ℃ and humidity of 60%;
3. sealing at 5 ℃;
4. lighting and opening.
The test results are shown in Table 8.
TABLE 8 physical stability of the respective forms
Note: v represents that the crystal form is not changed; and x represents the change of the crystal form.
As can be seen from the table: the crystal form C, E, F is transformed at 1 week, and the physical stability is poor; the crystal form B, D, H has no transformation after 1 month of stability and good physical stability.
Example 9
B, D, H samples of the three forms were subjected to different humidity conditions for chemical stability, and the results are shown in Table 9. The purity of the crystal form is detected by HPLC, the detection condition is Kromasil 100-5C18(4.6mm multiplied by 25cm, 5 mu m), and the mobile phase: methanol/water, detection wavelength: 230 nm.
TABLE 9 chemical stability of the respective forms
As can be seen from Table 9, the B, D, H crystal form has high purity, and the purity is not reduced basically under various conditions, and the stability is good.
Example 10
Respectively weighing B, D, H and I crystal forms of 20mg samples, placing in an inherent dissolution rate metal module, keeping for 30s under the condition of 20 pounds of pressure, respectively adding 20ml of SGF (simulated gastric juice)/FESSIF (simulated feeding state intestinal juice) physiological medium, keeping the temperature at 37 ℃, keeping 100rpm in the whole process, then respectively taking 0.5ml of solution at 5 min, 15 min, 30min, 45 min, 60 min, 90 min and 120min, filtering with 0.22um aqueous phase microfiltration membrane, simultaneously supplementing 0.5ml of the same physiological medium, and measuring the concentration according to an HPLC content measuring method. The results are shown in FIGS. 15 and 16.
The results show that: D. the dissolution rate of the H crystal form is basically the same as that of the I crystal form in SGF, and the dissolution rate of the B crystal form is obviously higher than that of the I crystal form. The dissolution rate of the B, D, H crystal form in FESSIF physiological medium is obviously faster than that of the I crystal form, the dissolution rates of the D crystal form and the H crystal form are very close, and the dissolution rate of the B crystal form is higher than that of the D crystal form and the H crystal form.
Claims (11)
1. A crystalline form D of a compound of formula (I) characterized by: using Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 theta angles is obtained, which has characteristic peaks at 2 theta angles of 6.715, 10.109, 13.515, 13.925, 14.78 and 16.28,
2. form D according to claim 1, characterized in that: using Cu-Ka radiation, an X-ray powder diffraction pattern was obtained expressed in terms of diffraction angle 2 θ, which had characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 20.815, 23.255, and 24.695.
3. Form D according to claim 1, characterized in that: using Cu-Ka radiation, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2 θ was obtained, which had characteristic peaks at 2 θ angles of 6.715, 10.109, 13.515, 13.925, 14.78, 16.28, 16.96, 20.815, 23.255, 24.695, 26.23, and 26.714.
4. Form D according to claim 1, characterized in that: the X-ray powder diffraction pattern obtained using Cu-ka radiation is shown in fig. 3.
5. A crystalline form of the compound of formula (I) according to any one of claims 1 to 4, characterized in that: the error range of the 2 theta angle is +/-0.2.
6. A pharmaceutical composition comprising the crystalline form D of the compound of formula (I) as claimed in claims 1-5, together with one or more pharmaceutically acceptable carriers, diluents or excipients.
7. A pharmaceutical composition prepared by mixing the form D of the compound of formula (I) as described in claims 1-5 with one or more pharmaceutically acceptable carriers, diluents or excipients.
8. A process for the preparation of a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, which comprises mixing form D of a compound of formula (I) as claimed in claims 1-5 with one or more pharmaceutically acceptable carriers, diluents or excipients.
9. A process for preparing form D of the compound of formula (I) as claimed in claims 1-5, comprising: dissolving the compound shown in the formula (I) in a proper amount of good solvent, adding an anti-solvent for crystallization, and filtering and crystallizing, wherein the good solvent is selected from one or more of tetrahydrofuran, dichloromethane, acetone, dioxane, acetonitrile, N-dimethylformamide, acetic acid, methyl isobutyl ketone, ethyl acetate, methanol, ethanol and isopropanol, and the anti-solvent is selected from one or more of water, petroleum ether, cyclohexane, N-heptane and N-hexane.
10. Use of the D crystalline form of the compound of formula (I) according to claims 1 to 5 or the pharmaceutical compositions according to claims 6 and 7 for the preparation of a medicament for the treatment of diseases related to the androgen receptor.
11. The use according to claim 10, wherein the disease is selected from prostate cancer.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711328911 | 2017-12-13 | ||
| CN2017113289117 | 2017-12-13 | ||
| CN201811514940.7A CN109912509B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811514940.7A Division CN109912509B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN112300076A true CN112300076A (en) | 2021-02-02 |
| CN112300076B CN112300076B (en) | 2022-10-25 |
Family
ID=66959897
Family Applications (3)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011180867.1A Active CN112300076B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN202011181358.0A Active CN112174895B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN201811514940.7A Active CN109912509B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
Family Applications After (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202011181358.0A Active CN112174895B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
| CN201811514940.7A Active CN109912509B (en) | 2017-12-13 | 2018-12-12 | Crystal form of androgen receptor inhibitor and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (3) | CN112300076B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014036897A1 (en) * | 2012-09-04 | 2014-03-13 | 上海恒瑞医药有限公司 | Imidazoline derivatives, preparation methods thereof, and their applications in medicine |
| WO2017041622A1 (en) * | 2015-09-10 | 2017-03-16 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
| CN106518773A (en) * | 2015-09-10 | 2017-03-22 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
-
2018
- 2018-12-12 CN CN202011180867.1A patent/CN112300076B/en active Active
- 2018-12-12 CN CN202011181358.0A patent/CN112174895B/en active Active
- 2018-12-12 CN CN201811514940.7A patent/CN109912509B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014036897A1 (en) * | 2012-09-04 | 2014-03-13 | 上海恒瑞医药有限公司 | Imidazoline derivatives, preparation methods thereof, and their applications in medicine |
| WO2017041622A1 (en) * | 2015-09-10 | 2017-03-16 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
| CN106518773A (en) * | 2015-09-10 | 2017-03-22 | 江苏恒瑞医药股份有限公司 | Crystalline form of androgen receptor inhibitor and preparation method thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109912509A (en) | 2019-06-21 |
| CN109912509B (en) | 2021-02-26 |
| CN112174895A (en) | 2021-01-05 |
| CN112174895B (en) | 2022-06-21 |
| CN112300076B (en) | 2022-10-25 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TW201313703A (en) | Novel crystalline forms of Azilsartan and preparation thereof | |
| EP3386956B1 (en) | Fumagillol derivatives and polymorphs thereof | |
| BR112019021447A2 (en) | fumarate salt, crystalline form i of said salt, methods for preparing them, pharmaceutical composition comprising the salt and crystalline form i and use of the fumarate salt, crystalline form i and the pharmaceutical composition | |
| WO2008013823A2 (en) | Co-crystals of (2r-trans)-6-chloro-5-[[4-[(4-fluorophenyl)methyl]-2,5-dimethyl-1-piperazinyl]carbonyl]-n,n,1-trimethyl-alpha-oxo-1h-indole-3-acetamide | |
| EP4438613A1 (en) | Mono-p-toluenesulfonate of axl kinase inhibitor and crystal form thereof | |
| JP6334065B2 (en) | Salt of quinazoline derivative or crystal thereof and method for producing them | |
| CN108779122B (en) | A kind of crystal form of bisulfate of JAK kinase inhibitor and preparation method thereof | |
| CN112174895B (en) | Crystal form of androgen receptor inhibitor and preparation method thereof | |
| EP3674304A1 (en) | Crystal form of parp-1 inhibitor and preparation method therefor | |
| TWI770934B (en) | Crystal form of monomaleate of tyrosine kinase inhibitor and preparation method thereof | |
| CN111108098B (en) | Crystal form of alkynyl pyridine prolyl hydroxylase inhibitor and preparation method thereof | |
| AU2016318700B2 (en) | Crystalline form of androgen receptor inhibitor and preparation method thereof | |
| US20250333381A1 (en) | Solid state forms | |
| CN115448895B (en) | A crystal form of vortioxetine prodrug, preparation method and application thereof | |
| CN110240562B (en) | Medicinal salt and crystal form of prolyl hydroxylase inhibitor and preparation method thereof | |
| CN109384791B (en) | Crystal form of imidazo isoindole derivative free alkali and preparation method thereof | |
| WO2025237212A1 (en) | Pyrimidine derivative meglumine salt and crystal forms thereof | |
| JP2023532217A (en) | Crystal forms of SHP2 inhibitors, compositions thereof, methods of preparation and applications thereof | |
| CA2657117A1 (en) | Crystals of benzoxadiazole derivative | |
| CN109422723B (en) | Crystal form of intestinal 2B type sodium phosphate cotransporter inhibitor and preparation method thereof | |
| CN120965677A (en) | A Sparsentan-type DCI, its preparation method and applications | |
| CN117567550A (en) | New crystal form of eloxibat, preparation method and application thereof | |
| HK40024614A (en) | Crystalline form of alkynyl pyridine prolyl hydroxylase inhibitor and method for preparing same | |
| EP3941588A1 (en) | Co-crystal forms of selinexor | |
| HK40050155A (en) | A crystal form of a maleate of tyrosine kinase inhibitor and preparation method therefor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |