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WO2024179558A1 - Forme cristalline de pirtobrutinib, son procédé de préparation et son utilisation - Google Patents

Forme cristalline de pirtobrutinib, son procédé de préparation et son utilisation Download PDF

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Publication number
WO2024179558A1
WO2024179558A1 PCT/CN2024/079501 CN2024079501W WO2024179558A1 WO 2024179558 A1 WO2024179558 A1 WO 2024179558A1 CN 2024079501 W CN2024079501 W CN 2024079501W WO 2024179558 A1 WO2024179558 A1 WO 2024179558A1
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Prior art keywords
crystalline
csi
csii
ray powder
diffraction pattern
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PCT/CN2024/079501
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English (en)
Chinese (zh)
Inventor
沈艺楠
史佳明
孟丽苹
Original Assignee
苏州科睿思制药有限公司
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Publication of WO2024179558A1 publication Critical patent/WO2024179558A1/fr

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Classifications

    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three 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
    • C07D231/38—Nitrogen atoms

Definitions

  • the present invention relates to the field of crystal chemistry, and in particular to a crystal form of Pirtobrutinib and a preparation method and use thereof.
  • BTK is a cytoplasmic, non-receptor tyrosine kinase belonging to the Tec family of kinases. Aberrant BTK expression and/or activity has been demonstrated in different cancers and autoimmune disorders.
  • Pirtobrutinib is an oral, non-covalent BTK inhibitor developed by Eli Lilly and has been approved for marketing in the United States for the treatment of mantle cell lymphoma (MCL), and has achieved positive clinical results for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL).
  • Pirtobrutinib (S)-5-amino-3-(4-((5-fluoro-2-methoxybenzamido)methyl)phenyl)-1-(1,1,1-trifluoropropan-2-yl)-1H-pyrazole-4-carboxamide (hereinafter referred to as "Compound I”), and its structural formula is as follows:
  • Crystals are solids in which compound molecules are arranged in a three-dimensional orderly manner in a microscopic structure to form a lattice.
  • Polymorphism refers to the phenomenon that a compound exists in multiple crystal forms. A compound may exist in one or more crystal forms, but its existence and characteristics cannot be specifically predicted.
  • Different solid forms of active pharmaceutical ingredients have different physicochemical properties, including physicochemical stability, thermal stability, solubility and hygroscopicity, which may lead to different dissolution and absorption of drugs in the body, thus affecting the clinical efficacy of drugs to a certain extent.
  • different solid forms of active pharmaceutical ingredients have different manufacturability, including yield, purification properties, filtration properties, drying properties, milling properties and stability relative to pressure during tableting, which may affect the processing of active pharmaceutical ingredients during production. Therefore, different solid forms of active pharmaceutical ingredients may have different characteristics, which in turn provides opportunities to improve drug performance.
  • WO2020028258A1 discloses Form A, Form B and Form C of Compound I, wherein Form B is a mixed crystal and Form C is a semi-1,4-dioxane solvate.
  • WO2022240920A1 discloses a cocrystal of adipic acid and camphoric acid of Compound I. In the prior art, Form A is the best developed form, but WO2020028258A1 discloses that Form A has poor solubility.
  • the inventors of the present application unexpectedly discovered the crystal form CSI and the crystal form CSII of the present invention, which have advantages in at least one aspect of solubility, hygroscopicity, purification effect, stability, adhesion, compressibility, fluidity, in vivo and in vitro dissolution, and bioavailability.
  • they have good solubility, low hygroscopicity, and good stability, which solves the problems existing in the prior art, is more suitable for the development of pharmaceutical preparations, and is of great significance to the development of drugs containing Compound I.
  • the present invention provides a crystal form of Compound I, a preparation method thereof, and a pharmaceutical composition comprising the crystal form.
  • the present invention provides a crystalline form CSI of Compound I (hereinafter referred to as "crystalline form CSI").
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 10.2° ⁇ 0.2°, 11.4° ⁇ 0.2°, and 25.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 16.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 22.0° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 16.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, and 22.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 16.2° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 29.1° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at diffraction angles 2 ⁇ of 16.2° ⁇ 0.2°, 24.6° ⁇ 0.2°, and 29.1° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSI has characteristic peaks at any three, or four, or five, or six, or seven, or eight, or nine of the diffraction angle 2 ⁇ values of 10.2° ⁇ 0.2°, 11.4° ⁇ 0.2°, 25.2° ⁇ 0.2°, 16.7° ⁇ 0.2°, 21.2° ⁇ 0.2°, 22.0° ⁇ 0.2°, 16.2° ⁇ 0.2°, 24.6° ⁇ 0.2°, 29.1° ⁇ 0.2°, 15.3° ⁇ 0.2°, 24.1° ⁇ 0.2°, and 28.6° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CSI is substantially as shown in FIG. 1 .
  • thermogravimetric analysis graph of Form CSI is substantially as shown in FIG. 3 , and there is no mass loss when heated to about 200° C.
  • the crystalline form CSI is an anhydrate.
  • the differential scanning calorimetry analysis diagram of the crystalline form CSI is basically as shown in Figure 4, wherein there is a first endothermic peak near 151°C, which is the melting endothermic signal of the crystalline form CSI; there is a first exothermic peak near 152°C; there is a second endothermic peak near 171°C; there is a second exothermic peak near 172°C; and there is an endothermic peak near 191°C.
  • the present invention also provides a method for preparing the crystalline CSI, which comprises: placing a solid of Compound I in water, or a mixed solvent of water and alcohol, and stirring to obtain the crystalline CSI.
  • the alcohol is preferably methanol; and the stirring temperature is preferably 4° C. to room temperature.
  • Crystalline CSI has higher solubility.
  • the crystalline form CSI of the present invention has higher solubility.
  • the solubility is 2-3 times that of the crystalline form of the prior art.
  • the solubility of the drug is good for improving the absorption of the drug in the human body and improving the bioavailability.
  • the higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • Crystalline CSI has low hygroscopicity.
  • the hygroscopic weight gain of the crystal CSI under 0%-80% RH conditions is 0.69%. Low hygroscopicity does not require harsh drug production and storage, reduces drug production, storage and quality control costs, and has strong economic value.
  • Crystalline CSI is suitable for the preparation of pharmaceutical preparations.
  • Crystalline CSI maintains its crystal form after ball milling. Mechanical external force is often required for mixing during the production of solid dosage forms. Crystalline CSI has good physical stability and can reduce the risk of reduced crystallinity of active pharmaceutical ingredients and solid form transformation during granulation.
  • Crystalline CSI has good stability.
  • the crystal form CSI has good humidity stability. After the crystal form CSI undergoes a humidity change from 0% RH to 95% RH to 0% RH, the crystal form of the crystal form CSI remains unchanged.
  • Crystalline CSI has good physical and chemical stability. Crystalline CSI is stable for at least 9 months when placed under 25°C/60%RH conditions, and the purity remains basically unchanged, maintaining above 99.9%. This indicates that the crystalline CSI API has good stability under long-term conditions. Crystalline CSI is stable for at least 6 months when placed under 40°C/75%RH conditions, and the purity remains basically unchanged, maintaining above 99.9%. This indicates that the crystalline CSI API has good stability under accelerated conditions.
  • Crystalline CSI has good stability, which is conducive to avoiding the impact of solid form changes on drug quality during drug storage, transportation, and production, thereby ensuring consistent and controllable quality of APIs and reducing changes in drug quality, bioavailability, and toxic side effects caused by solid form changes.
  • the present invention provides a crystalline form CSII of Compound I (hereinafter referred to as "crystalline form CSII").
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, and 15.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 16.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 22.0° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2 ⁇ of 16.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, and 22.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at one, two, or three of the diffraction angles 2 ⁇ of 11.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 24.0° ⁇ 0.2°; preferably, the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at diffraction angles 2 ⁇ of 11.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, and 24.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the crystalline form CSII has characteristic peaks at any three, or four, or five, or six, or seven, or eight, or nine of the diffraction angles 2 ⁇ of 6.5° ⁇ 0.2°, 13.3° ⁇ 0.2°, 15.0° ⁇ 0.2°, 16.8° ⁇ 0.2°, 19.6° ⁇ 0.2°, 22.0° ⁇ 0.2°, 11.8° ⁇ 0.2°, 18.5° ⁇ 0.2°, 24.0° ⁇ 0.2°, 14.0° ⁇ 0.2°, and 19.2° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form CSII is substantially as shown in FIG. 9 .
  • the crystalline form CSII is a hydrate.
  • the present invention also provides a method for preparing the crystalline form CSII, which comprises: mixing the solid compound I with hydroxypropyl- ⁇ -cyclodextrin, placing in water and stirring, and obtaining the crystalline form CSII after standing.
  • the stirring temperature is preferably 4° C. to room temperature.
  • the crystal form CSII of the present invention has higher solubility.
  • the solubility is 2-3 times that of the crystal form of the prior art.
  • the crystal form CSII provided by the present invention has higher solubility, which is beneficial to improve the absorption of the drug in the human body and improve the bioavailability.
  • higher solubility can reduce the dosage of the drug while ensuring the efficacy of the drug, thereby reducing the side effects of the drug and improving the safety of the drug.
  • Crystal form of CSII remains unchanged after ball milling. Mechanical external force is often required for mixing during the production of solid preparations. Crystal form CSII has good physical stability and can reduce the risk of reduced crystallinity of active pharmaceutical ingredients and solid form transformation during granulation.
  • Crystalline CSII has good physical and chemical stability. Crystalline CSII is placed under 30°C/65%RH conditions for at least 6 months without any change in crystal form, and the purity remains basically unchanged, maintaining above 99.9%.
  • Crystalline CSII has good stability, which is conducive to avoiding the impact of solid form changes on drug quality during drug storage, transportation, and production, thereby ensuring consistent and controllable quality of APIs and reducing changes in drug quality, bioavailability, and toxic side effects caused by solid form changes.
  • the present invention provides the use of crystal form CSI or crystal form CSII for preparing other crystal forms or salts of compound I.
  • the present invention provides a pharmaceutical composition, which comprises an effective therapeutic amount of crystalline form CSI or crystalline form CSII, and pharmaceutically acceptable excipients.
  • the present invention provides the use of crystal form CSI or crystal form CSII in the preparation of oral non-covalent BTK inhibitor drugs.
  • the present invention provides the use of crystal form CSI or crystal form CSII in the preparation of drugs for treating mantle cell lymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma.
  • Figure 1 is the XRPD diagram of crystal form CSI
  • Figure 2 is the XRPD image of crystal form CSI
  • Figure 3 is the TGA graph of crystal form CSI
  • Figure 4 is the DSC graph of crystalline CSI
  • Figure 5 is the DVS curve of crystal CSI
  • Figure 6 is a comparison of XRPD images of the crystal form CSI before and after DVS testing (from bottom to top: before DVS, after DVS)
  • Figure 7 is a comparison of XRPD images of crystal form CSI before and after ball milling (from bottom to top: before ball milling, after ball milling)
  • Figure 8 is a comparison of XRPD images of crystalline form CSI placed under different conditions (from bottom to top: before placement, after 6 months at 40°C/75%RH, after 9 months at 25°C/60%RH)
  • Figure 9 is the XRPD diagram of Form CSII
  • Figure 10 is a comparison of XRPD images of Form CSII before and after ball milling (from bottom to top: before ball milling, after ball milling)
  • FIG11 is a comparison of XRPD images of crystalline form CSII placed under different conditions (from bottom to top: before placement, after placement at 30°C/65% RH for 6 months)
  • the X-ray powder diffraction pattern of the present invention is collected on a Bruker X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction of the present invention are as follows:
  • Scanning range from 3.0 to 40.0 degrees or from 4.0 to 40.0 degrees
  • thermogravimetric analysis (TGA) graph of the present invention is collected on TA Q500.
  • the method parameters of the thermogravimetric analysis (TGA) of the present invention are as follows:
  • the differential scanning calorimetry (DSC) diagram of the present invention is collected on TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) of the present invention are as follows:
  • the dynamic moisture adsorption (DVS) graph of the present invention is collected on an Intrinsic dynamic moisture adsorption instrument produced by SMS (Surface Measurement Systems Ltd.).
  • the instrument control software is DVS-Intrinsic control software.
  • the method parameters of the dynamic moisture adsorption instrument are as follows:
  • Relative humidity range 0%RH-95%RH
  • the nuclear magnetic resonance hydrogen spectrum data ( 1 H NMR) of the present invention is collected from a Bruker Avance II DMX 400M HZ nuclear magnetic resonance spectrometer. 1-5 mg of sample is weighed and dissolved in 0.5 mL of deuterated dimethyl sulfoxide to prepare a 2-10 mg/mL solution.
  • the solubility detection method of the present invention is shown in Table 2.
  • the “stirring” is accomplished by conventional methods in the art, such as magnetic stirring or mechanical stirring, with a stirring speed of 50-1800 rpm, wherein the magnetic stirring is preferably 300-900 rpm, and the mechanical stirring is preferably 100-300 rpm.
  • the “separation” is accomplished by conventional methods in the art, such as centrifugation or filtration.
  • the “centrifugation” operation is: placing the sample to be separated in a centrifuge tube and centrifuging at a rate of 10,000 rpm until all the solids sink to the bottom of the centrifuge tube.
  • the "drying” can be carried out at room temperature or higher.
  • the drying temperature is from room temperature to about 80°C, or to 60°C, or to 40°C.
  • the drying time can be more than 0.5 hours, or overnight.
  • the drying is carried out in a fume hood, a forced air oven, or a vacuum oven.
  • room temperature is not a specific temperature value, but refers to the temperature range of 10-30°C.
  • anhydrous substance refers to a solid substance that does not contain crystal water or crystallization solvent.
  • the "hydrate” refers to a solid substance containing water of crystallization.
  • the “characteristic peak” refers to a representative diffraction peak used to identify crystals.
  • the peak position can usually have an error of ⁇ 0.2°.
  • crystal or “crystal form” can be characterized by X-ray powder diffraction.
  • X-ray powder diffraction pattern is affected by the conditions of the instrument, the preparation of the sample and the purity of the sample.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern may also change with the change of the experimental conditions, so the diffraction peak intensity cannot be used as the only or decisive factor for determining the crystal form.
  • the relative intensity of the diffraction peaks in the X-ray powder diffraction pattern is related to the preferred orientation of the crystal, and the diffraction peak intensity shown in the present invention is illustrative rather than for absolute comparison. Therefore, those skilled in the art will understand that the X-ray powder diffraction pattern of the crystal form protected by the present invention does not have to be completely consistent with the X-ray powder diffraction pattern in the embodiments referred to herein, and any crystal form having an X-ray powder diffraction pattern that is the same or similar to the characteristic peaks in these patterns belongs to the scope of the present invention. Those skilled in the art can compare the X-ray powder diffraction pattern listed in the present invention with the X-ray powder diffraction pattern of an unknown crystal form to confirm whether the two sets of patterns reflect the same or different crystal forms.
  • the crystalline form CSI and the crystalline form CSII of the present invention are pure, and substantially no other crystalline forms are mixed.
  • substantially no when used to refer to a new crystalline form means that this crystalline form contains less than 20% (by weight) of other crystalline forms, particularly less than 10% (by weight) of other crystalline forms, more preferably less than 5% (by weight) of other crystalline forms, and more preferably less than 1% (by weight) of other crystalline forms.
  • the compound I as a raw material includes but is not limited to solid form (crystalline or amorphous), oily, liquid form and solution.
  • the compound I as a raw material is in solid form.
  • the compound I used in the following examples can be prepared according to the prior art, for example, according to the method described in WO2020028258A1.
  • a certain mass of amorphous solid of Compound I was weighed and added to the corresponding volume of the solvent system. After stirring at 4°C for about 60 minutes, it was allowed to stand for about 140 minutes, and continued to stir for about 20 minutes. The obtained solids were marked as samples 1-3 respectively. Samples 1 and 2 were mixed and filtered, and then dried naturally at room temperature overnight after filtration. After testing, the obtained solid was crystalline CSI, and its XRPD pattern is shown in Figure 1, and the XRPD data is shown in Table 4. After filtration, sample 3 was tested by XRPD to be crystalline CSI, and its XRPD pattern is shown in Figure 2, and the XRPD data is shown in Table 5.
  • the TGA graph of crystalline CSI is shown in FIG3 . There is substantially no mass loss when it is heated to about 200° C., and crystalline CSI is anhydrous.
  • the DSC graph of crystalline CSI is shown in Figure 4.
  • the compound has two active hydrogens at the amino position on the pyrazole ring, which do not show any peaks in the NMR spectrum.

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Abstract

La présente invention concerne une nouvelle forme cristalline de pirtobrutinib, son procédé de préparation, une composition pharmaceutique contenant ladite forme cristalline, et l'utilisation de la forme cristalline dans la préparation d'un médicament inhibiteur de BTK non covalent oral et d'un médicament pour le traitement d'un lymphome cellulaire, d'une leucémie lymphocytaire chronique et d'un petit lymphome lymphocytaire.
PCT/CN2024/079501 2023-03-02 2024-03-01 Forme cristalline de pirtobrutinib, son procédé de préparation et son utilisation WO2024179558A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
CN202310188264 2023-03-02
CN202310188264.3 2023-03-02
CN202310465682.2 2023-04-27
CN202310465682 2023-04-27

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020028258A1 (fr) * 2018-07-31 2020-02-06 Loxo Oncology, Inc. Dispersions et formulations séchées par pulvérisation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido) méthyle)phényle)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
WO2022056100A1 (fr) * 2020-09-10 2022-03-17 Loxo Oncology, Inc. Procédés et intermédiaires pour la préparation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido)méthyl)phényl)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
WO2022143629A1 (fr) * 2020-12-29 2022-07-07 上海岸阔医药科技有限公司 Réactif et procédé pour le traitement de maladies ou d'affections cutanées associées à un agent antitumoral
WO2022240920A1 (fr) * 2021-05-14 2022-11-17 Loxo Oncology, Inc. Formes cocristallines d'un inhibiteur de la tyrosine kinase de bruton
CN115611810A (zh) * 2021-07-16 2023-01-17 深圳市塔吉瑞生物医药有限公司 取代的吡唑类化合物及包含该化合物的组合物及其用途

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020028258A1 (fr) * 2018-07-31 2020-02-06 Loxo Oncology, Inc. Dispersions et formulations séchées par pulvérisation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido) méthyle)phényle)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
WO2022056100A1 (fr) * 2020-09-10 2022-03-17 Loxo Oncology, Inc. Procédés et intermédiaires pour la préparation de (s)-5-amino-3-(4-((5-fluoro-2-méthoxybenzamido)méthyl)phényl)-1-(1,1,1-trifluoropropane-2-yl)-1 h-pyrazole-4-carboxamide
WO2022143629A1 (fr) * 2020-12-29 2022-07-07 上海岸阔医药科技有限公司 Réactif et procédé pour le traitement de maladies ou d'affections cutanées associées à un agent antitumoral
WO2022240920A1 (fr) * 2021-05-14 2022-11-17 Loxo Oncology, Inc. Formes cocristallines d'un inhibiteur de la tyrosine kinase de bruton
CN115611810A (zh) * 2021-07-16 2023-01-17 深圳市塔吉瑞生物医药有限公司 取代的吡唑类化合物及包含该化合物的组合物及其用途

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