WO2018072702A1 - Forme cristalline de composé imidazole, type de sel et son procédé de préparation - Google Patents

Forme cristalline de composé imidazole, type de sel et son procédé de préparation Download PDF

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Publication number
WO2018072702A1
WO2018072702A1 PCT/CN2017/106647 CN2017106647W WO2018072702A1 WO 2018072702 A1 WO2018072702 A1 WO 2018072702A1 CN 2017106647 W CN2017106647 W CN 2017106647W WO 2018072702 A1 WO2018072702 A1 WO 2018072702A1
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compound
crystal form
slightly soluble
crystalline form
benefit
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PCT/CN2017/106647
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English (en)
Chinese (zh)
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李宗斌
刘玲
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南京明德新药研发股份有限公司
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Publication of WO2018072702A1 publication Critical patent/WO2018072702A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing aromatic rings

Definitions

  • the invention discloses an imidazole compound crystal form, a salt form and a preparation method thereof, and also relates to the application of the crystal form and the salt form in preparing a medicament for treating cerebrovascular diseases.
  • Protein tyrosine kinases are a class of enzymes that catalyze the transfer of a phosphate group from ATP to a tyrosine residue located on a protein substrate that plays a role in normal cell growth.
  • Many growth factor receptor proteins act through tyrosine kinases and influence the signal through this process, which in turn regulates cell growth.
  • FGFR Fibroblast growth factor receptor
  • VEGFR Vascular endothelial growth factor receptor
  • PDGFR Platinum-derived growth factor receptor
  • these receptors either mutated or overexpressed, become abnormal, causing cell proliferation to be uncontrolled, leading to tumor growth, ultimately leading to a well-known disease, cancer.
  • Growth factor receptor protein tyrosine kinase inhibitors act to treat cancer and other diseases characterized by uncontrolled or abnormal cell growth by inhibiting the above-described phosphorylation process.
  • Angiogenesis has been associated with a large number of different types of cancer, including solid tumors and blood-borne tumors. Solid tumors associated with angiogenesis include, but are not limited to, rhabdomyosarcoma, retinoblastoma, Ewing's sarcoma, neuroblastoma, and osteosarcoma. Angiogenesis is associated with breast cancer, prostate cancer, lung cancer, and colon cancer. Angiogenesis is also associated with blood-carrying tumors such as leukemia, lymphoma, multiple myeloma, and any of various acute or chronic myeloid tumor diseases in which white blood cells are unrestricted.
  • Proliferation is usually accompanied by anemia, impaired blood clotting, and enlargement of lymph nodes, liver, and spleen. Also believe that angiogenesis is different in bone marrow Often plays a role, the abnormalities cause leukemia, lymphoma and multiple myeloma.
  • Angiogenesis plays a major role in the metastasis of cancer, and if it can inhibit or eliminate angiogenic activity, it will not grow despite the presence of the tumor. In the disease state, prevention of angiogenesis can reduce damage caused by invasion of the new microvascular system. Therapies directed to the control of vasogenic processes may result in the removal or alleviation of these diseases.
  • FGFR Fibroblast growth factor receptor
  • VEGFR Vascular endothelial growth factor receptor
  • PDGFR Platinum-derived growth factor receptor
  • the present invention provides Form A of Compound 1, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 20.39 ⁇ 0.2 °, 21.55 ⁇ 0.2 °, 24.06 ⁇ 0.2 °.
  • the X crystal powder diffraction pattern of the above Compound 1 has a characteristic diffraction peak at the following 2 ⁇ angles: 15.13 ⁇ 0.2°, 17.28 ⁇ 0.2°, 17.92 ⁇ 0.2°, 20.39 ⁇ 0.2°. , 21.55 ⁇ 0.2 °, 22.95 ⁇ 0.2 °, 24.06 ⁇ 0.2 °, 26.80 ⁇ 0.2 °.
  • the X-form analysis data of the A crystal form of the above Compound 1 is shown in Table 1.
  • the A crystalline form of Compound 1 above has a differential scanning calorimetry curve having an exothermic peak at 236.62 °C ⁇ 2 °C.
  • the A crystal form of the above compound 1 has a DSC pattern as shown in FIG.
  • the A crystal form of the above compound 1 has a thermogravimetric analysis curve having a weight loss of 0.3950 ⁇ 0.2% at 215.64 ⁇ 2°C.
  • the T crystal of Form A of Compound 1 above is shown in Figure 3.
  • the present invention also provides the hydrochloride salt of Compound 1, as shown in Compound 2.
  • the present invention also provides Form B of Compound 2, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 17.49 ⁇ 0.2 °, 25.40 ⁇ 0.2 °, 27.83 ⁇ 0.2 °.
  • the B crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 15.99 ⁇ 0.2°, 17.49 ⁇ 0.2°, 18.79 ⁇ 0.2°, 21.60 ⁇ 0.2°. , 24.22 ⁇ 0.2 °, 25.40 ⁇ 0.2 °, 26.11 ⁇ 0.2 °, 27.83 ⁇ 0.2 °.
  • the B crystal form of the above compound 2 has an XRPD pattern as shown in FIG.
  • the X-ray pattern analysis data of the B crystal form of the above compound 2 is shown in Table 2.
  • the B crystal form of the above compound 2 has a differential scanning calorimetry curve having a starting point of an exothermic peak at 234.93 ° C ⁇ 5 ° C.
  • the B crystal form of the above compound 2 has a DSC pattern as shown in FIG.
  • the B crystal form of the above compound 2 has a thermogravimetric analysis curve having a weight loss of 1.002 ⁇ 0.5% at 207.16 ⁇ 5 °C.
  • the B crystal form of the above compound 2 has a TGA pattern as shown in FIG.
  • the present invention also provides Form C of Compound 2, the X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 12.70 ⁇ 0.2 °, 16.21 ⁇ 0.2 °, 24.79 ⁇ 0.2 °.
  • the C crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 12.70 ⁇ 0.2°, 16.21 ⁇ 0.2°, 21.34 ⁇ 0.2°, 22.90 ⁇ 0.2°. , 23.57 ⁇ 0.2 °, 24.79 ⁇ 0.2 °, 33.54 ⁇ 0.2 °.
  • the C crystal form of the above compound 2 has an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 ⁇ angles: 12.70 ⁇ 0.2°, 15.88 ⁇ 0.2°, 16.21 ⁇ 0.2°, 21.34 ⁇ 0.2°. , 22.90 ⁇ 0.2 °, 23.57 ⁇ 0.2 °, 24.79 ⁇ 0.2 °, 33.54 ⁇ 0.2 °.
  • the C crystal form of the above compound 2 has an XRPD pattern as shown in FIG.
  • the C crystal form of Compound 2 above has a differential scanning calorimetry curve having an onset of an exothermic peak at 231.55 °C ⁇ 5 °C.
  • the C crystal form of the above Compound 2 has a DSC spectrum as shown in FIG.
  • the C crystal form of the above compound 2 has a thermogravimetric analysis curve having a weight loss of 0.9093 ⁇ 0.5% at 207.97 ⁇ 5°C.
  • the C crystal form of the above compound 2 has a TGA pattern as shown in FIG.
  • the present invention also provides a mesylate salt of Compound 1, as shown in Compound 3.
  • the present invention also provides a crystalline form of Compound 3 having an X-ray powder diffraction pattern having characteristic diffraction peaks at the following 2 theta angles: 15.48 ⁇ 0.2 °, 18.42 ⁇ 0.2 °, 22.74 ⁇ 0.2 °.
  • the X crystal form of the compound D of the above compound 3 has a characteristic diffraction peak at the following 2 theta angle: 14.85 ⁇ 0.2 °, 15.48 ⁇ 0.2 °, 18.42 ⁇ 0.2 °, 20.90 ⁇ 0.2 °. , 21.95 ⁇ 0.2 °, 22.74 ⁇ 0.2 °, 26.96 ⁇ 0.2 °, 29.42 ⁇ 0.2 °.
  • the X crystal form of the compound D of the above compound 3 is shown in Fig. 10.
  • the X crystal form analysis data of the D crystal form of the above compound 3 is shown in Table 4.
  • the D crystal form of Compound 3 above has a differential scanning calorimetry curve having a starting point of endothermic peak at 185.44 °C ⁇ 2 °C.
  • the D crystal form of the above compound 3 has a DSC pattern as shown in FIG.
  • the D crystal form of the above compound 3 has a thermogravimetric analysis curve having a weight loss of 0.6813 + 0.3% at 202.10 ⁇ 2 °C.
  • T crystal of Form D of Compound 3 above is shown in Figure 12.
  • the present invention also provides the use of the crystalline form A of Compound 1, Compound 2, Form B of Compound 2, Form C of Compound 2, Form D of Compound 3 or Compound 3 in the preparation of a medicament for treating cerebrovascular diseases.
  • the crystal form of Compound A, the B crystal form of Compound 2, the C crystal form of Compound 2, and the D crystal form of Compound 3 are stable, have low hygroscopicity, are good in water solubility, and have good pharmaceutical prospects.
  • intermediate compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, combinations thereof with other chemical synthesis methods, and those skilled in the art.
  • Well-known equivalents, preferred embodiments include, but are not limited to, embodiments of the invention.
  • the present invention employs the following abbreviations: DMF stands for dimethylformamide; MsOH stands for methanesulfonic acid; EtOH stands for ethanol; and NaOH stands for sodium hydroxide.
  • XRPD X-ray powder diffractometer
  • Test method Approximately 10-20 mg samples were used for XRPD detection.
  • DSC Differential Scanning Calorimeter
  • Test method A sample ( ⁇ 1 mg) was placed in a DSC aluminum pan for testing, and the sample was heated from 25 ° C to 300 ° C or 350 ° C at a heating rate of 10 ° C / min under 50 mL / min N 2 .
  • TGA Thermal Gravimetric Analyzer
  • Test method A sample (2 to 5 mg) was placed in a TGA platinum pot for testing, and the sample was heated from room temperature to 300 ° C at a heating rate of 10 ° C/min under a condition of 25 mL/min N 2 .
  • Figure 1 is an XRPD spectrum of Cu-K ⁇ radiation of Form A of Compound 1.
  • Figure 3 is a TGA spectrum of Form A of Compound 1.
  • Figure 5 is a DSC chart of Form B of Compound 2.
  • Figure 6 is a TGA spectrum of Form B of Compound 2.
  • Figure 7 is an XRPD spectrum of Cu-K ⁇ radiation of Form C of Compound 2.
  • Figure 8 is a DSC chart of Form C of Compound 2.
  • Figure 9 is a TGA spectrum of Form C of Compound 2.
  • Figure 10 is an XRPD spectrum of Cu-K ⁇ radiation of Form D of Compound 3.
  • Figure 11 is a DSC chart of Form D of Compound 3.
  • Figure 12 is a TGA spectrum of Form D of Compound 3.
  • Example 1B (37 g, 161 mmol), imidazole (22 g, 322 mmol), a mixture of potassium iodide (22 g, 322 mmol) and potassium carbonate (44.7 g, 323 mmol) in acetone (370 ml) Stir at 50 to 60 ° C for 3 hours. The filtrate was filtered, and the filtrate was poured into water (1. The combined organic layers were dried with EtOAc EtOAc.
  • Form B of Compound 2 30 mg was added to 0.1 mL of methanol to form a suspension.
  • the suspension sample was shaken on a constant temperature uniform (40 ° C) for 2 days (protected from light).
  • the residual solid was centrifuged and dried in a vacuum oven at 40 ° C overnight to obtain Form C of Compound 2.
  • Form A of Compound 1 (1.8 g) was placed in a 50 mL round bottom flask, purified water (5 mL) was added, and MsOH (0.93 g) was slowly added dropwise with stirring at room temperature, and stirred for 0.5 hour until the solution became clear. After the reaction mixture was lyophilized, the obtained solid was further added EtOH (5 mL) and water (0.5 mL), and the mixture was stirred for 0.5 hour, filtered, and dried to give the crystal crystals of Compound 3 (0.5 g, yield: 20%, white solid).
  • the solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form A of Compound 1 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 4) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 4.
  • the solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form B of Compound 2 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 6) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 6.
  • the solubility test was carried out by using a manual stepwise dilution method under normal temperature conditions while observing the dissolution condition. 2 to 2.5 mg of Form D of Compound 3 was added to a different liquid phase vial, and then an organic solvent or a solvent mixture (Table 8) was added in small portions to observe the dissolution of the compound. The solubility test results of the compounds are shown in Table 8.
  • TXA2 thromboxane A2 pathway
  • TXB2 thromboxane B2
  • the key enzyme of this pathway is thromboxane synthase, which is a specific inhibitor of the enzyme (test compound) in the in vitro coagulation process, which can inhibit the formation of TXA2 and reduce the content of TXB2.
  • the IC50 that inhibits the production of TXB2 reflects the activity of the test compound.
  • SD Male Sprague-Dawley (SD) rat purchased from Shanghai Slack Laboratory Animal Center
  • physiological saline solution 100M sodium hydroxide solution (solvent), 100uM thromboxane synthase inhibitor solution, isoflurane
  • TXB2 The content of TXB2 was detected using LC-MS/MS-AG (API 4000).
  • Control% (test tube TXB2 content - negative tube TXB2 content) / control tube TXB2 content ⁇ 100
  • Negative tube high concentration (100uM) thromboxane synthase inhibitor
  • Test sample (compound) Thromboxane synthase Ozagray 120nM Form B of Compound 2 A

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Urology & Nephrology (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (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)

Abstract

L'invention concerne une forme cristalline et un type de sel d'un composé imidazole, et son procédé de préparation, et comprend en outre l'utilisation de la forme cristalline et du type de sel pour la préparation de médicaments pour le traitement d'une maladie cérébrovasculaire.
PCT/CN2017/106647 2016-10-20 2017-10-18 Forme cristalline de composé imidazole, type de sel et son procédé de préparation WO2018072702A1 (fr)

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CN201610915634 2016-10-20

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Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504479A (en) * 1981-07-31 1985-03-12 A. Nattermann & Cie Gmbh 6-{5-[ω-(1-Imidazolyl)-alkyl]-thien-2-yl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof and a process for the treatment of inflammatory atherosclerotic and thrombo-embolic, illnesses in humans
US4507298A (en) * 1981-07-31 1985-03-26 A. Nattermann & Cie Gmbh 6-{4-(ω-(1-imidazolyl)-alkyl-phenyl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof, and a process for the treatment of inflammatory, atherosclerotic and thromboembolic illnesses in humans
US4643998A (en) * 1982-11-06 1987-02-17 A. Natterman & Cie Gmbh Imidazolylalkylthienyl tetrahydropyridazines and processes for their use
US20090269301A1 (en) * 2006-11-09 2009-10-29 Probiodrug Ag Novel Inhibitors of Glutaminyl Cyclase
WO2013049565A1 (fr) * 2011-09-30 2013-04-04 Endo Pharmaceuticals Inc. Dérivés imidazoles en tant qu'inhibiteurs de cyp17 pour le traitement du cancer
CN106065012A (zh) * 2015-04-24 2016-11-02 广东众生药业股份有限公司 咪唑类化合物

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4504479A (en) * 1981-07-31 1985-03-12 A. Nattermann & Cie Gmbh 6-{5-[ω-(1-Imidazolyl)-alkyl]-thien-2-yl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof and a process for the treatment of inflammatory atherosclerotic and thrombo-embolic, illnesses in humans
US4507298A (en) * 1981-07-31 1985-03-26 A. Nattermann & Cie Gmbh 6-{4-(ω-(1-imidazolyl)-alkyl-phenyl}-3-oxo-2,3,4,5-tetrahydro-pyridazines and acid addition salts thereof, and a process for the treatment of inflammatory, atherosclerotic and thromboembolic illnesses in humans
US4643998A (en) * 1982-11-06 1987-02-17 A. Natterman & Cie Gmbh Imidazolylalkylthienyl tetrahydropyridazines and processes for their use
US20090269301A1 (en) * 2006-11-09 2009-10-29 Probiodrug Ag Novel Inhibitors of Glutaminyl Cyclase
WO2013049565A1 (fr) * 2011-09-30 2013-04-04 Endo Pharmaceuticals Inc. Dérivés imidazoles en tant qu'inhibiteurs de cyp17 pour le traitement du cancer
CN106065012A (zh) * 2015-04-24 2016-11-02 广东众生药业股份有限公司 咪唑类化合物

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