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WO2016019909A1 - Nouvelle forme cristalline de composé anticancéreux, procédé de préparation et utilisation correspondants - Google Patents

Nouvelle forme cristalline de composé anticancéreux, procédé de préparation et utilisation correspondants Download PDF

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Publication number
WO2016019909A1
WO2016019909A1 PCT/CN2015/086408 CN2015086408W WO2016019909A1 WO 2016019909 A1 WO2016019909 A1 WO 2016019909A1 CN 2015086408 W CN2015086408 W CN 2015086408W WO 2016019909 A1 WO2016019909 A1 WO 2016019909A1
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WO
WIPO (PCT)
Prior art keywords
crystalline form
preparation
crystal form
lung cancer
compound
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.)
Ceased
Application number
PCT/CN2015/086408
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English (en)
Chinese (zh)
Inventor
杨宝海
熊龙
余俊
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangsu Hansoh Pharmaceutical Group Co Ltd
Original Assignee
Jiangsu Hansoh Pharmaceutical Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Jiangsu Hansoh Pharmaceutical Co Ltd filed Critical Jiangsu Hansoh Pharmaceutical Co Ltd
Priority to CN201580034413.4A priority Critical patent/CN106661064B/zh
Publication of WO2016019909A1 publication Critical patent/WO2016019909A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings
    • C07F9/58—Pyridine rings

Definitions

  • the invention relates to the field of medicinal chemical industry, in particular to an anticancer compound (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl Crystal form of 1-dimethylphosphonooxy-4-yl]pyridin-2-amine and preparation method thereof.
  • Lung cancer is the most common primary malignant tumor of the lung and is usually classified into non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Lung cancer is the cancer with the highest morbidity and mortality. Non-small cell lung cancer accounts for 80% to 85% of the total number of lung cancers, and its mortality rate is as high as 80% to 90%. According to the statistics of the World Health Organization (WHO), there were 1,332,132 new cases of lung cancer in 2002, accounting for 12.4% of the total number of new cancer cases, ranking first, the third time announced by the Ministry of Health of China on April 29, 2008. The main results of the national death cause survey show that the mortality rate of lung cancer in China has increased by 465% in the past 30 years. At present, lung cancer has replaced liver cancer as the cause of death in the first malignant tumor in China, accounting for 22.7% of malignant tumor deaths.
  • NSCLC non-small cell lung cancer
  • SCLC small cell lung cancer
  • the 5-year survival rate of lung cancer in developed countries is about 10% to 15%, which is lower in China. If the advanced NSCLC is not treated, the median survival time is about 4 to 5 months, and the 1-year survival rate is less than 10%.
  • the standard first-line chemotherapy regimen of advanced NSCLC is equivalent to the best supportive treatment, which can effectively prolong the median survival time and increase the 1-year survival period. Survival rate.
  • the current efficacy of chemotherapy seems to reach a platform, its objective efficiency is about 30%, the median survival time is 8 to 9 months, and the 1-year survival rate is 30% to 40%. Therefore, finding more effective and safe treatments has become a hot spot in current lung cancer research.
  • Tumor molecular targeted therapy is a treatment for other biological pathways.
  • NSCLC's targeted therapeutic drugs mainly include epidermal growth factor receptor (EGFR) family inhibitors, angiogenesis inhibitors, multi-target inhibitors, signal transduction inhibitors, and apoptosis inducers.
  • EGFR epidermal growth factor receptor
  • CSCO Clinical Oncology Collaborative Professional Committee
  • XALKORI provides us with a new path to explore future drug development and cancer treatment,” University of Colorado, Denver Cancer Research The heads of Professor Paul Bunn and the chief physician of James Dudley pointed out.
  • XALKORI is the first new drug to treat lung cancer approved by the FDA for more than 6 years, representing a shift in the treatment of non-small cell lung cancer. We are moving from a monolithic treatment regime to a treatment model through biomarker decision-making.”
  • the biomarker ALK fusion gene test result of the patient's tumor is positive to improve the possibility of responding to the treatment. This first test for lung cancer treatment allows researchers to observe good results in pre-screened patient populations.
  • ALK positive rate in non-small cell lung cancer is approximately 3-5%, meaning that there are approximately 650 to 11,000 ALK-positive non-small cell lung cancer patients in the United States each year.
  • NSCLC non-small cell lung cancer
  • Drug crystal research and solid-state drug development are of paramount importance in the pharmaceutical industry.
  • Drug molecules usually have different solid forms, including salts, polycrystals, eutectic, amorphous, hydrates and solvates; different crystal forms of the same drug molecule, in crystal structure, stability, manufacturability and bioavailability
  • any drug development requires a comprehensive system of polymorphic screening to find as many crystal forms as possible, and then use various solid-state methods to conduct in-depth research on these crystal forms to find the most suitable crystal form.
  • the crystalline XRPD pattern also exhibits a diffraction peak at 2 ⁇ ( ⁇ 0.2°) of 19.47, 20.06, 20.83, 22.43, 24.26, 26.18, 29.74.
  • the crystalline XRPD pattern is shown in Figure 1.
  • the crystal form of the present invention was subjected to thermogravimetric analysis (TGA) to show that the sample was kept constant from room temperature to 220 ° C, indicating that the sample contained no crystal water or an adsorption solvent. Then the sample began to lose weight. The sample weight loss was severe at around 260 °C, and the weight loss slowed down at about 400 °C, and the weight loss to 700 °C was about 62%.
  • TGA thermogravimetric analysis
  • the crystal form of the present invention exhibits an endothermic peak in the range of 180 ° C to 185 ° C by differential scanning calorimetry (DSC) and has a sharp absorption peak at 182 ⁇ 1 ° C.
  • It is also an object of the present invention to provide a process for preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, cooling and crystallization by stirring, and filtering to obtain a target crystalline form.
  • Another object of the present invention is to provide an alternative method of preparing the crystalline form comprising dissolving a compound of formula I with an organic solvent, adding an anti-solvent to agitate the crystal, and filtering to obtain a target crystalline form.
  • the drying temperature is 25 ° C or higher, preferably 70 ° C or higher, more preferably 80 ° C or higher.
  • the organic solvent is selected from the group consisting of acetonitrile, ethyl acetate and/or butyl acetate.
  • the anti-solvent is selected from the group consisting of isopropyl ether, n-heptane and/or n-hexane.
  • It is still another object of the present invention to provide a pharmaceutical composition comprising a therapeutically effective amount of the crystalline form and a pharmaceutically acceptable carrier.
  • Another object of the present invention is to provide the use of the crystalline form or the pharmaceutical composition for the preparation of an antitumor drug
  • the crystal form provided by the invention has high purity, good stability, no hygroscopicity and high bioavailability, and is suitable for medical preparations.
  • Figure 1 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • Figure 2 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • Figure 3 is a (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphonooxylate of the present invention.
  • DSC Differential Scanning Thermogram
  • the present invention (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethylphosphine
  • the X-ray powder diffraction pattern of the acyloxy-4-yl]pyridin-2-amine crystal form did not change significantly under different temperature conditions, indicating that the crystal form did not change, indicating good thermal stability.
  • the wettability test was carried out according to the Guiding Principles for Drug Hygroscopicity Test (Chinese Pharmacopoeia 2010 Edition Part II Appendix XIX J). Take a dry stuffed glass weighing bottle (outer diameter 50mm, height 15mm), placed in a suitable 25 ° C ⁇ 1 ° C constant temperature dryer (lower ammonium chloride saturated solution) on the day before the test, accurately weighed Weight (m1); suitable for the crystal form of the present invention The amount is laid flat in the above weighing bottle. The thickness of the test sample is generally about 1 mm, and the weight is accurately weighed (m2); the weighing bottle is opened and placed under the above constant temperature and humidity conditions with the bottle cap. 24 hours; cover the weighing bottle cap and accurately weigh (m3).
  • Deliquescence absorbs enough water to form a liquid
  • Hygroscopicity 2% ⁇ X% ⁇ 15%;
  • the (R)-3-[1-(2,6-dichloro-3-fluorophenyl)ethoxy]-5-[3-fluorophenyl-1-dimethyl group of the present invention was measured.
  • the weight gain percentage of the phosphinyloxy-4-yl]pyridin-2-amine crystal form compound was 0.02%, indicating that the crystal form of the present invention has no hygroscopicity and is hardly deliquescent under the influence of high humidity.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une forme cristalline d'un composé anticancéreux (R)-3-[1-(2, 6-dichloro-3-fluorophényl) éthoxy]-5-[3-fluorophényl-1-diméthyl phosphine acyl-oxy-4-yl] pyridine-2-amine et son procédé de préparation. La formule structurale de la forme cristalline est telle que représentée par la formule I. La forme cristalline présente des propriétés stables, une haute pureté, aucune hygroscopicité et une biodisponibilité élevée, et répond aux exigences pour une préparation pharmaceutique.
PCT/CN2015/086408 2014-08-07 2015-08-07 Nouvelle forme cristalline de composé anticancéreux, procédé de préparation et utilisation correspondants Ceased WO2016019909A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201580034413.4A CN106661064B (zh) 2014-08-07 2015-08-07 一种抗癌化合物的新晶型及其制备方法和用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201410387596.5 2014-08-07
CN201410387596 2014-08-07

Publications (1)

Publication Number Publication Date
WO2016019909A1 true WO2016019909A1 (fr) 2016-02-11

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PCT/CN2015/086408 Ceased WO2016019909A1 (fr) 2014-08-07 2015-08-07 Nouvelle forme cristalline de composé anticancéreux, procédé de préparation et utilisation correspondants

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CN (1) CN106661064B (fr)
WO (1) WO2016019909A1 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110317265B (zh) * 2018-03-28 2023-03-10 江苏豪森药业集团有限公司 比伐芦定晶型a及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116050A2 (fr) * 2011-02-24 2012-08-30 Eternity Bioscience Inc. Composés contenant du phosphore en tant qu'inhibiteurs de la protéine kinase

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004215428B2 (en) * 2003-02-26 2009-08-27 Sugen LLC Aminoheteroaryl compounds as protein kinase inhibitors
CN102105150B (zh) * 2008-05-21 2014-03-12 阿里亚德医药股份有限公司 用作激酶抑制剂的磷衍生物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012116050A2 (fr) * 2011-02-24 2012-08-30 Eternity Bioscience Inc. Composés contenant du phosphore en tant qu'inhibiteurs de la protéine kinase

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CN106661064B (zh) 2019-10-15

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