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WO2016124149A1 - Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline - Google Patents

Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline Download PDF

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Publication number
WO2016124149A1
WO2016124149A1 PCT/CN2016/073528 CN2016073528W WO2016124149A1 WO 2016124149 A1 WO2016124149 A1 WO 2016124149A1 CN 2016073528 W CN2016073528 W CN 2016073528W WO 2016124149 A1 WO2016124149 A1 WO 2016124149A1
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WIPO (PCT)
Prior art keywords
formula
compound
crystalline form
solvent
ray powder
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Ceased
Application number
PCT/CN2016/073528
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English (en)
Chinese (zh)
Inventor
陈敏华
张炎锋
李骄洋
张晓宇
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Crystal Pharmatech Co Ltd
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Crystal Pharmatech Co Ltd
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Publication of WO2016124149A1 publication Critical patent/WO2016124149A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the invention relates to the field of chemical medicine, in particular to a novel crystal form of an antiandrogen drug (ARN-509) for treating prostate cancer and a preparation method thereof.
  • ARN-509 an antiandrogen drug
  • ARN-509 a compound of formula (I), is a second generation androgen receptor signaling inhibitor.
  • the drug was developed by Aragon Pharmaceuticals of the United States and later acquired by Johnson & Johnson (JNJ). The drug is used to treat castration-resistant prostate cancer and is currently in clinical development. If approved, it will be able to meet the needs of a wider range of prostate cancer patients.
  • Drug polymorphism refers to the presence of two or more different crystalline forms of a drug. Polymorphism is widespread in medicine. Different crystal forms of the same drug have significant differences in solubility, melting point, density, stability, etc., which affect the stability, homogeneity, bioavailability, efficacy and safety of the drug to varying degrees. Therefore, the comprehensive systematic polymorph screening in drug development and the selection of the most suitable crystal form are one of the important research contents that cannot be ignored.
  • the present invention relates to two novel crystalline forms of the compound of formula (I), designated as Form I and Form II, respectively.
  • the crystal form of the invention has good stability, the solubility and the wettability are in compliance with the medicinal requirements, and the preparation method is simple and the cost is low, which is of great value for the optimization and development of the drug in the future.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 16.7 ° ⁇ 0.2 °, 20.4 ° ⁇ 0.2 °, and 12.1 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at 2theta values of 23.7° ⁇ 0.2°, 8.2° ⁇ 0.2°, and 16.0° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a characteristic peak at a 2theta value of 17.8 ° ⁇ 0.2 °, 25.0 ° ⁇ 0.2 °, and 27.8 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form I provided by the present invention has a value of 8.2 ° ⁇ 0.2 °, 12.1 ° ⁇ 0.2 °, 16.0 ° ⁇ 0.2 °, 16.7 ° ⁇ 0.2 °, 17.8 °. There are characteristic peaks at ⁇ 0.2°, 20.4° ⁇ 0.2°, 23.7° ⁇ 0.2°, 25.0° ⁇ 0.2°, and 27.8° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form I provided by the present invention is substantially as shown in FIG.
  • crystal form I provided by the present invention begins to exhibit an endothermic peak when heated to about 193 ° C, and the differential scanning calorimetry chart is substantially as shown in FIG. 2 .
  • the crystal form I provided by the present invention has a weight loss gradient of about 1.3% when heated to 160 ° C, and the thermogravimetric analysis chart is shown in FIG. 3 .
  • Another object of the present invention is to provide a process for the preparation of Form I comprising the addition of a compound of formula (I) to a crystallization solvent, by volatilization or suspension stirring.
  • the crystallization solvent is one or more kinds of alcohols, ketones, ethers, aliphatic hydrocarbons, esters, aromatic hydrocarbon solvents, preferably methanol, acetone, 1,4-dioxane
  • One or more kinds of cyclohexane, n-heptane, isopropyl acetate, ethyl acetate, toluene and xylene are mixed, and one or more kinds of cyclohexane, isopropyl acetate and toluene are more preferably mixed.
  • Another object of the invention is to provide a crystalline form II of a compound of formula (I).
  • the X-ray powder diffraction pattern of Form II provided by the present invention has characteristic peaks at 2theta values of 14.4 ° ⁇ 0.2 °, 16.6 ° ⁇ 0.2 °, and 17.9 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 7.6 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, and 15.5 ° ⁇ 0.2 °.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a characteristic peak at a 2theta value of 25.4° ⁇ 0.2°, 12.5° ⁇ 0.2°, and 13.3° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention has a value of 7.6 ° ⁇ 0.2 °, 8.9 ° ⁇ 0.2 °, 12.5 ° ⁇ 0.2 °, 13.3 ° ⁇ 0.2 °, 14.4 °. Characteristic peaks at ⁇ 0.2°, 15.5° ⁇ 0.2°, 16.6° ⁇ 0.2°, 17.9° ⁇ 0.2°, 25.4° ⁇ 0.2°.
  • the X-ray powder diffraction pattern of Form II provided by the present invention is substantially as shown in FIG.
  • crystal form II provided by the present invention starts to have an endothermic peak when heated to about 170 ° C, and the differential scanning thereof
  • the calorimetric analysis chart is basically as shown in Figure 6.
  • the crystal form II provided by the present invention has a weight loss gradient of about 1.6% when heated to 170 ° C, and the thermogravimetric analysis chart is shown in FIG. 7 .
  • Another object of the present invention is to provide a process for the preparation of Form II comprising dissolving a compound of formula (I) in a positive solvent and adding an anti-solvent dropwise to precipitate a solid to obtain Form II.
  • the positive solvent is a mixture of one or more of an ester, an aromatic hydrocarbon, and a ketone solvent, preferably one or more of toluene, isopropyl acetate, and 4-methyl-2-pentanone. .
  • the anti-solvent is an aliphatic hydrocarbon solvent, preferably n-heptane.
  • Another object of the present invention is to provide a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I), Form I, Form II or a mixture of both in any proportion and a pharmaceutical excipient.
  • a pharmaceutical composition or formulation is generally prepared by mixing a therapeutically effective amount of Form I, Form II, or both in any proportion of a compound of Formula (I) with one or more pharmaceutical excipients. Or the formulations are prepared in a manner well known in the pharmaceutical art.
  • a further object of the present invention is to provide use of Form I, Form II or a pharmaceutical composition thereof of a compound of formula (I) for the manufacture of a medicament for the treatment of cancer, in particular a prostate cancer.
  • the present invention breaks through the prior art and provides a variety of new crystalline forms suitable for drug development of the compounds of formula (I).
  • the crystal forms I and II provided by the present invention have good stability. It can well avoid drug storage and crystal transformation during development, thus avoiding changes in bioavailability and efficacy.
  • the crystal form provided by the invention has high solubility and low moisture permeability, meets the requirements of bioavailability and efficacy, and is not easily affected by humidity, and is convenient for long-term storage.
  • Figure 1 is an XRPD pattern of Form I of the compound of formula (I) of the present invention.
  • Figure 2 is a DSC chart of the crystalline form I of the compound of the formula (I) of the present invention.
  • Figure 3 is a TGA diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 4 is a DVS diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 5 is an XRPD pattern of Form II of the compound of formula (I) of the present invention.
  • Figure 6 is a DSC chart of the crystalline form II of the compound of the formula (I) of the present invention.
  • Figure 7 is a TGA diagram of Form II of the compound of formula (I) of the present invention.
  • Figure 8 is a comparison chart of XRPD of the 90-day stability test of the crystalline form I of the compound of the formula (I) according to the invention under different test conditions (A: crystalline form I starting sample; B: crystalline form I at 25 ° C / 60% relative humidity) Placed under 90 days; C: Form I at 40 ° C / 75% Placed under humidity for 90 days);
  • Figure 9 is a comparison diagram of the DVS of the solid of the compound of the formula (I) of the formula (I) and the compound of the formula (I) obtained by the repeated patent method (test conditions: 80% relative humidity;
  • A represents the formula obtained by the method of repeating the patent CN101454002B ( I) a compound solid, B represents a crystalline form I) of the compound of formula (I) of the present invention;
  • Figure 10 is a PLM diagram of Form I of the compound of formula (I) of the present invention.
  • Figure 11 is a PLM diagram of the solid of the compound of formula (I) prepared by the process of repeating the patent CN101454002B.
  • the crystal XRPD data prepared by different preparation methods may not be identical for the same crystal form, but those skilled in the art can determine that they belong to the same crystal form according to the main characteristic peaks according to the description of the specification.
  • test method is usually carried out according to conventional conditions or conditions recommended by the manufacturer, wherein room temperature means 25 ° C ⁇ 2 ° C.
  • the X-ray powder diffraction pattern of the present invention was collected on a Panalytical Empyrean X-ray powder diffractometer.
  • the method parameters of the X-ray powder diffraction described in the present invention are as follows:
  • Scan range: from 3.0 to 40.0 degrees
  • the differential scanning calorimetry (DSC) map of the present invention was acquired on a TA Q2000.
  • the method parameters of the differential scanning calorimetry (DSC) described in the present invention are as follows:
  • thermogravimetric analysis (TGA) map of the present invention was taken on a TA Q5000.
  • the method parameters of the thermogravimetric analysis (TGA) described in the present invention are as follows:
  • the dynamic moisture adsorption (DVS) pattern of the present invention was collected on an Intrinsic dynamic moisture adsorber manufactured by SMS Corporation (Surface Measurement Systems Ltd.).
  • the method parameters of the dynamic moisture adsorber are as follows:
  • Relative humidity range 0%RH-95%RH
  • the solid of the compound of formula (I) used in the following examples (i.e., ARN 509) was prepared according to the method disclosed in Chinese Patent No. CN101454002B.
  • the X-ray powder diffraction data of Form I obtained in this example are shown in Table 1, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 1 to 3, respectively.
  • the X-ray powder diffraction data of Form II obtained in this example are shown in Table 7, and the X-ray powder diffraction, DSC and TGA patterns thereof are shown in Figures 5 to 7, respectively.
  • the crystal form I samples of the compound of the formula (I) obtained by the present invention were respectively placed under conditions of 25 ° C / 60% relative humidity and 40 ° C / 75% relative humidity for 90 days, and samples were taken for testing on the 90th day.
  • the test results show that the crystalline form I of the present invention has good stability, and its XRPD comparison chart is shown in Fig. 8, wherein A represents the starting form of the crystalline form I; and B represents the standing at 25 ° C / 60% relative humidity for 90 days; Indicates that it is left for 90 days at 40 ° C / 75% relative humidity.
  • Deliquescence absorbs a sufficient amount of water to form a liquid
  • the wetting weight gain is not less than 15%
  • the wetting weight gain is less than 15% but not less than 2%;
  • wetting gain is less than 2% but not less than 0.2%
  • wetting gain is less than 0.2%.
  • the crystal form I of the compound of the formula (I) of the present invention is a relatively regular flaky crystal, has good fluidity, and has excellent properties such as easy filtration in process production, so that the crystal form I of the compound of the formula (I) is good, and its PLM diagram As shown in FIG. 10; the compound of the formula (I) obtained by the patent method has a solid agglomeration and a non-uniform particle, and has poor fluidity, and its PLM pattern is shown in FIG.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (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 nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, ledit médicament étant représenté par la formule I, et un procédé de préparation de la nouvelle forme cristalline. La forme cristalline a une bonne stabilité, et sa solubilité et hygroscopicité satisfont les exigences pharmaceutiques. Le procédé de préparation est simple et économique.
PCT/CN2016/073528 2015-02-06 2016-02-04 Nouvelle forme cristalline d'un médicament anti-androgène destiné à traiter le cancer de la prostate, et procédé de préparation de la nouvelle forme cristalline Ceased WO2016124149A1 (fr)

Applications Claiming Priority (2)

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CN201510064412 2015-02-06
CN201510064412.6 2015-02-06

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WO2016124149A1 true WO2016124149A1 (fr) 2016-08-11

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112001A1 (fr) 2016-12-13 2018-06-21 Watson Laboratories Inc. Formes à l'état solide de l'apalutamide
WO2019135254A1 (fr) 2018-01-02 2019-07-11 Mylan Laboratories Limited Polymorphes d'apalutamide et leur préparation
WO2020049598A2 (fr) 2018-09-08 2020-03-12 Cipla Limited Polymorphes d'apalutamide
IT201900003839A1 (it) 2019-03-15 2020-09-15 Olon Spa Sintesi di apalutamide amorfa stabile
WO2020234817A1 (fr) * 2019-05-21 2020-11-26 Laurus Labs Limited Formes polymorphes d'apalutamide et leur préparation
IT201900010593A1 (it) 2019-07-01 2021-01-01 Dipharma Francis Srl Forma cristallina di un inibitore di recettori degli androgeni
WO2025153768A1 (fr) * 2024-01-18 2025-07-24 Nanoform Finland Oyj Composition contenant de l'apalutamide nanométrique cristallin

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3812378A1 (fr) * 2018-06-20 2021-04-28 Crystal Pharmaceutical (Suzhou) Co., Ltd. Formes cristallines de l'arn-509, procédé de préparation correspondant et utilisation associée
CN110590740A (zh) * 2019-09-20 2019-12-20 武汉大学 一种阿帕鲁胺化合物及其药物制剂
CN112679468A (zh) * 2021-01-05 2021-04-20 四川科伦药物研究院有限公司 阿帕他胺的晶体形式、制备方法和用途

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007126765A2 (fr) * 2006-03-27 2007-11-08 The Regents Of The University Of California Modulateur de récepteur androgène pour le traitement du cancer de la prostate et de maladies associées au récepteur androgène
WO2008119015A2 (fr) * 2007-03-27 2008-10-02 Sloan-Kettering Institute For Cancer Research Synthèse de dérivés de la thiohydantoïne
WO2011103202A2 (fr) * 2010-02-16 2011-08-25 Aragon Pharmaceuticals, Inc. Modulateurs du récepteur des androgènes et leurs utilisations
WO2014190895A1 (fr) * 2013-05-29 2014-12-04 成都海创药业有限公司 Composé imidazole-dicétone et son utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007126765A2 (fr) * 2006-03-27 2007-11-08 The Regents Of The University Of California Modulateur de récepteur androgène pour le traitement du cancer de la prostate et de maladies associées au récepteur androgène
WO2008119015A2 (fr) * 2007-03-27 2008-10-02 Sloan-Kettering Institute For Cancer Research Synthèse de dérivés de la thiohydantoïne
WO2011103202A2 (fr) * 2010-02-16 2011-08-25 Aragon Pharmaceuticals, Inc. Modulateurs du récepteur des androgènes et leurs utilisations
WO2014190895A1 (fr) * 2013-05-29 2014-12-04 成都海创药业有限公司 Composé imidazole-dicétone et son utilisation

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018112001A1 (fr) 2016-12-13 2018-06-21 Watson Laboratories Inc. Formes à l'état solide de l'apalutamide
US11149017B2 (en) 2016-12-13 2021-10-19 Watson Laboratories Inc. Solid state forms of apalutamide
WO2019135254A1 (fr) 2018-01-02 2019-07-11 Mylan Laboratories Limited Polymorphes d'apalutamide et leur préparation
WO2020049598A2 (fr) 2018-09-08 2020-03-12 Cipla Limited Polymorphes d'apalutamide
WO2020049598A3 (fr) * 2018-09-08 2020-04-16 Cipla Limited Polymorphes d'apalutamide
IT201900003839A1 (it) 2019-03-15 2020-09-15 Olon Spa Sintesi di apalutamide amorfa stabile
WO2020234817A1 (fr) * 2019-05-21 2020-11-26 Laurus Labs Limited Formes polymorphes d'apalutamide et leur préparation
IT201900010593A1 (it) 2019-07-01 2021-01-01 Dipharma Francis Srl Forma cristallina di un inibitore di recettori degli androgeni
WO2025153768A1 (fr) * 2024-01-18 2025-07-24 Nanoform Finland Oyj Composition contenant de l'apalutamide nanométrique cristallin

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