WO2016169422A1 - Forme cristalline d'un inhibiteur de kinase dépendant des cyclines et procédé de préparation de celle-ci - Google Patents

Forme cristalline d'un inhibiteur de kinase dépendant des cyclines et procédé de préparation de celle-ci Download PDF

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Publication number
WO2016169422A1
WO2016169422A1 PCT/CN2016/079055 CN2016079055W WO2016169422A1 WO 2016169422 A1 WO2016169422 A1 WO 2016169422A1 CN 2016079055 W CN2016079055 W CN 2016079055W WO 2016169422 A1 WO2016169422 A1 WO 2016169422A1
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crystal
water
compound
formula
preparation
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PCT/CN2016/079055
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English (en)
Chinese (zh)
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武乖利
高晓晖
张全良
卢韵
吴玉霞
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江苏恒瑞医药股份有限公司
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Priority to CN201680001861.9A priority Critical patent/CN106795159B/zh
Publication of WO2016169422A1 publication Critical patent/WO2016169422A1/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
    • A61K31/495—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
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems

Definitions

  • the present invention relates to 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d] Pyrimidine-7(8H)-one and its Form II.
  • the compounds of formula (I) obtained by the process according to the invention are useful in the treatment of breast cancer.
  • Breast cancer is one of the most common malignant tumors in women. It has a high incidence and is invasive, but the progress of the disease is slow.
  • the China Population Association released the "China Breast Diseases Investigation Report” in Beijing on February 1, 2010. The report shows that The mortality rate of breast cancer in urban areas in China has increased by 38.91%.
  • Breast cancer has become the most threatening disease for women.
  • At least 156 kinds of breast cancer drugs are currently under research and market, 68% of which are targeted therapeutic drugs.
  • Tumors were found to be abnormally associated with the cell cycle. Mutations in mitotic signaling proteins and defects in anti-mitotic signaling proteins in tumor cells lead to proliferation disorders. At the same time, most tumors have genomic instability (GIN) and genomic instability (CIN). These three basic cell cycle defects are caused directly or indirectly by the loss of control of CDKs. Cyclin Dependent Kinase (CDK) inhibitors are increasingly becoming a hot target.
  • CDK Cyclin Dependent Kinase
  • the second-generation drugs of greatest concern include the CDK4&6 inhibitor PD-0332991 jointly developed by Pfizer and Onyx. It inhibits the phosphorylation of Rb by inhibiting the activity of CDK4&6, making E2F- The Rb complex is retained in the cytosol, blocking the initiation of the cell cycle.
  • Clinical trial results (NCT00721409) showed that progression-free survival (PFS) was 7.5 months in patients treated with letrozole monotherapy, whereas no progress was observed in patients treated with letrozole and PD-0332991. The survival period was extended to 26.1 months. This remarkable advantage has received wide attention. In early 2013, after reviewing the interim results of this drug, the FDA thought it might be a breakthrough anticancer drug.
  • WO2014183520 discloses a CDK4&6 inhibitor similar in structure to PD-0332991, which has significant inhibitory activity and high selectivity for CDK4&6, including the following compounds:
  • WO 2014183520 does not delve into the crystalline form of the compound. It is well known to those skilled in the art that the crystalline structure of the pharmaceutically active ingredient often affects the chemical stability of the drug, and the crystallization conditions and storage conditions may cause changes in the crystal structure of the compound, sometimes accompanied by other Form of crystal form. In general, amorphous drug products have no regular crystal structure and often have other defects, such as poor product stability, fine crystallization, difficult filtration, easy agglomeration, and poor fluidity. Therefore, it is necessary to improve the various properties of the above compounds, and we need to further study to find new crystal forms with higher crystal purity and good chemical stability.
  • the present invention provides 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyrido[2,3-d A new crystalline form of pyrimidine-7(8H)-one (as shown in formula (I)).
  • a series of crystalline products obtained by the compound of the formula (I) under different crystallization conditions the obtained crystalline product was subjected to X-ray diffraction and DSC detection, and it was found that the compound of the formula (I) can be obtained under the conventional crystallization conditions.
  • a crystal form with good stability we call it type II crystal.
  • the DSC pattern of the type II crystal in the present application shows a melting endothermic peak near 294.42 ° C, and the X-ray powder diffraction pattern is shown in Fig.
  • the invention also provides the preparation of 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperidin-4-yl)pyridin-2-yl)amino)pyridine [2,3 -d]
  • the acid is a mineral acid, preferably hydrochloric acid;
  • the base is an inorganic base, preferably sodium hydroxide or potassium hydroxide.
  • the solvent described in step 1) is methanol, ethanol, isopropanol, acetone, acetonitrile or methanol/water, ethanol/water, acetone/water, acetonitrile/water, isopropanol/water; Ethanol.
  • the method of recrystallization is not particularly limited and can be carried out by a usual recrystallization operation method.
  • the compound represented by the starting material (I) can be slowly cooled and crystallized by heating in an organic solvent, and after completion of crystallization, it can be dried by filtration to obtain a desired crystal.
  • the crystals to be filtered are usually subjected to vacuum drying under reduced pressure at a temperature of about 30 to 100 ° C, preferably 40 to 60 ° C, to obtain an effect of removing the recrystallization solvent.
  • the crystal form of the obtained compound of the formula (I) was examined by differential scanning calorimetry (DSC) and X-ray diffraction pattern measurement, and the solvent residue of the obtained crystal was examined.
  • the compound of the formula II type represented by the formula (I) prepared according to the method of the present invention does not contain or contains only a low content of residual solvent, and meets the requirements of the national pharmacopoeia for the residual solvent of the pharmaceutical product, so that the crystal of the present invention can be compared. It is used as a pharmaceutical active ingredient.
  • the type II crystal of the compound of the formula (I) prepared by the present invention has good stability under the conditions of illumination, high temperature and high humidity, and the crystal form stability is good under the conditions of grinding, pressure and heat. It can meet the medicinal requirements of production, transportation and storage.
  • the production process is stable and repeatable and controllable, and can be adapted to industrial production.
  • Figure 1 is an X-ray powder diffraction pattern of the compound II type crystal represented by the formula (I).
  • Figure 2 is a DSC chart of the compound type II crystal of the formula (I).
  • the crystals are at about 5.84 (15.12), 6.16 (14.35), 10.75 (8.22), 12.56 (7.04), 12.96 (6.82), 16.25 (5.45), 17.24 (5.14), 18.97 (4.67), 20.22 (4.39), 21.74. (4.08), 22.99 (3.87), and 25.85 (3.44) have characteristic peaks.
  • the DSC spectrum is shown in Figure 2. There is a sharp melting endotherm peak of 294.42 ° C. This crystal form is defined as Form II.
  • Example 1 The sample of the type II crystal product obtained in Example 1 was separately placed in an open position, and the stability of the sample under illumination (4500 Lux), heating (40 ° C, 60 ° C), and high humidity (RH 75%, RH 90%) was examined.
  • the sampling time was 5 days and 10 days, and the purity of HPLC was shown in Table 1.

Abstract

L'invention concerne la forme cristalline d'un inhibiteur de kinase dépendant des cyclines (CDK&6) et un procédé de préparation de celle-ci. En particulier, l'invention concerne des cristaux de type II de la 6-acétyl-8-cyclopentyl-5-méthyl-2-((5-(pipéridin-4-yl)pyridin-2-yl) amino)pyridino[2,3-d]pyrimidin-7(8H)-one (composé de formule (I)) et le procédé de préparation de ceux-ci, le cristal possédant un profil de diffraction de poudre aux rayons X tel qu'illustré sur la figure 1, une bonne stabilité chimique et une bonne stabilité de forme cristalline, et utilisant un solvant à faible toxicité et faible cristallisation résiduelle, de façon à être mieux utilisé pour un traitement clinique.
PCT/CN2016/079055 2015-04-22 2016-04-12 Forme cristalline d'un inhibiteur de kinase dépendant des cyclines et procédé de préparation de celle-ci WO2016169422A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201680001861.9A CN106795159B (zh) 2015-04-22 2016-04-12 一种周期素依赖性蛋白激酶抑制剂的结晶形式及其制备方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201510195879.4 2015-04-22
CN201510195879 2015-04-22

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WO2016169422A1 true WO2016169422A1 (fr) 2016-10-27

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Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017133542A1 (fr) * 2016-02-04 2017-08-10 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un dérivé pyridopyrimidine ou un sel de qualité pharmaceutique de ce dernier
JP2018534352A (ja) * 2015-09-30 2018-11-22 グアンジョウ ベベター メディシン テクノロジー カンパニー リミテッド ピリミジン又はピリドピロドン類化合物、及びその応用
WO2019144759A1 (fr) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Forme cristalline ciblant un inhibiteur de kinase cdk4/6
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
WO2020253808A1 (fr) * 2019-06-20 2020-12-24 江苏恒瑞医药股份有限公司 Composition pharmaceutique et son procédé de préparation

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WO2014183520A1 (fr) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales
CN105130986A (zh) * 2015-09-30 2015-12-09 广州科擎新药开发有限公司 嘧啶或吡啶并吡啶酮类化合物及其应用

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EA024026B1 (ru) * 2010-11-25 2016-08-31 Рациофарм Гмбх Новые соли и полиморфные формы афатиниба
CN102863365B (zh) * 2011-07-07 2014-04-16 广州白云山制药股份有限公司广州白云山制药总厂 一种结晶药物化合物及其制备方法和用途
CN105622638B (zh) * 2014-10-29 2018-10-02 广州必贝特医药技术有限公司 嘧啶或吡啶并吡啶酮类化合物及其制备方法和应用

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CN101001857A (zh) * 2002-01-22 2007-07-18 沃尼尔·朗伯有限责任公司 2－(吡啶－2－基氨基)－吡啶并[2,3－d]嘧啶－7－酮
WO2014183520A1 (fr) * 2013-05-17 2014-11-20 上海恒瑞医药有限公司 Dérivé de miazines de tiophène, son procédé de préparation et ses applications médicales
CN105130986A (zh) * 2015-09-30 2015-12-09 广州科擎新药开发有限公司 嘧啶或吡啶并吡啶酮类化合物及其应用

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2018534352A (ja) * 2015-09-30 2018-11-22 グアンジョウ ベベター メディシン テクノロジー カンパニー リミテッド ピリミジン又はピリドピロドン類化合物、及びその応用
WO2017133542A1 (fr) * 2016-02-04 2017-08-10 江苏恒瑞医药股份有限公司 Composition pharmaceutique comprenant un dérivé pyridopyrimidine ou un sel de qualité pharmaceutique de ce dernier
WO2019144759A1 (fr) * 2018-01-29 2019-08-01 海南轩竹医药科技有限公司 Forme cristalline ciblant un inhibiteur de kinase cdk4/6
CN110092775A (zh) * 2018-01-29 2019-08-06 海南轩竹医药科技有限公司 靶向cdk4/6激酶抑制剂的晶型
KR20200116132A (ko) * 2018-01-29 2020-10-08 수안주 (하이난) 바이오파마슈티컬 컴퍼니 리미티드 Cdk4/6 키나아제 억제제를 타겟팅하는 결정형
JP2021512170A (ja) * 2018-01-29 2021-05-13 シュエンジュウ （ハイナン） バイオファーマシューティカル カンパニー リミテッド Ｃｄｋ４／６キナーゼ阻害剤を標的とする結晶形
CN110092775B (zh) * 2018-01-29 2021-09-10 轩竹生物科技有限公司 靶向cdk4/6激酶抑制剂的晶型
US11299474B2 (en) 2018-01-29 2022-04-12 Xuanzhu Biopharmaceutical Co., Ltd. Crystal form targeting CDK4/6 kinase inhibitor
KR102531772B1 (ko) 2018-01-29 2023-05-11 수안주 바이오파마슈티컬 컴퍼니 리미티드 Cdk4/6 키나아제 억제제를 타겟팅하는 결정형
WO2020253808A1 (fr) * 2019-06-20 2020-12-24 江苏恒瑞医药股份有限公司 Composition pharmaceutique et son procédé de préparation

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TW201638090A (zh) 2016-11-01
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