(+)-trans-2-(2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 黄酮类化合物
• 英文名称: (+)-trans-2-(2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one
• 英文别名: 2-(2-chlorophenyl)-8-[2-(hydroxymethyl)-1-methylpyrrolidin-3-yl]-5,7-dimethoxychromen-4-one
• 化学式: C₂₃H₂₄ClNO₅
• 分子量: 429.9
• InChiKey: SGOPLMPANFDPFL-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  30
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  68.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (+)-trans-2-(2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one 在 盐酸 作用下， 以 甲醇 、 乙醚 为溶剂， 以93%的产率得到(+)-trans-2-(2-chlorophenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one hydrochloride
  参考文献：
  名称：

  NOVEL ENANTIOMERICALLY PURE COMPOUNDS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS

  摘要：

  本发明涉及一种由以下式（I）表示的化合物的对映纯（+）-反式对映体：其中R1、R2、R3、R4和R9如规范中定义；其对映纯中间体；制备对映纯化合物及其中间体的方法；以及包含对映纯化合物的药物组合物。式（I）的化合物对于治疗由细胞周期依赖性激酶抑制介导的疾病或紊乱，如癌症，是有用的。

  公开号：

  US20100179210A1
• 作为产物：
  描述：

  2-氯苯甲酸甲酯 、 (-)-trans-1-[2-hydroxy-3-(2-hydroxymethyl-1-methyl-pyrrolidine-3-yl)-4,6-dimethoxy-phenyl]-ethanone 在 sodium hydride 、 甲醇 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.17h， 以64%的产率得到(+)-trans-2-(2-chloro-phenyl)-8-(2-hydroxymethyl-1-methyl-pyrrolidin-3-yl)-5,7-dimethoxy-chromen-4-one
  参考文献：
  名称：

  NOVEL ENANTIOMERICALLY PURE COMPOUNDS FOR THE TREATMENT OF PROLIFERATIVE DISORDERS

  摘要：

  本发明涉及一种由以下式（I）表示的化合物的对映纯（+）-反式对映体：其中R1、R2、R3、R4和R9如规范中定义；其对映纯中间体；制备对映纯化合物及其中间体的方法；以及包含对映纯化合物的药物组合物。式（I）的化合物对于治疗由细胞周期依赖性激酶抑制介导的疾病或紊乱，如癌症，是有用的。

  公开号：

  US20100179210A1

文献信息

• [EN] AN IMPROVED PROCESS FOR PREPARATION OF AN INTERMEDIATE OF THE PYRROLIDINE SUBSTITUTED FLAVONES<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION D'UN INTERMÉDIAIRE DE FLAVONES SUBSTITUÉES PAR PYRROLIDINE
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2014128524A1

  公开（公告）日：2014-08-28

  The present invention relates to a process for the preparation of a key intermediate (as described herein) used in the synthesis of (+)-trans enantiomer of pyrrolidine substituted flavones, represented by the compounds of formula (1) or pharmaceutically acceptable salts thereof; which are inhibitors of cyclin dependant kinases (CDKs) and can be used in the treatment of proliferative disorders such as cancer. Formula (1) wherein R1 has the meaning as indicated in the claims. The process of the present invention has advantages of higher yield and purity, lower reaction temperature, is consistent and involves the use of non toxic solvents. The process of the present invention allows efficient large-scale synthesis and purity of the product obtained is greater than 97 %.

  本发明涉及一种用于制备一种关键中间体（如本文所述）的过程，该中间体用于合成嘧啶取代黄酮类化合物的（+）-反式对映体，该化合物由式（1）所表示，或其药学上可接受的盐；这些化合物是细胞周期依赖性激酶（CDKs）的抑制剂，可用于治疗癌症等增殖性疾病。式（1）中R1的含义如索引中所示。本发明的过程具有较高的产率和纯度优势，反应温度较低，一致性好，并且使用无毒溶剂。本发明的过程允许高效的大规模合成，所得产品的纯度大于97%。
• [EN] A PROCESS FOR PREPARATION OF AN INTERMEDIATE OF THE PYRROLIDINE SUBSTITUTED FLAVONES<br/>[FR] PROCÉDÉ DE PRÉPARATION D'UN INTERMÉDIAIRE DE FLAVONES SUBSTITUÉES PAR UNE PYRROLIDINE
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2014128523A1

  公开（公告）日：2014-08-28

  The present invention relates to a process for the preparation of a key intermediate (as described herein) used in the synthesis of (+)-trans enantiomer of pyrrolidine substituted flavones, represented by the compounds of formula (1) or pharmaceutically acceptable salts thereof; which are inhibitors of cyclin dependant kinases (CDKs) and can be used in the treatment of proliferative disorders such as cancer. Formula (1) wherein R has the meaning as indicated in the claims. The process of the present invention has advantages of higher yield and purity, lower reaction temperature, is consistent and involves the use of non toxic solvents. The process of the present invention allows efficient large-scale synthesis and purity of the product obtained is greater than 97 %.

  本发明涉及一种用于制备一种关键中间体（如本文所述）的方法，该中间体用于合成嘧啶基取代的黄酮类化合物的（+）-反式对映体，该化合物由式（1）所代表，或其药学上可接受的盐；这些化合物是细胞周期依赖性激酶（CDKs）的抑制剂，可用于治疗癌症等增殖性疾病。式（1）中R的含义如索权中所示。本发明的方法具有较高的产率和纯度优势，反应温度较低，稳定且使用无毒溶剂。本发明的方法允许高效的大规模合成，所得产品的纯度大于97％。
• [EN] A PHARMACEUTICAL COMBINATION FOR THE TREATMENT OF MELANOMA<br/>[FR] COMBINAISON PHARMACEUTIQUE POUR LE TRAITEMENT DU MÉLANOME
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2015004636A1

  公开（公告）日：2015-01-15

  The present invention relates to a pharmaceutical combination comprising a cyclin dependent kinase (CDK) inhibitor represented by a compound of formula I (as described herein) or a pharmaceutically acceptable salt thereof; and at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor, for use in the treatment of melanoma. The present invention also relates to a method for the treatment of melanoma comprising administering to a subject in need thereof, a therapeutically effective amount of a CDK inhibitor and a therapeutically effective amount of at least one anticancer agent selected from a BRAF inhibitor or a MEK inhibitor.

  本发明涉及一种制药组合物，包括一种由式I（如本文所述）的细胞周期蛋白依赖性激酶（CDK）抑制剂或其药学上可接受的盐所表示的CDK抑制剂；以及至少一种从BRAF抑制剂或MEK抑制剂中选择的抗癌剂，用于治疗黑色素瘤。本发明还涉及一种治疗黑色素瘤的方法，包括向需要该治疗的受试者投予治疗有效量的CDK抑制剂和至少一种从BRAF抑制剂或MEK抑制剂中选择的治疗有效量的抗癌剂。
• [EN] SOLID ORAL FORMULATION OF A PYRROLIDINE SUBSTITUTED FLAVONE COMPOUND<br/>[FR] FORMULATION ORALE SOLIDE D'UN COMPOSÉ DE FLAVONE SUBSTITUÉ PAR PYRROLIDINE
  申请人：PIRAMAL ENTPR LTD

  公开号：WO2014140695A1

  公开（公告）日：2014-09-18

  The present invention relates to a pharmaceutical composition providing a self emulsifying drug delivery system (SEDDS) for oral administration, comprising a compound, (+) trans-2-(2-chloro-phenyl)-5,7-dihydroxy-8-(2-hydroxymethyl-1- methyl-pyrrolidin-3-yl)-chromen-4-one or a pharmaceutically acceptable salt thereof, along with one or more surfactant and a solubilizer. The present invention also relates to a process for preparation of said pharmaceutical composition and use of the pharmaceutical composition in the treatment of a disease or disorder selected from cancer, polycystic kidney disease, nephrological disorder, psoriasis, immunological disorder involving unwanted proliferation of leukocytes, restenosis, proliferative smooth muscle disorder, radiation induced mucositis, viral infection, mycotic infection or cardiovascular abnormality.

  本发明涉及一种药物组合物，提供一种自乳化药物输送系统(SEDDS)用于口服给药，包括化合物(+)-trans-2-(2-氯苯基)-5,7-二羟基-8-(2-羟甲基-1-甲基-吡咯烷-3-基)-香豆素-4-酮或其药学上可接受的盐，以及一种或多种表面活性剂和一种溶解剂。本发明还涉及一种制备所述药物组合物的方法，以及将药物组合物用于治疗癌症、多囊肾病、肾病学疾病、牛皮癣、涉及白细胞不必要增殖的免疫学疾病、再狭窄、增生性平滑肌疾病、放射性黏膜炎、病毒感染、真菌感染或心血管异常的疾病或紊乱的用途。
• Inhibitors of cyclin-dependent kinases and their use
  申请人：——

  公开号：US20040106581A1

  公开（公告）日：2004-06-03

  The present invention relates to novel compounds for the inhibition of cyclin-dependent kinases, and more particularly, to chromenone derivatives of formula (Ia), 1 wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and A have the meanings indicated in the claims. The invention also relates to processes for the preparation of the compounds of formula (Ia), to methods of inhibiting cyclin-dependent kinases and of inhibiting cell proliferation, to the use of the compounds of formula (Ia) in the treatment and prophylaxis of diseases, which can be treated or prevented by the inhibition of cyclin-dependent kinases such as cancer, to the use of the compounds of formula (Ia) in the preparation of medicaments to be applied in such diseases. The invention further relates to compositions containing a compound of formula (Ia) either alone or in combination with another active agent, in admixture or otherwise in association with an inert carrier, in particular pharmaceutical compositions containing a compound of formula (Ia) either alone or in combination with another active agent, together with pharmaceutically acceptable carrier substances and auxiliary substances.

  本发明涉及一种新型化合物，用于抑制细胞周期蛋白依赖性激酶，尤其是公式（Ia）的香豆素衍生物，其中R1、R2、R3、R4、R5、R6、R7和A的含义如权利要求中所示。本发明还涉及制备公式（Ia）化合物的方法，抑制细胞周期蛋白依赖性激酶和细胞增殖的方法，使用公式（Ia）化合物治疗和预防由于细胞周期蛋白依赖性激酶抑制而可以治疗或预防的疾病，如癌症，使用公式（Ia）化合物制备用于治疗此类疾病的药物。本发明还涉及含有公式（Ia）化合物的组合物，单独或与另一活性剂结合，与惰性载体混合或以其他方式结合，特别是含有公式（Ia）化合物的药物组合物，单独或与另一活性剂结合，与药用可接受载体物质和辅助物质一起使用的制剂。