8-fluoro-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one | 1446260-82-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 8-fluoro-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one
• 英文别名: 11-Fluoro-6,7,16-triazatetracyclo[11.2.1.05,15.09,14]hexadeca-1(15),5,9(14),10,12-pentaen-8-one；11-fluoro-6,7,16-triazatetracyclo[11.2.1.05,15.09,14]hexadeca-1(15),5,9(14),10,12-pentaen-8-one
• CAS: 1446260-82-7
• 化学式: C₁₃H₁₀FN₃O
• 分子量: 243.24
• InChiKey: YKIBUJVDRWECHV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  18
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.23
• 拓扑面积：
  57.2
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  2-溴-5-氟-3-氨基苯甲酸甲酯 在 hydrazine hydrate 、 palladium diacetate 、 溶剂黄146 、 三乙胺 、 三(邻甲基苯基)磷 作用下， 以 甲醇 、 溶剂黄146 、 乙腈 为溶剂， 反应 36.0h， 生成 8-fluoro-2,3,5,10-tetrahydro-[1,2]diazepino[3,4,5,6-def]carbazol-6(1H)-one
  参考文献：
  名称：

  Discovery of Pamiparib (BGB-290), a Potent and Selective Poly (ADP-ribose) Polymerase (PARP) Inhibitor in Clinical Development

  摘要：

  Poly (ADP-ribose) polymerase (PARP) plays a significant role in DNA repair responses; therefore, this enzyme is targeted by PARP inhibitors in cancer therapy. Here we have developed a number of fused tetra- or pentacyclic dihydrodiazepinoindolone derivatives with excellent PARP enzymatic and cellular PARylation inhibition activities. These efforts led to the identification of pamiparib (BGB-290, 139), which displays excellent PARP-1 and PARP-2 inhibition with IC₅₀ of 1.3 and 0.9 nM, respectively. In a cellular PARylation assay, this compound inhibits PARP activity with IC₅₀ = 0.2 nM. Cocrystal of pamiparib shows similar binding sites with PARP with other PARP inhibitors, but pamiparib is not a P-gp substrate and shows excellent drug metabolism and pharmacokinetics (DMPK) properties with significant brain penetration (17-19%, mice). The compound is currently being investigated in phase III clinical trials as a maintenance therapy in platinum-sensitive ovarian cancer and gastric cancer.

  DOI：

  10.1021/acs.jmedchem.0c01346

文献信息

• [EN] FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARP INHIBITORS<br/>[FR] DIHYDRODIAZÉPINOCARBAZOLONES TÉTRA OU PENTACYCLIQUES FUSIONNÉS À UTILISER EN TANT QU'INHIBITEURS DE PARP
  申请人：BEIGENE LTD

  公开号：WO2013097225A1

  公开（公告）日：2013-07-04

  Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

  提供了某些融合的四环或五环化合物及其盐、组合物和使用方法。
• FUSED TETRA OR PENTA-CYCLIC DIHYDRODIAZEPINOCARBAZOLONES AS PARP INHIBITORS
  申请人：BEIGENE, LTD.

  公开号：US20150175617A1

  公开（公告）日：2015-06-25

  Provided are certain fused tetra or penta-cyclic compounds and salts thereof, compositions thereof, and methods of use thereof.

  提供了某些融合的四环或五环化合物及其盐，以及它们的组合物和使用方法。
• [EN] TREATMENT CANCERS USING COMBINATION COMPRISING PARP INHIBITORS<br/>[FR] TRAITEMENT DE CANCERS À L'AIDE D'UNE COMBINAISON COMPRENANT DES INHIBITEURS DE PARP
  申请人：BEIGENE LTD

  公开号：WO2018059437A1

  公开（公告）日：2018-04-05

  Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a chemotherapeutic agent. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, or a chemotherapeutic agent and the use thereof.

  本文公开了一种用于预防、延缓癌症进展或治疗受试者的方法，包括向需要该药物的受试者施用PARP抑制剂，特别是(R)-2-氟-10a-甲基-7、8、9、10、10a、11-六氢-5、6、7a、11-四氮杂环庚[def]环戊[a]芴-4(5H)-酮、其半水合物或其药学上可接受的盐，与免疫检查点抑制剂或化学治疗药物联合使用。同时，本文还公开了一种药物组合，包括PARP抑制剂，特别是(R)-2-氟-10a-甲基-7、8、9、10、10a、11-六氢-5、6、7a、11-四氮杂环庚[def]环戊[a]芴-4(5H)-酮、其半水合物或其药学上可接受的盐，与免疫检查点抑制剂或化学治疗药物联合使用，以及其使用方法。
• [EN] TREATMENT CANCERS USING A COMBINATION COMPRISING PARP INHIBITORS, TEMOZOLOMIDE AND/OR RADIATION THERAPY<br/>[FR] TRAITEMENT DE CANCERS À L'AIDE D'UNE COMBINAISON COMPRENANT DES INHIBITEURS DE PARP, DU TÉMOZOLOMIDE ET/OU UNE RADIOTHÉRAPIE
  申请人：BEIGENE LTD

  公开号：WO2019015561A1

  公开（公告）日：2019-01-24

  Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and/or radiation therapy. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R) -2-fluoro-10a-methyl-7, 8, 9, 10, 10a, 11-hexahydro-5, 6, 7a, 11-tetraazacyclohepta [def] cyclopenta [a] fluoren-4 (5H) -one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with temozolomide and the use thereof.

  本发明涉及一种用于预防、延缓癌症进展或治疗受试者的方法，包括向需要该药物的受试者施用PARP抑制剂，特别是(R)-2-氟-10a-甲基-7、8、9、10、10a、11-六氢-5、6、7a、11-四氮杂环庚[def]环戊[a]芴-4(5H)-酮，其半水合物或其药学上可接受的盐，与替莫唑胺和/或放射治疗结合使用。此外，本发明还涉及一种药物组合物，包括PARP抑制剂，特别是(R)-2-氟-10a-甲基-7、8、9、10、10a、11-六氢-5、6、7a、11-四氮杂环庚[def]环戊[a]芴-4(5H)-酮，其半水合物或其药学上可接受的盐，与替莫唑胺的结合使用及其使用方法。
• Treatment cancers using a combination comprising PARP inhibitors
  申请人：BeiGene, Ltd.

  公开号：US11202782B2

  公开（公告）日：2021-12-21

  Disclosed herein is a method for the prevention, delay of progression or treatment of cancer in a subject, comprising administering to the subject in need thereof a PARP inhibitor, particularly, (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor or a chemotherapeutic agent. Also, disclosed a pharmaceutical combination comprising a PARP inhibitor, particularly, (R)-2-fluoro-10a-methyl-7,8,9,10,10a,11-hexahydro-5,6,7a,11-tetraazacyclohepta[def]cyclopenta[a]fluoren-4(5H)-one, a sesqui-hydrate thereof, or a pharmaceutically acceptable salt thereof, in combination with an immune checkpoint inhibitor, or a chemotherapeutic agent and the use thereof.

  本文公开了一种用于预防、延缓或治疗受试者癌症的方法，包括向有需要的受试者施用 PARP 抑制剂，特别是(R)-2-氟-10a-甲基-7,8,9,10,10a、11-六氢-5,6,7a,11-四氮杂环庚二烯并[def]环戊二烯并[a]芴-4(5H)-酮、其倍半水合物或其药学上可接受的盐，与免疫检查点抑制剂或化疗剂联合使用。此外，还公开了一种药物组合物，其包含 PARP 抑制剂，特别是 (R)-2-氟-10a-甲基-7,8,9,10,10a,11-六氢-5,6,7a,11-四氮杂环庚[def]环戊并[a]芴-4(5H)-酮、其倍半水合物或其药学上可接受的盐，与免疫检查点抑制剂或化疗剂联合使用及其用途。