(2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid | 1146160-50-0

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: (2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid
• 英文别名: (2R,4S)-4-[[2-(2-methoxyphenyl)quinazolin-4-yl]amino]-1-[(2-methylpropan-2-yl)oxycarbonyl]pyrrolidine-2-carboxylic acid
• CAS: 1146160-50-0
• 化学式: C₂₅H₂₈N₄O₅
• 分子量: 464.521
• InChiKey: PHDOBHDXHULCIN-HNAYVOBHSA-N

物化性质

• 沸点：
  606.4±55.0 °C(predicted)
• 密度：
  1.312±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.2
• 重原子数：
  34
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  114
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid 在 三溴化硼 、 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 44.5h， 生成 (2R,4S)-4-(2-(2-hydroxyphenyl)quinazolin-4-ylamino)-N,N-dimethylpyrrolidine-2-carboxamide
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

  摘要：

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

  DOI：

  10.1021/jm101150b
• 作为产物：
  描述：

  (2R,4S)-1-叔丁基 2-甲基 4-氨基吡咯烷-1,2-二甲酸酯 在 lithium hydroxide monohydrate 、 水 、 三乙胺 作用下， 以 1,4-二氧六环 为溶剂， 反应 73.0h， 生成 (2R,4S)-1-(tert-butoxycarbonyl)-4-(2-(2-methoxyphenyl)quinazolin-4-ylamino)pyrrolidine-2-carboxylic acid
  参考文献：
  名称：

  Structure-Based Design of Potent and Selective 2-(Quinazolin-2-yl)phenol Inhibitors of Checkpoint Kinase 2

  摘要：

  Structure-based design was applied to the optimization of a series of 2-(quinazolin-2-yl)phenols to generate potent and selective ATP-competitive inhibitors of the DNA damage response signaling enzyme checkpoint kinase 2 (CHK2). Structure-activity relationships for multiple substituent positions were optimized separately and in combination leading to the 2-(quinazolin-2-yl)phenol 46 (IC(50) 3 nM) with good selectivity for CHK2 against CHK1 and a wider panel of kinases and with promising in vitro ADMET properties. Off-target activity at hERG ion channels shown by the core scaffold was successfully reduced by the addition of peripheral polar substitution. In addition to showing mechanistic inhibition of CHK2 in HT29 human colon cancer cells, a concentration dependent radioprotective effect in mouse thymocytes was demonstrated for the potent inhibitor 46 (CCT241533).

  DOI：

  10.1021/jm101150b

文献信息

• [EN] THERAPEUTIC OXY-PHENYL-ARYL COMPOUNDS AND THEIR USE<br/>[FR] COMPOSÉS OXY-PHÉNYL-ARYLES THÉRAPEUTIQUES ET LEUR UTILISATION
  申请人：CANCER REC TECH LTD

  公开号：WO2009053694A1

  公开（公告）日：2009-04-30

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明总体涉及治疗化合物领域，更具体地涉及如本文所述的某些氧基苯基芳基化合物（以下简称OPA化合物），其中，抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含此类化合物的药物组合物，以及使用此类化合物和组合物，在体内外抑制CHK2激酶功能，以及治疗由CHK2介导的疾病和状况，包括通过抑制CHK2激酶功能而改善的疾病和状况，等等，包括诸如癌症等增殖性疾病，可选地与另一剂联合使用，例如，（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）针对微管的药剂；（e）电离辐射。
• Therapeutic Oxy-Phenyl-Aryl Compounds and Their Use
  申请人：Collins Ian

  公开号：US20110201592A1

  公开（公告）日：2011-08-18

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明涉及治疗化合物领域，更具体地涉及某些氧苯基芳基化合物（以下简称OPA化合物），如本文所述，该化合物在其中抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含这种化合物的制药组合物，以及在体外和体内使用这种化合物和组合物来抑制CHK2激酶功能，并治疗由CHK2介导，通过抑制CHK2激酶功能改善的疾病和病况，包括增殖性疾病，如癌症等，可选择与另一种药物一起使用，例如（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）微管靶向药物；和（e）电离辐射。
• Therapeutic oxy-phenyl-aryl compounds and their use
  申请人：Cancer Research Technology Limited

  公开号：US08324226B2

  公开（公告）日：2012-12-04

  The present invention pertains generally to the field of therapeutic compounds, and more specifically to certain oxy phenyl aryl compounds (referred to herein as OPA compounds), as described herein, which, inter alia, inhibit Checkpoint Kinase 2 (CHK2) kinase function. The present invention also pertains to pharmaceutical compositions comprising such compounds, and the use of such compounds and compositions, both in vitro and in vivo, to inhibit CHK2 kinase function, and in the treatment of diseases and conditions that are mediated by CHK2, that are ameliorated by the inhibition of CHK2 kinase function, etc., including proliferative conditions such as cancer, etc., optionally in combination with another agent, for example, (a) a DNA topoisomerase I or II inhibitor; (b) a DNA damaging agent; (c) an antimetabolite or TS inhibitor; (d) a microtubule targeted agent; and (e) ionising radiation.

  本发明涉及治疗化合物领域，更具体地涉及某些氧代苯基芳基化合物（以下简称OPA化合物），如本文所述，它们可以抑制检查点激酶2（CHK2）激酶功能。本发明还涉及包含这些化合物的制药组合物，以及在体内外使用这些化合物和组合物来抑制CHK2激酶功能，并用于治疗由CHK2介导的疾病和病情，通过抑制CHK2激酶功能而改善的疾病和病情，包括增生性疾病如癌症等，可选择与另一种药物联合使用，例如：（a）DNA拓扑异构酶I或II抑制剂；（b）DNA损伤剂；（c）抗代谢物或TS抑制剂；（d）微管靶向剂；和（e）电离辐射。
• THERAPEUTIC OXY-PHENYL-ARYL COMPOUNDS AND THEIR USE
  申请人：Cancer Research Technology Limited

  公开号：EP2227460A1

  公开（公告）日：2010-09-15
• US8324226B2
  申请人：——

  公开号：US8324226B2

  公开（公告）日：2012-12-04