4-氯-5-溴-7-(三异丙基硅基)-7H-吡咯并[2,3-D]嘧啶 | 870706-51-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并嘧啶类
• 中文名称: 4-氯-5-溴-7-(三异丙基硅基)-7H-吡咯并[2,3-D]嘧啶
• 英文名称: 5-bromo-4-chloro-7-triisopropylsilanyl-7H-pyrrolo[2,3-d]pyrimidine
• 英文别名: 5-Bromo-4-chloro-7-(triisopropylsilyl)-7H-pyrrolo[2,3-d]pyrimidine；(5-bromo-4-chloropyrrolo[2,3-d]pyrimidin-7-yl)-tri(propan-2-yl)silane
• CAS: 870706-51-7
• 化学式: C₁₅H₂₃BrClN₃Si
• 分子量: 388.81
• InChiKey: VZOFJPQSKZVVRU-UHFFFAOYSA-N

物化性质

• 沸点：
  361.9±42.0 °C(Predicted)
• 密度：
  1.32±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.87
• 重原子数：
  21
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.6
• 拓扑面积：
  30.7
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-氯-5-溴-7-(三异丙基硅基)-7H-吡咯并[2,3-D]嘧啶 在 甲醇 、 正丁基锂 、 氨 、 caesium carbonate 、 N,N-二异丙基乙胺 、 cesium fluoride 作用下， 以 甲醇 、 乙醚 、 正己烷 、 异丁酰胺 、 二甲基亚砜 为溶剂， 反应 58.0h， 生成 [4-amino-7-(propan-2-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl][6-(methylamino)pyrazin-2-yl]methanone
  参考文献：
  名称：

  Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)

  摘要：

  Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K alpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K-i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.

  DOI：

  10.1021/jm201019k
• 作为产物：
  描述：

  4-氯-7-(三异丙基硅基)-7H-吡咯并[2,3-d]嘧啶 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以72%的产率得到4-氯-5-溴-7-(三异丙基硅基)-7H-吡咯并[2,3-D]嘧啶
  参考文献：
  名称：

  [EN] PYRROLOPYRIMIDINE DERIVATIVES USEFUL IN CANCER TREATMENT
  [FR] DERIVES PYRROLOPYRIMIDINIQUES CONVENANT AU TRAITEMENT DU CANCER

  摘要：

  该发明涉及公式（I）的化合物或其药学上可接受的盐、前药、溶剂合物或水合物，其中L、R'、R2、R3和R4如本文所定义。该发明还涉及含有公式（I）化合物的药物组合物，以及通过给予公式（I）化合物来治疗哺乳动物中的异常细胞生长，如癌症的方法。

  公开号：

  WO2005116035A1

文献信息

• [EN] PYRROLOPYRIMIDINE DERIVATIVES USEFUL IN CANCER TREATMENT<br/>[FR] DERIVES PYRROLOPYRIMIDINIQUES CONVENANT AU TRAITEMENT DU CANCER
  申请人：PFIZER PROD INC

  公开号：WO2005116035A1

  公开（公告）日：2005-12-08

  The invention relates to compounds of the formula (I) or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, wherein L, R', R2, R3 and R4 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula (I) and to methods of treating abnormal cell growth, such as cancer in a mammal by administering the compounds of formula (I).

  该发明涉及公式（I）的化合物或其药学上可接受的盐、前药、溶剂合物或水合物，其中L、R'、R2、R3和R4如本文所定义。该发明还涉及含有公式（I）化合物的药物组合物，以及通过给予公式（I）化合物来治疗哺乳动物中的异常细胞生长，如癌症的方法。
• Pyrrolopyrimidine derivatives useful in cancer treatment
  申请人：Marx A. Matthew

  公开号：US20060035912A1

  公开（公告）日：2006-02-16

  The invention relates to compounds of the formula 1 or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, wherein L, R 1 , R 2 R 3 and R 4 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating abnormal cell growth, such as cancer in a mammal by administering the compounds of formula 1.

  本发明涉及公式1的化合物或其药学上可接受的盐、前药、溶剂或水合物，其中L、R1、R2、R3和R4如定义所述。本发明还涉及含有公式1化合物的制药组合物，以及通过给哺乳动物施用公式1化合物治疗异常细胞生长（如癌症）的方法。
• Substituted pyrrolo[2,3-d]pyrimidine derivatives useful in cancer treatment
  申请人：Pfizer Inc.

  公开号：US07595325B2

  公开（公告）日：2009-09-29

  The invention relates to compounds of the formula 1 or a pharmaceutically acceptable salt, prodrug, solvate or hydrate thereof, wherein L, R1, R2, R3 and R4 are as defined herein. The invention also relates to pharmaceutical compositions containing the compounds of formula 1 and to methods of treating abnormal cell growth, such as cancer in a mammal by administering the compounds of formula 1.

  本发明涉及公式1的化合物或其药学上可接受的盐、前药、溶剂或水合物，其中L、R1、R2、R3和R4如本文所定义。本发明还涉及含有公式1化合物的制药组合物，以及通过给哺乳动物施用公式1化合物治疗异常细胞生长（如癌症）的方法。
• Discovery of Novel, Potent, and Selective Inhibitors of 3-Phosphoinositide-Dependent Kinase (PDK1)
  作者：Sean T. Murphy、Gordon Alton、Simon Bailey、Sangita M. Baxi、Benjamin J. Burke、Thomas A. Chappie、Jacques Ermolieff、RoseAnn Ferre、Samantha Greasley、Michael Hickey、John Humphrey、Natasha Kablaoui、John Kath、Steven Kazmirski、Michelle Kraus、Stan Kupchinsky、John Li、Laura Lingardo、Matthew A. Marx、Dan Richter、Steven P. Tanis、Khanh Tran、William Vernier、Zhi Xie、Min-Jean Yin、Xiao-Hong Yu

  DOI：10.1021/jm201019k

  日期：2011.12.22

  Analogues substituted with various amines at the 6-position of the pyrazine ring on (4-amino-7-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrazin-2-ylmethanone were discovered as potent and selective inhibitors of PDK1 with potential as anticancer agents. An early lead with 2-pyridine-3-ylethylamine as the pyrazine substituent showed moderate potency and selectivity. Structure-based drug design led to improved potency and selectivity against PI3K alpha through a combination of cyclizing the ethylene spacer into a saturated, five-membered ring and substituting on the 4-position of the aryl ring with a fluorine. ADME properties were improved by lowering the lipophilicity with heteroatom replacements in the saturated, five-membered ring. The optimized analogues have a PDK1 K-i of 1 nM and >100-fold selectivity against PI3K/AKT-pathway kinases. The cellular potency of these analogues was assessed by the inhibition of AKT phosphorylation (T308) and by their antiproliferation activity against a number of tumor cell lines.