1-[4-(8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-piperazin-1-yl]-2-pyridin-4-yl-ethanone

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并环庚烷吡啶
• 英文名称: 1-[4-(8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-piperazin-1-yl]-2-pyridin-4-yl-ethanone
• 英文别名: 8-CHLORO-5,6-DIHYDRO-11H-BENZO[5,6]CYCLO-HEPTA[1,2-b]PYRIDIN-11-YL-4-(4-PYRIDYLACETYL)-PIPERAZINE；1-[4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)piperazin-1-yl]-2-pyridin-4-ylethanone
• 化学式: C₂₅H₂₅ClN₄O
• 分子量: 432.953
• InChiKey: QIVUVRPLLRMTDC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  31
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  49.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为产物：
  描述：

  8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b] pyridine 在 N-甲基吗啉 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 37.0h， 生成 1-[4-(8-Chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)-piperazin-1-yl]-2-pyridin-4-yl-ethanone
  参考文献：
  名称：

  Inhibitors of Farnesyl Protein Transferase. 4-Amido, 4-Carbamoyl, and 4-Carboxamido Derivatives of 1-(8-Chloro-6,11-dihydro-5H-benzo[5,6]- cyclohepta[1,2-b]pyridin-11-yl)piperazine and 1-(3-Bromo-8-chloro-6,11- dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperazine

  摘要：

  The synthesis of a variety of novel 4-amido, 4-carbamoyl and 4-carboxamido derivatives of 1-(8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin -11-yl)piperazine to explore the SAR of of this series of FPT inhibitors is described. This resulted in the synthesis of the 4- and 3-pyridylacetyl analogues 45a and 50a, respectively, both of which were orally active but were found to be rapidly metabolized in vivo. Identification of the principal metabolites led to the synthesis of a variety of new compounds that would be less readily metabolized, the most interesting of which were the 3- and 4-pyridylacetyl N-oxides 80a and 83a. Novel replacements for the pyridylacetyl moiety were also sought, and this resulted in the discovery of the 4-N-methyl and 4-N-carboxamidopiperidinylacetyl derivatives 135a and 160a, respectively. All of these derivatives exhibited greatly improved pharmacokinetics. The synthesis of the corresponding 3-bromo analogues resulted in the discovery of the 4-pyridylacetyl N-oxides 83b (+/-) and 85b [11S(-)] and the 4-carboxamidopiperidinylacetamido derivative 160b (+/-), all of which exhibited potent FPT inhibition in vitro. All three showed excellent oral bioavailability in vivo in nude mice and cynomolgus monkeys and exhibited excellent antitumor efficacy against a series of tumor cell lines when dosed orally in nude mice.

  DOI：

  10.1021/jm970462w

文献信息

• Tricyclic amide and urea compounds useful for inhibition of G-protein
  申请人：Schering Corporation

  公开号：US05700806A1

  公开（公告）日：1997-12-23

  Novel compounds of Formula (7.0a), (7.0b) or (7.0c): ##STR1## are disclosed. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering a compound of the formula (7.0a), (7.0b) or (7.0c) to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being.

  本发明公开了公式（7.0a）、（7.0b）或（7.0c）的新化合物：##STR1##。同时还公开了一种抑制Ras功能并因此抑制细胞异常生长的方法。该方法包括向生物系统中注射公式（7.0a）、（7.0b）或（7.0c）的化合物。特别地，该方法抑制哺乳动物（如人类）中细胞的异常生长。
• Tricyclic amide and urea compounds useful for inhibition of g-protein
  申请人：Schering Corporation

  公开号：US05719148A1

  公开（公告）日：1998-02-17

  A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of Formula 1.0: ##STR1## to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds of formulas 5.0, 5.1 and 5.2, wherein R is --C(R.sup.20)(R.sup.21)(R.sup.46), and 5.3, 5.3A and 5.3B, wherein R is --N(R.sup.25)(R.sup.48), are disclosed. Also disclosed are processes for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3. Further disclosed are novel compounds which are intermediates in the process for making 3-substituted compounds of Formulas 5.0, 5.1, 5.2 and 5.3.

  本发明公开了一种抑制Ras功能并因此抑制细胞异常生长的方法。该方法包括向生物系统中注入化合物1.0的化合物：##STR1## 。特别是，该方法抑制哺乳动物（如人类）中细胞的异常生长。本发明还公开了公式5.0、5.1和5.2的新化合物，其中R为--C(R.sup.20)(R.sup.21)(R.sup.46)，以及公式5.3、5.3A和5.3B的新化合物，其中R为--N(R.sup.25)(R.sup.48)。还公开了制备公式5.0、5.1、5.2和5.3的3-取代化合物的方法。此外，还公开了制备公式5.0、5.1、5.2和5.3的3-取代化合物的过程中的新型中间体化合物。
• Tricyclic amide and urea compounds useful for inhibition of G-protein function and for treatment of proliferative diseases
  申请人：Schering Corporation

  公开号：US06242458B1

  公开（公告）日：2001-06-05

  A method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells is disclosed. The method comprises the administration of a compound of Formula 1.0: to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human being. Novel compounds of the formulas 5.1 and 5.2 are disclosed.

  本发明公开了一种抑制Ras功能并因此抑制细胞异常生长的方法。该方法包括将公式1.0的化合物注入生物系统中。特别是，该方法抑制哺乳动物（例如人类）中细胞的异常生长。还公开了公式5.1和5.2的新化合物。
• Antitumor 8-chlorobenzocycloheptapyridines: a new class of selective, nonpeptidic, nonsulfhydryl inhibitors of ras farnesylation
  作者：A.K. Mallams、F.G. Njoroge、R.J. Doll、M.E. Snow、J.J. Kaminski、R.R. Rossman、B. Vibulbhan、W.R. Bishop、P. Kirschmeier、M. Liu、M.S. Bryant、C. Alvarez、D. Carr、L. James、I. King、Z. Li、C.-C. Lin、C. Nardo、J. Petrin、S.W. Remiszewski、A.G. Taveras、S. Wang、J. Wong、J. Catino、V. Girijavallabhan、A.K. Ganguly

  DOI：10.1016/s0968-0896(96)00205-2

  日期：1997.1

  Ras farnesylation by farnesyl protein transferase (FPT) is an intracellular event that facilitates the membrane association of the ras protein and is involved in the signal transduction process. FPT inhibition could be a novel, noncytotoxic method of treating ras dependent tumor growth. We report here three structural classes of 8-chlorobenzocycloheptapyridines as novel, nonpeptidic, nonsulfhydryl FPT inhibitors having antitumor activity in mice when dosed orally. We discuss structural and conformational aspects of these compounds in relation to biological activities as well as a comparison to the conformation of a bound tetrapeptide FPT inhibitor. Copyright (C) 1997 Elsevier Science Ltd.
• Methods of Treating Seizure Disorders
  申请人：Massachusetts Institute of Technology

  公开号：US20130225671A1

  公开（公告）日：2013-08-29

  Seizure disorders are treated by Ras inhibitors. In an embodiment, the Ras inhibitor includes a farnesyl transferase inhibitor. In another embodiment, the farnesyl transferase inhibitor includes a 3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor. In another embodiment, the 3-hydroxy-3-methylglutaryl-Coenzyme A reductase inhibitor is not a Ras inhibitor. Subjects having fragile X syndrome, autism, Angelman syndrome, Costello syndrome, cardio facio cutaneous syndrome, neurofibromatosis type I, Noonan syndrome and Coffin-Lowry syndrome that have seizure disorders can be treated.