4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-YL)-N-METHYL-N-(3-PYRIDINYL)-1-PIPERAZINE-CARBOXAMIDE

• 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: 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-YL)-N-METHYL-N-(3-PYRIDINYL)-1-PIPERAZINE-CARBOXAMIDE
• 英文别名: 4-(13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl)-N-methyl-N-pyridin-3-ylpiperazine-1-carboxamide
• 化学式: C₂₅H₂₆ClN₅O
• 分子量: 447.967
• InChiKey: DIKKNRCBPSWRFQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  32
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  52.6
• 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 氢氧化钾 作用下， 以 四氢呋喃 、 二甲基亚砜 为溶剂， 反应 36.25h， 生成 4-(8-CHLORO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-b]PYRIDIN-11-YL)-N-METHYL-N-(3-PYRIDINYL)-1-PIPERAZINE-CARBOXAMIDE
  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 function and for treatment of proliferative diseases
  申请人：——

  公开号：US20020068742A1

  公开（公告）日：2002-06-06

  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: 1 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 2 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.

  本发明揭示了一种抑制Ras功能，从而抑制细胞异常生长的方法。该方法包括向生物系统中给予1.0:1化合物的管理。特别是，在哺乳动物如人类中，该方法抑制细胞异常生长。还揭示了公式2的新化合物。还揭示了制备公式5.0、5.1、5.2和5.3的3-取代化合物的过程。此外，还揭示了在制备公式5.0、5.1、5.2和5.3的3-取代化合物的过程中的新化合物，这些新化合物是中间体。
• Tricylic 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：EP1123931A1

  公开（公告）日：2001-08-16

  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 formulae (5.0, 5.1, 5.2, 5.3, 5.3A and 5.3B) are disclosed. Also disclosed are process for making the 3-substituted compound of formulae (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 formulae (5.0, 5.1, 5.2 and 5.3).

  本发明公开了一种抑制 Ras 功能从而抑制细胞异常生长的方法。该方法包括向生物系统施用式（1.0）化合物。特别是，该方法可抑制哺乳动物如人体内细胞的异常生长。本发明公开了式(5.0、5.1、5.2、5.3、5.3A 和 5.3B)的新型化合物。还公开了式 (5.0、5.1、5.2 和 5.3) 的 3-取代基化合物的制造工艺。还公开了作为式（5.0、5.1、5.2 和 5.3）3-取代化合物制造工艺中间体的新型化合物。
• US6242458B1
  申请人：——

  公开号：US6242458B1

  公开（公告）日：2001-06-05
• US6365588B1
  申请人：——

  公开号：US6365588B1

  公开（公告）日：2002-04-02
• [EN] TRICYCLIC AMIDE AND UREA COMPOUNDS USEFUL FOR INHIBITION OF G-PROTEIN FUNCTION AND FOR TREATMENT OF PROLIFERATIVE DISEASES<br/>[FR] COMPOSES TRICYCLIQUES A BASE D'AMIDES ET D'UREE UTILES POUR INHIBER LA FONCTION DE LA PROTEINE G ET AU TRAITEMENT DE MALADIES PROLIFERATIVES
  申请人：SCHERING CORPORATION

  公开号：WO1995010516A1

  公开（公告）日：1995-04-20

  (EN) 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 formulae (5.0, 5.1, 5.2, 5.3, 5.3A and 5.3B) are disclosed. Also disclosed are processes for making 3-substituted compounds of formulae (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 formulae (5.0, 5.1, 5.2 and 5.3).(FR) Un procédé qui permet d'inhiber la fonction Ras et donc des croissances cellulaires anormales, consiste à administrer à un organisme biologique un composé de formule (1.0). Ce procédé permet notamment d'inhiber des croissances cellulaires anormales chez un mammifère tel que l'homme. L'invention concerne de nouveaux composés de formules: (5.0, 5.1, 5.2, 5.3, 5.3A, 5.3B). L'invention concerne en outre des procédés donnant des composés à substitution en position 3 des formules (5.0, 5.1, 5.2 et 5.3). L'invention concerne enfin de nouveaux composés qui constituent des intermédiaires pour le procédé donnant des composés à substitution en position 3 correspondant à ces quatre formules.