4-<3,10-dibromo-8-chloro-5,6-dihydro-9-amino-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester | 193276-45-8

• 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-<3,10-dibromo-8-chloro-5,6-dihydro-9-amino-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester
• 英文别名: Ethyl 4-(9-amino-3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-ylidene)piperidine-1-carboxylate；ethyl 4-(14-amino-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(15),3(8),4,6,11,13-hexaen-2-ylidene)piperidine-1-carboxylate
• CAS: 193276-45-8
• 化学式: C₂₂H₂₂Br₂ClN₃O₂
• 分子量: 555.697
• InChiKey: YDFFVKXSKNVNRY-UHFFFAOYSA-N

物化性质

• 沸点：
  616.4±55.0 °C(Predicted)
• 密度：
  1.643±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  30
• 可旋转键数：
  2
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  68.4
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-<3,10-dibromo-8-chloro-5,6-dihydro-9-amino-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester 在 盐酸 、 乙胺嗪 、 亚膦酸 、 二异丁基氢化铝 、 1-羟基苯并三唑 、 三氟乙酸 、 sodium nitrite 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 114.67h， 生成 洛那法尼
  参考文献：
  名称：

  (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336):  A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent

  摘要：

  We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

  DOI：

  10.1021/jm980462b
• 作为产物：
  描述：

  4-<3-bromo-8-chloro-5,6-dihydro-9-nitro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester 在 水 、 溴 、 铁粉 、 溶剂黄146 、 calcium chloride 作用下， 以 乙醇 为溶剂， 反应 32.0h， 生成 4-<3,10-dibromo-8-chloro-5,6-dihydro-9-amino-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester
  参考文献：
  名称：

  (+)-4-[2-[4-(8-Chloro-3,10-dibromo-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]- pyridin-11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH-66336):  A Very Potent Farnesyl Protein Transferase Inhibitor as a Novel Antitumor Agent

  摘要：

  We have previously shown that appropriate modification of the benzocycloheptapyridine tricyclic ring system can provide potent farnesyl protein transferase (FPT) inhibitors with good cellular activity. Our laboratories have also established that incorporation of either pyridinylacetyl N-oxide or 4-N-carboxamidopiperidinylacetyl moieties results in pharmacokinetically stable inhibitors that are orally efficacious in nude mice. We now demonstrate that further elaboration of the tricyclic ring system by introducing a bromine atom at the 7- or the 10-position of the 3-bromo-8-chlorotricyclic ring system provides compounds that have superior potency and selectivity in FPT inhibition. These compounds have good serum levels and half-lives when given orally to rodents and primates. In vitro and in vivo evaluation of a panel of these inhibitors has led to identification of 15 (SCH 66336) as a highly potent (IC50 = 1.9 nM) antitumor agent that is currently undergoing human clinical trials.

  DOI：

  10.1021/jm980462b

文献信息

• [EN] TRICYCLIC AMIDES USEFUL FOR INHIBITION OF G-PROTEIN FUNCTION AND FOR TREATMENT OF PROLIFERATIVE DISEASES<br/>[FR] AMIDES TRICYCLIQUES DESTINES A L'INHIBITION DE LA FONCTION DE LA PROTEINE-G ET AU TRAITEMENT DES MALADIES PROLIFERATIVES
  申请人：SCHERING CORPORATION

  公开号：WO1997023478A1

  公开（公告）日：1997-07-03

  (EN) Novel compounds, such as formulae (1.0), (4.0), (22.0), (27.0), (32.0) and (39.0) are disclosed. Also disclosed are methods for inhibiting the abnormal growth of cells, for inhibiting farnesyl protein transferase and for treating cancers using the novel compounds.(FR) Nouveaux composés tels que ceux représentés par les formules (1.0), (4.0), (22.0) (27.0), (32.0) et (39.0), et procédés d'inhibition d'une croissance anormale des cellules, d'inhibition de la farnésyle protéine transférase et de traitement de cancers au moyen de ces nouveaux composés.

  （中）本发明公开了新化合物，如公式（1.0）、（4.0）、（22.0）、（27.0）、（32.0）和（39.0）。还公开了使用这些新化合物抑制细胞异常生长、抑制法尼酰基蛋白转移酶以及治疗癌症的方法。
• COMPOUNDS USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0942906B1

  公开（公告）日：2004-11-03
• TRICYCLIC ANTITUMOR COMPOUNDS BEING FARNESYL PROTEIN TRANSFERASE INHIBITORS
  申请人：SCHERING CORPORATION

  公开号：EP0929544B1

  公开（公告）日：2004-11-10
• BENZO(5,6)CYCLOHEPTA(1,2-B)PYRIDINE DERIVATIVES USEFUL FOR INHIBITION OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP1019398B1

  公开（公告）日：2004-09-15
• TRICYCLIC INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0929545B1

  公开（公告）日：2004-12-29