4-<3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidine | 193276-47-0

• 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-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidine
• 英文别名: 3,10-Dibromo-8-chloro-11-(piperidin-4-ylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine；6,15-dibromo-13-chloro-2-piperidin-4-ylidene-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene
• CAS: 193276-47-0；218453-59-9；218453-60-2
• 化学式: C₁₉H₁₇Br₂ClN₂
• 分子量: 468.618
• InChiKey: WXBHOUYXTMTWMC-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  24
• 可旋转键数：
  0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  24.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  4-<3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidine 在 乙胺嗪 、 二异丁基氢化铝 、 1-羟基苯并三唑 、 三氟乙酸 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 96.67h， 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-<3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidinecarboxylic acid ethyl ester 以90的产率得到4-<3,10-dibromo-8-chloro-5,6-dihydro-11H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-ylidene>-1-piperidine
  参考文献：
  名称：

  [EN] TRICYCLIC AMIDES USEFUL FOR INHIBITION OF G-PROTEIN FUNCTION AND FOR TREATMENT OF PROLIFERATIVE DISEASES
  [FR] AMIDES TRICYCLIQUES DESTINES A L'INHIBITION DE LA FONCTION DE LA PROTEINE-G ET AU TRAITEMENT DES MALADIES PROLIFERATIVES

  摘要：

  （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。

  公开号：

  WO1997023478A1

文献信息

• Process for producing (8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo&lsqb;5,6&rsqb;cyclohepta&lsqb;1,2-B&rsqb;pyridin-11-YL)-1-piperdine
  申请人：Schering Corporation

  公开号：US06706883B1

  公开（公告）日：2004-03-16

  A process for producing compounds of the formula: is disclosed. The compound of formula 1.0 is produced by: (1) separating the atropisomers of  to obtain the atropisomers (2) heating the atropisomer of formula 2.0B at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas 2.0A and 2.0B; (3) separating the atropisomers of formulas 2.0A and 2.0B of step (2); and (4) reducing the atropisomer of formula 2.0A to obtain a compound of formula 1.0. Preferably, R1 is Br, R2 is Cl and R3 is Br. Also disclosed is the (+)-atropisomer of formula 2.0 wherein R1 is Br, R2 is Cl and R3 is Br.

  公开了一种制备以下化合物的方法：公式1.0的化合物是通过以下步骤制备的：(1)分离对映异构体以获得对映异构体(2)在适当的溶剂中以适当的温度加热公式2.0B的对映异构体，以获得公式2.0A和2.0B的混合物的对映异构体；(3)分离步骤(2)中的公式2.0A和2.0B的对映异构体；(4)还原公式2.0A的对映异构体以获得公式1.0的化合物。优选地，R1是Br，R2是Cl，R3是Br。还公开了公式2.0的(+)-对映异构体，其中R1是Br，R2是Cl，R3是Br。
• Enzymatic Kinetic Resolution of Piperidine Atropisomers:  Synthesis of a Key Intermediate of the Farnesyl Protein Transferase Inhibitor, SCH66336
  作者：Brian Morgan、Aleksey Zaks、David R. Dodds、Jinchu Liu、Rama Jain、Sreeni Megati、F. George Njoroge、Viyyoor M. Girijavallabhan

  DOI：10.1021/jo991513v

  日期：2000.9.1

  The resolution of secondary amines via enzyme-catalyzed acylation is a relatively rare process. The kinetic resolution of a series of intermediates of SCH66336 (1), by either enzymatic acylation of the pendant piperidine (4, 5) or hydrolysis of the corresponding carbamate 3, was investigated. In the case of 4, the molecule exists as a pair of enantiomers due to atropisomerism about the exocyclic double

  通过酶催化的酰化作用分解仲胺是一个相对罕见的过程。通过悬垂哌啶（4、5）的酶促酰化反应或相应的氨基甲酸酯3的水解反应，研究了SCH66336（1）一系列中间体的动力学拆分。在4的情况下，由于围绕环外双键的阻转异构性，该分子以一对对映异构体的形式存在。（+/-）-4的酶促酰化在酰化剂，溶剂和水分含量方面进行了优化。使用脂肪酶，Toyobo LIP-300和三氟乙基异丁酸酯作为酰化剂可导致（+）-对映体的异丁酰化，该异丁酸酯化很容易与不需要的（-）-4分离。异丁酰胺6c的水解以高对映体过量产生所需的（+）-4。（-）-4可以从拆分步骤中恢复，外消旋化，
• [EN] PROCESS FOR PRODUCING (8- CHLORO-3,10- DIBROMO-6,11- DIHYDRO- 5H-BENZO [5,6]CYCLOHEPTA [1,2-B]PYRIDIN-11-YL)- 1-PIPERIDINE<br/>[FR] PROCEDE DE PRODUCTION DE LA (8-CHLORO-3,10-DIBROMO-6,11-DIHYDRO-5H-BENZO[5,6]CYCLOHEPTA[1,2-B]PYRIDINE-11-YL)-1-PIPERIDINE
  申请人：SCHERING CORP

  公开号：WO2000001689A1

  公开（公告）日：2000-01-13

  A process for producing compounds of formula (1.0) is disclosed. The compound of formula (1.0) is produced by: (1) separating the atropisomers of (2.0) to obtain the atropisomers (2.0A) and (2.0B); (2) heating the atropisomer of formula (2.0B) at a suitable temperature in a suitable solvent to obtain a mixture of atropisomers of formulas (2.0A) and (2.0B); (3) separating the atropisomers of formulas (2.0A) and (2.0B) of step (2); and (4) reducing the atropisomer of formula (2.0A) to obtain a compound of formula (1.0). Preferably, R1 is Br, R2 is Cl and R3 is Br. Also disclosed is the (+)-atropisomer of formula (2.0) wherein R1 is Br, R2 is Cl and R3 is Br.

  公开了一种制备式（1.0）化合物的方法。通过以下步骤制备式（1.0）化合物：（1）分离式（2.0）的对映异构体，得到式（2.0A）和（2.0B）的对映异构体；（2）在适当的溶剂中以适当的温度加热式（2.0B）的对映异构体，得到式（2.0A）和（2.0B）的对映异构体混合物；（3）分离步骤（2）中的式（2.0A）和（2.0B）的对映异构体；（4）还原式（2.0A）的对映异构体，得到式（1.0）化合物。最好的情况是，R1为Br，R2为Cl，R3为Br。还公开了式（2.0）的（+）-对映异构体，其中R1为Br，R2为Cl，R3为Br。
• 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