(+)-4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11(R)-yl)-1-<(4-piperidinyl)acetyl>piperidine | 193276-77-6

• 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-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11(R)-yl)-1-<(4-piperidinyl)acetyl>piperidine
• 英文别名: (R)-1-(4-(3,10-Dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridin-11-yl)piperidin-1-yl)-2-(piperidin-4-yl)ethanone；1-[4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-piperidin-4-ylethanone
• CAS: 193276-77-6
• 化学式: C₂₆H₃₀Br₂ClN₃O
• 分子量: 595.805
• InChiKey: FVZHXOFDPYQOAY-RUZDIDTESA-N

物化性质

• 熔点：
  104.1 °C
• 沸点：
  653.4±55.0 °C(Predicted)
• 密度：
  1.481±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  33
• 可旋转键数：
  3
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.54
• 拓扑面积：
  45.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  (+)-4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11(R)-yl)-1-<(4-piperidinyl)acetyl>piperidine 在 磺酰胺 作用下， 反应 120.0h， 以65%的产率得到4-[2-[4-[(2R)-6,15-dibromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-yl]piperidin-1-yl]-2-oxoethyl]piperidine-1-sulfonamide
  参考文献：
  名称：

  Identification of Pharmacokinetically Stable 3,10-Dibromo-8-chlorobenzocycloheptapyridine Farnesyl Protein Transferase Inhibitors with Potent Enzyme and Cellular Activities

  摘要：

  Farnesyl protein transferase (FPT) is a promising target for the development of cancer chemotherapeutics because it is responsible for the farnesylation of oncogenic p21 Ras proteins which are found in nearly 30% of all human cancers and necessary for cellular development and growth. The recent discovery and progression to phase II clinical trials of trihalobenzocycloheptapyridine Sch-66336 as a potent inhibitor of FPT with oral, in vivo efficacy in mice have spawned extensive structure-activity relationship studies (SAR) of this class of compounds. Of the many trihalobenzocycloheptapyridine analogues prepared, we have identified several which inhibit FPT and cellular proliferation at single-digit nanomolar concentrations and which have good pharmacokinetic properties in mice.

  DOI：

  10.1021/jm990059k
• 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 在 盐酸 、 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 64.67h， 生成 (+)-4-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11(R)-yl)-1-<(4-piperidinyl)acetyl>piperidine
  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

• A Novel Enantioselective Alkylation and Its Application to the Synthesis of an Anticancer Agent
  作者：Shen-Chun Kuo、Frank Chen、Donald Hou、Agnes Kim-Meade、Charles Bernard、Jinchu Liu、Stacy Levy、George G. Wu

  DOI：10.1021/jo034380t

  日期：2003.6.1

  A novel enantioselective alkylation of double benzylic substrates with secondary electrophiles is reported. A simple norephedrine-based chiral ligand was synthesized that gives alkylation product in 95% yield and 95% ee. A unique water effect on the enantioselectivity was unveiled. Good to excellent ee values were obtained with a number of double benzylic substrates and secondary electrophiles. This

  报道了具有仲亲电试剂的双苄基底物的新型对映选择性烷基化。合成了一种简单的基于去氧麻黄碱的手性配体，该烷基化产物的收率为95％，ee为95％。揭示了对对映选择性的独特水效应。使用许多双苄基底物和第二亲电试剂可获得良好至优异的ee值。该新反应已被应用于有希望的抗癌剂的合成。
• 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
• Trihalobenzocycloheptapyridine analogues of Sch 66336 as potent inhibitors of farnesyl protein transferase
  作者：F.George Njoroge、Bancha Vibulbhan、Patrick Pinto、Corey L Strickland、W.Robert Bishop、Paul Kirschmeir、V Girijavallabhan、Ashit K Ganguly

  DOI：10.1016/s0968-0896(02)00308-5

  日期：2003.1

  SCH 66336 is a trihalo tricyclic compound that is currently undergoing Phase 11 clinical trials for the treatment of solid tumors. Modifications of SCH 66336 by incorporating such groups as amides, acids, esters, ureas and lactams off the first or the distal piperidine (from the tricycle) provided potent FPT inhibitors some of which exhibited good cellular activity. A number of these compounds incorporate properties that might improve pharmacokinetic stability of these inhibitors by virtue of their increased solubility or by their change in log P. (C) 2002 Elsevier Science Ltd. All rights reserved.
• TRICYCLIC INHIBITORS OF FARNESYL PROTEIN TRANSFERASE
  申请人：SCHERING CORPORATION

  公开号：EP0929545B1

  公开（公告）日：2004-12-29
• [EN] ENANTIOSELECTIVE ALKYLATION OF TRICYCLIC COMPOUNDS<br/>[FR] PROCEDE ENANTIOSELECTIF
  申请人：SCHERING CORP

  公开号：WO2004031153A3

  公开（公告）日：2004-07-15