(R)-(+)-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-yl)-1-piperidine | 193276-49-2

• 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: (R)-(+)-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-yl)-1-piperidine
• 英文别名: (+)-4-(3,10-dibromo-8-chloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]-pyridin-11(R)-yl)-piperidine；(R)-3,10-Dibromo-8-chloro-11-(piperidin-4-yl)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine；(2R)-6,15-dibromo-13-chloro-2-piperidin-4-yl-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene
• CAS: 193276-49-2
• 化学式: C₁₉H₁₉Br₂ClN₂
• 分子量: 470.634
• InChiKey: OIPRWQHOCYCEBQ-GOSISDBHSA-N

物化性质

• 沸点：
  501.8±50.0 °C(Predicted)
• 密度：
  1.582±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  24
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 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：

  (R)-(+)-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-yl)-1-piperidine 在 盐酸 、 sodium hydroxide 、 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 N-甲基吡咯烷酮 、 乙醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 34.0h， 生成 洛那法尼
  参考文献：
  名称：

  一种新的对映选择性烷基化及其在抗癌剂合成中的应用。

  摘要：

  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。

  DOI：

  10.1021/jo034380t
• 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 、 二异丁基氢化铝 作用下， 以 甲苯 为溶剂， 反应 16.67h， 生成 (R)-(+)-(8-chloro-3,10-dibromo-6,11-dihydro-5H-benzo-<5,6>cyclohepta<1,2-b>pyridin-11-yl)-1-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

• Synthesis of [3H], [13C215N] and [14C]Sch 66336 (Sarasar?)
  作者：D. Hesk、D. Cesarz、C. Magatti、K. Voronin、C. Lavey、P. McNamara、D. Koharski、S. Saluja、S. Hendershot、H. Pham、V. Truong

  DOI：10.1002/jlcr.891

  日期：2005.1

  [3H]Sch 66336 was prepared at a specific activity of 1.35 Ci/mmol by Ru(Ph3P)3Cl2 catalysed exchange with tritiated water. [13CN]Sch 66336 was synthesized from potassium [13C]cyanide and [13C15N2]urea in 29% overall yield from potassium [13C]cyanide. [14C]Sch 66336 was synthesized from potassium [14C]cyanide in 31% yield. A second synthesis, from N-Boc-4-hydroxy[14C]piperidine, gave [14C]Sch 66336 labelled in a different site in 19% overall yield. Copyright © 2004 John Wiley & Sons, Ltd.

  [3H]Sch 66336 通过 Ru(Ph3P)3Cl2 催化与氚化水交换制备，比活度为 1.35 Ci/mmol。 [13CN]Sch 66336 由[13C]氰化钾和[13C15N2]脲合成，[13C]氰化钾总产率为29%。 [14C]Sch 66336 由[14C]氰化钾合成，产率 31%。第二次合成由 N-Boc-4-羟基[14C]哌啶合成，得到在不同位点标记的[14C]Sch 66336，总产率为 19%。版权所有 © 2004 约翰·威利父子有限公司
• Metabolites of tricyclic amides useful for inhibition of G-protein function and methods of treatment of proliferative diseases
  申请人：Schering Corporation

  公开号：US20040266810A1

  公开（公告）日：2004-12-30

  The present invention relates to metabolites of tricyclic amides, and structurally related compounds, represented by the structural formula (I): 1 and pharmaceutically acceptable isomers, salts, solvates or esters of the compound of formula (I), wherein: R 1 is selected from the group consisting of H and ═O; R 2 -R 5 can be the same or different, each being independently selected from the group consisting of H, —OH, halide, —NH 2 and ═O; and, the combination solid-dashed lines independently represent either single bonds or double bonds, wherein the number of combination solid-dashed lines that are double bonds is not greater than 2, and when, the double bonds are not adjacent, and when 0, one of R 1 -R 5 is not H. Also disclosed are methods of treatment of proliferative diseases and methods for inhibiting the abnormal growth of cells, and for inhibiting farnesyl protein transferase using the novel compounds.

  本发明涉及三环酰胺代谢物和结构相关化合物，其表示为结构式（I）： 其中：R1选自H和═O组成的群；R2-R5可以相同或不同，每个独立地选自H，—OH，卤素，—NH2和═O组成的群；以及组合的实虚线独立地表示单键或双键，其中双键的组合实虚线数不大于2，且当双键不相邻时，当0时，R1-R5中的一个不是H。 还公开了使用这些新化合物的方法，包括治疗增殖性疾病的方法，抑制细胞异常生长的方法，以及抑制法尼酰丝氨酸蛋白转移酶的方法。这些化合物的制剂也在本发明中公开。
• 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，
• ANTI-CANCER PHOSPHONATE ANALOGS
  申请人：Boojamra Constantine G.

  公开号：US20100022467A1

  公开（公告）日：2010-01-28

  The invention is related to phosphorus substituted anti-cancer compounds, compositions containing such compounds, and therapeutic methods that include the administration of such compounds, as well as to processes and intermediates useful for preparing such compounds.

  本发明涉及磷取代的抗癌化合物、含有这些化合物的组合物以及包括给予这些化合物的治疗方法，还涉及用于制备这些化合物的过程和中间体。