3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine | 183788-13-8

• 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: 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
• 英文别名: 3-bromo-8,11-dichloro-6,11-dihydro[5,6]cyclohepta[1,2-b]pyridine；6-Bromo-2,13-dichloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaene
• CAS: 183788-13-8
• 化学式: C₁₄H₁₀BrCl₂N
• 分子量: 343.05
• InChiKey: ZPSGMRJAQZIYLA-UHFFFAOYSA-N

物化性质

• 沸点：
  405.0±45.0 °C(Predicted)
• 密度：
  1.64±0.1 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：
  18
• 可旋转键数：
  0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  12.9
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine 在 N-甲基吗啉 、 硫酸 、 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 四氢呋喃 、 1,4-二氧六环 、 N,N-二甲基甲酰胺 为溶剂， 反应 39.0h， 生成 1-(3-Bromo-8-chloro-6,11-dihydro-5 H-benzo[5,6]-cyclohepta[1,2-b] pyridin-11-yl)-4-[(4-piperidinyl)acetyl]-piperazine
  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
• 作为产物：
  描述：

  6-Bromo-13-chloro-4-azatricyclo[9.4.0.03,8]pentadeca-1(11),3(8),4,6,12,14-hexaen-2-ol 在 氯化亚砜 作用下， 以 甲苯 为溶剂， 生成 3-bromo-8,11-dichloro-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine
  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

• Guiding farnesyltransferase inhibitors from an ECLiPS® library to the catalytic zinc
  作者：Chia-Yu Huang、Tara M. Stauffer、Corey L. Strickland、John C. Reader、He Huang、Ge Li、Alan B. Cooper、Ronald J. Doll、Ashit K. Ganguly、John J. Baldwin、Laura L. Rokosz

  DOI：10.1016/j.bmcl.2005.10.070

  日期：2006.2

  Farnesyltransferase inhibitors identified from an ECLiPS library were optimized using solution-phase synthesis. X-ray crystallography of inhibited complexes was used to identify substructures that coordinate to the active site zinc. The X-ray structures were ultimately used to guide the design of second-generation analogs with FTase IC(50)s of less than 1.0 nM.

  从ECLiPS库中鉴定出的法呢基转移酶抑制剂使用溶液相合成法进行了优化。抑制的复合物的X射线晶体学用于鉴定与活性位点锌配位的亚结构。X射线结构最终被用于指导FTase IC（50）小于1.0 nM的第二代类似物的设计。
• Tricyclic piperidinyl compounds useful as inhibitors of farnesyl-protein
  申请人：Schering Corporation

  公开号：US05965570A1

  公开（公告）日：1999-10-12

  Novel tricyclic compounds and pharmaceutical compositions are disclosed which are inhibitors of the enzyme, farnesyl protein transferase. Also disclosed is a method of inhibiting Ras function and therefore inhibiting the abnormal growth of cells. The method comprises administering the novel tricyclic compound to a biological system. In particular, the method inhibits the abnormal growth of cells in a mammal such as a human.

  揭示了一种新型三环化合物和药物组合物，它们是酶法尼醇蛋白转移酶的抑制剂。还公开了一种抑制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这种新型三环化合物。具体而言，该方法抑制了哺乳动物（如人类）中细胞的异常生长。
• 17 Beta-hydroxysteroid dehydrogenase type 3 inhibitors for the treatment of androgen dependent diseases
  申请人：SCHERING CORPORATION

  公开号：US20040138226A1

  公开（公告）日：2004-07-15

  In its many embodiments, the present invention provides a novel class of compounds as inhibitors of type 3 17&bgr;-hydroxysteroid dehydrogenase, methods of preparing such compounds, pharmaceutical compositions containing one or more such compounds, methods of preparing pharmaceutical formulations comprising one or more such compounds, and methods of treatment, prevention, inhibition, or amelioration of one or more diseases associated with type 3 17&bgr;-hydroxysteroid dehydrogenase using such compounds or pharmaceutical compositions.

  在其多种实施方式中，本发明提供了一类新型化合物，作为第3型17β-羟基类固醇脱氢酶的抑制剂，以及制备这种化合物的方法，含有一种或多种这种化合物的药物组合物，制备含有一种或多种这种化合物的药物制剂的方法，以及使用这种化合物或药物组合物进行治疗、预防、抑制或改善与第3型17β-羟基类固醇脱氢酶相关的一种或多种疾病的方法。
• [EN] TRICYCLIC FARNESYL PROTEIN TRANSFERASE INHIBITORS<br/>[FR] INHIBITEURS DE LA FARNESYL PROTEINE TRANSFERASE TRYCICLIQUE
  申请人：SCHERING CORP

  公开号：WO2000037459A1

  公开（公告）日：2000-06-29

  Disclosed are compounds of formula (1.0) wherein R13 represents an imidazole ring; R14 represents a carbamate, urea, amide or sulfonamide group; R8 represents H when the alkyl chain between the amide group and the R13 imidazole group is substituted, or R8 represents a substituent such aa arylalkyl, heteroarylalkyl or cycloalkyl; and the remaining substituents are as defined herein. Also disclosed are compounds wherein R8 is H, and the alkyl chain between the amide group and the R13 imidazole group is unsubstituted. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.

  本发明涉及式（1.0）的化合物，其中R13代表咪唑环；R14代表氨基甲酸酯，脲，酰胺或磺酰胺基团；当酰胺基团和R13咪唑基团之间的烷基链被取代时，R8代表H，或者R8代表取代基，例如芳基烷基，杂环芳基烷基或环烷基；其余取代基如本文所定义。本发明还涉及R8为H且酰胺基团和R13咪唑基团之间的烷基链未取代的化合物。本发明还涉及使用上述化合物治疗癌症的方法和抑制法尼醇蛋白转移酶的方法。
• [EN] FARNESYL PROTEIN TRANSFERASE INHIBITORS<br/>[FR] INHIBITEURS DE LA FARNESYL PROTEINE TRANSFERASE
  申请人：SCHERING CORP

  公开号：WO2000037458A1

  公开（公告）日：2000-06-29

  Disclosed are compounds of formula (1.0), wherein R8 represents a cyclic moiety to which is bound an imodazolylalkyl group; R9 represents a carbamate, urea, amide or sulfonamide group; and the remaining substituents are as defined herein. Also disclosed is a method of treating cancer and a method of inhibiting farnesyl protein transferase using the disclosed compounds.

  本发明涉及公式（1.0）的化合物，其中R8表示一个环状基团，该环状基团与一个咪唑烷基团相结合；R9表示一个氨基甲酸酯、脲、酰胺或磺酰胺基团；其余取代基的定义如本文所述。本发明还涉及使用上述化合物的治疗癌症的方法和抑制法尼酰基蛋白转移酶的方法。