4-(4-bromobenzoyl)-1'-(t-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine | 305794-45-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 4-(4-bromobenzoyl)-1'-(t-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine
• 英文别名: 4-(4-bromobenzoyl)-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine；4-[4-(4-bromobenzoyl)-1-piperidinyl]-4-methyl-1-piperidinecarboxylic acid 1,1-dimethylethyl ester；Tert-butyl 4-(4-bromobenzoyl)-4'-methyl-[1,4'-bipiperidine]-1'-carboxylate；tert-butyl 4-[4-(4-bromobenzoyl)piperidin-1-yl]-4-methylpiperidine-1-carboxylate
• CAS: 305794-45-0
• 化学式: C₂₃H₃₃BrN₂O₃
• 分子量: 465.431
• InChiKey: TVDQSWAAZXWYMG-UHFFFAOYSA-N

物化性质

• 沸点：
  531.5±50.0 °C(Predicted)
• 密度：
  1.266±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.4
• 重原子数：
  29
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-(4-bromobenzoyl)-1'-(t-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine 在 盐酸 、 4-(dicyanomethylene)-2-methyl-6-(p-dimethylaminostyryl)-4H-pyran 、 sodium acetate 作用下， 以 甲醇 为溶剂， 反应 72.0h， 生成 4-{(4-Bromo-phenyl)-[(Z)-ethoxyimino]-methyl}-4'-methyl-[1,4']bipiperidinyl-1'-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Discovery of 4-[(Z)-(4-Bromophenyl)- (ethoxyimino)methyl]-1‘-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4‘-methyl-1,4‘- bipiperidine N-Oxide (SCH 351125):  An Orally Bioavailable Human CCR5 Antagonist for the Treatment of HIV Infection

  摘要：

  Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K-i = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.

  DOI：

  10.1021/jm015526o
• 作为产物：
  描述：

  4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-piperidine 在 titanium(IV) isopropylate 、 盐酸 、 甲基溴化镁 作用下， 以 四氢呋喃 、 乙醚 、 乙酸乙酯 、 1,2-二氯乙烷 为溶剂， 反应 41.0h， 生成 4-(4-bromobenzoyl)-1'-(t-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine
  参考文献：
  名称：

  Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino-Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity

  摘要：

  We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl] -4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF3, 4-OCF3, 4-SO2Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, Pr-n, Pr-i, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.

  DOI：

  10.1021/jm0200815

文献信息

• [EN] QUINOLYL AMIDE DERIVATIVES AS CCR-5 ANTAGONISTS<br/>[FR] DERIVES DE QUINOLYLE AMIDE ANTAGONISTES DE CCR-5
  申请人：SCHERING AG

  公开号：WO2004113323A1

  公开（公告）日：2004-12-29

  The present invention relates to a series of compounds which are CCR-5 receptor antagonists of the general formula (I): or a pharmaceutically acceptable salt thereof, wherein the variables are defined herein.

  本发明涉及一系列化合物，其为一般式(I)的CCR-5受体拮抗剂，或其药学上可接受的盐，其中变量在此处定义。
• PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS
  申请人：SCHERING CORPORATION

  公开号：EP1175402B1

  公开（公告）日：2005-07-20
• Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino-Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity
  作者：Anandan Palani、Sherry Shapiro、Hubert Josien、Thomas Bara、John W. Clader、William J. Greenlee、Kathleen Cox、Julie M. Strizki、Bahige M. Baroudy

  DOI：10.1021/jm0200815

  日期：2002.7.1

  We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl] -4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF3, 4-OCF3, 4-SO2Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, Pr-n, Pr-i, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.
• Discovery of 4-[(<i>Z</i>)-(4-Bromophenyl)- (ethoxyimino)methyl]-1‘-[(2,4-dimethyl-3- pyridinyl)carbonyl]-4‘-methyl-1,4‘- bipiperidine <i>N</i>-Oxide (SCH 351125):  An Orally Bioavailable Human CCR5 Antagonist for the Treatment of HIV Infection
  作者：Anandan Palani、Sherry Shapiro、John W. Clader、William J. Greenlee、Kathleen Cox、Julie Strizki、Michael Endres、Bahige M. Baroudy

  DOI：10.1021/jm015526o

  日期：2001.10.1

  Structure-activity studies on piperidino-piperidine 3 led to the discovery of SCH 351125 (1), a selective CCR5 antagonist with potent activity against RANTES binding (K-i = 2 nM), which possesses subnanomolar activity in blocking viral entry and has excellent antiviral potency versus a panel of primary HIV-1 viral isolates. Compound 1, which has good oral bioavailability in rats, dogs, and monkeys, is proposed as a potential therapeutic agent for the treatment of HIV-1 and has entered human clinical trials.