4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine | 305794-43-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine
• 英文别名: 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1'-(t-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine；Tert-butyl 4-[4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]piperidin-1-yl]-4-methylpiperidine-1-carboxylate
• CAS: 305794-43-8
• 化学式: C₂₅H₃₇BrN₂O₄
• 分子量: 509.484
• InChiKey: WVNOXMCOGXURLH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.72
• 拓扑面积：
  51.2
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine 在 盐酸 、 sodium tetrahydroborate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 37.0h， 生成 [4-[4-[(4-Bromophenyl)-hydroxy-methyl]-1-piperidyl]-4-methyl-1-piperidyl]-(2,6-dimethylphenyl)methanone
  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
• 作为产物：
  描述：

  4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-piperidine 在 titanium(IV) isopropylate 、 甲基溴化镁 作用下， 以 四氢呋喃 、 乙醚 、 1,2-二氯乙烷 为溶剂， 反应 17.0h， 生成 4-[2-(4-bromophenyl)-1,3-dioxolan-2-yl]-1'-(tert-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

• PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS
  申请人：SCHERING CORPORATION

  公开号：EP1175402B1

  公开（公告）日：2005-07-20
• 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.
• 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.