1-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)benzyl]piperidine-4-carboxylic acid methyl amide | 1350411-38-9

• 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: 1-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)benzyl]piperidine-4-carboxylic acid methyl amide
• 英文别名: 1-[4-((2S,3'S)-2-methyl-[1,3]bipyrrolidinyl-1'-yl)-benzyl]-piperidine-4-carboxylic acid methylamide；N-methyl-1-[[4-[(3S)-3-[(2S)-2-methylpyrrolidin-1-yl]pyrrolidin-1-yl]phenyl]methyl]piperidine-4-carboxamide
• CAS: 1350411-38-9
• 化学式: C₂₃H₃₆N₄O
• 分子量: 384.565
• InChiKey: XPZHKJJZHLBUNO-AVRDEDQJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  28
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.7
• 拓扑面积：
  38.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)benzyl]piperidine-4-carboxylic acid methyl amide 在 盐酸 作用下， 以 乙醚 、 二氯甲烷 为溶剂， 生成 1-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)benzyl]piperidine-4-carboxylic acid methyl amide hydrochloride
  参考文献：
  名称：

  Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy

  摘要：

  Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S, 3'S)-2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S, 3'S)-2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H-3 receptor (H3R) affinity, good selectivity and weak human Ether-a-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at <= 10 mu M, and no significant induction of any major haemodynamic effect when intravenously administered at 3 mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.12.036
• 作为产物：
  描述：

  methyl 1-(4-bromobenzyl)piperidine-4-carboxylate 在 tris-(dibenzylideneacetone)dipalladium(0) 、 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl 、 sodium t-butanolate 作用下， 以 1,4-二氧六环 、 甲苯 为溶剂， 生成 1-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)benzyl]piperidine-4-carboxylic acid methyl amide
  参考文献：
  名称：

  Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy

  摘要：

  Lead compounds 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-benzamide (1), tetrahydro-pyran-4-carboxylic acid [((2S, 3'S)-2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-amide (2), and 3,5-dimethyl-isoxazole-4-carboxylic acid [((2S, 3'S)-2-methyl-[1,3'] bipyrrolidinyl-1'-yl)-phenyl]-amide (3) discovered in our laboratory, displayed high histamine H-3 receptor (H3R) affinity, good selectivity and weak human Ether-a-go-go-Related Gene (hERG) channel affinity with desirable overall physico-chemical and pharmacokinetic (PK) profiles. Herein, we describe the design and synthesis of a novel series of H3R antagonists utilizing a scaffold hopping strategy. Further structure-activity relationship (SAR) studies of the series culminated in the identification of ((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-naphthalene-2-carboxylic acid (tetrahydro-pyran-4-yl)-amide (4c) and -[4-((2S,3'S)-2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenyl]-N-(tetrahydro-pyran-4-yl)-acetamide (4d), which exhibited good H3R affinity in vitro, good selectivity, and desirable PK properties. Compounds 4c and 4d were also assessed in cardiac safety experiments. In particular, the effects of the compounds on action potentials recorded from ventricular myocytes isolated from guinea pigs were used to screen compounds that not only displayed a low affinity towards hERG channel, but also had lower interference with other cardiac ion channels. Compound 4c did not alter the major parameters in this model system at <= 10 mu M, and no significant induction of any major haemodynamic effect when intravenously administered at 3 mg/kg dose to anaesthetized mongrel dogs. Compound 4c is a new promising lead as orally potent and selective H3R antagonist belonging to a distinct structural class. (C) 2014 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2014.12.036

文献信息

• [EN] SUBSTITUTED N-HETEROCYCLOALKYL BIPYRROLIDINYLPHENYL AMIDE DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF<br/>[FR] DÉRIVÉS DE N-HÉTÉROCYCLOALKYL-BIPYRROLIDINYLPHÉNYLAMIDE SUBSTITUÉS, PRÉPARATION ET UTILISATION THÉRAPEUTIQUE DE CEUX-CI
  申请人：SANOFI SA

  公开号：WO2011143161A1

  公开（公告）日：2011-11-17

  The present invention discloses and claims a series of substituted N- heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I). (Formula (I)) Wherein R, R1, R2, R3, R4, X, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this invention also discloses methods of preparation of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I) and intermediates therefor.

  本发明公开并声明了一系列式（I）的取代N-杂环烷基双吡咯啉基苯酰胺衍生物。其中R、R1、R2、R3、R4、X、m、n和p如本文所述。更具体地，本发明的化合物是H3受体调节剂，因此在治疗和/或预防包括与中枢神经系统相关的疾病在内的多种受H3受体调节的疾病方面作为药用剂特别有用。此外，本发明还公开了制备式（I）的取代N-杂环烷基双吡咯啉基苯酰胺衍生物及其中间体的方法。
• SUBSTITUTED N-HETEROCYCLOALKYL BIPYRROLIDINYLPHENYL AMIDE DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF
  申请人：SANOFI

  公开号：US20130059891A1

  公开（公告）日：2013-03-07

  The present disclosure relates to a series of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I). wherein R, R 1 , R 2 , R 3 , R 4 , X, m, n and p are as described herein. More specifically, the compounds of this invention are modulators of H3 receptors and are, therefore, useful as pharmaceutical agents, especially in the treatment and/or prevention of a variety of diseases modulated by H3 receptors including diseases associated with the central nervous system. Additionally, this disclosure relates to methods of preparation of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of formula (I) and intermediates therefor.

  本公开涉及一系列公式（I）的取代N-杂环烷基双吡咯烷基苯酰胺衍生物，其中R，R1，R2，R3，R4，X，m，n和p如本文所述。更具体地说，本发明的化合物是H3受体调节剂，因此在治疗和/或预防包括与中枢神经系统相关的多种H3受体调节疾病中，特别是作为药物剂量是有用的。此外，本公开还涉及制备公式（I）的取代N-杂环烷基双吡咯烷基苯酰胺衍生物及其中间体的方法。
• US8754095B2
  申请人：——

  公开号：US8754095B2

  公开（公告）日：2014-06-17