2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenylamine | 1146415-36-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenylamine
• 英文别名: 2-methyl-4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenylamine；4-(2-methyl-[1,3']bipyrrolidinyl-1'-yl)-phenylamine；2-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]aniline
• CAS: 1146415-36-2
• 化学式: C₁₆H₂₅N₃
• 分子量: 259.395
• InChiKey: RAICQPFLQTZKOQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.62
• 拓扑面积：
  32.5
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  2-四氢呋喃甲酸 、 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenylamine 在 N-甲基吗啉 、 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 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 N-[2-methyl-4-[3-(2-methylpyrrolidin-1-yl)pyrrolidin-1-yl]phenyl]oxolane-2-carboxamide
  参考文献：
  名称：

  Discovery of a potent, selective, and orally bioavailable histamine H3 receptor antagonist SAR110068 for the treatment of sleep–wake disorders

  摘要：

  Previous studies have shown that compound 1 displayed high affinity towards histamine H-3 receptor (H3R), (human (h-H3R), K-i = 8.6 nM, rhesus monkey (rh-H3R), K-i = 1.2 nM, and rat (r-H3R), K-i = 16.5 nM), but exhibited high affinity for hERG channel. Herein, we report the discovery of a novel, potent, and highly selective H3R antagonist/inverse agonist 5a(SS) (SAR110068) with acceptable hERG channel selectivity and desirable pharmacological and pharmacokinetic properties through lead optimization sequence. The significant awakening effects of 5a(SS) on sleep-wake cycles studied by using EEG recording in rats during their light phase support its potential therapeutic utility in human sleep-wake disorders. (c) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.09.006
• 作为产物：
  描述：

  2-甲基吡咯烷 在 盐酸 、 palladium 10% on activated carbon 、 氢气 、 三乙酰氧基硼氢化钠 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 甲醇 、 二甲基亚砜 、 1,2-二氯乙烷 为溶剂， 反应 5.0h， 生成 2-methyl-4-(2-methyl-[1,3′]bipyrrolidinyl-1′-yl)phenylamine
  参考文献：
  名称：

  发现作为治疗肥胖症的有效和选择性组胺H 3受体拮抗剂的芳基脲和芳基酰胺（第一部分）

  摘要：

  通过优化HTS铅作为选择性组胺H 3受体（H 3 R）拮抗剂，获得了一系列结构新颖的芳基脲。探索了SAR，获得的数据为进一步优化奠定了起点和基础。如化合物2l，5b，5d和5e所示，最有效的工具化合物在体外人-H 3 R FLIPR分析和恒河猴H 3 R结合分析中显示出亚纳摩尔范围的拮抗力。

  DOI：

  10.1016/j.bmcl.2013.03.080

文献信息

• [EN] SUBSTITUTED N-PHENYL-BIPYRROLIDINE CARBOXAMIDES AND THERAPEUTIC USE THEREOF<br/>[FR] CARBOXAMIDES DE N-PHÉNYL-BIPYRROLIDINE SUBSTITUÉS ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI AVENTIS

  公开号：WO2009052065A1

  公开（公告）日：2009-04-23

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I), Wherein R, R1, R2, R3 and R4 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-phenyl-bipyrrolidine carboxamides and intermediates therefor.

  本发明公开并声明了一系列式(I)的取代N-苯基-双吡咯烷羧酰胺，其中R、R1、R2、R3和R4如本文所述。更具体地说，本发明的化合物是H3受体调节剂，因此在制药方面特别有用，尤其是在治疗和/或预防通过H3受体调节的各种疾病，包括与中枢神经系统相关的疾病。此外，本发明还公开了取代N-苯基-双吡咯烷羧酰胺及其中间体的制备方法。
• [EN] SUBSTITUTED TETRAHYDROPYRAN SPIRO PYRROLIDINONE AND PIPERIDINONE, PREPARATION AND THERAPEUTIC USE THEREOF<br/>[FR] PYRROLIDINONE ET PIPÉRIDINONE SPIRO À SUBSTITUTION DE TÉTRAHYDROPYRANNE, SA PREPARATION ET SON UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI AVENTIS

  公开号：WO2010065798A1

  公开（公告）日：2010-06-10

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I) Wherein R1, R2, 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-phenyl-bipyrrolidine carboxamides and intermediates therefor.

  本发明披露并声称一系列式（I）的取代N-苯基双吡咯烷羧酰胺化合物，其中R1、R2、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，因此在制药剂中非常有用，特别是在治疗和/或预防由H3受体调节的各种疾病中，包括与中枢神经系统相关的疾病。此外，本发明还披露了取代N-苯基双吡咯烷羧酰胺及其中间体的制备方法。
• [EN] SUBSTITUTED N-PHENYL-BIPYRROLIDINE UREAS AND THERAPEUTIC USE THEREOF<br/>[FR] URÉES DE N-PHÉNYL-BIPYRROLIDINE SUBSTITUÉES ET LEUR UTILISATION THÉRAPEUTIQUE
  申请人：SANOFI AVENTIS

  公开号：WO2009052068A1

  公开（公告）日：2009-04-23

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine ureas of formula (I) 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-phenyl-bipyrrolidine ureas and intermediates therefor.

  本发明披露并声明一系列取代的N-苯基双吡咯啉脲（式（I）如本文所述）。更具体地说，本发明的化合物是H3受体的调节剂，因此在医药制剂中特别用于治疗和/或预防多种由H3受体调节的疾病，包括与中枢神经系统相关的疾病。此外，本发明还披露了制备取代的N-苯基双吡咯啉脲及其中间体的方法。
• Discovery of aryl ureas and aryl amides as potent and selective histamine H3 receptor antagonists for the treatment of obesity (Part II)
  作者：Zhongli Gao、William J. Hurst、Etienne Guillot、Werngard Czechtizky、Ulrike Lukasczyk、Raisa Nagorny、Marie-Pierre Pruniaux、Lothar Schwink、Juan Antonio Sanchez、Siegfried Stengelin、Lei Tang、Irvin Winkler、James A. Hendrix、Pascal G. George

  DOI：10.1016/j.bmcl.2013.03.081

  日期：2013.6

  A novel series of histamine H3 receptor (H3R) antagonists was derived from an arylurea lead series (1) via bioisosteric replacement of the urea functionality by an amide linkage. The arylamide series was optimized through SAR studies by a broad variation of substituents in the left-hand side benzoyl residue (analogs 2a–2ag) or replacement of the benzoyl moiety by heteroarylcarbonyl residues (analogs

  一种新的组胺H 3受体（H 3 R）拮抗剂系列是通过酰胺键对尿素官能团进行生物等位取代而从芳基脲前导系列（1）衍生而来的。通过SAR研究优化了芳基酰胺系列，方法是左侧苯甲酰基残基中的取代基变化很大（类似物2a - 2ag），或杂芳基羰基残基取代了苯甲酰基部分（类似物5a - 5n）。在该系列中，化合物2p和2q被鉴定为具有可接受总体轮廓的强效和选择性H 3 R拮抗剂/反向激动剂。化合物2q在饮食诱发的肥胖（DIO）小鼠中口服抑制食物摄入。化合物2q代表一种新颖的H 3 R拮抗剂模板，具有增强的体外效价和口服功效，具有作为进一步优化的新线索的优点。
• SUBSTITUTED N-PHENYL-BIPYRROLIDINE CARBOXAMIDES AND THERAPEUTIC USE THEREOF
  申请人：CZECHTIZKY Werngard

  公开号：US20120065234A1

  公开（公告）日：2012-03-15

  The present invention discloses and claims a series of substituted N-phenyl-bipyrrolidine carboxamides of formula (I). wherein R, R 1 , R 2 , R 3 and R 4 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-phenyl-bipyrrolidine carboxamides and intermediates therefor.

  本发明揭示和声明了一系列式（I）的取代N-苯基双吡咯烷羧酰胺化合物，其中R、R1、R2、R3和R4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有关的多种受H3受体调节的疾病方面，尤其是作为药物剂量非常有用。此外，本发明还揭示了取代N-苯基双吡咯烷羧酰胺化合物的制备方法及其中间体。