tert-butyl 4-(2-(4-bromophenyl)acetamido)piperidine-1-carboxylate | 1334001-49-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: tert-butyl 4-(2-(4-bromophenyl)acetamido)piperidine-1-carboxylate
• 英文别名: 4-[2-(4-Bromo-phenyl)acetylamino]-piperidine-1-carboxylic acid tert-butyl ester；tert-butyl 4-[[2-(4-bromophenyl)acetyl]amino]piperidine-1-carboxylate
• CAS: 1334001-49-8
• 化学式: C₁₈H₂₅BrN₂O₃
• 分子量: 397.312
• InChiKey: TYNVREAHYQUWQI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  24
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl 4-(2-(4-bromophenyl)acetamido)piperidine-1-carboxylate 在 盐酸 、 苯硫酚 、 potassium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 二氯甲烷 为溶剂， 反应 7.0h， 生成 2-[4-((2S,3'S)-2-methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]-N-piperidin-4-yl-acetamide hydrochloride
  参考文献：
  名称：

  [EN] SUBSTITUTED N-HETEROCYCLOALKYL BIPYRROLIDINYLPHENYL AMIDE DERIVATIVES, PREPARATION AND THERAPEUTIC USE THEREOF
  [FR] DÉRIVÉS DE N-HÉTÉROCYCLOALKYL-BIPYRROLIDINYLPHÉNYLAMIDE SUBSTITUÉS, PRÉPARATION ET UTILISATION THÉRAPEUTIQUE DE CEUX-CI

  摘要：

  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。

  公开号：

  WO2011143161A1
• 作为产物：
  描述：

  1-Boc-4-氨基哌啶 、 对溴苯乙酸 在 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以99%的产率得到tert-butyl 4-(2-(4-bromophenyl)acetamido)piperidine-1-carboxylate
  参考文献：
  名称：

  [EN] SUBSTITUTED AMINO TRIAZOLES, AND METHODS USING SAME
  [FR] TRIAZOLES AMINO-SUBSTITUÉS ET PROCÉDÉS D'UTILISATION

  摘要：

  公开了化合物的新型替代氨基三唑的结构，其化学式为（I），以及其药学上可接受的盐。化合物的化学式（I）是酸性哺乳动物几丁质酶（AMCase）的抑制剂，并且在非限制性示例中用于治疗哮喘。还提供了含有本发明至少一种化合物或其药学上可接受的盐、水合物或溶剂化合物的药物组合物，以及至少一种药学上可接受的载体、溶剂、辅料或稀释剂，并使用这些化合物和/或组合物来治疗哮喘和/或监测哮喘治疗的方法。

  公开号：

  WO2015095701A1

文献信息

• 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。
• Substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives, preparation and therapeutic use thereof
  申请人：Sanofi

  公开号：US08754095B2

  公开（公告）日：2014-06-17

  The present disclosure relates to a series of substituted N-heterocycloalkyl bipyrrolidinylphenyl amide derivatives of 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 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有关的多种H3受体调节的疾病中，特别是作为药物剂量使用。此外，本公开还涉及制备取代N-杂环烷基双吡咯烷基苯酰胺衍生物的方法以及其中间体。
• Design and synthesis of a novel series of histamine H3 receptor antagonists through a scaffold hopping strategy
  作者：Zhongli Gao、William J. Hurst、Daniel Hall、Ryan Hartung、William Reynolds、Jiesheng Kang、Raisa Nagorny、James A. Hendrix、Pascal G. George

  DOI：10.1016/j.bmc.2014.12.036

  日期：2015.2

  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.
• Targeting Acidic Mammalian chitinase Is Effective in Animal Model of Asthma
  作者：Marzena Mazur、Jacek Olczak、Sylwia Olejniczak、Robert Koralewski、Wojciech Czestkowski、Anna Jedrzejczak、Jakub Golab、Karolina Dzwonek、Barbara Dymek、Piotr L. Sklepkiewicz、Agnieszka Zagozdzon、Tom Noonan、Keyvan Mahboubi、Bruce Conway、Ryan Sheeler、Paul Beckett、William M. Hungerford、Alberto Podjarny、Andre Mitschler、Alexandra Cousido-Siah、Firas Fadel、Adam Golebiowski

  DOI：10.1021/acs.jmedchem.7b01051

  日期：2018.2.8

  This article highlights our work toward the identification of a potent, selective, and efficacious acidic mammalian chitinase (AMCase) inhibitor. Rational-design, guided by X-ray analysis of several inhibitors bound to human chitotriosidase (hCHIT1), led to the identification of compound 7f as a highly potent AMCase inhibitor (IC50 values of 14 and 19 nM against human and mouse enzyme, respectively) and selective (>150X against mCHIT1) with very good PK properties. This compound dosed once daily at 30 mg/kg po showed significant anti-inflammatory efficacy in HDM-induced allergic airway inflammation in mice, reducing inflammatory cell influx in the BALF and total IgE concentration in plasma, which correlated with decrease of chitinolytic activity. Therapeutic efficacy Of compound 7f in the clinically relevant aeroallergen-induced acute asthma model in mice provides a rationale for developing AMCase inhibitor for the treatment of asthma.
• SUBSTITUTED AMINO TRIAZOLES, AND METHODS USING SAME
  申请人：The Institute For Drug Delivery

  公开号：EP3082805A1

  公开（公告）日：2016-10-26