N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide | 185030-05-1

• 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: N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide
• 英文别名: N-(1-t-butoxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide；tert-butyl 4-[(2-cyclobutyl-2-hydroxy-2-phenylacetyl)amino]piperidine-1-carboxylate
• CAS: 185030-05-1
• 化学式: C₂₂H₃₂N₂O₄
• 分子量: 388.507
• InChiKey: OUIKVUZAQJLPJE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  78.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide 以 盐酸 、 1,4-二氧六环 为溶剂， 反应 16.0h， 以to obtain 0.83 g of the title compound的产率得到N-[1-(4-methyl-3-pentenyl)-piperidin-4-yl]-2-cyclobutyl-2-hydroxy-2-phenylacetamide
  参考文献：
  名称：

  1,4-di-substituted piperidine derivatives

  摘要：

  本发明提供了一种新型的1,4-二取代哌啶衍生物，其一般式为：\x9bI! ##STR1## 以及其药学上可接受的盐，其中：Ar代表苯基或五元或六元杂环芳基，其中一或两个杂原子选自氧原子、硫原子和氮原子，环上的一或两个氢原子可以被卤素原子和较低的烷基取代基所替代；R.sup.1代表3到6个碳原子的环烷基或3到6个碳原子的环烯基；R.sup.2代表5到15个碳原子的饱和或不饱和脂肪烃基；X代表O或NH。这些化合物具有选择性的M.sub.3胆碱能受体拮抗活性，因此可以安全地使用，副作用最小。

  公开号：

  US05750540A1
• 作为产物：
  描述：

  2-环丁基-2-羟基-2-苯基乙酸 、 1-Boc-4-氨基哌啶 在 1-羟基苯并三唑 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 氯仿 为溶剂， 反应 15.0h， 以78%的产率得到N-(1-tert-butyloxycarbonylpiperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide
  参考文献：
  名称：

  J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors

  摘要：

  A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M-3 receptors over M-2 receptors. Subsequent synthetic derivatizations resulted in highly potent M-3 receptor antagonists with selectivity greater than two orders of magnitude for M-3 over M-2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for Mg receptors (K-i = 4.2 nM) over M-2 receptors (K-i = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K-B value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(99)00177-7

文献信息

• 1,4-di-substituted piperidine derivatives
  申请人：Banyu Pharmaceutical Co., Ltd.

  公开号：US05750540A1

  公开（公告）日：1998-05-12

  This invention provides novel 1,4-di-substituted piperidine derivatives of the general formula \x9bI! ##STR1## and the pharmaceutically acceptable salts thereof, wherein: Ar represents a phenyl group or a five- or six-membered heteroaromatic group having one or two hetero atoms selected from the group consisting of an oxygen atom, a sulfur atom and a nitrogen atom in which one or two optional hydrogen atoms on the ring may be replaced by substituent groups selected from the group consisting of a halogen atom and a lower alkyl group; R.sup.1 represents a cycloalkyl group of 3 to 6 carbon atoms or a cycloalkenyl group of 3 to 6 carbon atoms; R.sup.2 represents a saturated or unsaturated aliphatic hydrocarbon radical of 5 to 15 carbon atoms; and X represents O or NH. These compounds have selective antagonistic activity against the muscarinic M.sub.3 receptors and can hence be used safely with a minimum of side effects.

  该发明提供了一种新型的1,4-二取代哌啶衍生物，其通式为##STR1##及其药学上可接受的盐，其中：Ar代表苯基或含有一个或两个异原子（选自氧原子、硫原子和氮原子）的五元或六元杂环芳基，环上的一个或两个可选氢原子可被卤素原子和较低的烷基基团替代；R1代表3到6个碳原子的环烷基基团或3到6个碳原子的环烯烃基团；R2代表5到15个碳原子的饱和或不饱和脂肪烃基团；X代表O或NH。这些化合物对M.sub.3胆碱能受体具有选择性拮抗活性，因此可以安全地使用，并具有最少的副作用。
• 1,4-DISUBSTITUTED PIPERIDINE DERIVATIVES
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP0823423B1

  公开（公告）日：2004-06-16
• US5750540A
  申请人：——

  公开号：US5750540A

  公开（公告）日：1998-05-12
• J-104129, a novel muscarinic M3 receptor antagonist with high selectivity for M3 over M2 receptors
  作者：Morihiro Mitsuya、Toshiaki Mase、Yoshimi Tsuchiya、Kumiko Kawakami、Hiromi Hattori、Kensuke Kobayashi、Yoshio Ogino、Toru Fujikawa、Akio Satoh、Toshifumi Kimura、Kazuhito Noguchi、Norikazu Ohtake、Koji Tomimoto

  DOI：10.1016/s0968-0896(99)00177-7

  日期：1999.11

  A new class of 4-acetamidopiperidine derivatives has been synthesized and investigated for human muscarinic receptor subtype selectivity. Introduction of a hydrocarbon chain of appropriate length into the piperidine nitrogen of the racemic N-(piperidin-4-yl)-2-cyclobutyl-2-hydroxy-2-phenylacetamide platform conferred up to 70-fold selectivity for human muscarinic M-3 receptors over M-2 receptors. Subsequent synthetic derivatizations resulted in highly potent M-3 receptor antagonists with selectivity greater than two orders of magnitude for M-3 over M-2 receptors, from which the analogue 4r was selected. Preparation of both enantiomers of 4r led to the identification of (2R)-N-[1-(4-methyl-3-pentenyl)piperidin-4-yl]-2-cyclopentyl-2-hydroxy-2-phenylacetamide (J-104129, (R)-4r), which exhibited 120-fold selectivity for Mg receptors (K-i = 4.2 nM) over M-2 receptors (K-i = 490 nM). In isolated rat trachea, (R)-4r potently and specifically antagonized acetylcholine (ACh)-induced responses with a K-B value of 3.3 nM. The highly subtype-selective profile was also seen in isolated rat tissue assays (50-fold) and in anesthetized rats (> 250-fold). Oral administration of J-104129 ((R)-4r) antagonized ACh-induced bronchoconstriction with an ED50 value of 0.58 mg/kg in rats. Thus, J-104129 ((R)-4r) may effectively facilitate bronchodilation in the treatment of obstructive airway disease. (C) 1999 Elsevier Science Ltd. All rights reserved.