(2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide | 203321-26-0

• 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: (2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide
• 英文别名: N-(1-Benzyl-piperidin-4-yl)-2-(3,3-difluoro-cyclopentyl)-2-hydroxy-2-phenyl-acetamide
• CAS: 203321-26-0
• 化学式: C₂₅H₃₀F₂N₂O₂
• 分子量: 428.522
• InChiKey: KTCCCXMNJFFEIS-BWKNWUBXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  31
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  52.6
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide 在 20percent Pd(OH)2 氢气 、 potassium carbonate 、 potassium iodide 作用下， 以 乙醇 、 乙腈 为溶剂， 70.0 ℃ 、101.33 kPa 条件下， 反应 25.0h， 生成 (2R)-N-[1-(4-tert-butoxycarbonylamino-3-fluorobenzyl)piperidin-4-yl]-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide
  参考文献：
  名称：

  A Potent, Long-Acting, Orally Active (2R)-2-[(1R)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetamide:  A Novel Muscarinic M₃ Receptor Antagonist with High Selectivity for M₃ over M₂ Receptors

  摘要：

  A novel series of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M-3 receptor selective antagonist 1, to develop a potent, long-acting, orally active M-3 antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(IR)-3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M-3 over M-2 receptors in comparison With the corresponding cyclopentylphenylacetic acid group: However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1;(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M-3 receptors (K-i = 2.8 nM) over M-2 receptors (K-i = 530 nM) in a human binding assay and-good in vitro metabolic stability in dog and human hepatic microsomes:was identified; This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced : bronchoconstriction in dogs, and may be useful in clinical situations in which M-3 over M-2 selectivity is desirable.

  DOI：

  10.1021/jm0003135
• 作为产物：
  描述：

  (2R,5R)-2-(tert-butyl)-5-[(1R)-3-oxocyclopentyl]-5-phenyl-1,3-dioxolan-4-one 在 sodium hydroxide 、 二乙胺基三氟化硫 、 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 甲醇 、 氯仿 为溶剂， 反应 31.5h， 生成 (2R)-N-(1-benzylpiperidin-4-yl)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamide
  参考文献：
  名称：

  A Potent, Long-Acting, Orally Active (2R)-2-[(1R)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetamide:  A Novel Muscarinic M₃ Receptor Antagonist with High Selectivity for M₃ over M₂ Receptors

  摘要：

  A novel series of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M-3 receptor selective antagonist 1, to develop a potent, long-acting, orally active M-3 antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(IR)-3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M-3 over M-2 receptors in comparison With the corresponding cyclopentylphenylacetic acid group: However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1;(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M-3 receptors (K-i = 2.8 nM) over M-2 receptors (K-i = 530 nM) in a human binding assay and-good in vitro metabolic stability in dog and human hepatic microsomes:was identified; This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced : bronchoconstriction in dogs, and may be useful in clinical situations in which M-3 over M-2 selectivity is desirable.

  DOI：

  10.1021/jm0003135

文献信息

• FLUORINATED 1,4-DISUBSTITUTED PIPERIDINE DERIVATIVES
  申请人：BANYU PHARMACEUTICAL CO., LTD.

  公开号：EP0930298B1

  公开（公告）日：2002-12-18
• US5948792A
  申请人：——

  公开号：US5948792A

  公开（公告）日：1999-09-07
• US6040449A
  申请人：——

  公开号：US6040449A

  公开（公告）日：2000-03-21
• A Potent, Long-Acting, Orally Active (2<i>R</i>)-2-[(1<i>R</i>)-3,3-Difluorocyclopentyl]-2-hydroxy-2-phenylacetamide:  A Novel Muscarinic M₃ Receptor Antagonist with High Selectivity for M₃ over M₂ Receptors
  作者：Morihiro Mitsuya、Kensuke Kobayashi、Kumiko Kawakami、Atsushi Satoh、Yoshio Ogino、Taro Kakikawa、Norikazu Ohtake、Toshifumi Kimura、Hiroyasu Hirose、Akio Sato、Tomosige Numazawa、Takuro Hasegawa、Kazuhito Noguchi、Toshiaki Mase

  DOI：10.1021/jm0003135

  日期：2000.12.1

  A novel series of (2R)-2-[(1R)-3,3-difluorocyclopentyl]-2-hydroxy-2-phenylacetamides was designed and synthesized based on the structure and biological profiles of an active metabolite 2 of our prototype muscarinic M-3 receptor selective antagonist 1, to develop a potent, long-acting, orally active M-3 antagonist for the treatment of urinary tract disorders, irritable bowel syndrome, and respiratory disorders. Investigation of (2R)-2-[(IR)-3,3-difluorocyclopentyl] -2-hydroxy-2-phenylacetamides containing a phenyl or heterocyclic ring as the piperidinyl side chain in place of the 4-methyl-3-pentenyl moiety of 15a revealed that this acid moiety was a versatile template for improving the selectivity for M-3 over M-2 receptors in comparison With the corresponding cyclopentylphenylacetic acid group: However, since the in vitro metabolic stability of these analogues was insufficient compared with that of 2, further derivatization was performed by introducing an appropriate hydrophilic group into the phenyl or 2-pyridyl ring. Thus, the 1;(6-aminopyridin-2-ylmethyl)piperidine analogue 15y exhibiting 190-fold selectivity for M-3 receptors (K-i = 2.8 nM) over M-2 receptors (K-i = 530 nM) in a human binding assay and-good in vitro metabolic stability in dog and human hepatic microsomes:was identified; This compound has excellent oral activity at 4 h after oral dosing (1 mg/kg), inhibiting methacholine-induced : bronchoconstriction in dogs, and may be useful in clinical situations in which M-3 over M-2 selectivity is desirable.