tert-butyl (3R,4S)-3-(2,4-difluorophenyl)-4-{[(3R,4R,5S)-4-(3,4-difluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1-yl]carbonyl}pyrrolidine-1-carboxylate | 862283-13-4

• 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: tert-butyl (3R,4S)-3-(2,4-difluorophenyl)-4-{[(3R,4R,5S)-4-(3,4-difluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1-yl]carbonyl}pyrrolidine-1-carboxylate
• CAS: 862283-13-4
• 化学式: C₂₉H₃₄F₄N₂O₄
• 分子量: 550.594
• InChiKey: UFERSARMOWBAIY-LPWJOQCDSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  39.0
• 可旋转键数：
  3.0
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  70.08
• 氢给体数：
  1.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  tert-butyl (3R,4S)-3-(2,4-difluorophenyl)-4-{[(3R,4R,5S)-4-(3,4-difluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1-yl]carbonyl}pyrrolidine-1-carboxylate 在 盐酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 生成 (3R,4R,5S)-4-(3,4-difluorophenyl)-1-{[(3S,4R)-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3,5-dimethylpiperidin-4-ol hydrochloride
  参考文献：
  名称：

  Pharmaceutically active compounds

  摘要：

  本发明涉及一类通式（I）所示的黑素皮质素MCR4激动剂，其中R1、R2、R3、R4和R5如本文所定义，特别涉及选择性MCR4激动剂化合物，它们在医学上的应用，含有它们的组合物，用于它们制备的工艺以及用于这些工艺的中间体。

  公开号：

  US20050176772A1
• 作为产物：
  描述：

  (3S,4R)-1-tert-butoxycarbonyl-4-(2,4-difluorophenyl)pyrrolidin-3-carboxylic acid 、 (3R,4s,5S)-4-(3,4-difluorophenyl)-3,5-dimethylpiperidin-4-ol 在 1-丙基磷酸酐 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 16.0h， 以77%的产率得到tert-butyl (3R,4S)-3-(2,4-difluorophenyl)-4-{[(3R,4R,5S)-4-(3,4-difluorophenyl)-4-hydroxy-3,5-dimethylpiperidin-1-yl]carbonyl}pyrrolidine-1-carboxylate
  参考文献：
  名称：

  Pharmaceutically active compounds

  摘要：

  本发明涉及一类通式（I）所示的黑素皮质素MCR4激动剂，其中R1、R2、R3、R4和R5如本文所定义，特别涉及选择性MCR4激动剂化合物，它们在医学上的应用，含有它们的组合物，用于它们制备的工艺以及用于这些工艺的中间体。

  公开号：

  US20050176772A1

文献信息

• Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans
  作者：Mark I. Lansdell、David Hepworth、Andrew Calabrese、Alan D. Brown、Julian Blagg、Denise J. Burring、Peter Wilson、David Fradet、T. Bruce Brown、Faye Quinton、Neela Mistry、Kim Tang、Natalie Mount、Peter Stacey、Nick Edmunds、Cathryn Adams、Samantha Gaboardi、Stevie Neal-Morgan、Chris Wayman、Susan Cole、Joanne Phipps、Mark Lewis、Hugh Verrier、Val Gillon、Neil Feeder、Anne Heatherington、Stefan Sultana、Scott Haughie、Steven W. Martin、Maria Sudworth、Sarah Tweedy

  DOI：10.1021/jm9017866

  日期：2010.4.22

  The relevance of the melanocortin system to sexual activity is well established, and nonselective peptide agonists of the melanocortin receptors have shown evidence of efficacy in human sexual dysfunction. The role of the MC4 receptor subtype has received particular scrutiny, but the sufficiency of its selective activation in potentiating sexual response has remained uncertain owing to conflicting data from studies in preclinical species. We describe here the discovery of a novel series of small-molecule MC4 receptor agonists derived from library hit 2. The addition of methyl substituents at C3 and C5 of the 4-phenylpiperidin-4-ol ring was found to be markedly potency-enhancing, enabling the combination of low nanomolar potencies with full rule-of-five compliance. In general, the series shows only micromolar activity at other melanocortin receptors. Our preferred compound 40a provided significant systemic exposure in humans on both sublingual and oral administration and was safe and well tolerated up to the maximum tested dose. In a pilot clinical study of male erectile dysfunction, the highest dose of 40a tested (200 mg) provided a similar level of efficacy to sildenafil.
• US7649002B2
  申请人：——

  公开号：US7649002B2

  公开（公告）日：2010-01-19