(3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid | 455957-95-6

• 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: (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid
• 英文别名: 3-Pyrrolidinecarboxylic acid, 4-(2,4-difluorophenyl)-1-(1,1-dimethylethyl)-, (3R,4S)-
• CAS: 455957-95-6
• 化学式: C₁₅H₁₉F₂NO₂
• 分子量: 283.318
• InChiKey: VREKTDQOMSTPDN-NEPJUHHUSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.2
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.53
• 拓扑面积：
  40.5
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (3R,4s,5S)-3,5-dimethyl-4-phenylpiperidin-4-ol 、 (3R,4S)-1-tert-butyl-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylic acid 在 草酰氯 、 N,N-二甲基甲酰胺 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 26.0h， 生成 (3R,4S,5S)-1-{[(3R,4S)-1-tert-Butyl-4-(2,4-difluorophenyl)pyrrolidin-3-yl]carbonyl}-3,5-dimethyl-4-phenylpiperidin-4-ol
  参考文献：
  名称：

  Discovery of a Selective Small-Molecule Melanocortin-4 Receptor Agonist with Efficacy in a Pilot Study of Sexual Dysfunction in Humans

  摘要：

  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.

  DOI：

  10.1021/jm9017866

文献信息

• Pharmaceutically active compounds
  申请人：Calabrese Antony Andrew

  公开号：US20050176772A1

  公开（公告）日：2005-08-11

  The present invention relates to a class of melanocortin MCR4 agonists of general formula (I) wherein R 1 , R 2 , R 3 , R 4 and R 5 are as defined herein and especially to selective MCR4 agonist compounds, to their use in medicine, to compositions containing them, to processes for their preparation and to intermediates used in such processes.

  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。
• Acylated piperidine derivatives as melanocortin-4 receptor agonists
  申请人：——

  公开号：US20030225060A1

  公开（公告）日：2003-12-04

  Certain novel 4-substituted N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

  某些新颖的4-取代N-酰化哌啶衍生物是人类黑色素皮质激素受体的激动剂，特别是人类黑色素皮质激素受体-4（MC-4R）的选择性激动剂。因此，它们对于治疗、控制或预防对MC-4R激活敏感的疾病和紊乱是有用的，如肥胖症、糖尿病、性功能障碍，包括勃起功能障碍和女性性功能障碍。
• Piperidine derivatives as melanocortin-4 receptor agonists
  申请人：Sings Heather

  公开号：US20060128963A1

  公开（公告）日：2006-06-15

  Certain novel piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

  某些新型哌啶衍生物是人类黑色素细胞激素受体的激动剂，特别是人类黑色素细胞激素-4受体（MC-4R）的选择性激动剂。因此，它们可用于治疗、控制或预防对MC-4R的激活有反应的疾病和障碍，如肥胖症、糖尿病、性功能障碍，包括勃起功能障碍和女性性功能障碍。
• Acylated spiropiperidine derivatives as melanocortin-4 receptor agonists
  申请人：Guo Liangqin

  公开号：US20060183904A1

  公开（公告）日：2006-08-17

  Certain novel N-acylated spiropiperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

  某些新型N-酰化螺环吡啶衍生物是人类黑素细胞素受体的激动剂，特别是人类黑素细胞素-4受体（MC-4R）的选择性激动剂。因此，它们可用于治疗、控制或预防对MC-4R的激活有反应的疾病和障碍，如肥胖症、糖尿病、性功能障碍，包括勃起功能障碍和女性性功能障碍。
• Bicyclic piperidine derivatives as melanocortin-4 receptor agonists
  申请人：Nargund P. Ravi

  公开号：US20060194780A1

  公开（公告）日：2006-08-31

  Certain novel bicyclic N-acylated piperidine derivatives are agonists of the human melanocortin receptor(s) and, in particular, are selective agonists of the human melanocortin-4 receptor (MC-4R). They are therefore useful for the treatment, control, or prevention of diseases and disorders responsive to the activation of MC-4R, such as obesity, diabetes, sexual dysfunction, including erectile dysfunction and female sexual dysfunction.

  某些新型双环N-酰化哌啶衍生物是人类黑色素细胞素受体的激动剂，特别是人类黑色素细胞素-4受体(MC-4R)的选择性激动剂。因此，它们可用于治疗、控制或预防对MC-4R激活有响应的疾病和障碍，如肥胖症、糖尿病、性功能障碍，包括勃起功能障碍和女性性功能障碍。