(R)-1,1,1,3,3,3-hexafluoro-2-(4-(3-((4-fluorophenyl)sulfonyl)pyrrolidin-3-yl)phenyl)propan-2-ol

• 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: (R)-1,1,1,3,3,3-hexafluoro-2-(4-(3-((4-fluorophenyl)sulfonyl)pyrrolidin-3-yl)phenyl)propan-2-ol
• 英文别名: (R)-1,1,1,3,3,3-hexafluoro-2-(4-(3-((4-fluorophenyl)sulfonyl)pyrrolidin-3-yl)phenyl)propan-2-ol hydrochloride；1,1,1,3,3,3-hexafluoro-2-[4-[(3R)-3-(4-fluorophenyl)sulfonylpyrrolidin-3-yl]phenyl]propan-2-ol
• 化学式: C₁₉H₁₆F₇NO₃S
• 分子量: 471.396
• InChiKey: OMYNIZMYRGKJIF-INIZCTEOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  74.8
• 氢给体数：
  2
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  (R)-1,1,1,3,3,3-hexafluoro-2-(4-(3-((4-fluorophenyl)sulfonyl)pyrrolidin-3-yl)phenyl)propan-2-ol 在 C₅H₁₂N₄O 、 (benzotriazo-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate 、 N,N-二异丙基乙胺 、 三苯基膦 、 sodium hydroxide 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 甲苯 为溶剂， 反应 5.5h， 生成
  参考文献：
  名称：

  发现2,6-二氟苄基醚系列的苯基（（R）-3-苯基吡咯烷烃-3-基）砜是令人惊讶的有效，选择性和口服生物利用的RORγt反向激动剂。

  摘要：

  在努力发现的ROR口服反向激动剂γ吨治疗炎症性疾病中，发现了新的2,6-二氟苄醚系列环戊基砜的比相应的醇衍生物出人意料地更有效。当与更优化的苯基（（组合[R）-3-苯基吡咯烷-3-基）砜模板时，2,6-二氟苄醚，得到一组非常有效的ROR γ吨反向激动剂（例如，化合物26，ROR γ吨Gal4 EC 50 11 nM），对PXR，LXRα和LXRβ具有高度选择性。在优化人和小鼠肝微粒体的稳定性后，对体内化合物29和38进行了评估并且在小鼠中具有良好的口服生物利用度（分别为56％和101％）。化合物的X-射线共晶体结构27在ROR γ吨显示，该笨重的苄基醚基使蛋白质的螺旋11，以部分地开卷以创建新的，扩大的结合位点，这很好地容纳苄醚部分，导致净效能提升。

  DOI：

  10.1016/j.bmcl.2020.127441
• 作为产物：
  描述：

  2-[4-(溴甲基)苯基]-1,1,1,3,3,3-六氟丙烷-2-醇 在 盐酸 、 20% palladium hydroxide-activated charcoal 、 氢气 、 乙酸酐 、 potassium carbonate 、 二乙胺 、 三氟乙酸 作用下， 以 甲醇 、 二氯甲烷 、 二氧化碳 、 水 、 N,N-二甲基甲酰胺 为溶剂， 60.0 ℃ 、10.0 MPa 条件下， 反应 65.17h， 生成 (R)-1,1,1,3,3,3-hexafluoro-2-(4-(3-((4-fluorophenyl)sulfonyl)pyrrolidin-3-yl)phenyl)propan-2-ol
  参考文献：
  名称：

  Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists

  摘要：

  A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of ROR gamma t inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at Nl-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXR alpha, and LXR beta. Further optimization led to the discovery of (1R,40-44(R)-34(4-fluorophenyl)sulfony1)-3-(4-(perfluoropropan-2-yOphenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.

  DOI：

  10.1021/acsmedchemlett.9b00010

文献信息

• PYRROLIDINYL SULFONE RORGAMMA MODULATORS
  申请人：Bristol-Myers Squibb Company

  公开号：US20150191483A1

  公开（公告）日：2015-07-09

  Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.

  描述了公式（I）的RORγ调节剂，或其立体异构体、互变异构体、药物可接受的盐、溶剂化物或前药，其中所有取代基都在此定义。还提供了包含相同成分的药物组合物。这类化合物和组合物在调节细胞中RORγ活性的方法和治疗受疾病或紊乱困扰的主体中是有用的，例如，主体将从调节RORγ活性中获益的自免疫和/或炎症紊乱。
• PYRROLIDINYL SULFONE DERIVATIVES AND THEIR USE AS ROR GAMMA MODULATORS
  申请人：Bristol-Myers Squibb Company

  公开号：EP3092229A1

  公开（公告）日：2016-11-16
• US9458171B2
  申请人：——

  公开号：US9458171B2

  公开（公告）日：2016-10-04
• [EN] PYRROLIDINYL SULFONE DERIVATIVES AND THEIR USE AS ROR GAMMA MODULATORS<br/>[FR] DÉRIVÉS DE PYRROLIDINYLE SULFONE ET LEUR UTILISATION EN TANT QUE MODULATEURS DE ROR GAMMA
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2015103509A1

  公开（公告）日：2015-07-09

  Described are RORγ modulators of the formula (I), or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein all substituents are defined herein. Also provided are pharmaceutical compositions comprising the same. Such compounds and compositions are useful in methods for modulating RORγ activity in a cell and methods for treating a subject suffering from a disease or disorder in which the subject would therapeutically benefit from modulation of RORγ activity, for example, autoimmune and/or inflammatory disorders.
• Structure-based Discovery of Phenyl (3-Phenylpyrrolidin-3-yl)sulfones as Selective, Orally Active RORγt Inverse Agonists
  作者：James J.-W. Duan、Zhonghui Lu、Bin Jiang、Sylwia Stachura、Carolyn A. Weigelt、John S. Sack、Javed Khan、Max Ruzanov、Michael A. Galella、Dauh-Rurng Wu、Melissa Yarde、Ding-Ren Shen、David J. Shuster、Virna Borowski、Jenny H. Xie、Lisa Zhang、Sridhar Vanteru、Arun Kumar Gupta、Arvind Mathur、Qihong Zhao、William Foster、Luisa M. Salter-Cid、Percy H. Carter、T. G. Murali Dhar

  DOI：10.1021/acsmedchemlett.9b00010

  日期：2019.3.14

  A new phenyl (3-phenylpyrrolidin-3-yl)sulfone series of ROR gamma t inverse agonists was discovered utilizing the binding conformation of previously reported bicyclic sulfonamide 1. Through a combination of structure-based design and structure-activity relationship studies, a polar set of amides at Nl-position of the pyrrolidine ring and perfluoroisopropyl group at para-position of the 3-phenyl group were identified as critical structural elements to achieve high selectivity against PXR, LXR alpha, and LXR beta. Further optimization led to the discovery of (1R,40-44(R)-34(4-fluorophenyl)sulfony1)-3-(4-(perfluoropropan-2-yOphenyl)pyrrolidine-1-carbonyl)cyclohexane-1-carboxylic acid (26), which displayed excellent selectivity, desirable liability and pharmacokinetic properties in vitro, and a good pharmacokinetic profile in mouse. Oral administration of 26 demonstrated dose-dependent inhibition of IL-17 production in a mouse IL-2/IL-23-induced pharmacodynamic model and biologic-like efficacy in an IL-23-induced mouse acanthosis model.