((1R,3S)-1-amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate | 1883345-27-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: ((1R,3S)-1-amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate
• 英文别名: 7D9Ome8bvv；[(1R,3S)-1-amino-3-[(6S)-6-[2-(2-methoxyphenyl)ethyl]-5,6,7,8-tetrahydronaphthalen-2-yl]cyclopentyl]methyl dihydrogen phosphate
• CAS: 1883345-27-4
• 化学式: C₂₅H₃₄NO₅P
• 分子量: 459.522
• InChiKey: CDZQINDPHHFTHS-FMNCTDSISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  102
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  2-(4-((5R,7S)-2-oxo-3-oxa-1-azaspiro[4.4]nonan-7-yl)phenyl)acetic acid 在 N,N-二甲基丙烯基脲 、 aluminum (III) chloride 、 bis-triphenylphosphine-palladium(II) chloride 、 copper(l) iodide 、 草酰氯 、 焦磷酰氯 、 氢气 、 palladium(II) hydroxide 、 三乙胺 、 N,N-二甲基甲酰胺 、 sodium hydroxide 、 lithium diisopropyl amide 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 8.5h， 生成 ((1R,3S)-1-amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methyl dihydrogen phosphate
  参考文献：
  名称：

  Identification and Preclinical Pharmacology of ((1R,3S)-1-Amino-3-((S)-6-(2-methoxyphenethyl)-5,6,7,8-tetrahydronaphthalen-2-yl)cyclopentyl)methanol (BMS-986166): A Differentiated Sphingosine-1-phosphate Receptor 1 (S1P₁) Modulator Advanced into Clinical Trials

  摘要：

  Recently, our research group reported the identification of BMS-986104 (2) as a differentiated S1P(1) receptor modulator. In comparison to fingolimod (1), a full agonist of S1P(1) currently marketed for the treatment of relapse remitting multiple sclerosis (RRMS), 2 offers several potential advantages having demonstrated improved safety multiples in preclinical evaluations against undesired pulmonary and cardiovascular effects. In clinical trials, 2 was found to exhibit a pharmacokinetic half-life (T-1/2) longer than that of 1, as well as a reduced formation of the phosphate metabolite that is required for activity against S1P(1). Herein, we describe our efforts to discover highly potent, partial agonists of S1P(1) with a shorter T-1/2 and increased in vivo phosphate metabolite formation. These efforts culminated in the discovery of BMS-986166 (14a), which was advanced to human clinical evaluation. The pharmacokinetic/pharmacodynamic (PK/PD) relationship as well as pulmonary and cardiovascular safety assessments are discussed. Furthermore, efficacy of 14a in multiple preclinical models of autoimmune diseases are presented.

  DOI：

  10.1021/acs.jmedchem.8b01695

文献信息

• [EN] SUBSTITUTED BICYCLIC COMPOUNDS<br/>[FR] COMPOSÉS BICYCLIQUES SUBSTITUÉS
  申请人：BRISTOL MYERS SQUIBB CO

  公开号：WO2016028959A1

  公开（公告）日：2016-02-25

  Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V) and/or a salt thereof, wherein R1 is OH or OP(O)(OH)2, and X1, X2, X3, R2, R2a, Ra, Rb, and Rc are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  揭示了Formula（I）、（II）、（III）、（IV）和（V）及/或其盐的化合物，其中R1为OH或OP（O）（OH）2，X1、X2、X3、R2、R2a、Ra、Rb和Rc在此处有定义。还揭示了将这些化合物用作选择性G蛋白偶联受体S1P1的激动剂的方法，以及包含这些化合物的药物组合物。这些化合物在治疗、预防或减缓多种治疗领域的疾病或疾病的进展方面是有用的，如自身免疫疾病和血管疾病。
• SUBSTITUTED BICYCLIC COMPOUNDS
  申请人：Bristol-Myers Squibb Company

  公开号：US20160052888A1

  公开（公告）日：2016-02-25

  Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V): and/or a salt thereof, wherein R 1 is —OH or —OP(O)(OH) 2 , and X 1 , X 2 , X 3 , R 2 , R 2a , R a , R b , and R c are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P 1 , and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  公开了公式（I）、（II）、（III）、（IV）和（V）的化合物及/或其盐，其中R1为—OH或—OP（O）（OH）2，X1、X2、X3、R2、R2a、Ra、Rb和Rc的定义如本文所述。还公开了使用这些化合物作为选择性G蛋白偶联受体S1P1激动剂的方法，以及包括这些化合物的药物组合物。这些化合物在治疗、预防或减缓多种治疗领域的疾病或障碍方面有用，例如自身免疫性疾病和血管疾病。
• Substituted bicyclic compounds
  申请人：BRISTOL-MYERS SQUIBB COMPANY

  公开号：US10166249B2

  公开（公告）日：2019-01-01

  Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V): and/or a salt thereof, wherein R1 is —OH or —OP(O)(OH)2, and X1, X2, X3, R2, R2a, Ra, Rb, and Rc are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.

  所公开的是式 (I)、(II)、(III)、(IV) 和 (V) 的化合物： 和/或其盐，其中 R1 是-OH 或-OP(O)(OH)2，X1、X2、X3、R2、R2a、Ra、Rb 和 Rc 在本文中定义。还公开了将此类化合物用作 G 蛋白偶联受体 S1P1 选择性激动剂的方法，以及包含此类化合物的药物组合物。这些化合物可用于治疗、预防或减缓各种治疗领域的疾病或失调，如自身免疫性疾病和血管疾病。
• US9522888B2
  申请人：——

  公开号：US9522888B2

  公开（公告）日：2016-12-20
• US9770459B2
  申请人：——

  公开号：US9770459B2

  公开（公告）日：2017-09-26