2-[(4S,4aS,10bS)-10b-(4-chlorophenyl)sulfonyl-7,10-difluoro-2,4,4a,5-tetrahydro-1H-pyrano[3,4-c]chromen-4-yl]ethyl 4-methylbenzenesulfonate | 1100361-35-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-[(4S,4aS,10bS)-10b-(4-chlorophenyl)sulfonyl-7,10-difluoro-2,4,4a,5-tetrahydro-1H-pyrano[3,4-c]chromen-4-yl]ethyl 4-methylbenzenesulfonate
• CAS: 1100361-35-0
• 化学式: C₂₇H₂₅ClF₂O₇S₂
• 分子量: 599.073
• InChiKey: QWCVEWGIGKKEFR-DDZLNHKNSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.1
• 重原子数：
  39
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  113
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  2-[(4S,4aS,10bS)-10b-(4-chlorophenyl)sulfonyl-7,10-difluoro-2,4,4a,5-tetrahydro-1H-pyrano[3,4-c]chromen-4-yl]ethyl 4-methylbenzenesulfonate 在 三乙胺 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 C₂₃H₂₆ClF₂NO₆S₂
  参考文献：
  名称：

  Design and synthesis of water soluble β-aminosulfone analogues of SCH 900229 as γ-secretase inhibitors

  摘要：

  In this paper we describe our strategy to improve the aqueous solubility of SCH 900229, a potent PS1-selective gamma-secretase inhibitor for the treatment of Alzheimer's disease. Incorporation of ionizable amino groups into the side chain terminal generates water soluble beta-aminosulfone analogues of SCH 900229 that maintain robust in vitro potency and in vivo efficacy. (C) 2016 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2016.04.095
• 作为产物：
  描述：

  2-[(4-chloro-phenylsulfanyl)-(2,3,6-trifluoro-phenyl)-methyl]-malonic acid dimethyl ester 在 oxone 、 lithium aluminium tetrahydride 、 三氟甲磺酸三甲基硅酯 、 三氟化硼乙醚 、 potassium tert-butylate 、 戴斯-马丁氧化剂 、 臭氧 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 丙酮 为溶剂， 生成 2-[(4S,4aS,10bS)-10b-(4-chlorophenyl)sulfonyl-7,10-difluoro-2,4,4a,5-tetrahydro-1H-pyrano[3,4-c]chromen-4-yl]ethyl 4-methylbenzenesulfonate
  参考文献：
  名称：

  Structure activity relationship studies of tricyclic bispyran sulfone γ-secretase inhibitors

  摘要：

  An investigation is detailed of the structure activity relationships (SAR) of two sulfone side chains of compound (-)-1a (SCH 900229), a potent, PS1-selective gamma-secretase inhibitor and clinical candidate for the treatment of Alzheimer's disease. Specifically, 4-CF3 and 4-Br substituted arylsulfone analogs, (-)-1b and (-)-1c, are equipotent to compound (-)-1a. On the right hand side chain, linker size and terminal substituents of the pendant sulfone group are also investigated. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.11.047

文献信息

• Discovery of SCH 900229, a Potent Presenilin 1 Selective γ-Secretase Inhibitor for the Treatment of Alzheimer’s Disease
  作者：Wen-Lian Wu、Martin Domalski、Duane A. Burnett、Hubert Josien、Thomas Bara、Murali Rajagopalan、Ruo Xu、John Clader、William J. Greenlee、Andrew Brunskill、Lynn A. Hyde、Robert A. Del Vecchio、Mary E. Cohen-Williams、Lixin Song、Julie Lee、Giuseppe Terracina、Qi Zhang、Amin Nomeir、Eric M. Parker、Lili Zhang

  DOI：10.1021/ml300044f

  日期：2012.11.8

  of γ-secretase inhibitors led to the identification of compound (−)-16 (SCH 900229), which is a potent and PS1 selective inhibitor of γ-secretase (Aβ40 IC50 = 1.3 nM). Compound (−)-16 demonstrated excellent lowering of Aβ after oral administration in preclinical animal models and was advanced to human clinical trials for further development as a therapeutic agent for the treatment of Alzheimer’s disease

  对新型三环系列 γ-分泌酶抑制剂侧链 SAR 的探索导致化合物 (-)- 16 (SCH 900229) 的鉴定，这是一种有效的 PS1 选择性 γ-分泌酶抑制剂 (Aβ40 IC 50 = 1.3 nM）。化合物 (-)- 16在临床前动物模型中口服给药后表现出极好的 Aβ 降低，并已进入人体临床试验以进一步开发作为治疗阿尔茨海默病的治疗剂。
• [EN] GAMMA SECRETASE INHIBITORS<br/>[FR] INHIBITEURS DE GAMMA SÉCRÉTASE
  申请人：MERCK SHARP & DOHME

  公开号：WO2013036464A1

  公开（公告）日：2013-03-14

  Disclosed herein are compounds of Formula (I) (I) and pharmaceutically acceptable salts thereof, wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the compound of Formula (I) and use of the compound in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.

  本文披露了公式(I) (I)的化合物及其药学上可接受的盐，其中每个取代基的定义如规范和权利要求所述。还披露了含有公式(I)化合物的药物组合物以及使用该化合物治疗神经退行性疾病或病症，如阿尔茨海默病。
• TETRAHYDROPYRANOCHROMENE GAMMA SECRETASE INHIBITORS
  申请人：Wu Wen-Lian

  公开号：US20110236400A1

  公开（公告）日：2011-09-29

  Disclosed are novel gamma secretase inhibitors of the formula. Also disclosed are methods of inhibiting gamma-secretase, methods of treating neurodegenerative diseases, and methods of treating Alzheimer's Disease. Also disclosed are processes for preparing alkenes in one reaction step using a mixture of an aldehyde (or ketone) and an alkyl substituted with two electron withdrawing groups, and reacting the mixture with: (a) a sulfonyl halide (e.g., a sulfonyl chloride) and a basic tertiary amine, or, (b) a sulfonyl anhydride and a basic amine, or (c) an aryl-C(O)-halide and a basic tertiary amine, or (d) an aryl-C(O)—O—C(O)-aryl and a basic tertiary amine, or (e) an heteroaryl-C(O)-halide and a basic tertiary amine, or (f) a heteroaryl-C(O)—O—C(O)-heteroaryl and a basic tertiary amine.

  本发明涉及一种新型伽马分泌酶抑制剂的公开。还公开了抑制伽马分泌酶的方法、治疗神经退行性疾病的方法和治疗阿尔茨海默病的方法。还公开了一种使用醛（或酮）和烷基取代的两个电子提取基团的混合物，在一步反应中制备烯烃的方法，并将该混合物与：（a）磺酰卤化物（例如磺酰氯）和碱性三级胺反应，或（b）磺酰酐和碱性胺反应，或（c）芳基-C（O）-卤和碱性三级胺反应，或（d）芳基-C（O）-O-C（O）-芳基和碱性三级胺反应，或（e）杂环芳基-C（O）-卤和碱性三级胺反应，或（f）杂环芳基-C（O）-O-C（O）-杂环芳基和碱性三级胺反应。
• [EN] TETRAHYDROPYRANOCHROMENE GAMMA SECRETASE INHIBITORS<br/>[FR] INHIBITEURS DE LA TÉTRAHYDROPYRANOCHROMÈNE GAMMA SECRÉTASE
  申请人：SCHERING CORP

  公开号：WO2009008980A3

  公开（公告）日：2009-03-19
• GAMMA SECRETASE INHIBITORS
  申请人：Wu Wen-Lian

  公开号：US20140018342A1

  公开（公告）日：2014-01-16

  Disclosed herein are compounds of Formula (I) and pharmaceutically acceptable salts thereof, wherein each of the substituents is given the definition as set forth in the specification and claims. Also disclosed are pharmaceutical compositions containing the compound of Formula (I) and use of the compound in the treatment of neurodegenerative diseases or conditions such as Alzheimer's disease.