SCH 900229 | 1100361-36-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: SCH 900229
• 英文别名: (4S,4aS,10bS)-10b-((4-chlorophenyl)sulfonyl)-7,10-difluoro-4-(2-(methylsulfonyl)ethyl)-1,2,4,4a,5,10b-hexahydropyrano[3,4-c]chromene；(4S,4aS,10bS)-10b-(4-chlorophenyl)sulfonyl-7,10-difluoro-4-(2-methylsulfonylethyl)-2,4,4a,5-tetrahydro-1H-pyrano[3,4-c]chromene
• CAS: 1100361-36-1
• 化学式: C₂₁H₂₁ClF₂O₆S₂
• 分子量: 506.976
• InChiKey: AMXSRXZYBDALJG-XERREHJYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  104
• 氢给体数：
  0
• 氢受体数：
  8

制备方法与用途

SCH 900229 是一种有效的早老素1选择性且具有口服活性的 γ-分泌酶抑制剂（aβ40 IC50为1.3 nM），在临床前动物模型中展现出优异的β淀粉样蛋白降低效果。

反应信息

• 作为反应物：
  描述：

  SCH 900229 在 Selectfluor 、 水 作用下， 以 乙腈 为溶剂， 反应 20.0h， 生成 C₂₁H₂₁ClF₂O₇S₂
  参考文献：
  名称：

  A-ring modification of SCH 900229 and related chromene sulfone γ-secretase inhibitors

  摘要：

  Attempts to block metabolism by incorporating a 9-fluoro substituent at the A-ring of compound 1 (SCH 900229) using electrophilic Selectfluor (TM) led to an unexpected oxidation of the A-ring to give difluoroquinone analog 1a. Oxidation of other related chromene gamma-secretase inhibitors 2-8 resulted in similar difluoroquinone analogs 2a-8a, respectively. These quinone products exhibited comparable in vitro potency in a gamma-scretase membrane assay, but were several fold less potent in a cell-based assay in lowering A beta 40-42, compared to their parent compounds. (c) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.11.054
• 作为产物：
  描述：

  C₂₀H₁₉ClF₂O₅S 在 四丁基碘化铵 、 三乙胺 作用下， 以 四氢呋喃 为溶剂， 生成 SCH 900229
  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。
• 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.
• US8664411B2
  申请人：——

  公开号：US8664411B2

  公开（公告）日：2014-03-04