[6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(carbonylamino-acetic acid)-5'-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide | 1159705-98-2

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(carbonylamino-acetic acid)-5'-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide
• 英文别名: 2-[[(1'R,4R,10'S)-1,1-dioxo-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13'-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene]-5'-carbonyl]amino]acetic acid
• CAS: 1159705-98-2
• 化学式: C₁₉H₂₂F₃N₃O₅S
• 分子量: 461.462
• InChiKey: FTXLLHSEKWJGJZ-HDMKZQKVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  31
• 可旋转键数：
  4
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  124
• 氢给体数：
  3
• 氢受体数：
  10

反应信息

• 作为反应物：
  描述：

  4-(三氟甲基)哌啶 、 [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(carbonylamino-acetic acid)-5'-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide 在 O-(1H-benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate 、 N,N-二异丙基乙胺 作用下， 以 乙腈 为溶剂， 生成 (1'R,4R,10'S)-1,1-dioxo-N-[2-oxo-2-[4-(trifluoromethyl)piperidin-1-yl]ethyl]-2-(2,2,2-trifluoroethyl)spiro[1,2,5-thiadiazolidine-4,13'-tricyclo[8.2.1.03,8]trideca-3(8),4,6-triene]-5'-carboxamide
  参考文献：
  名称：

  Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity

  摘要：

  The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methyipyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED50 of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.

  DOI：

  10.1021/jm900056p
• 作为产物：
  描述：

  [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(carbonylamino-acetic acid methyl ester)-5'-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide 在 sodium hydroxide 、 盐酸 作用下， 以 四氢呋喃 、 水 为溶剂， 反应 5.5h， 以0.213 g的产率得到[6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(carbonylamino-acetic acid)-5'-(2,2,2-trifluoroethyl)-spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide
  参考文献：
  名称：

  Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity

  摘要：

  The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methyipyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED50 of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.

  DOI：

  10.1021/jm900056p

文献信息

• [EN] HETEROARYL SUBSTITUTED SPIROCYCLIC SULFAMIDES FOR INHIBITION OF GAMMA SECRETASE<br/>[FR] SULFAMIDES SPIROCYCLIQUES SUBSTITUES PAR HETEROARYLE UTILISES COMME INHIBITEURS DE LA GAMMA-SECRETASE
  申请人：MERCK SHARP & DOHME

  公开号：WO2003093252A1

  公开（公告）日：2003-11-13

  Compounds of formula I are disclosed: in which X is a 5-membered heteroaryl ring and R is as defined herein. The compounds are inhibitors of the processing of APP by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.

  公式I的化合物已被披露：其中X是一个5-成员杂环芳基环，R如本文所定义。这些化合物是γ-分泌酶对APP加工的抑制剂，因此在治疗或预防阿尔茨海默病中是有用的。
• Heteroaryl substituted spirocyclic sulfamides for inhibition of gamma secretase
  申请人：Collins James Ian

  公开号：US20080070895A1

  公开（公告）日：2008-03-20

  Compounds of formula I are disclosed: in which X is a 5-membered heteroaryl ring and R is as defined herein. The compounds are inhibitors of the processing of APP by gamma-secretase, and hence are useful in the treatment or prevention of Alzheimer's disease.

  公开了式子I的化合物：其中X是5-成员的杂环芳基环，R如此定义。这些化合物是γ-分泌酶处理APP的抑制剂，因此在治疗或预防阿尔茨海默病方面是有用的。
• US7282513B2
  申请人：——

  公开号：US7282513B2

  公开（公告）日：2007-10-16
• Novel Orally Bioavailable γ-Secretase Inhibitors with Excellent in Vivo Activity
  作者：Linda E. Keown、Ian Collins、Laura C. Cooper、Timothy Harrison、Andrew Madin、Jayesh Mistry、Michael Reilly、Mohamed Shaimi、Christopher J. Welch、Earl E. Clarke、Huw D. Lewis、Jonathan D. J. Wrigley、Jonathan D. Best、Fraser Murray、Mark S. Shearman

  DOI：10.1021/jm900056p

  日期：2009.6.11

  The development of potent gamma-secretase inhibitors having substituted heterocycles attached to a benzobicyclo[4.2.1]nonane core is described. This work led to the identification of [6S,9R,11R]-2',3',4',5,5',6,7,8,9,10-decahydro-2-(5-(4-fluorophenyl)-1-methyipyrazol-3-yl)-5'-(2,2,2-trifluoroethyl)spiro[6,9-methanobenzocyclooctene-11,3'-[1,2,5]thiadiazole] 1',1'-dioxide (16), which has excellent in vitro potency (0.06 nM) and which reduced amyloid-beta in APP-YAC mice with an ED50 of 1 mg/kg (po). 16 had a good pharmacokinetic profile in three preclinical species.