(S)-1-Aza-bicyclo[3.2.1]oct-(6E)-ylidene-cyano-acetic acid ethyl ester | 781596-68-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: (S)-1-Aza-bicyclo[3.2.1]oct-(6E)-ylidene-cyano-acetic acid ethyl ester
• 英文别名: ethyl 2-[(5S)-1-azabicyclo[3.2.1]octan-6-ylidene]-2-cyanoacetate
• CAS: 781596-68-7
• 化学式: C₁₂H₁₆N₂O₂
• 分子量: 220.271
• InChiKey: XDJBQHIYFDSPDN-SECBINFHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  16
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  53.3
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (S)-1-Aza-bicyclo[3.2.1]oct-(6E)-ylidene-cyano-acetic acid ethyl ester 在 palladium on activated charcoal 二氯化二硫 、 氢气 、 sodium ethanolate 、 亚硝酸异戊酯 作用下， 以 乙醇 为溶剂， 反应 5.0h， 生成 (R)-6-Chloro-6-(4-chloro-[1,2,5]thiadiazol-3-yl)-1-aza-bicyclo[3.2.1]octane
  参考文献：
  名称：

  Muscarinic Analgesics with Potent and Selective Effects on the Gastrointestinal Tract:  Potential Application for the Treatment of Irritable Bowel Syndrome

  摘要：

  Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along with potency for normalization of GI motility (ED(50) = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.

  DOI：

  10.1021/jm9602470
• 作为产物：
  描述：

  1-氮杂双环[3.2.1]辛烷-6-酮 在 ammonium acetate 、 溶剂黄146 作用下， 以 甲苯 为溶剂， 反应 40.0h， 生成 (S)-1-Aza-bicyclo[3.2.1]oct-(6E)-ylidene-cyano-acetic acid ethyl ester
  参考文献：
  名称：

  Muscarinic Analgesics with Potent and Selective Effects on the Gastrointestinal Tract:  Potential Application for the Treatment of Irritable Bowel Syndrome

  摘要：

  Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along with potency for normalization of GI motility (ED(50) = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.

  DOI：

  10.1021/jm9602470

文献信息

• Muscarinic Agonists with Antipsychotic-like Activity:  Structure−Activity Relationships of 1,2,5-Thiadiazole Analogues with Functional Dopamine Antagonist Activity
  作者：Per Sauerberg、Lone Jeppesen、Preben H. Olesen、Thøger Rasmussen、Michael D. B. Swedberg、Malcolm J. Sheardown、Anders Fink-Jensen、Christian Thomsen、Henning Thøgersen、Karin Rimvall、John S. Ward、David O. Calligaro、Neil W. DeLapp、Frank P. Bymaster、Harlan E. Shannon

  DOI：10.1021/jm981048e

  日期：1998.10.1

  Muscarinic agonists were tested in two models indicative of clinical antipsychotic activity: conditioned avoidance responding (CAR) in rats and inhibition of apomorphine-induced climbing in mice. The standard muscarinic agonists oxotremorine and pilocarpine were both active in these tests but showed little separation between efficacy and cholinergic side effects. Structure-activity relationships of

  在两种指示临床抗精神病活性的模型中测试了毒蕈碱激动剂：大鼠的条件回避反应（CAR）和小鼠中的阿扑吗啡诱导的爬升抑制。标准毒蕈碱激动剂oxotremorine和毛果芸香碱在这些测试中均很活跃，但在功效和胆碱能副作用之间几乎没有分离。显示了烷硫基1,2,5-噻二唑氮杂环型毒蕈碱部分激动剂的结构-活性关系，揭示了exo-6-（3-丙基/丁基硫代1,2,5-噻二唑-4-基）-1 -氮杂双环[3.2.1]辛烷类似物（4a，b和9a，b）是最有效的抗精神病药，在疗效和胆碱能副作用之间有较大的分隔。对映异构体选择性的缺乏表明药效团元素在化合物的镜平面中。提供了一个解释紧密相关化合物功效差异的模型。数据表明毒蕈碱激动剂起功能性多巴胺拮抗剂的作用，它们可能成为精神病患者的新型治疗方法。
• Muscarinic Analgesics with Potent and Selective Effects on the Gastrointestinal Tract:  Potential Application for the Treatment of Irritable Bowel Syndrome
  作者：Charles H. Mitch、Thomas J. Brown、Frank P. Bymaster、David O. Calligaro、Donna Dieckman、Leander Merrit、Steven C. Peters、Steven J. Quimby、Harlan E. Shannon、Lisa A. Shipley、John S. Ward、Kristian Hansen、Preben H. Olesen、Per Sauerberg、Malcolm J. Sheardown、Michael D. B. Swedberg、Peter Suzdak、Beverley Greenwood

  DOI：10.1021/jm9602470

  日期：1997.2.1

  Irritable bowel syndrome (IBS) is a pathopysiolocal condition characterized by abnormal bowel habits that are frequently accompanied by abdominal pain. Current therapy based on reducing high-amplitude GI contractions with nonselective muscarinic antagonists is limited in efficacy due to typical muscarinic side effects and provides no pain relief. We have previously found potent antinociceptive agents acting through muscarinic receptors. In the present work, new 1,2,5-thiadiazole-based structures with muscarinic activity have been evaluated both for activity as analgesics in the mouse withing assay and for activity in normalizing spontaneous cluster contractions in ferret jejunum as a model of IBS in humans. (5R,6R)-exo-6-[4-[(4,4,4-Trifluorobutyl)thio]-1,2,5-thiadiazol-3-yl]-1-azabicyclo[3.2.1]octane (35, LY316108/NNC11-2192) was found to offer an exceptional profile combining analgesic potency in mouse writhing (ED(50) = 0.1 mg/kg) along with potency for normalization of GI motility (ED(50) = 0.17 mg/kg). This combination of GI and analgesic potency suggests 35 as an excellent candidate for evaluation as a potential treatment of IBS.