ethyl (3-exo)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate | 99658-64-7

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 托烷生物碱
• 英文名称: ethyl (3-exo)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
• 英文别名: endo-N-(ethoxycarbonyl)-8-aza-bicyclo[3.2.1]octane-3-carbaldehyde
• CAS: 99658-64-7
• 化学式: C₁₁H₁₇NO₃
• 分子量: 211.261
• InChiKey: FAPZNZUXAPWINX-OWUUHHOZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.58
• 重原子数：
  15.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  46.61
• 氢给体数：
  0.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  ethyl (3-exo)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate 、 1'-(methylsulfonyl)-1',2'-dihydrospiro[piperidine-4,3'-pyrrolo[2,3-b]pyridine] 在 三乙酰氧基硼氢化钠 作用下， 以 二氯甲烷 为溶剂， 反应 19.0h， 以100%的产率得到C₂₃H₃₄N₄O₄S
  参考文献：
  名称：

  发现N-磺酰基-7-氮杂二氢吲哚衍生物作为有效的，口服可利用的和选择性的M 4毒蕈碱型乙酰胆碱受体激动剂

  摘要：

  我们设计和合成了新型的N-磺酰基-7-氮杂二氢吲哚衍生物，作为选择性的M 4毒蕈碱乙酰胆碱受体激动剂。化合物2（一种M 4毒蕈碱乙酰胆碱受体（mAChR）偏爱的激动剂）的N-甲乙氧基哌啶部分的修饰导致了化合物1（一种选择性的M 4 mAChR激动剂）。化合物1显示出高度选择性的M 4 mAChR激动活性，体外hERG抑制作用较弱。体内化合物1的药代动力学研究表明，大鼠具有良好的生物利用度和脑渗透性。化合物1 逆转了甲基苯丙胺诱导的大鼠运动过度活跃（1-10 mg / kg，口服）。

  DOI：

  10.1016/j.bmcl.2014.04.083
• 作为产物：
  描述：

  ethyl (1RS, 5SR)-8H-spiro[8-azabicyco[3.2.1]octane-3,2’-oxirane]-8-carboxylate 在 三氟化硼乙醚 作用下， 以 四氢呋喃 为溶剂， 以84%的产率得到ethyl (3-exo)-3-formyl-8-azabicyclo[3.2.1]octane-8-carboxylate
  参考文献：
  名称：

  Discovery of NovelN-Substituted Oxindoles as Selective M₁and M₄Muscarinic Acetylcholine Receptors Partial Agonists

  摘要：

  Activation of the M-1 and M-4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M-1 and M-4 over M-2, M-3, and M-5. Among these oxindoles, compound 1 showed high selectivity for the M-1 and M-4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects.

  DOI：

  10.1021/ml300372f

文献信息

• [EN] MODULATORS OF MUSCARINIC RECEPTORS<br/>[FR] MODULATEURS DES RECEPTEURS MUSCARINIQUES
  申请人：VERTEX PHARMA

  公开号：WO2006023852A3

  公开（公告）日：2006-08-31
• Discovery of dihydroquinazolinone derivatives as potent, selective, and CNS-penetrant M1 and M4 muscarinic acetylcholine receptors agonists
  作者：Yoshiharu Uruno、Yasuko Konishi、Atsushi Suwa、Kentaro Takai、Kengo Tojo、Tomokazu Nakako、Mutsuko Sakai、Takeshi Enomoto、Harumi Matsuda、Atsushi Kitamura、Takaaki Sumiyoshi

  DOI：10.1016/j.bmcl.2015.09.032

  日期：2015.11

  We designed and synthesized a series of dihydroquinazolinone derivatives as selective M-1 and M-4 muscarinic acetylcholine receptors agonists. Introduction of the N-carbethoxy piperidine unit into a HTS hit compound followed by optimization of the amine linker and the carbamoyl moiety led to the identification of compound 1 as a potential candidate. The identified compound 1 showed high selectivity for M-1 and M-4 muscarinic acetylcholine receptors with M-4 partial agonistic activity. In addition, compound 1 showed good brain penetration and reversed methamphetamine-induced hyperlocomotion in rats (ED50 = 3.0 mg/kg, sc). (C) 2015 Elsevier Ltd. All rights reserved.
• Discovery of Novel<i>N</i>-Substituted Oxindoles as Selective M₁and M₄Muscarinic Acetylcholine Receptors Partial Agonists
  作者：Takaaki Sumiyoshi、Takeshi Enomoto、Kentaro Takai、Yoko Takahashi、Yasuko Konishi、Yoshiharu Uruno、Kengo Tojo、Atsushi Suwa、Harumi Matsuda、Tomokazu Nakako、Mutsuko Sakai、Atsushi Kitamura、Yasuaki Uematsu、Akihiko Kiyoshi

  DOI：10.1021/ml300372f

  日期：2013.2.14

  Activation of the M-1 and M-4 muscarinic acetylcholine receptors is thought to play an important role in improving the symptoms of schizophrenia. However, discovery of selective agonists for these receptors has been a challenge, considering the high sequence homology and conservation of the orthosteric acetylcholine binding site among muscarinic acetylcholine receptor subtypes. We report in this study the discovery of novel N-substituted oxindoles as potent muscarinic acetylcholine receptor partial agonists selective for M-1 and M-4 over M-2, M-3, and M-5. Among these oxindoles, compound 1 showed high selectivity for the M-1 and M-4 receptors with remarkable penetration into the central nervous system. Compound 1 reversed methamphetamine- and apomorphine-induced psychosis-like behaviors with low potency to extrapyramidical and peripheral side effects.
• Discovery of N-sulfonyl-7-azaindoline derivatives as potent, orally available and selective M4 muscarinic acetylcholine receptor agonists
  作者：Atsushi Suwa、Yasuko Konishi、Yoshiharu Uruno、Kentaro Takai、Tomokazu Nakako、Mutsuko Sakai、Takeshi Enomoto、Yoshiaki Ochi、Harumi Matsuda、Atsushi Kitamura、Yasuaki Uematsu、Akihiko Kiyoshi、Takaaki Sumiyoshi

  DOI：10.1016/j.bmcl.2014.04.083

  日期：2014.7

  designed and synthesized novel N-sulfonyl-7-azaindoline derivatives as selective M4 muscarinic acetylcholine receptor agonists. Modification of the N-carbethoxy piperidine moiety of compound 2, an M4 muscarinic acetylcholine receptor (mAChR)-preferring agonist, led to compound 1, a selective M4 mAChR agonist. Compound 1 showed a highly selective M4 mAChR agonistic activity with weak hERG inhibition in

  我们设计和合成了新型的N-磺酰基-7-氮杂二氢吲哚衍生物，作为选择性的M 4毒蕈碱乙酰胆碱受体激动剂。化合物2（一种M 4毒蕈碱乙酰胆碱受体（mAChR）偏爱的激动剂）的N-甲乙氧基哌啶部分的修饰导致了化合物1（一种选择性的M 4 mAChR激动剂）。化合物1显示出高度选择性的M 4 mAChR激动活性，体外hERG抑制作用较弱。体内化合物1的药代动力学研究表明，大鼠具有良好的生物利用度和脑渗透性。化合物1 逆转了甲基苯丙胺诱导的大鼠运动过度活跃（1-10 mg / kg，口服）。