N-(3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: N-(3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide
• 英文别名: N'-[3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1H-indol-6-yl]thiophene-2-carboximidamide
• 化学式: C₂₀H₂₀N₄S
• 分子量: 348.472
• InChiKey: MELCLAMYTKAENH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  25
• 可旋转键数：
  3
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  85.6
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为产物：
  描述：

  3-奎宁环酮盐酸盐 在 hydrazine hydrate 、 potassium hydroxide 作用下， 以 甲醇 、 乙醇 、 水 为溶剂， 反应 60.03h， 生成 N-(3-(1-azabicyclo[2.2.2]oct-2-en-3-yl)-1H-indol-6-yl)thiophene-2-carboximidamide
  参考文献：
  名称：

  Discovery of N-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain

  摘要：

  3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.

  DOI：

  10.1021/jm201063u

文献信息

• 1,5 And 3,6- substituted indole compounds having NOS inhibitory activity
  申请人：Maddaford Shawn

  公开号：US20070254940A1

  公开（公告）日：2007-11-01

  The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, or chronic pain.

  本发明涉及一种一氧化氮合酶（NOS）的抑制剂，特别是那些选择性地抑制神经一氧化氮合酶（nNOS）而不是其他NOS同工酶。本发明的NOS抑制剂，单独或与其他药用活性剂联合使用，可用于治疗或预防诸如中风、再灌注损伤、神经退行性疾病、头部创伤、冠状动脉搭桥手术（CABG）、有或无先兆的偏头痛、伴有触痛的偏头痛、中枢性中风后疼痛（CPSP）、神经病性疼痛或慢性疼痛等病症。
• 1,5 AND 3,6- SUBSTITUTED INDOLE COMPOUNDS HAVING NOS INHIBITORY ACTIVITY
  申请人：Neuraxon Inc.

  公开号：EP2010527B1

  公开（公告）日：2013-08-14
• US7989447B2
  申请人：——

  公开号：US7989447B2

  公开（公告）日：2011-08-02
• [EN] 1,5 AND 3,6- SUBSTITUTED INDOLE COMPOUNDS HAVING NOS INHIBITORY ACTIVITY<br/>[FR] INDOLES 1,5- ET 3,6-SUBSTITUÉS À ACTIVITÉ INHIBITRICE VIS-À-VIS DE NOS
  申请人：NEURAXON INC

  公开号：WO2007118314A1

  公开（公告）日：2007-10-25

  [EN] The present invention features inhibitors of nitric oxide synthase (NOS), particularly those that selectively inhibit neuronal nitric oxide synthase (nNOS) in preference to other NOS isoforms. The NOS inhibitors of the invention, alone or in combination with other pharmaceutically active agents, can be used for treating or preventing conditions such as, for example, stroke, reperfusion injury, neurodegeneration, head trauma, CABG, migraine headache with and without aura, migraine with allodynia, central post-stroke pain (CPSP), neuropathic pain, or chronic pain.
  [FR] La présente invention concerne des inhibiteurs de l'oxyde nitrique synthétase (NOS), en particulier ceux qui inhibent de façon sélective l'oxyde nitrique synthétase neuronale (nNOS) préférentiellement aux autres isoformes de NOS. Les inhibiteurs de NOS selon l'invention, seuls ou combinés à d'autres principes actifs pharmaceutiques, peuvent être employés dans le traitement prophylactique ou thérapeutique d'états pathologiques tels que, par exemple, les accidents cérébrovasculaires, les lésions de reperfusion, la neurodégénérescence, les traumatismes crâniens, les pontages coronariens, les migraines avec et sans aura, les migraines avec allodynie, les douleurs centrales après accidents cérébrovasculaires, les douleurs névropathiques ou les douleurs chroniques.
• Discovery of <i>N</i>-(3-(1-Methyl-1,2,3,6-tetrahydropyridin-4-yl)-1<i>H</i>-indol-6-yl) thiophene-2-carboximidamide as a Selective Inhibitor of Human Neuronal Nitric Oxide Synthase (nNOS) for the Treatment of Pain
  作者：Subhash C. Annedi、Shawn P. Maddaford、Gabriela Mladenova、Jailall Ramnauth、Suman Rakhit、John S. Andrews、David K. H. Lee、Dongqin Zhang、Frank Porreca、David Bunton、Lee Christie

  DOI：10.1021/jm201063u

  日期：2011.10.27

  3,6-Disubstituted indole derivatives were designed, synthesized, and evaluated as inhibitors of human nitric oxide synthase (NOS). Bulky amine containing substitution on the 3-position of the indole ring such as an azabicyclic system showed better selectivity over 5- and 6-membered cyclic amine substitutions. Compound (-)-19 showed the best selectivity for neuronal NOS over endothelial NOS (90-fold) and inducible NOS (309-fold) among the current series. Compounds 16 and (-)-19 were shown to be either inactive or very weak inhibitors of human cytochrome P450 enzymes, indicating a low potential for drug drug interactions. Compound 16 was shown to reverse thermal hyperalgesia in vivo in the Chung model of neuropathic pain. Compound 16 was also devoid of any significant vasoconstrictive effect in human coronary arteries, associated with the inhibition of human eNOS. These results suggest that 16 may be a useful tool for evaluating the potential role of selective nNOS inhibitors in the treatment of pain such as migraine and CTTH.