N-(1-(pyrrolidin-3-yl)indolin-5-yl)thiophene-2-carboximidamide | 1063408-85-4

• 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-(1-(pyrrolidin-3-yl)indolin-5-yl)thiophene-2-carboximidamide
• 英文别名: N'-(1-pyrrolidin-3-yl-2,3-dihydroindol-5-yl)thiophene-2-carboximidamide
• CAS: 1063408-85-4
• 化学式: C₁₇H₂₀N₄S
• 分子量: 312.439
• InChiKey: BRSFLOUTQGEAHB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  22
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  81.9
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(1-(pyrrolidin-3-yl)indolin-5-yl)thiophene-2-carboximidamide 在 盐酸 作用下， 以 甲醇 、 乙醚 为溶剂， 反应 0.17h， 生成 N-(1-(pyrrolidin-3-yl)indolin-5-yl)thiophene-2-carboximidamide
  参考文献：
  名称：

  Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine

  摘要：

  We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K+ channel inhibition (IC50 = 4.7 mu m) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F-po = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.07.006
• 作为产物：
  描述：

  3-(2,3-dihydro-1H-indol-1-yl)pyrrolidine-1-carboxylic acid tert-butyl ester 在 盐酸 、 tris-(dibenzylideneacetone)dipalladium(0) 、 N-溴代丁二酰亚胺(NBS) 、 三叔丁基膦 、 四丁基氟化铵 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 正己烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 N-(1-(pyrrolidin-3-yl)indolin-5-yl)thiophene-2-carboximidamide
  参考文献：
  名称：

  Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine

  摘要：

  We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K+ channel inhibition (IC50 = 4.7 mu m) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F-po = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain. (C) 2012 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2012.07.006

文献信息

• QUINOLONE AND TETRAHYDROQUINOLONE AND RELATED COMPOUNDS HAVING NOS INHIBITORY ACTIVITY
  申请人：MADDAFORD Shawn

  公开号：US20080234237A1

  公开（公告）日：2008-09-25

  The present invention features quinolones, tetrahydroquinolines, and related compounds that inhibit 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 various medical conditions.

  本发明涉及抑制一氧化氮合酶（NOS）的喹诺酮、四氢喹啉和相关化合物，特别是那些选择性地抑制神经型一氧化氮合酶（nNOS）而不是其他NOS同工型的化合物。本发明的NOS抑制剂，单独或与其他药用活性剂结合使用，可用于治疗或预防各种医疗状况。
• Quinolone and tetrahydroquinolone and related compounds having NOS inhibitory activity
  申请人：NeurAxon, Inc.

  公开号：US08173813B2

  公开（公告）日：2012-05-08

  The present invention features quinolones, tetrahydroquinolines, and related compounds that inhibit 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 various medical conditions.

  本发明涉及喹诺酮、四氢喹诺酮和相关化合物，它们抑制一氧化氮合酶（NOS），特别是选择性地抑制神经元一氧化氮合酶（nNOS）而不是其他NOS亚型。本发明的NOS抑制剂，单独或与其他药理活性剂联合使用，可用于治疗或预防各种医学疾病。
• US8173813B2
  申请人：——

  公开号：US8173813B2

  公开（公告）日：2012-05-08
• [EN] QUINOLONE AND TETRAHYDROQUINOLINE AND RELATED COMPOUNDS HAVING NOS INHIBITORY ACTIVITY<br/>[FR] QUINOLONES ET TÉTRAHYDROQUINOLÉINES ET COMPOSÉS APPARENTÉS AYANT UNE ACTIVITÉ INHIBITRICE DE NOS
  申请人：NEURAXON INC

  公开号：WO2008116308A1

  公开（公告）日：2008-10-02

  [EN] The present invention features quinolones, tetrahydroquinolines, and related compounds that inhibit 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 various medical conditions.
  [FR] La présente invention porte sur des quinolones, des tétraydroquinoléines et des composés apparentés qui inhibent l'oxyde nitrique synthase (NOS), en particulier sur celles et ceux qui inhibent de façon sélective l'oxyde nitrique synthase neuronal (nNOS) de préférence à d'autres isoformes de NOS. Les inhibiteurs de NOS de l'invention, individuellement ou en combinaison avec d'autres agents pharmaceutiquement actifs, peuvent être utilisés pour traiter ou prévenir divers états médicaux.
• Discovery of a potent, orally bioavailable and highly selective human neuronal nitric oxide synthase (nNOS) inhibitor, N-(1-(piperidin-4-yl)indolin-5-yl)thiophene-2-carboximidamide as a pre-clinical development candidate for the treatment of migraine
  作者：Subhash C. Annedi、Shawn P. Maddaford、Jailall Ramnauth、Paul Renton、Taras Rybak、Sarah Silverman、Suman Rakhit、Gabriela Mladenova、Peter Dove、John S. Andrews、Dongqin Zhang、Frank Porreca

  DOI：10.1016/j.ejmech.2012.07.006

  日期：2012.9

  We recently reported a series of 1,6-disubstituted indoline-based thiophene amidine compounds (5) as selective neuronal nitric oxide synthase (nNOS) inhibitors to mitigate the cardiovascular liabilities associated with hERG K+ channel inhibition (IC50 = 4.7 mu m) with previously reported tetrahydroquinoline-based selective nNOS inhibitors (4). The extended structure activity relationship studies within the indoline core led to the identification of 43 as a selection candidate for further evaluations. The in vivo activity in two different pain (spinal nerve ligation and migraine pain) models, the excellent physicochemical and pharmacokinetic properties, oral bioavailability (F-po = 91%), and the in vitro safety profile disclosed in this report make 43 an ideal candidate for further evaluation in clinical applications related to migraine pain. (C) 2012 Elsevier Masson SAS. All rights reserved.