N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)formamidine | 570385-04-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯并吡啶类
• 英文名称: N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)formamidine
• 英文别名: (E)-N,N-dimethyl-N′-(1H-pyrrolo[2,3-c]pyridin-5-yl)formimidamide；N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)-formamidine；N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)methanimidamide
• CAS: 570385-04-5
• 化学式: C₁₀H₁₂N₄
• 分子量: 188.232
• InChiKey: IRFHNJSDKJUYNA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  14
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  44.3
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)formamidine 在 N-碘代丁二酰亚胺 、 四(三苯基膦)钯 、 四丁基溴化铵 、 甲酸铵 、 potassium carbonate 、 钯 、 sodium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 51.5h， 生成 4-cyano-N-(3-(1-(cyclopentanecarbonyl)piperidin-4-yl)-1-methyl-1H-pyrrolo[2,3-c]pyridin-5-yl)picolinamide
  参考文献：
  名称：

  3-氰基-N-（3-（1-异丁酰基哌啶-4-基）-1-甲基-4-（三氟甲基）-1 H-吡咯并[2,3 - b ]吡啶-5-基）苯甲酰胺的发现：有力，选择性和口服生物可用的视黄酸受体相关的孤儿受体C2反激动剂。

  摘要：

  核激素受体视黄酸受体相关的孤儿C2（RORC2，也称为RORγt）是治疗自身免疫性疾病的有希望的靶标。预期该受体的小分子反向激动剂会减少关键的促炎细胞因子IL-17的产生。通过高通量筛选方法，我们鉴定了一种分子，该分子显示出对RORC2的有希望的结合亲和力，抑制Th17细胞中IL-17的产生以及对相关RORA和RORB受体同工型的选择性。铅优化以提高这种命中的效力和代谢稳定性为重点，主要集中在两个关键设计策略上，即，通过提高亲脂性效率和结构指导的构象限制驱动的迭代优化，以实现最佳的基态能量学和最大化受体停留时间。N-（3-（1-异丁酰基哌啶-4-基）-1-甲基-4-（三氟甲基）-1 H-吡咯并[2,3 - b ]吡啶-5-基）苯甲酰胺为强效且选择性的RORC2逆激动剂，在临床前体内动物模型中，口服给药后表现出良好的代谢稳定性，口服生物利用度以及降低IL-17水平和皮肤炎症的能力。

  DOI：

  10.1021/acs.jmedchem.8b00392
• 作为产物：
  描述：

  2-氨基-4-甲基-5-硝基吡啶 在 palladium on activated charcoal 氢气 作用下， 以 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 20.0~110.0 ℃ 、275.79 kPa 条件下， 反应 24.0h， 生成 N,N-dimethyl-N'-(1H-pyrrolo[2,3-c]pyridin-5-yl)formamidine
  参考文献：
  名称：

  Novel Potent 5-HT_1F Receptor Agonists:  Structure−Activity Studies of a Series of Substituted N-[3-(1-Methyl-4-piperidinyl)-1H-pyrrolo[3,2-b]pyridin-5-yl]amides

  摘要：

  Compound 1a (LY334370), a selective 5-HT1F receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1 was greater than 100-fold selective over both the 5-HT1B and 5-HT1D receptors, it exhibited appreciable 5-HT1A receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT1 receptor subtypes. The pyrrolo [3,2-b] pyridine analogue 3a showed high 5-HT1F receptor affinity but offered no improvement in selectivity compared to 1. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT1A, 5-HT1B, and 5-HT1D receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT1F receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.

  DOI：

  10.1021/jm030020m

文献信息

• Indazole compounds
  申请人：Ericsson M. Anna

  公开号：US20070282101A1

  公开（公告）日：2007-12-06

  Novel compounds of Formula (I) or pharmaceutically acceptable salts, prodrugs and biologically active metabolites thereof of Formula (I) wherein the substituents are as defined herein, which are useful as therapeutic agents.

  本发明提供了化合物(I)或其药学上可接受的盐、前药和生物活性代谢物，其中取代基如定义所述，这些化合物可用作治疗剂。
• Novel Potent 5-HT_1F Receptor Agonists:  Structure−Activity Studies of a Series of Substituted <i>N</i>-[3-(1-Methyl-4-piperidinyl)-1<i>H</i>-pyrrolo[3,2-<i>b</i>]pyridin-5-yl]amides
  作者：Sandra A. Filla、Brian M. Mathes、Kirk W. Johnson、Lee A. Phebus、Marlene L. Cohen、David L. Nelson、John M. Zgombick、Jon A. Erickson、Kathryn W. Schenck、David B. Wainscott、Theresa A. Branchek、John M. Schaus

  DOI：10.1021/jm030020m

  日期：2003.7.1

  Compound 1a (LY334370), a selective 5-HT1F receptor agonist (SSOFRA), inhibited dural inflammation in the neurogenic plasma protein extravasation model of migraine and demonstrated clinical efficacy for the acute treatment of migraine. Although 1 was greater than 100-fold selective over both the 5-HT1B and 5-HT1D receptors, it exhibited appreciable 5-HT1A receptor affinity. Described here is the synthesis and evaluation of a series of pyrrolo[2,3-c]pyridine and pyrrolo[3,2-b]pyridine (2a and 3a) as well as pyrrolo[3,2-d]pyrimidine (4a) analogues of 1, compounds prepared in an effort to identify SSOFRAs with improved selectivity over other 5-HT1 receptor subtypes. The pyrrolo [3,2-b] pyridine analogue 3a showed high 5-HT1F receptor affinity but offered no improvement in selectivity compared to 1. However, the C-5 acetamide derivative, 3b, was greater than 100-fold selective over the 5-HT1A, 5-HT1B, and 5-HT1D receptors. SAR studies of this series determined that alkylamides in particular exhibited high selectivity for the 5-HT1F receptor. Replacement at C-5 with other substituents decreased affinity or selectivity. These SAR studies identified SSOFRAs that demonstrated oral activity in the neurogenic plasma protein extravasation model, a model indicative of antimigraine activity.
• Discovery of 3-Cyano-<i>N</i>-(3-(1-isobutyrylpiperidin-4-yl)-1-methyl-4-(trifluoromethyl)-1<i>H</i>-pyrrolo[2,3-<i>b</i>]pyridin-5-yl)benzamide: A Potent, Selective, and Orally Bioavailable Retinoic Acid Receptor-Related Orphan Receptor C2 Inverse Agonist
  作者：Mark E. Schnute、Mattias Wennerstål、Jennifer Alley、Martin Bengtsson、James R. Blinn、Charles W. Bolten、Timothy Braden、Tomas Bonn、Bo Carlsson、Nicole Caspers、Ming Chen、Chulho Choi、Leon P. Collis、Kimberly Crouse、Mathias Färnegårdh、Kimberly F. Fennell、Susan Fish、Andrew C. Flick、Annika Goos-Nilsson、Hjalmar Gullberg、Peter K. Harris、Steven E. Heasley、Martin Hegen、Alexander E. Hromockyj、Xiao Hu、Bolette Husman、Tomasz Janosik、Peter Jones、Neelu Kaila、Elisabet Kallin、Björn Kauppi、James R. Kiefer、John Knafels、Konrad Koehler、Lars Kruger、Ravi G. Kurumbail、Robert E. Kyne、Wei Li、Joakim Löfstedt、Scott A. Long、Carol A. Menard、Scot Mente、Dean Messing、Marvin J. Meyers、Lee Napierata、Daniel Nöteberg、Philippe Nuhant、Matthew J. Pelc、Michael J. Prinsen、Patrik Rhönnstad、Eva Backström-Rydin、Johnny Sandberg、Maria Sandström、Falgun Shah、Maria Sjöberg、Aron Sundell、Alexandria P. Taylor、Atli Thorarensen、John I. Trujillo、John D. Trzupek、Ray Unwalla、Felix F. Vajdos、Robin A. Weinberg、David C. Wood、Li Xing、Edouard Zamaratski、Christoph W. Zapf、Yajuan Zhao、Anna Wilhelmsson、Gabriel Berstein

  DOI：10.1021/acs.jmedchem.8b00392

  日期：2018.12.13

  The nuclear hormone receptor retinoic acid receptor-related orphan C2 (RORC2, also known as RORγt) is a promising target for the treatment of autoimmune diseases. A small molecule, inverse agonist of the receptor is anticipated to reduce production of IL-17, a key proinflammatory cytokine. Through a high-throughput screening approach, we identified a molecule displaying promising binding affinity for

  核激素受体视黄酸受体相关的孤儿C2（RORC2，也称为RORγt）是治疗自身免疫性疾病的有希望的靶标。预期该受体的小分子反向激动剂会减少关键的促炎细胞因子IL-17的产生。通过高通量筛选方法，我们鉴定了一种分子，该分子显示出对RORC2的有希望的结合亲和力，抑制Th17细胞中IL-17的产生以及对相关RORA和RORB受体同工型的选择性。铅优化以提高这种命中的效力和代谢稳定性为重点，主要集中在两个关键设计策略上，即，通过提高亲脂性效率和结构指导的构象限制驱动的迭代优化，以实现最佳的基态能量学和最大化受体停留时间。N-（3-（1-异丁酰基哌啶-4-基）-1-甲基-4-（三氟甲基）-1 H-吡咯并[2,3 - b ]吡啶-5-基）苯甲酰胺为强效且选择性的RORC2逆激动剂，在临床前体内动物模型中，口服给药后表现出良好的代谢稳定性，口服生物利用度以及降低IL-17水平和皮肤炎症的能力。