8-methyl-3-[(1S)-1-pyrrolidin-1-ylethyl]quinolin-7-amine | 1373823-09-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 8-methyl-3-[(1S)-1-pyrrolidin-1-ylethyl]quinolin-7-amine
• CAS: 1373823-09-6
• 化学式: C₁₆H₂₁N₃
• 分子量: 255.363
• InChiKey: MWFTVKZFTCSJBF-LBPRGKRZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  42.2
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-溴苯甲酰氯 、 8-methyl-3-[(1S)-1-pyrrolidin-1-ylethyl]quinolin-7-amine 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 16.0h， 以81%的产率得到3-bromo-N-[8-methyl-3-(1-pyrrolidin-1-ylethyl)quinolin-7-yl]benzamide
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities

  摘要：

  Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.

  DOI：

  10.1021/jm300167z
• 作为产物：
  描述：

  7-氨基-8-甲基喹啉-3-甲醛 在 盐酸 、 氯化亚砜 、 potassium carbonate 、 三乙胺 、 potassium iodide 作用下， 以 四氢呋喃 、 乙醇 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 54.0h， 生成 8-methyl-3-[(1S)-1-pyrrolidin-1-ylethyl]quinolin-7-amine
  参考文献：
  名称：

  Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities

  摘要：

  Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-{3-[(1R)-1-{[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.

  DOI：

  10.1021/jm300167z

文献信息

• Synthesis, Structure–Activity Relationship, and Pharmacological Studies of Novel Melanin-Concentrating Hormone Receptor 1 Antagonists 3-Aminomethylquinolines: Reducing Human Ether-a-go-go-Related Gene (hERG) Associated Liabilities
  作者：Shizuo Kasai、Makoto Kamata、Shinichi Masada、Jun Kunitomo、Masahiro Kamaura、Tomohiro Okawa、Kazuaki Takami、Hitomi Ogino、Yoshihide Nakano、Shuntarou Ashina、Kaoru Watanabe、Tomoko Kaisho、Yumi N. Imai、Sunghi Ryu、Masaharu Nakayama、Yasutaka Nagisa、Shiro Takekawa、Koki Kato、Toshiki Murata、Nobuhiro Suzuki、Yuji Ishihara

  DOI：10.1021/jm300167z

  日期：2012.5.10

  Recently, we discovered 3-aminomethylquinoline derivative 1, a selective, highly potent, centrally acting, and orally bioavailable human MCH receptor 1 (hMCHR1) antagonist, that inhibited food intake in F344 rats with diet-induced obesity (DIO). Subsequent investigation of 1 was discontinued because 1 showed potent hERG K+ channel inhibition in a patch-clamp study. To decrease hERG K+ channel inhibition, experiments with ligand-based drug designs based on 1 and a docking study were conducted. Replacement of the terminal p-fluorophenyl group with a cyclopropylmethoxy group, methyl group introduction on the benzylic carbon at the 3-position of the quinoline core, and employment of a [2-(acetylamino)ethyl]amino group as the amine portion eliminated hERG K+ channel inhibitory activity in a patch-clamp study, leading to the discovery of N-3-[(1R)-1-[2-(acetylamino)ethyl]amino}ethyl]-8-methylquinolin-7-yl}-4-(cyclopropylmethoxy)benzamide (R)-10h. The compound (R)-10h showed potent inhibitory activity against hMCHR1 and dose-dependently suppressed food intake in a 2-day study on DIO-F344 rats. Furthermore, practical chiral synthesis of (R)-10h was performed to determine the molecule's absolute configuration.