trans-3,4-dihydro-4-<(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy>-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: trans-3,4-dihydro-4-<(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy>-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile
• 英文别名: (3R,4S)-3-hydroxy-2,2-dimethyl-4-(1-methyl-6-oxopyridazin-3-yl)oxy-3,4-dihydrochromene-6-carbonitrile
• 化学式: C₁₇H₁₇N₃O₄
• 分子量: 327.34
• InChiKey: RIBYSHCVSQIIJE-JKSUJKDBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  24
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  95.2
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  trans-3,4-dihydro-4-<(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy>-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 在 4-二甲氨基吡啶 、 sodium hydroxide 作用下， 以 四氢呋喃 、 吡啶 为溶剂， 反应 4.25h， 生成 Symakalim
  参考文献：
  名称：

  4-Heterocyclyloxy-2H-1-benzopyran potassium channel activators

  摘要：

  The reaction of 2,4-dihydroxypyridine (2) with 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1) yielded the 4-[(1,2-dihydro-2-oxo-4-pyridyl)oxy] compound 3a, accompanied by small amounts of the isomeric 4-(1,2-dihydro-4-hydroxy-2-oxo-1-pyridyl) compound 4. This could also be prepared by hydrogenation of the benzyloxy derivative 5. Reaction of 3,6-pyridazinediol (10) with 1 (R = CN) gave the 4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy] compound 11a, which in turn rearranged on heating with NaH in DMSO into the 4-(1,6-dihydro-3-hydroxy-6-oxo-1-pyridazinyl) compound 12. A series of 6-substituted analogues (R = CO2Me, CSNH2, NO2, Br) of 3a and 11a were synthesized. N-Alkylation led to compounds 14a-c (R = Me, Et, CHMe2). The 4-heterocyclyloxychromenes 9 and 16a were obtained by alkaline hydrolysis of their 3-camphorsulfonates. The racemic pyridazinyloxy compounds 11a and 14a could be resolved via their diastereomeric camphorsulfonates or camphanates. The differences between the 4-heterocyclyloxychromanols and the isomeric N-substituted compounds 4 and 12 were elucidated in the course of extensive NMR investigations. While in DMSO the former appeared to be conformationally flexible molecules the latter were rigid. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats, using doses of 1 mg/kg. High and long lasting activities were found for the pyridyloxy compounds 3a and 3d, the pyridazinyloxy compound 11a, and its N-alkylation products, as well as for the 3S,4R-enantiomers 20a and 22a. (-)-(3S,4R)-3,4-Dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)oxy]-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (22a) was selected for further development.

  DOI：

  10.1021/jm00172a013
• 作为产物：
  描述：

  3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile 在 吡啶 作用下， 以 乙醇 、 丙酮 为溶剂， 反应 7.0h， 生成 trans-3,4-dihydro-4-<(1,6-dihydro-1-methyl-6-oxo-3-pyridazinyl)oxy>-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile
  参考文献：
  名称：

  4-Heterocyclyloxy-2H-1-benzopyran potassium channel activators

  摘要：

  The reaction of 2,4-dihydroxypyridine (2) with 3,4-epoxy-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (1) yielded the 4-[(1,2-dihydro-2-oxo-4-pyridyl)oxy] compound 3a, accompanied by small amounts of the isomeric 4-(1,2-dihydro-4-hydroxy-2-oxo-1-pyridyl) compound 4. This could also be prepared by hydrogenation of the benzyloxy derivative 5. Reaction of 3,6-pyridazinediol (10) with 1 (R = CN) gave the 4-[(1,6-dihydro-6-oxo-3-pyridazinyl)oxy] compound 11a, which in turn rearranged on heating with NaH in DMSO into the 4-(1,6-dihydro-3-hydroxy-6-oxo-1-pyridazinyl) compound 12. A series of 6-substituted analogues (R = CO2Me, CSNH2, NO2, Br) of 3a and 11a were synthesized. N-Alkylation led to compounds 14a-c (R = Me, Et, CHMe2). The 4-heterocyclyloxychromenes 9 and 16a were obtained by alkaline hydrolysis of their 3-camphorsulfonates. The racemic pyridazinyloxy compounds 11a and 14a could be resolved via their diastereomeric camphorsulfonates or camphanates. The differences between the 4-heterocyclyloxychromanols and the isomeric N-substituted compounds 4 and 12 were elucidated in the course of extensive NMR investigations. While in DMSO the former appeared to be conformationally flexible molecules the latter were rigid. All compounds were tested for oral antihypertensive activity in spontaneously hypertensive rats, using doses of 1 mg/kg. High and long lasting activities were found for the pyridyloxy compounds 3a and 3d, the pyridazinyloxy compound 11a, and its N-alkylation products, as well as for the 3S,4R-enantiomers 20a and 22a. (-)-(3S,4R)-3,4-Dihydro-4-[(1,6-dihydro-1-methyl-6-oxo-3- pyridazinyl)oxy]-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (22a) was selected for further development.

  DOI：

  10.1021/jm00172a013

文献信息

• Chromanderivate
  申请人：MERCK PATENT GmbH

  公开号：EP0363883A1

  公开（公告）日：1990-04-18

  Die Erfindung betrifft neue Chromanderivate der Formel I worin R¹, R², R³, R⁴ R⁵ R⁶ R⁷ R⁸ und Z die in Patentanspruch 1 angegebene Bedeutungen haben, sowie ihre Salze zeigen Wirkungen auf das cardiovaskuläre System und können verwendet werden zur Behandlung bzw. Prophylaxe von Herzinsuffizienz, Angina pectoris, Blut­hochdruck, Inkontinenz und Alopezie.

  本发明涉及式 I 的新色烷衍生物 其中 R¹、R²、R³、R⁴ R⁵ R⁶ R⁷ R⁸ 和 Z 具有权利要求 1 中给出的含义、 以及它们的盐类对心血管系统有作用，可用于治疗或预防心力衰竭、心绞痛、高血压、尿失禁和脱发。
• BERGMANN, ROLF;EIERMANN, VOLKER;GERICKE, ROLF, J. MED. CHEM., 33,(1990) N0, C. 2759-2767
  作者：BERGMANN, ROLF、EIERMANN, VOLKER、GERICKE, ROLF

  DOI：——

  日期：——
• US5387587A
  申请人：——

  公开号：US5387587A

  公开（公告）日：1995-02-07
• US6040308A
  申请人：——

  公开号：US6040308A

  公开（公告）日：2000-03-21
• US6153627A
  申请人：——

  公开号：US6153627A

  公开（公告）日：2000-11-28