3-Methyl-4-oxo-4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-butyric acid methyl ester | 144062-53-3

• 分子结构分类: 有机化合物 - 有机杂环化合物
• 英文名称: 3-Methyl-4-oxo-4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-butyric acid methyl ester
• 英文别名: methyl 4-(3,4-dihydro-2,2,4-trimethyl-3-oxo-1,4(2H)-benzoxazin-7-yl)-4-oxo-3-methylbutyrate；methyl 3-methyl-4-oxo-4-(2,2,4-trimethyl-3-oxo-1,4-benzoxazin-7-yl)butanoate
• CAS: 144062-53-3
• 化学式: C₁₇H₂₁NO₅
• 分子量: 319.357
• InChiKey: WWUJNFQUAJVYKS-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  23
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-Methyl-4-oxo-4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-butyric acid methyl ester 在 肼 作用下， 以 乙醇 为溶剂， 生成 6-(2,2,4-trimethyl-3,4-dihydro-3-oxo-1,4-benzoxazin-7-yl)-2,3,4,5-tetrahydro-5-methylpyridazin-3-one
  参考文献：
  名称：

  6-Benzoxazinylpyridazin-3-ones: potent, long-acting positive inotrope and peripheral vasodilator agents

  摘要：

  A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models. Additional benzoxazin-6-yl and -8-yl compounds were also prepared. Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED50) from 77 to 5.4 micrograms/kg while substitution at the 8-position reduced potency. Methyl substitution at various sites in the molecule was also examined. Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 micrograms/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described. Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.

  DOI：

  10.1021/jm00163a061
• 作为产物：
  描述：

  4-oxo-4-(2,2-dimethyl-3,4-dihydro-3-oxo-1,4-benzoxazin-7-yl)-3-methylbutyric acid 、 碘甲烷 在 sodium hydride 作用下， 生成 3-Methyl-4-oxo-4-(2,2,4-trimethyl-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-7-yl)-butyric acid methyl ester
  参考文献：
  名称：

  6-Benzoxazinylpyridazin-3-ones: potent, long-acting positive inotrope and peripheral vasodilator agents

  摘要：

  A series of 6-benzoxazinylpyridazin-3-ones was prepared and evaluated for inhibition of cardiac phosphodiesterase (PDE) fraction III in vitro and for positive inotropic activity in vivo. 6-[3,4-Dihydro-3-oxo-1,4(2H)-benzoxazin-7-yl]-2,3,4,5-tetrahydro-5 - methylpyridazin-3-one (bemoradan) was found to be an extremely potent and selective inhibitor of canine PDE fraction III and a long-acting, potent, orally active inotropic vasodilator agent in various canine models. Additional benzoxazin-6-yl and -8-yl compounds were also prepared. Altering the pyridazinone substitution from the 6-position to the 7-position produced a 14-fold increase in the iv cardiotonic potency (ED50) from 77 to 5.4 micrograms/kg while substitution at the 8-position reduced potency. Methyl substitution at various sites in the molecule was also examined. Positive inotropic activity was maintained for between 8 and 24 h after a single oral dose (100 micrograms/kg) of bemoradan in dogs, thus making it one of the most potent and long-acting orally effective inotropes yet described. Bemoradan is currently under development as a cardiotonic agent for use in the management of congestive heart failure.

  DOI：

  10.1021/jm00163a061

文献信息

• Process for the preparation of
  申请人：Ortho Pharmaceutical Corporation

  公开号：US05221742A1

  公开（公告）日：1993-06-22

  The invention relates to a process for the synthesis of compounds of the formula I ##STR1## wherein R.sub.1 -R.sub.5 are as defined herein. The process is a multistep process which comprises acylating a 2-benzoxazolinone with an alkanoic anhydride to form an acylated carbamate, hydrolyzing the carbamate, reacting the resultant aminophenol with haloalkanoyl halide to form a substituted benzoxazine, reacting the benzoxazine with an aldehyde, alkylating the resultant aminomethyl compound with an alkylating agent to form a quaternary ammonium salt, reacting the salt with an alkali metal cyanide to form a nitrile, hydrolyzing the nitrile and reacting the resultant carboxylic acid with hydrazine. The compounds are useful as cardiotonic and vasodilating agents and as inhibitors of phosphodiesterase fraction III and platelet aggregation. In addition, the compounds are active as smooth muscle relaxants and bronchodilators.

  本发明涉及一种合成式I的化合物的方法，其中R.sub.1-R.sub.5的定义如本文所述。该方法是一种多步骤的过程，包括用烷基酸酐酰化2-苯并噁唑酮形成酰化的氨基甲酸酯，水解氨基甲酸酯，将生成的氨基酚与卤代烷酰卤反应形成取代苯并噁嗪，将苯并噁嗪与醛反应，用烷基化剂烷基化生成的氨甲基化合物形成季铵盐，将盐与碱金属氰化物反应形成腈，水解腈并将生成的羧酸与肼反应。这些化合物可用作心脏强心和扩血管剂，以及磷酸二酯酶III分数和血小板聚集的抑制剂。此外，这些化合物还具有平滑肌松弛剂和支气管扩张剂的活性。
• US5221742A
  申请人：——

  公开号：US5221742A

  公开（公告）日：1993-06-22