1,2-dihydro-6,7-dimethoxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylic acid | 212489-07-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 1,2-dihydro-6,7-dimethoxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylic acid
• 英文别名: 3-carboxy-6,7-dimethoxy-4-(3,4,5-trimethoxyphenyl)-1(2H)-isoquinolinone；6,7-dimethoxy-1-oxo-4-(3,4,5-trimethoxyphenyl)-2H-isoquinoline-3-carboxylic acid
• CAS: 212489-07-1
• 化学式: C₂₁H₂₁NO₈
• 分子量: 415.4
• InChiKey: YOAZIUQDGUHVBR-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  30
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  113
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  甲醇 、 1,2-dihydro-6,7-dimethoxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylic acid 在 硫酸 作用下， 反应 8.0h， 以85%的产率得到6,7-Dimethoxy-1-oxo-4-(3,4,5-trimethoxy-phenyl)-1,2-dihydro-isoquinoline-3-carboxylic acid methyl ester
  参考文献：
  名称：

  Novel, Potent, and Selective Phosphodiesterase 5 Inhibitors:  Synthesis and Biological Activities of a Series of 4-Aryl-1-isoquinolinone Derivatives

  摘要：

  A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-iso-quinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)- 3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC50 = 1.0 nM) with high isozyme selectivities (IC50 ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC30 = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.

  DOI：

  10.1021/jm000558h
• 作为产物：
  描述：

  3,4-dimethoxy-6-(3,4,5-trimethoxybenzoyl)benzoic acid 在 盐酸 、 ammonium hydroxide 、 potassium carbonate 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 6.0h， 生成 1,2-dihydro-6,7-dimethoxy-2-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylic acid
  参考文献：
  名称：

  Novel, Potent, and Selective Phosphodiesterase 5 Inhibitors:  Synthesis and Biological Activities of a Series of 4-Aryl-1-isoquinolinone Derivatives

  摘要：

  A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-iso-quinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)- 3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC50 = 1.0 nM) with high isozyme selectivities (IC50 ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC30 = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.

  DOI：

  10.1021/jm000558h

文献信息

• Method of inhibiting neoplastic cells with isoquinoline derivatives
  申请人：Cell Pathways Inc

  公开号：US06486155B1

  公开（公告）日：2002-11-26

  A method for inhibiting neoplasia, particularly cancerous and precancerous lesions by exposing the affected cells to isoquinoline derivatives.

  通过将受影响的细胞暴露于异喹啉衍生物，抑制新生物形成的方法，特别是癌症和癌前病变。
• [EN] ISOQUINOLINONE DERIVATIVES, PROCESS FOR PREPARING THE SAME, AND THEIR USE AS PHOSPHODIESTERASE INHIBITORS<br/>[FR] DERIVES D'ISOQUINOLINONE, PROCEDE DE PREPARATION DESDITS DERIVES ET LEUR UTILISATION EN TANT QU'INHIBITEURS DE PHOSPHODIESTERASE
  申请人：TANABE SEIYAKU CO., LTD.

  公开号：WO1998038168A1

  公开（公告）日：1998-09-03

  (EN) An isoquinolinone derivative of formula (I) wherein Ring A and Ring B are substituted or unsubstituted benzene, R1 is (1) H, (2) substituted or unsubstituted lower alkyl, (3) substituted or unsubstituted cyclo-lower alkyl, (4) substituted or unsubstituted aryl, (5) substituted or unsubstituted heterocycle, or (6) amino optionally having one or two substitutents, R2 is -COOR3 or -CON(R4)(R5), R3 is H or ester residue, and -N(R4)(R5) is substituted or unsubstituted nitrogen-containing aliphatic heterocycle or substituted or unsubstituted amino, provided that when R1 is H or substituted or unsubstituted lower alkyl, then at least one of Ring A and Ring B is benzene being substituted by two or more lower alkoxy, or a pharmaceutically acceptable salt thereof, these compounds showing cGMP-specific PDE inhibitory activity, especially, selective phosphodiesterase V (PDEV) inhibitory activity, and hence, being useful for the prophylaxis or treatment of various diseases such as chronic heart failure, angina, pulmonary hypertension, erectile dysfunction, etc.(FR) Dérivés d'isoquinolinone de formule (I) dans laquelle le noyau A et le noyau B sont benzène substitué ou non substitué, R1 est (1) H, (2) alkyle inférieur substitué ou non substitué, (3) cycloalkyle inférieur substitué ou non substitué, (4) aryle substitué ou non substitué, (5) hétérocycle substitué ou non substitué ou (6) amino ayant éventuellement un ou deux substituants, R2 est -COOR3 ou -CON(R4)(R5), R3 est H ou un reste ester et -N(R4)(R5) est un hétérocycle aliphatique contenant azote substitué ou non substitué ou amino substitué ou non substitué, à condition que lorsque R1 est H ou alkyle inférieur substitué ou non substitué, au moins l'un des noyaux A et B soit benzène substitué par deux alcoxy inférieur ou plus, ou sel pharmaceutiquement acceptable desdits composés. Lesdits composés présentent une activité d'inhibition de la photodiestérase spécifique de cGMP, en particulier une activité sélective d'inhibition de la phosphodiestérase V, et sont donc utiles pour la prophylaxie ou le traitement de diverses maladies telles que l'insuffisance cardiaque chronique, l'angine de poitrine, l'hypertension pulmonaire, la dysérection, etc.

  (I)式中的异喹啉酮衍生物，其中环A和环B是取代或未取代的苯，R1为(1)H，(2)取代或未取代的低烷基，(3)取代或未取代的环低烷基，(4)取代或未取代的芳基，(5)取代或未取代的杂环，或(6)氨基，可选地具有一个或两个取代基，R2为-COOR3或-CON(R4)(R5)，R3为H或酯残基，而-N(R4)(R5)是取代或未取代的含氮脂肪杂环或取代或未取代的氨基，但当R1为H或取代或未取代的低烷基时，至少有一个环A和环B为取代了两个或更多的低烷氧基的苯，或其药学上可接受的盐。这些化合物显示出cGMP特异性PDE抑制活性，特别是选择性磷酸二酯酶V（PDEV）抑制活性，因此，它们对于预防或治疗各种疾病如慢性心力衰竭、心绞痛、肺动脉高压、勃起功能障碍等是有用的。
• US6486155B1
  申请人：——

  公开号：US6486155B1

  公开（公告）日：2002-11-26
• Novel, Potent, and Selective Phosphodiesterase 5 Inhibitors:  Synthesis and Biological Activities of a Series of 4-Aryl-1-isoquinolinone Derivatives
  作者：Tatsuzo Ukita、Yoshinori Nakamura、Akira Kubo、Yasuo Yamamoto、Yasunori Moritani、Kunio Saruta、Takanori Higashijima、Jun Kotera、Michino Takagi、Kohei Kikkawa、Kenji Omori

  DOI：10.1021/jm000558h

  日期：2001.6.1

  A novel class of potent and selective phosphodiesterase 5 (PDE5) inhibitors, 4-aryl-1-iso-quinolinone derivatives, which have been designed by the comparison of the structure of cGMP and a previously reported 1-arylnaphthalene lignan, was disclosed. Among these compounds, methyl 2-(4-aminophenyl)-1,2-dihydro-1-oxo-7-(2-pyridinylmethoxy)-4-(3,4,5-trimethoxyphenyl)- 3-isoquinoline carboxylate dihydrochloride (36a) exhibited potent PDE5 inhibitory activity (IC50 = 1.0 nM) with high isozyme selectivities (IC50 ratio: PDE1/PDE5 = 1300, PDE2/PDE5 > 10 000, PDE3/PDE5 > 10 000, PDE4/PDE5 = 4700, PDE6/PDE5 = 28). Compound 36a also showed the most potent relaxant effect on isolated rabbit corpus cavernosum (EC30 = 7.9 nM). Compound 63 (T-1032), the sulfate form of 36a, was selected for further biological and pharmacological evaluation of erectile dysfunction.