methyl 7-benzyloxy-2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate | 212492-68-7

• 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: methyl 7-benzyloxy-2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate
• 英文别名: Methyl 2-[4-[(2-methylpropan-2-yl)oxycarbonylamino]phenyl]-1-oxo-7-phenylmethoxy-4-(3,4,5-trimethoxyphenyl)isoquinoline-3-carboxylate
• CAS: 212492-68-7
• 化学式: C₃₈H₃₈N₂O₉
• 分子量: 666.728
• InChiKey: KIFXSVPWTQJGHI-UHFFFAOYSA-N

物化性质

• 熔点：
  148-149 °C
• 沸点：
  770.9±60.0 °C(Predicted)
• 密度：
  1.270±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  49
• 可旋转键数：
  13
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  122
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  methyl 7-benzyloxy-2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate 在 10percent Pd/C 氢气 、 potassium carbonate 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 生成 methyl 2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-7-(3-pyridylmethoxy)-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate
  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：

  N,N-dimethyl(3,4,5-trimethoxyphenyl)carboxamide 在 盐酸 、 sodium hydroxide 、 sodium chlorite 、 正丁基锂 、 acetate buffer 、 potassium carbonate 、 N,N-二异丙基乙胺 、 间苯二酚 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 甲醇 、 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 17.25h， 生成 methyl 7-benzyloxy-2-[(4-tert-butoxycarbonylamino)phenyl]-1,2-dihydro-1-oxo-4-(3,4,5-trimethoxyphenyl)-3-isoquinolinecarboxylate
  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

• Characterization of T-5 <i>N</i>-Oxide Formation as the First Highly Selective Measure of CYP3A5 Activity
  作者：Xiaohai Li、Valer Jeso、Scott Heyward、Gregory S. Walker、Raman Sharma、Glenn C. Micalizio、Michael D. Cameron

  DOI：10.1124/dmd.113.054726

  日期：2014.3

  Almost half of prescription medications are metabolized by cytochrome P450 3A4 and 3A5. CYP3A4 and 3A5 have significant substrate overlap, and there is currently no way to selectively monitor the activity of these two enzymes, which has led to the erroneous habit of attributing the cumulative activity to CYP3A4. While CYP3A4 expression is ubiquitous, CYP3A5 expression is polymorphic, with large individual differences in CYP3A5 expression level. The CYP3A5 genotype has been shown to alter the pharmacokinetics of drugs in clinical trials. We report the first tool compound capable of determining CYP3A5 activity in biologic samples containing both enzymes. Oxidation of T-5 by CYP3A5 yields an N -oxide metabolite that is over 100-fold selective over CYP3A4. Formation of T-5 N -oxide highly correlates with the CYP3A5 genotype and CYP3A5 expression levels in human liver microsomes and human hepatocytes.

  几乎一半的处方药都是通过细胞色素 P450 3A4 和 3A5 代谢的。CYP3A4 和 3A5 的底物有很大的重叠，目前还没有办法选择性地监测这两种酶的活性，这导致了将累积活性归因于 CYP3A4 的错误习惯。CYP3A4 的表达无处不在，而 CYP3A5 的表达则是多态的，CYP3A5 表达水平的个体差异很大。临床试验表明，CYP3A5 基因型会改变药物的药代动力学。我们报告了第一种能够测定含有两种酶的生物样本中 CYP3A5 活性的工具化合物。CYP3A5 氧化 T-5 会产生一种 N -氧化物代谢物，其选择性是 CYP3A4 的 100 倍以上。T-5 N -氧化物的形成与人肝微粒体和人肝细胞中的 CYP3A5 基因型和 CYP3A5 表达水平高度相关。
• 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.