4-Methyl-2-methylsulfanyl-15-nitro-5-oxo-8,9,10,11-tetrahydro-5H,7H,16bH-6-oxa-12-thia-1,3-diaza-dibenzo[a,c]cyclododecene-1-carboxylic acid tert-butyl ester | 145457-81-4

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 4-Methyl-2-methylsulfanyl-15-nitro-5-oxo-8,9,10,11-tetrahydro-5H,7H,16bH-6-oxa-12-thia-1,3-diaza-dibenzo[a,c]cyclododecene-1-carboxylic acid tert-butyl ester
• 英文别名: Tert-butyl 6-methyl-4-methylsulfanyl-19-nitro-8-oxo-9-oxa-15-thia-3,5-diazatricyclo[14.4.0.02,7]icosa-1(16),4,6,17,19-pentaene-3-carboxylate
• CAS: 145457-81-4
• 化学式: C₂₃H₂₉N₃O₆S₂
• 分子量: 507.632
• InChiKey: UATIWSLVDVZWAA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.7
• 重原子数：
  34
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  165
• 氢给体数：
  0
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  4-Methyl-2-methylsulfanyl-15-nitro-5-oxo-8,9,10,11-tetrahydro-5H,7H,16bH-6-oxa-12-thia-1,3-diaza-dibenzo[a,c]cyclododecene-1-carboxylic acid tert-butyl ester 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 生成 4-Methyl-2-methylsulfanyl-15-nitro-3,8,9,10,11,16b-hexahydro-7H-6-oxa-12-thia-1,3-diaza-dibenzo[a,c]cyclododecen-5-one
  参考文献：
  名称：

  Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators

  摘要：

  Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect on channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.

  DOI：

  10.1021/jm00001a017
• 作为产物：
  描述：

  2-(5-Nitro-2-(5-tert-butyldimethylsilyloxy)-pentylthiophenylmethylene)-3-oxobutanoic acid, 2-(trimethylsilyl)ethyl ester 在 4-二甲氨基吡啶 、 四丁基氟化铵 、 2-氯-1-甲基吡啶碘化物 、 sodium acetate 、 三乙胺 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 8.5h， 生成 4-Methyl-2-methylsulfanyl-15-nitro-5-oxo-8,9,10,11-tetrahydro-5H,7H,16bH-6-oxa-12-thia-1,3-diaza-dibenzo[a,c]cyclododecene-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators

  摘要：

  Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect on channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.

  DOI：

  10.1021/jm00001a017

文献信息

• Calcium Entry Blockers and Activators: Conformational and Structural Determinants of Dihydropyrimidine Calcium Channel Modulators
  作者：George C. Rovnyak、S. David Kimball、Barbara Beyer、Gabriella Cucinotta、John D. DiMarco、Jack Gougoutas、Anders Hedberg、Mary Malley、James P. McCarthy

  DOI：10.1021/jm00001a017

  日期：1995.1

  Dihydropyrimidines 4, 6, and 15, uniquely designed to unambiguously establish structural and conformational determinants for DHP receptor occupation and for modulation of calcium channel function, were prepared and examined for calcium channel modulation. Our results confirm and firmly establish a preference for syn-orientation of an unsymmetrically substituted aryl moiety at the DHP receptor (15d vs 15e). We propose a normal vs capsized DHP boat model to explain structural and conformational requirements for modulation of calcium channel function that requires an obligatory left-hand side alkoxy cis-carbonyl interaction for maximal DHP receptor affinity, the effect on channel function being determined by orientation of the 4-aryl group. Enantiomers having an up-oriented pseudoaxial aryl group (normal DHP boat) will elicit calcium antagonist activity, whereas enantiomers having a down-oriented pseudoaxial aryl group (capsized DHP boat) will elicit calcium agonist activity. Single enantiomers of macrocyclic lactone 15b demonstrate opposite channel activity. Antagonist activity resides in enantiomer 15b-A (S-configuration, left-hand side alkoxy cis-carbonyl with up-oriented pseudoaxial aryl group and normal DHP boat), whereas agonist activity resides in enantiomer 15b-B (R-configuration, left-hand side alkoxy cis-carbonyl with down-oriented pseudoaxial aryl group and capsized DHP boat). Moreover, this model is consistent with and provides a rational explanation of previous literature in this area, most notably the observation of chiral inversion and potency diminution upon replacement of ester by hydrogen in the Bay K 8644 series.