2-[4-(benzyloxy)phenyl]-5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitrile | 147807-45-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 2-[4-(benzyloxy)phenyl]-5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitrile
• 英文别名: 3-[2-(4-Benzyloxy-phenyl)-5-oxo-5,6-dihydro-[1,3,4]oxadiazin-4-yl]-propionitrile；3-[5-oxo-2-(4-phenylmethoxyphenyl)-1,3,4-oxadiazin-4-yl]propanenitrile
• CAS: 147807-45-2
• 化学式: C₁₉H₁₇N₃O₃
• 分子量: 335.362
• InChiKey: UXBPSMVHPAHYEK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  74.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  2-[4-(benzyloxy)phenyl]-5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitrile 在 吡啶 、 tetraphosphorus decasulfide 作用下， 反应 2.0h， 以76%的产率得到3-[2-(4-Benzyloxy-phenyl)-5-thioxo-5,6-dihydro-[1,3,4]oxadiazin-4-yl]-propionitrile
  参考文献：
  名称：

  5-[4-(Benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives and related analogs: new reversible, highly potent, and selective monoamine oxidase type B inhibitors

  摘要：

  Thirty-three new 5-[4-(benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives including related analogues, designed as inhibitors of monoamine oxidase type B (MAO B), were synthesized and investigated both in vitro and ex vivo for their abilities to inhibit selectively rat brain MAO B over MAO A. Three inhibitors were found to act as reversible, highly potent, and selective MAO B inhibitors, namely the nitrile derivative 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (12a) and two closely related homologues, the corresponding oxadiazolethione 13a and the alcohol 14b. Their IC50(MAO B) values are in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated by the ratio of IC50 values (A/B), are from 3200 to >71 400. Compound 12a exhibited the highest activity against MAO B. Its IC50 was evaluated to be 1.4 nM with a quasitotal selectivity (>71 400) toward this enzyme. In ex vivo studies, 12a showed a reversible and short duration of action. MAO B was markedly inhibited with the oral dose of 1 mg/kg without any alteration of MAO A, and the inhibition almost did not exceed 24 h. Its ED50 (1 h after oral administration) was evaluated to be 0.56 mg (1.7 mumol)/kg. Remarkably, MAO A was not affected at doses as high as 1500 mg/kg, po. In addition, no apparent toxicity or behavioral anomaly was observed during the treatment even at the maximum administrated dose. SAR studies emphasize the existence of three binding sites to the enzyme with a special importance of the terminal phenyl. Analysis of the inhibition kinetics indicated that 12a acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO B with a K(i) value of 0.22 muM and an overall K(i)* value at equilibrium of 0.7 nM.

  DOI：

  10.1021/jm00061a006
• 作为产物：
  描述：

  4-苄氧基苯甲酸甲酯 在 一水合肼 作用下， 以 乙醇 、 氯仿 为溶剂， 反应 79.0h， 生成 2-[4-(benzyloxy)phenyl]-5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitrile
  参考文献：
  名称：

  Synthesis and Biological Screening of 2-Substituted 5,6-Dihydro-5-oxo- 4H-1,3,4-oxadiazine-4-propanenitriles and of Their Intermediates

  摘要：

  To evaluate the effect of substituents on biological activities of electron-rich N-containing heterocycles, the variably 2-substituted 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles 26-33 were synthesized and evaluated for antibacterial, antifungal, and enzyme-inhibition activities. The target compounds were obtained from alkyl 4- or 3-hydroxy benzoates 1 and 2, respectively, and from methyl indoleacetate 3. The phenolic OH group of benzoates I and 2 were substituted with p-toluenesulfonyl ( --> 4 and 5), benzoyl ( 6 and 7), and benzyl groups ( 8 and 9) and then converted to 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles. To establish structure-activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO-A inhibiting properties and intermediates 12,24,28, and 29 appreciable antifungal activities. Compound 7 inhibits a-chymotrypsin.

  DOI：

  10.1002/1522-2675(200202)85:2<559::aid-hlca559>3.0.co;2-a

文献信息

• 5-[4-(Benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives and related analogs: new reversible, highly potent, and selective monoamine oxidase type B inhibitors
  作者：Fathi Mazouz、Salah Gueddari、Claude Burstein、Daniel Mansuy、Rene Milcent

  DOI：10.1021/jm00061a006

  日期：1993.4

  Thirty-three new 5-[4-(benzyloxy)phenyl]-1,3,4-oxadiazol-2(3H)-one derivatives including related analogues, designed as inhibitors of monoamine oxidase type B (MAO B), were synthesized and investigated both in vitro and ex vivo for their abilities to inhibit selectively rat brain MAO B over MAO A. Three inhibitors were found to act as reversible, highly potent, and selective MAO B inhibitors, namely the nitrile derivative 5-[4-(benzyloxy)phenyl]-3-(2-cyanoethyl)-1,3,4-oxadiazol-2(3H)-one (12a) and two closely related homologues, the corresponding oxadiazolethione 13a and the alcohol 14b. Their IC50(MAO B) values are in the low nanomolar range of 1.4-4.6 nM and their selectivities, estimated by the ratio of IC50 values (A/B), are from 3200 to >71 400. Compound 12a exhibited the highest activity against MAO B. Its IC50 was evaluated to be 1.4 nM with a quasitotal selectivity (>71 400) toward this enzyme. In ex vivo studies, 12a showed a reversible and short duration of action. MAO B was markedly inhibited with the oral dose of 1 mg/kg without any alteration of MAO A, and the inhibition almost did not exceed 24 h. Its ED50 (1 h after oral administration) was evaluated to be 0.56 mg (1.7 mumol)/kg. Remarkably, MAO A was not affected at doses as high as 1500 mg/kg, po. In addition, no apparent toxicity or behavioral anomaly was observed during the treatment even at the maximum administrated dose. SAR studies emphasize the existence of three binding sites to the enzyme with a special importance of the terminal phenyl. Analysis of the inhibition kinetics indicated that 12a acts in a two-step mechanism as a competitive, slow, and tight-binding inhibitor of MAO B with a K(i) value of 0.22 muM and an overall K(i)* value at equilibrium of 0.7 nM.
• Synthesis and Biological Screening of 2-Substituted 5,6-Dihydro-5-oxo- 4H-1,3,4-oxadiazine-4-propanenitriles and of Their Intermediates
  作者：Khalid Mohammed Khan、Shagufta Rahat、Muhammad Iqbal Choudhary、Atta-ur-Rahman、Usman Ghani、Shahnaz Perveen、Shagufta Khatoon、Ahsana Dar、Abdul Malik

  DOI：10.1002/1522-2675(200202)85:2<559::aid-hlca559>3.0.co;2-a

  日期：2002.2

  To evaluate the effect of substituents on biological activities of electron-rich N-containing heterocycles, the variably 2-substituted 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles 26-33 were synthesized and evaluated for antibacterial, antifungal, and enzyme-inhibition activities. The target compounds were obtained from alkyl 4- or 3-hydroxy benzoates 1 and 2, respectively, and from methyl indoleacetate 3. The phenolic OH group of benzoates I and 2 were substituted with p-toluenesulfonyl ( --> 4 and 5), benzoyl ( 6 and 7), and benzyl groups ( 8 and 9) and then converted to 5,6-dihydro-5-oxo-4H-1,3,4-oxadiazine-4-propanenitriles. To establish structure-activity relationships (SAR), a pharmacological screening of the intervening intermediates was also conducted, which revealed that the intermediate hydrazide 11 possesses significant antimicrobial and MAO-A inhibiting properties and intermediates 12,24,28, and 29 appreciable antifungal activities. Compound 7 inhibits a-chymotrypsin.