3,5-dimethyl-4-<<3-<3-(methoxyethyl)-5-isoxazolyl>propyl>oxy>benzonitrile | 153168-57-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: 3,5-dimethyl-4-<<3-<3-(methoxyethyl)-5-isoxazolyl>propyl>oxy>benzonitrile
• 英文别名: 4-<<3-<3-(methoxyethyl)-5-isoxazolyl>propyl>oxy>-3,5-dimethylbenzonitrile；3,5-Dimethyl-4-{3-[3-(2-methoxyethyl)isoxazol-5-yl]propyloxy}benzonitrile；4-[3-[3-(2-methoxyethyl)-1,2-oxazol-5-yl]propoxy]-3,5-dimethylbenzonitrile
• CAS: 153168-57-1
• 化学式: C₁₈H₂₂N₂O₃
• 分子量: 314.384
• InChiKey: SNXXXOBMYCWFQX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.3
• 重原子数：
  23
• 可旋转键数：
  8
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  68.3
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3,5-dimethyl-4-<<3-<3-(methoxyethyl)-5-isoxazolyl>propyl>oxy>benzonitrile 在 盐酸羟胺 、 sodium methylate 作用下， 以 甲醇 为溶剂， 反应 2.5h， 生成 N-Hydroxy-4-{3-[3-(2-methoxy-ethyl)-isoxazol-5-yl]-propoxy}-3,5-dimethyl-benzamidine
  参考文献：
  名称：

  Picornavirus Inhibitors: Trifluoromethyl Substitution Provides a Global Protective Effect against Hepatic Metabolism

  摘要：

  Several modifications of the oxazoline ring of WIN 54954, a broad spectrum antipicornavirus compound, have been prepared in order to address the acid lability and metabolic instability of this compound. We have previously shown that the oxadiazole analogue 3 displayed comparable activity against a variety of rhinoviruses and appeared to be stable to acid. A monkey liver microsomal assay was developed to examine the metabolic stability in vitro of both compounds, and it was determined that WIN 54954 displayed 18 metabolic products while 3 was converted to 8 products. Two major products of 3 were determined by LC-MS/MS to be monohydroxylated at each of the terminal methyl groups. Replacement of the methyl on the isoxazole ring with a trifluoromethyl group, while preventing hydroxylation at this position, did not reduce the sensitivity of the molecule to microsomal metabolism at other sites. However, the (trifluoromethyl)oxadiazole 9 not only prevented hydroxylation at this position but also provided protection at the isoxazole end of the molecule, resulting in only two minor products to the extent of 4%. The major product was identified as the monohydroxylated compound 23. The global metabolic protective effect of trifluoromethyl group on the oxadiazole ring was further demonstrated by examining a variety of analogues including heterocyclic replacements of the isoxazole ring. In each case, the trifluoromethyl analogue displayed a protective effect when compared to the corresponding methyl analogue.

  DOI：

  10.1021/jm00008a014
• 作为产物：
  描述：

  5-氯戊炔 在 吡啶 、 N-氯代丁二酰亚胺 、 potassium carbonate 、 三乙胺 、 potassium iodide 作用下， 以 various solvent(s) 为溶剂， 反应 26.0h， 生成 3,5-dimethyl-4-<<3-<3-(methoxyethyl)-5-isoxazolyl>propyl>oxy>benzonitrile
  参考文献：
  名称：

  Oxadiazoles as Ester Bioisosteric Replacements in Compounds Related to Disoxaril. Antirhinovirus Activity

  摘要：

  A series of 1,2,4-oxadiazoles has been prepared as ester bioisosteres and tested against 15 human rhinovirus serotypes, and the MIC(80), the concentration which inhibits 80% or 12 of the serotypes tested, was determined. Homologation of the alkyl group attached to the oxadiazole ring resulted in a reduction in activity with increased chain length. Introduction of hydrophilic groups in this position rendered the compounds inactive. Increasing the length of the side chain attached to the isoxazole ring resulted in an increase in activity. Replacement of the methyl with alkoxyalkyl substituents retained activity; however, introduction of a hydroxyl group on to the side chain reduced activity. Compound 8a, where both the isoxazole and oxadiazole rings were substituted with methyl groups, was one of the most active compounds in the series. A comparison was made between 8a and the two isomeric oxadiazoles 41 and 46, and an attempt was made to explain the difference in activity by examining electrostatic potential maps and by an energy profiling study. No conclusive results were obtained from these studies.

  DOI：

  10.1021/jm00041a022

文献信息

• 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use a s antiviral agents
  申请人：STERLING WINTHROP INC.

  公开号：EP0566199A1

  公开（公告）日：1993-10-20

  Compounds of the formula wherein : R1 is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl or hydroxyalkoxy ; Y is alkylene of 3 to 9 carbon atoms, R2 and R3 independently are hydrogen, alkyl, alkoxy, halo, trifluoromethyl or nitro ; R4 is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl, cycloalkyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, 2,2,2-trifluoroethyl, (4-methylphenyl)sulfonyloxymethyl, N=Q or CON=Q, where N=Q is amino, alkylamino or dialkylamino; or pharmaceutically acceptable acid-addition salts thereof are useful as antiviral agents. Preferred compounds are those wherein Y is alkylene of 3 to 5 carbon atoms and especially when R2 and R3 are in the 2- and 6- positions of the phenyl ring.

  式中的化合物 其中： R1 是烷基、烷氧基、羟基、环烷基、羟基烷基、烷氧基烷基或羟基烷氧基； Y 是 3 至 9 个碳原子的亚烷基、 R2 和 R3 分别是氢、烷基、烷氧基、卤代、三氟甲基或硝基； R4 是烷氧基、羟基、卤代甲基、二卤代甲基、三卤代甲基、环烷基、烷氧基羰基、羟基烷基、烷氧基烷基、烷羰氧基烷基、氰基、2,2,2-三氟乙基、（4-甲基苯基）磺酰氧基甲基、N=Q 或 CON=Q，其中 N=Q 是氨基、烷基氨基或二烷基氨基；或其药学上可接受的酸加成盐可用作抗病毒剂。 优选的化合物是其中 Y 为 3 至 5 个碳原子的亚烷基，特别是当 R2 和 R3 位于苯基环的 2- 和 6- 位时。
• 1,2,4-Oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral agents
  申请人：SANOFI

  公开号：EP0566199B1

  公开（公告）日：2000-03-01
• US5349068A
  申请人：——

  公开号：US5349068A

  公开（公告）日：1994-09-20
• US5643929A
  申请人：——

  公开号：US5643929A

  公开（公告）日：1997-07-01
• Oxadiazoles as Ester Bioisosteric Replacements in Compounds Related to Disoxaril. Antirhinovirus Activity
  作者：Guy D. Diana、Deborah L. Volkots、Theodore J. Nitz、Thomas R. Bailey、Melody A. Long、Niranjan Vescio、Suzanne Aldous、Daniel C. Pevear、Frank J. Dutko

  DOI：10.1021/jm00041a022

  日期：1994.7

  A series of 1,2,4-oxadiazoles has been prepared as ester bioisosteres and tested against 15 human rhinovirus serotypes, and the MIC(80), the concentration which inhibits 80% or 12 of the serotypes tested, was determined. Homologation of the alkyl group attached to the oxadiazole ring resulted in a reduction in activity with increased chain length. Introduction of hydrophilic groups in this position rendered the compounds inactive. Increasing the length of the side chain attached to the isoxazole ring resulted in an increase in activity. Replacement of the methyl with alkoxyalkyl substituents retained activity; however, introduction of a hydroxyl group on to the side chain reduced activity. Compound 8a, where both the isoxazole and oxadiazole rings were substituted with methyl groups, was one of the most active compounds in the series. A comparison was made between 8a and the two isomeric oxadiazoles 41 and 46, and an attempt was made to explain the difference in activity by examining electrostatic potential maps and by an energy profiling study. No conclusive results were obtained from these studies.