N'-hydroxy-3,5-dimethyl-4-(pent-4-yn-1-yloxy)benzimidamide | 153168-52-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: N'-hydroxy-3,5-dimethyl-4-(pent-4-yn-1-yloxy)benzimidamide
• 英文别名: N'-hydroxy-3,5-dimethyl-4-pent-4-ynoxybenzenecarboximidamide
• CAS: 153168-52-6
• 化学式: C₁₄H₁₈N₂O₂
• 分子量: 246.309
• InChiKey: TYTSXHXBMJXBAJ-UHFFFAOYSA-N

物化性质

• 沸点：
  399.2±52.0 °C(predicted)
• 密度：
  1.06±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  67.8
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  N'-hydroxy-3,5-dimethyl-4-(pent-4-yn-1-yloxy)benzimidamide 在 吡啶 、 三乙胺 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 ethyl 5-(3-{2,6-dimethyl-4-[5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl]phenoxy}propyl)isoxazole-3-carboxylate
  参考文献：
  名称：

  新型pleconaril衍生物：异恶唑和苯环中的取代基对肠病毒的抗病毒活性的影响。

  摘要：

  如今，没有药物可治疗肠病毒和鼻病毒感染。在本研究中，合成了一系列在异恶唑和苯环上具有取代基的新型pleconaril衍生物，并评估了它们对一组pleconaril敏感和耐药肠病毒的抗病毒活性。结构活性关系的研究表明，异恶唑环中的N，N-二甲基氨基甲酰基对抗pleconaril的病毒具有抗病毒活性。另外，苯环中的一个或两个取代基直接影响抗肠病毒活性的光谱。3-（3-甲基-4-（3-（3-N，N-二甲基氨基甲酰基-异恶唑-5-基）丙氧基）苯基）-5-三氟甲基-1,2，10克4-恶二唑是表现出最强抗pleconaril耐药性和pleconaril易感性肠病毒活性的化合物，在该系列中IC50值为0.02至5.25μM。化合物10g的CYP3A4诱导作用比普乐那利明显少，是非诱变的，在小鼠胃内给药后可被生物利用。这些结果突出了化合物10g作为广谱肠病毒和鼻病毒抑制剂有希望的潜在候选物，用于进一步的临床前研究。

  DOI：

  10.1016/j.ejmech.2019.112007
• 作为产物：
  描述：

  4-溴-2,6-二甲基苯酚 在 盐酸羟胺 、 potassium carbonate 、 potassium iodide 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 36.0h， 生成 N'-hydroxy-3,5-dimethyl-4-(pent-4-yn-1-yloxy)benzimidamide
  参考文献：
  名称：

  新型pleconaril衍生物：异恶唑和苯环中的取代基对肠病毒的抗病毒活性的影响。

  摘要：

  如今，没有药物可治疗肠病毒和鼻病毒感染。在本研究中，合成了一系列在异恶唑和苯环上具有取代基的新型pleconaril衍生物，并评估了它们对一组pleconaril敏感和耐药肠病毒的抗病毒活性。结构活性关系的研究表明，异恶唑环中的N，N-二甲基氨基甲酰基对抗pleconaril的病毒具有抗病毒活性。另外，苯环中的一个或两个取代基直接影响抗肠病毒活性的光谱。3-（3-甲基-4-（3-（3-N，N-二甲基氨基甲酰基-异恶唑-5-基）丙氧基）苯基）-5-三氟甲基-1,2，10克4-恶二唑是表现出最强抗pleconaril耐药性和pleconaril易感性肠病毒活性的化合物，在该系列中IC50值为0.02至5.25μM。化合物10g的CYP3A4诱导作用比普乐那利明显少，是非诱变的，在小鼠胃内给药后可被生物利用。这些结果突出了化合物10g作为广谱肠病毒和鼻病毒抑制剂有希望的潜在候选物，用于进一步的临床前研究。

  DOI：

  10.1016/j.ejmech.2019.112007

文献信息

• 1,2,4-oxadiazolyl-phenoxyalkylisoxazoles and their use as antiviral
  申请人：Sterling Winthrop Inc.

  公开号：US05464848A1

  公开（公告）日：1995-11-07

  Compounds of the formula ##STR1## wherein: R.sub.1 is alkyl, alkoxy, hydroxy, cycloalkyl, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkylthioalkyl, alkylsulfinylalkyl, alkylsulfonylalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxycarbonyl, carboxy, or cyanomethyl; Y is alkylene of 3 to 9 carbon atoms, R.sub.2 and R.sub.3 independently are hydrogen, alkyl, alkoxy, halo, cyano, trifluoromethyl and nitro; R.sub.4 is alkoxy, hydroxy, halomethyl, dihalomethyl, trihalomethyl, dihaloethyl, cycloalkyl, heterocyclyl, alkoxycarbonyl, hydroxyalkyl, alkoxyalkyl, alkanecarbonyloxyalkyl, cyano, halo, thioalkyl, alkylthioalkyl, alkylthio, thio, 2,2,2-trifluoro-ethyl, (4-methylphenyl)sulfonyloxymethyl, N.dbd.Q or CON.dbd.Q, where N.dbd.Q is amino, alkylamino or dialkylamino; R.sub.5 is hydrogen or halo or alkyl.

  公式为##STR1##的化合物，其中：R.sub.1为烷基，烷氧基，羟基，环烷基，羟基烷基，烷氧基烷基，羟基烷氧基，烷基硫代烷基，烷基亚砜基烷基，烷基磺酰基烷基，氨基烷基，烷基氨基烷基，二烷基氨基烷基，烷氧羰基，羧基或氰甲基；Y为碳原子数为3至9的烷基，R.sub.2和R.sub.3独立地为氢，烷基，烷氧基，卤素，氰基，三氟甲基和硝基；R.sub.4为烷氧基，羟基，卤甲基，二卤甲基，三卤甲基，二卤乙基，环烷基，杂环烷基，烷氧羰基，羟基烷基，烷氧基烷基，烷基羧酸酯氧基烷基，氰基，卤素，硫代烷基，烷基硫代烷基，烷基硫，硫，2,2,2-三氟乙基，(4-甲基苯基)磺酰氧甲基，N.dbd.Q或CON.dbd.Q，其中N.dbd.Q为氨基，烷基氨基或二烷基氨基；R.sub.5为氢或卤素或烷基。
• Polymorphic and solvate structures of ethyl ester and carboxylic acid derivatives of WIN 61893 analogue and their stability in solution
  作者：Kirsi Salorinne、Tanja Lahtinen、Varpu Marjomäki、Hannu Häkkinen

  DOI：10.1039/c4ce01152j

  日期：——

  ester- (1) and 3-carboxylic acid-isoxazole (2) derivatives of an antiviral drug analogue WIN 61893 were synthesized and characterized by X-ray crystallography and NMR spectroscopy. Crystallization experiments afforded two polymorphic structures for the ethyl ester derivative and two solvate structures for the carboxylic acid derivative based on their ability to form intermolecular hydrogen bonding interactions

  3-乙基酯-（1）和3-羧酸-异恶唑（2合成了抗病毒药物类似物WIN 61893的衍生物，并通过X射线晶体学和NMR光谱进行了表征。结晶实验基于它们与溶剂分子形成分子间氢键相互作用的能力，为乙酯衍生物提供了两个多晶型结构，为羧酸衍生物提供了两个溶剂化结构。衍生物的构型在很大程度上取决于平面异恶唑和苯基-恶二唑环体系相对于彼此的取向，并且发现它们具有垂直，线性或倾斜的构型。此外，还观察到羧酸衍生物在DMSO溶液中通过脱羧反应发生异恶唑环裂解，并在几天内转化为β-酮腈开环产物。
• 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。
• 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.
• Picornavirus Inhibitors: Trifluoromethyl Substitution Provides a Global Protective Effect against Hepatic Metabolism
  作者：Guy D. Diana、Patrick Rudewicz、Daniel C. Pevear、Theodore J. Nitz、Suzanne C. Aldous、David J. Aldous、David T. Robinson、Tandy Draper、Frank J. Dutko、Christopher Aldi、Guy Gendron、R. Christopher Oglesby、Deborah L. Volkots、Michael Reuman、Thomas R. Bailey、Richard Czerniak、Tracey Block、Robert Roland、James Oppermann

  DOI：10.1021/jm00008a014

  日期：1995.4.1

  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.