2-(3,5-dimethylphenyl)-4,5-dihydrooxazole | 686753-00-4

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 2-(3,5-dimethylphenyl)-4,5-dihydrooxazole
• 英文别名: 2-(3,5-Dimethylphenyl)-4,5-dihydro-1,3-oxazole；2-(3,5-dimethylphenyl)-4,5-dihydro-1,3-oxazole
• CAS: 686753-00-4
• 化学式: C₁₁H₁₃NO
• 分子量: 175.23
• InChiKey: VHIWYCUMPDFPOH-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  21.6
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2-(3,5-dimethylphenyl)-4,5-dihydrooxazole 在 盐酸 、 nickel(IV) oxide 、 硫酸 、 potassium nitrate 、 tin(ll) chloride 作用下， 以 四氢呋喃 、 苯 为溶剂， 反应 50.0h， 生成
  参考文献：
  名称：

  Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist

  摘要：

  Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (similar to100%) in rats, high potency (ETA IC50 = 0.08 nM), and optimal ETA/ETB selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

  DOI：

  10.1021/jm030528p
• 作为产物：
  描述：

  3,5-二甲基苯甲酸 在 吡啶 、 氯化亚砜 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 生成 2-(3,5-dimethylphenyl)-4,5-dihydrooxazole
  参考文献：
  名称：

  Discovery, Modeling, and Human Pharmacokinetics of N-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist

  摘要：

  Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (similar to100%) in rats, high potency (ETA IC50 = 0.08 nM), and optimal ETA/ETB selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).

  DOI：

  10.1021/jm030528p

文献信息

• Highly efficient synthesis of β-nitrate ester carboxamides through the ring-opening of 2-oxazolines
  作者：Kai Qiao、Xin Yuan、Li Wan、Ming-Wei Zheng、Dong Zhang、Bing-Bing Fan、Zhe-Chen Di、Zheng Fang、Kai Guo

  DOI：10.1039/c7gc02682j

  日期：——

  A novel method for the synthesis of β-nitrate ester carboxamides using non-corrosive tert-butyl nitrite (TBN) as the nitro source and easily available oxygen as the oxidant has been developed. Variously substituted 2-oxazolines were efficiently ring-opened to deliver the corresponding products in excellent yields. Notably, this reaction provides fast access to pharmaceuticals such as nicorandil.

  已经开发出一种新的合成方法，该方法使用非腐蚀性的亚硝酸叔丁酯（TBN）作为硝基源，并利用易获得的氧气作为氧化剂来合成β-硝酸酯羧酰胺。有效地开环了各种取代的2-恶唑啉，以优异的产率递送相应的产物。值得注意的是，该反应提供了对药物如尼可地尔的快速访问。
• An Efficient, Eco-Friendly, One-Pot Protocol for the Synthesis of 2-Oxazolines Promoted by Ionic Liquid/Indium Chloride
  作者：R. Kamakshi、Boreddy S. R. Reddy

  DOI：10.1071/ch06061

  日期：——

  2-Oxazolines have been synthesized using a solventless ionic liquid melt in good yields at ambient temperatures. The efficiency of various Lewis acid catalysts for the same reaction has been compared. The effectiveness of different alkyl chains in the ionic liquids for the synthesis of oxazolines has been studied and a butylmethylimidazolinium chloride/indium chloride melt has been found to be the best media for promoting the reaction.

  使用无溶剂离子液体熔体合成了 2-恶唑啉类化合物，并在常温下获得了良好的产率。比较了各种路易斯酸催化剂在相同反应中的效率。研究了离子液体中不同烷基链对合成噁唑啉的有效性，发现丁基甲基氯化咪唑啉鎓/氯化铟熔体是促进反应的最佳介质。
• Discovery, Modeling, and Human Pharmacokinetics of <i>N</i>-(2-Acetyl-4,6-dimethylphenyl)-3-(3,4-dimethylisoxazol-5-ylsulfamoyl)thiophene-2-carboxamide (TBC3711), a Second Generation, ET_A Selective, and Orally Bioavailable Endothelin Antagonist
  作者：Chengde Wu、E. Radford Decker、Natalie Blok、Huong Bui、Tony J. You、Junmei Wang、Andree R. Bourgoyne、Vippra Knowles、Kurt L. Berens、George W. Holland、Tommy A. Brock、Richard A. F. Dixon

  DOI：10.1021/jm030528p

  日期：2004.4.1

  Sitaxsentan (1) (Wu et al. J. Med. Chem. 1997, 40, 1690) is our first endothelin antagonist being evaluated in clinical trials. It has demonstrated biological effects in an acute hemodynamic study in CHF (Givertz et al. Circulation 2000, 101, 2922), an open-label 20-patient pulmonary hypertension trial (Barst et al. Chest 2002, 121, 1860-1868), and a 31-patient trial in essential hypertension (Calhoun et al. AHA Scientific Sessions 2000). In a phase 2b/3 pulmonary arterial hypertension trial, once a day treatment of 100 mg of sitaxsentan statistically significantly improved 6-min walk distance and NYHA class at 12 weeks (Barst et al. Am. J. Respir. Crit. Care Med. 2004, 169, 441). We have since reported on our efforts in generating follow-up compounds (Wu et al. J. Med. Chem. 1999, 42, 4485) and recently communicated that an ortho acyl group on the anilino ring enhanced oral absorption in this category of compounds (Wu et al. J. Med. Chem. 2001, 44, 1211). Here we report an expansion of this work by substituting a variety of electron-withdrawing groups at the ortho position and evaluating their effects on oral bioavailability as well as structure-activity relationships. As a result, TBC3711 (7z) was identified as our second endothelin antagonist to enter the clinic due to its good oral bioavailability (similar to100%) in rats, high potency (ETA IC50 = 0.08 nM), and optimal ETA/ETB selectivity (441 000-fold). Compound 7z has completed phase-I clinical development and was well tolerated with desirable pharmacokinetics in humans (t(1/2) = 6-7 h, oral availability > 80%).