1-(2-氨基-3,5-二甲基苯基)-2-氯乙酮 | 61871-83-8

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 1-(2-氨基-3,5-二甲基苯基)-2-氯乙酮
• 英文名称: 1-(2-amino-3,5-dimethylphenyl)-2-chloroethanone
• 英文别名: Ethanone, 1-(2-amino-3,5-dimethylphenyl)-2-chloro-
• CAS: 61871-83-8
• 化学式: C₁₀H₁₂ClNO
• 分子量: 197.664
• InChiKey: ZSGQNRUYHJMIBL-UHFFFAOYSA-N

物化性质

• 沸点：
  334.7±37.0 °C(Predicted)
• 密度：
  1.182±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.3
• 拓扑面积：
  43.1
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  1-(2-氨基-3,5-二甲基苯基)-2-氯乙酮 在 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 3-{[(4-chloro-3-methyl-5-isoxazolyl)amino]sulfonyl}-N-(2,4-dimethyl-6-[2-(methylsulfonyl)acetyl]-phenyl}-2-thiophenecarboxamide
  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：

  氯乙腈 、 2,4-二甲基苯胺 在 三氯化硼 、 盐酸 作用下， 以 1,2-二氯乙烷 、 甲醇 为溶剂， 生成 1-(2-氨基-3,5-二甲基苯基)-2-氯乙酮
  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

• [1,2]-Aryl migration in the synthesis of substituted indoles: scope, mechanism, and high throughput experimentation
  作者：Tao Pei、David M. Tellers、Eric C. Streckfuss、Cheng-yi Chen、Ian W. Davies

  DOI：10.1016/j.tet.2008.11.026

  日期：2009.4

  A mild regioselective synthesis of substituted indoles from readily accessible 1-(2-aminophenyl)-2-chloroethanones is described. Addition of a range of carbon nucleophiles to α-chloro acetophenones 1 generates 2-substituted indoles 2 in moderate to excellent yields. A reaction mechanism involving a [1,2]-aryl migration is proposed. This useful transformation is further examined using high throughput

  描述了从容易获得的1-（2-氨基苯基）-2-氯乙炔轻度区域选择性合成取代的吲哚的方法。在α-氯苯乙酮1中加入一定范围的碳亲核试剂，可以中等至极好的收率生成2-取代的吲哚2。提出了一种涉及[1,2]-芳基迁移的反应机理。使用高通量实验将进一步检查这种有用的转换。
• Sulfonamides and derivatives thereof that modulate the activity of endothelin
  申请人：Texas Biotechnology Corporation

  公开号：US20010056183A1

  公开（公告）日：2001-12-27

  Thienyl-, furyl-, pyrrolyl- and phenylsulfonamides, formulations of pharmaceutically-acceptable derivatives thereof and methods for modulating or altering the activity of the endothelin family of peptides are provided. In particular, N-(isoxazolyl)thienylsulfonamides, N-(isoxazolyl)furylsulfonamides, N-(isoxazolyl)pyrrolylsulfonamides and N-(isoxazolyl)phenylsulfonamides, formulations thereof and methods using these sulfonamides for inhibiting the binding of an endothelin peptide to an endothelin receptor by contacting the receptor with the sulfonamide are provided. Methods for treating endothelin-mediated disorders by administering effective amounts of one or more of these sulfonamides or pharmaceutically acceptable derivatives thereof that inhibit the activity of endothelin are also provided.

  提供了噻吩基、呋喃基、吡咯基和苯基磺酰胺，以及其药学上可接受的衍生物的配方和调节或改变内皮素家族肽活性的方法。具体而言，提供了N-(异噁唑基)噻吩基磺酰胺、N-(异噁唑基)呋喃基磺酰胺、N-(异噁唑基)吡咯基磺酰胺和N-(异噁唑基)苯基磺酰胺，以及这些磺酰胺的配方和使用这些磺酰胺通过与受体接触来抑制内皮素肽与内皮素受体的结合的方法。还提供了通过给予这些磺酰胺或药学上可接受的抑制内皮素活性的衍生物的有效量来治疗内皮素介导的疾病的方法。
• Expanding the [1,2]-Aryl Migration to the Synthesis of Substituted Indoles
  作者：Tao Pei、Cheng-yi Chen、Peter G. Dormer、Ian W. Davies

  DOI：10.1002/anie.200705804

  日期：2008.5.19
• SULFONAMIDES AND DERIVATIVES THEREOF THAT MODULATE THE ACTIVITY OF ENDOTHELIN
  申请人：ENCYSIVE PHARMACEUTICALS INC.

  公开号：EP1244657B1

  公开（公告）日：2004-12-29
• US6686382B2
  申请人：——

  公开号：US6686382B2

  公开（公告）日：2004-02-03