2-氨基-3,5-二甲基苯甲腈 | 146351-93-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 中文名称: 2-氨基-3,5-二甲基苯甲腈
• 中文别名: 2-氨基-3,5-二甲基苯腈
• 英文名称: 2-amino-3,5-dimethylbenzonitrile
• 英文别名: 2-Cyano-4,6-dimethylaniline
• CAS: 146351-93-1
• 化学式: C₉H₁₀N₂
• 分子量: 146.192
• InChiKey: VCWAINGMZPOJFI-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  11
• 可旋转键数：
  0
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.22
• 拓扑面积：
  49.8
• 氢给体数：
  1
• 氢受体数：
  2

安全信息

• 安全说明：
  S26
• 危险类别码：
  R20/21/22,R36/37/38
• 危险品运输编号：
  UN 3439

反应信息

• 作为反应物：
  描述：

  2-氨基-3,5-二甲基苯甲腈 在 盐酸 作用下， 以 四氢呋喃 、 甲醇 为溶剂， 反应 2.0h， 生成 N-(4-chloro-3-methyl-5-isoxazolyl)-2-(2-carbamoyl-4,6-dimethylphenylaminocarbonyl)thiophene-3-sulfonamide
  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：

  2,4-二甲基苯胺 、 alkaline earth salt of/the/ methylsulfuric acid 在 N-溴代丁二酰亚胺(NBS) 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 11.0h， 生成 2-氨基-3,5-二甲基苯甲腈
  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

• N-heteroaryl aryl-substituted thienyl-furyl-and pyrrolyl-sulfonamides and derviatives thereof that modulate the activity of endothelin
  申请人：Texas Biotechnology Corporation

  公开号：US06420567B1

  公开（公告）日：2002-07-16

  Thienyl-, furyl- and pyrrolyl-sulfonamides, formulations of pharmaceutically-acceptable salts 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 and N-(isoxazolyl)pyrrolylsulfonamides, 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 prodrugs thereof that inhibit the activity of endothelin are also provided.

  噻吩基、呋喃基和吡咯基磺酰胺，以及它们的药物可接受盐的配方，以及调节或改变内皮素肽家族活性的方法。特别是，提供N-(异恶唑基)噻吩磺酰胺、N-(异恶唑基)呋喃磺酰胺和N-(异恶唑基)吡咯磺酰胺，它们的配方以及使用这些磺酰胺通过将受体与磺酰胺接触来抑制内皮素肽与内皮素受体结合的方法。还提供了通过给予有效量的一个或多个这些磺酰胺或抑制内皮素活性的前药来治疗内皮素介导的疾病的方法。
• Metal-free synthesis of 2-difluoromethylated quinolines via DBU-promoted cascade michael addition / cyclization of methyl 4,4-difluorobut-2-ynoate with 2-aminobenzonitriles
  作者：Zhenhua Fan、Shanxue Yang、Xin Peng、Cheng Zhang、Jing Han、Jie Chen、Hongmei Deng、Min Shao、Hui Zhang、Weiguo Cao

  DOI：10.1016/j.tet.2019.01.001

  日期：2019.2

  A facile synthesis of 2-difluoromethylated quinolines via DBU-promoted cascade Michael addition/cyclization between functionalized 2-aminobenzonitriles and methyl 4,4-difluorobut-2-ynoate has been developed. Various highly functionalized quinolines were assembled in moderate to good yields under mild metal-free reaction conditions.

  已经开发了一种通过DBU促进的功能化2-氨基苯甲腈和4,4-二氟丁-2-酸甲酯之间的级联Michael加成/环化反应来轻松合成2-二氟甲基化喹啉的方法。在温和的无金属反应条件下，以中等到良好的产率组装了各种高度官能化的喹啉。
• Synthesis of Benzotriazine and Aryltriazene Derivatives Starting from 2-Azidobenzonitrile Derivatives
  作者：Azadeh Nakhai、Birgitta Stensland、Per H. Svensson、Jan Bergman

  DOI：10.1002/ejoc.201000328

  日期：2010.12

  3-Substituted 3,4-dihydro-4-imino-1,2,3-benzotriazine derivatives 7 were formed from 2-azidobenzonitriles 4 as starting materials on treatment with Grignard or lithium organic reagents. In some cases these procedures gave aryltriazenes 10 and 11 as products. All compounds were identified by NMR spectroscopy and the structures of three products, namely 7a, 10a and 11i, were corroborated by X-ray crystallography

  3-取代的 3,4-二氢-4-亚氨基-1,2,3-苯并三嗪衍生物 7 由 2-叠氮苯甲腈 4 作为起始原料，用格氏试剂或锂有机试剂处理形成。在某些情况下，这些程序得到芳基三氮烯 10 和 11 作为产物。所有化合物均通过 NMR 光谱鉴定，三种产物的结构，即 7a、10a 和 11i，通过 X 射线晶体学得到证实。
• Phase-Transfer-Catalyzed Asymmetric Synthesis of Axially Chiral Anilides
  作者：Kun Liu、Xiangfei Wu、S. B. Jennifer Kan、Seiji Shirakawa、Keiji Maruoka

  DOI：10.1002/asia.201301036

  日期：2013.12

  Catalytic asymmetric synthesis of axially chiral o‐iodoanilides and o‐tert‐butylanilides as useful chiral building blocks was achieved by means of binaphthyl‐modified chiral quaternary ammonium‐salt‐catalyzed N‐alkylations under phase‐transfer conditions. The synthetic utility of axially chiral products was demonstrated in various transformations. For example, axially chiral N‐allyl‐o‐iodoanilide was

  的催化不对称合成轴向手性ö -iodoanilides和ö -叔-butylanilides作为有用的手性结构单元是由联萘改性手季铵盐催化的相转移条件下的N-烷基化来实现。轴向手性产品的合成用途已在各种转化中得到证明。例如，轴向手性的N-烯丙基-邻碘苯胺通过自由基环化反应被转化为3-甲基二氢吲哚，并具有从轴向手性向C-中心手性的高手性转移。此外，立体化学在轴手性信息ø -叔叔丁基苯胺可以用作控制后续转化的立体化学的模板。在苯胺铵的X射线晶体结构的基础上，讨论了本相转移反应的过渡态结构，该结构是由联萘改性的手性溴化铵和邻碘苯胺制备的。手性四烷基溴化铵作为相转移催化剂可以识别苯胺上邻位取代基之间的空间差异，从而获得高对映选择性。邻位的大小和结构效应研究了苯胺上的取代基，可以合成具有高对映选择性的各种具有各种官能团的轴向手性苯胺。该方法是迄今报道的以高度对映选择性的方式获得各种轴向手性苯胺的唯一通用方法。
• [EN] AMIDO COMPOUNDS AS AhR MODULATORS<br/>[FR] COMPOSÉ AMIDO UTILISÉS COMME MODULATEURS DU AHR
  申请人：IDEAYA BIOSCIENCES INC

  公开号：WO2019018562A1

  公开（公告）日：2019-01-24

  Provided herein are compounds, compositions and methods of using the compounds and compositions for the treatment of diseases modulated, as least in part, by AhR. The compounds are represented by formulae Formula (I), (II), (III), (iv): wherein the letters and symbols a, b, c, d, e, f, g, Z, R1b, R2a and R2b have the meanings provided in the specification.

  本文提供了化合物、组合物及使用这些化合物和组合物治疗至少部分受AhR调节的疾病的方法。这些化合物由以下公式表示：公式（I）、（II）、（III）、（iv）：其中字母和符号a、b、c、d、e、f、g、Z、R1b、R2a和R2b的含义如规范中所述。