4-(2-methylpyridin-4-yl)benzene-1,2-diamine | 1430720-26-5

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 4-(2-methylpyridin-4-yl)benzene-1,2-diamine
• CAS: 1430720-26-5
• 化学式: C₁₂H₁₃N₃
• 分子量: 199.255
• InChiKey: AKNVOKOXKMDXEM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.5
• 重原子数：
  15
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.08
• 拓扑面积：
  64.9
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-ethyl-3-(N-(ethylcarbamoyl)-C-methylsulfanylcarbonimidoyl)urea 、 4-(2-methylpyridin-4-yl)benzene-1,2-diamine 在 溶剂黄146 作用下， 以 水 为溶剂， 反应 5.0h， 以48%的产率得到1-ethyl-3-[6-(2-methylpyridin-4-yl)-1H-benzimidazol-2-yl]urea
  参考文献：
  名称：

  Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

  摘要：

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

  DOI：

  10.1021/jm301891t
• 作为产物：
  描述：

  4-溴邻苯二胺 、 2-甲基-4-吡啶硼酸 在 1,1'-双(二苯膦基)二茂铁二氯化钯(II)二氯甲烷复合物 、 potassium carbonate 作用下， 以 1,4-二氧六环 、 水 为溶剂， 反应 1.5h， 生成 4-(2-methylpyridin-4-yl)benzene-1,2-diamine
  参考文献：
  名称：

  Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant

  摘要：

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.

  DOI：

  10.1021/jm301891t

文献信息

• 5-(Pyridinyl)-benzimidazole derivatives and preparation
  申请人：STERLING DRUG INC.

  公开号：EP0055453A2

  公开（公告）日：1982-07-07

  5-(Py-Y)-1H-benzimidazol-2-ol or 5-(Py-Y-1H-benzimidazole-2-thiol or lower-alkyl ethers or thioethers thereof or pharmaceutically-acceptable acid-addition salts thereof where Y is a direct linkage or lower-alkylene having one or two carbon atoms and Py is 4- or 3-pyridinyl, optionally having one or two lower-alkyl substituents, or 1-oxide of such pyridinyl, useful as cardiotonics, are prepared by reacting 4-(Py-Y)-1,2-benzenediamine with urea or carbony-Idiimidazole to produce 5-(Py-Y)-1H-benzimidazol-2-ol or with thiourea, an alkali metal lower-alkyl xanthate orthiocar- bonyldiimidazole to produce 5-(Py-Y)-1H-benzimidazole-2-thiol and by reacting 5-(Py-Y)-lH-benzimidazole-2-thiol with a lower-alkylating agent to produce 2-(lower-alkylthio-)-5-(Py-Y)-1 H-benzimidazole. 2-(Lower-alkoxy)-5-(Py-Y)-1 H-benzimidazoles are prepared by reacting 4-(Py-Y)1,2-benzenediamine with tetra-(lower-alkoxy)methane. The N-oxides may be prepared by reaction with a per-organic acid in a suitable solvent.

  5-(Py-Y)-1H-苯并咪唑-2-醇或 5-(Py-Y)-1H-苯并咪唑-2-硫醇或其低级烷基醚或硫醚或其药学上可接受的酸加成盐，其中 Y 为直接连接或具有一个或两个碳原子的低级亚烷基，Py 为 4-或 3-吡啶基，可选具有一个或两个低级烷基取代基，或此类吡啶基的 1-氧化物，可用作强心剂、4-(Py-Y)-1,2-苯二胺与脲或碳二咪唑反应生成 5-(Py-Y)-1H-苯并咪唑-2-醇，或与硫脲反应生成 5-(Py-Y)-1H-苯并咪唑-2-醇、碱金属低级烷基黄原酸盐原碳二咪唑，生成 5-(Py-Y)-1H-苯并咪唑-2-硫醇，并将 5-(Py-Y)-lH-苯并咪唑-2-硫醇与低级烷基化剂反应，生成 2-(低级烷基硫代)-5-(Py-Y)-1H-苯并咪唑。2-(低级烷氧基)-5-(Py-Y)-1 H-苯并咪唑是通过 4-(Py-Y)1,2-苯二胺与四(低级烷氧基)甲烷反应制备的。N-氧化物可通过在合适的溶剂中与过有机酸反应制备。
• Pyridinyl-substituted-benz imidazole derivatives and preparation
  申请人：STERLING DRUG INC.

  公开号：EP0056260A1

  公开（公告）日：1982-07-21

  2-R-5-(Py-Y)-lH-benzimidazole or pharmaceutically-acceptable acid-addition salt thereof, useful as a cardiotonic, is prepared by reacting 4-(Py-Y)-1,2-benzenediamine with a tri-(lower-alkyl)ortho-(lower-alkanoate) of the formula R-C(ORI)3, where R is hydrogen or lower-alkyl, Y is a direct linkage or lower-alkylene having one or two carbon atoms, and Py is 4- or 3-pyridinyl or 4- or 3-pyridinyl having one or two lower-alkyl substituents, or with dimethylformamide dimethyl acetal or dimethylacetamide dimethyl acetal to produce said 2-R-5-(Py-Y)-1H-benzimidazole where R is methyl or ethyl respectively. The same compound where R is lower-alkyl is prepared in two steps by first reacting 4-(Py-Y)-1,2-benzenediamine with an alkanoylating agent providing alkanoyl of the formula R'-C=O to produce N2[R'C(=O)]-4-(Py-Y)-1,2-benzenediamine and heating the latter compound to produce said 2-R'-5-(Py-Y)-1H-benzimidazole, where R' is lower-alkyl. Also shown is 1-hydroxy-2-R-6-(Py-Y)-1H-benzimidazole or pharmaceutically-acceptable acid-addition salt thereof, useful as a cardiotonic and prepared by reacting 3-nitro-N-(RCO)-4-(Py-Y)-benzeneamine with hydrogen under catalytic hydrogen conditions.

  可用作强心剂的 2-R-5-(Py-Y)-lH-苯并咪唑或其药学上可接受的酸加成盐，是通过 4-(Py-Y)-1,2-苯二胺与式 R-C(ORI)3（其中 R 为氢或低级烷基）的三(低级烷基)原(低级烷酸)酯反应制备的、Y 是具有一个或两个碳原子的直链烷基或低级烷基，Py 是 4-或 3-吡啶基或具有一个或两个低级烷基取代基的 4-或 3-吡啶基，或与二甲基甲酰胺二甲基缩醛或二甲基乙酰胺二甲基缩醛生成所述 2-R-5-(Py-Y)-1H-苯并咪唑，其中 R 分别为甲基或乙基。R 为低级烷基的相同化合物分两步制备，首先将 4-(Py-Y)-1,2-苯二胺与提供式 R'-C=O 烷酰基的烷酰化剂反应，生成 N2[R'C(=O)]-4-(Py-Y)-1,2-苯二胺，然后加热后一种化合物，生成所述 2-R'-5-(Py-Y)-1H-苯并咪唑，其中 R' 为低级烷基。图中还显示了 1-羟基-2-R-6-(Py-Y)-1H-苯并咪唑或其药学上可接受的酸加成盐，可用作强心剂，其制备方法是在催化氢条件下使 3-硝基-N-(RCO)-4-(Py-Y)-苯胺与氢反应。
• US4331671A
  申请人：——

  公开号：US4331671A

  公开（公告）日：1982-05-25
• US4335132A
  申请人：——

  公开号：US4335132A

  公开（公告）日：1982-06-15
• Discovery of New Benzothiazole-Based Inhibitors of Breakpoint Cluster Region-Abelson Kinase Including the T315I Mutant
  作者：Seunghee Hong、Jinhee Kim、Sun-Mi Yun、Hyunseung Lee、Yoonsu Park、Soon-Sun Hong、Sungwoo Hong

  DOI：10.1021/jm301891t

  日期：2013.5.9

  The existence of drug resistance caused by mutations in the break-point cluster region-Abelson tyrosine kinase (Bcr-Abl) kinase domain remains a clinical challenge due to limited effective treatment options for chronic myeloid leukemia (CML). Herein we report a novel series of benzothiazole-based inhibitors that are effective against wild-type and T315I mutant Bcr-Abl kinases. The original hit compound, nocodazole, was extensively modified through a structure-based drug design strategy, especially by varying the groups at the C2 and C6 positions of the scaffold. In addition, the introduction of water-solubilizing groups at the terminal ethyl group resulted in enhanced physicochemical properties and potency in cellular inhibition. Several compounds inhibited the kinase activity of both wild-type Bcr-Abl and the T315I mutant with IC50 values in the picomolar range and exhibited good antiproliferative effects on Ba/F3 cell lines transformed with either wild-type or T315I mutant Bcr-Abl.