1-methyl-2-[2-(4-cyanophenyl)-ethyl]-5-amino-benzimidazole | 256492-47-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-5-amino-benzimidazole
• 英文别名: 5-amino-2-[2-(4-cyanophenyl)-ethyl]-1-methyl-benzimidazole；4-[2-(5-amino-1-methylbenzimidazol-2-yl)ethyl]benzonitrile
• CAS: 256492-47-4
• 化学式: C₁₇H₁₆N₄
• 分子量: 276.341
• InChiKey: MVHBVNLJLODOAJ-UHFFFAOYSA-N

物化性质

• 沸点：
  559.2±40.0 °C(Predicted)
• 密度：
  1.20±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.18
• 拓扑面积：
  67.6
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  1-methyl-2-[2-(4-cyanophenyl)-ethyl]-5-amino-benzimidazole 在 吡啶 、 potassium carbonate 作用下， 以 丙酮 为溶剂， 生成 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-5-[N-(ethoxycarbonylmethyl)-quinoline-8-sulphonylamino]-benzimidazole
  参考文献：
  名称：

  Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors

  摘要：

  The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.

  DOI：

  10.1021/jm0109513
• 作为产物：
  描述：

  4-氰基-3-苯基丙酸 在 10percent Pd/C 氢气 、 溶剂黄146 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 生成 1-methyl-2-[2-(4-cyanophenyl)-ethyl]-5-amino-benzimidazole
  参考文献：
  名称：

  Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors

  摘要：

  The clinical syndromes of thromboembolism are evoked by an excessive stimulation of the coagulation cascade. In this context, the serine protease thrombin plays a key role. Considerable efforts have therefore been devoted to the discovery of safe, orally active inhibitors of this enzyme. On the basis of the X-ray crystal structure of the peptidelike thrombin inhibitor NAPAP complexed with bovine thrombin, we have designed a new structural class of nonpeptidic inhibitors employing a 1,2,5-trisubstituted benzimidazole as the central scaffold. Supported by a series of X-ray structure analyses, we optimized the activity of these compounds. Thrombin inhibition in the lower nanomolar range could be achieved although the binding energy mainly results from nonpolar, hydrophobic interactions. To improve in vivo potency, we increased the overall hydrophilicity of the molecules by introducing carboxylate groups. The very polar compound 24 (BIBR 953) exhibited the most favorable activity profile in vivo. This zwitterionic molecule was converted into the double-prodrug 31 (BIBR 1048), which showed strong oral activity in different animal species. On the basis of these results, 31 was chosen for clinical development.

  DOI：

  10.1021/jm0109513

文献信息

• Arylysulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
  申请人：Boehringer Ingelheim Pharma KG

  公开号：US06365584B1

  公开（公告）日：2002-04-02

  Arylsulphonamide-substituted benzimidazole derivatives of formula (I) having tryptase-inhibiting activity. Exemplary are: 1-Methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(2-diethylaminoethyl)-benzenesulphonylamino]-benzimidazole; 1-Methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(2-diethlylaminoethyl)-benzylsulfonylamino]-benzimidazole; and, 1-Methyl-2-[2-(4-amidinophenyl)-ethyl]-5-[N-(3-diethylaminopropyl)-benzenesulphonylamino]-benzimidazole.

  式（I）的芳基磺胺基苯并咪唑衍生物具有胰蛋白酶抑制活性。例如：1-甲基-2-[2-(4-氨基苯基)-乙基]-5-[N-(2-二乙基氨基乙基)-苯磺胺氨基]-苯并咪唑；1-甲基-2-[2-(4-氨基苯基)-乙基]-5-[N-(2-二乙胺基乙基)-苯基磺酰胺基]-苯并咪唑；以及1-甲基-2-[2-(4-氨基苯基)-乙基]-5-[N-(3-二乙胺基丙基)-苯磺胺氨基]-苯并咪唑。
• Carboxamide-substituted benzimidazoles having tryptase-inhibiting activity
  申请人：Boehringer Ingelheim Pharma KG

  公开号：US06407130B1

  公开（公告）日：2002-06-18

  The invention relates to carboxamide-substituted benzimidazole derivatives of general formula (I) wherein the groups R1, R2, R3 and R4 may have the meanings given in the claims and in the specification, processes for preparing them and the use of carboxamide-substituted benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting effect.

  本发明涉及通式(I)的羧酰胺取代苯并咪唑衍生物，其中基团R1、R2、R3和R4可以具有在权利要求和说明书中给出的含义，以及制备它们的过程，以及将羧酰胺取代苯并咪唑衍生物用作制药组合物，特别是用作具有抑制替普酶效应的制药组合物的用途。
• Benzimidazole derivatives, processes for preparing them and their use as pharmaceutical compositions
  申请人：——

  公开号：US20030105137A1

  公开（公告）日：2003-06-05

  Disclosed are carboxamide-substituted benzimidazole derivatives of general formula (I) 1 wherein the groups X, R 1 , R 2 , R 3 and R 4 may have the meanings given in the claims and specification, processes for preparing them and the use of carboxamide-substituted benzimidazole derivatives as pharmaceutical compositions, particularly as pharmaceutical compositions with a tryptase-inhibiting activity.

  本发明涉及一般式（I）的羧酰胺取代苯并咪唑衍生物，其中X、R1、R2、R3和R4基团可以具有权利要求和说明书中给出的含义，制备它们的过程以及将羧酰胺取代苯并咪唑衍生物用作制药组合物，特别是作为具有胰蛋白酶抑制活性的制药组合物。
• Arylsulphonamide-substituted benzimidazoles having tryptase-inhibiting activity
  申请人：Boehringer Ingelheim Pharma KG

  公开号：US06413990B1

  公开（公告）日：2002-07-02

  Bezimidazole derivatives of general formula (I) having tryptase-inhibitory activity. Exemplary are: N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(4-ethoxycarbonyl-benzenesulphonamide)-hydrochloride, N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(dansylamide)-dihydrochloride, and N-{2-[2-(4-amidinophenyl)-ethyl]-1-methyl-benzimidazol-5-yl}-N-diethylaminoethyl-(3-bromo-benzenesulphonamide)-hydrochloride.

  通式为(I)的苯并咪唑衍生物具有胰蛋白酶抑制活性。例如：N-＆lcub; 2-＆lsqb; 2-（4-氨基苯甲酰基）-乙基＆rsqb; -1-甲基苯并咪唑-5-基＆rcub; -N-二乙基氨基乙基-（4-乙酰氧基苯磺酰胺）-盐酸盐，N-＆lcub; 2-＆lsqb; 2-（4-氨基苯甲酰基）-乙基＆rsqb; -1-甲基苯并咪唑-5-基＆rcub; -N-二乙基氨基乙基-（丹磺酰胺）-二盐酸盐，以及N-＆lcub; 2-＆lsqb; 2-（4-氨基苯甲酰基）-乙基＆rsqb; -1-甲基苯并咪唑-5-基＆rcub; -N-二乙基氨基乙基-（3-溴苯磺酰胺）-盐酸盐。
• US6121308
  申请人：——

  公开号：——

  公开（公告）日：——