4-[(5-nitro-1H-benzimidazol-2-yl)-methyl]-benzonitrile | 236417-26-8

• 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: 4-[(5-nitro-1H-benzimidazol-2-yl)-methyl]-benzonitrile
• 英文别名: 4-[(6-nitro-1H-benzimidazol-2-yl)methyl]benzonitrile
• CAS: 236417-26-8
• 化学式: C₁₅H₁₀N₄O₂
• 分子量: 278.27
• InChiKey: IKQFJYNQNDNSBB-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.07
• 拓扑面积：
  98.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-[(5-nitro-1H-benzimidazol-2-yl)-methyl]-benzonitrile 在 10percent Pd/C 吡啶 、 氢气 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 生成 4-[(5-benzenesulphonylamino-1H-benzimidazol-2-yl)-methyl]-benzonitrile
  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-硝基邻苯二胺 在 溶剂黄146 、 N,N'-羰基二咪唑 作用下， 以 四氢呋喃 为溶剂， 生成 4-[(5-nitro-1H-benzimidazol-2-yl)-methyl]-benzonitrile
  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

• Bicyclic heterocycles, the preparation thereof, and their use as
  申请人：Boehringer Ingelheim Pharma KG

  公开号：US06114532A1

  公开（公告）日：2000-09-05

  The present invention relates to 5-membered heterocyclic condensed benzoderivatives of formula ##STR1## wherein R.sub.a to R.sub.c, A, X and Y are defined as in claim 1, the tautomers, stereoisomers, mixtures thereof and the salts thereof, particularly the physiologically acceptable salts thereof with inorganic or organic acids or bases which have valuable properties. The compounds of the above formula I wherein R.sub.c denotes a cyano group are valuable intermediates for preparing the other compounds of formula I, and the compounds of the above formula I wherein R.sub.c denotes one of the following amidino groups and the tautomers and stereoisomers thereof have valuable pharmacological properties, particularly an antithrombotic activity.

  本发明涉及公式##STR1##的5-成员杂环融合苯衍生物，其中R.sub.a至R.sub.c，A，X和Y的定义如权利要求1中所定义，其互变异构体，立体异构体，其混合物及其盐，特别是其与具有有价值性质的无机或有机酸或碱的生理上可接受的盐。上述公式I中R.sub.c表示氰基的化合物是制备公式I的其他化合物的有价值中间体，上述公式I中R.sub.c表示以下氨基甲酰基基团之一的化合物及其互变异构体和立体异构体具有有价值的药理学性质，特别是抗血栓活性。
• [DE] 5-GLIEDRIGE BENZOKONDENSIERTE HETEROCYCLEN ALS ANTITHROMBOTIKA<br/>[EN] FIVE-MEMBERED, BENZO-CONDENSED HETEROCYCLES USED AS ANTITHROMBOTIC AGENTS<br/>[FR] HETEROCYCLES BENZO CONDENSES A 5 CHAINONS UTILISES COMME AGENTS ANTITHROMBOTIQUES
  申请人：BOEHRINGER INGELHEIM PHARMA KG

  公开号：WO1999040072A1

  公开（公告）日：1999-08-12

  (DE) Die vorliegende Erfindung betrifft neue 5-gliedrige heterocyclische kondensierte Benzoderivate der allgemeinen Formel (I), in der Ra bis Rc, A, Ar, X und Y wie im Anspruch 1 difiniert sind, deren Tautomere, deren Stereoisomere, deren Gemische und deren Salze, insbesondere deren physiologisch verträgliche Salze mit anorganischen oder organischen Säuren oder Basen, welche wertvolle Eigenschaften aufweisen. Die Verbindungen der obigen allgemeinen Formel (I), in denen Rc eine Cyanogruppe darstellt, stellen wertvolle Zwischenprodukte zur Herstellung der übrigen Verbindungen der allgemeinen Formel (I) dar, und die Verbindungen der obigen allgemeinen Formel (I), in denen Rc eine der nachfolgenden Amidinogruppen darstellt, sowie deren Tautomere und deren Stereoisomere weisen wertvolle pharmakologische Eigenschaften auf, insbesondere eine antithrombotische Wirkung.(EN) The invention relates to new five-membered, heterocyclic condensed benzoderivatives of the general formula (I), in which Ra to Rc, A, Ar, X and Y have the meanings assigned in claim 1, and their tautomers, stereoisomers, mixtures and salts, especially their physiologically compatible salts with inorganic or organic acids or bases, which have valuable properties. The compounds of the general formula (I) above, in which Rc is a cyano group, present valuable intermediate products for the production of the remaining compounds of the general formula (I), and the compounds of the above general formula (I), in which Rc is one of the following amidino groups, as well as their tautomers and stereoisomers, have valuable pharmacological properties, especially an antithrombotic activity.(FR) L'invention concerne de nouveaux dérivés benzo condensés hétérocycliques à 5 chaînons de la formule générale (I) dans laquelle Ra à Rc, A, Ar, X et Y ont la signification mentionnée dans la revendication 1, leurs tautomères, leurs stéréoisomères, leurs mélanges et leurs sels, notamment leurs sels physiologiquement compatibles avec des acides inorganiques ou organiques ou des bases, présentant des propriétés précieuses. Les composés de la formule générale (I) précitée, dans laquelle Rc représente un groupe cyano, constituent des produits intermédiaires précieux pour préparer les autres composés de la formule générale (I), et les composés de la formule générale (I) précitée, dans laquelle Rc représente un des groupes amidino subséquent, ainsi que leurs tautomères et leurs stéréoisomères présentent des propriétés pharmacologiques précieuses, notamment une action antithrombotique.

  本发明涉及一种新型的5元环偶烷基苯并质子化物，该化合物的一般式为 (I)，其中 Ra至 Rc、A、Ar、X 和 Y 的含义与权利要求 1 中相同；以及它们的环化异构体、它们的立体异构体、它们的混合物和它们的盐，尤其是它们的生理相容性盐，这些盐可以和无机或有机酸或碱盐中和，具有宝贵的性质。在一般式为 (I) 的化合物中，Ra至 Rc、A、Ar、X 和 Y 的含义与权利要求 1 中相同；以及它们的环化异构体、它们的立体异构体、它们的混合物和它们的盐，尤其是它们的生理相容性盐，这些盐可以和无机或有机酸或碱盐中和，具有宝贵的性质。 在上述一般式为 (I) 的化合物中，Rc表示一个氰基团，这样的化合物为重要的中间产物，用于生产一般式为 (I) 中的余下化合物；而在上述一般式为 (I) 的化合物中，Rc表示其后列 amidino 组中的一个，则如此类化合物及其环化异构体和立体异构体具有宝贵的药理性质，尤其是抗凝血作用。上述一般式为 (I) 的化合物中，Rc表示一个 Cyanoguppe，则此类化合物为重要中间体，用于生产一般式为 (I) 中余下的化合物；而在上述一般式为 (I) 的化合物中，Rc表示一个 amidino 组中的一个，则如此类化合物及其环化异构体和立体异构体具有宝贵的药理性质，尤其是在抗凝血作用方面。
• 5-GLIEDRIGE BENZOKONDENSIERTE HETEROCYCLEN ALS ANTITHROMBOTIKA
  申请人：Boehringer Ingelheim Pharma KG

  公开号：EP1060166A1

  公开（公告）日：2000-12-20
• US6114532A
  申请人：——

  公开号：US6114532A

  公开（公告）日：2000-09-05
• Structure-Based Design of Novel Potent Nonpeptide Thrombin Inhibitors
  作者：Norbert H. Hauel、Herbert Nar、Henning Priepke、Uwe Ries、Jean-Marie Stassen、Wolfgang Wienen

  DOI：10.1021/jm0109513

  日期：2002.4.1

  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.