[1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester | 179026-34-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester
• 英文别名: 1-(4-cyanophenylmethyl)-1H-imidazol-5-ylacetic acid methyl ester；methyl [1-(4-cyanobenzyl)-1H-imidazol-5-yl]acetate；methyl 1-(4-cyanophenylmethyl)-5-imidazoleacetate；methyl 2-[3-[(4-cyanophenyl)methyl]imidazol-4-yl]acetate
• CAS: 179026-34-7
• 化学式: C₁₄H₁₃N₃O₂
• 分子量: 255.276
• InChiKey: LZMJLUMIJMDWNP-UHFFFAOYSA-N

物化性质

• 沸点：
  465.1±35.0 °C(Predicted)
• 密度：
  1.18±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.21
• 拓扑面积：
  67.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester 在 lithium hydroxide 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 、 三乙胺 、 3-羟基-1,2,3-苯并三嗪-4(3H)-酮 作用下， 以 四氢呋喃 、 N,N-二甲基甲酰胺 为溶剂， 反应 32.0h， 生成 2(S)-<2-[(2(S)-<2-[3-(4-cyanobenzyl)-3H-imidazol-4-yl]acetylamino>-3(S)-methylpentyl)naphthalen-1-ylmethylamino]acetylamino>-4-(methylsulfanyl)butyric acid methyl ester
  参考文献：
  名称：

  Design and in Vivo Analysis of Potent Non-Thiol Inhibitors of Farnesyl Protein Transferase

  摘要：

  Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1,5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated. The biochemical. behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar. One of the inhibitors, as its methyl prodrug, was evaluated in two in vivo models of tumor growth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ras transgenic animal model.

  DOI：

  10.1021/jm990080l
• 作为产物：
  描述：

  甲基(1-trityl-1H-imidazol-4-yl)乙酸酯 在 甲醇 作用下， 以 乙腈 为溶剂， 反应 18.5h， 生成 [1-(4-Cyanobenzyl)-1H-imidazol-5-yl]acetic acid methyl ester
  参考文献：
  名称：

  Design and in Vivo Analysis of Potent Non-Thiol Inhibitors of Farnesyl Protein Transferase

  摘要：

  Inhibitors of farnesyl protein transferase (FPTase) based upon a pseudotripeptide template are described that comprise an imidazole group substituted with a hydrophobic substituent. (1,5)-Disubstitution of the imidazole group is shown to be the optimal array that leads to potent and selective inhibitors of FPTase. A variety of aryl and isoprenyl substituents are shown to afford effective inhibitors, and the mechanism by which these compounds inhibit FPTase has been investigated. The biochemical. behavior of these compounds suggests that they bind to FPTase at the site usually occupied by the protein substrate. In experiments in cell culture, the methyl ester prodrugs of these inhibitors are cell permeant and potently inhibit the posttranslational modification of H-Ras protein. Additionally, these molecules revert the phenotype of ras transformed cells as evidenced by their ability to slow the growth of ras transformed cell lines in soft agar. One of the inhibitors, as its methyl prodrug, was evaluated in two in vivo models of tumor growth. The compound selectively inhibited the growth of tumors derived from H-ras transformed cells, in nude mice, and caused the regression of preexisting tumors in an H-ras transgenic animal model.

  DOI：

  10.1021/jm990080l

文献信息

• Inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05627202A1

  公开（公告）日：1997-05-06

  The present invention comprises analogs of the CA.sup.1 A.sup.2 X motif of the protein Ras that is modified by farnesylation in vivo. These CA.sup.1 A.sup.2 X analogs inhibit the farnesyl-protein transferase and the farnesylation of certain proteins. Furthermore, these CA.sup.1 A.sup.2 X analogs differ from those previously described as inhibitors of farnesyl-protein transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. The compounds of the instant invention also incorporate a cyclic amine moiety in the A.sup.2 position of the motif. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明包括蛋白质Ras的CA.sup.1 A.sup.2 X基序的类似物，该基序在体内通过法尼酰化进行修饰。这些CA.sup.1 A.sup.2 X类似物抑制法尼酰蛋白转移酶和某些蛋白质的法尼酰化。此外，这些CA.sup.1 A.sup.2 X类似物与先前描述的抑制法尼酰蛋白转移酶的类似物不同，因为它们不具有硫醇基团。缺乏硫醇基团在改善动物的药代动力学行为、预防依赖硫醇的化学反应（如快速自氧化和与内源硫醇形成二硫键）以及减少全身毒性方面提供了独特优势。本发明的化合物还在该基序的A.sup.2位置包含一个环胺基团。本发明还包括含有这些法尼酰转移酶抑制剂的化疗组合物以及其生产方法。
• Arylheteroaryl inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05859035A1

  公开（公告）日：1999-01-12

  The present invention is directed to compounds which inhibit famesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting famesyl-protein transferase and the famesyl of the oncogene protein Ras.

  本发明涉及抑制法美基蛋白转移酶（FTase）和致癌基因蛋白Ras的法尼酰化的化合物。该发明还涉及含有本发明化合物的化疗组合物以及用于抑制法美基蛋白转移酶和致癌基因蛋白Ras的法美基的方法。
• Heterocycle-containing inhibitors of farnesyl-protein transferase
  申请人：Merck & Co., Inc.

  公开号：US05652257A1

  公开（公告）日：1997-07-29

  The present invention comprises analogs of the CAAX motif of the protein Ras that is modified by farnesylation in vivo. These CAAX analogs inhibit the farnesylation of Ras. Furthermore, these CAAX analogues differ from those previously described as inhibitors of Ras farnesyl transferase in that they do not have a thiol moiety. The lack of the thiol offers unique advantages in terms of improved pharmacokinetic behavior in animals, prevention of thiol-dependent chemical reactions, such as rapid autoxidation and disulfide formation with endogenous thiols, and reduced systemic toxicity. Further contained in this invention are chemotherapeutic compositions containing these farnesyl transferase inhibitors and methods for their production.

  本发明包括蛋白质Ras的CAAX基序的类似物，该基序在体内通过法尼酰化进行修饰。这些CAAX类似物抑制了Ras的法尼酰化。此外，这些CAAX类似物与以前描述的抑制Ras法尼基转移酶的类似物不同，因为它们不具有硫醇基团。缺乏硫醇基团在改善动物体内药代动力学行为、预防硫醇依赖的化学反应（如快速自氧化和与内源硫醇的二硫键形成）以及减少系统毒性方面提供了独特优势。此外，本发明还包括含有这些法尼基转移酶抑制剂的化疗组合物和其生产方法。
• N-benzyl imidazole derivatives and their use as aldosterone synthase inhibitors
  申请人：Maastricht University

  公开号：EP2095819A1

  公开（公告）日：2009-09-02

  The invention relates to the use of a N-benzyl 5-substituted imidazole derivative having the general formula I wherein R is (C1-3)alkyl, (C1-3)alkyloxy, halogen, nitro or cyano; R1 is (C1-6)alkyl, optionally substituted with OH, (C1-3)alkyloxy, (C1-3)alkylcarbonyloxy, (C1-3)alkyloxycarbonyl or halogen, or (C1-3)alkyloxycarbonyl; or R1 is phenyl, optionally substituted with 1-3 substituents independently selected from (C1-3)alkyl, (C1-3)alkyloxy, hydroxylmethyl and halogen; or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment of a disorder or disease in a subject mediated by aldosterone synthase or responsive to inhibition of aldosterone synthase.

  该发明涉及使用具有通式I的N-苄基5-取代咪唑衍生物，其中R为(C1-3)烷基，(C1-3)烷氧基，卤素，硝基或氰基；R1为(C1-6)烷基，可选择地取代为羟基，(C1-3)烷氧基，(C1-3)烷基羰氧基，(C1-3)烷氧羰基或卤素，或(C1-3)烷氧羰基；或R1为苯基，可选择地取代为1-3个独立选择自(C1-3)烷基，(C1-3)烷氧基，羟甲基和卤素的取代基；或其药学上可接受的盐，用于制备一种药物，用于治疗由醛固酮合酶介导或对醛固酮合酶抑制响应的受体引起的主体的紊乱或疾病。
• [EN] INHIBITORS OF FARNESYL-PROTEIN TRANSFERASE<br/>[FR] INHIBITEURS DE FARNESYL-PROTEINE TRANSFERASE
  申请人：MERCK & CO., INC.

  公开号：WO1996030343A1

  公开（公告）日：1996-10-03

  (EN) The present invention is directed to compounds which inhibit farnesyl-protein transferase (FTase) and the farnesylation of the oncogene protein Ras. The invention is further directed to chemotherapeutic compositions containing the compounds of this invention and methods for inhibiting farnesyl-protein transferase and the farnesylation of the oncogene protein Ras.(FR) La présente invention concerne des composés qui inhibent la farnésyl-protéine transférase (FTase) et la farnélysation de l'oncogène Ras protéique. L'invention concerne en outre des compositions chimiothérapeutiques contenant les composés de cette invention, et des procédés servant à inhiber la farnésyl-protéine transférase et la farnélysation de la protéine d'oncogène Ras.

  该发明涉及抑制法尼酰-蛋白转移酶（FTase）和癌基因蛋白Ras的法尼酰化的化合物。该发明进一步涉及含有该发明化合物的化疗组合物和抑制法尼酰-蛋白转移酶和癌基因蛋白Ras的法尼酰化的方法。