3-(1H-benzimidazol-2-yl)-3-tert-butoxycarbonylaminopropionic acid benzyl ester | 480446-80-8

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(1H-benzimidazol-2-yl)-3-tert-butoxycarbonylaminopropionic acid benzyl ester
• 英文别名: benzyl (3S)-3-(1H-benzimidazol-2-yl)-3-[(2-methylpropan-2-yl)oxycarbonylamino]propanoate
• CAS: 480446-80-8
• 化学式: C₂₂H₂₅N₃O₄
• 分子量: 395.458
• InChiKey: KVWLMCMWWZYLQG-SFHVURJKSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  9
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  93.3
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  三氟乙酸 、 3-(1H-benzimidazol-2-yl)-3-tert-butoxycarbonylaminopropionic acid benzyl ester 生成
  参考文献：
  名称：

  对含有阿片类药效团 Dmt-Tic 的先导化合物的进一步研究。

  摘要：

  一些含有 Dmt-Tic 药效团的参考阿片类药物，尤其是 δ 激动剂 H-Dmt-Tic-Gly-NH-Ph (1) 和 H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid (4) ) (UFP-512) 评估了用天冬氨酸取代 Gly 的影响、其手性，以及 -NH-Ph 和 N(1)H-Bid 氢在 δ 激动诱导中的重要性。结果提供以下结论： (i) Asp 通过降低 mu 亲和力增加 delta 选择性；(ii) -NH-Ph 和 N(1)H-Bid 氮甲基化将 delta 激动剂转化为 delta 拮抗剂；(iii)在δ激动剂H-Dmt-Tic-Gly-NH-Ph中用L-Asp/D-Asp取代Gly得到δ拮抗剂；δ 激动剂 H-Dmt-Tic-NH-CH2-Bid 中的相同取代产生更具选择性的激动剂 H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid 和 H-Dmt-Tic-NH

  DOI：

  10.1021/jm800587e
• 作为产物：
  描述：

  Boc-L-天冬氨酸 4-苄酯 在 N-甲基吗啉 、 溶剂黄146 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 生成 3-(1H-benzimidazol-2-yl)-3-tert-butoxycarbonylaminopropionic acid benzyl ester
  参考文献：
  名称：

  Potent δ-Opioid Receptor Agonists Containing the Dmt−Tic Pharmacophore

  摘要：

  Conversion of delta-opioid receptor antagonists containing the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent delta-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NH-CH(R)-R'. The distance between Tic and Bid is a determining factor responsible for the acquisition of delta agonism (2, 2', 3, 4, 6) or delta antagonism (8). Compounds containing a C-terminal Ala (1, 1'), Asp (5), or Asn (7) with an amide (1, 1', 5) or free acid group (7) served as delta-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2') or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent delta agonism and moderatey agonism, although delta-receptor affinity decreased about 10-fold for 4 while mu affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH2-Bid)COOH (6) maintained high delta affinity (K-i = 0.042 nM) and delta agonism (IC50 = 0.015 nM), but attachment of the free acid group to Bid [H-Dmt-Tic-NH-CH2-Bid(CH2-COOH) (9)] reconstituted delta antagonism (K-e = 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent delta agonism and weaky agonism from a parent delta antagonist.

  DOI：

  10.1021/jm020336e

文献信息

• An efficient one-pot conversion of carboxylic acids into benzimidazoles <i>via</i> an HBTU-promoted methodology
  作者：Leonard Barasa、Sabesan Yoganathan

  DOI：10.1039/c8ra07773h

  日期：——

  Benzimidazole is a privileged, and routinely used pharmacophore in the drug discovery process. Herein, we report a mild, acid-free and one-pot synthesis of indole, alkyl and alpha-amino benzimidazoles through a novel HBTU-promoted methodology. An extensive library of indole-carboxylic acids, alkyl carboxylic acids and N-protected alpha-amino acids has been converted into the corresponding benzimidazoles

  苯并咪唑是药物发现过程中一种特殊且常规使用的药效基团。在此，我们报告了通过 HBTU 推广的新型方法温和、无酸、一锅法合成吲哚、烷基和 α-氨基苯并咪唑。广泛的吲哚羧酸、烷基羧酸和N保护的 α-氨基酸库已被转化为相应的苯并咪唑，产率为 80-99%。由于α-氨基苯并咪唑是非常有用的合成子，可作为化学催化以及药物发现工作的手性配体，因此我们报道的方法提供了通过简单的一锅操作从市售羧酸直接获得该支架的方法。
• Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic
  作者：Gianfranco Balboni、Stella Fiorini、Anna Baldisserotto、Claudio Trapella、Yusuke Sasaki、Akihiro Ambo、Ewa D. Marczak、Lawrence H. Lazarus、Severo Salvadori

  DOI：10.1021/jm800587e

  日期：2008.8.1

  Some reference opioids containing the Dmt-Tic pharmacophore, especially the delta agonists H-Dmt-Tic-Gly-NH-Ph (1) and H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid (4) (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the -NH-Ph and N(1)H-Bid hydrogens in the inductions of delta agonism. The results provide the following conclusions:

  一些含有 Dmt-Tic 药效团的参考阿片类药物，尤其是 δ 激动剂 H-Dmt-Tic-Gly-NH-Ph (1) 和 H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid (4) ) (UFP-512) 评估了用天冬氨酸取代 Gly 的影响、其手性，以及 -NH-Ph 和 N(1)H-Bid 氢在 δ 激动诱导中的重要性。结果提供以下结论： (i) Asp 通过降低 mu 亲和力增加 delta 选择性；(ii) -NH-Ph 和 N(1)H-Bid 氮甲基化将 delta 激动剂转化为 delta 拮抗剂；(iii)在δ激动剂H-Dmt-Tic-Gly-NH-Ph中用L-Asp/D-Asp取代Gly得到δ拮抗剂；δ 激动剂 H-Dmt-Tic-NH-CH2-Bid 中的相同取代产生更具选择性的激动剂 H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid 和 H-Dmt-Tic-NH
• Potent δ-Opioid Receptor Agonists Containing the Dmt−Tic Pharmacophore
  作者：Gianfranco Balboni、Severo Salvadori、Remo Guerrini、Lucia Negri、Elisa Giannini、Yunden Jinsmaa、Sharon D. Bryant、Lawrence H. Lazarus

  DOI：10.1021/jm020336e

  日期：2002.12.1

  Conversion of delta-opioid receptor antagonists containing the 2',6'-dimethyl-L-tyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) pharmacophore into potent delta-agonists required a third heteroaromatic nucleus, such as 1H-benzimidazole-2-yl (Bid) and a linker of specified length both located C-terminally to Tic in the general formula H-Dmt-Tic-NH-CH(R)-R'. The distance between Tic and Bid is a determining factor responsible for the acquisition of delta agonism (2, 2', 3, 4, 6) or delta antagonism (8). Compounds containing a C-terminal Ala (1, 1'), Asp (5), or Asn (7) with an amide (1, 1', 5) or free acid group (7) served as delta-antagonist controls lacking the third heteroaromatic ring. A change in chirality of the spacer (2, 2') or inclusion of a negative charge via derivatives of Asp (4, 6) resulted in potent delta agonism and moderatey agonism, although delta-receptor affinity decreased about 10-fold for 4 while mu affinity fell by over 2 orders of magnitude. Repositioning of the negative charge in the linker altered activity: H-Dmt-Tic-NH-CH(CH2-Bid)COOH (6) maintained high delta affinity (K-i = 0.042 nM) and delta agonism (IC50 = 0.015 nM), but attachment of the free acid group to Bid [H-Dmt-Tic-NH-CH2-Bid(CH2-COOH) (9)] reconstituted delta antagonism (K-e = 0.27 nM). The data demonstrate that a linker separating the Dmt-Tic pharmacophore and Bid, regardless of the presence of a negative charge, is important in the acquisition of opioids exhibiting potent delta agonism and weaky agonism from a parent delta antagonist.