4-<<5-<(cyclopentylmethyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxybenzoic acid | 110707-80-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 4-<<5-<(cyclopentylmethyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxybenzoic acid
• 英文别名: 4-[[5-(Cyclopentylmethylcarbamoyl)-1-methylindol-3-yl]methyl]-3-methoxybenzoic acid
• CAS: 110707-80-7
• 化学式: C₂₅H₂₈N₂O₄
• 分子量: 420.508
• InChiKey: FZNPYKLRCOCHPX-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.5
• 重原子数：
  31
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  80.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  邻,对甲苯磺酰胺 、 4-<<5-<(cyclopentylmethyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxybenzoic acid 在 4-二甲氨基吡啶 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 二氯甲烷 为溶剂， 以51%的产率得到4-<<5-<(2-cyclopentylmethyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxy-N-<(2-methylphenyl)sulfonyl>benzamide
  参考文献：
  名称：

  1,3,6-三取代的吲哚作为肽白三烯拮抗剂：具有第二个极性吡咯取代基的优点。

  摘要：

  含有酰基氨基和N-芳基磺酰基酰胺附件的1，6-取代的和3,5-取代的吲哚和吲唑是肽白三烯LTD4和LTE4的有效拮抗剂。3，5-取代的吲哚系列的化合物，N- [4-[[5-[[（环戊氧基）]]]甲基] [甲基] [3-基]甲基] -3-甲氧基苯甲酰基] -2-甲基-苯磺酰胺（ICI 204,219）正在接受哮喘的临床评估。该系列拮抗剂引入了结构多样性的两个新元素。对1，6-取代的吲哚中吡咯取代基的研究表明，C-2处的取代对生物活性有害，但在C-3处引入亲水基团是有益的。在C-3处引入丙酰胺部分将活性提高了1个数量级。N- [4-[[6-（环戊基乙酰胺基）-3-] [2-（N-甲基氨基甲酰基）乙基]吲哚-1-基]甲基] -3-甲氧基-苯甲酰基]苯磺酰胺（15c）的pKB为10.7豚鼠气管上的LTD4受体。二取代拮抗剂的酰基氨基部分的修饰表明酰胺CO和NH原子的转位是可行的。在1，6-和3，5

  DOI：

  10.1021/jm00091a010
• 作为产物：
  描述：

  benzyl 1H-indole-5-carboxylate 在 palladium on activated charcoal 4-二甲氨基吡啶 、 lithium hydroxide 、 氢气 、 sodium hydride 、 1-(3-二甲基氨基丙基)-3-乙基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 80.0 ℃ 、344.73 kPa 条件下， 反应 95.5h， 生成 4-<<5-<(cyclopentylmethyl)carbamoyl>-1-methylindol-3-yl>methyl>-3-methoxybenzoic acid
  参考文献：
  名称：

  Substituted 3-(phenylmethyl)-1H-indole-5-carboxamides and 1-(phenylmethyl)indole-6-carboxamides as potent, selective, orally active antagonists of the peptidoleukotrienes

  摘要：

  Substituted indole-5-carboxamides and indole-6-carboxamides have been found to be potent and selective antagonists of the peptidoleukotrienes. Initial derivatives of these series (4-[[5-[(cyclopentylmethyl)carbamoyl]-1-methylindol-3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl] benzamide (5a) and 4-[[6-[(cyclopentylmethyl)carbamoyl]-3-methylindol-1-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide (6a), respectively), when compared to the corresponding indole amides (e.g. 28 and 29), were found to be approximately 10-fold less potent in vitro and substantially less active when administered orally to guinea pigs. Efforts to improve the potency of the title series by variation of the amide, indole, or sulfonamide substituents led to compounds of comparable in vitro potency to ICI 204,219, but of somewhat lower oral activity. A trend which suggested that more lipophilic transposed amides were needed to increase oral activity was exploited with some success and has led to the discovery of 5q (4-[[5-[(2-ethylbutyl)-carbamoyl]-1-ethylindol-3-yl]methyl]-3-methoxy-N-[(2-methylphenyl)sulfonyl]benzamide), a trans-posed amide with subnanomolar affinity for the leukotriene receptor and an oral ED50 of 5 mg/kg in a model of asthma in guinea pigs. In this model, ICI 204,219 was active at 0.4 mg/kg. The absolute bioavailability of 5q has been found to be 28% in the rat, as compared to 68% for ICI 204,219, with significant levels of 5q observed in the blood of rats up to 24 h postdose.

  DOI：

  10.1021/jm00055a011

文献信息

• 1,3,6-Trisubstituted indoles as peptidoleukotriene antagonists: benefits of a second, polar, pyrrole substituent
  作者：Frederick J. Brown、Laura A. Cronk、David Aharony、David W. Snyder

  DOI：10.1021/jm00091a010

  日期：1992.6

  for asthma. Two new elements of structural diversity were introduced to this series of antagonists. An investigation of pyrrole substituents in the 1,6-substituted indoles demonstrated that substitution at C-2 was detrimental to biological activity, but the incorporation of hydrophilic groups at C-3 was beneficial. The introduction of a propionamide moiety at C-3 enhanced activity by 1 order of magnitude;

  含有酰基氨基和N-芳基磺酰基酰胺附件的1，6-取代的和3,5-取代的吲哚和吲唑是肽白三烯LTD4和LTE4的有效拮抗剂。3，5-取代的吲哚系列的化合物，N- [4-[[5-[[（环戊氧基）]]]甲基] [甲基] [3-基]甲基] -3-甲氧基苯甲酰基] -2-甲基-苯磺酰胺（ICI 204,219）正在接受哮喘的临床评估。该系列拮抗剂引入了结构多样性的两个新元素。对1，6-取代的吲哚中吡咯取代基的研究表明，C-2处的取代对生物活性有害，但在C-3处引入亲水基团是有益的。在C-3处引入丙酰胺部分将活性提高了1个数量级。N- [4-[[6-（环戊基乙酰胺基）-3-] [2-（N-甲基氨基甲酰基）乙基]吲哚-1-基]甲基] -3-甲氧基-苯甲酰基]苯磺酰胺（15c）的pKB为10.7豚鼠气管上的LTD4受体。二取代拮抗剂的酰基氨基部分的修饰表明酰胺CO和NH原子的转位是可行的。在1，6-和3，5
• Jacobs Robert T., Brown Frederick J., Cronk Laura A., Aharony David, Buck+, J. Med. Chem., 36 (1993) N 3, S 394-409
  作者：Jacobs Robert T., Brown Frederick J., Cronk Laura A., Aharony David, Buck+

  DOI：——

  日期：——
• Carboxamide derivatives
  申请人：ICI AMERICAS INC.

  公开号：EP0220066B1

  公开（公告）日：1992-03-25
• US4918094A
  申请人：——

  公开号：US4918094A

  公开（公告）日：1990-04-17
• US5049576A
  申请人：——

  公开号：US5049576A

  公开（公告）日：1991-09-17