1-[2-Hydroxy-3-propyl-4-(4-{2-[4-(1H-tetrazol-5-yl)-butyl]-2H-tetrazol-5-ylmethyl}-phenoxymethyl)-phenyl]-ethanone | 122267-97-4

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-[2-Hydroxy-3-propyl-4-(4-{2-[4-(1H-tetrazol-5-yl)-butyl]-2H-tetrazol-5-ylmethyl}-phenoxymethyl)-phenyl]-ethanone
• 英文别名: 1-[2-hydroxy-3-propyl-4-[[4-[[2-[4-(2H-tetrazol-5-yl)butyl]tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone
• CAS: 122267-97-4
• 化学式: C₂₅H₃₀N₈O₃
• 分子量: 490.565
• InChiKey: SHVOCOXHKWYMBA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5
• 重原子数：
  36
• 可旋转键数：
  13
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  145
• 氢给体数：
  2
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  5-溴戊腈 在 sodium hydroxide 、 三正丁基叠氮化锡 作用下， 以 四氢呋喃 、 乙二醇二甲醚 为溶剂， 反应 116.0h， 生成 1-[2-Hydroxy-3-propyl-4-(4-{2-[4-(1H-tetrazol-5-yl)-butyl]-2H-tetrazol-5-ylmethyl}-phenoxymethyl)-phenyl]-ethanone
  参考文献：
  名称：

  (Phenylmethoxy)phenyl derivatives of w-oxo- and w-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists

  摘要：

  Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the OMEGA-[(phenylmethoxy)phenyl]-OMEGA-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5-oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pK(B) of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.4 mg/kg iv). Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds. In the OMEGA-[5-[[(phenylmethoxy)phenyl]alkyl]tetrazolyl]alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD4 pressor response in rat. The pK(B) value in the guinea pig ileum for 1-[2-hydroxy-3-propyl-4-[[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone (25) was 7.87 and the ED50 for antagonism of the LTD4 pressor response was 4.0 mg/kg iv. The sodium salts of 8 (9) and 25 (26) given by the iv route of administration antagonized LTD4-induced cardiovascular alterations in anesthetized rat and LTD4-induced bronchoconstriction in guinea pig in a dose-dependent manner. Oral activity was also demonstrated against the LTD4-induced bronchoconstriction in guinea pig.

  DOI：

  10.1021/jm00113a014

文献信息

• Leukotriene antagonists
  申请人：ELI LILLY AND COMPANY

  公开号：EP0305085A1

  公开（公告）日：1989-03-01

  The instant invention provides disubstituted tetrazoles that antagonizes the effect of leukotrienes C₄, D₄ and E₄ in selected tissues. The disubstituted tetrazoles are used in pharmaceutical formulations and methods of treatment of conditions caused by excessive amounts of leukotrienes C₄, D₄ or E₄ or any combination thereof, and have the formula: wherein: R₁ is C₁ to C₃ alkyl; R₂ is C₁ to C₆ alkyl or C₃ to C₆ alkenyl; R₃ is a hydrogen atom, chloro, bromo, nitro, or a group of the formula -NRaRb wherein Ra and Rb are the same or different and are a hydrogen atom, C₁ to C₄ alkyl, phenyl, benzyl, or C₁ to C₄ acyl; R₄ and R₅ are the same or different and are a hydrogen atom or C₁ to C₃ alkyl; W is from one to six; Z is O, S or a group of the formula -NRe , (wherein Re is a hydrogen atom, C₁ to C₄ alkyl, C₁ to C₄ acyl, phenyl, or benzyl); n is 0 to 6; Rc and Rd are the same or different and are hydrogen, hydroxy, halo or an ether group of the formula -O-(C₁ to C₆ alkyl); [Tet] is a disubstituted 1H- or 2H-tetrazolyl ring of the formula wherein: L is 1) C₁ to C₁₀ alkylidene; or 2) a group of the formula wherein y is 1 to 3 (and the phenyl ring is bonded to A); A is 1) 5-(tetrazolyl); 2) carboxy; 3) -NRfRg,wherein Rf and Rg are the same or different and are a hydrogen atom, C₁ to C₄ alkyl, phenyl, benzyl or C₁ to C₄ acyl; or 4) a group of the formula wherein q is 0, 1 or 2 and Rh is C₁ to C₄ alkyl, phenyl or benzyl; or a pharmaceutically-acceptable salt thereof.

  本发明提供了能拮抗白三烯 C₄、D₄ 和 E₄ 在选定组织中的作用的二取代四唑。本发明的二取代四唑可用于治疗由白三烯 C₄、D₄ 或 E₄或它们的任何组合过量引起的疾病的药物制剂和方法，其式如下 其中 R₁ 是 C₁ 至 C₃ 烷基； R₂ 是 C₁ 至 C₆ 烷基或 C₃ 至 C₆ 烯基； R₃ 是氢原子、氯、溴、硝基或式 1 所示的基团 -NRaRb 其中，Ra 和 Rb 可以相同或不同，并且是氢原子、C₁ 至 C₄ 烷基、苯基、苄基、炔基或式 -NRaRb 的基团、 苯基、苄基或 C₁ 至 C₄酰基； R₄ 和 R₅ 相同或不同，并且是氢原子或 C₁ 至 C₃ 烷基； W 为 1 至 6； Z 是 O、S 或一个式中的基团 -NRe、 (其中 Re 是氢原子、C₁ 至 C₄烷基、C₁ 至 C₄酰基、苯基或苄基）； n 为 0 至 6； Rc 和 Rd 相同或不同，并且是氢、羟基、卤代或式 -O- （C₁ 至 C₆烷基）的醚基； [Tet] 是式中的二取代 1H- 或 2H- 四唑环 其中 L 是 1) C₁ 至 C₁₀ 亚烷基；或 2) 式中的基团 其中 y 为 1 至 3（苯基环与 A 键合）； A 是 1) 5-(四唑基) 2) 羧基 3) -NRfRg，其中 Rf 和 Rg 相同或不同，并且是氢原子、C₁ 至 C₄ 烷基、苯基、苄基或 C₁ 至 C₄酰基；或 4) 式中的基团 其中 q 为 0、1 或 2，Rh 为 C₁ 至 C₄ 烷基、苯基或苄基； 或其药学上可接受的盐。
• (Phenylmethoxy)phenyl derivatives of w-oxo- and w-tetrazolylalkanoic acids and related tetrazoles. Synthesis and evaluation as leukotriene D4 receptor antagonists
  作者：Robert D. Dillard、Richard A. Hahn、Doris McCullough、F. Patrick Carr、Lynn E. Rinkema、Carlos R. Roman、Jerome H. Fleisch

  DOI：10.1021/jm00113a014

  日期：1991.9

  Two series of (phenylmethoxy)phenyl compounds derived from the structure of LY163443 were synthesized and evaluated as leukotriene D4 receptor antagonists. In the OMEGA-[(phenylmethoxy)phenyl]-OMEGA-oxoalkanoic acid series, 5-[4-[(4-acetyl-2-ethyl-3-hydroxyphenyl)methoxy]phenyl]-3,3-dimethyl-5-oxopentanoic acid (8) was the most potent antagonist of LTD4-induced contractions of guinea pig ileum (pK(B) of 7.60) and LTD4 pressor response in pithed rats (ED50 of 1.4 mg/kg iv). Replacing the carboxylic acid function with 5-tetrazole gave slightly more potent compounds. In the OMEGA-[5-[[(phenylmethoxy)phenyl]alkyl]tetrazolyl]alkanoic acid series, replacing the carboxylic acid with 5-tetrazole gave compounds that were equally effective in the guinea pig ileum but more potent in vivo against the LTD4 pressor response in rat. The pK(B) value in the guinea pig ileum for 1-[2-hydroxy-3-propyl-4-[[4-[[2-[3-(1H-tetrazol-5-yl)propyl]-2H-tetrazol-5-yl]methyl]phenoxy]methyl]phenyl]ethanone (25) was 7.87 and the ED50 for antagonism of the LTD4 pressor response was 4.0 mg/kg iv. The sodium salts of 8 (9) and 25 (26) given by the iv route of administration antagonized LTD4-induced cardiovascular alterations in anesthetized rat and LTD4-induced bronchoconstriction in guinea pig in a dose-dependent manner. Oral activity was also demonstrated against the LTD4-induced bronchoconstriction in guinea pig.