(E)-[5-(2-Diethylcarbamoyl-1-methylvinyl)-2-(diphenylmethoxy)-phenoxy]-acetic acid

• 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: (E)-[5-(2-Diethylcarbamoyl-1-methylvinyl)-2-(diphenylmethoxy)-phenoxy]-acetic acid
• 英文别名: 2-[2-benzhydryloxy-5-[(E)-4-(diethylamino)-4-oxobut-2-en-2-yl]phenoxy]acetic acid
• 化学式: C₂₉H₃₁NO₅
• 分子量: 473.569
• InChiKey: GSEDSUKYJKVJSE-DYTRJAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.9
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为产物：
  描述：

  diethyl <(diethylcarbamoyl)methyl>phosphonate 在 sodium hydroxide 、 sodium hydride 作用下， 以 甲醇 为溶剂， 反应 20.0h， 生成 (E)-[5-(2-Diethylcarbamoyl-1-methylvinyl)-2-(diphenylmethoxy)-phenoxy]-acetic acid
  参考文献：
  名称：

  Carboxy-Substituted Cinnamides:  A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists

  摘要：

  A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B-4 (LTB4) receptor. Binding was determined through measurement of [H-3]-LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.

  DOI：

  10.1021/jm980540v

文献信息

• ARYL-SUBSTITUTED ACRYLAMIDES WITH LEUKOTRIENE B4 (LTB-4) RECEPTOR ANTAGONIST ACTIVITY
  申请人：Novartis AG

  公开号：EP0942903A1

  公开（公告）日：1999-09-22
• US6291530B1
  申请人：——

  公开号：US6291530B1

  公开（公告）日：2001-09-18
• [EN] ARYL-SUBSTITUTED ACRYLAMIDES WITH LEUKOTRIENE B4 (LTB-4) RECEPTOR ANTAGONIST ACTIVITY<br/>[FR] ACRYLAMIDES SUBSTITUES PAR DE L'ARYLE AYANT UNE ACTIVITE ANTAGONISTE DU RECEPTEUR LEUCOTRIENE B4 (LTB-4)
  申请人：NOVARTIS AG

  公开号：WO1998013347A1

  公开（公告）日：1998-04-02

  (EN) Disclosed are compounds of formula (I) wherein W is CH or N; R is (mono- or di-carbocyclic or heterocyclic aryl)-lower alkyl; R1 is hydrogen or lower alkyl; R2 and R3 are hydrogen, lower alkyl, lower alkoxy-lower alkyl or aryl-lower alkyl; or R2 and R3 joined together represent lower alkylene optionally interrupted by O, NH, N-lower alkyl or S so as to form a ring with the amide nitrogen; X is O, S, SO, SO2 or a direct bond; X1 is O, S, SO, SO2 or a direct bond; Y is a direct bond, lower alkylene or lower alkylidene; and Z is carboxyl, 5-tetrazolyl, hydroxymethyl or carboxyl derivatized in the form of a pharmaceutically acceptable ester; and pharmaceutically acceptable salts thereof; which are useful as LTB-4 antagonists.(FR) L'invention concerne les composés présentant la formule (I). Dans cette dernière, W représente CH ou N; R est (aryle mono- ou di-carbocyclique ou hétérocyclique)-alkyle inférieur; R1 est hydrogène ou alkyle inférieur; R2 et R3 sont hydrogène, alkyle inférieur, alcoxy inférieur-alkyle inférieur ou aryle-alkyle inférieur; ou R2 et R3 assemblés représentent de l'alkylène inférieur éventuellement interrompu par O, NH, N-alkyle inférieur ou S pour former une chaîne avec l'azote d'amide; X est O, S, SO, SO2 ou une liaison directe; X1 est O, S, SO, SO2 ou une liaison directe; Y est une liaison directe, de l'alkylène inférieure ou de l'alkylidène inférieur, et Z est carboxyle, 5-tétrazolyle, hydroxyméthyle ou du carboxyle dérivé sous forme d'un ester pharmaceutiquement acceptable. L'invention traite aussi de sels pharmaceutiquement acceptables de ces derniers qui sont utiles comme antagonistes de la leucotriène B-4.
• Carboxy-Substituted Cinnamides:  A Novel Series of Potent, Orally Active LTB₄ Receptor Antagonists
  作者：Paul D. Greenspan、Roger A. Fujimoto、Paul J. Marshall、Anil Raychaudhuri、Kenneth E. Lipson、Huanghai Zhou、Robert A. Doti、David E. Coppa、Lijuan Zhu、Roberta Pelletier、Susan Uziel-Fusi、Robert H. Jackson、Michael H. Chin、Bernard L. Kotyuk、John J. Fitt

  DOI：10.1021/jm980540v

  日期：1999.1.1

  A series of carboxy-substituted cinnamides were investigated as antagonists of the human cell surface leukotriene B-4 (LTB4) receptor. Binding was determined through measurement of [H-3]-LTB4 displacement from human neutrophils. Receptor antagonism was confirmed through a functional assay, which measures inhibition of Ca2+ release in human neutrophils. Potent antagonists were discovered through optimization of a random screening hit, a p-(alpha-methylbenzyloxy)cinnamide, having low-micromolar activity. Substantial improvement of in vitro potency was realized by the attachment of a carboxylic acid moiety to the cinnamide phenyl ring through a flexible tether, leading to identification of compounds with low-nanomolar potency. Modification of the benzyloxy substituent, either through ortho-substitution on the benzyloxy phenyl group or through replacement of the ether oxygen with a methylene or sulfur atom, produced achiral antagonists of equal or greater potency. The most potent compounds in vitro were assayed for oral activity using the arachidonic acid-induced mouse ear edema model of inflammation. Several compounds in this series were found to significantly inhibit edema formation and myeloperoxidase activity in this model up to 17 h after oral administration. Representatives of this series have been shown to be potent and long-acting orally active inhibitors of the LTB4 receptor.