(5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, t-butyl ester | 524714-15-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯酚醚
• 英文名称: (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, t-butyl ester
• 英文别名: tert-butyl 2-((2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynyloxy)acetate；tert-butyl 2-[(2S,3R,4E,6E,10E,12S)-13-(4-fluorophenoxy)-2,3,12-trihydroxytrideca-4,6,10-trien-8-ynoxy]acetate
• CAS: 524714-15-6
• 化学式: C₂₅H₃₁FO₇
• 分子量: 462.515
• InChiKey: MBLGHVUNVLXDBJ-JKESKNCGSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  33
• 可旋转键数：
  13
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, t-butyl ester 在 甲醇 、 sodium hydroxide 、 水 、 盐酸 作用下， 以 甲醇 为溶剂， 反应 3.0h， 生成 ZK-994
  参考文献：
  名称：

  Crystalline acid of lipoxin A4 analogs and method of making

  摘要：

  本发明涉及一种晶体酸，其为公式（II）中的脂氧素A4类似物，其中：R1为—O—，—S（O）t—（其中t为0、1或2），或直链或支链烷基链；R2为芳基（可选地被一种或多种取代基所取代，所述取代基选择自烷基、烷氧基、卤、卤代烷基和卤代烷氧基）或芳基烷基（可选地被一种或多种取代基所取代，所述取代基选择自烷基、烷氧基、卤、卤代烷基和卤代烷氧基）；并且公式（II）化合物是单一立体异构体或任何立体异构体混合物。该晶体酸在治疗炎症等疾病状态方面具有用途，例如人类的炎症性和自身免疫性疾病或肺部或呼吸道炎症。本文还描述了制备该晶体酸的方法。

  公开号：

  US20080182901A1
• 作为产物：
  描述：

  (2S,3E)-4-溴-1-(4-氟苯氧基)-3-丁烯-2-醇 在 copper(l) iodide 、 四(三苯基膦)钯 、 溶剂黄146 、 二乙胺 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 22.0h， 生成 (5S,6R,7E,9E,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-3-oxahexadeca-7,9,13-trien-11-ynoic acid, t-butyl ester
  参考文献：
  名称：

  Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo

  摘要：

  Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.

  DOI：

  10.1021/jm030569l

文献信息

• Intermediates for the preparation of lipoxin A4 analogs
  申请人：Bauman G. John

  公开号：US20070037864A1

  公开（公告）日：2007-02-15

  This invention is directed to lipoxin A 4 analogs of the following formula (I) and (II): wherein R 1 , R 2 , R 3 , R 4 and R 5 are described herein. These analogs are useful in treating inflammatory and autoimmune disorders in humans. These analogs are also useful in treating pulmonary or respiratory tract inflammation in humans.

  本发明涉及以下公式（I）和（II）的脂氧素A4类似物：其中R1，R2，R3，R4和R5如本文所述。这些类似物在治疗人类的炎症和自身免疫性疾病方面非常有用。这些类似物还在治疗人类的肺部或呼吸道炎症方面非常有用。
• ANHYDROUS AND HYDRATE FORMS OF CRYSTALLINE 2- ( (2S, 3R, 4E, 6E, 1OE, 12S) -13- (4-FLUOROPHENOXY) -2,3, 12- (TRIHYDROXYTRIDECA-4, 6, 10-TRIEN-8-YNYL) OXY) ACETIC ACID
  申请人：Bayer Schering Pharma Aktiengesellschaft

  公开号：EP2288414A1

  公开（公告）日：2011-03-02
• US7928255B2
  申请人：——

  公开号：US7928255B2

  公开（公告）日：2011-04-19
• [EN] ANHYDROUS AND HYDRATE FORMS OF CRYSTALLINE 2- ( (2S, 3R, 4E, 6E, 1OE, 12S) -13- (4-FLUOROPHENOXY) -2,3, 12- (TRIHYDROXYTRIDECA-4, 6, 10-TRIEN-8-YNYL) OXY) ACETIC ACID<br/>[FR] FORMES ANHYDRES ET HYDRATÉES D'ACIDE ACÉTIQUE CRISTALLIN 2-((2S, 3R, 4E, 6E, 1OE, 12S)-13-(4-FLUOROPHÉNOXY)-2,3,12-(TRIHYDROXYTRIDÉCA-4, 6, 10-TRIÉN-8-YNYL) OXY)
  申请人：BAYER SCHERING PHARMA AG

  公开号：WO2009140984A1

  公开（公告）日：2009-11-26

  This invention is directed to a crystalline acid of a lipoxin A4 analog in an anhydrous form which exhibits characteristic peaks at d = 20.48 A and at d = 4.34 A and in a hydrate form which exhibits characteristic peaks at d = 9.8 A and at d = 4.6 A.
• Novel 3-Oxa Lipoxin A₄ Analogues with Enhanced Chemical and Metabolic Stability Have Anti-inflammatory Activity in Vivo
  作者：William J. Guilford、John G. Bauman、Werner Skuballa、Shawn Bauer、Guo Ping Wei、David Davey、Caralee Schaefer、Cornell Mallari、Jennifer Terkelsen、Jih-Lie Tseng、Jun Shen、Babu Subramanyam、Arndt J. Schottelius、John F. Parkinson

  DOI：10.1021/jm030569l

  日期：2004.4.1

  Lipoxin A(4) (LXA(4)) is a structurally and functionally distinct natural product called an eicosanoid, which displays immunomodulatory and anti-inflammatory activity but is rapidly metabolized to inactive catabolites in vivo. A previously described analogue of LXA(4), methyl (5R,6R,7E,9E,11Z,13E,15S)-16-(4-fluorophenoxy)-5,6,15-trihydroxy-7,9,11,13-hexadecatetraenoate (2, ATLa), was shown to have a poor pharmacokinetic profile after both oral and intravenous administration, as well as sensitivity to acid and light. The chemical stability of the corresponding E,E,E-trien-11-yne analogue, 3, was improved over 2 without loss of efficacy in the mouse air pouch model of inflammation. Careful analysis of the plasma samples from the pharmacokinetic assays for both 2 and 3 identified a previously undetected metabolite, which is consistent with metabolism by beta-oxidation. The formation of the oxidative metabolites was eliminated with the corresponding 3-oxatetraene, 4, and the 3-oxatrien-11-yne, 5, analogues of 2. Evaluation of 3-oxa analogues 4 and 5 in calcium ionophore-induced acute skin inflammation model demonstrated similar topical potency and efficacy compared to 2. The 3-oxatrien-11-yne analogue, 5, is equipotent to 2 in an animal model of inflammation but has enhanced metabolic and chemical stability and a greatly improved pharmacokinetic profile.