1-bromobenzyl-3-[3-tert-butylsulfanyl-5-(methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester | 1031435-50-3

• 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: 1-bromobenzyl-3-[3-tert-butylsulfanyl-5-(methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
• 英文别名: 3-(1-(4-bromobenzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl)-2,2-dimethylpropionic acid ethyl ester；3-[1-(4-Bromo-benzyl)-3-tert-butylsulfanyl-5-methoxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester；ethyl 3-[1-[(4-bromophenyl)methyl]-3-tert-butylsulfanyl-5-methoxyindol-2-yl]-2,2-dimethylpropanoate
• CAS: 1031435-50-3
• 化学式: C₂₇H₃₄BrNO₃S
• 分子量: 532.542
• InChiKey: FXNQAMOYEIDJGW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.2
• 重原子数：
  33
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.44
• 拓扑面积：
  65.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-bromobenzyl-3-[3-tert-butylsulfanyl-5-(methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester 在 aluminum (III) chloride 叔丁基硫醇 、 水 、 盐酸 作用下， 以 二氯甲烷 、 水 为溶剂， 生成 3-[1-(4-bromo-benzyl)-3-tert-butylsulfanyl-5-hydroxy-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein Inhibitor

  摘要：

  描述了一种FLAP抑制剂：3-[3-叔丁基硫基-1-[4-(6-乙氧基-吡啶-3-基)-苄基]-5-(5-甲基-吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸，或其药用可接受盐。还描述了制备该FLAP抑制剂的方法，或其药用可接受盐，包括水合物和其多晶型。还描述了适合给予哺乳动物的药物组合物，包括FLAP抑制剂，或其药用可接受盐，以及使用此类药物组合物治疗呼吸系统疾病或疾病的方法，以及治疗其他白三烯依赖性或白三烯介导的条件或疾病的方法。

  公开号：

  US20090291981A1
• 作为产物：
  描述：

  1-(4-methoxyphenyl)-1-bromobenzylhydrazine dihydrochloride 、 5-(叔丁基硫代)-2,2-二甲基-4-氧代戊酸乙酯 在 sodium acetate 、 溶剂黄146 作用下， 以 甲苯 为溶剂， 反应 96.0h， 以55%的产率得到1-bromobenzyl-3-[3-tert-butylsulfanyl-5-(methoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid ethyl ester
  参考文献：
  名称：

  5-Lipoxygenase-Activating Protein Inhibitors: Development of 3-[3-tert-Butylsulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic Acid (AM103)

  摘要：

  The potent and selective 5-lipoxygenase-activating protein leukotriene synthesis inhibitor 3-[3-tert-butyl-sulfanyl-1-[4-(6-methoxy-pyridin-3-yl)-benzyl]-5-(pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethylpropionic acid (11j) is described. Lead optimization was designed to afford compounds with superior in vitro and in vivo inhibition of leukotriene synthesis in addition to having excellent pharmacokinetics and safety in rats and dogs. The key structural features of these new compounds are incorporation of heterocycles on the indole N-benzyl substituent and replacement of the quinoline group resulting in compounds with excellent in vitro and in vim activities, superior pharmacokinetics, and improved physical properties. The methoxypyridine derivative 11j has an IC50 of 4.2 nM in a 5-lipoxygenase-activating protein (FLAP) binding assay, an IC50 of 349 nM in the human blood LTB4 inhibition assay, and is efficacious in a murine ovalbumin model of allergen-induced asthma. Compound 11j was selected for clinical development and has successfully completed phase I trials in healthy volunteers.

  DOI：

  10.1021/jm900945d

文献信息

• 5-Lipoxygenase-Activating Protein Inhibitor
  申请人：SCHAAB Kevin Murray

  公开号：US20090291981A1

  公开（公告）日：2009-11-26

  Described herein is the FLAP inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, or a pharmaceutically acceptable salt thereof. Also described are methods of preparing the FLAP inhibitor, or a pharmaceutically acceptable salt thereof, including solvates, and polymorphs thereof. Also described herein are pharmaceutical compositions suitable for administration to a mammal that include the FLAP inhibitor, or a pharmaceutically acceptable salt thereof, and methods of using such pharmaceutical compositions for treating respiratory conditions or diseases, as well as other leukotriene-dependent or leukotriene mediated conditions or diseases.

  描述了一种FLAP抑制剂：3-[3-叔丁基硫基-1-[4-(6-乙氧基-吡啶-3-基)-苄基]-5-(5-甲基-吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸，或其药用可接受盐。还描述了制备该FLAP抑制剂的方法，或其药用可接受盐，包括水合物和其多晶型。还描述了适合给予哺乳动物的药物组合物，包括FLAP抑制剂，或其药用可接受盐，以及使用此类药物组合物治疗呼吸系统疾病或疾病的方法，以及治疗其他白三烯依赖性或白三烯介导的条件或疾病的方法。
• COMPOSITIONS AND TREATMENTS COMPRISING 5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITORS AND NITRIC OXIDE MODULATORS
  申请人：Hutchinson John H.

  公开号：US20100068301A1

  公开（公告）日：2010-03-18

  Disclosed herein are compositions and compounds that combine an inhibitor of 5 -lipoxygenase activating protein (FLAP) and a modulator of NO levels in a mammal. The NO modulator can be an agent that induces the production of NO in a mammal, or can be an agent that itself produces NO in the mammal. Further disclosed herein are strategies for synthesizing such compounds, and methods for testing whether the combination compounds and compositions provide a desired benefit. Also disclosed herein are pharmaceutical compositions and formulations that combine a FLAP inhibitor and an NO modulator. Further described herein are methods for using such compositions and compounds for the treatment of diseases, conditions, and disorders in a mammal, including a human. Such treatment methods include the separate administration of a FLAP inhibitor and a NO modulator to the mammal, and the simultaneous administration of a FLAP inhibitor and a NO modulator to the mammal.

  本文揭示了一种将5-脂氧合酶激活蛋白（FLAP）抑制剂和哺乳动物中NO水平调节剂结合的组合物和化合物。NO调节剂可以是在哺乳动物中诱导NO产生的药物，也可以是在哺乳动物中自身产生NO的药物。本文还揭示了合成这种化合物的策略，以及测试组合化合物和组合物是否提供所需益处的方法。本文还揭示了将FLAP抑制剂和NO调节剂结合的制药组合物和配方。本文还进一步描述了使用这些组合物和化合物治疗哺乳动物（包括人类）的疾病、状况和障碍的方法。这种治疗方法包括将FLAP抑制剂和NO调节剂分别给哺乳动物，以及同时给哺乳动物FLAP抑制剂和NO调节剂。
• 5-LIPOXYGENASE ACTIVATING PROTEIN (FLAP) INHIBITOR
  申请人：REWOLINSKI Melissa Virginia

  公开号：US20100075934A1

  公开（公告）日：2010-03-25

  Described herein are methods for the synthesis of 3-[5-(pyridin-2-ylmethoxy)-3-(2-methyl-2-propylthio)-1-[4-(2-methoxypyridin-5-yl)benzyl]-indol-2-yl]-2,2-dimethyl-propionic acid, pharmaceutically acceptable salts, pharmaceutically acceptable solvates thereof. Also described are pharmaceutical compositions suitable for oral administration to a mammal that include, as well as methods of using such oral pharmaceutical compositions for treating respiratory conditions or diseases, as well as other leukotriene-dependent or leukotriene mediated conditions or diseases.

  本文描述了一种合成3-[5-(吡啶-2-基甲氧基)-3-(2-甲基-2-丙基硫)-1-[4-(2-甲氧基吡啶-5-基)苯基]-吲哚-2-基]-2,2-二甲基丙酸及其药学上可接受的盐和可接受的溶剂的方法。还描述了适用于口服给哺乳动物的药物组合物，以及使用这种口服药物组合物治疗呼吸道疾病或疾病以及其他白三烯依赖性或白三烯介导的疾病或疾病的方法。
• 5-LIPOXYGENASE-ACTIVATING PROTEIN INHIBITOR
  申请人：Schaab Kevin Murray

  公开号：US20110160249A1

  公开（公告）日：2011-06-30

  A pharmaceutically acceptable salt comprising 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionate as the anion and a cation selected from Na + , K + , Li + , Ca 2+ , NH 4 + , the protonated form of dicyclohexylamine, the protonated form of N-methyl-D-glucamine, the protonated form of tris(hydroxymethyl)methylamine, the protonated form of arginine, and the protonated form of lysine is disclosed, along with formulations and methods of using the same.

  本发明涉及一种药物可接受的盐，其包括3-[3-叔丁基磺酰基-1-[4-(6-乙氧基吡啶-3-基)-苄基]-5-(5-甲基吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸根离子和从Na+、K+、Li+、Ca2+、NH4+、二环己基胺质子化形式、N-甲基-D-葡萄糖胺质子化形式、三羟甲基甲基胺质子化形式、精氨酸质子化形式和赖氨酸质子化形式中选择的阳离子，以及使用它们的制剂和方法。
• 5-lipoxygenase-activating protein inhibitor
  申请人：Schaab Kevin Murray

  公开号：US08772495B2

  公开（公告）日：2014-07-08

  Described herein is the FLAP inhibitor 3-[3-tert-butylsulfanyl-1-[4-(6-ethoxy-pyridin-3-yl)-benzyl]-5-(5-methyl-pyridin-2-ylmethoxy)-1H-indol-2-yl]-2,2-dimethyl-propionic acid, or a pharmaceutically acceptable salt thereof. Also described are methods of preparing the FLAP inhibitor, or a pharmaceutically acceptable salt thereof, including solvates, and polymorphs thereof. Also described herein are pharmaceutical compositions suitable for administration to a mammal that include the FLAP inhibitor, or a pharmaceutically acceptable salt thereof, and methods of using such pharmaceutical compositions for treating respiratory conditions or diseases, as well as other leukotriene-dependent or leukotriene mediated conditions or diseases.

  本文描述了FLAP抑制剂3-[3-叔丁基硫基-1-[4-(6-乙氧基吡啶-3-基)-苄基]-5-(5-甲基吡啶-2-基甲氧基)-1H-吲哚-2-基]-2,2-二甲基丙酸或其药学上可接受的盐。还描述了制备FLAP抑制剂或其药学上可接受的盐，包括溶剂化合物和多晶形式的方法。本文还描述了适用于哺乳动物的制药组合物，包括FLAP抑制剂或其药学上可接受的盐，并且使用这种制药组合物治疗呼吸系统疾病或疾病的方法，以及其他白三烯依赖性或白三烯介导的疾病或疾病的方法。