2-(methylthio)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiophene | 161386-85-2

• 分子结构分类: 有机化合物 - 有机硫化合物 - 硫醚类
• 英文名称: 2-(methylthio)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiophene
• 英文别名: 4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)-2-methylthiothiophene；2,2,4-Trimethyl-4-(5-methylsulfanylthiophen-3-yl)-1,3-dioxolane
• CAS: 161386-85-2
• 化学式: C₁₁H₁₆O₂S₂
• 分子量: 244.379
• InChiKey: LMTDBEKLMFJARP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  15
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  72
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-(methylthio)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiophene 在 potassium carbonate 、 sodium thiomethoxide 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 2.0h， 生成 4'-<<4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl>thio>acetophenone
  参考文献：
  名称：

  Chiral Dioxolane Inhibitors of Leukotriene Biosynthesis: Structure-Activity Relationships and Syntheses Using Asymmetric Dihydroxylation

  摘要：

  1,3-Dioxolanes have been described as chiral inhibitors of 5-lipoxygenase (5LO). In the present work, this series has been developed further to provide agents which showed comparable or superior potency in vivo to ZD2138, a methoxytetrahydropyran inhibitor of 5LO, which is currently undergoing clinical evaluation. An asymmetric synthesis was developed to these dioxolanes based on asymmetric dihydroxylation. (S)-N-Methyl-4'-[[4-(2,2,4-trimethyl-1,3 dioxolan-4-yl)thien-2-yl]thio]acetanilid ((S)-10d) inhibited leukotriene B-4 (LTB(4)) synthesis in A23187-stimulated human whole blood in vitro with IC50 0.039 mu M, 25-fold more potent than (R)-10d. In vivo, (S)-10d inhibited LTB(4) synthesis by 70% in zymosan-inflamed air pouch exudate in rat 10 h after an oral dose of 1.5 mg/kg. Structure-activity relationship considerations suggested that the dioxolane and methoxytetrahydropyran series are related, a conclusion which can be supported by molecular modeling.

  DOI：

  10.1021/jm00020a008
• 作为产物：
  描述：

  1-(Tetrahydro-pyran-2-yloxy)-2-thiophen-3-yl-propan-2-ol 在 盐酸 、 正丁基锂 、 对甲苯磺酸 作用下， 以 甲醇 、 丙酮 为溶剂， 反应 2.25h， 生成 2-(methylthio)-4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thiophene
  参考文献：
  名称：

  Chiral Dioxolane Inhibitors of Leukotriene Biosynthesis: Structure-Activity Relationships and Syntheses Using Asymmetric Dihydroxylation

  摘要：

  1,3-Dioxolanes have been described as chiral inhibitors of 5-lipoxygenase (5LO). In the present work, this series has been developed further to provide agents which showed comparable or superior potency in vivo to ZD2138, a methoxytetrahydropyran inhibitor of 5LO, which is currently undergoing clinical evaluation. An asymmetric synthesis was developed to these dioxolanes based on asymmetric dihydroxylation. (S)-N-Methyl-4'-[[4-(2,2,4-trimethyl-1,3 dioxolan-4-yl)thien-2-yl]thio]acetanilid ((S)-10d) inhibited leukotriene B-4 (LTB(4)) synthesis in A23187-stimulated human whole blood in vitro with IC50 0.039 mu M, 25-fold more potent than (R)-10d. In vivo, (S)-10d inhibited LTB(4) synthesis by 70% in zymosan-inflamed air pouch exudate in rat 10 h after an oral dose of 1.5 mg/kg. Structure-activity relationship considerations suggested that the dioxolane and methoxytetrahydropyran series are related, a conclusion which can be supported by molecular modeling.

  DOI：

  10.1021/jm00020a008

文献信息

• Acetanilide derivatives
  申请人：ZENECA LIMITED

  公开号：EP0610032A1

  公开（公告）日：1994-08-10

  The invention concerns acetanilide derivatives of the formula I wherein R⁴ is (1-4C)alkyl; R⁵ is hydrogen or (1-4C)alkyl; Ar¹ is phenylene, pyridinediyl or pyrimidinediyl; A¹ is a direct link to X¹ or A¹ is (1-4C)alkylene; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is thiophenediyl, furandiyl, thiazolediyl, oxazolediyl, thiadiazolediyl or oxadiazolediyl; R¹ and R² together form a group of the formula -A²-X²-A³- which together with the oxygen atom to which A² is attached and with the carbon atom to which A³ is attached define a ring having 5 or 6 ring atoms, wherein each of A² and A³ is (1-3C)alkylene and X² is oxy, thio, sulphinyl or sulphonyl and which ring may bear one, two or three (1-4C)alkyl substituents; and R³ is (1-4C)alkyl; or pharmaceutically-acceptable salts thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

  该发明涉及具有以下式I的乙酰苯胺衍生物，其中R⁴是(1-4C)烷基；R⁵是氢或(1-4C)烷基；Ar¹是苯基、吡啶二基或嘧啶二基；A¹是直接连接到X¹的链或A¹是(1-4C)烷基；X¹是氧、硫、亚砜基或砜基；Ar²是噻吩二基、呋喃二基、噻唑二基、噁唑二基、噻二唑二基或噁二唑二基；R¹和R²一起形成一个具有5或6个环原子的环的基团，其中A²和A³各自是(1-3C)烷基，X²是氧、硫、亚砜基或砜基，该环可能具有一个、两个或三个(1-4C)烷基取代基；R³是(1-4C)烷基；或其药用可接受盐；其制备方法；含有它们的药物组合物以及它们作为5-脂氧合酶抑制剂的用途。
• Oxime derivatives as 5-lipoxygenase inhibitors
  申请人：ZENECA LIMITED

  公开号：EP0555068A1

  公开（公告）日：1993-08-11

  The invention concerns oxime derivatives of the formula I wherein R⁴ includes hydrogen, carboxy, carbamoyl, amino, cyano, trifluoromethyl, (1-4C)alkylamino, di-(1-4C)alkylamino and (1-4C)alkyl; R⁵ includes hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl and hydroxy-(2-4C)alkyl; Ar¹ is phenylene or a heteroaryl diradical; A¹ is a direct link to X¹, or A¹ is (1-4C)alkylene; X¹ is oxy, thio, sulphinyl or sulphonyl; Ar² is phenylene or a heteroaryl diradical; R¹ is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R² and R³ together form a group of the formula -A²-x²-A³- which together with the carbon atom to which A² and A³ are attached define a ring having 5 or 6 ring atoms, wherein each of A² and A³ is (1-3C)alkylene and X² is oxy, thio, sulphinyl, sulphonyl or imino; or a pharmaceutically-acceptable salt thereof; processes for their manufacture; pharmaceutical compositions containing them and their use as 5-lipoxygenase inhibitors.

  本发明涉及式 I 的肟衍生物 其中 R⁴包括氢、羧基、氨基甲酰基、氨基、氰基、三氟甲基、(1-4C)烷基氨基、二(1-4C)烷基氨基和(1-4C)烷基； R⁵ 包括氢、(1-4C)烷基、(3-4C)烯基、(3-4C)炔基、(2-5C)烷酰基、卤素-(2-4C)烷基和羟基-(2-4C)烷基； Ar¹ 是亚苯基或二元杂芳基； A¹ 是与 X¹ 的直接连接，或 A¹ 是（1-4C）亚烷基； X¹ 是氧基、硫代、亚砜基或磺酰基； Ar² 是亚苯基或二元杂芳基； R¹ 是(1-4C)烷基、(3-4C)烯基或(3-4C)炔基；以及 R² 和 R³ 一起形成式 -A²-x²-A³- 的基团，该基团与 A² 和 A³ 所连接的碳原子一起定义了一个具有 5 或 6 个环原子的环，其中 A² 和 A³ 均为 (1-3C)亚烷基，X² 为氧基、硫代、亚砜基、磺酰基或亚氨基； 或其药学上可接受的盐； 它们的制造工艺；含有它们的药物组合物及其作为 5-脂氧合酶抑制剂的用途。
• US5332757A
  申请人：——

  公开号：US5332757A

  公开（公告）日：1994-07-26
• US5482966A
  申请人：——

  公开号：US5482966A

  公开（公告）日：1996-01-09
• Chiral Dioxolane Inhibitors of Leukotriene Biosynthesis: Structure-Activity Relationships and Syntheses Using Asymmetric Dihydroxylation
  作者：Graham C. Crawley、Malcolm T. Briggs

  DOI：10.1021/jm00020a008

  日期：1995.9

  1,3-Dioxolanes have been described as chiral inhibitors of 5-lipoxygenase (5LO). In the present work, this series has been developed further to provide agents which showed comparable or superior potency in vivo to ZD2138, a methoxytetrahydropyran inhibitor of 5LO, which is currently undergoing clinical evaluation. An asymmetric synthesis was developed to these dioxolanes based on asymmetric dihydroxylation. (S)-N-Methyl-4'-[[4-(2,2,4-trimethyl-1,3 dioxolan-4-yl)thien-2-yl]thio]acetanilid ((S)-10d) inhibited leukotriene B-4 (LTB(4)) synthesis in A23187-stimulated human whole blood in vitro with IC50 0.039 mu M, 25-fold more potent than (R)-10d. In vivo, (S)-10d inhibited LTB(4) synthesis by 70% in zymosan-inflamed air pouch exudate in rat 10 h after an oral dose of 1.5 mg/kg. Structure-activity relationship considerations suggested that the dioxolane and methoxytetrahydropyran series are related, a conclusion which can be supported by molecular modeling.