(S)-4'-<<4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl>thio>acetophenone | 161387-22-0

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (S)-4'-<<4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl>thio>acetophenone
• 英文别名: 4'-{4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thien-2-ylthio}acetophenone；1-[4-[4-[(4S)-2,2,4-trimethyl-1,3-dioxolan-4-yl]thiophen-2-yl]sulfanylphenyl]ethanone
• CAS: 161387-22-0
• 化学式: C₁₈H₂₀O₃S₂
• 分子量: 348.487
• InChiKey: QXFUZAYIMAGSKV-GOSISDBHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  89.1
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (S)-4'-<<4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl>thio>acetophenone 在 盐酸羟胺 、 sodium acetate 作用下， 以 乙醇 为溶剂， 反应 2.0h， 以99%的产率得到(S)-4'-<<4-(2,2,4-trimethyl-1,3-dioxolan-4-yl)thien-2-yl>thio>acetophenone oxime
  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-(5-溴噻吩-3-基)乙酮 在 AD-mix-α 、 正丁基锂 、 水 、 potassium carbonate 、 对甲苯磺酸 、 sodium thiomethoxide 作用下， 以 N,N-二甲基甲酰胺 、 丙酮 、 叔丁醇 为溶剂， 反应 28.25h， 生成 (S)-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

文献信息

• Oxime derivatives
  申请人：Zeneca Limited

  公开号：US05482966A1

  公开（公告）日：1996-01-09

  The invention concerns oxime derivatives of the formula I ##STR1## wherein R.sup.4 includes hydrogen, carboxy, carbamoyl, amino, cyano, trifluoromethyl, (1-4C)alkylamino, di-(1-4C)alkylamino and (1-4C)alkyl; R.sup.5 includes hydrogen, (1-4C)alkyl, (3-4C)alkenyl, (3-4C)alkynyl, (2-5C)alkanoyl, halogeno-(2-4C)alkyl and hydroxy-(2-4C)alkyl; Ar.sup.1 is phenylene or a heteroaryl diradical; A.sup.1 is a direct link to X.sup.1, or A.sup.1 is (1-4C)alkylene; X.sup.1 is oxy, thio, sulphinyl or sulphonyl; Ar.sup.2 is phenylene or a heteroaryl diradical; R.sup.1 is (1-4C)alkyl, (3-4C)alkenyl or (3-4C)alkynyl; and R.sup.2 and R.sup.3 together form a group of the formula --A.sup.2 --X.sup.2 --A.sup.3 -- which together with the carbon atom to which A.sup.2 and A.sup.3 are attached define a ring having 5 or 6 ring atoms, wherein each of A.sup.2 and A.sup.3 is (1-3C)alkylene and X.sup.2 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：##STR1##其中R.sup.4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；R.sup.5包括氢，(1-4C)烷基，(3-4C)烯基，(3-4C)炔基，(2-5C)烷酰基，卤代(2-4C)烷基和羟基-(2-4C)烷基；Ar.sup.1是苯基或杂环双自由基；A.sup.1是直接连接到X.sup.1的链或(1-4C)烷基；X.sup.1是氧，硫，亚砜或亚磺酰基；Ar.sup.2是苯基或杂环双自由基；R.sup.1是(1-4C)烷基，(3-4C)烯基或(3-4C)炔基；R.sup.2和R.sup.3共同形成一个式为--A.sup.2--X.sup.2--A.sup.3--的基团，其中A.sup.2和A.sup.3各自为(1-3C)烷基，X.sup.2是氧，硫，亚砜，亚磺酰基或亚胺基；或其药学上可接受的盐；制造它们的过程；含有它们的制药组合物及其作为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.