methyl 6-(tert-butylthio)-2,2-dimethyl-5-oxohexanoate | 147936-55-8

• 分子结构分类: 有机化合物 - 脂质和类脂质分子 - 脂肪酰基
• 英文名称: methyl 6-(tert-butylthio)-2,2-dimethyl-5-oxohexanoate
• 英文别名: methyl 6-t-butylthio-2,2-dimethyl-5-oxohexanoate；methyl 6-tert-butylsulfanyl-2,2-dimethyl-5-oxohexanoate
• CAS: 147936-55-8
• 化学式: C₁₃H₂₄O₃S
• 分子量: 260.398
• InChiKey: MVWSMGOZPLZVII-UHFFFAOYSA-N

物化性质

• 沸点：
  331.2±22.0 °C(predicted)
• 密度：
  1.010±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.7
• 重原子数：
  17
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  68.7
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  methyl 6-(tert-butylthio)-2,2-dimethyl-5-oxohexanoate 在 lithium hydroxide 、 sodium acetate 、 sodium hydride 、 对甲苯磺酸 、 溶剂黄146 作用下， 以 四氢呋喃 、 甲醇 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 46.75h， 生成 4-[1-(4-Chloro-benzyl)-4-methyl-6-(5-phenyl-pyridin-2-ylmethoxy)-4,5-dihydro-1H-3-thia-1-aza-acenaphthylen-2-yl]-2,2-dimethyl-butyric acid
  参考文献：
  名称：

  Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816

  摘要：

  Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropyl]-1H-tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16,75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg;2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

  DOI：

  10.1021/jm00071a008
• 作为产物：
  描述：

  2,2-二甲基戊二酸二甲酯 在 盐酸 、 氯化亚砜 、 四丁基溴化铵 、 potassium carbonate 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 水 为溶剂， 反应 91.0h， 生成 methyl 6-(tert-butylthio)-2,2-dimethyl-5-oxohexanoate
  参考文献：
  名称：

  Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816

  摘要：

  Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropyl]-1H-tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16,75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg;2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

  DOI：

  10.1021/jm00071a008

文献信息

• Thiopyrano[2,3,4-c,d]indoles as inhibitors of leukotriene biosynthesis
  申请人：Merck Frosst Canada, Inc.

  公开号：US05202321A1

  公开（公告）日：1993-04-13

  Compounds having the formula I: ##STR1## are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, psoriasis, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.

  化学式为I的化合物：##STR1## 是白三烯生物合成的抑制剂。这些化合物可作为抗哮喘、抗过敏、抗炎和细胞保护剂使用。它们还可用于治疗心绞痛、脑血管痉挛、肾小球肾炎、肝炎、内毒素血症、银屑病、葡萄膜炎和移植排斥，并可预防动脉粥样硬化斑块的形成。
• Thiopyrano (2,3,4-c,d) indoles as inhibitors of leukotriene biosynthesis
  申请人：MERCK FROSST CANADA INC.

  公开号：EP0518426A1

  公开（公告）日：1992-12-16

  Compounds having the formula I: are inhibitors of leukotriene biosynthesis. These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating angina, cerebral spasm, glomerular nephritis, hepatitis, endotoxemia, psoriasis, uveitis and allograft rejection and in preventing the formation of atherosclerotic plaques.

  具有式 I 的化合物： 是白三烯生物合成的抑制剂。这些化合物可用作抗哮喘、抗过敏、抗炎和细胞保护剂。它们还可用于治疗心绞痛、脑痉挛、肾小球肾炎、肝炎、内毒素血症、银屑病、葡萄膜炎和异体移植排斥反应，以及预防动脉粥样硬化斑块的形成。
• US5202321A
  申请人：——

  公开号：US5202321A

  公开（公告）日：1993-04-13
• Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816
  作者：J. H. Hutchinson、D. Riendeau、C. Brideau、C. Chan、D. Delorme、D. Denis、J. P. Falgueyret、R. Fortin、J. Guay

  DOI：10.1021/jm00071a008

  日期：1993.9

  Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpropyl]-1H-tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16,75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg;2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.