4-<1-(4-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)ethylene>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>-3,3-dimethylbutyronitrile | 150461-56-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 4-<1-(4-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)ethylene>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>-3,3-dimethylbutyronitrile
• CAS: 150461-56-6
• 化学式: C₃₇H₃₄ClN₃S
• 分子量: 588.216
• InChiKey: XZIFZJFQNDMHFT-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  10.09
• 重原子数：
  42.0
• 可旋转键数：
  8.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  41.61
• 氢给体数：
  0.0
• 氢受体数：
  4.0

反应信息

• 作为反应物：
  描述：

  4-<1-(4-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)ethylene>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>-3,3-dimethylbutyronitrile 在 palladium on activated charcoal 氢气 、 三正丁基叠氮化锡 作用下， 以 甲醇 、 乙酸乙酯 、 邻二氯苯 为溶剂， 反应 19.0h， 生成 5-<3-<1-(4-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)ethyl>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>-2,2-dimethylpropyl>-1H-tetrazole
  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：

  1-(4-chlorobenzyl)-1-(4-allyloxy phenyl)hydrazine hydrochloride 在 吡啶 、 manganese(IV) oxide 、 palladium diacetate 、 lithium aluminium tetrahydride 、 锂硼氢 、 sodium acetate 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 乙基二苯基膦 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 125.5h， 生成 4-<1-(4-chlorobenzyl)-4-methyl-6-<(5-phenylpyridin-2-yl)ethylene>-4,5-dihydro-1H-thiopyrano<2,3,4-c,d>indol-2-yl>-3,3-dimethylbutyronitrile
  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