Ethyl [1-(4-chlorobenzyl)-3-t-butylthio-5-allyloxyindol-2-yl]carboxylate | 144397-02-4

• 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: Ethyl [1-(4-chlorobenzyl)-3-t-butylthio-5-allyloxyindol-2-yl]carboxylate
• 英文别名: ethyl 3-tert-butylsulfanyl-1-[(4-chlorophenyl)methyl]-5-prop-2-enoxyindole-2-carboxylate
• CAS: 144397-02-4
• 化学式: C₂₅H₂₈ClNO₃S
• 分子量: 458.021
• InChiKey: LKELVLAMNVZQCA-UHFFFAOYSA-N

物化性质

• 沸点：
  600.2±55.0 °C(Predicted)
• 密度：
  1.15±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  31
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.32
• 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：

  Ethyl [1-(4-chlorobenzyl)-3-t-butylthio-5-allyloxyindol-2-yl]carboxylate 在 potassium carbonate 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 24.0h， 生成 ethyl 1-(4-chlorobenzyl)-4-methyl-6-hydroxy-4,5-dihydro-1H-thiopyrano<2,3,4-cd>indole-2-carboxylate
  参考文献：
  名称：

  新型硫吡喃并吲哚环系统的形成

  摘要：

  通过将t-BuS基团分子内环化到烯丙基取代基上，由取代的吲哚制备新的噻喃并[2,3,4-c，d]吲哚环系统。反应在质子酸，路易斯酸或亲电试剂（Br 2，I 2，Hg（OAc）2）的影响下以高收率进行

  DOI：

  10.1016/s0040-4039(00)61266-2
• 作为产物：
  描述：

  4-(allyloxy)aniline hydrochloride 在 sodium dithionite 、 sodium acetate 、 溶剂黄146 、 三乙胺 、 sodium nitrite 作用下， 以 乙醚 、 水 、 甲苯 为溶剂， 反应 26.75h， 生成 Ethyl [1-(4-chlorobenzyl)-3-t-butylthio-5-allyloxyindol-2-yl]carboxylate
  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

• Aryl thiopyrano[2,3,4-C,D]indoles as inhibitors of leukotriene
  申请人：Merck Frosst Canada, Inc.

  公开号：US05314900A1

  公开（公告）日：1994-05-24

  Compounds having the formula I: ##STR1## are inhibitors of 5-lipoxygenase and 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I式化合物的化合物：##STR1##是5-脂氧合酶的抑制剂和白细胞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。它们还有助于治疗心绞痛、脑血管痉挛、肾小球肾炎、肝炎、内毒素血症、银屑病、葡萄膜炎和异体移植排斥，并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：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.

  具有公式I的化合物：##STR1## 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、脑血管痉挛、肾小球肾炎、肝炎、内毒素血症、牛皮癣、葡萄膜炎和移植排斥，并预防动脉粥样硬化斑块的形成。
• Thiopyrano[2,3,4-cd]indoles as 5-Lipoxygenase Inhibitors: Synthesis, Biological Profile, and Resolution of 2-[2-[1-(4-Chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic Acid
  作者：J. H. Hutchinson、D. Riendeau、C. Brideau、C. Chan、J.-P. Falgueyret、J. Guay、T. R. Jones、C. Lepine、D. Macdonald

  DOI：10.1021/jm00034a013

  日期：1994.4

  Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd] indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[ (5-phenylpyridin-2-yl)methoxy]-4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB(4) biosynthesis by human PMN leukocytes and human whole blood (IC(50)s Of 22 nM, 7 nM and 3.8 mu M, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB(4), ED(50) = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea(50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in R(L) and 68% inhibition in the decrease in C-dyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 mu g/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 mu M) Or competition in a FLAP binding assay (IC5O > 10 mu M). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB(4) biosynthesis of human PMN leukocytes and human whole blood with IC(50)s Of 8 nM, 4 nM, and 1 mu M respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB(4) biosynthesis and urinary LTE(4) excretion in clinical trials.