5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide | 913828-83-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 噻吩类
• 英文名称: 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide
• 英文别名: 5-({[t-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide；5-({[t-Butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide；5-[[tert-butyl(dimethyl)silyl]oxymethyl]-3-ethyl-N'-hydroxythiophene-2-carboximidamide
• CAS: 913828-83-8
• 化学式: C₁₄H₂₆N₂O₂SSi
• 分子量: 314.524
• InChiKey: FANWZXQGKSHHID-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.93
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  96.1
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide 在 四丁基氟化铵 、 1-羟基苯并三唑 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 {4-ethyl-5-[5-(3-fluoro-4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methanol
  参考文献：
  名称：

  Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist

  摘要：

  S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC50 value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID50 value was determined at 0.407 mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.12.019
• 作为产物：
  描述：

  ((4-bromothiophene-2-yl)methoxy)(tert-butyl)dimethylsilane 在 正丁基锂 、 1,3-bis[(diphenylphosphino)propane]dichloronickel(II) 、 盐酸羟胺 、 羟胺 、 三乙胺 、 N,N'-二环己基碳二亚胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 甲苯 为溶剂， 生成 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide
  参考文献：
  名称：

  Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist

  摘要：

  S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC50 value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID50 value was determined at 0.407 mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2011.12.019
• 作为试剂：
  描述：

  、 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethylthiophene-2-carbonitrile 、 、 、 羟胺 在 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide 、 crude product 作用下， 生成 、 5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3-ethyl-N'-hydroxythiophene-2-carboximidamide
  参考文献：
  名称：

  Heterocyclic compound

  摘要：

  具有低毒性的免疫抑制活性化合物或其药物盐。该化合物具有下面所示的一般式（I）或其药理学上可接受的盐或药理学上可接受的前药。

  公开号：

  US07687491B2

文献信息

• 3-AZETIDINECARBOXYLIC ACID DERIVATIVES FOR USE AS IMMUNOSUPPRESSANTS
  申请人：Daiichi Sankyo Company, Limited

  公开号：EP1873153B1

  公开（公告）日：2010-07-07
• Synthesis and evaluation of CS-2100, a potent, orally active and S1P3- sparing S1P1 agonist
  作者：Tsuyoshi Nakamura、Masayoshi Asano、Yukiko Sekiguchi、Yumiko Mizuno、Kazuhiko Tamaki、Futoshi Nara、Yumi Kawase、Yoshiyuki Yabe、Daisuke Nakai、Emi Kamiyama、Yoko Urasaki-Kaneno、Takaichi Shimozato、Hiromi Doi-Komuro、Takashi Kagari、Wataru Tomisato、Ryotaku Inoue、Miyuki Nagasaki、Hiroshi Yuita、Keiko Oguchi-Oshima、Reina Kaneko、Takahide Nishi

  DOI：10.1016/j.ejmech.2012.02.022

  日期：2012.5

  Modulators of sphingosine phosphate receptor-1 (S1P(1)) have recently been focused as a suppressant of autoimmunity. We have discovered a 4-ethylthiophene-based S1P(1) agonist 1-(4-Ethyl-5-[5-(4-phenoxyphenyl)-1,2,4-oxadiazol-3-yl]-2-thienyl}methyl)azetidine-3-carboxylic acid (CS-2100, 8) showing potent S1P(1) agonist activity against S1P(3) and an excellent in vivo potency. We report herein the synthesis of CS-2100 (8) and pharmacological effects such as S1P(1) and S1P(3) agonist activity in vitro, peripheral blood lymphocyte lowering effects and the suppressive effects on adjuvant-induced arthritis and experimental autoimmune encephalomyelitis (EAE) in animal models. The pharmacokinetic data were also reported. CS-2100 (8) had >5000-fold greater agonist activity for human S1P(1) (EC50; 4.0 nM) relative to S1P(3) (EC50; >20000 nM). Following administration of single oral doses of 0.1 and 1 mg/kg of CS-2100 (8) in rats, lymphocyte counts decreased significantly, with a nadir at 8 and/or 72 h post-dose and recovery to vehicle control levels by 24-48 h post-dose. CS-2100 (8) is efficacious in the adjuvant-induced arthritis model in rats (ID50; 0.44 mg/kg). In the EAE model compared to the vehicle-treated group, significant decreases in the cumulative EAE scores were observed for 0.3 and 1 mg/kg CS-2100 (8) groups in mice. While CS-2100 (8) showed potent efficacy in various animal disease models, it was also revealed that the central 1,2,4-oxadiazole ring of CS-2100 (8) was decomposed by enterobacteria in intestine of rats and monkeys, implicating the latent concern about an external susceptibility in its metabolic process in the upcoming clinical studies. (C) 2012 Elsevier Masson SAS. All rights reserved.
• Discovery of CS-2100, a potent, orally active and S1P3-sparing S1P1 agonist
  作者：Tsuyoshi Nakamura、Masayoshi Asano、Yukiko Sekiguchi、Yumiko Mizuno、Kazuhiko Tamaki、Takako Kimura、Futoshi Nara、Yumi Kawase、Takaichi Shimozato、Hiromi Doi、Takashi Kagari、Wataru Tomisato、Ryotaku Inoue、Miyuki Nagasaki、Hiroshi Yuita、Keiko Oguchi-Oshima、Reina Kaneko、Nobuaki Watanabe、Yasuyuki Abe、Takahide Nishi

  DOI：10.1016/j.bmcl.2011.12.019

  日期：2012.2

  S1P(3)-sparing S1P(1) agonists have attracted attention as a suppressant of autoimmunity with reduced side effects. Our synthetic efforts and extensive SAR studies led to the discovery of 10b named CS-2100 with the EC50 value of 4.0 nM for human S1P(1) and over 5000-fold selectivity against S1P(3). The in vivo immunosuppressive efficacy was evaluated in rats on host versus graft reaction and the ID50 value was determined at 0.407 mg/kg. The docking studies of CS-2100 with the homology model of S1P(1) and S1P(3) showed that the ethyl group on the thiophene ring of CS-2100 was sterically hindered by Phe263 in S1P(3), not in the case of Leu276 in S1P(1). This observation gives an explanation for the excellent S1P(3)-sparing characteristic of CS-2100. (C) 2011 Elsevier Ltd. All rights reserved.
• Heterocyclic compound
  申请人：Nishi Takahide

  公开号：US20080113961A1

  公开（公告）日：2008-05-15

  A compound having immunosuppressive activity with low toxicity or a pharmacological salt thereof. The compound has a general formula (I) shown below or a pharmacologically acceptable salt thereof, or a pharmacologically acceptable prodrug thereof

  具有低毒性免疫抑制活性的化合物或其药理盐。该化合物具有下面所示的一般式（I）或其药理学上可接受的盐，或其药理学上可接受的前体。