methyl [6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate | 1258856-65-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: methyl [6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate
• 英文别名: methyl 2-(6-(5-(3-cyano-4-isopropoxyphenyl)-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydroisoquinolin-2(1H)-yl)acetate；methyl 2-[6-[5-(3-cyano-4-propan-2-yloxyphenyl)-1,2,4-oxadiazol-3-yl]-5-methyl-3,4-dihydro-1H-isoquinolin-2-yl]acetate
• CAS: 1258856-65-3
• 化学式: C₂₅H₂₆N₄O₄
• 分子量: 446.506
• InChiKey: KRDWPOLBYQTPET-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.1
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.36
• 拓扑面积：
  102
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  methyl [6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate 在 吡啶 、 水 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 sodium hydroxide 作用下， 以 N-甲基吡咯烷酮 、 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 22.66h， 生成 2-[(1-methylethyl)oxy]-5-[3-(2,3,4,5-tetrahydro-1,4-benzoxazepin-9-yl)-1,2,4-oxadiazol-5-yl]benzonitrile trifluoroacetate
  参考文献：
  名称：

  Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose

  摘要：

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-{2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).

  DOI：

  10.1021/jm200609t
• 作为产物：
  描述：

  3-氰基-4-异丙氧基苯甲酸 在 N,N-二甲基甲酰胺 吡啶 、 草酰氯 、 potassium carbonate 作用下， 以 二氯甲烷 、 甲苯 、 乙腈 为溶剂， 反应 21.33h， 生成 methyl [6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl-3,4-dihydro-2(1H)-isoquinolinyl]acetate
  参考文献：
  名称：

  [EN] S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
  [FR] AGONISTES DE S1P1 COMPRENANT UN CYCLE AZOTÉ BICYCLIQUE

  摘要：

  本发明涉及具有S1P1激动剂活性的式(I)新化合物，其制备方法，包含它们的药物组合物及其用于治疗各种疾病的应用。

  公开号：

  WO2010146105A1

文献信息

• [EN] S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING<br/>[FR] AGONISTES DE S1P1 COMPRENANT UN CYCLE AZOTÉ BICYCLIQUE
  申请人：GLAXO GROUP LTD

  公开号：WO2010146105A1

  公开（公告）日：2010-12-23

  The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有S1P1激动剂活性的式(I)新化合物，其制备方法，包含它们的药物组合物及其用于治疗各种疾病的应用。
• S1P1 AGONISTS COMPRISING A BICYCLIC N-CONTAINING RING
  申请人：Bailey James Matthew

  公开号：US20120101083A1

  公开（公告）日：2012-04-26

  The present invention relates to novel compounds of formula (I) having S1P1 agonist activity, processes for their preparation, pharmaceutical compositions containing them and their use in the treatment of various disorders.

  本发明涉及具有S1P1激动剂活性的公式（I）的新化合物，其制备过程，含有它们的药物组合物以及它们在治疗各种疾病中的应用。
• Discovery of a Brain-Penetrant S1P₃-Sparing Direct Agonist of the S1P₁ and S1P₅ Receptors Efficacious at Low Oral Dose
  作者：Emmanuel H. Demont、Sandra Arpino、Rino A. Bit、Colin A. Campbell、Nigel Deeks、Sapna Desai、Simon J. Dowell、Pam Gaskin、James R. J. Gray、Lee A. Harrison、Andrea Haynes、Tom D. Heightman、Duncan S. Holmes、Philip G. Humphreys、Umesh Kumar、Mary A. Morse、Greg J. Osborne、Terry Panchal、Karen L. Philpott、Simon Taylor、Robert Watson、Robert Willis、Jason Witherington

  DOI：10.1021/jm200609t

  日期：2011.10.13

  2-Amino-2-(4-octylphenethyl)propane-1,3-diol 1 (fingolimod, FTY720) has been recently marketed in the United States for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). Its efficacy has been primarily linked to the agonism on T cells of S1P(1), one of the five sphingosine 1-phosphate (S1P) G-protein-coupled receptors, while its cardiovascular side effects have been associated with activity at S1P(3). Emerging data suggest that the ability of this molecule to cross the blood-brain barrier and to interact with both S1P(1) and S1P(5) in the central nervous system (CNS) may contribute to its efficacy in treating patients with RAMS. We have recently disclosed the structure of an advanced, first generation S1P(3)-sparing S1P(1) agonist, a zwitterion with limited CNS exposure. In this Article, we highlight our strategy toward the identification of CNS-penetrant S1P(3)-sparing S1P(1) and S1P5 agonists resulting in the discovery of 5-(3-2-[2-hydroxy-1- (hydroxymethyl)ethyl]-5-methyl-1,2,3,4-tetrahydro-6-isoquinolinyl}-1,2,4-oxadiazol-5-yl)-2-[(1-methylethyl)oxy]benzonitrile 15. Its exceptional in vivo potency and good pharmacokinetic properties translate into a very low predicted therapeutic dose in human (< 1 mg p.o. once daily).
• Discovery of a Selective S1P₁ Receptor Agonist Efficacious at Low Oral Dose and Devoid of Effects on Heart Rate
  作者：Emmanuel H. Demont、Benjamin I. Andrews、Rino A. Bit、Colin A. Campbell、Jason W. B. Cooke、Nigel Deeks、Sapna Desai、Simon J. Dowell、Pam Gaskin、James R. J. Gray、Andrea Haynes、Duncan S. Holmes、Umesh Kumar、Mary A. Morse、Greg J. Osborne、Terry Panchal、Bela Patel、Alcide Perboni、Simon Taylor、Robert Watson、Jason Witherington、Robert Willis

  DOI：10.1021/ml2000214

  日期：2011.6.9

  Gilenya (fingolimod, FTY720) was recently approved by the U.S. FDA for the treatment of patients with remitting relapsing multiple sclerosis (RRMS). It is a potent agonist of four of the five sphingosine 1-phosphate (SIP) G-protein-coupled receptors (S1P(1) and S1P(3-5)). It has been postulated that fingolimod's efficacy is due to S1P(1) agonism, while its cardiovascular side effects (transient bradycardia and hypertension) are due to S1P(3) agonism. We have discovered a series of selective S1P(1), agonists, which includes 3-[6- (5-3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-5-methyl- 3,4-dihydro-2(1H)-isoquinolinyl]propanoate, 20, a potent, S1P(3)-sparing, orally active S1P(1) agonist. Compound 20 is as efficacious as fingolimod in a collagen-induced arthritis model and shows excellent pharmacokinetic properties preclinically. Importantly, the selectivity of 20 against S1P(3) is responsible for an absence of cardiovascular signal in telemetered rats, even at high dose levels.