1-(4-{[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}phenyl)-4-(4-methylphenyl)butan-1-one

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 1-(4-{[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}phenyl)-4-(4-methylphenyl)butan-1-one
• 英文别名: 1-[4-[[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl]phenyl]-4-(4-methylphenyl)butan-1-one
• 化学式: C₂₂H₂₉NO₃
• 分子量: 355.477
• InChiKey: HKVMTNIGZGBJRF-QFIPXVFZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.5
• 重原子数：
  26
• 可旋转键数：
  10
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.41
• 拓扑面积：
  72.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-(4-{[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}phenyl)-4-(4-methylphenyl)butan-1-one 在 盐酸 作用下， 以 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 1.0h， 以2.2 g的产率得到1-(4-{[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}phenyl)-4-(4-methylphenyl)butan-1-one hydrochloride
  参考文献：
  名称：

  Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists

  摘要：

  We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P₁ receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P₁ and S1P₃ agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P₁/S1P₃ selectivity. These changes of the S1P₁ and S1P₃ agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P₁ X-ray crystal structure and S1P₃ homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P₁/S1P₃ selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.

  DOI：

  10.1016/j.bmc.2014.05.035
• 作为产物：
  描述：

  tert-butyl (4R)-2,2,4-trimethyl-4-[({4-[4-(4-methylphenyl)butanoyl]benzyl}oxy)methyl]-1,3-oxazolidine-3-carboxylate 在 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 0.5h， 生成 1-(4-{[(2S)-2-amino-3-hydroxy-2-methylpropoxy]methyl}phenyl)-4-(4-methylphenyl)butan-1-one
  参考文献：
  名称：

  Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists

  摘要：

  We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P₁ receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P₁ and S1P₃ agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P₁/S1P₃ selectivity. These changes of the S1P₁ and S1P₃ agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P₁ X-ray crystal structure and S1P₃ homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P₁/S1P₃ selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.

  DOI：

  10.1016/j.bmc.2014.05.035

文献信息

• [EN] PHOSPHORODIAMIDATES AND OTHER PHOSPHORUS DERIVATIVES OF FINGOLIMOD AND RELATED S1 P RECEPTOR MODULATORS<br/>[FR] PHOSPHORODIAMIDATES ET AUTRES DÉRIVÉS DE PHOSPHORE DE FINGOLIMOD ET MODULATEURS DE RÉCEPTEUR S1 P ASSOCIÉS
  申请人：UNIV COLLEGE CARDIFF CONSULTANTS LTD

  公开号：WO2019064012A1

  公开（公告）日：2019-04-04

  Compounds of general formula (I): (Formula I)) wherein R1, Q, R3, R4, R5, R6, R7 and Ar1 are as defined herein are inhibitors of class I histone deacetylases and are of use in the treatment of lysosomal storage disorders, especially Niemann-Pick type C disease, as well as other lysosomal storage disorders, defective autophagy, accumulation of free cholesterol and mycobacterial diseases.

  通式（I）的化合物：（式I）其中R1、Q、R3、R4、R5、R6、R7和Ar1的定义如下，是类I组蛋白去乙酰化酶的抑制剂，可用于治疗溶酶体贮积症，特别是尼曼-匹克C型疾病，以及其他溶酶体贮积症、缺陷自噬、游离胆固醇积累和分枝杆菌病。
• Kinase-independent phosphoramidate S1P 1 receptor agonist benzyl ether derivatives
  作者：Edward James、Fabrizio Pertusati、Andrea Brancale、Chris McGuigan

  DOI：10.1016/j.bmcl.2017.02.011

  日期：2017.3

  Previously published S1P receptor modulator benzyl ether derivatives have shown potential as being viable therapeutics for the treatment of neurodegenerative diseases, however, two of the most S1P1-selective compounds are reported as being poorly phosphorylated by kinases in vivo. Phosphoramidates of BED compounds (2a, 2b) were synthesised with the aim of producing kinase-independent S1P receptor modulators

  先前公开的S1P受体调节剂苄基醚衍生物已显示出作为治疗神经退行性疾病的可行疗法的潜力，但是，据报道，大多数S1P1选择性化合物中的两种在体内被激酶磷酸化的程度很低。合成了BED化合物（2a，2b）的磷酸氨基甲酸酯，目的是产生不依赖激酶的S1P受体调节剂。进行了羧肽酶，人血清和细胞裂解物的加工实验。发现ProTide BED类似物在酸性和碱性条件下具有可接受的稳定性水平，体外代谢加工实验表明它们已加工成所需的药理活性单磷酸酯。这项研究描述了一个全新的治疗剂家族的发展。
• PHOSPHORODIAMIDATES AND OTHER PHOSPHORUS DERIVATIVES OF FINGOLIMOD AND RELATED S1 P RECEPTOR MODULATORS
  申请人：University College Cardiff Consultants Ltd

  公开号：EP3675869A1

  公开（公告）日：2020-07-08
• Synthesis and SAR studies of benzyl ether derivatives as potent orally active S1P1 agonists
  作者：Takashi Tsuji、Keisuke Suzuki、Tsuyoshi Nakamura、Taiji Goto、Yukiko Sekiguchi、Takuya Ikeda、Takeshi Fukuda、Toshiyasu Takemoto、Yumiko Mizuno、Takako Kimura、Yumi Kawase、Futoshi Nara、Takashi Kagari、Takaichi Shimozato、Chizuko Yahara、Shinichi Inaba、Tomohiro Honda、Takashi Izumi、Masakazu Tamura、Takahide Nishi

  DOI：10.1016/j.bmc.2014.05.035

  日期：2014.8

  We report herein the synthesis and structure-activity relationships (SAR) of a series of benzyl ether compounds as an S1P₁ receptor modulator. From our SAR studies, the installation of substituents onto the central benzene ring of 2a was revealed to potently influence the S1P₁ and S1P₃ agonistic activities, in particular, an ethyl group on the 2-position afforded satisfactory S1P₁/S1P₃ selectivity. These changes of the S1P₁ and S1P₃ agonistic activities caused by the alteration of substituents on the 2-position were reasonably explained by a docking study using an S1P₁ X-ray crystal structure and S1P₃ homology modeling. We found that compounds 2b and 2e had a potent in vivo immunosuppressive efficacy along with acceptable S1P₁/S1P₃ selectivity, and confirmed that these compounds had less in vivo bradycardia risk through the evaluation of heart rate change after oral administration of the compounds (30 mg/kg, p.o.) in rats.