3,5-Diisopropylparacetamol | 1988-14-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3,5-Diisopropylparacetamol
• 英文别名: N-(3,5-di-iso-propyl-4-hydroxyphenyl)-acetamide；N-(3,5-di-isopropyl-4-hydroxyphenyl)acetamide；N-(4-Hydroxy-3,5-diisopropyl-phenyl)-acetamide；N-[4-hydroxy-3,5-di(propan-2-yl)phenyl]acetamide
• CAS: 1988-14-3
• 化学式: C₁₄H₂₁NO₂
• 分子量: 235.326
• InChiKey: PHSJJLICQTWSOW-UHFFFAOYSA-N

物化性质

• 沸点：
  377.72°C (rough estimate)
• 密度：
  1.0247 (rough estimate)

计算性质

• 辛醇/水分配系数(LogP)：
  2.6
• 重原子数：
  17
• 可旋转键数：
  3
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  49.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3,5-Diisopropylparacetamol 在 4-碘化甲苯二乙酸酯 、 溶剂黄146 作用下， 以 二氯甲烷 为溶剂， 反应 6.0h， 生成 4-hydroxy-3,5-diisopropylphenyl 4-methylbenzenesulfonate
  参考文献：
  名称：

  N-乙酰基和N-[1-（芳基磺酰亚胺基）乙基] -1,4-苯醌亚胺与芳烃亚磺酸钠的反应

  摘要：

  根据1,4，在醌环的2-和/或6-位没有取代基的N-乙酰基和N- [1-（芳基磺酰亚胺基）乙基] -1,4-苯醌亚胺优先与芳烃亚磺酸钠反应-加法模式。ArSO 2 N基团的存在有利于自由基离子反应并形成1，6-加成产物。

  DOI：

  10.1134/s1070428014090097
• 作为产物：
  描述：

  丙泊酚 在 吡啶 、 盐酸 、 sodium hydroxide 、 tin 、 硫酸 、 硝酸 作用下， 以 乙醇 为溶剂， 反应 3.5h， 生成 3,5-Diisopropylparacetamol
  参考文献：
  名称：

  Propofol Analogues. Synthesis, Relationships between Structure and Affinity at GABA_A Receptor in Rat Brain, and Differential Electrophysiological Profile at Recombinant Human GABA_A Receptors

  摘要：

  A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABA(A) receptors determined by the inhibition of the specific [S-35]-tert-butylbicyclophosphorothionate ([S-35]TBPS) binding to rat whole brain membranes. Introduction of halogen (Cl, Br, and I) and benzoyl substituents in the para position of the phenyl group resulted in ligands with higher potency at inhibiting [S-35]TBPS binding. A quantitative structure-affinity relationship (QSAR) study demonstrated that affinity is enhanced by increases in lipophilicity of the ligand whereas affinity is adversely affected by increases in size of the substituent para to the phenolic hydroxyl group. Consistent with the displacement of [S-35]TBPS and with the activation of GABA(A) receptors, we demonstrate that ligands displaying high affinity (i.e., 2-4, and 8) are able to increase GABA-stimulated chloride currents in oocytes expressing human GABA(A) receptors and to directly activate chloride currents in an electrophysiological assay. Among them, compound 4 showed a rather peculiar profile in the electrophysiological examination with cloned alpha(1) beta(2) gamma(2) GABA(A) receptors. Indeed, compared to propofol, it displayed a much greater efficacy at potentiating GABA-elicited chloride currents, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to compound 4 pharmacological properties that are more similar to anxiolytic and anticonvulsant drugs than to those of general anesthetics.

  DOI：

  10.1021/jm970681h

文献信息

• Design, synthesis and biological testing of a novel series of anti-inflammatory drugs
  作者：Judith C Duffy、John C Dearden、Chris Rostron

  DOI：10.1211/0022357011778043

  日期：2010.2.18

  Many of the non-steroidal anti-inflammatory drugs (NSAIDs) currently marketed produce severe gastro-toxic side effects. The benefits of producing NSAIDs without these side effects are obvious, particularly for patients requiring long-term therapy. The aim of this investigation was to produce novel NSAIDs, based on paracetamol, that exhibit little or no gastro-toxicity. The work covers design, synthesis and testing of 13 drug candidates. The analgesic and anti-inflammatory potencies of the drug candidates were measured using the mouse abdominal constriction assay and the carrageenan-induced rat paw oedema assay, respectively. The stomachs of the rats were examined post-mortem, to assess the gastro-toxicity of the drugs. Of the 13 compounds described herein, 11 were shown to possess analgesic activity at 2–10 times the potency of aspirin, while 8 demonstrated anti-inflammatory activity at 3–10 times the potency of aspirin. Significantly, all of the compounds showed very low gastro-toxicity when compared with aspirin. The results of this study indicate that it is possible to develop novel, potent NSAIDs based on the structure of paracetamol. These compounds have the advantage of demonstrating much lower gastro-toxicity than NSAIDs currently available. Drugs of this type may, in future, provide effective treatments for inflammatory disorders.

  摘要：目前市场上许多非甾体抗炎药（NSAIDs）会产生严重的胃毒性副作用。生产无这些副作用的NSAIDs的好处显而易见，特别是对于需要长期治疗的患者。本研究的目的是基于对扑热息痛的研究，生产出几乎没有胃毒性的新型NSAIDs。该研究涵盖了13种药物候选物的设计、合成和测试。通过使用小鼠腹部收缩实验和大鼠卡拉胶诱导的脚肿胀实验来测量这些药物候选物的镇痛和抗炎作用。大鼠的胃在死后进行检查，以评估药物的胃毒性。在这里描述的13种化合物中，11种显示出镇痛活性，其效力是阿司匹林的2-10倍，而8种显示出抗炎活性，其效力是阿司匹林的3-10倍。值得注意的是，与阿司匹林相比，所有化合物的胃毒性都非常低。这项研究的结果表明，可以基于对扑热息痛的结构开发出新型、有效的NSAIDs。这些化合物具有比目前市场上的NSAIDs更低的胃毒性。这类药物可能在未来为炎症性疾病提供有效的治疗。
• DPPH radical scavenging activity of paracetamol analogues
  作者：Maria Alessandra Alisi、Mario Brufani、Nicola Cazzolla、Francesca Ceccacci、Patrizia Dragone、Marco Felici、Guido Furlotti、Barbara Garofalo、Angela La Bella、Osvaldo Lanzalunga、Francesca Leonelli、Rinaldo Marini Bettolo、Caterina Maugeri、Luisa Maria Migneco、Vincenzo Russo

  DOI：10.1016/j.tet.2012.09.098

  日期：2012.12

  Biochemical studies suggest a direct relationship between the radical scavenging activity of paracetamol (I) and its antipyretic and analgesic action. To evaluate the effect of chemical modifications on the radical scavenging activity of compounds of type I, analogues 1-14 were prepared and submitted to a stable free radical (DPPH; 1,1-diphenyl-2-picryl-hydrazyl) assay. All paracetamol derivatives showed a significant higher efficiency than the parent compound. This study showed that radical scavenging activity can be increased by decreasing the phenolic ortho substituents steric hindrance or by introducing substituents on the acyl moiety like an indazole ring or the ionic N-methyl morpholinium group. A significant activating effect was also observed by replacing the 1,4-acylamidophenol with a 1,4-acylamidonaphthol system. (C) 2012 Elsevier Ltd. All rights reserved.
• Burmistrov, K. S.; Burmistrov, S. I., Journal of Organic Chemistry USSR (English Translation), 1980, vol. 16, # 7, p. 1279 - 1284
  作者：Burmistrov, K. S.、Burmistrov, S. I.

  DOI：——

  日期：——
• Rat liver microsomal cytochrome P450-dependent oxidation of 3,5-disubstituted analogues of paracetamol
  作者：J. G. M. Bessems、J. M. Te Koppele、P. A. Van Dijk、L. L. P. Van Stee、J. N. M. Commandeur、N. P. E. Vermeulen

  DOI：10.3109/00498259609046740

  日期：1996.1

  1. The cytochrome P450-dependent binding of paracetamol and a series of 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, -iC(3)H(7)) have been determined with beta-naphthoflavone (beta NF)-induced rat liver microsomes and produced reverse type I spectral changes. K-s,K-app varied from 0.14 mM for 3,5-diiC(3)H(7)-paracetamol to 2.8 mM for paracetamol.2. All seven analogues underwent rat liver microsomal cytochrome P450-dependent oxidation, as reflected by the formation of GSSG in the presence of GSH. The GSSG-formation was increased in all cases upon pretreatment of rats by beta-naphthoflavone (beta NF) and was generally decreased upon pretreatment by phenobarbital (PB).3. Rat liver microsomal cytochrome P450 as well as horseradish peroxidase catalysed the formation of 3,5-disubstituted NAPQI analogues from the corresponding parent compounds, as identified by UV-spectrophotometry of the NAPQI analogues and by GC/MS detection of the following GSH-conjugates: 2-glutathione-S-yl-3,5-dimethyl-1,4-dihydroxybenzene, 2-glutathione-S-yl-3,5-dichloro-paracetamol, and 2-glutathione-S-yl-3,5-dibromo-paracetamol.4. In liver microsomal (beta NF-induced) incubations, apparent K,values, as determined for the cytochrome P450 catalysis-dependent oxidation of GSH, for seven 3,5-disubstituted paracetamol analogues (R = -F, -Cl, -Br, -I, -CH3, -C2H5, iC(3)H(7)) varied from 0.07 to 0.64 mM. Paracetamol exhibited an apparent K-m of 0.73 mM. Apparent V-max values for the cytochrome P450 catalysis dependent oxidation of GSH varied from 0.66 nmol min(-1) mg(-1)protein for paracetamol to 3.0 nmol min(-1) mg(-1) protein for 3,5-dimethyl-paracetamol.
• Propofol Analogues. Synthesis, Relationships between Structure and Affinity at GABA_A Receptor in Rat Brain, and Differential Electrophysiological Profile at Recombinant Human GABA_A Receptors
  作者：Giuseppe Trapani、Andrea Latrofa、Massimo Franco、Cosimo Altomare、Enrico Sanna、Marcello Usala、Giovanni Biggio、Gaetano Liso

  DOI：10.1021/jm970681h

  日期：1998.5.1

  A number of propofol (2,6-diisopropylphenol) congeners and derivatives were synthesized and their in vitro capability to affect GABA(A) receptors determined by the inhibition of the specific [S-35]-tert-butylbicyclophosphorothionate ([S-35]TBPS) binding to rat whole brain membranes. Introduction of halogen (Cl, Br, and I) and benzoyl substituents in the para position of the phenyl group resulted in ligands with higher potency at inhibiting [S-35]TBPS binding. A quantitative structure-affinity relationship (QSAR) study demonstrated that affinity is enhanced by increases in lipophilicity of the ligand whereas affinity is adversely affected by increases in size of the substituent para to the phenolic hydroxyl group. Consistent with the displacement of [S-35]TBPS and with the activation of GABA(A) receptors, we demonstrate that ligands displaying high affinity (i.e., 2-4, and 8) are able to increase GABA-stimulated chloride currents in oocytes expressing human GABA(A) receptors and to directly activate chloride currents in an electrophysiological assay. Among them, compound 4 showed a rather peculiar profile in the electrophysiological examination with cloned alpha(1) beta(2) gamma(2) GABA(A) receptors. Indeed, compared to propofol, it displayed a much greater efficacy at potentiating GABA-elicited chloride currents, but a much lower efficacy at producing a direct activation of the chloride channel in the absence of GABA. This behavior may give to compound 4 pharmacological properties that are more similar to anxiolytic and anticonvulsant drugs than to those of general anesthetics.