3-[4-(methylsulfonyl)phenyl]-1-phenylprop-2-yn-1-one | 742699-92-9

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 直链 1,3-二芳基丙烷
• 英文名称: 3-[4-(methylsulfonyl)phenyl]-1-phenylprop-2-yn-1-one
• 英文别名: 3-(4-methanesulfonylphenyl)-1-phenylprop-2-yn-1-one；1,3-Diarylprop-2-yn-1-one, 13a；3-(4-methylsulfonylphenyl)-1-phenylprop-2-yn-1-one
• CAS: 742699-92-9
• 化学式: C₁₆H₁₂O₃S
• 分子量: 284.335
• InChiKey: OIHHELVXIPDXIK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  20
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.06
• 拓扑面积：
  59.6
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  3-吡啶乙酸乙酯 、 3-[4-(methylsulfonyl)phenyl]-1-phenylprop-2-yn-1-one 在 sodium hydride 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以38.2%的产率得到4-(4-Methanesulfonyl-phenyl)-6-phenyl-3-pyridin-3-yl-pyran-2-one
  参考文献：
  名称：

  Design, Synthesis, and Structure−Activity Relationship Studies of 3,4,6-Triphenylpyran-2-ones as Selective Cyclooxygenase-2 Inhibitors

  摘要：

  A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO2 pharmacophore at the paraposition of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC50 = 0.02 muM; COX-1 IC50 > 100 muM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC50 = 0.07 muM; SI = 474) and rofecoxib (COX-2 IC50 = 0.50 muM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID50 = 5.6 mg/kg) than celecoxib (ID50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC50 = 0.45 muM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO2Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO2Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO2Me pharmacophore within the COX-2 secondary pocket.

  DOI：

  10.1021/jm049939b
• 作为产物：
  描述：

  4-溴茴香硫醚 在 manganese(IV) oxide 、 bis-triphenylphosphine-palladium(II) chloride 、 Oxone 、 copper(l) iodide 、 正丁基锂 、 sodium hydride 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 正己烷 、 丙酮 、 苯 为溶剂， 反应 7.05h， 生成 3-[4-(methylsulfonyl)phenyl]-1-phenylprop-2-yn-1-one
  参考文献：
  名称：

  1,3-二芳基丙-2-yn-1-ones的合成及其与构效关系的研究：环氧合酶和脂氧合酶的双重抑制剂。

  摘要：

  设计，合成和评估了一组具有C-3 p-SO2Me COX-2药效基团的1,3-二芳基丙-2-yn-1-ones（13、17、23、26和27），作为潜在的双重抑制剂环氧合酶1/2（COX-1 / 2）和5 / 15-脂氧合酶（5 / 15-LOX）具有体内抗炎和镇痛作用。在这类化合物中，3-（4-甲磺酰基苯基）-1-（4-氟苯基）丙-2-炔-1-酮（13h）被确定为有效和选择性的COX-2抑制剂（COX-2 IC50 = 0.1 microM； SI = 300），效力比罗非昔布高5倍（COX-2 IC50 = 0.5 microM； SI> 200）。在大鼠角叉菜胶诱导的爪水肿测定中，口服30 mg / kg剂量后3 h，13h表现出中等的抗炎活性（炎症抑制26％）。相关的双重COX-1 / 2和5 / 15-LOX抑制剂3-（4-甲磺酰基苯基）-1-（4-氰基苯基）丙-2-炔-1-酮（13g，COX-1

  DOI：

  10.1021/jm0510474

文献信息

• Access to ¹⁸ F-labelled isoxazoles by ruthenium-promoted 1,3-dipolar cycloaddition of 4-[¹⁸ F]fluoro-<i>N</i> -hydroxybenzimidoyl chloride with alkynes
  作者：Silvia Roscales、Torsten Kniess

  DOI：10.1002/jlcr.3708

  日期：2019.6.30

  4-[18F]Fluoro-N-hydroxybenzimidoyl chloride (18FBIC), an 18F-labelled aromatic nitrile oxide, was developed as building block for Ru-promoted 1,3-dipolar cycloaddition with alkynes. 18FBIC is obtained in a one-pot synthesis in up to 84% radiochemical yield (RCY) starting from [18F]fluoride with 4-[18F]fluorobenzaldehyde (18FBA) and 4-[18F]fluorobenzaldehyde oxime (18FBAO) as intermediates, by reaction of 18FBAO with N-chlorosuccinimide (NCS). 18FBIC was found to be a suitable and stable synthon to give access to 18F-labelled 3,4-diarylsubstituted isoxazoles by [Cp*RuCl(cod)]-catalysed 1,3-dipolar cycloaddition with various alkynes. So the radiosynthesis of a fluorine-18–labelled COX-2 inhibitor [18F]1b, a close derivative of valdecoxib, was performed with 18FBIC and 1-ethynyl-4-(methylsulfonyl)benzene, providing [18F]1b in up to 40% RCY after purification in 85 minutes. The application of 18FBIC as a building block in the synthesis of 18F-labelled heterocycles will generally extend the portfolio of available PET radiotracers.

  4-[18F]氟-N-羟基苯并咪唑氯化物（18FBIC）是一种18F标记的芳香氰氧化物，作为铑促进的1,3双极环加成反应与炔烃的构建单元。18FBIC通过从[18F]氟化物出发，利用4-[18F]氟苯甲醛（18FBA）和4-[18F]氟苯甲腙（18FBAO）作为中间体，在一锅合成中获得，放射化学产率（RCY）高达84%。该反应是通过将18FBAO与N-氯琥珀酰亚胺（NCS）反应得到的。研究发现，18FBIC是一个合适且稳定的合成单元，可以通过[Cp*RuCl(cod)]催化的1,3双极环加成反应与多种炔烃反应，合成18F标记的3,4-二芳基取代异恶唑。因此，利用18FBIC和1-乙炔基-4-(甲基磺酰)苯进行了氟-18标记的COX-2抑制剂[18F]1b的放射合成，作为与瓦尔德考昔（valdecoxib）相近的衍生物，经过85分钟的纯化后，得到[18F]1b，RCY最高可达40%。将18FBIC作为18F标记杂环合成的构建单元，通常将扩展可用的正电子发射断层扫描（PET）放射示踪剂的种类。
• Novel valdecoxib derivatives by ruthenium(<scp>ii</scp>)-promoted 1,3-dipolar cycloaddition of nitrile oxides with alkynes – synthesis and COX-2 inhibition activity
  作者：Silvia Roscales、Nicole Bechmann、Daniel Holger Weiss、Martin Köckerling、Jens Pietzsch、Torsten Kniess

  DOI：10.1039/c7md00575j

  日期：——

  Novel valdecoxib-based cyclooxygenase-2 inhibitors were synthesized in one step via 1,3-dipolar cycloaddition of nitrile oxides with a series of eleven aryl alkynes, six of them described for the first time. Application of Ru(II)-catalysis leads preferably to the formation of the 3,4-diaryl-substituted isoxazoles, while under thermal heating with base the 3,5-diaryl substitution pattern is favoured

  通过将腈与一系列十一个芳基炔烃进行1,3-偶极环加成反应，一步合成了一种新的基于valdecoxib的环氧合酶-2抑制剂，其中六个首次被描述。Ru（II）催化的应用优选导致3，4-二芳基取代的异恶唑的形成，而在与碱一起热加热下，有利于3，5-二芳基取代的模式。具有小的取代基（H和Me）的新的3,4-二芳基取代的异恶唑显示出高的COX-2抑制亲和力（IC 50= 0.042–0.073μM）和优异的选择性（COX-2 SI> 2000）。相反，3，5-二芳基取代的化合物几乎没有表现出COX活性。4-氟苯基取代基的引入导致保留了较高的COX-2亲和力，使这些化合物与可行的一步反应一起有望成为开发氟18标记的放射性示踪剂的候选物。
• Synthesis and biological evaluation of 1,3-diphenylprop-2-yn-1-ones as dual inhibitors of cyclooxygenases and lipoxygenases
  作者：P.N. Praveen Rao、Qiao-Hong Chen、Edward E. Knaus

  DOI：10.1016/j.bmcl.2005.07.036

  日期：2005.11

  A new class of 1,3-diphenylprop-2-yn-1-ones possessing a P-MeSO2 COX-2 phamacophore on the C-3 phenyl ring was designed for evaluation as dual inhibitors of cyclooxygenase (COX) and lipoxygenase (LOX). Among the group of compounds evaluated, 1-(4-fluorophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one (11j) exhibited excellent COX-2 inhibitory potency (COX-2 IC50 = 0.1 mu M) and selectivity (SI = 300), whereas 1-(4-eyanophenyl)-3-(4-methanesulfonylphenyl)prop-2-yn-1-one (11d) exhibited an optimal combination of COX and LOX inhibition (COX-2 IC50 = 1.0 mu M; COX-2 SI = 31.5; 5-LOX IC50 = 1 -0 mu M; 15-LOX IC50 = 3.2 mu M). (c) 2005 Elsevier Ltd. All rights reserved.
• Design, Synthesis, and Structure−Activity Relationship Studies of 3,4,6-Triphenylpyran-2-ones as Selective Cyclooxygenase-2 Inhibitors
  作者：P. N. Praveen Rao、Md. Jashim Uddin、Edward E. Knaus

  DOI：10.1021/jm049939b

  日期：2004.7.1

  A group of regioisomeric 3,4,6-triphenylpyran-2-ones with a MeSO2 pharmacophore at the paraposition of either a C-3 phenyl or a C-4 phenyl substituent on the central six-membered pyran-2-one ring were prepared and evaluated in vitro for their abilities to inhibit the isozymes COX-1 and COX-2. Structure-activity relationship (SAR) data, acquired by substituent modification at the para-position of the C-6 phenyl ring attached to the central pyranone, showed that 6-(4-methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was the most potent and selective COX-2 inhibitor (COX-2 IC50 = 0.02 muM; COX-1 IC50 > 100 muM) with a high COX-2 selectivity index (SI > 5000) relative to the reference drugs celecoxib (COX-2 IC50 = 0.07 muM; SI = 474) and rofecoxib (COX-2 IC50 = 0.50 muM; SI > 200). 6-(4-Methoxyphenyl)-3-(4-methanesulfonylphenyl)-4-phenylpyran-2-one (12e) was a more potent oral antiinflammatory agent (ID50 = 5.6 mg/kg) than celecoxib (ID50 = 10.8 mg/kg) in a carrageenan-induced rat paw edema assay. In a 4% NaCl-induced abdominal constriction assay, a 5 mg/kg oral dose of 12e exhibited good analgesic activity at different time intervals producing 37.5 and 69% inhibition of writhing at 30 and 60 min, respectively. In contrast, the corresponding 6-(4-methoxyphenyl)-4-(4-methanesulfonylphenyl)-3-phenylpyran-2-one regiosiomer (12o) was a less potent and selective COX-2 inhibitor (COX-2 IC50 = 0.45 muM; SI = 70). A molecular modeling study for 12e indicated that the p-OMe substituent on the C-6 phenyl ring interacts with the COX-2 binding site amino acids Ile(345), Val(349), Leu(359), Leu(531), and Met(535) and that the OMe substituent may be responsible for proper orientation of the C-3 p-SO2Me-phenyl ring within the COX-2 secondary pocket (Gln(192), Arg(513), and Phe(518)). These results show that the COX-2 selectivity and potency of 3,4,6-triphenylpyranone regioisomers can be modulated by appropriate placement of the p-SO2Me pharmacophore on either the C-3 or C-4 phenyl moiety. In addition, electronic properties at the para-position of a C-6 phenyl substituent on the central pyranone ring govern COX-2 inhibitory potency and selectivity by controlling the orientation of the p-SO2Me pharmacophore within the COX-2 secondary pocket.
• Synthesis and Structure−Activity Relationship Studies of 1,3-Diarylprop-2-yn-1-ones:  Dual Inhibitors of Cyclooxygenases and Lipoxygenases
  作者：P. N. Praveen Rao、Qiao-Hong Chen、Edward E. Knaus

  DOI：10.1021/jm0510474

  日期：2006.3.1

  (COX-1/2) and 5/15-lipoxygenases (5/15-LOX) that exhibit vivo antiinflammatory and analgesic activities. Among this class of compounds, 3-(4-methanesulfonylphenyl)-1-(4-fluorophenyl)prop-2-yn-1-one (13h) was identified as a potent and selective inhibitor of COX-2 (COX-2 IC50 = 0.1 microM; SI = 300), being 5-fold more potent than rofecoxib (COX-2 IC50 = 0.5 microM; SI > 200). In a rat carrageenan-induced

  设计，合成和评估了一组具有C-3 p-SO2Me COX-2药效基团的1,3-二芳基丙-2-yn-1-ones（13、17、23、26和27），作为潜在的双重抑制剂环氧合酶1/2（COX-1 / 2）和5 / 15-脂氧合酶（5 / 15-LOX）具有体内抗炎和镇痛作用。在这类化合物中，3-（4-甲磺酰基苯基）-1-（4-氟苯基）丙-2-炔-1-酮（13h）被确定为有效和选择性的COX-2抑制剂（COX-2 IC50 = 0.1 microM； SI = 300），效力比罗非昔布高5倍（COX-2 IC50 = 0.5 microM； SI> 200）。在大鼠角叉菜胶诱导的爪水肿测定中，口服30 mg / kg剂量后3 h，13h表现出中等的抗炎活性（炎症抑制26％）。相关的双重COX-1 / 2和5 / 15-LOX抑制剂3-（4-甲磺酰基苯基）-1-（4-氰基苯基）丙-2-炔-1-酮（13g，COX-1