methyl (5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-methylphenyl]-6-(tributylstannyl)hex-5-enoate | 722497-33-8

• 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: methyl (5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-methylphenyl]-6-(tributylstannyl)hex-5-enoate
• 英文别名: methyl 6-(tributylstannyl)-6-[4-methoxy-5-methoxycarbonyl-3-methylphenyl]-hex-5-enoate；methyl 6-(4-methoxy-5-methoxycarbonyl-3-methylphenyl)-6-(tributylstannyl)hex-5-enoate；methyl 6-(tributylstannyl)-6-[4-methoxy-5-methoxycarbonyl-3-methylphenyl]hex-5-enoate；6-(tributylstannyl)-6-[4-methoxy-5-methoxycarbonyl-3-methylphenyl]hex-5-enoate；methyl 2-methoxy-5-[(E)-6-methoxy-6-oxo-1-tributylstannylhex-1-enyl]-3-methylbenzoate
• CAS: 722497-33-8；414861-66-8
• 化学式: C₂₉H₄₈O₅Sn
• 分子量: 595.407
• InChiKey: UQFPOVSUXZBXIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  7.91
• 重原子数：
  35
• 可旋转键数：
  19
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.66
• 拓扑面积：
  61.8
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  methyl (5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-methylphenyl]-6-(tributylstannyl)hex-5-enoate 在 四(三苯基膦)钯 、 碘 、 sodium carbonate 作用下， 以 二氯甲烷 、 水 、 乙腈 为溶剂， 反应 14.83h， 生成 5-[(E)-1-(3,4-Dimethoxy-phenyl)-5-methoxycarbonyl-pent-1-enyl]-2-methoxy-3-methyl-benzoic acid methyl ester
  参考文献：
  名称：

  具有不同芳环的烯基二芳基甲烷（ADAM）非核苷HIV-1逆转录酶抑制剂的合成。

  摘要：

  现有的用于合成烯基二芳基甲烷（ADAM）非核苷逆转录酶抑制剂的方法从对称的二苯甲酮开始，因此得到具有相同芳环的产物。因此，已经设计出用于制备具有不同芳族环的立体化学定义的ADAM的新方法。新路线依赖于钯催化的反应，包括Sonogashira，Suzuki，Stille和加氢芳构化方法。一些新的ADAM在亚微摩尔浓度下抑制了HIV-1在细胞培养中的细胞病变作用和HIV-1逆转录酶。

  DOI：

  10.1016/s0968-0896(01)00282-6
• 作为产物：
  描述：

  三正丁基氢锡 、 2-Methoxy-5-(5-methoxycarbonyl-pent-1-ynyl)-3-methyl-benzoic acid methyl ester 在 四(三苯基膦)钯 作用下， 以 四氢呋喃 为溶剂， 反应 4.17h， 生成 methyl (5E)-6-[4-methoxy-5-(methoxycarbonyl)-3-methylphenyl]-6-(tributylstannyl)hex-5-enoate
  参考文献：
  名称：

  Alkenyldiarylmethanes, Fused Analogs And Syntheses Thereof

  摘要：

  HIV-1反转录酶的非核苷类抑制剂被描述。这些抑制剂可以作为治疗HIV感染的联合疗法的一部分使用。本文描述的化合物具有抗病毒效力。此外，本文描述的化合物具有代谢稳定性。本文还描述了制备HIV-1反转录酶非核苷类抑制剂的过程。

  公开号：

  US20080300288A1

文献信息

• Synthesis of alkenyldiarylmethanes (ADAMs) containing benzo[d]isoxazole and oxazolidin-2-one rings, a new series of potent non-nucleoside HIV-1 reverse transcriptase inhibitors
  作者：Bo-Liang Deng、Yujie Zhao、Tracy L. Hartman、Karen Watson、Robert W. Buckheit Jr.、Christophe Pannecouque、Erik De Clercq、Mark Cushman

  DOI：10.1016/j.ejmech.2008.09.013

  日期：2009.3

  stable bioisosteres, compounds bearing benzo[d]isoxazole and oxazolidine-2-one rings were designed and evaluated as a new series of potent HIV-1 non-nucleoside reverse transcriptase inhibitors with anti-HIV activity. All of the resulting ADAMs were found to inhibit HIV-1 RT with poly(rC)·oligo(dG) as the template primer. The most promising compound in this series was ADAM 3, with EC50 values of 40 nM (vs

  为了继续用稳定的生物等排体取代链烯基二芳基碳酸铅的代谢不稳定的甲基酯（ADAM），设计了带有苯并[ d ]异恶唑和恶唑烷-2-酮环的化合物，并将其评估为一系列新的有效HIV-1非-具有抗HIV活性的核苷逆转录酶抑制剂。发现所有所得的ADAM均以poly（rC）·oligo（dG）为模板引物抑制HIV-1 RT。该系列中最有前途的化合物是ADAM 3，其EC 50值为40 nM（vs HIV-1 RF）和20 nM（vs HIV-1 IIIB）。化合物3还抑制HIV-1逆转录酶，IC 50为0.91μM。ADAM 4在CEM-SS细胞中具有0.6μM的抗病毒EC 50和51.4分钟的血浆半衰期。
• Synthesis, Anti-HIV Activity, and Metabolic Stability of New Alkenyldiarylmethane HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors
  作者：Bo-Liang Deng、Tracy L. Hartman、Robert W. Buckheit,、Christophe Pannecouque、Erik De Clercq、Phillip E. Fanwick、Mark Cushman

  DOI：10.1021/jm050452s

  日期：2005.9.1

  Non-nucleoside inhibitors of HIV-1 reverse transcriptase (NNRTIs) are part of the combination therapy currently used to treat HIV infection. Based on analogy with known HIV-1 NNRT inhibitors, 18 novel alkenyldiarylmethanes (ADAMs) containing 5-chloro-2-methoxyphenyl, 3-eyanophenyl, or 3-fluoro-5-trifluoromethylphenyl groups were synthesized and evaluated as HIV inhibitors. Their stabilities in rat plasma have also been investigated. Although introducing 5-chloro-2-methoxyphenyl or 3-fluoro-5-trifluoromethylphenyl groups into alkenyldiarylmethanes does not maintain the antiviral potency, the structural modification of alkenyldiarylmethanes with a 3-cyanophenyl substituent can be made without a large decrease in activity. The oxazolidinonyl group was introduced into the alkenyldiarylmethane framework and found to confer enhanced metabolic stability in rat plasma.
• Design, Synthesis, Anti-HIV Activities, and Metabolic Stabilities of Alkenyldiarylmethane (ADAM) Non-nucleoside Reverse Transcriptase Inhibitors
  作者：Maximilian A. Silvestri、Muthukaman Nagarajan、Erik De Clercq、Christophe Pannecouque、Mark Cushman

  DOI：10.1021/jm049916x

  日期：2004.6.1

  The alkenyldiarylmethane (ADAM) HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) are effective anti-HIV agents in cell culture. However, the potential clinical utility of the ADAMs is expected to be limited by the presence of methyl ester moieties that are likely to be metabolized by nonspecific esterases in blood plasma to biologically inactive carboxylic acid derivatives. The present investigation was therefore undertaken to investigate the anti-HIV activities of the ADAMs versus HIV-1(IIIB) and HIV-2(ROD) in MT-4 cells and the stabilities of the biologically active ADAMs in rat plasma. The ADAMs displayed a wide range of metabolic stabilities in rat plasma, with half-lives ranging from 0.9 to 76.6 min. A wide assortment of structural modifications was tolerated, with 18 of the 32 compounds tested displaying EC50 values between 0.3 and 3.7 muM versus HIV-1(IIIB) in MT-4 cells, 3 compounds in the EC50 = 13.2-35.4 muM range, and the remaining compounds inactive. Consistent with the mechanism of action of the ADAMs as NNRTIs, they were inactive or displayed comparatively low activity versus HIV-2ROD. The replacement of the two aromatic methyl ester substituents in one of the most active ADAMs (EC50 = 0.6 muM) with two methyl thioester groups resulted in an increase in plasma half-life from 5.8 to 55.3 min, while maintaining the antiviral potency at the EC50 = 1.8 muM level. At the same time, the bis(thioester) modification was less cytotoxic to uninfected MT-4 cells, with a CC50 of >224 muM versus 160 muM for the parent compound.
• Synthesis and anti-HIV activity of new alkenyldiarylmethane (ADAM) non-nucleoside reverse transcriptase inhibitors (NNRTIs) incorporating benzoxazolone and benzisoxazole rings
  作者：Bo-Liang Deng、Matthew D. Cullen、Zhigang Zhou、Tracy L. Hartman、Robert W. Buckheit、Christophe Pannecouque、Erik De Clercq、Phillip E. Fanwick、Mark Cushman

  DOI：10.1016/j.bmc.2005.11.014

  日期：2006.4

  The HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) constitute a large and structurally diverse set of compounds, several of which are currently used in the treatment of AIDS. A series of novel alkenyldiarylmethanes (ADAMs) were designed and synthesized as part of an ongoing investigation to replace the metabolically labile methyl ester moieties found in the ADAM pharmacophore with stable modifications that retain the potent anti-HIV activity of the parent compounds. Unsurprisingly, the rat plasma half-lives of the new ADAMs were not improved when compared to the parent compounds, but all of the synthesized ADAMs inhibited the cytopathic effect of HIV-1 in cell culture. The most potent compound identified was (E)-5-[1-(3,7-dimethyl-2oxo-2,3-dihydro-benzoxazol-5-yl)-5-methoxycarbonyl-pent-1-enyl]-2-methoxy-3-methylbenzoic acid methyl ester (7), which inhibited the cytopathic effects of both HIV-1(RF) and HIV-1(IIIB) strains in cell cultures with EC50 values of 30 and 90 nM, respectively, and inhibited HIV-1 reverse transcriptase with an IC50 of 20 nM. (c) 2005 Elsevier Ltd. All rights reserved.
• Replacement of the Metabolically Labile Methyl Esters in the Alkenyldiarylmethane Series of Non-Nucleoside Reverse Transcriptase Inhibitors with Isoxazolone, Isoxazole, Oxazolone, or Cyano Substituents
  作者：Bo-Liang Deng、Tracy L. Hartman、Robert W. Buckheit,、Christophe Pannecouque、Erik De Clercq、Mark Cushman

  DOI：10.1021/jm060449o

  日期：2006.8.1

  The alkenyldiarylmethanes (ADAMs) are a unique class of non-nucleoside reverse transcriptase inhibitors that have potential value in the treatment of HIV/AIDS. However, the potential usefulness of the ADAMs is limited by the presence of metabolically labile methyl ester moieties. A series of novel ADAMs were therefore designed and synthesized in order to replace the metabolically labile methyl ester moieties of the existing ADAM lead compounds with hydrolytically stable, fused isoxazolone, isoxazole, oxazolone, or cyano substituents on the aromatic rings. The methyl ester and methoxy substituents on both of the aromatic rings in the parent compound 1 were successfully replaced with metabolically stable moieties with retention of anti-HIV activity and a general decrease in cytotoxicity.