2-Methoxy-5-(5-methoxycarbonyl-pent-1-ynyl)-3-methyl-benzoic acid methyl ester | 414861-65-7

• 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: 2-Methoxy-5-(5-methoxycarbonyl-pent-1-ynyl)-3-methyl-benzoic acid methyl ester
• 英文别名: Methyl 6-[4-methoxy-5-(methoxycarbonyl)-3-methylphenyl]hex-5-ynoate；methyl 2-methoxy-5-(6-methoxy-6-oxohex-1-ynyl)-3-methylbenzoate
• CAS: 414861-65-7
• 化学式: C₁₇H₂₀O₅
• 分子量: 304.343
• InChiKey: PCNLPVYHQNHOCA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.41
• 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：

  2-Methoxy-5-(5-methoxycarbonyl-pent-1-ynyl)-3-methyl-benzoic acid methyl ester 在 palladium on activated charcoal 氢气 作用下， 以 乙酸乙酯 为溶剂， 反应 14.0h， 以85.5%的产率得到2-Methoxy-5-(5-methoxycarbonyl-pentyl)-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：

  5-己炔酸甲酯 、 5-碘-2-甲氧基-3-甲基苯甲酸甲酯 在 palladium diacetate copper(l) iodide 、 三乙胺 、 三苯基膦 作用下， 以 乙酸乙酯 为溶剂， 反应 12.0h， 以41%的产率得到2-Methoxy-5-(5-methoxycarbonyl-pent-1-ynyl)-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

文献信息

• Alkenyldiarylmethanes, Fused Analogs And Syntheses Thereof
  申请人：Cushman Mark S.

  公开号：US20080300288A1

  公开（公告）日：2008-12-04

  Non-nucleoside inhibitors of HIV-1 reverse transcriptase are described. Such inhibitors may be used as part of a combination therapy to treat HIV infection. Compounds described herein exhibit antiviral potency. In addition, compounds described herein exhibit metabolic stability. Also described herein are processes for preparing Non-nucleoside inhibitors of HIV-1 reverse transcriptase.

  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。
• Synthesis and Biological Evaluation of Alkenyldiarylmethane HIV-1 Non-Nucleoside Reverse Transcriptase Inhibitors That Possess Increased Hydrolytic Stability
  作者：Matthew D. Cullen、Bo-Liang Deng、Tracy L. Hartman、Karen M. Watson、Robert W. Buckheit,、Christophe Pannecouque、Erik De Clercq、Mark Cushman

  DOI：10.1021/jm070382k

  日期：2007.10.1

  Non-nucleoside inhibitors of HIV reverse transcriptase (NNRTIs), albeit not the mainstays of HIV/AIDS treatment, have become increasingly important in highly active antiretroviral therapy (HAART) due to their unique mechanism of action. Several years ago our group identified the alkenyldiarylmethanes (ADAMs) as a potent and novel class of NNRTIs; however, the most active compounds were found to be

  HIV逆转录酶（NNRTIs）的非核苷抑制剂尽管不是HIV / AIDS治疗的主要手段，但由于其独特的作用机理，在高活性抗逆转录病毒疗法（HAART）中已变得越来越重要。几年前，我们的研究小组将烯基二芳基甲烷（ADAMs）鉴定为一种有效的新型NNRTIs。然而，发现活性最高的化合物在代谢上不稳定。随后的工作通过用各种杂环，腈和硫代酯代替不稳定的酯，从而合成了33种具有改善的代谢特性的类似物。结果，在纳摩尔浓度范围内鉴定出许多具有抗HIV活性的水解稳定的NNRTI。此外，基于新的ADAM系列，开发了一种改进的药效团模型，
• 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.
• Investigation of the alkenyldiarylmethane non-nucleoside reverse transcriptase inhibitors as potential cAMP phosphodiesterase-4B2 inhibitors
  作者：Matthew D. Cullen、York-Fong Cheung、Miles D. Houslay、Tracy L. Hartman、Karen M. Watson、Robert W. Buckheit、Christophe Pannecouque、Erik De Clercq、Mark Cushman

  DOI：10.1016/j.bmcl.2007.12.015

  日期：2008.2

  The alkenyldiarylmethanes ( ADAMs) are currently being investigated as non- nucleoside HIV- 1 reverse transcriptase inhibitors ( NNRTIs) of potential value in the treatment of HIV infection and AIDS. During the course of these studies, a number of ADAM analogues have been identified that protect HIV- infected cells from the cytopathic effects of the virus by an unknown, HIV- 1 RT- independent mechanism. Since the phosphodiesterase 4 family is required for HIV infection, the effect of various ADAMs on the activity of PDE4B2 was investigated in an effort to determine if the ADAMs could possibly be targeting phosphodiesterases. Six compounds representative of the ADAM class were tested for inhibition of cAMP hydrolysis by PDE4B2 enzymatic activity. Four ADAMs were found to be weak inhibitors of PDE4B2 and two of them were inactive. The experimental results are consistent with an antiviral mechanism that does not include inhibition of PDE4 isoforms. (C) 2007 Elsevier Ltd. All rights reserved.