3-cyano-5-n-propyl-6-methylpyridin-2(1H)-one | 139548-84-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: 3-cyano-5-n-propyl-6-methylpyridin-2(1H)-one
• 英文别名: 6-methyl-2-oxo-5-propyl-1H-pyridine-3-carbonitrile
• CAS: 139548-84-8
• 化学式: C₁₀H₁₂N₂O
• 分子量: 176.218
• InChiKey: GKZKBARRJATKGH-UHFFFAOYSA-N

物化性质

• 沸点：
  353.5±35.0 °C(Predicted)
• 密度：
  1.10±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.8
• 重原子数：
  13
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  52.9
• 氢给体数：
  1
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-cyano-5-n-propyl-6-methylpyridin-2(1H)-one 在 镍 盐酸 、 正丁基锂 、 四甲基乙二胺 、 硫酸 、 苄基三乙基氯化铵 、 氢气 、 硝酸 、 三乙胺 、 三氯氧磷 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 乙腈 为溶剂， 80.0 ℃ 、202.65 kPa 条件下， 反应 167.0h， 生成 3-amino-4-[(3,5-dimethylphenyl)methyl]-6-methyl-5-propyl-1H-pyridin-2-one
  参考文献：
  名称：

  4-Benzyl and 4-Benzoyl-3-dimethylaminopyridin-2(1H)-ones:  In Vitro Evaluation of New C-3-Amino-Substituted and C-5,6-Alkyl-Substituted Analogues against Clinically Important HIV Mutant Strains

  摘要：

  In a program to optimize the anti-HIV activity of the 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 and 10, lead compounds in a new class of highly potent non-nucleoside type inhibitors of HIV-1 reverse transcriptase, modification of the alkyl substitutents at the C-5 and C-6 positions on the pyridinone ring and of the substitutents on the C-3 amino group has been studied. Of the 17 new 5/6-modified analogues prepared, compounds 31b and 32b substituted at C-5 by an extended nonpolar chain containing an ether function and a C-6 methyl group and compound 35 bearing a C-5 ethyl/C-6 hydroxymethyl substituent pattern were selected on the basis of their in vitro activity against wild-type HIV and the three principle mutant strains, K103N, Y181C, and Y188L. When tested further, it was shown that these molecules, and in particular compound 35, are globally more active than 9, 10, and efavirenz against an additional eight single [L100I, K101E, V106A, E138K, V179E, G190A/S, and F227C] and four double HIV mutant strains [L1001 + K103N, K101E + K103N, K103N + Y181C, and F227L + V106A] which are clinically relevant. Concerning modulation of the N-3 substituent, 36 new analogues were prepared. Of these, the N-methyl-N-(2-methoxyethyl)-substituted compounds 40, 42, and 62, as well as the doubly modified compounds 77a and 77b, were selected from the initial screen and were subsequently shown to be active at sub-micromolar concentrations (IC50'S) against all the other mutant strains except K103N + Y181C and F227L + V106A. Two possible, but distinct, modes of binding of these analogues in RT were suggested from molecular modeling studies. The preferred mode of binding for compound 62, corresponding to the predicted "orientation 1", was revealed in the X-ray crystal structure of the compound 62-RT complex.

  DOI：

  10.1021/jm0408621
• 作为产物：
  描述：

  2-己酮 在 sodium methylate 、 哌啶乙酸盐 作用下， 以 乙醚 、 乙醇 、 水 为溶剂， 反应 3.5h， 生成 3-cyano-5-n-propyl-6-methylpyridin-2(1H)-one
  参考文献：
  名称：

  2-吡啶酮衍生物作为HIV-1特异性逆转录酶抑制剂的合成和评估。1.邻苯二甲酰亚胺基烷基和-烷基氨基类似物。

  摘要：

  一种有效的（IC50 = 30 nM）特异性非核苷HIV-1逆转录酶（RT）抑制剂3- [N-（邻苯二甲酰亚胺甲基）氨基] -5-乙基-6-甲基吡啶-2（1H）-一（1）是通过体外筛选程序发现的。该化合物不会抑制（IC50> 300微米）其他DNA和RNA聚合酶，包括HIV-2 RT和SIV-RT。不幸的是，这种（氨基甲基）邻苯二甲酰亚胺的水解不稳定性不能用作抗病毒剂。在本系列的第一篇论文中，描述了初步开发工作，该工作生产了乙基邻苯二甲酰亚胺20，该水解稳定的化合物具有降低的HIV-1 RT抑制活性（100倍）和在H9细胞中的抗病毒活性弱（CIC95 = 40 microM）。结构活性研究表明了5-乙基的重要性，吡啶酮环上的6-甲基取代基图案以及在吡啶酮和邻苯二甲酰亚胺杂环之间需要一个灵活的两个原子的连接基。这些引线1和20为进一步开发这种抑制剂结构类型提供了基础，从中选择了几种化合物（随附报告的主题）进行临床评估。

  DOI：

  10.1021/jm00099a006

文献信息

• Inhibitors of HIV reverse transcriptase
  申请人：MERCK & CO. INC.

  公开号：EP0462800A2

  公开（公告）日：1991-12-27

  Novel pyridones inhibit HIV reverse transcriptase, and are useful in the prevention or treatment of infection by HIV and the treatment of AIDS, either as compounds, pharmaceutically acceptable salts, pharmaceutical composition ingredients, whether or not in combination with other antivirals, anti-infectives, immunomodulators, antibiotics or vaccines. Methods of treating AIDS and methods of preventing or treating infection by IV are also described.

  新型吡啶酮类药物可抑制艾滋病病毒逆转录酶，可用于预防或治疗艾滋病病毒感染和治疗艾滋病，可作为化合物、药学上可接受的盐、药物组合成分，无论是否与其他抗病毒药、抗感染药、免疫调节剂、抗生素或疫苗联合使用。还描述了治疗艾滋病的方法和预防或治疗 IV 感染的方法。
• 1,2-Dihydro-2-oxopyridine als Angiotensin II-Antagonisten
  申请人：MERCK PATENT GmbH

  公开号：EP0530702A1

  公开（公告）日：1993-03-10

  Neue 1,2-Dihydro-2-oxo-pyridine der Formel I worin Rden Rest bedeutet und R¹ bis R⁶ und Xdie in Patentanspruch 1 angegebene Bedeutung haben, sowie deren Salze zeigen angiotensin II-antagonistische Eigenschaften und können zur Behandlung von Hypertension, Aldosteronismus und Herzinsuffizienz verwendet werden.

  式 I 的新 1,2-二氢-2-氧代吡啶 其中 Rden 表示基团 和 R¹ 至 R⁶ 和 X 具有权利要求 1 所述含义、 及其盐类具有血管紧张素 II 拮抗特性，可用于治疗高血压、醛固酮增多症和心力衰竭。
• US5332750A
  申请人：——

  公开号：US5332750A

  公开（公告）日：1994-07-26
• 4-Benzyl and 4-Benzoyl-3-dimethylaminopyridin-2(1<i>H</i>)-ones:  In Vitro Evaluation of New C-3-Amino-Substituted and C-5,6-Alkyl-Substituted Analogues against Clinically Important HIV Mutant Strains
  作者：Abdellah Benjahad、Martine Croisy、Claude Monneret、Emile Bisagni、Dominique Mabire、Sophie Coupa、Alain Poncelet、Imre Csoka、Jérôme Guillemont、Christophe Meyer、Koen Andries、Rudi Pauwels、Marie-Pierre de Béthune、Daniel M. Himmel、Kalyan Das、Eddy Arnold、Chi Hung Nguyen、David S. Grierson

  DOI：10.1021/jm0408621

  日期：2005.3.1

  In a program to optimize the anti-HIV activity of the 4-benzyl and 4-benzoyl-3-dimethylaminopyridinones 9 and 10, lead compounds in a new class of highly potent non-nucleoside type inhibitors of HIV-1 reverse transcriptase, modification of the alkyl substitutents at the C-5 and C-6 positions on the pyridinone ring and of the substitutents on the C-3 amino group has been studied. Of the 17 new 5/6-modified analogues prepared, compounds 31b and 32b substituted at C-5 by an extended nonpolar chain containing an ether function and a C-6 methyl group and compound 35 bearing a C-5 ethyl/C-6 hydroxymethyl substituent pattern were selected on the basis of their in vitro activity against wild-type HIV and the three principle mutant strains, K103N, Y181C, and Y188L. When tested further, it was shown that these molecules, and in particular compound 35, are globally more active than 9, 10, and efavirenz against an additional eight single [L100I, K101E, V106A, E138K, V179E, G190A/S, and F227C] and four double HIV mutant strains [L1001 + K103N, K101E + K103N, K103N + Y181C, and F227L + V106A] which are clinically relevant. Concerning modulation of the N-3 substituent, 36 new analogues were prepared. Of these, the N-methyl-N-(2-methoxyethyl)-substituted compounds 40, 42, and 62, as well as the doubly modified compounds 77a and 77b, were selected from the initial screen and were subsequently shown to be active at sub-micromolar concentrations (IC50'S) against all the other mutant strains except K103N + Y181C and F227L + V106A. Two possible, but distinct, modes of binding of these analogues in RT were suggested from molecular modeling studies. The preferred mode of binding for compound 62, corresponding to the predicted "orientation 1", was revealed in the X-ray crystal structure of the compound 62-RT complex.
• Synthesis and evaluation of 2-pyridinone derivatives as HIV-1 specific reverse transcriptase inhibitors. 1. Phthalimidoalkyl and -alkylamino analogs
  作者：Jacob M. Hoffman、John S. Wai、Craig M. Thomas、Rhonda B. Levin、Julie A. O'Brien、Mark E. Goldman

  DOI：10.1021/jm00099a006

  日期：1992.10

  A potent (IC50 = 30 nM), specific nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor 3-[N-(phthalimidomethyl)amino]-5-ethyl-6-methylpyridin-2(1H) -one (1), was discovered through an in vitro screening program. This compound did not inhibit (IC50 > 300 microns) other DNA and RNA polymerases, including HIV-2 RT and SIV-RT. Unfortunately, hydrolytic instability of this (aminomethyl)phthalimide precluded

  一种有效的（IC50 = 30 nM）特异性非核苷HIV-1逆转录酶（RT）抑制剂3- [N-（邻苯二甲酰亚胺甲基）氨基] -5-乙基-6-甲基吡啶-2（1H）-一（1）是通过体外筛选程序发现的。该化合物不会抑制（IC50> 300微米）其他DNA和RNA聚合酶，包括HIV-2 RT和SIV-RT。不幸的是，这种（氨基甲基）邻苯二甲酰亚胺的水解不稳定性不能用作抗病毒剂。在本系列的第一篇论文中，描述了初步开发工作，该工作生产了乙基邻苯二甲酰亚胺20，该水解稳定的化合物具有降低的HIV-1 RT抑制活性（100倍）和在H9细胞中的抗病毒活性弱（CIC95 = 40 microM）。结构活性研究表明了5-乙基的重要性，吡啶酮环上的6-甲基取代基图案以及在吡啶酮和邻苯二甲酰亚胺杂环之间需要一个灵活的两个原子的连接基。这些引线1和20为进一步开发这种抑制剂结构类型提供了基础，从中选择了几种化合物（随附报告的主题）进行临床评估。