3-amino-4-(3,5-dimethylbenzyl)-5-methyl-6-isopropylpyridin-2(1H)-one | 248248-09-1

• 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-amino-4-(3,5-dimethylbenzyl)-5-methyl-6-isopropylpyridin-2(1H)-one
• 英文别名: 3-amino-4-[(3,5-dimethylphenyl)methyl]-6-isopropyl-5-methyl-1H-pyridin-2-one；3-amino-4-[(3,5-dimethylphenyl)methyl]-5-methyl-6-propan-2-yl-1H-pyridin-2-one
• CAS: 248248-09-1
• 化学式: C₁₈H₂₄N₂O
• 分子量: 284.401
• InChiKey: BHYHGBKARXNCIA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  55.1
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  3-amino-4-(3,5-dimethylbenzyl)-5-methyl-6-isopropylpyridin-2(1H)-one 、 聚合甲醛 在 sodium cyanoborohydride 、 溶剂黄146 作用下， 以 乙腈 为溶剂， 反应 8.0h， 以77%的产率得到3-(dimethylamino)-4-[(3,5-dimethylphenyl)methyl]-6-isopropyl-5-methyl-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：

  3,5-二甲基溴苄 在 盐酸 、 正丁基锂 、 四甲基乙二胺 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 3-amino-4-(3,5-dimethylbenzyl)-5-methyl-6-isopropylpyridin-2(1H)-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

文献信息

• 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.