Therkelsen Frans D, Hansen Anne-Lene L, Pedersen Erik B, Nielsen Claus
Nucleic Acid Center, Department of Chemistry, University of Southern Denmark, Campusvej 55, DK-5230 Odense M, Denmark.
Org Biomol Chem. 2003 Aug 21;1(16):2908-18. doi: 10.1039/b303658h.
Condensation of 3-(3,5-dimethylphenyl)-2-oxocyclopentanecarboxamide (11) with oxalyl chloride and condensation of ethyl 2-benzylamino-5-methyl-3-phenylcyclopent-1-enecarboxylate (17a) with trimethylsilyl isothiocyanate gave 7-(3,5-dimethylphenyl)-6,7-dihydro-5H-cyclopenta[e][1,3]oxazine-2,4-dione (12) and 1-benzyl-5-methyl-7-phenyl-2-thioxo-1,2,3,5,6,7- hexahydrocyclopentapyrimidin-4-one (18a), respectively. Acid catalyzed ring-closure of 6-(4-methyl-1-phenylpent-3-enyl)-2-thioxo-2,3-dihydro-1H-pyrimidin-4-one (26) and radical mediated ring-closure of 1,3-bis(benzyloxymethyl)-5-bromo-6-(1-phenylbut-3-enyl)-1H-pyrimidine-2,4- dione (32a) gave 5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline-2,4- dione (28) and 1,3-bis(benzyloxymethyl)-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (33), respectively. Annelated emivirine analogues 7-(3,5-dimethylphenyl)-1- ethoxymethyl-1,5,6,7-tetrahydrocyclopentapyrimidine-2,4-dione (4), 1-ethoxymethyl-5,5-dimethyl-8-phenyl-5,6,7,8-tetrahydro-1H-quinazoline- 2,4-dione (5) and 1-ethoxymethyl-5-methyl-7-phenyl-1,5,6,7- tetrahydrocyclopentapyrimidine-2,4-dione (6) were obtained in few steps from 12, 28 and 18a/33, respectively. These new analogues can be considered as conformationally locaTed analogues of emivirine. However, the compounds 4 6 showed lower activities against HIV-1 than emivirine and it is concluded that the locked conformation disfavours activity against HIV-1.
3-(3,5-二甲基苯基)-2-氧代环戊烷甲酰胺(11)与草酰氯缩合，以及2-苄基氨基-5-甲基-3-苯基环戊-1-烯羧酸乙酯(17a)与三甲基甲硅烷基异硫氰酸酯缩合，分别得到7-(3,5-二甲基苯基)-6,7-二氢-5H-环戊并[e][1,3]恶嗪-2,4-二酮(12)和1-苄基-5-甲基-7-苯基-2-硫代-1,2,3,5,6,7-六氢环戊并嘧啶-4-酮(18a)。6-(4-甲基-1-苯基戊-3-烯基)-2-硫代-2,3-二氢-1H-嘧啶-4-酮(26)的酸催化闭环反应以及1,3-双(苄氧基甲基)-5-溴-6-(1-苯基丁-3-烯基)-1H-嘧啶-2,4-二酮(32a)的自由基介导闭环反应，分别得到5,5-二甲基-8-苯基-5,6,7,8-四氢-1H-喹唑啉-2,4-二酮(28)和1,3-双(苄氧基甲基)-5-甲基-7-苯基-1,5,6,7-四氢环戊并嘧啶-2,4-二酮(33)。稠合的依米韦仑类似物7-(3,5-二甲基苯基)-1-乙氧基甲基-1,5,6,7-四氢环戊并嘧啶-2,4-二酮(4)、1-乙氧基甲基-5,5-二甲基-8-苯基-5,6,7,8-四氢-1H-喹唑啉-2,4-二酮(5)和1-乙氧基甲基-5-甲基-7-苯基-1,5,6,7-四氢环戊并嘧啶-2,4-二酮(6)分别由12、28和18a/33经几步反应制得。这些新的类似物可被视为依米韦仑的构象定位类似物。然而，化合物4至6对HIV-1的活性低于依米韦仑，得出的结论是锁定构象不利于对HIV-1的活性。
