Temple C, Rener G A
Kettering-Meyer Laboratory, Southern Research Institute, Birmingham, Alabama 35255-5305.
J Med Chem. 1992 Mar 20;35(6):988-93. doi: 10.1021/jm00084a003.
Metabolism studies with ethyl [5-amino-1,2-dihydro-2-methyl-3-phenylpyrido[3,4-b]pyrazin-7 - yl]carbamate (1) in mice were reported previously to give a hydroxylated metabolite, which was methylated to give a methoxy derivative. The metabolite and its derivatives were considered to be 4-(substituted)phenyl compounds, which have been confirmed by the synthesis of the [1,2-dihydro-3-(4-hydroxyphenyl)- and [1,2-dihydro-3-(4-methoxyphenyl)pyrido[3,4-b]-pyrazin-7-yl]carbama tes (17 and 16). Both the S- and R-isomers of 17 are active in several biological systems, but the S-isomer is more potent then the R-isomer. The difference in activity between the S- and R-isomers of 17 is similar with that observed for S- and R-isomers of 1. As model reactions, several O-substituted derivatives were prepared by alkylation of (RS)-17 with benzyl chloride and condensation of (RS)-17 with butyl isocyanate and (S)-17 with 2-chloroethyl isocyanate.
先前报道了在小鼠中对[5-氨基-1,2-二氢-2-甲基-3-苯基吡啶并[3,4-b]吡嗪-7-基]氨基甲酸乙酯（1）进行的代谢研究，结果显示产生了一种羟基化代谢物，该代谢物经甲基化生成一种甲氧基衍生物。该代谢物及其衍生物被认为是4-（取代）苯基化合物，这已通过合成[1,2-二氢-3-（4-羟基苯基）-和[1,2-二氢-3-（4-甲氧基苯基）吡啶并[3,4-b]吡嗪-7-基]氨基甲酸酯（17和16）得到证实。17的S-异构体和R-异构体在多个生物系统中均具有活性，但S-异构体比R-异构体更具效力。17的S-异构体和R-异构体之间的活性差异与1的S-异构体和R-异构体所观察到的差异相似。作为模型反应，通过用苄基氯对（RS）-17进行烷基化以及使（RS）-17与异氰酸丁酯和（S）-17与2-氯乙基异氰酸酯缩合制备了几种O-取代衍生物。
