Bailey S, Harnden M R, Jarvest R L, Parkin A, Boyd M R
Beecham Pharmaceuticals Research Division, Biosciences Research Centre, Epsom, Surrey, U.K.
J Med Chem. 1991 Jan;34(1):57-65. doi: 10.1021/jm00105a010.
Reaction of alkenoxyamines (3,5) or (R,S)-, (R)-, and (S)-hydroxy-protected derivatives of hydroxyalkoxyamines (20a,b, 37a-c) with 4,6-dichloro-2,5-diformamidopyrimidine (4) and cyclization of the resultant 6-[(alkenoxy)amino]-and 6-(alkoxyamino)pyrimidines (6,7,21a,b, 38a,b,c) by heating with diethoxymethyl acetate afforded 9-alkenoxy- and 9-alkoxy-6-chloropurines (9,10,22a,b, 39a-c, 40a). These were subsequently converted to 9-(2,3-dihydroxypropoxy), 9-(3,4-dihydroxybutoxy), and 9-(1,4-dihydroxybut-2-oxy) derivatives of guanine and 2-aminopurine (13-16, 25-28, 41a-c, 42a). A 2-amino-6-methoxypurine derivative (17) was also prepared. The racemic guanine derivative 13 showed potent and selective activity against herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), but was less active against varicella zoster virus (VZV). Its antiviral activity is attributable to the S isomer (28), which was found to be more active than acyclovir against HSV-1 and HSV-2 and about 4 times less active than acyclovir against VZV. The S enantiomer of 9-(1,4-dihydroxybut-2-oxy)guanine (41c) also showed noteworthy antiviral activity in cell culture. Although this acyclonucleoside (41c) is only weakly active against HSV-1 and inactive against HSV-2, it is about twice as active as acyclovir against VZV.
烯氧基胺（3,5）或羟基烷氧基胺（20a,b, 37a - c）的（R,S）-、（R）-和（S）-羟基保护衍生物与4,6 - 二氯 - 2,5 - 二甲酰氨基嘧啶（4）反应，所得的6 - [（烯氧基）氨基] - 和6 - （烷氧基氨基）嘧啶（6,7,21a,b, 38a,b,c）通过与乙酸二乙氧基甲酯加热环化，得到9 - 烯氧基 - 和9 - 烷氧基 - 6 - 氯嘌呤（9,10,22a,b, 39a - c, 40a）。随后将这些化合物转化为鸟嘌呤和2 - 氨基嘌呤的9 - （2,3 - 二羟基丙氧基）、9 - （3,4 - 二羟基丁氧基）和9 - （1,4 - 二羟基丁 - 2 - 氧基）衍生物（13 - 16, 25 - 28, 41a - c, 42a）。还制备了一种2 - 氨基 - 6 - 甲氧基嘌呤衍生物（17）。外消旋鸟嘌呤衍生物13对1型和2型单纯疱疹病毒（HSV - 1和HSV - 2）表现出强效和选择性活性，但对水痘带状疱疹病毒（VZV）的活性较低。其抗病毒活性归因于S异构体（28），发现该异构体对HSV - 1和HSV - 2的活性比阿昔洛韦高，对VZV的活性比阿昔洛韦低约4倍。9 - （1,4 - 二羟基丁 - 2 - 氧基）鸟嘌呤（41c）的S对映体在细胞培养中也表现出显著的抗病毒活性。尽管这种无环核苷（41c）对HSV - 1的活性较弱且对HSV - 2无活性，但它对VZV的活性约为阿昔洛韦的两倍。
