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首页> 外文期刊>Journal of Medicinal Chemistry >Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.
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Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.

机译：作为喷昔洛韦潜在前药的2-氨基-9-（3-羟甲基-4-烷氧基羰基氧基丁-1-基）嘌呤的合成和评价。

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A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).
机译：一系列2-氨基-9-（3-羟甲基-4-烷氧基羰基氧基丁-1-基）嘌呤（4-10）和2-氨基-9-（2-（2-oxo-1,3-dioxan-5合成了（yl）乙基）嘌呤（1）作为喷昔洛韦的潜在前药，并对其在小鼠和大鼠中口服喷昔洛韦的生物利用度进行了评估。在THF中用1,1'-羰基二咪唑处理2-（2-苄氧基乙基）丙烷-1,3-二醇（11），然后氢解除去所得环状碳酸酯12的苄基，得到5-（2-羟乙基） -1,3-二恶烷-2-酮（13）。醇13的甲磺酸化，然后使用无水Cs2CO3在DMF中将生成的甲磺酸酯14与2-氨基-6-氯嘌呤偶联反应，得到2-氨基-6-氯-9-（2-（2-氧代-1,3在硅胶上通过快速柱色谱纯化后，使用EtOAc / MeCN / Et 3 N作为洗脱剂，得到-（二恶烷-5-基）乙基）嘌呤（16）。用活化的SiO 2作为路易斯酸将6-氯代环状碳酸酯16氢化，然后在适当的醇和CHCl 3的混合物中，将6-脱氧环状碳酸酯1开环反应，得到相应的烷基单碳酸酯衍生物3-10。中等至高产。在小鼠中测试的前药中，一碳酸异丙酯6的平均尿回收率达到喷昔洛韦的最高（53％），其次依次为一碳酸丙酯5（51％），一碳酸异戊酯10（51％），一碳酸乙酯4 （50％）和泛昔洛韦（48％）。在大鼠中，单碳酸甲酯3、4、6，正丁基碳酸氢盐7和10（39-41％）显示喷昔洛韦的平均尿回收水平与泛昔洛韦（40％）相似。发现单碳酸烷基酯4-10在水性缓冲溶液中非常稳定，其中6种最稳定，在pH下半衰期（t1 / 2）为88，> 200、61和26天。分别为1.2、6.0、7.4和8.0。此外，6在水中的溶解度很高（138.8 mg / mL，20摄氏度）。

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