Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.
Synthesis and antiviral activity of certain 4-substituted and 2,4-disubstituted 7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidines.
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DOI：
10.1021/jm00403a005
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发表时间：
1988-08
影响因子：
7.3
通讯作者：
N. Saxena;B. M. Hagenow;G. Genzlinger;S. R. Turk;J. Drach;L. Townsend
中科院分区：
文献类型：
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作者：
N. Saxena;B. M. Hagenow;G. Genzlinger;S. R. Turk;J. Drach;L. Townsend
用（2-乙酰氧基乙氧基）甲基溴（3）处理4-氯-2-（甲硫基）吡咯并[2，3-d]嘧啶（2）的钠盐，得到4-氯-2-（甲硫基）-7[（2-乙酰氧基乙氧基）甲基]吡咯并[2，3- d]嘧啶（4）。4在室温下氨解得到4-氯-2-（甲硫基）-7-[（2-羟基乙氧基）甲基]吡咯并[2，3- d]嘧啶（5）。然而，在130 ℃下5的氨解得到4-氨基-2-（甲硫基）-7-[（2-羟基乙氧基）甲基]-吡咯并[2，3- d]嘧啶（6），其在用阮内镍脱硫后得到4-氨基-7-[（2-羟基乙氧基）-甲基]吡咯并[2，3-d]嘧啶（7）（杀结核菌素的无环类似物）。用间氯过苯甲酸氧化6得到砜衍生物8。用甲氧基阴离子亲核取代8上的2-甲磺酰基得到4-氨基-2-甲氧基-7-[（2-羟基乙氧基）甲基]吡咯并[2，3-d]嘧啶（9）。9用碘三甲基硅烷脱甲基得到4-氨基-2-羟基-7-[（2-羟基乙氧基）甲基]吡咯并[2，3-d]嘧啶（10）。用3处理2，4-二氯吡咯并[2，3-d]嘧啶（11），得到受保护的无环化合物12，在受控反应条件下进行脱乙酰基和氨解，分别得到2，4-二氯-7-[（2-羟基乙氧基）-甲基]吡咯并[2，3-d]嘧啶（13）和4-氨基-2-氯-7-[（2-羟基乙氧基）甲基]吡咯并[2，3- d]嘧啶（14）。2-乙酰氨基-4-氯吡咯并[2，3-d]嘧啶（15）与3缩合得到保护的无环化合物16，其在高温下与甲醇氨一起脱乙酰基和氨解，以中等产率得到2，4-二氨基-7-[（2-羟基乙氧基）甲基]吡咯并[2，3-d]嘧啶（17）。在涉及人巨细胞病毒（HCMV）和单纯疱疹病毒1型（HSV-1）的试验中，仅观察到轻微的活性和细胞毒性。活性最强的化合物（12和13）对HCMV的活性略高于阿昔洛韦，但两种化合物对HSV-1均无活性。然而，抗HCMV的活性与细胞毒性没有很好地分开，导致这些化合物不值得进一步研究的结论。
Treatment of the sodium salt of 4-chloro-2-(methylthio)pyrrolo[2,3-d]pyrimidine (2) with (2-acetoxyethoxy)methyl bromide (3) has provided 4-chloro-2-(methylthio)-7[(2-acetoxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (4). Ammonolysis of 4 at room temperature gave 4-chloro-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (5). However, ammonolysis of 5 at 130 degrees C furnished 4-amino-2-(methylthio)-7-[(2-hydroxyethoxy)methyl]-pyrrolo[2,3- d]pyrimidine (6), which on desulfurization with Raney Ni yielded 4-amino-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (7) (acyclic analogue of tubercidin). The oxidation of 6 with m-chloroperbenzoic acid provided the sulfone derivative 8. A nucleophilic displacement of the 2-methylsulfonyl group from 8 with methoxide anion provided 4-amino-2-methoxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (9). Demethylation of 9 with iodotrimethylsilane gave 4-amino-2-hydroxy-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (10). Treatment of 2,4-dichloropyrrolo[2,3-d]pyrimidine (11) with 3 gave the protected acyclic compound 12, which on deacetylation and ammonolysis under controlled reaction conditions gave 2,4-dichloro-7-[(2-hydroxyethoxy)-methyl]pyrrolo[2,3-d]pyrimidine (13) and 4-amino-2-chloro-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3- d]pyrimidine (14), respectively. The condensation of 2-acetamido-4-chloropyrrolo[2,3-d]pyrimidine (15) with 3 gave the protected acyclic compound 16, which on concomitant deacetylation and ammonolysis with methanolic ammonia at an elevated temperature yielded 2,4-diamino-7-[(2-hydroxyethoxy)methyl]pyrrolo[2,3-d]pyrimidine (17) in moderate yield. In tests involving human cytomegalovirus (HCMV) and herpes simplex virus type 1 (HSV-1), only slight activity and cytotoxicity were observed. The most active compounds (12 and 13) were slightly more active against HCMV than acyclovir, but both compounds were inactive against HSV-1. The activity against HCMV, however, was not well separated from cytotoxicity leading to the conclusion that these compounds did not merit further study.