Angelo M, Ortwine D, Worth D, Werbel L M, McCall J W
J Med Chem. 1983 Sep;26(9):1258-67. doi: 10.1021/jm00363a010.
A series of N-[4-[[4-alkoxy-3-[(dialkylamino)methyl]phenyl]amino]- 2-pyrimidinyl]-N'-phenylguanidines have been synthesized for antifilarial evaluation. Reaction of the appropriate benzenamines with N-cyanoguanidine, followed by condensation of the resultant N-phenylimidodicarbonimidic diamides (V) with ethyl 4,4,4-trifluoro-3-oxobutanoate provided the intermediate N-(4-hydroxy-2-pyrimidinyl)-N'-phenylguanidines VIa. Alternatively, compounds VIa were synthesized by reaction of the requisite beta-keto esters (VII) with N-cyanoguanidine to give the (4-hydroxy-2-pyrimidinyl)cyanamides (VIII), followed by treatment with the desired benzenamines. Chlorination with POCl3 and condensation with the appropriate benzenamines (IX) generated the desired guanidines (X). Antifilarial activity was confined to adult Litomosoides carinii infections, and a structure-activity relationship for this activity is discussed. Lack of activity against L. carinii microfilaria and adult Brugia pahangi infections preclude further work in this area pending evaluation in additional experimental models.
已合成了一系列N-[4-[[4-烷氧基-3-[(二烷基氨基)甲基]苯基]氨基]-2-嘧啶基]-N'-苯基胍用于抗丝虫评估。合适的苯甲胺与N-氰基胍反应，随后所得的N-苯基亚氨基二碳酸二酰胺(V)与4,4,4-三氟-3-氧代丁酸乙酯缩合得到中间体N-(4-羟基-2-嘧啶基)-N'-苯基胍VIa。另外，化合物VIa通过所需的β-酮酯(VII)与N-氰基胍反应得到(4-羟基-2-嘧啶基)氰胺(VIII)，然后用所需的苯甲胺处理来合成。用POCl3氯化并与合适的苯甲胺(IX)缩合生成所需的胍(X)。抗丝虫活性仅限于成年卡氏丝虫感染，并讨论了该活性的构效关系。对卡氏丝虫微丝蚴和成年彭亨布鲁线虫感染缺乏活性，这使得在该领域的进一步研究在等待其他实验模型评估之前无法进行。
