Ampicillin及びAmoxicillin誘導体の研究(第1報)N-(Pyrido[2,3-d]pyrimidine-6-carbonyl)ampicillin及び-amoxicillin誘導体の合成と抗菌活性

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A series of N-(pyrido [2,3-d] pyrimidine-6-carbonyl) ampicillin and -amoxicillin derivatives (1-3) were synthesized and tested for antibacterial activity and acute toxicity in mice. 5,8-Dihydro-2-(1-piperazinyl)-5-oxopyrido [2,3-d] pyrimidine-6-carboxylic acid (7) was converted to N-acyl- and -alkylpiperazinyl derivatives (8 and 9) by acylation and alkylation, respectively ; a part of 9 was alternatively prepared by the reactions involving the displacement of N-alkylpiperazines with sulfoxide 11 which was derived from ethyl 5,8-dihydro-2-methylthio-5-oxopyrido [2,3-d] pyrimidine-6-carboxylate (10). Treatment of 4,5,8 and 9 with ethyl chloroformate followed by the reaction with ampicillin and amoxicillin gave the desired N-acylampicillin (2) and -amoxicillins (1 and 3), respectively. Among compounds 1-3,sodium 6-[D-(-)-2-(2-(4-formyl-1-piperazinyl)-5,8-dihydro-5-oxopyrido [2,3-d] pyrimidine-6-carboxamido)-p-hydroxyphenylacetamido] penicillanate (3l, PL-385) was found to be the most excellent in antibacterial activity and to be the less potent in acute toxicity in mice. An alternative route for the synthesis of PL-385 was accomplished, consisting of the reaction of an active ester 13 with amoxicillin. Structure-activity relationships of 1-3 were discussed.
公益社団法人日本薬学会の論文
1987-08-25