Chemical modification of sulfazecin. Synthesis of 4-(substituted methyl)-2-azetidinone-1-sulfonic acid derivatives

In expectation of improving the antibacterial activity of sulfazecin by chemical modification at the 3- and 4-positions, a number of 3-[2-(2-aminothiazol-4-yl)-(Z)-2-(substituted oxyimino)-acetamido]-4-(substituted methyl)-2-azetidinone-1-sulfonic acids were synthesized. Among various 4-substituents explored, the carbamoyloxymethyl group was found to provide a good effect to the antibacterial activity of these 2-azetidinone derivatives. An extensive study of structure-activity relationships led to selecting (3S, 4S)-3-[2-(2-aminothiazol-4-yl)-(Z)-2-carboxymethoxyiminoacetamido]-4-carbamoyloxymethyl-2-azetidinone-1-sulfonic acid, AMA- 1080 (Ro 17-2301), which has highly potent antibacterial activity against Gram-negative bacteria including Pseudomonas aeruginosa, for further biological and subsequent clinical evaluation.