Cephalosporins. II. 7-(O-Aminomethyl-phnylacetamido) cephalosporanic acids with six membered heterocycles in the C-3 side chain.
7-(o-Aminomethylphenylacetamido)cephalosporanic acids with six-membered heterocycles in the C-3 side chain were prepared by nucleophillic substitution of 7-ACA at the C-3 acetoxy group followed by N-acylation of the 7-amino group. The 7-side chain acid, o-aminomethylphenylacetic acid (5), was prepared by two new convenient routes, which involved Schmidt reaction of indanone (2) followed by cleavage of the lactam ring or reduction of o-cyanophenylacetic acid (10) starting from o-nitrotoluene. The antibacterial activity of the cephalosporins in this series depends on the heterocycle in the C-3 side chain. In general pyridazines gave cephalosporin derivatives possessing better activity than those with a pyridine or pyrimidine ring. The most active member of the new cephalosporins was 7-(o-aminomethylphenylacetamido)-3-(6-hydroxypyridazin-3-ylthilmethyl)-3-cephem-4-carboxylic acid (BB-S 150) (1g) which has in vitro antibacterial activity superior to cephalothin and cefazolin against both gram-negative and gram-positive organisms. The in vitro activity of BB-S 150 determined in mice was superior to cephalothin and comparable to cefazolin.