Starting from 3,5-dimethylisoxazole the carboxylic acids I and V, the amino adds VIII CL,-) and IX (D-), and the ureido adds X (L-) and XI (D-) were prepared, which were used for the synthesis of the new cephalosporins XVIIb, XXa--c (L-), and XXIb (D-). The/n v/tro antibacterial activity of these semi-synthetic antibiotics was studied. The resorption of XVIIb was investigated in mice.During the past decades numerous semi-synthetic cephalosporins carrying an alkyl-, alkenyl-, or a heteroarylthioacetamido sidechain have been synthesized [1][2][3][4][5][6][7], and the preparation of oxa-analogues with a related structure has also been reported [4]. Of these semi-synthetic antibiotics only Cefotetan is introduced to medicinal therapy ('Ihble 1). It is surprising, however, that relatively less cephalosporin molecules fuuctionalized with an oxazolyl- [8, 9] or isor, azolyl group [10, 11] at positions 3 or 7 have been prepared, despite the fact that the therapeutic value of similar semi-synthetic penicillins (e.g. Oxacillin, etc.) has been long recognized.To fdl in this gap, the present paper reports our studies on the chemical synthesis and in vitro structure-antibacterial activity relationship of new, diversely substituted isoxazolylacetamido-and thioacetamido cephalosporins.
CHEMISTRYThe preparation of 3,5-dimethylisoxazol-4-ylacetic acid (I), suitable for the acylation of the cephalosporin nucleus, was carried out [12] in three steps (Scheme 1) from 3,5-dimethylisoxazole (II), and the product was identical with that reported by March in 1901 [13]. Besides the 1H-NMR data [200 MHz, CDC13, 8 ppm: 2.25 and 2.38 (3H, s, 3-and 5-CH3); 3.38 (2H, s, --CH2--); 8.80 (1H, br, COOH)], the structure of acid I was also supported by transformation into the crystalline 3,5-dimethylisoxazol-4-ylacetic acid N-hydroxysuccinimine ester III in excellent yield, which was then used for the acylation.5-Bromgmethyl-4-chloro-3-methylisoxazole (IV), required for the introduction of various isoxazol-5-ylthioacetamido side chains, was also obtained from II [14]. Treatment of bromide IV with thioglycolic acid in 80% aqueous acetone in the presence of triethylamine (20~ 24 h) readily furnished 5-(carboxymethylthio)methyl-4-chloro-3-methylisoxazole which was isolated in form of the potassium salt V. Oxidation of the latter with hydrogen peroxide in glacial acetic acid afforded 5-(carboxymethylsulfonyl)methyl-4-chloro-3-methylisoxazole (VI).The reaction of IV with L-cysteine (VII; R 2 = R 3 = H) and D-penicillamine (VII; R 2 = R 3 = CH3) was carried out in abs. ethanol in the presence of sodium methoxide (20 ~ 1 h), and the new amino acids VIII (L-) and IX (D-), respectively, were isolated after acidification (pH -5) of the reaction mixture. Treatment of acids VIII and IX with potassium cyanide in refluxing water at pH -2 gave the highly crystalline a-ureido compounds X (L-) and XI (D-), respectively. The reaction of VIII with Boc20 (20~ 2 h) [15] yielded the N-Boc-amino acid XII as a brown syrup, which was used without further purification. ...
