Twogroups of cephalosporins substituted with a variety of heterocyclic catechols in the C3 side chain were synthesized. One is a group of 3-(heterocyclic catechol-substituted methyl)cephalosporins and another is 3-[(is)-3-heterocyclic catechol-substituted l-propen-l-yl]cephalosporins. Cephalosporins in the latter group showed higher in vivo efficacies than those in the former group having the same heterocyclic catechol, especially against Pseudomonas aeruginosa A9843A, although there was no significant difference between their in vitro activity. Among the latter group, the 5,6-dihydroxybenzimidazole derivative (6e) and the 2,6-dihydro-7-hydroxy-6-oxo-isoquinoline derivative (6b) showed much higher activity than ceftazidime (CAZ) and imipenem (IPM) against P. aeruginosa A9843Aboth in in vitro and in vivo studies.In our previous paper1*, we reported synthesis of a variety of cephalosporins having a catechol moiety in the C3 side chain. Among them, 7-[(Z)-2-(2-aminothiazol-4-yl)-2-(l-carboxy-l-methylethoxyimino)acetamido]cephalosporins having a catechol-substituted methyl and a catechol-substituted propenyl as C3 side chain showed excellent in vitro antibacterial activity especially against Gram-negative bacteria. In order to explore more potent derivatives, we synthesized both types of the cephalosporins substituted with a heterocyclic catechol in the C3 side chain. This report describes the synthesis of the above cephalosporins and their in vitro and in vivo structure-activity relationships, together with comparison of their activities with those of ceftazidime (CAZ) and imipenem (IPM).
Synthesis 3-(Heterocyclic Catechol-substituted Methyl)cephalosporins (Group A)Scheme1 illustrates the synthesis of 3-(heterocyclic catechol-substituted methyl)cephalosporins. In order to prevent the formation of undesirable A 2-isomer of cephalosporin, 3-iodomethylcephalosporins 1-oxide (1)2) was employed in the coupling reactions with 6,7-dihydroxyphthalazine, which was prepared from 6,7-dimethoxyphthalazine3).The reaction product was reduced with phosphorus tribromide, followed by deblocking with trifluoroacetic acid to give 3a after purification by column chromatography. In a similar way, coupling of 1 and 5,6-dihydroxybenzimidazole4) afforded 3b. The coupling of the iodide (2)2) with 4,5-dihydroxypyridazine5) in the presence of 7V,0-bis(trimethylsilyl)acetamide in dichloromethane afforded 3c without generation of the its A 2-isomer after deblocking. Methylation of 4, the intermediate for the preparation of 3b with methyl iodide, followed by deblocking afforded the quaternary ammonium Correspondence should be addressed to Jun Okumura, Bristol-Myers
7-[(Z)-2-(2-Aminothiazol-4-yl)-2-methoxy-(or hydroxy)-iminoacetamido]-3-[propen-l-yl]cephalosporins having a variety of heterocyclic catechol in 3-position of the propenyl group were synthesized. Among them, 6,7-dihydroxyisoquinoline derivatives, 2a and 2b, showed very high and prolonged blood levels after intramuscular administration to mice and higher in vivo antibacterial activity than expected from their in vitro activity. The former cephalosporin (2a) gave wellbalanced in vitro and in vivo antibacterial spectra including anti-methicillin-resistant Staphylococcus aureus (MRSA) activity. The latter cephalosporin (2b) also showed good in vitro and in vivo activities against Gram-positive bacteria, especially against S. aureus A15036, a strain of MRSA, the in vivo activity being comparable to vancomycin but was lacking in anti-pseudomonal activity. During the course of exploring new cephalosporins having a heterocyclic catechol in the C3 side chain1}, we have found that certain derivatives showed high blood levels after intramuscular administration in mice. Since then, many derivatives have been synthesized and it was found that 6,7-dihydroxyisoquinoline derivatives of cephalosporins, 2a and 2b, showed extremely high blood levels. This report describes the synthesis and the relationship between the structures and blood levels of the cephalosporins, together with their in vitro and in vivo activities. Synthesis Scheme 1 shows the synthesis of 3-[(£)-3-heterocyclic catechol-substituted l-propen-l-yl]cephalo
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