Penicillanic acid derivatives

The circular dichroism curves for a variety of penicillanic acid derivatives have been published and discussed (B-77MI51100) and have been used to support extended Hiickel MO calculations (77T711). 

Methylfurazancarboxylic acid chloride was transformed into the corresponding acetic acid 66, which was used for the preparation of penicillanic acid derivatives (Scheme 46) (67USP3322751). 

Penicillanic acid derivatives are synthetically produced /3-lactamase inhibitors. 

After clavulanic acid, the penicillanic acid derivatives (particularly the corresponding sulfone analogs) have been the subject of intense research in the -lactamase inhibitor area. From this extensive investigation, two compounds (sulbactam and tazobactam) from this class have been successfully introduced into clinical use. The penicillanic acid sulfones are /3-laclamasc inhibitors that are quite homologous to clavulanate in both their mechanism of action and in the spectrum of -lactamases susceptible to their action. The first notable success in this field was the discovery of sulbactam 7 (Fig. 7), which was reported by Pfizer chemists in 1978 and shown to possess potent inhibitory activity, principally for class A //-lactamases. It had greater affinity for class C types than clavulanate. From careful comparison of its structure to clavulanate, a rational basis for the similarities between the two is apparent. Both lack a C-6 substituent. Since the absence (or presence) of this substituent is an important, but not exclusive, factor in //-lactamase recogni-... 

Over the past decade the essential goal in the modification of sulbactam or tazobactam has been to extend their activity towards the class C cephalosporinases. In spite of an enormous amount of effort, there has not been much success in achieving this goal. The penicillanic acid derivatives, as a class, show a good /3-lactamase inhibitory profile against class A... 

Azole approach. The /8-lactam ring in penicillanic acid derivatives can be expanded to a pyrimidine ring. Thus methyl 6/8-phthalimidopenicillanate (506) is transformed by CSI into the corresponding fused pyrimidine (507) with retention of the stereochemistry (78JCS(P1)817). Treatment of penicillanate S-oxides (508) with acyl isocyanates in a similar manner yields fused pyrimidines which subsequently eliminate water from the rearranged sulfoxide (74USP3850933). 

Penicillanic acid derivatives are synthetically produced P-lactamase inhibitors. Penicillanic acid sulphone (Fig. 10.6D) protects ampicillin from hydrolysis by staphylococcal P-lactamase and some, but not all, of the P-lactamases produced by Gram-negative bacteria, but is less potent than... 

Several review articles have appeared during the past two years. " The rearrangements of penicillanic acid derivatives have been the subject of one review, while the total synthesis of nuclear analogues of penicillin and cephalosporins and recent developments in the chemistry of the j3-lactam antibiotics have also been reviewed. " ... 

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