- 6-amido-1-methyl carbapenems
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New antibacterial 6-amido-1-methylcarbapenems and process for their synthesis involving new azetidinone intermediates.
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- A COMPARISON OF THE ANTIBACTERIAL AND β-LACTAMASE INHIBITING PROPERTIES OF PENAM AND (2,3)-β-METHYLENEPENAM DERIVATIVES THE DISCOVERY OF A NEW β-LACTAMASE INHIBITOR. CONFORMATIONAL REQUIREMENTS FOR PENICILLIN ANTIBACTERIAL ACTIVITY
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The antibacterial potencies of 2a and 4 are shown to be diminished considerably from their penam analogues, penicillin G (1a) and mecillinam (3).Despite this, 2a is a substrate for bacterial β-lactamases, and compounds 6a, 8 and 10 were found to be β-lactamase inhibitors.Penicillin-binding protein (PBP) studies indicate that penicillin G and mecillinam have much greater affinity to these enzymes than the (2,3)-β-methylenepenam analogues.Based on a comparison of hydrolytic stabilities, it is proposed that the change in biological properties is due to conformational differences between the two types of penam nuclei.The cyclopropyl methylene of 2a and 4 blocks the side chain from forming an oxazolone with the β-lactam carbonyl.Hence, activation of the β-lactam is prevented and the molecules are rendered less active.We thus conclude that 19 is the biologically active conformation of penicillin antibacterials, and futher suggest that the interaction of such antibiotics with their bacterial enzyme targets involves intermediates such as 25-27.
- Keith, D. D.,Tengi, J.,Rossman, P.,Todaro, L.,Weigele, M.
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p. 2445 - 2458
(2007/10/02)
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- Bis-penicillanoyloxy-alkanes
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The present invention relates to hitherto unknown esters of the below formula I, to salts of the esters of formula I with pharmaceutically acceptable acids, to methods for producing said new compounds, to pharmaceutical compositions containing said new compounds, and to methods of treating patients suffering from infectious diseases using said new compounds. The compounds of the invention, which are valuable in the human and veterinary practice, have the formula I STR1 in which R1 and R2 represent the same or different substituents, and each represents hydrogen or lower alkyl; A represents a carbon chain having from 5 to 8 carbon atoms, in which optionally an oxygen or a sulphur atom can be substituted for a methylene group; or the grouping STR2 represents a bicyclic system containing from 5 to 10 carbon atoms, or a bicyclic system containing from 4 to 9 carbon atoms, in which optionally an oxygen or a sulphur atom is substituted for a methylene group; or the grouping STR3 represent a spirocyclic system containing from 7 to 10 carbon atoms; R3 represents hydrogen or lower alkyl, halogen substituted lower alkyl, and unsubstituted and substituted aryl and aralkyl. The esters of the present invention are absorbed efficiently when given orally and are non-toxic when given parenterally. After the absorption the esters are converted to the corresponding penicillanic acids by enzymatic hydrolysis. Furthermore, these esters are chemically more stable then the corresponding free acids.
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