Pfizer Corporation

Michael S Kellogg

Robert A Volkmann

Ernest S Hamanaka

Vytautas J Jasys

V John Jasys

Novel beta lactam compounds having potent elastrase inhibition activity are disclosed. These compounds are characterized by the general structural formulae I, II, and III: ##STR1## These compounds are further characterized such that X and Y are each --S-- or --CH.sub.2 --, with at least one of X and Y being --S--, or alternatively, X is --SO-- or --SO.sub.2 -- and Y is --CH.sub.2 --; R.sup.1 is hydrogen, tri(lower alkyl)silyl, --COOR' or --CONHR'', wherein R' and R'' are each lower alkyl or phenyl(lower alkyl), and may be the same or different; R.sup.3 is hydrogen, lower alkyl or (lower alkyl)oxy; one of B and D is (lower alkyl)oxycarbonyl, (lower alkenyl)oxycarbonyl, allyloxycarbonyl or phenyl(lower alkyl)oxycarbonyl; and the other of B and D is hydrogen or lower alkyl. The compounds are useful as anti-inflammatory agents, particularly in the treatment of adult respiratory distress syndrome and rheumatoid arthritis.

Beta-lactam elastase inhibitors

6-.beta.-Substituted penicillanic acids and derivatives thereof as useful enhancers of the effectiveness of several .beta.-lactam antibiotics against many .beta.-lactamase producing bacteria, and 6-.beta.-substituted penicillanic acid derivatives wherein the carboxy group is protected by a conventional penicillin carboxy protecting group as useful intermediates leading to said synergistic agents. A process for converting 6,6-disubstituted penicillanic acid derivatives to the corresponding 6-.beta.-substituted penicillanic acid congeners.

6-.beta.-substituted penicillanic acid compound free of the

6-(2-Amino-2-[4-acyloxyphenyl]acetamido)penicillanoyloxymethyl esters of penicillanic acid 1,1-dioxide are useful as antibacterial agents. Derivatives of the aforesaid antibacterial agents which have an amino protecting group on the amino function in the 2-amino-2-(4-acyloxyphenyl)acetamido side chain are useful intermediates to the antibacterial agents themselves.

Antibacterial

6-.beta.-Substituted penicillanic acids as .beta.-lactamase inhibitors

Penicillanic acid derivative

Useful antibacterial agents in which a penicillin and/or a beta-lactamase inhibitor are linked via 1,1-alkanediol dicarboxylates are of the formula ##STR1## where A is the residue of certain dicarboxyic acids, R.sup.3 is H or (C.sub.1 -C.sub.3), n is zero or 1 such that when n is zero R is P or B and R.sup.1 is the residue of certain esters, H or a salt thereof; and when n is 1, one of R and R.sup.1 is P and the other is B, and P is ##STR2## where R.sup.2 is H or certain acyl groups, and B is the residue of a beta-lactamase inhibiting carboxylic acid; a method for their use, pharmaceutical compositions thereof and intermediates useful in their production.

1,1-Alkanediol dicarboxylate linked antibacterial agents

6-beta-Halopenicillanic acid 1,1-dioxides, physiologically acceptable salts thereof and esters thereof readily hydrolyzable; pharmaceutical compositions containing a 6-beta-halopenicillanic acid 1,1-dioxide, a physiologically acceptable salt thereof or an ester thereof readily hydrolyzable; and a method for enhancing the effectiveness of a beta-lactam antibiotic, using a 6-beta-halopenicillanic acid 1,1-dioxide, a physiologically acceptable salt thereof or an ester thereof readily hydrolyzable.

6-beta-Halopenicillanic acid 1,1-dioxides as beta-lactamase inhibitors

Process for converting 6,6-disubstituted penicillanic acid derivatives

Bis-Esters of 1,1-alkanediols with 6-beta(hydroxymethyl)penicillanic acid 1,1-dioxide and 6-betaacylaminopenicillanic acids are useful as antibacterial agents. Intermediates useful for the preparation of these compounds include halomethyl, alkylsulfonyloxymethyl and arylsulfonyloxymethylesters of 6-beta(hydroxymethyl)penicillanic acid 1,1-dioxide and 6-beta-aminopenicillanoyloxymethyl-6'-beta-(hydroxymethyl)penicillanate 1,1-dioxide.

Bis-esters of 1,1-alkanediols with 6-beta-hydroxymethylpenicillanic acid

Bis-Esters of 1,1-alkanediols with 6-beta(hydroxymethyl)penicillanic acid 1,1-dioxide and 6-betaacylaminopenicillanic acids are useful as antibacterial agents. Intermediates useful for the preparation of these compounds include halomethyl, alkylsulfonyloxymethyl and arylsulfonyloxymethylesters of 6-beta(hydroxymethyl)penicillanic acid 1,1-dioxide and 6-beta-aminopenicillanoyloxymethyl-6-'-beta-(hydroxymethyl)-penicillanate 1,1-dioxide.

6.beta.-Hydroxyalkylpenicillanic acids and derivatives thereof as useful enhancers of the effectiveness of several .beta.-lactam antibiotics against many .beta.-lactamase producing bacteria, and 6.beta.-substituted penicillanic acid benzyl ester derivatives as useful intermediates leading to said agents which enhance the effectiveness of .beta.-lactam antibiotics.

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Waterford, CT, United States of America

Michael S Kellogg