Bis-tetrazolmethyl substituted .beta.-lactam antibiotics
AssigneeEli Lilly and Company
InventorAllen S. Katner
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Abstract
Broad spectrum .beta.-lactam antibiotics represented by the formula ##STR1## wherein R is the residue of a carboxylic acid, R.sub.2 is H or OCH.sub.3, and R.sub.4 is hydrogen or C.sub.1 -C.sub.3 alkyl; are obtained by reacting a 7-acylamino-3-halomethyl-1-oxa-.beta.-lactam ester with the desired 1- or 2-tetrazolemethyl substituted 1H or 2H tetrazole-5-thiol. Alternatively, a 7-amino-3-halo-methyl-1-oxa-.beta.-lactam ester is first reacted with the bis-tetrazole thiol and then the product is N-acylated with the desired carboxylic acid.
Claims27
A compound of the formula ##STR41## wherein R is hydrogen or an acyl group of the formula ##STR42## wherein R.degree. is an aryl or aralkyl group of the formula
- R.sup.1 --CH.sub.2).sub.n,
- wherein R.sup.1 is phenyl or phenyl substituted by halogen, hydroxy, amino, acetamido, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, cyano, carboxy, carboxamido, carboxymethyl, C.sub.1 -C.sub.4 alkoxycarbonylmethyl, hydroxymethyl, or aminomethyl;
- or R.sup.1 is a di- or tri-substituted phenyl group of the formula ##STR43## wherein each of a, a', and a'' are independently hydrogen, halogen, hydroxy, C.sub.1 -C.sub.4 alkyl or C.sub.1 -C.sub.4 alkoxy;
- and
- n is 0 or 1;
- or R.degree. is an aryloxymethyl or arylthiomethyl group of the formula
- R.sup.1 --(Z)--CH.sub.2 --
- wherein R.sup.1 has the same meanings as defined above, and Z is O or S;
- or R.degree. is a heterocyclic methyl group of the formula
- R.sup.2 --CH.sub.2 --
- wherein R.sup.2 is thienyl, furyl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl, ##STR44## wherein each b is hydrogen, amino, protectedamino, C.sub.1 -C.sub.3 alkyl or phenyl;
- or R.degree. is a group of the formula ##STR45## wherein R.sup.3 is R.sup.1 as defined above and in addition 1,4-cyclohexadienyl, thienyl or furyl, and Q is hydroxy, carboxy, sulfo, or amino;
- or R.degree. is an oximino substituted group represented by the formula ##STR46## wherein R.sup.4 is R.sup.1 as defined above and in addition thienyl, furyl, or ##STR47## wherein b has the same meanings as defined above and R.sup.5 is hydrogen, or C.sub.1 -C.sub.4 alkyl;
- or R.degree. is a group of the formula ##STR48## wherein R.sup.3 is as defined above and R.sup.6 is phenyl substituted by 1-3 hydroxy groups or pyridyl substituted with from 1-3 hydroxy groups;
- or R.sup.6 is a group of the formula ##STR49## wherein R.sup.7 is C.sub.1 -C.sub.4 alkylamino, phenyl, chlorophenyl, furyl, styrryl, chlorostyrryl, or nitrostyrryl;
- or R.sup.6 is a group of the formula ##STR50## wherein n' is 1 or 2 and m is 2 or 3 with the limitation that when n' is 2, m is 2;
- and R.sup.8 is hydrogen, C.sub.1 -C.sub.3 alkyl, C.sub.2 -C.sub.4 alkanoyl, or C.sub.1 -C.sub.3 alkylsulfonyl;
- R.sub.1 is hydrogen or a carboxy-protecting group;
- R.sub.2 is hydrogen or methoxy;
- R.sub.3 is a bis-tetrazolemethyl group of the formula ##STR51## wherein each R.sub.4 is hydrogen or C.sub.1 -C.sub.3 alkyl;
- and when R.sub.1 is hydrogen, the pharmaceutically acceptable non-toxic salts thereof.
Dependencies are inferred from the claim text.