Bis-tetrazolemethyl substituted beta-lactam antibiotics, their preparation and pharmaceutical formulations containing them.

摘要

Broad spectrum β-lactam antibiotics are described. They are represented by the formula
<Chemistry id="chema01" num="0001"><Image id="ia01" he="25" wi="53" file="IMGA0001.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R is hydrogen or an acyl group of the formula
<Chemistry id="chema02" num="0002"><Image id="ia02" he="9" wi="25" file="IMGA0002.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R° is an aryl or aralkyl group of the formula
<Chemistry id="chema03" num="0003"><Image id="ia03" he="9" wi="28" file="IMGA0003.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R' is phenyl or phenyl substituted by halogen, hydroxy amino, acetamido, C,-C<Sub>4</Sub> alkyl, C<Sub>1</Sub>-C<Sub>4</Sub> alkoxy, cyano, carboxy, carboxamido, carboxymethyl, C,-C<Sub>4</Sub> alkoxycarbony-Imethyl, hydroxymethyl, or aminomethyl; or R' is a di- or tri-substituted phenyl group of the formula
<Chemistry id="chema04" num="0004"><Image id="ia04" he="21" wi="28" file="IMGA0004.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein each of a, a', and a" are independently hydrogen, halogen, hydroxy, C<Sub>1</Sub>-C<Sub>4</Sub> alkyl or C<Sub>1</Sub>-C<Sub>4</Sub> alkoxy; and
<Chemistry id="chema05" num="0005"><Image id="ia05" he="8" wi="36" file="IMGA0005.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>or R° is an aryloxymethyl or arylthiomethyl group of the formula
<Chemistry id="chema06" num="0006"><Image id="ia06" he="12" wi="42" file="IMGA0006.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R' has the same meanings as defined above. and z is O or S; or R° is a heterocyclic methyl group of the formula
<Chemistry id="chema07" num="0007"><Image id="ia07" he="9" wi="23" file="IMGA0007.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R<Sup>2</Sup> is thienyl, furyl, 1H-tetrazol-1-yl, 1H-tetrazol-5-yl,<!-- EPO <DP n="2"> --><Chemistry id="chema08" num="0008"><Image id="ia08" he="24" wi="61" file="IMGA0008.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein each b is hydrogen, amino, protected-amino, C<Sub>1</Sub>-C<Sub>3</Sub> alkyl or phenyl; or R° is a group of the formula
<Chemistry id="chema09" num="0009"><Image id="ia09" he="16" wi="18" file="IMGA0009.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R<Sup>3</Sup> is R' as defined above and in addition 1,4-cyclohexadienyl, thienyl or furyl, and Q is hydroxy, carboxy, sulfo, or amino; or R° is an oximino substituted group represented by the formula
<Chemistry id="chema10" num="0010"><Image id="ia10" he="16" wi="25" file="IMGA0010.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R<Sup>4</Sup> is R' as defined above and in addition thienyl, furyl, or
<Chemistry id="chema11" num="0011"><Image id="ia11" he="16" wi="22" file="IMGA0011.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein b has the same meanings as defined above and R<Sup>5</Sup> is hydrogen, or C<Sub>1</Sub>-C<Sub>4</Sub> alkyl; or R° is a group of the formula
<Chemistry id="chema12" num="0012"><Image id="ia12" he="22" wi="24" file="IMGA0012.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R<Sup>3</Sup> is as defined above and R<Sup>6</Sup> is phenyl substituted by 1-3 hydroxy groups or pyridyl substituted with from 1-3 hydroxy groups; or R<Sup>6</Sup> is a group of the formula
<Chemistry id="chema13" num="0013"><Image id="ia13" he="18" wi="22" file="IMGA0013.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R' is C<Sub>1</Sub>-C<Sub>4</Sub> alkylamino, phenyl, chlorophenyl, furyl, styrryl, chlorostyrryl, or nitrostyrryl; or R<Sup>6</Sup> is a group of the formula
<Chemistry id="chema14" num="0014"><Image id="ia14" he="23" wi="21" file="IMGA0014.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>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</Sup> is hydrogen, C<Sub>1</Sub>-C<Sub>3</Sub> alkyl, C<Sub>2</Sub>-C<Sub>4</Sub> alkanoyl, or C<Sub>1</Sub>-C<Sub>3</Sub> alkylsulfonyl; R, is hydrogen or a carboxy protecting group; R<Sub>2</Sub> is hydrogen or methoxy; R<Sub>3</Sub> is a bis-tetrazolemethyl group of the formula
<Chemistry id="chema15" num="0015"><Image id="ia15" he="32" wi="55" file="IMGA0015.TIF" imgContent="chem" imgFormat="TIFF" inline="no" /></Chemistry>wherein R<Sub>4</Sub> is hydrogen or C<Sub>1</Sub>-C<Sub>3</Sub> alkyl; and when R, is hydrogen, the pharmaceutically acceptable salts thereof.

The compounds are obtained by reacting a 7-acylamino-3-halomethyl-1-oxa-β-lactam ester with the desired 1- or 2-tetrazolemethyl substituted 1H or 2H tetrazole-5-thiol, or alternatively by reacting a 7-amino-3-halomethyl-1-oxa-b-lactam ester with the bis-tetrazole thiol and then N-acylating with the desired carboxylic acid.