Tetrahydropyridyl derivatives of clavulanic acid, a process for their preparation and their use
AssigneeBeecham Group Limited
InventorsIrene Stirling, Brian P. Clarke
Life of this patent
Estimating the term…
Abstract
The compounds of the formula (I): ##STR1## and esters thereof wherein R.sub.1 is a lower alkyl group or a phenyl group and R.sub.2 is a hydrogen atom or R.sub.2 together with R.sub.1 represents the residue of a fused benzene ring are .beta.-lactamase inhibitors and anti-bacterial agents. Their preparation and use is described.
Claims75
A compound of the formula (I):
- ##STR10## a zwitterion of the formula (II) ##STR11## or an ester thereof, or an acid addition salt of such an ester of the formula (III) or (IV):
- ##STR12## wherein R.sub.1 is lower alkyl or phenyl and R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring, A.sub.1 is alkyl of 1 to 6 carbon atoms unsubstituted or substituted by alkoxyl or alkanoyloxy of 1 to 7 carbon atoms, phthalidyl, tetrahydropyranyl or tetrahydrofuranyl, A.sub.2 is alkenyl or alkynyl of up to 5 carbon atoms or phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro, alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms;
- and A.sub.3 is hydrogen, alkyl of up to 4 carbon atoms, or phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro, alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms.
An ester of a zwitterion of the formula (II):
- ##STR13## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and the ester is the methyl, ethyl, n-proply, n-butyl, allyl, CH.sub.2 --C.dbd.CH, methoxymethyl, acetoxymethyl, propionoxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, dimethoxyphthalidyl, benzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, or chlorobenzyl ester.
An ester of the formula (III):
- ##STR14## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and A.sub.1 is of the formula (c), (d) or (e):
- --CHA.sub.5 --OA.sub.6 (c)
- --CHA.sub.5 --COA.sub.6 (d) or
- --CHA.sub.5 --CO.sub.2 A.sub.6 (e)
- wherein A.sub.5 is hydrogen or methyl, A.sub.6 is alkyl of up to 4 carbon atoms or phenyl or benzyl, said phenyl or benzyl being unsubstituted or substituted by 1 or 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro;
- or A.sub.5 is joined to A.sub.6 to form an ortho-phenylene moiety which ortho-phenylene ring is unsubstituted or substituted by 1 or 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro.
A pharmaceutical composition useful for treating bacterial infections in mammals including humans which comprises an antibacterially effective amount of an ester of a zwitterion of the formula (II):
- ##STR15## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and the ester is the methyl, ethyl, n-proply, n-butyl, allyl, CH.sub.2 --C.dbd.CH, methoxymethyl, acetoxymethyl, propionoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, dimethoxyphthalidyl, benzyl methoxybenzyl, ethoxybenzyl, nitrobenzyl, or chlorobenzyl ester, as the sole antibacterial agent in combination with a pharmaceutically acceptable carrier.
A pharmaceutical composition useful for treating bacterial infections in mammals including humans which comprises an antibacterially effective amount of a compound of the formula (I) ##STR16## a zwitterion of the formula (II) ##STR17## or an ester thereof, or an acid addition salt of such an ester of the formula (III) or (IV):
- ##STR18## wherein R.sub.1 is lower alkyl or phenyl and R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring, A.sub.1 is alkyl of 1 to 6 carbon atoms unsubstituted or substituted by alkoxyl or alkonoyloxy of 1 to 7 carbon atoms, phthalidyl, tetrahydropyranyl or tetrahydrofuranyl;
- A.sub.2 is alkenyl or alkynyl of up to 5 carbon atoms or phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro,alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms;
- and A.sub.3 is hydrogen, alkyl of up to 4 carbon atoms, or phenyl unsubstituted or substituted by fluoro, chloro, bromo, nitro, alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms as the sole antibacterial agent in combination with a pharmaceutically acceptable carrier.
A pharmaceutical composition useful for treating bacterial infections in mammals including humans which comprises an antibacterially effective amount of an ester of the formula (III):
- ##STR19## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and A.sub.1 is of the formula (c), (d) or (e):
- --CHA.sub.5 --OA.sub.6 (c),
- --CHA.sub.5 --COA.sub.6 (d) or
- --CHA.sub.5 --CO.sub.2 A.sub.6 (e)
- wherein A.sub.5 is hydrogen or methyl, A.sub.6 is alkyl of up to 4 carbon atoms or phenyl or benzyl, said phenyl or benzyl being unsubstituted or substituted by 1 or 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro;
- or A.sub.5 is joined to A.sub.6 to form an ortho-phenylene moiety which orthophenylene ring is unsubstituted or substituted by 1 or 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro as the sole antibacterial agent, in combination with a pharmaceutically acceptable carrier.
A method of treating bacterial infections in mammals including humans which comprises administering to such a mammal an antibacterially effective amount of an ester of a zwitterion of the formula (II):
- ##STR20## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and the ester is the methyl, ethyl, n-proply, n-butyl, allyl, CH.sub.2 --C.dbd.CH methoxymethyl, acetoxymethyl, propionoxymethyl, pivaloyloxymethyl, ethoxycarbonyloxmethyl, methoxycarbonyloxyethyl, ethoxycarbonyloxyethyl, dimethoxyphthalidyl, benzyl, methoxybenzyl, ethoxybenzyl, nitrobenzyl, or chlorobenzyl ester, in combination with a pharmaceutically acceptable carrier.
A method of treating bacterial infections in mammals including humans which comprises administering to such a mammal an antibacterially effective amount of a compound the formula (I) ##STR21## a zwitterion of the formula (II) ##STR22## or an ester thereof, or an acid addition salt of such an ester of the formula (III) or (IV):
- ##STR23## wherein R.sub.1 is lower alkyl or phenyl and R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring, A.sub.1 is alkyl of 1 to 6 carbon atoms unsubstituted or substituted by alkoxyl or alkonoyloxy of 1 to 7 carbon atoms, phthalidyl, tetrahydropyranyl or tetrahydrofuranyl;
- A.sub.2 is alkenyl or alkynyl of up to 5 carbon atoms or phenyl unsubstituted or substituted by fluoro,chloro, bromo, nitro,alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms;
- and A.sub.3 is hydrogen, alkyl of up to 4 carbon atoms, or phenyl unsubstituted or substituted by fluoro,chloro, bromo, nitro, alkyl of up to 4 carbon atoms or alkoxyl of up to 4 carbon atoms, in combination with a pharmaceutically acceptable carrier.
A method of treating bacterial infections in mammals including humans which comprises administering to such a mammal an antibacterially effective amount of an ester of the formula (III):
- ##STR24## wherein R.sub.1 is lower alkyl or phenyl, R.sub.2 is hydrogen or R.sub.2 together with R.sub.1 and the carbon atoms to which they are attached form a benzene ring and A.sub.1 is of the formula (c), (d) or (e):
- --CHA.sub.5 --OA.sub.6 (c),
- --CHA.sub.5 --COA.sub.6 (d) or
- --CHA.sub.5 --CO.sub.2 A.sub.6 (e)
- wherein A.sub.5 is hydrogen or methyl, A.sub.6 is alkyl of up to 4 carbon atoms or phenyl or benzyl, said phenyl or benzyl, being unsubstituted or substituted by 1 to 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro;
- or A.sub.5 is joined to A.sub.6 to form an ortho-phenylene moiety which ortho-phenylene ring is unsubstituted or substituted by 1 or 2 alkyl or alkoxyl moieties of up to 3 carbon atoms or by fluoro, chloro, bromo or nitro, in combination with a pharmaceutically acceptable carrier.
Dependencies are inferred from the claim text.