Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-07-20
1996-11-26
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
540214, 540215, A61K 31395, C07D50148
Patent
active
055785913
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 National Stage Application of PCT/GB93/00068, filed on Jan. 14, 1993.
This invention relates to novel .beta.-lactam compounds, their preparation and their use, and in particular to a novel class of 2-isocephems. These compounds have antibacterial properties, and are therefore of use in the treatment of bacterial infections in humans and animals caused by a wide range of organisms.
J. Med. Chem. (1988), 31, 1190-1196 discloses 0-2-isocephems of general formula (A): ##STR2## wherein R.sup.a, R.sup.b and R.sup.c are various substituents.
We have found a particularly advantageous class of 2-isocephems bearing a cyclic ether or thio-ether substituent at the 3-position of the cephem nucleus.
The present invention provides a compound of formula (I) or a salt thereof: ##STR3## wherein R.sup.1 is hydrogen, methoxy or formamido; cephalosporin; readily removable carboxy protecting group or a pharmaceutically acceptable salt-forming group or in vivo hydrolysable ester group; present on any of the carbon atoms in the ring system shown, selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkylamino, CO.sub.2 R, CONR.sub.2, SO.sub.2 NR.sub.2 where R is hydrogen or alkyl, aryl and heterocyclyl, which may be the same or different and wherein any R.sup.4 alkyl substituent is optionally substituted by one or more substituents selected from the list from which R.sup.4 is selected; is 1 or 2.
The bonding carbon atom of the cyclic ether or thio-ether moiety which links the ring to the cephem nucleus is generally asymmetric. The present invention includes either stereoisomer, as well as mixtures of both isomers.
In compounds of formula (I) wherein R.sup.1 is formamido, the formamido group can exist in conformations wherein the hydrogen atoms of the --NH--CHO moiety are cis- or trans-; of these the cis conformation normally predominates.
Since the compounds of the present invention are intended for use as therapeutic agents for antibacterial use in pharmaceutical compositions, it will be readily appreciated that preferred compounds within formula (I) are pharmaceutically acceptable, i.e. are compounds of formula (Ia) or pharmaceutically acceptable salts or pharmaceutically acceptable in vivo hydrolysable esters thereof: ##STR4## wherein R.sup.1, R.sup.2, R.sup.4, m, n, X and Y are as defined with respect to formula (I) and the group CO.sub.2 R.sup.6 is CO.sub.2 R.sup.3 where CO.sub.2 R.sup.3 is a carboxy group or a carboxylate anion.
Accordingly, the present invention provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use as a therapeutic agent, and in particular an in vivo hydrolysable ester thereof for use as an orally administrable therapeutic agent.
The present invention further provides a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for use in the treatment of bacterial infections, more particularly an in vivo hydrolysable ester thereof for use in the oral treatment of bacterial infections.
The present invention also includes a method of treating bacterial infections in humans and animals which comprises the administration of a therapeutically effective amount of an antibiotic compound of the formula (Ia) or a pharmaceutically acceptable in vivo hydrolysable ester thereof, in particular the oral administration of a therapeutically effective amount of an in vivo hydrolysable ester.
In addition, the present invention includes the use of a compound of formula (Ia) or a pharmaceutically acceptable salt or in vivo hydrolysable ester thereof, for the manufacture of a medicament for the treatment of bacterial infections, in particular the use of an in vivo hydrolysable ester for the manufacture of a medicament for the oral treatment of bacterial infections.
Those compounds of the formula (I) wherein R.sup.3 is a readily removable carboxy protecting group other than a pharmaceutically acceptable in vivo hydrolysable ester or which are in non-
REFERENCES:
patent: 4440682 (1984-04-01), Bose et al.
patent: 5378697 (1995-01-01), Chautat et al.
patent: 5385897 (1995-01-01), Teutsch et al.
Burton George
Fell Stephen C. M.
Gasson Brian C.
Ginsburg Paul H.
Ling Lorraine B.
Myers, Jr. Richard S.
Pfizer Inc.
Richardson Peter C.
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