Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1994-06-01
1997-02-11
Shah, Mukund J.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514201, 540221, 540222, 540301, A61K 31545
Patent
active
056021178
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/GB 92/02231 filed Dec. 01, 1992.
This invention relates to novel .beta.-lactam containing compounds, their preparation and their use, and in particular to a novel class of cephalosporins. 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.
We have found a particular class of cephalosporins bearing a cyclic thio-ether substituent at the 3-position of the cephalosporin nucleus that possesses prolonged and high levels of antibacterial activity, and shows good absorption both parentally and orally, especially orally.
The present invention provides a compound of formula (I) or a salt thereof: ##STR2## wherein
R.sup.1 is hydrogen, methoxy or formamido;
R.sup.2 is an acyl group, in particular that of an antibacterially active cephalosporin;
CO.sub.2 R.sup.3 is a carboxy group or a carboxylate anion, or R.sup.3 is a readily removable carboxy protecting group (such as a pharmaceutically acceptable in vivo hydrolysable ester group); R.sup.4 represents hydrogen or up to four substituents selected from alkyl, alkenyl, alkynyl, alkoxy, hydroxy, halogen, amino, alkylamino, acylamino, dialkyimino, CO.sub.2 R, CONR.sub.2, SO.sub.2 NR.sub.2 (where R is hydrogen or C.sub.1-6 alkyl), aryl and heterocyclyl, which may be the same or different and wherein any R.sup.4 alkyl substituent is optionally substituted by any other R.sup.4 substituent; X is S,SO,SO.sub.2,O or CH.sub.2 ; Y is S, SO or SO.sub.2 ; and m is 1 or 2.
The bonding carbon atom of the cyclic thio-ether moiety which links the ring to the cephalosporin nucleus is generally asymmetric. The present 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 .beta.-lactam antibiotic compounds of the present invention are intended for use as therapeutic agents 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: ##STR3## wherein R.sup.1, R.sup.2, R.sup.4, m and X 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 this invention 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 ca
REFERENCES:
patent: 5036034 (1991-07-01), Gotschi
patent: 5276024 (1994-01-01), Schneider et al.
Conant, The Chemistry of Organic Compounds pp. 269, 520-523 (1934).
Burton George
Fell Stephen C. M.
Ginsburg Paul H.
Ling Lorraine B.
Pfizer Inc.
Richardson Peter C.
Shah Mukund J.
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