Carbacephalosporin compound, their preparation and use

Details Carbacephalosporin compound, their preparation and use Carbacephalosporin compound, their preparation and use

1996-01-18

1997-09-09

McKane, Joseph

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

540205, A61K 31395, C07D22106

Patent

active

056657170

DESCRIPTION:

BRIEF SUMMARY
This application is a filing under 35 U.S.C. 371 of PCT/EP94/00811, filed Mar. 10, 1994.
This invention relates to novel .beta.-lactam compounds, their preparation and their use, and in particular to a novel class of carbacephalosporins. 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 now found a particularly advantageous class of polycyclic compounds based upon a carbacephalosporin nucleus.
The present invention provides a carbacephalosporin compound of formula (I) or a salt thereof: ##STR2## wherein; R.sup.1 is hydrogen, methoxy or formamido; cephalosporin; readily removable vivo hydrolysable ester group; substituent; bond between the two carbon atoms shown; of formula: ##STR3## wherein X represents --O-- or --NR.sup.8 --, wherein each R.sup.8 may be the same or different and independently represents hydrogen or a substituent, or two groups R.sup.8 may be linked into a ring system, or any two adjacent --CR.sup.8.sub.2 -- units may be replaced by a --CR.sup.8 .dbd.CR.sup.8 -- unit, and wherein n is an integer 1 to 7, m is O, 1, 2 or 3.
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, R.sup.5, R.sup.6, and R.sup.7 are as defined with respect to formula (I) and the group CO.sub.2 R.sup.11 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 mount 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-pharmaceutically acceptable salt form are primarily useful as intermediates in the preparation of compounds of the formula (Ia) or a pharmaceutically acceptable salt or pharmaceutically acceptable in vivo hydrolysable ester thereof.
Suitable readily removable carboxy protecting groups for the group R.sup.3 include groups forming ester derivatives of the carboxylic acid, including in vivo hydrolysable esters. The derivative is preferably one which may readily be cleaved in vivo.
Also

REFERENCES:
patent: 4485110 (1984-11-01), Osborne
patent: 4544549 (1985-10-01), Harbridge
patent: 4798828 (1989-01-01), Osborne
patent: 5099015 (1992-03-01), Hornback et al.
Greengrass et al., Studies on 1-carbadethiacephems, part III, Tetrahedron Letters, vol.23, No. 23, pp. 2419-2422.
Sato et al., Agric. Biol. Chem., vol. 47, No. 4, pp. 799-806.
Doyle et al., Can. J. Chem., vol. 57, No. 2, pp. 222-226.

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