Details for Patent: 7,112,592

Title:	Azabicyclic compounds, preparation thereof and use as medicines, in particular as antibacterial agents
Abstract:	The invention relates to new heterocyclic compounds of general formula (I), and their salts with a base or an acid: ##STR00001## The invention also relates to a process for the preparation of these compounds as well as their use as medicaments, in particular as anti-bacterial agents.
Inventor(s):	Lampilas; Maxime (Romainville, FR), Aszodi; Jozsef (Tucson, AZ), Rowlands; David Alan (Poissy, FR), Fromentin; Claude (Paris, FR)
Assignee:	Aventis Pharma S.A. (FR)
Filing Date:	Jul 24, 2001
Application Number:	10/343,315
Claims:	1. A compound of the formula, or one of its salts with a base or an acid: ##STR00013## R.sub.1 is selected from the group consisting of hydrogen, --COOH, --CN, --COOR, --CONR.sub.6,R.sub.7, --(CH.sub.2).sub.n'R.sub.5 and -- ##STR00014## R is selected from the group consisting of alkyl of 1 to 6 carbon atoms optionally substituted by a member selected from the group consisting of pyridyl and carbamoyl, --CH.sub.2-alkenyl of 3 to 9 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl being unsubstituted or substituted by a member selected from the group consisting of --OH, --NH.sub.2, --NO.sub.2, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and at least one halogen, R.sub.6 and R.sub.7 are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 1 to 6 carbon atoms and aralkyl of 7 to 11 carbon atoms, unsubstituted or substituted by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl, unsubstituted or substituted on the phenyl by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl, R.sub.2 is hydrogen; R.sub.3 is hydrogen; A is ##STR00015## R.sub.4 is hydrogen, or --(CH.sub.2).sub.n'1R.sub.5, n'.sub.1 is equal to 1 or 2 and R.sub.5 is selected from the group consisting of --COOH, --CN, --OH, --NH.sub.2, --CO--NR.sub.6R.sub.7, --COOR, --OR, --OCOH, --OCOR, --OCOOR, --OCONHR, --OCONH.sub.2, --NHR, --NHCOH, --NHSO.sub.2R, --NH--COOR, --NH--CO--NHR and --NHCONH.sub.2; R is selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted by pyridyl or carbamoyl, --CH.sub.2-alkenyl of 3 to 9 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl unsubstituted or substituted by a member selected from the group consisting of --OH, --NH.sub.2, --NO.sub.2, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms or by and at least one halogen, R.sub.6 and R.sub.7 being as defined above, the dotted line being an optional bond with one or other of the carbon carriers of the substituents R.sub.1 and R.sub.2; n is 1; X is --C(O)--B-- attached to the nitrogen by the carbon, n' is equal to 1 or 2, R.sub.5 is selected from the group consisting of --COOH, --CN, --OH, --NH.sub.2, --CO--NR.sub.6R.sub.7, --COOR, --OR, --OCOH, --OCOR, --OCOOR, --OCONHR, --OCONH.sub.2, --NHR, --NHCOH, --NHCOR, --NHSO.sub.2R, --NH--COOR, --NH--CO--NHR and --NHCONH.sub.2, R, R.sub.6 and R.sub.7 being as defined above; R.sub.2 is hydrogen or --(CH.sub.2).sub.n'1R.sub.5, n'.sub.1 being equal to 0, 1 or 2 and R.sub.5 being as defined above; R.sub.3 is hydrogen or alkyl of 1 to 6 carbon atoms; A is ##STR00016## R.sub.4 is hydrogen or --(CH.sub.2).sub.n'1R.sub.5, n'.sub.1 and R.sub.5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of --R.sub.1 and R.sub.2; n is 1; x is --C(O)--B-- attached to the nitrogen atom by the carbon atom, B is --O--(CH.sub.2).sub.n''-- attached to the carbonyl by the oxygen, or --NR.sub.8--(CH.sub.2).sub.n''-- or --NR.sub.8--O-- attached to the carbonyl by the nitrogen, n'' is 0 and R.sub.8 is selected from the group consisting of hydrogen, --OH, --R, --OR, --Y, --OY, --Y.sub.1, --OY.sub.1, --Y.sub.2, --OY.sub.2, --Y.sub.3, --OCH.sub.2CH.sub.2SO.sub.mR, OSiRaRbRc and SiR.sub.aR.sub.bR.sub.c, R.sub.a, R.sub.b and R.sub.c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2; Y is selected from the group consisting of --COH, --COR, --COOR, --CONH.sub.2, --CONHR, --CONHOH, --CONHSO.sub.2R, --CH.sub.2COOH, --CH.sub.2COOR, --CH.sub.2CONHOH, --CH.sub.2CONHCN, --CH.sub.2 tetrazole, protected --CH.sub.2 tetrazole, --CH.sub.2SO.sub.3H, --CH.sub.2SO.sub.2R, --CH.sub.2PO(OR).sub.2, --CH.sub.2PO(OR)(OH), --CH.sub.2PO(R)(OH) and --CH.sub.2PO(OH).sub.2, Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOH, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, --SO.sub.2NHCONH.sub.2 and --SO.sub.3H, Y.sub.2 is selected from the group consisting of --PO(OH).sub.2, --PO(OR).sub.2, --PO(OH)(OR) and --PO(OH)R, Y.sub.3 is selected from the group consisting of tetrazole, tetrazole substituted by the R, squarate, --NH or --NR tetrazole, --NH or --NR tetrazole substituted by the R, --NHSO.sub.2R and --NRSO.sub.2R, R being as defined above; it being understood that when n is equal to 1 and A is ##STR00017## in which R.sub.4 is hydrogen and either X is --C(O)--O--(CH.sub.2).sub.n'' in which n'' is 0, or X is --CO--NR.sub.8--(CH.sub.2).sub.n'' in which n'' is 1 and R.sub.8 is isopropyl, or X is --CO--NR.sub.8--(CH.sub.2).sub.n'' in which n'' is 0 and R.sub.8 is hydrogen or phenyl, so all three of R.sub.1, R.sub.2 and R.sub.3 cannot be hydrogen at the same time. 2. A compound of claim 1, wherein R.sub.4 is hydrogen. 3. A compound of claim 1, wherein X is --CO--B in which B is --NR.sub.8--(CH.sub.2).sub.n''. 4. A compound of claim 1, wherein --R.sub.8 is --Y.sub.1 or --OY.sub.1, in which Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, --SO.sub.3H and R is as defined in claim 1. 5. A compound of claim 1, wherein R.sub.1 is --CONR.sub.6,R.sub.7. 6. A compound of claim 1, wherein R.sub.2 is H. 7. A compound of claim 1, wherein R.sub.3 is H. 8. A compound selected from the group consisting of: trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(phenylmethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-- 2-carboxamide and its base salts, trans-7-oxo-N-(4-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(3-pyridinyl methyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, trans-7-oxo-N-(2-amino 2-oxo ethyl)-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxamide and its base salts, and phenylmethyl trans-7-oxo-6-(sulphooxy)-1,6-diazabicyclo[3,2,1]octane-2-carboxylate. 9. A compound of the formula, or one of its salts with a base or an acid: ##STR00018## wherein R.sub.1 is selected from the group consisting of hydrogen, --COOH, --CN, --COOR, --CONR.sub.6,R.sub.7, --(CH.sub.2).sub.n'R.sub.5 and -- ##STR00019## R is selected from the group consisting of alkyl of 1 to 6 carbon atoms, optionally substituted by pyridyl or carbamoyl, --CH.sub.2-alkenyl of 3 to 9 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, the ring of the aryl or aralkyl unsubstituted or substituted by a member selected from the group consisting of --OH, --NH.sub.2, --NO.sub.2, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms and by at least one halogen, R.sub.6 and R.sub.7 individually, are selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, unsubstituted or substituted by a member selected from the group consisting of carbamoyl, ureido and dimethylamino, and alkyl of 1 to 6 carbon atoms substituted by pyridyl, n' is equal to 1 or 2, R.sub.5 is selected from the group consisting of --COOH, --CN, --OH, --NH.sub.2, --CO--NR.sub.6R.sub.7, --COOR, --OR, --OCOH, --OCOR, --OCOOR, --OCONHR, --OCONH.sub.2, --NHR, --NHCOH, --NHCOR, --NHSO.sub.2R, --NH--COOR, --NH--CO--NHR and --NHCONH.sub.2, R, R.sub.6 and R.sub.7 being as defined above; R.sub.2 is hydrogen or --(CH.sub.2).sub.n'1R.sub.5, n'.sub.1 being equal to 0, 1 or 2 and R.sub.5 being as defined above; R.sub.3 is hydrogen or alkyl of 1 to 6 carbon atoms; A is ##STR00020## R.sub.4 hydrogen or --(CH.sub.2).sub.n'1R.sub.5, n'.sub.1 and R.sub.5 being as defined above, the dotted line representing an optional bond with one or other of the carbon carriers of --R.sub.1 and R.sub.2; n is equal to 1; X is --C(O)--B-- attached to the nitrogen atom by the carbon, B is --NR.sub.8--(CH.sub.2).sub.n''-- attached to the carbonyl by the nitrogen atom, n'' is equal to 0 or 1 and R.sub.8 is selected from the group consisting of hydrogen, --OH, --R, --OR, --Y, --OY, --Y.sub.1, --OY.sub.1, --Y.sub.2, --OY.sub.2, --Y.sub.3, --OCH.sub.2CH.sub.2SO.sub.mR, --OSiRaRbRc and --SiR.sub.aR.sub.bR.sub.c, R.sub.a, R.sub.b and R.sub.c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2; Y is selected from the group consisting of --COH, --COR, --COOR, --CONH.sub.2, --CONHR, --CONHOH, --CONHSO.sub.2R, --CH.sub.2COOH, --CH.sub.2COOR, --CH.sub.2CONHOH, --CH.sub.2CONHCN, --CH.sub.2tetrazole, protected --CH.sub.2 tetrazole, --CH.sub.2SO.sub.3H, --CH.sub.2SO.sub.2R --CH.sub.2PO(OR).sub.2, --CH.sub.2PO(OR)(OH), --CH.sub.2PO(R)(OH) and --CH.sub.2PO(OH).sub.2, Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOH, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, --SO.sub.2NHCONH.sub.2 and --SO.sub.3H, Y.sub.2 is selected from the group consisting of --PO(OH).sub.2, --PO(OR).sub.2, --PO(OH)(OR) and --PO(OH)(R), Y.sub.3 is selected from the group consisting of tetrazole, tetrazole substituted by R, squarate, --NH or --NR tetrazole, --NH or --NR tetrazole substituted by R, --NHSO.sub.2R and --NRSO.sub.2R, R being as defined above; it being understood that when n is 1 and A is ##STR00021## in which R.sub.4 is hydrogen and either X is --C(O)--O--(CH.sub.2).sub.n'' in which n'' is 0 or X is --CO--NR.sub.8--(CH.sub.2).sub.n'' in which n'' is 0 and R.sub.8 is hydrogen or phenyl, so all three of R.sub.1, R.sub.2 and R.sub.3 cannot represent hydrogen at the same time. 10. A compound of claim 9, wherein R.sub.4 is hydrogen. 11. A compound of claim 9, wherein in group B, --R.sub.8 is --Y.sub.1 or --OY.sub.1, in which --Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, --SO.sub.3H wherein R is as defined in claim 9. 12. A compound of claim 9, wherein R.sub.1 is --CONR.sub.6,R.sub.7. 13. A compound of claim 9, wherein R.sub.2 is H. 14. A compound of claim 9, wherein R.sub.3 is H. 15. A compound of the formula, or one of its salts with a base or an acid: ##STR00022## wherein R.sub.1 is --CONR.sub.6R.sub.7; R.sub.6 and R.sub.7 are individually selected from the group consisting of hydrogen, alkyl of 1 to 6 carbon atoms, aryl of 6 to 10 carbon atoms and aralkyl of 7 to 11 carbon atoms, B is --NR.sub.8--(CH.sub.2).sub.n'' attached to the carbonyl by the nitrogen atom, n'' is 0 and R.sub.8 is selected from the group consisting of hydrogen, --OH, --R, --OR, --Y, --OY, --Y.sub.1, --OY.sub.1, --Y.sub.2, --OY.sub.2, --Y.sub.3, --OCH.sub.2CH.sub.2SO.sub.mR, --OSiRaRbRc and SiR.sub.aR.sub.bR.sub.c, R.sub.a, R.sub.b and R.sub.c are individually alkyl of 1 to 6 carbon atoms or aryl of 6 to 10 carbon atoms, R being as defined above and m being equal to 0, 1 or 2; Y is selected from the group consisting of --COH, --COR, --COOR, --CONH.sub.2, --CONHR, --CONHOH, --CONHSO.sub.2R, --CH.sub.2COOH, --CH.sub.2COOR, --CH.sub.2CONHOH, --CH.sub.2CONHCN, --CH.sub.2 tetrazole, protected CH.sub.2 tetrazole, --CH.sub.2SO.sub.3H, --CH.sub.2SO.sub.2R, --CH.sub.2PO(OR).sub.2, --CH.sub.2PO(OR)(OH), --CH.sub.2PO(R)(OH) and --CH.sub.2PO(OH).sub.2, Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOH, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, --SO.sub.2NHCONH.sub.2 and --SO.sub.3H, Y.sub.2 is selected from the group consisting of --PO(OH).sub.2, --PO(OR).sub.2, --PO(OH)(OR) and --PO(OH)(R), Y.sub.3 is selected from the group consisting of tetrazole, tetrazole substituted by the R, squarate, --NH or --NR tetrazole, --NH or --NR tetrazole substituted by the R, --NHSO.sub.2R and --NRSO.sub.2R, R being as defined above. 16. A compound of claim 15, wherein R.sub.4 is hydrogen. 17. A compound of claim 15, wherein in group B, --R.sub.8 is --Y.sub.1 or --OY.sub.1, in which --Y.sub.1 is selected from the group consisting of --SO.sub.2R, --SO.sub.2NHCOR, --SO.sub.2NHCOOR, --SO.sub.2NHCONHR, and --SO.sub.3H wherein R is as defined in claim 15. 18. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 1 and a pharmaceutical acceptable carrier. 19. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 8 and a pharmaceutical acceptable carrier. 20. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 9 and a pharmaceutical acceptable carrier. 21. A pharmaceutical compositions comprising, as active ingredient, at least one product of claim 15 and a pharmaceutical acceptable carrier. 22. A method of treating bacterial infections in warm-blooded animals comprising administering to warm-blooded animals in need thereof a bactericidally effective amount of a compound of claim 1.