Claims for Patent: 5,164,402

Summary for Patent: 5,164,402

Title:	Azabicyclo quinolone and naphthyridinone carboxylic acids
Abstract:	Quinolone carboxylic acids 7-substituted by azabicyclo groups have antibacterial activity.
Inventor(s):	Brighty; Katherine E. (Groton, CT)
Assignee:	Pfizer Inc (New York, NY)
Application Number:	07/650,835
Patent Claims:	1. A compound of the formula ##STR17## or a pharmaceutically acceptable acid addition salt thereof, wherein R.sup.1 is hydrogen, a pharmaceutically acceptable cation, or (C.sub.1 -C.sub.6) alkyl; Y is ethyl, vinyl, cyclopropyl, 2-fluoroethyl, p-fluorophenyl, or o,p-difluorophenyl; W is hydrogen, fluoro, chloro, bromo, C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, amino or aminomethyl; A is CH, CR, CCl, COCH.sub.3, C--CH.sub.3, C--CN or N; and R.sup.2 ##STR18## wherein R.sup.3, R.sup.6, R.sup.7, R.sup.9, R.sup.10, and R.sup.25 are each independently H, CH.sub.3, CH.sub.2 NH.sub.2, CH.sub.2 NHCH.sub.3 or CH.sub.2 NHC.sub.2 H.sub.5, and R.sup.6, R.sup.7, and R.sup.9 may also independently be NH.sub.2, NHCH.sub.3 or NHC.sub.2 H.sub.5, provided that not more than three of R.sup.3, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.25 are other than hydrogen and if three of these substituents are not hydrogen, at least one of them is methyl; and prodrugs of those compounds of formula I having free amino groups. 2. A compound according to claim 1 wherein R.sup.1 is hydrogen. 3. A compound according to claim 1 wherein Y is cyclopropyl or o,p-difluorophenyl. 4. A compound according to claim 1 wherein W is hydrogen, and A is CH or N. 5. A compound according to claim 1 wherein W is hydrogen and A is N. 6. A compound according to claim 1 wherein one or two of R.sup.3, R.sup.6, R.sup.7, R.sup.9, R.sup.10 and R.sup.25 are other than hydrogen. 7. A compound according to claim 6 wherein one of R.sup.3, R.sup.6, R.sup.7, R.sup.9, or R.sup.10 is CH.sub.2 NH.sub.2 or CH.sub.2 NHCH.sub.3, and another of R.sup.3, R.sup.6, R.sup.7, R.sup.9, R.sup.10 or R.sup.25 may be methyl. 8. A compound according to claim 6 wherein one of R.sup.6, R.sup.7, or R.sup.9 is NH.sub.2 or NHCH.sub.3 and another of R.sup.6, R.sup.7 or R.sup.9 or one of R.sup.3, R.sup.10 or R.sup.25 may be methyl. 9. A compound according to claim 8 wherein R.sup.6, R.sup.7 or R.sup.9 is amino and one of R.sup.3, R.sup.6, R.sup.7, R.sup.9, R.sup.10 or R.sup.25 may be methyl. 10. A compound according to claim 9 wherein R.sup.7 is amino and one of R.sup.3, R.sup.6, R.sup.9, R.sup.10 or R.sup.25 may be methyl. 11. A compound according to claim 6 wherein R.sup.7 is amino and R.sup.3, R.sup.6, R.sup.9, R.sup.10 or R.sup.25 are each hydrogen. 12. A compound according to claim 1, wherein said compound is 7-(1-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4 -dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7-([1.alpha.,2.beta.,5.alpha.,6.alpha.]-6-amino-2-methyl-3-azabicyclo[3.1.0 .pi.-hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphth yridine-3-carboxylic acid, 7-([1.alpha.,6.alpha.,6.alpha.]-6-[(N-methyl)amino]-3-azabicyclo[3.1.0]hex- 3-yl(-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3 -carboxylic acid, or 7-([1.alpha.,5.alpha.,6.alpha.]-6-aminomethyl-3-azabicyclo[3.1.0]-hex-3-yl) -6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carb oxylic acid. 13. A compound according to claim 1, wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-1-cycl opropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl(-6-fluo ro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, p-toluenesulfonic acid salt, or 7-([1.alpha.,5.alpha.,6.beta.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluor o-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid. 14. A compound according to claim 1 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluo ro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, or 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluo ro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrate. 15. A compound according to claim 1 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha. -6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4- dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, hydrochloride salt, or 7-([1.alpha.,5.alpha.,6.alpha.]-6-amino-3-azabicyclo[3.1.0]hex-3-yl)-6-fluo ro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic acid, methanesulfonic acid salt. 16. A compound according to claim 1 wherein R.sup.6, R.sup.7 or R.sup.9 contains an amino group which is covalently bonded through a peptide bond to one amino acid residue. 17. A compound according to claim 1 wherein R.sup.6, R.sup.7 or R.sup.9 contains an amino group which is covalently bonded through a peptide bond to a polypeptide of two or more amino acids. 18. A compound according to claim 1 wherein R.sup.6, R.sup.7 or R.sup.9 contains an amino group which is covalently bonded through a peptide bond to a polypeptide of two amino acids. 19. A compound according to claim 11 wherein the amino group of R.sup.7 is covalently bonded through a peptide bond to one amino acid residue. 20. A compound according to claim 11 wherein the amino group of R.sup.7 is covalently bonded rough a peptide bond to a polypeptide of two or more amino acids. 21. A compound according to claim 11 wherein the amino group of R.sup.7 is covalently bonded through a peptide bond to a polypeptide of two amino acids. 22. A compound according to claim 11 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6-(L-Ala-amino)-3-azabicyclo[3.1.0]hex-3-yl -6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxylic acid, hydrochloride salt. 23. A compound according to claim 21 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6-(L-Ala-L-Leu-amino)-3-azabicyclo[3.1.0]-h ex-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridin e-3-carboxylic acid hydrochloride salt. 24. A compound according to claim 21 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6-(L-Ala-L-Ala-amino)-3-azabicyclo[3.1.0]he x-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid, hydrochloride salt, or 7-([1.alpha.,5.alpha.,6.alpha.]-6-(L-Ala-L-Ala-amino)-3-azabicyclo[3.1.0]he x-3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine -3-carboxylic acid, methanesulfonic acid salt. 25. A compound according to claim 21 wherein said compound is 7-([1.alpha.,5.alpha.,6.alpha.]-6(L-Ala-L-Ala-amino)-3-azabicyclo[3.1.0]hex -3-yl)-6-fluoro-1-(2,4-difluorophenyl)-1,4-dihydro-4-oxo-1,8-naphthyridine- 3-carboxylic acid. 26. An antibacterial composition comprising an antibacterially effective amount of a compound according to claim 1 and a pharmaceutically acceptable carrier. 27. A method for the treatment of a bacterial infection which comprises administering to a subject affected by a bacterial infection an antibacterially effective amount of a compound according to claim 1.