New isothiazoloquinolones and related compounds as anti-infective agents

Abstract

The invention provides certain compounds and salts of Formula I and Formula II: which possess antimicrobial activity. The invention also provides novel synthetic intermediates useful in making compounds of Formula I and Formula II. The variables A 1 , R 2 , R 3 , R 5 , R 6 , R 7 , A 8 and R 9 are defined herein. Certain compounds of Formula I and Formula II disclosed herein are potent and selective inhibitors of bacterial DNA synthesis and bacterial replication. The invention also provides antimicrobial compositions, including pharmaceutical compositions, containing one or more compounds of Formula I or Formula II and one or more carriers, excipients, or diluents. Such compositions may contain a compound of Formula I or Formula II as the only active agent or may contain a combination of a compound of Formula I or Formula II and one or more other active agents. The invention also provides methods for treating microbial infections in animals.

1 . A compound or pharmaceutically acceptable salt thereof, wherein the compound is:
 9-cyclopropyl-6-fluoro-8-methoxy-7-(2-methylpyridin-4-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-8-methoxy-7-(6-methylpyridin-3-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-8-methoxy-7-((R)-1-methylisoindolin-5-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   7-(3-amino-4-fluorophenyl)-9-cyclopropyl-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-8-methoxy-7-(2-methylpyridin-4-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   (E)-4-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-7-yl)picolinaldehyde O-methyl oxime;   9-cyclopropyl-6-fluoro-7-(2-(hydroxymethyl)pyridin-4-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(6-fluoropyridin-3-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(2-fluoropyridin-3-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(2-fluoropyridin-4-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-7-(4-(hydroxymethyl)phenyl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-7-(3-hydroxyphenyl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   7-(4-aminophenyl)-9-cyclopropyl-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   7-(4-amino-3,5-dimethylphenyl)-9-cyclopropyl-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   7-(4-amino-3,5-dimethylphenyl)-9-cyclopropyl-6-fluoroisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(4-(hydroxymethyl)phenyl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-7-(2-fluoropyridin-4-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(2-methylpyridin-4-yl)isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   9-cyclopropyl-7-(2,6-dimethylpyridin-4-yl)-6-fluoroisothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   9-cyclopropyl-8-methoxy-7-(pyridin-3-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   5-(9-cyclopropyl-6-fluoro-3,4-dioxo-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-7-yl)nicotinonitrile;   5-(9-cyclopropyl-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-7-yl)nicotinonitrile;   5-(9-cyclopropyl-6-fluoro-8-methoxy-3,4-dioxo-2,3,4,9-tetrahydroisothiazolo[5,4-b]quinolin-7-yl)nicotinonitrile;   9-cyclopropyl-7-(6-fluoro-2-methylpyridin-3-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(6-fluoro-2-methylpyridin-3-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-7-(2,6-dimethylpyridin-3-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(pyridin-4-yl)isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(6-methylpyridin-3-yl)isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(pyridin-3-yl)isothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   7-(4-(aminomethyl)phenyl)-9-cyclopropyl-6-fluoroisothiazolo[5,4-b][1,8]naphthyridine-3,4(2H,9H)-dione;   9-cyclopropyl-7-(2,6-difluoropyridin-3-yl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   9-cyclopropyl-6-fluoro-7-(3-hydroxyphenyl)-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione;   7-(4-aminophenyl)-9-cyclopropyl-6-fluoro-8-methoxyisothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione; or 9-cyclopropyl-6-fluoro-8-methoxy-7-(pyridin-3-yl)isothiazolo[5,4-b]quinoline-3,4(2H,9H)-dione.   
     
     
         2 . An anti-bacterial composition comprising a compound or salt of  claim 1  together with a carrier, diluent, or excipient. 
     
     
         3 . A pharmaceutical composition comprising a compound or salt of  claim 1  together with a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         4 . A pharmaceutical composition of  claim 3 , wherein the composition is formulated as an injectable fluid, an aerosol, a cream, a gel, a pill, a capsule, a tablet, a syrup, a transdermal patch, or an ophthalmic solution. 
     
     
         5 . A composition comprising a compound or salt of  claim 1  in combination with another one or more other antibacterial agent, antiprotozoal agent, antifungal agent, antiviral agent, interferon, efflux-pump inhibitor, or beta-lactamase inhibitor. 
     
     
         6 . A package comprising the pharmaceutical composition of  claim 3  in a container and instructions for using the composition to treat a patient suffering from a microorganism infection. 
     
     
         7 . The package of  claim 6  wherein the instructions are instructions for using the composition to treat a patient suffering from a bacterial infection. 
     
     
         8 . A method for treating a bacterial infection in an animal comprising administering to the animal a therapeutically effective amount of a compound or salt of  claim 1 . 
     
     
         9 . The method of  claim 8  wherein the bacterial or prtozoal infection is a urinary tract infection, pyelonephritis, lower respiratory tract infection, skin infection, skin-structure infection, urethral gonococcal infection, cervical gonococcal infection, urethral chlamydial infection, cervical chlamydial infection, bone infection, joint infection, gram-negative bacterial infection, infectious diarrhea, typhoid fever, prostatitis, acute sinusitis, acute exacerbation of chronic bronchitis, pneumonia, intra-abdominal infection, gynecologic infection, or pelvic infection. 
     
     
         10 . The method of  claim 8  wherein the animal is a fish, amphibian, reptile, bird, or mammal. 
     
     
         11 . The method of  claim 8  wherein the animal is a mammal. 
     
     
         12 . The method of  claim 11  wherein the mammal is a human.