Antimicrobial 4-oxoquinolizines
This invention provides novel 4-oxoquinolizine compounds and their uses for a series of broad-spectrum antibiotics having no cross-resistance to existing or emerging classes of antibiotics. In addition the novel 4-oxoquinolizine compounds are useful against CDC Category A and B pathogens. The invention also provides pharmaceutical compositions comprising certain 4-oxoquinolizines in combination with subinhibitory concentrations of polymyxin B against clinical isolates which are resistant to quinolones, carbapenems and other antimicrobial agents.
1. A pharmaceutical composition comprising Polymyxin B and a 4-oxoquinolizine compound of formula IIIc:
or a pharmaceutically acceptable salt thereof, wherein
R 1 is hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, —OR X , —N(R X ) 2 , —C(O)R X , —C(O)OR X , or —C(O)N(R X ) 2 , wherein each R X is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl; and
Y is aryl or heteroaryl, each of which is substituted with either —N(R Y1 ) 2 or —C 1 -C 8 alkyl-R Y and further optionally substituted by one to four groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y ,
wherein R Y is nitro, cyano, —OR Y1 , —SR Y1 , —N(R Y1 ) 2 , —C(O)R Y1 , —C(O)OR Y1 , —C(O)N(R Y1 ) 2 , —OC(O)R Y1 , —OC(O)OR Y1 , —OC(O)N(R Y1 ) 2 , —N(R Y1 )C(O)R Y1 , —N(R Y1 )C(O)OR Y1 , —N(R Y1 )C(O)N(R Y1 ) 2 , —S(O) 2 R Y1 , —S(O) 2 OR Y1 , —S(O) 2 N(R Y1 ) 2 , —OS(O) 2 R Y1 , —OS(O) 2 OR Y1 , —OS(O) 2 N(R Y1 ) 2 , —N(R Y1 )S(O) 2 R Y1 , —N(R Y1 )S(O) 2 OR Y1 , or —N(R Y1 )S(O) 2 N(R Y1 ) 2 ;
wherein each R Y1 is independently hydrogen, C 1-8 alkyl, or C 1-8 haloalkyl.
2. The pharmaceutical composition according to claim 1 , wherein R 1 is hydrogen or halogen.
3. The pharmaceutical composition according to claim 1 , wherein
Y is phenyl substituted with one group which is —N(R Y1 ) 2 or —C 1-8 alkyl-N(R Y1 ) 2 , and optionally substituted by one or two groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y ;
Y is a 5-membered or 6-membered heteroaryl each of which is substituted with either —N(R Y1 ) 2 or —C 1 -C 8 alkyl-R Y and optionally substituted by one to four groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y ; or
Y is a bicyclic heteroaryl substituted with either —N(R Y1 ) 2 or —C 1 -C 8 alkyl-R Y and optionally substituted by one to four groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y .
4. A pharmaceutical composition according to claim 2 , wherein
Y is phenyl substituted with one group which is —N(R Y1 ) 2 or, —C 1-8 alkyl-N(R Y1 ) 2 , and optionally substituted by one or two groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y ;
Y is a 5-membered or 6-membered heteroaryl each of which is substituted with either —N(R Y1 ) 2 or —C 1 -C 8 alkyl-R Y and optionally substituted by one to four groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y ; or
Y is a bicyclic heteroaryl substituted with either —N(R Y1 ) 2 or —C 1 -C 8 alkyl-R Y and optionally substituted by one to four groups that are each independently halogen, C 1-8 alkyl, C 1-8 haloalkyl, C 3-8 cycloalkyl, heterocyclyl, aryl, heteroaryl, C 3-8 cycloalkyl(C 1-8 ) alkyl, heterocyclyl(C 1-8 )alkyl, aryl(C 1-8 )alkyl, heteroaryl(C 1-8 )alkyl, —R Y , or —C 1-8 alkyl-R Y .
5. A pharmaceutical composition according to claim 1 , wherein the 4-oxoquinolizine compound is selected from the group consisting of:
Compound 1
8-(3-fluoro-4-amino-phenyl)- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 4
8-(3-fluoro-4-aminomethyl- phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 5
8-(4-aminomethyl-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 6
8-(4-aminomethyl-phenyl)-1- cyclopropyl-7-fluoro-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 7
8-(4-amino-phenyl)-1- cyclopropyl-7-fluoro-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 8
8-(4-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 9
8-(3-amino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 11
8-(2-chloro-4-amino-5- methyl-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 12
8-[5-aminomethyl)-2-furyl]- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 13
8-[5-aminomethyl)-2- thienyl]-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 16
8-(4-amino-3-ethyl-5-methyl- phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 17
8-(3-fluoro-4-amino-phenyl)- 1-cyclopropyl-7-fluoro-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 18
8-(3-amino-phenyl)-1- cyclopropyl-7-fluoro-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 20
8-(2-fluoro-4-amino-phenyl)- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 21
8-(3-amino-4-fluoro-phenyl)- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 22
8-(3-amino-5-fluoro-phenyl)- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 24
8-(3-chloro-4-amino- phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 25
8-(3-methoxy-4-amino- phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 28
8-(4-methylamino-phenyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 31
8-(3-methyl-4-amino- phenyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 33
8-(6-amino-3-pyridyl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 37
8-(4-dimethylamino-phenyl)- 1-cyclopropyl-9-methyl-4- oxo-quinolizine-3-carboxylic acid
Compound 57
8-(2-aminopyrimidin-5-yl)-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 60
8-(6-amino-3-pyridyl)-1- cyclopropyl-7-fluoro-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 69
8-[3-methyl-4- (methylamino)phenyl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 72
8-[3-(aminomethyl)-4- hydroxy-phenyl]-1- cyclopropyl-9-methyl-4-oxo- quinolizine-3-carboxylic acid
Compound 73
8-(2-amino-1,3-benzothiazol- 5-yl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 76
8-[3-(aminomethyl)-4-amino- phenyl]-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 78
8-[6-(methylamino)-3- pyridyl]-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 79
8-(6-amino-5-methyl-3- pyridyl)-1-cyclopropyl-9- methyl-4-oxo-quinolizine-3- carboxylic acid
Compound 87
8-(6-amino-3-pyridyl)-1- cyclopropyl-7,9-dimethyl-4- oxo-quinolizine-3-carboxylic acid
Compound 89
8-(6-amino-3-pyridyl)-1- cyclopropyl-9-methoxy-4- oxo-quinolizine-3-carboxylic acid
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition according to claim 1 , wherein the Polymyxin B is present in a subinhibitory concentration.
7. A method for treatment of a bacterial infection in an individual in need thereof comprising administering to the individual a pharmaceutical composition according to claim 1 .
8. A method for treatment of a bacterial infection in an individual in need thereof, wherein the bacterial infection is infection by a multiresistant strain, comprising administering to the individual a pharmaceutical composition according to claim 1 .
9. A method for treatment of a bacterial infection in an individual in need thereof, wherein the infection is infection by one or more bacteria of a genus selected from the group consisting of Acinetobacter, Bacillus, Bordetella, Borrelia, Brucella, Camphylobacter, Chlamydia, Clostridium, Corynebacterium, Enterococcus, Escherichia, Fransisella, Haemophilus, Helicobacter, Legionella, Leptospira, Listeria, Mycobacterium, Mycoplasma, Neisseria, Propionibacterium, Pseudomonas, Rickettsia, Salmonella, Shigella, Staphylococcus, Streptococcus, Treponema, Vibrio and Yersinia , comprising administering to the individual a pharmaceutical composition according to claim 1 .
10. A compound which is 8-(6-amino-3-pyridyl)-1-cyclopropyl-7-fluoro-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
11. The compound according to claim 10 , wherein the compound is a pharmaceutically acceptable salt, and the pharmaceutically acceptable salt is a hydrochloric acid salt.
12. A compound which is 8-[3-(aminomethyl)-4-hydroxy-phenyl]-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
13. A compound which is 8-(2-amino-1,3-benzothiazol-5-yl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.
14. A compound which is 8-(6-amino-5-methyl-3-pyridyl)-1-cyclopropyl-9-methyl-4-oxo-quinolizine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof.