ANTIMICROBIAL COMPOSITIONS AND METHODS OF USE
The present invention is directed to compounds of formula I, pharmaceutical compositions comprising the compounds, and methods for making and using the inventive compounds.
1 . A compound having the structure
where X is O, S, N, or C,
exactly one of V and W is N, and the other is C—R 1 ,
R is optionally substituted aryl or heteroaryl,
R 1 is H, C 1-4 alkyl, or C 1-4 alkoxy,
Y is optionally substituted 1H-benzimidazol-2-ylmethyl, 1H-imidazol-2-ylmethyl or 2-(4-oxo-4,4a-dihydroquinolin-2-yl)hydrazine and
Z is an optionally substituted amino, thio, or heterocyclyl group,
as well as diastereomers, enantiomers or a pharmaceutically acceptable salt, solvates, esters and pro-drugs thereof.
2 . The compound of claim 1 , wherein X═O and R 1 is H.
3 . The compound of claim 2 , wherein R is a quinoline or a phenyl group bearing at least one substituent selected from the group consisting of halo, C 1-6 alkyl, C 1-6 alkoxy, trifluoromethyl, trifluoromethoxy, methylenedioxy, and cyano.
4 . The compound of claim 3 , wherein R is a phenyl group bearing at least one substituent selected from the group consisting of F, Cl, Me, OMe, CF 3 , CF 3 O, methylenedioxy, and cyano.
5 . The compound of claim 4 , wherein R is selected from the group consisting of 5-chloro-quinol-6-yl, 5-chloro-8-methoxy-quinol-6-yl, 2,4-dichlorophenyl, 2-chloro-4-methoxyphenyl, 3,4-dimethoxyphenyl, 2-chloro-4-fluorophenyl, 2-methyl-4-fluorophenyl, 2,4-difluorophenyl, 4-trifluoromethoxyphenyl, 3-methyl-4-chlorophenyl, 3,4-methylenedioxphenyl, 4-methoxyphenyl, 2-chloro-4-cyanophenyl, 2-chloro-4-trifluoromethylphenyl, 3,4,5-trimethoxyphenyl, 2,4-dichloro-3-methylphenyl, and 2-chloro4,5-dimethoxyphenyl groups.
6 . The compound of claim 5 , wherein R is selected from the group consisting of 5-chloro-quinol-6-yl, 5-chloro-8-methoxy-quinol-6-yl, 2,4-dichlorophenyl, 2-chloro-4-methoxyphenyl, and 2-chloro4,5-dimethoxyphenyl.
7 . The compound of claim 1 , wherein Z is selected from the group consisting of Z is NR a R b , where R a and R b are independently selected from the group consisting of H and lower alkyl, and the optionally substituted morphin-1-yl, thiomorphin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, imidazol-1-yl, piperidin-1-yl, and 1,4-diazepan-1-yl.
8 . The compound of claim 1 , wherein Z is selected from the group consisting of optionally substituted morpholin-4-yl, dimethylamino, 4-acetylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-[2-(dimethylamino)ethyl]piperazin-1-yl, 3-hydroxypyrrolidin-1-yl, 3-oxopiperazin-1-yl, 4-(furan-2-ylcarbonyl)piperazin-1-yl, 4-methyl-1H-imidazol-1-yl, 4-morpholin-4-ylpiperazin-1-yl, 4-acetyl-1,4-diazepan-1-yl, 4-pyrimidin-2-ylpiperazin-1-yl, 4-(cyclopropylcarbonyl)piperazin-1-yl, 1,1-dioxidothiomorpholin-4-yl, 4-pyridin-2-ylpiperazin-1-yl, 3-[acetyl(ethyl)amino]pyrrolidin-1-yl, 4-(2-methylpropanoyl)piperazin-1-yl, 4-[5-(trifluoromethyl)pyridin-2-yl]piperazin-1-yl, 4-pyrazin-2-ylpiperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl, 4-pyridin-4-ylpiperazin-1-yl, 4-(4-methoxypyrimidin-2-yl)piperazin-1-yl, 3-oxo-1,4-diazepan-1-yl, 4-(1,3,5-triazin-2-yl)piperazin-1-yl, 4-(1,3-thiazol-2-yl)piperazin-1-yl, 4-[2-(1H-imidazol-1-yl)ethyl]piperazin-1-yl, 4-[(1,3-thiazol-2-ylamino)acetyl]piperazin-1-yl, 4-(morpholin-4-ylcarbonyl)piperazin-1-yl, 4-(pyrrolidin-1-ylcarbonyl)piperazin-1-yl, 4-[2-(2-methyl-1H-imidazol-1-yl)ethyl]piperazin-1-yl, 4-(2-pyrrolidin-1-ylethyl)piperazin-1-yl, or 4-[(2-oxopyrrolidin-1-yl)methyl]piperidin-1-yl.
9 . The compound of claim 8 , wherein Z is selected from the group consisting of optionally substituted 4-acetylpiperazin-1-yl, 3-oxopiperazin-1-yl, dimethylamino, 4-pyrimidin-2-ylpiperazin-1-yl, 3,5-dimethylpiperazin-1-yl, 4-(cyclopropylcarbonyl)piperazin-1-yl, 4-pyridin-2-ylpiperazin-1-yl, 4-(2-methylpropanoyl)piperazin-1-yl, 4-(2-morpholin-4-ylethyl)piperazin-1-yl.
10 . The compound of claim 1 wherein V═CH and W═N.
11 . The compound of claim 10 , selected from the group consisting of
12 . The compound of claim 1 , wherein V═N and W═CH.
13 . The compound of claim 12 , selected from the group consisting of
14 . A pharmaceutical composition, comprising a compound of claim 1 and a pharmaceutically acceptable diluent or carrier.
15 . A method of making a compound of claim 1 , comprising the step of treating a compound of formula I
where
x═O,
R is optionally substituted phenyl or quinol-6-yl,
exactly one of V and W is N, and the other is CH,
and Y and Z are both selected from the group consisting of halo, alkylthio, alkylsulfonate, alkylsulfinate and optionally substituted 1H-benzimidazol-2-ylmethyl
16 . A method for treating a bacterial infection in a patient, comprising administering to the patient an effective amount of a pharmaceutical composition of claim 14 .
17 . The method of claim 16 , wherein the bacterium is Gram-positive.
18 . The method of claim 17 , wherein the Gram-positive bacterium is selected from the group consisting of Staphylococcus, Streptococcus, Enterococcus, Clostridium, Haemophilus , and Listeria spp.
19 . The method of claim 18 , wherein the bacterium is Staphylococcus aureus.
20 . The compound of claim 16 , wherein the compound is administered at a dosage between about 1 and 1000 mg/kg.
21 . The compound of claim 20 , wherein the dosage is between about 100 and 1000 mg/kg.
22 . The compound of claim 21 , wherein the dosage is between about 10 and 100 mg/kg.
23 . The method of claim 16 , wherein the pharmaceutical composition is administered by a route selected from the group consisting of intravenous, oral, rectal, intramuscular, subcutaneous, and pulmonary administration.