COMT inhibiting methods and compositions
The present inventions include a method of inhibiting COMT enzyme in a subject as well as compounds of formula I, or a pharmaceutically acceptable salt thereof, that are useful in the treatment of various disorders mediated by COMT, including Parkinson's disease and/or schizophrenia.
1. A catechol O-methyltransferase (COMT)-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:
wherein:
X is selected from hydrogen, chlorine and fluorine;
Z is selected from SO 2 R 1 and SO 2 NR 2 R 3 ;
wherein when X is hydrogen, Z is SO 2 R 1 , and R 1 is selected from C 4 alkyl, C 8 alkyl, tetrahydropyran and propylcyclopropane;
when X is chlorine and Z is SO 2 R 1 , R 1 is selected from C 3 alkyl, C 4 alkyl and C 5 -C 6 cycloalkyl, thiazolyl, pyridyl, pyridyl-N-oxide, and phenyl substituted with one or two groups selected from fluoro, chloro, methyl, trifluoromethyl, phenyl and tert-butyl;
when X is chlorine and Z is SO 2 NR 2 R 3 , R 2 and R 3 come together to form an unsubstituted, 1-pyrrolidinyl ring; and
when X is fluorine, Z is SO 2 R 1 , and R 1 is selected from pyridyl, cyclopentyl, and phenyl substituted with fluoro, or trifluoromethyl.
2. A compound of claim 1 , wherein the compound is selected from the group consisting of:
5-isobutylsulfonylquinolin-8-ol;
5-octylsulfonylquinolin-8-ol;
5-tetrahydropyran-4-ylsulfonylquinolin-8-ol;
5-(3-cyclopropylpropylsulfonyl)quinolin-8-ol;
7-chloro-5-cyclopentylsulfonyl-quinolin-8-ol;
7-chloro-5-pyrrolidin-1-ylsulfonyl-quinolin-8-ol;
7-chloro-5-isobutylsulfonyl-quinolin-8-ol;
7-chloro-5-isopropylsulfonyl-quinolin-8-ol;
7-chloro-5-cyclohexylsulfonyl-quinolin-8-ol;
7-chloro-5-(4-fluorophenyl)sulfonyl-quinolin-8-ol;
7-fluoro-5-(4-fluorophenyl)sulfonyl-quinolin-8-ol;
5-cyclopentylsulfonyl-7-fluoro-quinolin-8-ol;
7-fluoro-5-[4-(trifluoromethyl)phenyl]sulfonyl-quinolin-8-ol;
7-fluoro-5-(2-pyridylsulfonyl)quinolin-8-ol;
7-chloro-5-(3,4-dimethylphenyl)sulfonyl-quinolin-8-ol;
7-chloro-5-[4-(trifluoromethyl)phenyl]sulfonyl-quinolin-8-ol;
7-chloro-5-(2-pyridylsulfonyl)quinolin-8-ol;
7-chloro-5-(2,4-dimethylphenyl)sulfonyl-quinolin-8-ol;
7-chloro-5-(3,5-dichlorophenyl)sulfonyl-quinolin-8-ol;
7-chloro-5-thiazol-2-ylsulfonyl-quinolin-8-ol;
7-chloro-5-(3,4-dichlorophenyl)sulfonyl-quinolin-8-ol;
7-chloro-5-(3-phenylphenyl)sulfonyl-quinolin-8-ol;
5-(4-tert-butylphenyl)sulfonyl-7-chloro-quinolin-8-ol;
7-chloro-5-(3-pyridylsulfonyl)quinolin-8-ol, and
7-chloro-5-(1-oxidopyridin-1-ium-3-yl)sulfonyl-quinolin-8-ol.
3. A pharmaceutical composition comprising a catechol O-methyltransferase (COMT) enzyme-inhibiting compound of claim 1 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
4. A pharmaceutical composition comprising a catechol O-methyltransferase (COMT) enzyme-inhibiting compound of claim 2 , or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.
5. A catechol O-methyltransferase (COMT)-inhibiting compound in accordance with formula I, or a pharmaceutically acceptable salt thereof:
wherein: X is fluorine, Z is SO 2 R 1 , and R 1 is selected from pyridyl, cyclopentyl, and phenyl substituted with fluoro, or trifluoromethyl.