Chroman derivatives
View Patent ↗The invention relates to novel chroman derivatives, stereoisomers and pharmaceutically acceptable salts of Formula I wherein the substituents are as defined in the specification. They are useful in the treatment of disorders mediated by lipoxygenase, such as immune diseases, respiratory diseases and cardiovascular diseases, as well as in the treatment of neurodegenerative disorders and/or mitochondria) disorders. They are also useful in the manufacture of pharmaceutical formulations for the treatment of such conditions.
1. A compound represented by Formula I
wherein:
-A-B— is —CH 2 —CH 2 —, —CH═CH—, —CH 2 —O—, or —CH 2 —S—;
n is 0;
R 1 is C 1-4 alkyl;
R 2 is C 1-4 alkyl;
R 3 is
cycloalkyl, aryl, or saturated, partially unsaturated or unsaturated heterocyclyl, all rings optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —SO 2 NR 2 , and —C(O)OR, with the proviso that the heterocyclyl is not substituted or unsubstituted 4,5-dihydro-isoxazol-3-yl or substituted or unsubstituted chroman; or
haloalkenyl;
R 4 is hydrogen, optionally substituted C 1-4 alkyl, C 2-12 alkenyl, hydroxyalkyl, acyl, glucoside, phosphoryl, phosphoryloxyalkyl, carboxyalkylcarbonyl, aminoalkylcarbonyl, or alkylketocarbonyl;
R 5 and R 6 are independently of each other C 1-6 alkyl, C 2-12 alkenyl, or halogen; and
R is hydrogen or C 1-4 alkyl;
or
single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
2. The compound of claim 1 , wherein R 5 and R 6 are C 1-4 alkyl and R 4 is hydrogen.
3. The compound of claim 2 , wherein R 1 , R 2 , R 5 and R 6 are methyl and R 4 is hydrogen.
4. The compound of claim 1 , wherein R 3 is aryl or saturated, partially saturated or unsaturated heterocyclyl both optionally substituted with one or more substituents selected from alkyl, haloalkyl, hydroxy, alkoxy, halogen, oxo, cyano, nitro, amino, —SO 2 NR 2 , and —C(O)OR.
5. The compound of claim 4 , selected from:
5-(4-Methoxy-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
2,2,7,8-Tetramethyl-5-phenyl-chroman-6-ol;
4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzoic acid methyl ester;
4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzoic acid;
2,2,7,8-Tetramethyl-5-pyridin-4-yl-chroman-6-ol;
2,2,7,8-Tetramethyl-5-pyridin-3-yl-chroman-6-ol;
5-(4-Methanesulfonyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
5-(4-Dimethylamino-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
5-(4-Chloro-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzenesulfonamide;
2,2,7,8-Tetramethyl-5-(3-nitro-phenyl)-chroman-6-ol;
2,2,7,8-Tetramethyl-5-(4-trifluoromethyl-phenyl)-chroman-6-ol;
5-(4-tert-Butyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
2,2,7,8-Tetramethyl-5-(3,4,5-trimethoxy-phenyl)-chroman-6-ol;
5-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
4-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzonitrile;
5-(2,5-Dimethoxy-3,4-dimethyl-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
5-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-benzene-1,2,3-triol;
5-(6-Hydroxy-2,2,7,8-tetramethyl-chroman-5-yl)-2,3-dimethyl-benzene-1,4-diol;
5-(2-Chloro-phenyl)-2,2,7,8-tetramethyl-chroman-6-ol;
5-Furan-2-yl-2,2,7,8-tetramethyl-chroman-6-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.
6. A pharmaceutical composition comprising a compound of claim 1 admixed with a pharmaceutically acceptable excipient.
7. The compound of claim 1 , where aryl is substituted phenyl or unsubstituted phenyl.
8. The compound of claim 4 , where aryl is substituted phenyl or unsubstituted phenyl.
9. The compound of claim 1 , where -A-B— is —CH 2 —CH 2 —.
10. The compound of claim 4 , where -A-B— is —CH 2 —CH 2 —.
11. The compound of claim 5 , selected from
2,2,7,8-Tetramethyl-5-(3-nitro-phenyl)-chroman-6-ol;
and single stereoisomers, mixtures of stereoisomers, or pharmaceutically acceptable salts thereof.