Patent EA-001730-B1 (EA)
Title: Quinoxalinediones
Inventor: BULL DAVID JOHN
IPC: C07D401/04
Filed: 1997-02-27
Abstract: 1. A compound of the formula:   or a pharmaceutically acceptable salt thereof, wherein R is a 5-membered ring heteroaryl group containing 3 or 4 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon or nitrogen atom, or is a 6-membered ring heteroaryl group containing from 1 to 3 nitrogen heteroatoms which is linked to the quinoxalinedione ring by a ring carbon atom, either of said groups being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, C3-C7 cycloalkyloxy, -COOH, C1-C4 alkoxycarbonyl, -CONR<3>R<4>, -NR<3>R<4>, -S(O)p(C1-C4 alkyl), -SO2NR<3>R<4>, aryl, aryloxy, aryl(C1-C4)alkoxy and het, said C1-C4 alkyl being optionally substituted by C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyloxy, C3-C7 cycloalkyl(C1-C4)alkoxy, -COOH, C1-C4 alkoxycarbonyl, -CONR<3>R<4>, -NR<3>R<4>, -S(O)p(C1-C4 alkyl), -SO2(aryl), -SO2NR<3>R<4>, morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or het, and said C2-C4 alkenyl being optionally substituted by aryl; R<1> and R<2> are each independently selected from H, fluoro, chloro, bromo, C1-C4 alkyl and halo(C1-C4)alkyl; R<3> and R<4> are either each independently selected from H and C1-C4 alkyl or, when taken together, are C5-C7 alkylene; p is 0, 1 or 2; "aryl", used in the definition of R and "het", means phenyl or naphthyl, each optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, hydroxy, halo, halo(C1-C4)alkyl and -NR<3>R<4>; "het", used in the definition of R, means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted, including in the benzo-fused portion, by 1 or 2 substituents each independently selected from C1-C4 alkyl, C3-C7 cycloalkyl, C1-C4 alkoxy, halo, hydroxy, -COOH, C1-C4 alkoxycarbonyl, allyloxycarbonyl, -CONR<3>R<4>, -NR<3>R<4>, -S(O)p(C1-C4 alkyl), -SO2NR<3>R<4>, halo(C1-C4)alkyl, hydroxy(C1-C4)alkyl, C1-C4 alkoxy(C1-C4)alkyl, R<3>R<4>NCO(C1-C4)alkyl, aryl, arylalkyl, het<1> and het<1>(C1-C4)alkyl, and/or by an oxido substituent on a ring nitrogen heteroatom when "het" includes a pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group; and "het<1>", used in the definition of "het", means furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each optionally substituted by 1 or 2 C1-C4 alkyl substituents. 2. A compound as claimed in Claim 1 wherein R is triazolyl or tetrazolyl, each substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxycarbonyl, aryl and "het", said C1-C4 alkyl being optionally substituted by halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyl(C1-C4)alkoxy, -COOH, C1-C4 alkoxycarbonyl, -NR<3>R<4>, -SO2(aryl), morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or "het"; or is pyridinyl or pyrimidinyl. 3. A compound as claimed in Claim 1 or 2 wherein R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl or tetrazol-5-yl, each substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, C2-C4 alkenyl, C3-C7 cycloalkyl, halo, hydroxy, C1-C4 alkoxycarbonyl, aryl and "het", said C1-C4 alkyl being optionally substituted by halo, hydroxy, C1-C4 alkoxy, halo(C1-C4)alkoxy, C3-C7 cycloalkyl(C1-C4)alkoxy, -COOH, C1-C4 alkoxycarbonyl, -NR<3>R<4>, -SO2(aryl), morpholino, aryl, aryloxy, aryl(C1-C4)alkoxy or "het"; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl. 4. A compound as claimed in any one of Claims 1-3 wherein R<3> and R<4> are each independently selected from H and C1-C4 alkyl. 5. A compound as claimed in any one of Claims 1-4 wherein "aryl" means phenyl optionally substituted by 1 or 2 substituents each independently selected from methyl, methoxy, hydroxy, chloro-, trifluoromethyl and dimethylamino. 6. A compound as claimed in any one of Claims 1-5 wherein "het" means thienyl, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl, each being optionally benzo-fused and optionally substituted by 1 or 2 substituents each independently selected from C1-C4 alkyl, -COOH, -NR<3>R<4> and phenyl, and/or by an oxido substituent on a ring nitrogen heteroatom of said pyridinyl, pyridazinyl, pyrimidinyl or pyrazinyl group. 7. A compound as claimed in any one of Claims 1-6 wherein R is 1,2,3-triazol-4-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-4-yl or tetrazol-5-yl, each substituted by 1 or 2 substituents each independently selected from methyl, ethyl, propyl, allyl, cyclopropyl, cyclohexyl, bromo-, hydroxy, ethoxycarbonyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, 4-dimethylaminophenyl, 2-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl, 2-methylphenyl, phenyl, 4-trifluoromethylphenyl, 2-amino-1,3,4-oxadiazol-5-yl, 2-carboxypyridin-5-yl, 1,5-dimethyl-lH-pyrazol-3-yl, 1H-imidazol-1-yl, 1-methylimidazol-2-yl, 1-methylimidazol-4-yl, 1-methylimidazol-5-yl, 3-methylisothiazol-4-yl, 4-methyl-lH-imidazol-5-yl, 3-methyl-1,2,4-oxadiazol-5-yl, 1-methyl-1H-pyrazol-4-yl, 5-methyl-1H-pyrazol-3-yl, 1-methyl-1H-pyrazol-5-yl, 1-oxidopyridin-3-yl, 2-methylpyridin-3-yl, 2-methylpyridin-5-yl, 1-phenylimidazol-4-yl, 5-phenylpyridin-3-yl, 2-phenylpyridin-5-yl, 1-methylpyrrol-2-yl, 4-methyl-1,2,3-thiadiazol-5-yl, 2-methylthiazol-4-yl, 1-methyl-1H-1,2,4-triazol-5-yl, 3-(prop-1-yl)-1H-pyrazol-5-yl, pyrazin-2-yl, 1H-pyrazol-4-yl, pyridazin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, thien-2-yl, 1H-1,2,4-triazol-5-yl, 1H-1,2,3-triazol-5-yl, quinolin-3-yl and quinolin-6-yl, said methyl, ethyl or propyl being optionally substituted by fluoro-, hydroxy, methoxy, ethoxy, 2,2,2-trifluoroethoxy, cyclohexylmethoxy, cyclopentylmethoxy, -COOH, methoxycarbonyl, dimethylamino, 4-chlorophenylsulphonyl, morpholino, phenyl, phenoxy, benzyloxy, pyridin-2-yl, pyridin-3-yl or pyridin-4-yl; or is pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl or pyrimidin-5-yl. 8. A compound as claimed in any one of Claims 1-7 wherein R is 1-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl, 1-(2-hydroxyethyl)-4-phenyl-1,2,3-triazol-5-yl, 2-(2-hydroxyethyl)-5-phenyl-1,2,3-triazol-4-yl, 1-methyl-5-phenyl-1,2,3-triazol-4-yl, 1-methyl-4-phenyl-1,2,3-triazol-5-yl, 2-methyl-5-phenyl-1,2,3-triazol-4-yl, 5-phenyl-1H-1,2,3-triazol-4-yl, 1-methyl-1H-1,2,4-triazol-3-yl, 2-methyl-2H-1,2,4-triazol-3-yl, 4-(2-hydroxyethyl)-4H-1,2,4-triazol-3-yl, 4-methyl-4H-1,2,4-triazol-3-yl, 3-(2-amino-1,3,4-oxadiazol-5-yl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-benzyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-benzyloxymethyl-5-(pyridin-3-yl)-4H-l,2,4-triazol-4-yl, 3-bromo-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(3-carboxyprop-1-yl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(2-carboxypyridin-5-yl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(2-chlorophenyl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(2-chlorophenyl)-5-methyl-4H-l,2,4-triazol-4-yl, 3-(3-chlorophenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(4-chlorophenyl)-5-methyl-4H-l,2,4-triazol-4-yl, 3-(4-chlorophenylsulphonylmethyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-cyclohexylmethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-cyclopentylmethoxymethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-cyclopropyl-5-methyl-4H-1,2,4-triazol-4-yl, 3,5-di(methoxymethyl)-4H-1,2,4-triazol-4-yl, 3-(N,N-dimethylaminomethyl)-5-ethyl-4H-1,2,4-triazol-4-yl, 3-(N,N-dimethylaminomethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-(4-dimethylaminophenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methoxymethyl-4H-1,2,4-triazol-4-yl, 3-(1,5-dimethyl-1H-pyrazol-3-yl)-5-methyl-4H-1,2,4-triazol-4-yl, 3,5-dimethyl-4H-1,2,4-triazol-4-yl, 3,5-diphenyl-4H-1,2,4-triazol-4-yl, 3-(2-ethoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-ethoxymethyl-5-(pyridin-3-yl)-4H-l,2,4-triazol-4-yl, 3-ethoxycarbonyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(2-chlorophenyl)-4H-l,2,4-triazol-4-yl, 3-ethyl-5-(2-methoxyphenyl)-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(1-methylpyrazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-ethyl-5-methyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-morpholinomethyl-4H-1,2,4-triazol-4-yl, 3-ethyl-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-ethyl-4H-1,2,4-triazol-4-yl, 3-(2-hydroxyethyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-hydroxymethyl-5-methyl-4H-l,2,4-triazol-4-yl, 3-hydroxymethyl-5-phenyl-4H-1,2,4-triazol-4-yl, 3-hydroxymethyl-5-(pyridin-3-yl)-4H-l,2,4-triazol-4-yl, 3-hydroxymethyl-4H-1,2,4-triazol-4-yl, 3-hydroxy-5-methyl-4H-1,2,4-triazol-4-yl, 3-(2-hydroxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(1H-imidazol-1-yl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(2-methoxyethyl)-5-(pyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1-methyl-1H-pyrazol-5-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(2-methylpyridin-5-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(2-methylthiazol-4-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1-oxidopyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(1-phenylimidazol-4-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(5-phenylpyridin-3-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(2-phenylpyridin-5-yl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(pyridin-3-yl)-4H-l,2,4-triazol-4-yl, 3-methoxymethyl-5-(pyridin-3-ylmethyl)-4H-1,2,4-triazol-4-yl, 3-methoxymethyl-5-(quinolin-3-yl)-4H-l,2,4-triazol-4-yl, 3-methoxymethyl-5-(quinolin-6-yl)-4H-1,2,4-triazol-4-yl, 3-(2-methoxyphenyl)-5-methyl-4H-l,2,4-triazol-4-yl, 3-(3-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-(4-methoxyphenyl)-5-methyl-4H-1,2,4-triazol-4-yl, 3-methy