Patent EA-004931-B1 (EA)
Title: 3,4,5-trisubstituted aryl nitrone compounds and pharmaceutical compositions containing the same
Inventor: WATERBURY L DAVID
IPC: C07C291/02
Filed: 1999-12-01
Abstract: 1. A compound of formula I: wherein R<1> is selected from the group consisting of: each R<2> is independently selected from a group of the formula: R<3> is hydrogen; R<4> is selected from the group consisting of C1-10 alkyl, which may be substituted by a thioalkoxy group or a hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, or C3-10 cycloalkyl; R<5> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl group, C3-10 cycloalkyl; R<6> and R<7> are independently selected from the group consisting of a hydrogen atom, C1-10 alkyl, which may be substituted by C1-6 alkoxycarbonyl or an C1-6 alkoxy group, C3-10 cycloalkyl, or R<6> and R<7> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<8> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl group and C3-10 cycloalkyl; R<9> is selected from the group consisting of a hydrogen atom, C1-10 alkyl, C3-10 cycloalkyl; or R<8> and R<9> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<10>, R<11> and R<12> are independently selected from the group consisting of alkyl having from 1 to 6 carbon atoms; X is oxygen, W is oxygen; and pharmaceutically-acceptable salts thereof. 2. The compound of Claim 1 wherein R<4> is selected from the group consisting of C1-6 alkyl, which may be substituted by thioalkoxy or a hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, or C3-10 cycloalkyl. 3. The compound of Claim 2 wherein R<4> is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy) but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 4. The compound of Claim 1 wherein R<5> is selected from the group consisting of C1-6 alkyl, C1-6 alkoxyalkyl C3-10 cycloalkyl. 5. The compound of Claim 4 wherein R<5> is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl. 6. The compound of Claim 1 wherein R<7> is hydrogen and R<6> is selected from the group consisting of C1-6 alkyl or C1-6 alkoxycarbonylalkyl. 7. The compound of Claim 6 wherein R<6> groups is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2-(ethoxycarbonyl) ethyl. 8. The compound of Claim 1 wherein X is oxygen; R<9> is hydrogen; and R<8> is C1-6 alkyl or C1-6 alkoxyalkyl. 9. The compound of Claim 8 wherein R<8> is selected from the group consisting of methyl and methoxyethyl. 10. The compound of Claim 9 wherein R<10>, R<11> and R<12> are methyl. 11. A compound of formula: wherein R<13> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl, C3-10 cycloalkyl; R<4> is selected from the group consisting of C1-10 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, and C3-10 cycloalkyl; and pharmaceutically-acceptable salts thereof. 12. The compound of Claim 11 wherein R<13> is alkyl having from 1 to 6 carbon atoms. 13. The compound of Claim 11 wherein R<4> is selected from the group consisting of C1-6 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, and C3-10 cycloalkyl. 14. The compound of Claim 13 wherein R<4> is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3- (thiomethoxy) but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 15. A compound of formula: wherein R<15> and R<16> are independently selected from the group consisting of hydrogen, C1-10 alkyl, which may be substituted by C1-6 alkoxycarbonyl or C1-6 alkoxy group, or C3-10 cycloalkyl; or R<15> and R<16> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<4> is selected from the group consisting of C1-10 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, and C3-10 cycloalkyl; and pharmaceutically-acceptable salts thereof. 16. The compound of Claim 15 wherein R<16> is hydrogen and R<15> is selected from the group consisting of C1-10 alkyl or C1-6 alkoxycarbonylalkyl. 17. The compound of Claim 16 wherein R<15> is selected from the group consisting of ethyl, n-propyl, isopropyl, n-butyl, ethoxycarbonylmethyl and 2 (ethoxycarbonyl) ethyl. 18. The compound of Claim 15 wherein R<4> is selected from the group consisting of C1-6 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, or C3-10 cycloalkyl. 19. The compound of Claim 18 wherein R<4> is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy) but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 20. A compound of formula: wherein R<18> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl or C3-10 cycloalkyl; R<19> is selected from the group consisting of hydrogen, C1-10 alkyl or C1-10 alkyl; or R<18> and R<19> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<4> is selected from the group consisting of C1-10 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, and C3-10 cycloalkyl; and pharmaceutically-acceptable salts thereof. 21. The compound of Claim 20 wherein R<19> is hydrogen and R<18> is C1-10 alkyl or C1-10 alkoxyalkyl. 22. The compound of Claim 21 wherein R<18> is methyl or methoxyethyl. 23. The compound of Claim 20 wherein R<4> is selected from the group consisting of C1-6 alkyl, which may be substituted by thioalkoxy group or hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, and C3-10 cycloalkyl. 24. The compound of Claim 23 wherein R<4> is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3- (thiomethoxy) but-1-yl, cyclohexyl, 4-trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 25. A compound selected from the group consisting of: alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone; alpha-(4-isobutanoyloxy-3,5-di-tert-butylphenyl)-N tert-butylnitrone; alpha-(4-n-butanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone; alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-isopropylnitrone; alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-1-hydroxy-2-methylprop-2-ylnitrone; alpha-(4-n-pentanoyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone; alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-4-trifluoromethylbenzylnitrone; alpha-(4-propionyloxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone; alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-methylnitrone; alpha-(4-acetoxy-3,5-di-tert-butylphenyl)-N-3,4,5-trimethoxybenzylnitrone; alpha-4-(ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl-N-tert-butylnitrone; alpha-4-(n-propylaminocarbonyloxy)-3,5-di-tert-butylphenyl-N-tert butylnitrone; alpha-4-(n-butylaminocarbonyloxy)-3,5-di-tert-butylphenyl-N-tert butylnitrone; alpha-4-(2-ethoxycarbonyl) ethylaminocarbonyloxy)-3,5-di-tert-butylphenyl N-tert-butylnitrone; alpha-4-(2-ethoxycarbonyl) methylaminocarbonyloxy)-3,5-di-tert butylphenyl-N-tert-butylnitrone; alpha-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-tert-butylnitrone; alpha-4-(2-methoxy)ethoxymethoxy-3,5-di-tert-butylphenyl]-N-tert butylnitrone; alpha-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-3-(thiomethoxy) but-1-ylnitrone; alpha-(4-methoxymethoxy-3,5-di-tert-butylphenyl)-N-3-thiomethoxypropylnitrone; and pharmaceutically acceptable salts thereof. 26. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of formula I: wherein R<1> is selected from the group consisting of: each R<2> is independently selected from a group of the formula: R<3> is hydrogen; R<4> is selected from the group consisting of C1-10 alkyl, which may be substituted by a thioalkoxy group or a hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, or C3-10 cycloalkyl; R<5> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl group, C3-10 cycloalkyl; R<6> and R<7> are independently selected from the group consisting of a hydrogen atom, C1-10 alkyl, which may be substituted by C1-6 alkoxycarbonyl or an C1-6 alkoxy group, C3-10 cycloalkyl, or R<6> and R<7> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<8> is selected from the group consisting of C1-10 alkyl, C1-10 alkoxyalkyl group and C3-10 cycloalkyl; R<9> is selected from the group consisting of a hydrogen atom, C1-10 alkyl, C3-10 cycloalkyl; or R<8> and R<9> can be joined to form an alkylene group having from 2 to 10 carbon atoms; R<10>, R<11> and R<12> are independently selected from the group consisting of alkyl having from 1 to 6 carbon atoms; X is oxygen, W is oxygen; and pharmaceutically-acceptable salts thereof. 27. The pharmaceutical composition of Claim 26 wherein R<4> is selected from the group consisting of C1-6 alkyl, which may be substituted by thioalkoxy or a hydroxy group, or phenyl substituted by trifluoromethyl or C1-6 alkoxy group, or C3-10 cycloalkyl. 28. The pharmaceutical composition of Claim 27 wherein R<4> is selected from the group consisting of methyl, n-propyl, isopropyl, 1-hydroxy-2-methylprop-2-yl, n-butyl, tert-butyl, 3-thiomethylpropyl, 3-(thiomethoxy) but-1-yl, cyclohexyl, 4trifluoromethybenzyl and 3,4,5-trimethoxybenzyl. 29. The pharmaceutical composition of Claim 26 wherein R<5> is selected from the group consisting of C1-6 alkyl, C1-6 alkoxyalkyl C3-10 cycloalkyl. 30. The pharmaceutical composition of Claim 29 wherein R<5> is selected from the group consisting of methyl, ethyl, n-propyl, isopropyl and n-butyl. 31. The pharmaceu