Inhibitors of inflammation and reperfusion injury and methods of use thereof

摘要

The invention provides a novel class of substituted nucleoside derivatives having the formula: A-Z1-L-Z2-G wherein: A and G are connected via Z₁ and Z₂ respectively, to a linker, L; and A is: wherein: X₁ and X₂ are N; X₃ is -N-CH; R₁ and R₂ are independently H, alkyl, NH₂, OH, SH, Cl, NHR₉, or N-NR₉, where R₉ is alkyl, aryl, or arylalkyl; R₅ and R₆ are independently alkyl, or R₅ and R₆ taken together form a -C(CH₃)₂- group; Z₁ is -CH₂O-, -CH₂NR₁₀-, -CH₂NR₁₀C(O)-, -CONR₁₀-, -CO₂-, -CH₂NHCONH-, -CH₂-, -CH₂NHCSNH-, -CO-, -CH₂CO₂-, -NHCO₂-, -S-, -SO₂-, -CH₂S-, or -SO-; Z₂ is -NR₁₀CO-, -C(O)NR₁₀-, -NHCONH-, -OC(O)-, -C(O)O-, NHCS, -CSNH-, -NHCSNH-, -O-, -CO-, -OCO-, -OCONH-, -NH-, -CH₂-, -CH-alkyl-, -NHCO₂-, -S-, -SO₂-, CS-, or -SO-; L is H, O, S, C1-15 alkylene chain optionally substituted in one or more positions, a 5, 6 or 7 membered carbocycle, piperidine, piperazine, pyrole, imidazole, benzimidazole, tetrazoles, indole, isoquinoline, quinoline, or pyrrolidine, any of the 5, 6 or 7 membered carbocycle, piperidine, piperazine, pyrole, imidazole, benzimidazole, tetrazoles, indole, isoquinoline, quinoline, or pyrrolidine groups being unsubstituted or substituted with one or more lower alkyl, hydroxyl, keto, amino, aminoalkyl, halo, or alkoxy groups, provided that L is not H when Z₁ is O, and when L=H, Z₂ and G are absent; and G is H, OH, SH, NH₂, CO₂H, unsubstituted or substituted alkyl, aryl, alkylaryl, carbocyclic, biphenyl, piperidine, piperazine, pyrole, imidazole, benzimidazole, tetrazole, indole, isoquinoline, quinoline, isoindolinyl, tetrahydroindolinonyl, phthalimidyl, or pyrrolidine. Pharmaceutical compositions, and methods of making and using the compounds, or pharmaceutically acceptable salts, hydrates, or mixtures thereof are also described.