Substituted bicyclic 8-pyrr0lidinoxanthines, methods for their production, pharmaceutical formulations and their use

A method for the treatment of elevated blood glucose levels and the diseases associated therewith consisting of the administration of a pharmaceutical composition comprising one or more compounds selected from the group consisting of a compound of formula I:

• wherein:
• R1, R2 and R3 independently of one another are selected from the group consisting of H, (C1-C10)-alkyl, (C3-C10)-cycloalkyl, (C2-C10)-alkenyl, (C2-C10)-alkynyl, (C6-C10)-aryl, heterocycle, where the alkyl, cycloalkyl, alkenyl, alkynyl, aryl and heterocycle R-groups may be substituted one or more times by F, Cl, Br, I, CN, NO2, SH, OH, (C1-C6)-alkyl, —CF3, —OCF3, —SCF3, (C2-C6)-alkenyl, (C2-C6)-alkynyl, OR7, OP(O)(OR7)2, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8, OCONR7R8, (C1-C6)-alkylene-OR7, (C1-C6)-alkylene-NR7R8, (C1-C6)-alkylene-NR7SO2R7, (C1-C6)-alkylene-SR7, alkylene-S(O) R7, alkylene-S(O)2R7, alkylene-S(O)2NR7R8, (C1-C6)-alkylene-COR7, (C1-C6)-alkylene-COOR7, (C1-C6)-alkylene-CONR7R8, SR7, SOR7, SO2R7, SO2NR7R8, NR7SO2R7, (C1-C6)-alkylene-(C3-C10)-cycloalkyl, (C1-C6)-alkylene-(C6-C10)-aryl, (C1-C6)-alkylene-heterocycle, (C3-C10)-cycloalkyl, (C6-C10)-aryl or heterocycle;
• R7 and R8 independently of one another are selected from the group consisting of H, (C1-C6)-alkyl, —CF3, (C3-C10)-cycloalkyl, (C6-C10)-aryl, heterocycle, C1-C6)-alkylene-CONR9R10, CONR9R10, (C1-C6)-alkylene-COOR9, COOR9, COR9, (C1-C6)-alkylene-COR9, (C1-C6)-alkylene-OR9, (C1-C6)-alkylene-NR9R10, (C1-C6)-alkylene-SR9, (C1-C6)-alkylene-S(O)R9, (C1-C6)-alkylene-S(O)2R9, S(O)R9, S(O)2R9, (C1-C4)-alkylene-(C6-C10)-aryl or (C1-C4)-alkylene-heterocycle;
• R9 and R10 independently of one another are selected from the group consisting of H, (C1-C6)-alkyl, (C1-C6)-alkylene-(C6-C10)-aryl, -(C6-C10)-aryl, heterocycle, (C1-C6)-alkylene-heterocycle;
• R4 and R5 together form the group —CH2—CH2—NH—, where R6 is H, or
• R5 and R6 together form the group —CH2—NH—CH2—, where R4 is H;
• or a physiologically tolerated salt thereof in a pharmaceutically acceptable carrier

A composition for the treatment of elevated blood glucose levels and the diseases associated therewith consisting of the compound of formula I

• wherein:
• R1 is (C1-C10)-alkyl, where the alkyl radical may be substituted by COR7;
• R2 is (C1-C10)-alkyl;
• R3 is (C1-C10)-alkyl, (C2-C10)-alkenyl;
• R7 is (C6-C10)-aryl;
• R4 and R5 together form the group —CH2—CH2—NH—;
• and
• R6 is H;
• or a physiologically tolerated salt thereof.
• in combination with a second active agent. wherein the second active ingredient is selected from the group consisting of one or more antidiabetic agents, anti-hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, bisguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, CB-1 receptor antagonists, MCH antagonists, MC4 agonists, orexin agonists, H-3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β3 agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombazine agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β agonists, amphetamines and suitable mixtures thereof.

A method for the treatment of elevated blood glucose levels and the diseases associated therewith comprising the administration of a composition consisting of the compound of formula I

• wherein:
• R1 is (C1-C10)-alkyl, where the alkyl radical may be substituted by COR7;
• R2 is (C1-C10)-alkyl;
• R3 is (C1-C10)-alkyl, (C2-C10)-alkenyl;
• R7 is (C6-C10)-aryl;
• R4 and R5 together form the group —CH2—CH2—NH—;
• and
• R6 is H;
• or a physiologically tolerated salt thereof.
• in combination with a second active agent. wherein the second active agent is selected from the group consisting of one or more antidiabetic agents, anti-hypoglycemic agents, HMGCoA reductase inhibitors, cholesterol absorption inhibitors, PPAR gamma agonists, PPAR alpha agonists, PPAR alpha/gamma agonists, fibrates, MTP inhibitors, bile acid absorption inhibitors, CETP inhibitors, polymeric bile acid adsorbents, LDL receptor inducers, ACAT inhibitors, antioxidants, lipoprotein lipase inhibitors, ATP-citrate lyase inhibitors, squalene synthetase inhibitors, lipoprotein(a) antagonists, lipase inhibitors, insulins, sulfonylureas, bisguanides, meglitinides, thiazolidinediones, α-glucosidase inhibitors, active ingredients which act on the ATP-dependent potassium channel of the beta cells, CART agonists, NPY agonists, CB-1 receptor antagonists, MCH antagonists, MC4 agonists, orexin agonists, H-3 agonists, TNF agonists, CRF agonists, CRF BP antagonists, urocortin agonists, β agonists, MSH (melanocyte-stimulating hormone) agonists, CCK agonists, serotonin reuptake inhibitors, mixed serotoninergic and noradrenergic compounds, 5HT agonists, bombesin agonists, galanin antagonists, growth hormones, growth hormone-releasing compounds, TRH agonists, uncoupling protein 2 or 3 modulators, leptin agonists, DA agonists (bromocriptine, Doprexin), lipase/amylase inhibitors, PPAR modulators, RXR modulators, TR-β agonists, amphetamines and suitable mixtures thereof.