Substituted pyrazines and their use in the treatment of disease

摘要

The present invention relates to compounds of general formula (I);
and the tautomers and the salts thereof, particularly the pharmaceutically acceptable salts thereof, which have valuable pharmacological properties, particularly an inhibitory effect on epithelial sodium channels, the use thereof for the treatment of diseases, particularly diseases of the lungs and airways.

主权项

1. A compound of formula (I), characterized in that R1 denotes halogen, X− denotes acetate, halide, sulfate, hydrogen sulfate, succinate, malate, hydrogen carbonate, sulfate ×0.5 or carbonate ×0.5, L1 denotes a group of formula (i), whereinRL1 denotes C1-6-alkyl, orRL1 denotes a C1-6-alkylene bridge by replacing one of the hydrogen atoms of formula (i), forming a bicyclic ring system,n and m independently from each other denote 1, 2 or 3, L2 denotes —CH2or —CH(C(O)NHRL2)—, wherein
RL2 denotes H, C1-8-alkyl, phenyl, C6-10-aryl-C5-6-cycloalkyl-, C6-10-aryl-C1-4-alkyl-, HO—C2-6-alkyl-, C1-4-alkoxy-, C1-4-alkoxy-C 2-6-alkyl, heteroaryl, C-linked hererocyclyl, C-linked herecyclyl-C1-4-alkyl, C-linked heterocyclyl-COO—C1-4-alkyl-, aryl- heterocyclyl-C1-4-alkyl, N-linked heterocyclyl-C2-4-alkyl, C6-10-aryl-(HOOC)C1-4-alkyl-, —CH(C1-3-alkyl-C6-10-aryl)(COO—C1-4-alkyl),—CH(C1-3-alkyl-C6-10-aryl)(COOH), —C1-3-alkyl-C6-10-aryl-COO—C1-4-alklyl, —C6-10-aryl-COO—C1-4-alkyl or —C(R3.1R3.2)phenyl,whereinR3.1R3.2 together with the carbon atom they are attached to form a 5-7 -membered heterocyclyl. L3 denotes hydrogen, —COOH, —CO-phenyl, —COO—C1-3-alkyl, —COO—C1-3-alkyl-C6-10-aryl-C6-10-aryl-COO—C1-4-alkyl, —C(O)NR2R3, heteroaryl, C1-3-alkyl, C2-5-alkenyl, C2-3-alkynyl, C3-7-cycloalkyl, C5-7-cycloalkenyl, HO—C1-7-alkyl-, C1-4-alkoxy-C1-5-alkyl-, C1-4-alkyl-S(O)p—C1-3-alkyl-, C-linked heterocyclyl, —CO-heterocyclyl, —CO—heterocyclyl-heteroaryl, —CO—heterocyclyl—COO—C1-4-alkyl, —CO-heterocyclyl—COOH—CN, or phenyl of formula (ii), RL3.1, RL3.2, RL3.3, RL3.4 and RL3.5 independently -denote H, —OH, —O—C1-4-alkyl, C1-4-alkyl, —S—C1-4-alkyl, —S—CF3, —CF3, —O—CH2-phenyl, —O—CF3, —CH2—OH, —CH2COOH, halogen, —SO2—C1-4-alkyl , —COO—C1-4-alkyl, —CONH2, —C1-4-alkyl-phenyl-CN, —CONHC1-4-alkyl, —CON(C1-4-alkyl)2, —CO—NH-heterocyclyl, or CN,
wherein,
p is 0, 1 or 2,R2 and R3 independently denote H, C1-8-alkyl, phenyl, C6-10-aryl-C5-6-cycloalkyl-, C6-10-aryl-C1-4-alkyl- wherein said C6-10-aryl may be substituted with —Cl, —CN, —C(O)OCH3, or —C(O)OH, HO—C2-6-alkyl-, C1-4-alkoxy-, C1-4-alkoxy-C2-6-alkyl-, heteroaryl, C-linked heterocyclyl, C-linked heterocyclyl-C1-4-alkyl, C-linked heterocyclyl —COO—C1-4-alkyl-, aryl-C-linked heterocyclyl-C1-4-alkyl, N-linked heterocyclyl-C2-4-alkyl, C6-10-aryl-(HOOC)C1-4-alkyl-, —CH(C1-3-alkyl-C6-10-aryl)(COO—C1-4-alkyl), —CH(C1-3-alkyl-C6-10-aryl)(COOH), —C1-3-alkyl-C6-10-aryl-COO—C1-4-alkyl, —C6-10-aryl-COO—C1-4-alkyl or —C(R3.1R3.2)phenyl,whereinR3.1R3.2 together with the carbon atom they are attached to form a 5-7-membered heterocyclyl,orR2 and R3 together with the nitrogen atom they are attached to form a 5-7-membered heterocyclyl, optionally substituted by a carboxylic acid or a heterroaryl,and tautomers and pharmaceutically acceptable salts thereof.