TERTIARY AMINES FOR USE IN THE TREATMENT OF CARDIAC DISORDERS

摘要

The present invention relates to tertiary amines of formula (I) for use in therapy, particularly for use in treating cardiovascular disorders. The compounds have been found to regulate phospholamban phosphorylation by interfering with the A-kinase anchor protein 18delta (AKAP185) binding to the PKA substrate phospholamban. The compounds share a tri(alkylaryl/alkylheteroaryl)amine structure.

主权项

1. A compound of formula (I) for use in therapy: wherein L1, L2 and L3 independently denote C1-C4-alkylene optionally substituted with one phenyl; Ar1, Ar2 and Ar3 independently denote a 5-10 membered heteroaryl optionally substituted with —C(═O)Z or one or more R; or a 6-10 membered aryl optionally substituted with one or more R; Z denotes ORa or NRbRc; Ra denotes H, C1-C4-alkyl, C3-C6-cycloalkyl, C2-C4-alkylene-O—C1-C4-alkyl, C2-C4-alkylene-CN; C1-C4-alkyl substituted with one or two Ar4; Rb denotes H, C1-C4-alkyl, C3-C6 cycloalkyl, C2-C4-alkylene-CN; C2-C4-alkylene-O—C1-C4-alkyl; or C1-C4-alkyl substituted with one or two Ar4; Rc denotes H, C1-C8 alkyl, C3-C6 cycloalkyl, Ar4, C1-C4-alkyl substituted with one or two Ar4; OH, O—C1-C4-alkyl, C2-C4-alkyl-O—C1-C4-alkyl, or C2-C4-alkyl-NRaRa; or together NRbRc denotes wherein X denotes CHZ1, O, or NZ1; Z1 denotes H, C(═O)H, C(═O)C1-C4-alkyl, C(═O)ORz, Ar4, C1-C4-alkyl, C3-C6-cycloalkyl, C1-C4-alkyl substituted with one or two Ar4; C2-C4—NRdRe, or C2-C4—ORf; Z2 denotes ORa or NRgRg; Ar4 denotes 5-6 membered heteroaryl; or phenyl optionally substituted with one or more R; Rd, Re and Rf independently denote H or C1-C4-alkyl; Rg denotes Rb; Rz denotes H, C1-C4-alkyl or C3-C6 cycloalkyl; R independently denotes F, Cl, Br, I, C1-C4-haloalkyl, OR1, SR1, NO2, NR2R3, R4, C(═O)Y, SO3H, C1-C4-alkyl, C1-C4-alkyl-phenyl, a 5-membered heteroaryl; or a phenyl substituted with a 5-membered heteroaryl; R1 denotes H, C1-C4-alkyl or C1-C4-alkyl-phenyl; or together two adjacent OR1 groups denote —O—CH2—O—; R2 and R3 independently denote H or C1-C4-alkyl; or NR2R3 denotes —NHC(═O)—NHAr5; or together two adjacent NR2R3 groups denote —NR2—CH—N— or —NR2—CH2—NR2—; or together with an adjacent OR1 group, NR2R3 denotes —NR2—CH2—O— or —N—CH—O—; or together with an adjacent SR1 group, NR2R3 denotes —NR2—CH2—S— or —N—CH—S—; Ar5 denotes phenyl optionally substituted with Rh; Rh denotes halogen or C1-C4 alkyl; R4 denotes C1-C4-alkyl; or together with an adjacent OR1 group, R4 denotes —CH2CH2—O—; or together two adjacent R4 groups denote —(CH)4— or —(CH2)4—; Y denotes OR5 or NR6R7; R5 denotes H or C1-C4-alkyl; and R6 and R7 independently denote H, C1-C8-alkyl or C3-C6 cycloalkyl.