1,2,3,4-tetrahydronaphthalene and 1,2,3,4-tetrahydro-2-naphthalenol derivatives and pharmaceuticals thereof, and their use as potassium channel inhibitors useful for treating cardiac arrhythmias

摘要

A compound of formula (I), wherein: t is 1, or 2; A and B are each H; or taken together form a bond between the substituted carbons. R1 is H; alkyl; or is optionally substituted aryl, heteroaryl, heterocyclyl or carbocycloalkyl, with the proviso that when R1 is an optionally substituted aryl, then R1 is not a dialkoxyphenyl. Y2 is (CH2)q; (CH2)wO; HC=CH; or ethynyl; with the proviso that if Y2 is (CH2)q and q=0, then R1 cannot be H. X2 is C=0, C=S, or S02; with the proviso that if Y2 is (CH2)wO, then X2 is not SO2. R3 is H; alkyl; or optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl; heterocyclyl, carbocycloalkyl; or an alkylene-(substituted amino). Z is H; alkyl; alkyenyl; alkylene(heterocyclyl); alkylene (heteroaryl); alkylene-NHC(O)(alkyl); alkylene-NHC(O)(aryl); alkylene-NHC(O)(heterocyclyl); alkylene-NHC(O)(heteroaryl); alkylene-NHC(O)-(alkylene-heterocyclyl); alkylene-NHC(O)-(heteroaralkyl); alkylene-C(O)(alkyl); alkylene-C(O)O(alkyl); OR14; SR14; or NR15R16. R2 is H; alkyl; optionally substituted aryl, aralkyl, heteroaryl, heterocyclyl, heteroaralkyl, carbocycloalkyl; Ra-O-; or RbRc-N-. Y1 is (CH2)p; CHR17(CH2)o; HC=CH; or ethynyl; X1 is C=O; C=S; SO2; or (CH2)n. R4 is H; alkyl; optionally substituted aryl, aralkyl, heteroaryl, heteroaralkyl; heterocyclyl, carbocycloalkyl; or alkylene-(substituted amino). With the provisos that: (i) If Y1 is (CH2)p, p is 0 and X1 is not (CH2)n then R2 is not H, (ii) If R2 is Ra-O and Y1 is (CH2)p with p=0, then X1 is not SO2 and (iii) If Z is not H, OR14, SR14 or NR15R16, then X2 must be SO2. Also described is a pharmaceutical composition comprising the compound of formula (I) and a pharmaceutically acceptable diluent or carrier. The compounds of formula (I) are useful for inhibiting potassium transport across cellular membranes possessing potassium channels. The compounds of formula (I) are particularly useful for treating cardiac arrhythmias.