Potassium channel inhibitors and method

A method for preventing or treating cardiac arrhythmia, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound which has the structure including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein

• A, B and D are CH;
• X.sup.1 is ##STR481## wherein oxygen atom is linked to the aromatic ring;
• (where R.sup.3 and R.sup.4 are independently H, alkyl, arylalkyl or cycloalkyl, or R.sup.3 and R.sup.4 can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring);
• R is H, alkyl, alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl, or cycloalkylalkyl;
• R.sup.1 is alkyl, arylalkyl, aryl, alkenyl, heterocycle, heterocycloalkyl, ##STR482## (where R.sup.5a can be H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl), cycloalkyl, cycloalkylalkyl or ##STR483## (where R.sup.6 and R.sup.7 are independently selected from H, aryl, alkyl, arylalkyl or cycloalkyl, or R.sup.6 and R.sup.7 can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring);
• or R and R.sup.1 can be taken together with the --N--S-- atoms to form a 5- to 8-membered ring;
• X.sup.2 is a bond, ##STR484## or --O-- (where R.sup.8 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
• R.sup.2 is H, alkyl, arylalkyl, ##STR485## (where R.sup.10 and R.sup.11 are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R.sup.10 and R.sup.11 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring);
• and
• Q is ##STR486## (where R.sup.12 is ##STR487## heterocycle, heterocycloalkyl, ##STR488## where R.sup.14 can be any of the R.sup.8 groups), CF.sub.3, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl), and where R.sup.15 and R.sup.16 are independently selected from H, alkyl, arylalkyl, heterocyclo, amino, aminoalkyl, cycloalkyl or heterocycloalkyl, or R.sup.15 and R.sup.16 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring which may optionally contain an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring);
• and
• R.sup.13 is ##STR489## (wherein this moiety is as defined with respect to R.sup.12 and at least one of R.sup.15 and R.sup.16 is other than lower alkyl);
• wherein the term heterocyclo by itself or as part of heterocycloalkyl refers to a cycloheteroalkyl group or a heteroalkyl croup wherein cycloheteroalkyl is a 5-, 6- or 7-memebered saturated ring which includes 1 to 2 hetero atoms which are nitrogen, oxygen and/or sulfur, which may be optionally substituted with 1 to 4 substituents, and which optionally can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring, and heteroaryl is a 5- or 6-membered aromatic ring which includes 1, 2, 3 or 4 hetero atoms which are nitrogen, oxygen and/or sulfur, which may be optionally substituted with 1 or 2 substituents, and which optionally can be fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring.

A method for preventing or treating atrial arrhythmia, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound which has the structure ##STR490## including pharmaceutically acceptable salts thereof, prodrug esters thereof, and all stereoisomers thereof, wherein

• A, B and D are CH;
• X.sup.1 is ##STR491## wherein the oxygen atom is linked to the aromatic ring;
• (where R.sup.3 and R.sup.4 are independently H, alkyl, arylalkyl or cycloalkyl, or R.sup.3 and R.sup.4 can be taken together with the carbon to which they are attached to form a 5 to 8 carbon containing ring);
• R is H, alkyl, alkenyl, aryl, arylalkyl, heterocycloalkyl, cycloalkyl, or cycloalkylalkyl;
• R.sup.1 is alkyl, arylalkyl, aryl, alkenyl, heterocycle, heterocycloalkyl, ##STR492## (where R.sup.5a can be H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl), cycloalkyl, cycloalkylalkyl or ##STR493## (where R.sup.6 and R.sup.7 are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R.sup.6 and R.sup.7 can be taken together with the nitrogen atom to which they are attached to form a 5 to 8 membered ring);
• or R and R.sup.1 can be taken together with the --N--S-- atoms to form a 5- to 8-membered ring;
• X.sup.2 is a bond, ##STR494## or --O-- (where R.sup.8 is H, alkyl, alkenyl, aryl, arylalkyl, cycloalkyl or cycloalkylalkyl);
• R.sup.2 is H, alkyl, arylalkyl, ##STR495## (where R.sup.10 and R.sup.11 are independently selected from H, alkyl, arylalkyl or cycloalkyl, or R.sup.10 and R.sup.11 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring);
• and
• Q is ##STR496## (where R.sup.12 is ##STR497## heterocycle, heterocycloalkyl, ##STR498## (where R.sup.14 can be any of the R.sup.8 groups), CF.sub.3, aryloxy, arylalkoxy, cycloalkyl or cycloalkylalkyl), and where R.sup.15 and R.sup.16 are independently selected from H, alkyl, arylalkyl, heterocyclo, amino, aminoalkyl, cycloalkyl or heterocycloalkyl, or R.sup.15 and R.sup.16 can be taken together with the nitrogen to which they are attached to form a 5- to 8-membered ring which may optionally contain an additional nitrogen atom in the ring and/or an amino group or an aminoalkyl group attached to the ring);
• and
• R.sup.13 is ##STR499## (wherein this moiety is as defined with respect to R.sup.12 and at least one of R.sup.15 and R.sup.16 is other than lower alkyl);
• wherein the term heterocyclo by itself or as part of heterocycloalkyl refers to a cycloheteroalkyl group or a heteroalkyl group wherein cycloheteroalkyl is a 5-, 6- or 7-memebered saturated ring which includes 1 to 2 hetero atoms which are nitrogen, oxygen and/or sulfur, which may be optionally substituted with 1 to 4 substituents, and which optionally can be fused to a cycloalkyl, aryl, heteroaryl or cycloheteroalkyl ring, and heteroaryl is a 5- or 6-membered aromatic rind which includes 1, 2, 3 or 4 hetero atoms which are nitrogen, oxygen and/or sulfur, which may be optionally substituted with 1 or 2 substituents, and which optionally can be fused to an aryl, cycloalkyl, heteroaryl or cycloheteroalkyl ring.