Thieno[2,3-B] pyridines as potassium channel inhibitors
The invention provides compounds of the formula: wherein R1 is aryl, heteroaryl, cycloalkyl or alkyl; R2 is H, alkyl, nitro, CO 2 R7, CONR5R6 or halo; R3 and R4 are H, NR5R6, NC(O)R7, halo, trifluromethyl, alkyl, CONR5R6, CO 2 R7, nitrile or alkoxy; R5 and R6 may be the same or different and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R5 and R6 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S; R7 is H or alkyl; A is H, halo, or a group of formula X-L-Y; X is O, S or NR8; R8 is H or alkyl; L is (CH 2 ) n , where n is 0, 1, 2, 3 or 4; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; the products of mono- and di-oxidation of sulphur and/or mono-oxidation of nitrogen moieties in compounds of formula I; or a pharmaceutically acceptable salt thereof. These compounds find use as inhibitors of potassium ion channels and thus are useful in the treatment of various conditions including arrhythmia and type-2 diabetes mellitus.
1. A compound of the formula:
wherein
R1 is optionally substituted aryl, optionally substituted heteroaryl, or optionally substituted cycloalkyl;
R2 is H, optionally substituted alkyl, nitro, CO 2 R7, CONR5R6 or halo;
R3 and R4 are H, NR5R6, NC(O)R7, halo, trifluoromethyl, optionally substituted alkyl, CONR5R6, CO 2 R7, cyano or optionally substituted alkoxy;
R5 and R6 may be the same or different and may be H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl; or R5 and R6 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S;
R7 is H or optionally substituted alkyl;
A is halo, or a group of formula X-L-Y;
X is O, S or NR8;
R8 is H or optionally substituted alkyl;
L is (CH 2 ) n , where n is 1, 2, 3 or 4; and
Y is optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted cycloalkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound as claimed in claim 1 , or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl, optionally substituted cycloalkyl or optionally substituted heteroaryl; R2 is H or optionally substituted alkyl; R3 is H, NR5R6, optionally substituted alkoxy or optionally substituted alkyl; X is O or NR8; R8 is H or optionally substituted alkyl; n is 1, 2, 3 or 4 and Y is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
3. The compound as claimed in claim 2 , or a pharmaceutically acceptable salt thereof, wherein R1 is optionally substituted aryl or optionally substituted heteroaryl; R2 is H or optionally substituted alkyl; R3 is H, NR5R6, optionally substituted alkoxy or optionally substituted alkyl; X is NR8; R8 is H or methyl; n is 1 or 2 and Y is optionally substituted aryl or optionally substituted heteroaryl.
4. The compound as claimed in claim 3 which is:
(3-Phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine,
2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino }-ethanol,
2-((2-Hydroxy-ethyl)-{3-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-amino)-ethanol,
(6-Chloro-3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine,
[3-(4-Fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine,
2-[{3-(4-Fluoro-phenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-(2-hydroxy-ethyl)-amino]-ethanol,
2-[{(3-(4-Fluoro-phenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-(2-hydroxy-ethyl)-amino]-ethanol,
2-{3-(4-Fluoro-phenyl)-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino}-ethanol,
2-{3-(4-Fluoro-phenyl)-4-[(6-methyl-pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino}-ethanol,
2-{2-Methyl-3-phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-ylamino}-ethanol,
[6-Chloro-3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-pyridin-2-ylmethyl-amine,
[6-Chloro-3-(4-fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-(6-methyl-pyridin-2-ylmethyl)-amine,
[3-(4-Fluoro-phenyl)-thieno[2,3-b]pyridin-4-yl]-(6-methyl-pyridin-2-ylmethyl)-amine,
2-{3-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-thieno[2,3-b]pyridin-6-yl}-propane-1,3-diol, or
(4-Chloro-3-phenyl-thieno[2,3-b]pyridin-6-yl)-pyridin-2-ylmethyl-amine;
or a pharmaceutically acceptable salt thereof.
5. A compound of the formula:
wherein:
R1 is optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl or optionally substituted alkyl;
R2 is H, optionally substituted alkyl, nitro, CO 2 R7, CONR5R6 or halo;
R3 and R4 are H, NR5R6, NC(O)R7, halo, trifluoromethyl, optionally substituted alkyl, CONR5R6, CO 2 R7, cyano or optionally substituted alkoxy;
R5 and R6 may be the same or different and may be H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl; or R5 and R6 may together form a saturated, unsaturated or partially saturated 4 to 7 member ring, wherein said ring may optionally comprise one or more further heteroatoms selected from N, O or S;
R7 is H or optionally substituted alkyl;
X is O, S or NR8;
R8 is H or optionally substituted alkyl;
L is (CH 2 ) n , where n is 1, 2 or 3; and
Y is optionally substituted aryl, an optionally substituted heterocyclic group, optionally substituted alkyl, optionally substituted alkenyl or optionally substituted cycloalkyl;
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising at least one compound of claim 1 .
7. The pharmaceutical composition according to claim 6 further comprising one or more pharmaceutically acceptable excipients, diluents, carriers, and mixtures thereof.
8. A pharmaceutical composition comprising at least one compound of claim 3 .
9. A pharmaceutical composition comprising at least one compound of claim 5 .
10. The pharmaceutical composition according to claim 8 further comprising one or more pharmaceutically acceptable excipients, diluents, carriers, and mixtures thereof.