Furanopyrimidine compounds as potassium ion channel inhibitors
A compound of formula (I) wherein R 1 is aryl, heteroaryl, cycloalkyl or alkyl; R 2 is H, alkyl, nitro, —CO 2 R 7 , CONR 4 R 5 or halo; R 3 is H, NR 4 R 5 , NC(O)R 8 , halo, trifluoromethyl, alkyl, nitrile or alkoxy; R 4 and R 5 may be the same or different, and may be H, alkyl, aryl, heteroaryl or cycloalkyl; or R 4 and R 5 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; X is O, S or NR 6 ; R 6 is H or alkyl; R 7 is hydrogen, methyl or ethyl; R 8 is methyl or ethyl; L is (CH 2 ) n , where n is 1, 2 or 3; and Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl; together with pharmaceutically acceptable salts thereof. The use of these compounds as potassium channel inhibitors is also described.
1. A compound of formula
wherein
R 1 is aryl, heteroaryl, or cycloalkyl, each of which is optionally substituted;
R 2 is H, optionally substituted alkyl, nitro, CO 2 R 7 , CONR 4 R 5 or halo;
R 3 is H, NR 4 R 5 , NHC(O)R 8 , halo, trifluoromethyl, optionally substituted alkyl, cyano or alkoxy;
R 4 and R 5 may be the same or different, and may be H, optionally substituted alkyl, optionally substituted aryl, optionally substituted heteroaryl or optionally substituted cycloalkyl; or
R 4 and R 5 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;
X is O, S or NR 6 ;
R 6 is H or optionally substituted alkyl;
R 7 is hydrogen, methyl or ethyl;
R 8 is methyl or ethyl; L is (CH 2 ) n , where n is 1, 2 or 3; and
Y is aryl, a heterocyclic group, alkyl, alkenyl or cycloalkyl, each of which is optionally substituted;
or pharmaceutically acceptable salts thereof;
provided that the compound is not 4-diethylamino-5-phenylfuro [2,3-d]pyrimidine.
2. A compound according to claim 1 wherein R 1 is optionally substituted aryl or optionally substituted heteroaryl, R 2 is H or optionally substituted alkyl, R 3 is H, NR 4 R 5 , alkoxy or optionally substituted alkyl, X is O or NR 6 , R 6 is H, n is 1 or 2 and Y is optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl or optionally substituted heteroaryl.
3. A compound according to claim 2 wherein R 1 is optionally substituted aryl or optionally substituted heteroaryl, R 2 is H or methyl, R 3 is H, NR 4 R 5 , alkoxy or optionally substituted alkyl, X is NR 6 , R 6 is H, n is 1 and Y is optionally substituted aryl or optionally substituted heteroaryl.
4. A compound according to claim 1 wherein Y is phenyl, furanyl, thienyl or pyridyl, each of which is optionally substituted.
5. A compound according to claim 1 wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl or optionally substituted pyridin-2-yl.
6. A compound as claimed in claim 1 which is:
5-Phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
5-(4-Chlorophenyl-N-(pyridin-2-ylmethyl)furo[2,3 -d]pyrimidin-4-amine,
6-Methyl-5-phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
(2-Morpholin-4-yl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine,
2-((2-Hydroxyethyl)-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-furo[-2,3-d]pyrimidin-2-yl }-amino)-ethanol,
2-((2-Hydroxyethyl)-{5-(4-fluorophenyl)-4[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,
N 2 -(2-Methoxyethyl)-5-phenyl-N 4 -pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino] furo[2,3-d]pyrimidin-2-ylamino}-propane-1,3-diol,
N 2 ,N 2 -Dimethyl-5-phenyl-N 4 -pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
N 2 ,N 2 -Dimethyl-N 4 -(6-methyl-pyridin-2-ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-2,4-diamine, or
[2-(2-Methoxyethoxy)-5-phenyl-furo [2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine.
7. A process for preparing a compound according to claim 1 comprising:
(i) reacting a compound of formula II
with a suitable nucleophile X-L-Y, optionally in the presence of a solvent and a base, and optionally at elevated temperature or with microwave irradiation; or
(ii) reacting a compound of formula VI
by displacement of the 2-methanesulphonyl substituent with a suitable nucleophilic species; or
(iii) reacting a compound of formula X
by displacement of the 4-chloro substituent with a suitable nucleophilic species.
8. A pharmaceutical composition comprising at least one compound according to claim 1 and one or more excipients, diluents, carriers, and mixtures thereof.
9. A pharmaceutical composition comprising a compound according to claim 6 and one or more excipients, diluents, carriers, and or mixtures thereof.
10. A method of treating arrhythmia, comprising administering to a subject an effective amount of at least one compound according to claim 1 .
11. A method of treating arrhythmia, comprising administering to a subject an effective amount of at least one compound according to claim 6 .
12. A compound according to claim 2 , wherein Y is phenyl, furanyl, thienyl, or pyridyl.
13. A compound according to claim 3 , wherein Y is phenyl, furanyl, thienyl, or pyridyl.
14. A compound according to claim 2 , wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl.
15. A compound according to claim 2 , wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl and R 6 is H.
16. A compound according to claim 3 , wherein Y is optionally substituted phenyl, optionally substituted furan-2-yl, or optionally substituted pyridin-2-yl.
17. The process according to claim 7 , wherein the compound prepared is selected from the group consisting of
5-Phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
5-(4-Chlorophenyl-N-(pyridin-2-ylmethyl)furo[2,3 -d]pyrimidin-4-amine,
6-Methyl-5-phenyl-N-(pyridin-2-ylmethyl)furo[2,3-d]pyrimidin-4-amine,
(2-Morpholin-4-yl-5-phenyl-furo[2,3-d]pyrimidin-4-yl)-pyridin-2-ylmethyl-amine,
2-((2-Hydroxyethyl)-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl }-amino)-ethanol,
2-((2-Hydroxyethyl)-{5-(4-fluorphenyl)-4[(pyridin-2-ylmethyl)-amino]-furo[2,3-d]pyrimidin-2-yl}-amino)-ethanol,
N 2 -(2-Methoxyethyl)-5-phenyl-N 4 -pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
2-{5-Phenyl-4-[(pyridin-2-ylmethyl)-amino]furo[2,3-d]pyrimidin-2-ylamino}-propane-1,3-diol,
N 2 ,N 2 -Dimethyl-5-phenyl-N 4 -pyridin-2-ylmethyl-furo[2,3-d]pyrimidine-2,4-diamine,
N 2 ,N 2 -Dimethyl-N 4 -(6-methyl-pyridin-2-ylmethyl)-5-phenyl-furo[2,3-d]pyrimidine-2,4-diamine, and
[2-(2-Methoxyethoxy)-5-pheny-furo[2,3-d]pyrimidin-4-yl]-pyridin-2-ylmethylamine.
18. A compound according to claim 1 wherein R 1 is aryl, heteroaryl or cycloalkyl, each of which is unsubstituted.
19. A compound according to claim 1 wherein Y is heteroaryl, alkyl, alkenyl or cycloalkyl, each of which is unsubstituted.
20. A compound according to claim 1 wherein R 6 is H.