Naphthyridine derivatives as potassium channel modulators
View Patent ↗This invention provided compounds of formula I where W and Z are, independently, CH or N, and where other substituents are defined herein. Such compounds are potassium channel modulators. The invention also provides a composition comprising a pharmaceutically acceptable carrier or excipient and at least one of the following: a pharmaceutically effective amount of a compound of formula I; a pharmaceutically acceptable salt of a compound of formula I; a pharmaceutically acceptable ester of a compound of formula I. The invention also provides a method of preventing or treating a disease or disorder which is affected by activities of potassium channels, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of formula I or a salt or ester or solvate thereof.
1. A compound of formula IB
where W and Z are, independently, CH or N;
where R 1 and R 2 , are, independently, H, halogen, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl, CH 2 C(═O)C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, NHC(═O)C 1 -C 6 alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6 alkyl, C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CH 2 ) m Ar 1 , phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, furyl, thienyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;
or R 1 and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF 3 , or C 1 -C 3 alkyl;
R′ is H, halogen, CF 3 , or C 1 -C 3 alkyl;
R 3 and R 4 are, independently, H, NH 2 , (C 1 -C 3 alkyl)NH, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl, all said C 1 -C 3 alkyl groups and said C 1 -C 6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C 1 -C 3 alkyl, OC 1 -C 3 alkyl, and trifluoromethyl;
R 5 is C 1 -C 6 alkyl, (CHR 6 ), C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C 1 -C 6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl and trifluoromethyl; R 6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof.
2. A compound of formula IA
where W and Z are CH, R′ is halogen, C 1 -C 3 alkyl, or H,
R 1 and R 2 , are, independently, H, halogen, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl, CH 2 C(═O)C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, NHC(═O)C 1 -C 6 alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6 alkyl, C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CH 2 ) m Ar 1 , phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, furyl, thienyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;
or R 1 and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF 3 , or C 1 -C 3 alkyl;
R 3 and R 4 are, independently, H, NH 2 , (C 1 -C 3 alkyl)NH, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl, all said C 1 -C 3 alkyl groups and said C 1 -C 6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C 1 -C 3 alkyl, OC 1 -C 3 alkyl, and trifluoromethyl;
R 5 is C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C 1 -C 6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl; R 6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof.
3. The compound of claim 1 , where W and Z are CH and R′ is halogen, C 1 -C 3 alkyl, or H.
4. A compound of formula IA
where W and Z are both N, R′ is halogen, C 1 -C 3 alkyl, or H,
R 1 and R 2 , are, independently, H, halogen, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, C(═O)C 1 -C 6 alkyl, CH 2 C(═O)C 1 -C 6 alkyl, NH—C 1 -C 6 alkyl, NHC(═O)C 1 -C 6 alkyl, C(═O)N(CH 3 ) 2 , C(═O)N(Et) 2 , C(═O)NH—C 1 -C 6 alkyl, C(═O)OC 1 -C 6 alkyl, OC(═O)C 1 -C 6 alkyl, OC 1 -C 6 alkyl, SC 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (CH 2 ) m C 3 -C 6 cycloalkyl, C 3 -C 6 cycloalkenyl, (CH 2 ) m C 3 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CH 2 ) m Ar 1 , phenyl, pyridyl, pyrrolyl, (CH 2 ) m imidazolyl, (CH 2 ) m pyrazyl, furyl, thienyl, (CH 2 ) m oxazolyl, (CH 2 ) m isoxazolyl, (CH 2 ) m thiazolyl, (CH 2 ) m isothiazolyl, (CH 2 ) m phenyl, (CH 2 ) m pyrrolyl, (CH 2 ) m pyridyl, or (CH 2 ) m pyrimidyl, which cycloalkyl and said cycloalkenyl groups optionally contain one or two heteroatoms selected independently from O, N, and S, and which alkyl, cycloalkyl, cycloalkenyl, alkenyl, alkynyl, imidazolyl, pyrazyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, phenyl, pyrrolyl, pyridyl, or pyrimidyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methyl, ethyl, and trifluoromethyl, where m is zero, 1, or 2;
or R 1 and R 2 , together with the ring carbon atoms to which they are attached, form a 5- or 6-member fused ring, which ring may be saturated, unsaturated, or aromatic, which optionally contains one or two heteroatoms selected independently from O, N, and S, and which is optionally substituted with halogen, CF 3 , or C 1 -C 3 alkyl;
R 3 and R 4 are, independently, H, NH 2 , (C 1 -C 3 alkyl)NH, CN, halogen, CF 3 , OCF 3 , OC 1 -C 3 alkyl, or C 1 -C 3 alkyl, all said C 1 -C 3 alkyl groups and said C 1 -C 6 alkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, C 1 -C 3 alkyl, OC 1 -C 3 alkyl, and trifluoromethyl;
R 5 is C 1 -C 6 alkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, CR 6 ═CH—C 3 -C 6 cycloalkyl, CH═CR 6 —C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ) w C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ar 1 , (CHR 6 ) w Ar 1 , CH 2 (CHR 6 ) w Ar 1 , or (CHR 6 ) w CH 2 Ar 1 , where w=0-3, Ar 1 is phenyl, pyridyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, or imidazolyl, wherein said C 1 -C 6 alkyl group is optionally substituted with hydroxy, methoxy, methylthio, or halogen, and where said cycloalkyl and cycloalkenyl groups are optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl; R 6 is hydrogen, methyl, halogen, or methoxy; or a pharmaceutically acceptable salt thereof.
5. The compound of claim 1 , where W and Z are both N, and R′ is halogen, C 1 -C 3 alkyl, or H.
6. The compound of claim 1 , where W is N, Z is CH, and R′ is halogen, C 1 -C 3 alkyl, or H.
7. The compound of claim 2 , where R 3 and R 4 are, independently, methyl, amino, aminomethyl, methoxy, trifluoromethyl, or chloro.
8. The compound of claim 3 , where R 3 and R 4 are, independently, methyl, amino, aminomethyl, methoxy, trifluoromethyl, or chloro.
9. The compound of claim 7 , where R 3 and R 4 are, independently chloro, trifluoromethyl, methoxy, or methyl, R 5 is C 5 -C 6 alkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, said C 5 -C 6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl.
10. The compound of claim 8 , where R 3 and R 4 are, independently chloro, trifluoromethyl, methoxy, or methyl, and R 5 is C 5 -C 6 alkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, said C 5 -C 6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl.
11. The compound of claim 9 , where R 3 and R 4 are, independently chloro, trifluoromethyl, or methyl, and R 5 is C 5 -C 6 alkyl, (CHR 6 ) w CH 2 C 3 -C 6 cycloalkyl, or CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, said C 5 -C 6 alkyl group optionally substituted with methoxy or halogen, and said cycloalkyl groups optionally substituted with one or two groups selected, independently, from OH, halogen, cyano, methoxy, methyl, ethyl, and trifluoromethyl.
12. The compound of claim 10 , where R 1 is H, halogen, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, or C(═O)C 1 -C 6 alkyl.
13. The compound of claim 11 , where R 1 is H, halogen, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, or C(═O)C 1 -C 6 alkyl.
14. The compound of claim 12 , where R 5 is C 5 -C 6 alkyl or CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, where w=1 and R 6 is H, methyl, or methoxy.
15. The compound of claim 13 , where R 5 is C 5 -C 6 alkyl or CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, where w=1 and R 6 is H, methyl, or methoxy.
16. The compound of claim 14 , where R 3 and R 4 are both methyl, and R 5 is neopentyl or 2-cyclohexyl ethyl.
17. The compound of claim 15 , where R 3 and R 4 are both methyl, and R 5 is neopentyl or 2-cyclohexyl ethyl.
18. The compound of claim 16 , where R 1 is F or CF 3 , and R 2 is H or F.
19. The compound of claim 17 , where R 1 is F or CF 3 , and R 2 is H or F.
20. The compound of claim 2 selected from the group consisting of:
21. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 1 ; and ii) a pharmaceutically acceptable salt of the compound of claim 1 .
22. The composition of claim 21 , in which the pharmaceutically acceptable carrier is microcrystalline cellulose.
23. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 1 or a salt thereof.
24. The tablet of claim 23 , further comprising a lubricant.
25. The tablet of claim 23 , further comprising a disintegrant.
26. The tablet of claim 23 , wherein the tablet is chewable.
27. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 1 or a salt thereof.
28. The compound of claim 4 , wherein the compound is:
29. A compound selected from the group consisting of:
30. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 2 ; and ii) a pharmaceutically acceptable salt of the compound of claim 2 .
31. The composition of claim 30 , in which the pharmaceutically acceptable carrier is microcrystalline cellulose.
32. A composition comprising a pharmaceutically acceptable carrier and at least one of the following: i) a pharmaceutically effective amount of the compound of claim 4 ; and ii) a pharmaceutically acceptable salt of the compound of claim 4 .
33. The composition of claim 32 , in which the pharmaceutically acceptable carrier is microcrystalline cellulose.
34. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 2 or a salt thereof.
35. The tablet of claim 34 , further comprising a lubricant.
36. The tablet of claim 34 , further comprising a disintegrant.
37. The tablet of claim 34 , wherein the tablet is chewable.
38. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 2 or a salt thereof.
39. A tablet for oral dosing comprising a pharmaceutically acceptable carrier and from approximately 100 to approximately 700 mg of the compound of claim 4 or a salt thereof.
40. The tablet of claim 39 , further comprising a lubricant.
41. The tablet of claim 39 , further comprising a disintegrant.
42. The tablet of claim 39 , wherein the tablet is chewable.
43. A pharmaceutical syrup for pediatric use, comprising from approximately 100 to approximately 700 mg per dose of the compound of claim 4 or a salt thereof.