Substituted arylamino-1,2,3,4-tetrahydro naphthalenes and -2,3-dihydro-
View Patent ↗This invention provides compounds of formula I where Ar 1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally substituted; where the —NR 3 R 4 group is situated ortho to the NHC(═X) group; n=1 or 2; X=O or S; Y is O or S; and q=1 or 0. The invention also provides pharmaceutical compositions comprising compounds of formula I and/or salts, esters, and prodrugs thereof. These compounds modulate the activation and inactivation of potassium channels. The compounds are useful for the treatment and prevention of diseases and disorders—such as seizure disorders—which are affected by modulation of potassium ion channels.
1. A method of treating seizure disorders which are affected by modulation of potassium channels, comprising administering to a patient a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of formula I or a salt or ester thereof:
where Ar 1 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 heteroatoms selected independently from N, O, and S; R 1 and R 2 are selected, independently, from H, CN, halogen, CH 2 CN, OH, NO 2 , CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , C 1 -C 6 alkyl, OR 8 , C(═O)R 9 , C(═O)OR 10 , OC(═O)R 11 , SR 12 , NR 13 C(═O)R 14 , C(═O)NR 15 R 16 , CH 2 C(═O)NR 15 R 16 , NR 17 R 18 , SO 2 R 19 , N(R 20 )SO 2 R 21 , SO 2 NR 22 R 23 , C 3 -C 6 cycloalkyl, C 5 -C 6 cycloalkenyl, C 2 -C 6 alkenyl, or C 2 -C 6 alkynyl; where the —NR 3 R 4 group is situated ortho to the NHC(═X) group and R 3 and R 4 are, independently, H or C 1-6 alkyl, which C 1-6 alkyl group optionally substituted with 1 or 2 groups selected, independently, from methyl, halogen, methoxy, and hydroxy, or R 3 and R 4 together form a 5- or 6-membered ring, optionally substituted with halogen, methyl, methoxy, or hydroxy and optionally containing one or two double bonds; n=1 or 2; X=O or S; Y is O or S; q=1 or 0; 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, (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 2 , (CHR 6 ) w Ar 2 , CH 2 (CHR 6 ) w Ar 2 , or (CHR 6 ) w CH 2 Ar 2 , where w=0-3, Ar 2 is a 5- to 10-member mono- or bicyclic aromatic group, optionally containing 1-4 ring heteroatoms selected independently from N, O, and S; R 6 is C 1 -C 3 alkyl; and R 8 -R 23 are, independently, H, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, (CHR 6 ) w C 3 -C 6 cycloalkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, where all said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, groups are optionally substituted with one or two substituents selected independently from C 1 -C 3 alkyl, halogen, OH, OMe, CN, CH 2 F, and trifluoromethyl; where, additionally, said alkenyl and alkynyl groups are optionally substituted with phenyl or C 3 -C 6 cycloalkyl; and where all said cycloalkyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S.
2. The method of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═O)R 5 or NHC(═O)OR 5 .
3. The method of claim 2 , where Ar 1 is
4. The method of claim 3 , where R 1 is F, CH 2 F, CHF 2 , or CF 3 .
5. The method of claim 4 , where n is 1 and R 1 is para.
6. The method of claim 4 , where R 2 is H, C 1 -C 3 alkyl, or halogen.
7. The method of claim 4 , where n is 1 and R 1 is meta.
8. The method of claim 7 , where R 2 is H, C 1 -C 3 alkyl, or halogen.
9. The method of claim 1 , where the compound of formula I is a compound of formula IA
where Q=CR 7 or N, where R 7 is H or C 1 -C 6 alkyl.
10. The method of claim 9 , where the compound of formula IA is a compound of formula IA-1 or a compound of formula IA-2
11. The method of claim 9 , where the compound of formula IA is a compound of formula IA-3 or a compound of formula IA-4
12. The method of claim 10 , where Q is N; R 2 , R 3 , and R 4 are, independently, H or CH 3 ; and R 5 is C 1 -C 6 alkyl or (CHR 6 ) w C 3 -C 6 cycloalkyl, where R 6 is H or CH 3 and w is 1 or 2.
13. The method of claim 10 , where Q is CH; R 2 , R 3 , and R 4 are, independently, H, CH 3 or CH 2 CH 3 ; and R 5 is C 1 -C 6 alkyl or (CHR 6 ) w C 3 -C 6 cycloalkyl, where R 6 is H or CH 3 and w is 1 or 2.
14. The method of claim 11 , where Q is N, R 2 and R 3 are H, R 4 is H or CH 3 , and R 5 is C 1 -C 6 alkyl or (CHR 6 ) w C 3 -C 6 cycloalkyl, where R 6 is H or CH 3 and w is 1 or 2.
15. The method of claim 11 , where Q is CH, R 2 and R 3 are H, R 4 is H or CH 3 , and R 5 is C 1 -C 6 alkyl, or (CHR 6 ) w C 3 -C 6 cycloalkyl, where R 6 is H or CH 3 and w is 1 or 2.
16. The method of claim 12 , where R 1 is meta or para to NH and is halogen or methyl or ethyl, said methyl or ethyl optionally substituted with 1-3 fluorine atoms.
17. The method of claim 13 , where R 1 is meta or para to NH and is halogen or methyl or ethyl, said methyl or ethyl optionally substituted with 1-3 fluorine atoms.
18. The method of claim 14 , where R 1 is meta or para to NH and is halogen or methyl or ethyl, said methyl or ethyl optionally substituted with 1-3 fluorine atoms.
19. The method of claim 15 , where R 1 is meta or para to NH and is halogen or methyl or ethyl, said methyl or ethyl optionally substituted with 1-3 fluorine atoms.
20. The method of claim 1 , wherein the compound is one of the following: