1,4 diamino bicyclic retigabine analogues as potassium channel modulators
View Patent ↗This invention is directed to compounds of formula I, where G is —O—, —S—, —C(g 1 )(g 2 )-, or —NH—, and n=1, 2, or 3. Such compounds modulate potassium channels. The compounds are useful for the treatment and prevention of diseases and disorders which are affected by modulation of potassium ion channels. One such condition is seizure disorders.
1. A compound of formula I,
wherein G is —O—, —S—, —C(g 1 )(g 2 )-, or —NH—, where g 1 and g 2 are, independently, H, phenyl, halogen, methoxy, halomethyl, methoxymethyl, or C 1 -C 3 alkyl; n=1, 2, or 3;
each Ar 1 is independently 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 , NR 13 C(═NH)R 14 , C(═O)NR 15 R 16 , CH 2 C(═O)NR 15 R 16 , CH 3 NHC(═NH)—, CH 3 C(═NH)NH—, CH 2 C(═NH)NH 2 , NR 17 R 18 , SO 2 R 19 , N(R 20 ) SO 2 R 2 l, 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; U is N or CR′;
R′, R 3 , and R 4 are, independently, H, halogen, trifluoromethyl, C 1-6 alkyl, which C 1-6 alkyl group optionally substituted with 1 or 2 groups selected, independently, from OH, halogen, C 1 -C 3 alkyl, OC 1 -C 3 alkyl, or trifluoromethyl;
X═O or S; Y is O or S; Z is H, halogen, OH, CN, CH 2 CN, C 1 -C 6 alkyl, C 3 -C 6 cycloalkyl, O—C 1 -C 6 alkyl, (CH 2 ), C 3 -C 6 cycloalkyl, O—C 3 -C 6 cycloalkyl, 0-(CH 2 )wC3-C6 cycloalkyl, q=1 or 0;
R 5 is C 1 -C 6 alkyl, (CHR 6 ), C 3 -C 6 cycloalkyl, (CHR 6 ) w CH 2 C 3 -C 6 CH 2 (CHR 6 ) w C 3 -C 6 cycloalkyl, (CHR 6 ) w C 5 -C 6 cycloalkenyl, CH 2 (CHR 6 ), 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,
each Ar 2 is independently 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 H or 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 alkenyl, C 2 -C 6 alkynyl, where all 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, the alkenyl and alkynyl groups are optionally substituted with phenyl or C 3 -C 6 cycloalkyl; and where all cycloalkyl groups optionally contain one or two ring heteroatoms selected independently from N, O, and S;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═O)R 5 .
3. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═O)OR 5 .
4. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═S)SR 5 .
5. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═S)R 5 .
6. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═S)OR 5 .
7. The compound of claim 1 , where NH—C(═X)—(Y) q —R 5 is NHC(═O)SR 5 .
8. A compound of formula I-N,
where all variables are as defined in claim 1 .
9. A compound of formula I-O,
where all variables are as defined in claim 1 .
10. A compound of formula I-S,
where all variables are as defined in claim 1 .
11. A compound of formula I-Cgg,
where all variables are as defined in claim 1 .
12. The compound of claim 1 which is a compound of formula IA
wherein Q=CR 7 or N, where R 7 is H or C 1 -C 6 alkyl and all other variables are as defined in claim 1 .
13. The compound of claim 12 which is a compound of formula I-N-A,
14. The compound of any of claims 1 - 13 , where Ar 1 is phenyl or pyridyl, and n is 1.
15. The compound of any of claims 1 - 13 , where Ar 1 is phenyl or pyridyl, and n is 2.
16. The compound of any of claims 1 - 13 , where Ar 1 is phenyl or pyridyl, and n is 3.
17. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Ar 1 is phenyl; and n is 1.
18. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Ar 1 is phenyl; and n is 2.
19. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Ar 1 is phenyl; and n is 3.
20. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Z is H, halogen, or methyl; R 3 is H, CH 3 , Cl, or F; Ar 1 is phenyl; and n is 1.
21. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Z is H, halogen, or methyl; R 3 is H, CH 3 , Cl, or F; Ar 1 is phenyl; and n is 2.
22. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Z is H, halogen, or methyl; R 3 is H, CH 3 , Cl, or F; Ar 1 is phenyl; and n is 3.
23. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; and n is 1.
24. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Z is H, halogen, or methyl; R 3 is H, CH 3 , Cl, or F; Ar 1 is phenyl; X is O; and n is 2.
25. The compound of any of claims 1 - 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; Z is H, halogen, or methyl; R 3 is H, CH 3 , Cl, or F; Ar 1 is phenyl; X is O; and n is 3.
26. The compound of any of claims 1 - 11 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ) w C 3 -C 6 cycloalkyl; and n is 1.
27. The compound of any of claims 1 - 11 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ), C 3 -C 6 cycloalkyl; and n is 2.
28. The compound of any of claims 1 - 11 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ) w C 3 -C 6 cycloalkyl; and n is 3.
29. The compound of claim 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ), C 3 -C 6 cycloalkyl; and n is 1.
30. The compound of claim 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; Ar 1 is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ), C 3 -C 6 cycloalkyl; and n is 2.
31. The compound of claim 13 , where R 1 is H, CH 3 , CF 3 , Cl, or F; R 2 is H, F, or Cl; Z is H; R 3 is H, CH 3 , Cl, or F; R 4 is H or CH 3 ; MI is phenyl; X is O; U is CH; q is zero; R 5 is C 5 -C 6 alkyl or (CHR 6 ) w C 3 -C o cycloalkyl; and n is 3.
32. A composition comprising a pharmaceutically acceptable carrier and one or more of the following:
i. a compound of formula I according to claim 1 ;
ii. a pharmaceutically acceptable salt of said compound of formula I; or
iii. a pharmaceutically acceptable ester of said compound of formula I.
33. The composition of claim 32 , wherein the compound of formula I is a compound of formula I-N, I-O, I-S or I-Cgg:
wherein all variable are as described in claim 1 .
34. A compound selected from one of the following:
i) N-(5-(4-fluorophenylamino)-1,3-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
ii) N-(1,3-dimethyl-5-(4-(trifluoromethyl)phenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
iii) N-(1,3-dimethyl-5-(3,4-dichlorophenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
iv) N-(1,3-dimethyl-5-(4-chlorophenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
v) N-(1,3-dimethyl-5-(4-bromophenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
vi) N-(1,3-dimethyl-5-(3-chlorophenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
vii) N-(1,3-dimethyl-5-(3,5-difluorophenylamino)-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
viii) N-(1-(4-fluorophenylamino)-4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
ix) N-(4,6-dimethyl-1-(4-(trifluoromethyl)phenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
x) N-(4,6-dimethyl-1-(4-chlorophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xi) N-(4,6-dimethyl-1-(4-bromophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xii) N-(4,6-dimethyl-1-(3-chlorophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xiii) N-(4,6-dimethyl-1-(3,4-dichlorophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xxiv) N-(4,6-dimethyl-1-(3,4-difluorophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xxv) N-(4,6-dimethyl-1-(3,5-difluorophenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xxvi) N-(1-(6-fluoropyridin-3-ylamino)-4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xxvii) N-(1-(6-trifluoromethylpyridin-3-ylamino)-4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
xxviii) Ethyl 1-(4-fluorophenylamino)-2,3-dihydro-1H-inden-5-yl-carbamate, or
xxiv) N-[4-bromo-1,3-dimethyl-5-(4-trifluoromethyl-phenylamino)-5,6,7,8-tetrahydro-naphthalen-2-yl]-3,3-dimethyl-butyramide.
35. A compound selected from one of the following:
i) (−)N-(5-(4-fluorophenylamino)-1,3-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
ii) (+)N-(5-(4-fluorophenylamino)-1,3-dimethyl-5,6,7,8-tetrahydronaphthalen-2-yl)-3,3-dimethylbutanamide;
iii) (−)N-(1-(4-fluorophenylamino)-4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
iv) (+)N-(1-(4-fluorophenylamino)-4,6-dimethyl-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide;
v) (−)N-(4,6-dimethyl-1-(4-(trifluoromethyl)phenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide, or
vi) (+)N-(4,6-dimethyl-1-(4-(trifluoromethyl)phenylamino)-2,3-dihydro-1H-inden-5-yl)-3,3-dimethylbutanamide.
36. A composition comprising a pharmaceutically acceptable carrier or diluent, a syrup for pediatric use, and at least one of the following: a pharmaceutically effective amount of a compound of formula I according to claim 1 , and a pharmaceutically acceptable salt of said compound of formula I.
37. A tablet comprising a pharmaceutically acceptable carrier or diluent, and at least one of the following: a pharmaceutically effective amount of a compound of formula I according to claim 1 , and a pharmaceutically acceptable salt of said compound of formula I.
38. The tablet of claim 37 , where the tablet is chewable.