Amide compounds as ion channel ligands and uses thereof
Compounds are disclosed that have a formula represented by the following: The compounds may be prepared as pharmaceutical compositions, and may be used for the prevention and treatment of a variety of conditions in mammals including humans, including by way of non-limiting example, pain, inflammation, traumatic injury, and others.
1. A compound of the formula I′:
or a pharmaceutically acceptable salt, or stereoisomers, or tautomers thereof, wherein:
each of W, X, Y and Z is independently CR 4 ;
R 1′ is aryl, substituted aryl, heteroaryl, substituted heteroaryl aralkyl, heteroaralkyl, amino or substituted amino;
each R 4 is independently hydrogen, substituted or unsubstituted alkyl, hydroxyalkyl, haloalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkoxy, aryloxy, heteroaryloxy, aminoalkoxy, alkoxy, cycloalkylalkoxy, alkoxycarbonyl, arylalkyloxy, aryl, heteroaryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, carboxy, carbamoyl, cyano, cycloheteroalkyl, halo, heteroalkyl, hydroxyl, or thiol; and
the subscript n and the subscript m are independently 0, 1, 2, 3, or 4.
2. A compound according to claim 1 , wherein the compound is of the formula II′:
wherein W, X, Y, Z, R 1′ and R 4 are as in claim 1 ; A is halo, alkyl, substituted alkyl, alkoxy, amino, substituted amino or SO 2 R 1″ ; R 1″ is aryl, heteroaryl, aralkyl, heteroaralkyl, amino or substituted amino; and the subscript n is 0, 1, 2, or 3.
3. A compound according to claim 2 , wherein each W, X, Y and Z is CH.
4. A compound according to claim 2 , wherein each R 4 is H.
5. A compound according to claim 1 , wherein the compound is of the formula III′:
wherein A is halo, alkyl, substituted alkyl, alkoxy, amino, substituted amino or SO 2 R 1″ , R 1″ is alkyl, aryl, heteroaryl, aralkyl, heteroaralkyl, amino or substituted amino; and the subscript n is 0, 1, 2, or 3; R 1′ and R 4 are as in claim 1 ; and the subscript x is 0, 1, 2, 3, or 4.
6. A compound according to claim 5 , wherein A is F, Cl, CF 3 , OMe, NMe 2 or SO 2 Me.
7. A compound according to any one of claims 2 - 6 , wherein R 1′ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
8. A compound according to any one of claims 2 - 6 , wherein R 1′ is phenyl or substituted phenyl.
9. A compound according to any one of claims 2 - 6 , wherein R 1′ is amino or substituted amino.
10. A compound according to any one of claims 2 - 6 , wherein R 1′ is NR 2′ R 2′ ; wherein each R 2′ is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
11. A compound according to any one of claims 2 - 6 , wherein R 1′ is NR 2′ R 2′ ; and the R 2′ s are independently alkyl.
12. A compound according to any one of claims 2 - 6 , wherein R 1′ is NR 2′ R 2′ ; and the R 2′ s are joined together to form a cycloheteroalkyl ring of 5-7 atoms.
13. A compound according to claim 1 , wherein the compound is of the formula IV′:
and wherein R 1′ is aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
14. A compound according to claim 13 , wherein R 1′ is substituted or unsubstituted phenyl or pyridyl.
15. A compound according to claim 13 , wherein R 1′ is 4-methylphenyl, 4-fluorophenyl, 4-chlorophenyl or 4-trifluoromethylphenyl.
16. A compound according to claim 13 , wherein R 1′ is benzyl.
17. A compound according to claim 2 , wherein the compound is of the formula V′:
wherein each R 2′ is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
18. A compound according to claim 1 , wherein the compound is of the formula VI′:
wherein each R 2′ is independently hydrogen, alkyl, substituted alkyl, cycloalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl.
19. A compound according to claim 18 , wherein each R 2′ is H.
20. A compound according to claim 18 , wherein each R 2′ is independently alkyl.
21. A compound according to claim 18 , wherein each R 2′ is independently H, Me, or Et.
22. A compound of the formula VII′:
or a pharmaceutically acceptable salt, or stereoisomers, or tautomers thereof, wherein:
each of W, X, Y and Z is independently CR 4 ;
ring P is cycloheteroalkyl, substituted cycloheteroalkyl, heteroaryl, or substituted heteroaryl; each R 4 is independently hydrogen, substituted or unsubstituted alkyl, hydroxyalkyl, haloalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkoxy, aryloxy, heteroaryloxy, aminoalkoxy, alkoxy, cycloalkylalkoxy, alkoxycarbonyl, arylalkyloxy, aryl, heteroaryl, arylalkyl, sulfo, sulfonyl, sulfanyl, aminosulfonyl, arylsulfonyl, carboxy, carbamoyl, cyano, cycloheteroalkyl, halo, heteroalkyl, hydroxyl, or thiol; and
the subscript n and the subscript m are each independently 0, 1, 2, 3, or 4.
23. A compound according to claim 22 , wherein the compound is of the formula VII′:
wherein A is F, Cl, CF 3 or SO 2 Me.
24. A compound according to either of claim 22 or 23 , wherein the ring P is selected from substituted or unsubstituted
and wherein R 2″ is selected from H and alkyl.
25. A compound according to claim 1 selected from the group consisting of:
or a pharmaceutically acceptable salt, or stereoisomers, or tautomers thereof.
26. A compound selected from the group consisting of:
STRUCTURE
NAME
4-(3-Chloro-pyridin-2-yl)-N-[4-(morpholine-4- sulfonyl)-phenyl]-benzamide;
4-(3-Fluoro-pyridin-2-yl)-N-[4-(morpholine-4- sulfonyl)-phenyl]-benzamide;
4-(3-Fluoro-pyridin-2-yl)-N-(4-sulfamoyl-phenyl)- benzamide;
4-(3-Methanesulfonyl-pyridin-2-yl)-N-(4-sulfamoyl- phenyl)-benzamide;
4-(3-Chloro-pyridin-2-yl)-N-[4-(4-methyl-piperazine- 1-sulfonyl)-phenyl]-benzamide;
4-(3-Chloro-pyridin-2-yl)-N-[4-(4-propyl-piperazine-1- sulfonyl)-phenyl]-benzamide;
4-(3-Chloro-pyridin-2-yl)-N-[4-(4-isopropyl- piperazine-1-sulfonyl)-phenyl]-benzamide; and
N-[4-(4-Isopropyl-piperazine-1-sulfonyl)-phenyl]-4- pyridin-2-yl-benzamide;
27. A pharmaceutical composition comprising a pharmaceutically acceptable carrier and a pharmaceutically effective amount of a compound of any one of claims 1 , 22 , and 26 .
28. The pharmaceutical composition of claim 27 , wherein the carrier is a parenteral carrier.
29. The pharmaceutical composition of claim 27 , wherein the carrier is an oral carrier.
30. The pharmaceutical composition of claim 27 , wherein the carrier is a topical carrier.