Benzimidazole derivatives and use thereof
The invention provides compounds that are useful as sodium channel blockers. In one aspect, the invention provides compounds of Formula I: and pharmaceutically acceptable salts, solvates, hydrates, or diastereomers thereof, wherein W 1 , W 2 , W 3 , W 4 , U, G, m, R 1 , and R 2 are defined in the disclosure. In certain embodiments, the invention provides compounds of Formulae II to V as set forth supra. The invention also provides the use of compounds of any of the above discussed formulae to treat a disorder responsive to blockade of sodium channels. In one embodiment, Compounds of the Invention are useful for treating pain.
1. The compound of Formula V, or a pharmaceutically acceptable salt, or diastereomer thereof:
Wherein
Y is —O—;
m is 0, 1, or 2;
M is halogen, haloalkyl, haloalkoxy, (alkyl)amino, amino, or (dialkyl)amino;
R 1 and R 2 , each independently, are H or (C 1-3 )alkyl;
R 3 is H, (C 1-3 )alkyl, (C 1-3 )alkoxy, amino, hydroxyl, or halogen;
G is
piperidinyl optionally substituted by one or more substituents independently selected from the group consisting of
a) —(C 0-3 )alkyl-C(O)N(R 7 ) 2 further optionally substituted by one or more substituents independently selected from the group consisting of (C 1-3 )alkyl, —(C 0-3 )alkyl-OH, —(C 1-3 )alkoxy, —(C 0-3 ) alkyl-C(O)OH, —(C 0-3 )alkyl-S(O) 2 NH 2 , and —(C 0-3 )alkyl-C(O)NH 2 ;
b) (C 1-3 )alkyl optionally substituted by one or more substituents independently selected from the group consisting of (C 1-3 )alkyl, hydroxyl, —NH 2 , —(C 0-3 )alkyl-OH, halogen, —(C 0-3 )alkyl-C(O)OH, and —(C 0-3 )alkyl-C(O)N(R 7 ) 2 ;
c) (C 1-3 )alkoxy optionally substituted by one or more same or different halogens;
d) halogen;
e) —S(O) 2 (C 1-3 )alkyl;
f) —C(O)O(C 1-3 )alkyl; and
g) —C(O)(C 1-3 )alkyl;
and, R 7 independently is H or (C 1-3 )alkyl.
2. The compound of claim 1 , wherein M is halogen or haloalkyl.
3. The compound of claim 1 , wherein one of R 1 and R 2 is H, and the other is (C 1-3 )alkyl.
4. The compound of claim 1 , wherein G is piperidinyl that is
wherein R 9 is H, —(C 1-3 )alkyl-C(O)NH 2 , —C( 1-3 )alkyl-C(O)N((C 1-3 )alkyl) 2 , C(O)NH 2 , —C(O)(C 1-3 )alkyl, C(O)O(C1-3)alkyl, —S(O) 2 (C 1-3 )alkyl, (C 1-3 )alkyl, or halogen.
5. The compound of claim 1 , wherein said compound is selected from the group consisting of:
1-(4-(4-Fluorophenoxy)phenyl)-2-(2-(piperidin-1-yl)ethyl)-1H-benzo[d]imidazole (Compound 17);
tert-Butyl 4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidine-1-carboxylate (Compound 19);
1-(4-(4-Fluorophenoxy)phenyl)-2-(piperidin-4-yl)-1H-benzo[d]imidazole (Compound 20);
2-(4-(1-(4-(4-Fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide (Compound 23); and
N,N-diethyl-2-(4-(1-(4-(4-fluorophenoxy)phenyl)-1H-benzo[d]imidazol-2-yl)piperidin-1-yl)acetamide (Compound 24);
and pharmaceutically acceptable salts, solvates, hydrates, and diastereomers thereof.
6. A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier or diluent.
7. A method for treating pain in a mammal identified as in need thereof, comprising administering to said mammal an effective amount of a compound of claim 1 .
8. A method of modulating Nav1.7 sodium channel in a mammal, comprising administering to the mammal at least one compound of claim 1 .
9. The compound of claim 4 , wherein G is
10. The compound of claim 4 , wherein
G is
and
R 9 is H, —C( 1-3 )alkyl-C(O)NH 2 , —C( 1-3 )alkyl-C(O)N((C 1-3 )alkyl) 2 , or C(O)O(C1-3)alkyl.