Quaternized amines as sodium channel blockers

摘要

The present disclosure provides substituted pyridine and pyrimidine compounds of Formula (I): A1-X-A2-Z-R1 (I) and the pharmaceutically acceptable salts, solvates and prodrugs thereof, wherein A, X, A, Z, and R are defined as set forth in the specification. The present disclosure is also directed to the use of compounds of Formula (I) to treat a disorder responsive to the blockade of sodium channels. Compounds of the present disclosure are especially useful for treating pain.

主权项

1. A compound having Formula I:
A1-X-A2-Z—R1  Ior a pharmaceutically acceptable salt, or solvate thereof, wherein:
A1-X-A2-is: R11, R11a, R12, R12a, are each independently, selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, halogen, haloalkyl, hydroxyalkyl, hydroxy, nitro, amino, cyano, amide, carboxyalkyl, alkoxyalkyl, ureido, alkylcarbonylamino, thiol, alkylcarbonyloxy, azido, mercaptoalkyl, alkoxy, carboxy, and carboxamido; Z is selected from the group consisting of: R2a, R2b, and R2c are each independently selected from the group consisting of hydrogen; alkyl; halo; nitro; cyano; hydroxy; amino; alkylamino; dialkylamino; haloalkyl; hydroxyalkyl; alkoxy; haloalkoxy; and alkoxyalkyl; R1 is selected from the group consisting of —C(O)R5; —SO2NR5; and —N(R6)(R7a)(R7b)+A−; R5 is selected from the group consisting of:wherein:
R6 is alkyl; R7a is selected from the group consisting of optionally substituted alkyl and hydroxyalkyl; R7b is selected from the group consisting of optionally substituted alkyl and hydroxyalkyl; or R7a and R7b taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered optionally substituted heterocyclo; R7c is selected from the group consisting of optionally substituted alkyl and hydroxyalkyl R8a is selected from the group consisting of hydrogen and optionally substituted alkyl; R8b is selected from the group consisting of hydrogen and optionally substituted alkyl; R9a, R9b, R9c, R9d, R9e, and R9f are each independently selected from the group consisting of hydrogen and optionally substituted alkyl; R10a and R10b are each independently selected from the group consisting of hydrogen and optionally substituted alkyl; L1 is —(CR10aR10b)r—Y—(CR10aR10b)s—; L2 is —(CR10aR10b)t—; L3 is —(CR10aR10b)u—; Y is absent; or Y is selected from the group consisting of optionally substituted cycloalkyl; optionally substituted aryl; and optionally substituted heteroaryl m, n, o, p, r, s, t, and u are each independently 0, 1, 2, or 3; q is 1, 2, or 3; and A is an anionic counter-ion, with the proviso that when Y is absent then the sum of r plus s is 2, 3, 4, 5, or 6.