Pyrimidine diol amides as sodium channel blockers
AssigneePurdue Pharma L.P.
InventorBin Shao
Life of this patent
Estimating the term…
Abstract
The present disclosure provides pyrimidine diol amides of Formula (I), and the pharmaceutically acceptable solvates and prodrugs thereof, wherein A1, X, A2, W1, W2, W3, R1, R2, and R4 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.
Claims20
A method of treating a disorder responsive to blockade of Nay 1.7 sodium channels in a mammal suffering from said disorder, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
- wherein
- W1 and W2 are N and W3 is CR3;
- or
- W1 and W3 are N and W2 is CR3;
- or
- W2 and W3 are N and W1 is CR3;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- cycloalkyl, aralkyl;
- (heterocyclo)alkyl;
- (heteroaryl)alkyl;
- (amino)alkyl;
- (alkylamino)alkyl;
- (dialkylamino)alkyl;
- carboxyalkyl;
- (alkoxycarbonyl)alkyl;
- (carboxamido)alkyl;
- (cyano)alkyl;
- alkoxyalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- and heteroalkyl;
- wherein the alkyl and the cycloalkyl group may optionally be substituted;
- R2 is selected from the group consisting of hydrogen and alkyl;
- or
- R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
- R3 is selected from the group consisting of hydrogen;
- halo;
- nitro;
- cyano;
- hydroxy;
- amino;
- alkylamino;
- dialkylamino;
- haloalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- alkoxy;
- haloalkoxy;
- and alkoxyalkyl;
- R4 is C2-6 dihydroxyalkyl;
- A1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
- X is selected from the group consisting of —O—;
- —S—;
- —SO—;
- —SO2—;
- —(CR5aR5b)m—;
- —NR6—;
- —SO2NR7—;
- and —NR7SO2—;
- each R5a and R5b, which can be identical or different, is selected from the group consisting of hydrogen;
- halo;
- and alkyl;
- m is 0, 1, 2, or 3;
- R6 is selected from the group consisting of hydrogen and alkyl;
- R7 is selected from the group consisting of hydrogen and alkyl;
- and
- A2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.
A method for treating pain anesthesia in the mammal, comprising administering to a mammal in need of such treatment an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
- wherein:
- W1 and W2 are N and W3 is CR3;
- or
- W1 and W3 are N and W2 is CR3;
- or
- W2 and W3 are N and W1 is CR3;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- cycloalkyl, aralkyl;
- (heterocyclo)alkyl;
- (heteroaryl)alkyl;
- (amino)alkyl;
- (alkylamino)alkyl;
- (dialkylamino)alkyl;
- carboxyalkyl;
- (alkoxycarbonyl)alkyl;
- (carboxamido)alkyl;
- (cyano)alkyl;
- alkoxyalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- and heteroalkyl;
- wherein the alkyl and the cycloalkyl group may optionally be substituted;
- R2 is selected from the group consisting of hydrogen and alkyl;
- or
- R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
- R3 is selected from the group consisting of hydrogen;
- halo;
- nitro;
- cyano;
- hydroxy;
- amino;
- alkylamino;
- dialkylamino;
- haloalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- alkoxy;
- haloalkoxy;
- and alkoxyalkyl;
- R4 is C2-6 dihydroxyalkyl:
- A1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
- X is selected from the group consisting of —O—;
- —S—;
- —SO—;
- —SO2—;
- —(CR5aR5b)m—;
- —NR6—;
- —SO2NR7—;
- and —NR7SO2;
- each R5a and R5b, which can be identical or different, is selected from the group consisting of hydrogen;
- halo;
- and alkyl;
- m is 0, 1, 2, or 3;
- R6 is selected from the group consisting of hydrogen and alkyl;
- R7 is selected from the group consisting of hydrogen and alkyl;
- and
- A2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.
A method of modulating sodium channels in a mammal, comprising administering to the mammal at least one compound of Formula I, or a pharmaceutically acceptable salt, solvate, or prodrug thereof:
- wherein
- W1 and W2 are N and W3 is CR3;
- or
- W1 and W3 are N and W2 is CR3;
- or
- W2 and W3 are N and W1 is CR3;
- R1 is selected from the group consisting of hydrogen;
- alkyl;
- cycloalkyl, aralkyl;
- (heterocyclo)alkyl;
- (heteroaryl)alkyl;
- (amino)alkyl;
- (alkylamino)alkyl;
- (dialkylamino)alkyl;
- carboxyalkyl;
- (alkoxycarbonyl)alkyl;
- (carboxamido)alkyl;
- (cyano)alkyl;
- alkoxyalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- and heteroalkyl;
- wherein the alkyl and the cycloalkyl group may optionally be substituted;
- R2 is selected from the group consisting of hydrogen and alkyl;
- or
- R1 and R2 taken together with the nitrogen atom to which they are attached form a 3- to 8-membered optionally substituted heterocyclo;
- R3 is selected from the group consisting of hydrogen;
- halo;
- nitro;
- cyano;
- hydroxy;
- amino;
- alkylamino;
- dialkylamino;
- haloalkyl;
- monohydroxyalkyl;
- dihydroxyalkyl;
- alkoxy;
- haloalkoxy;
- and alkoxyalkyl;
- R4 is C2-6 dihydroxyalkyl;
- A1 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl;
- X is selected from the group consisting of —S—;
- —S—;
- —SO—;
- —SO2—;
- —(CR5aR5b)m—;
- NR6—;
- and —SO2NR7—;
- and —NR7SO2;
- each R5a and R5b, which can be identical or different, is selected from the group consisting of hydrogen;
- halo;
- and alkyl;
- m is 0, 1, 2, or
- R6 is selected from the group consisting of hydrogen and alkyl;
- R7 is selected from the group consisting of hydrogen and alkyl;
- and
- A2 is selected from the group consisting of optionally substituted aryl and optionally substituted heteroaryl.
Dependencies are inferred from the claim text.