Substituted pyrimidines for treatment of a cough selected from chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough
Methods for treating cough, chronic cough and urges to cough associated with respiratory diseases with a P2X3 and/or a P2X2/3 receptor antagonist, the methods comprising administering to a subject in need thereof an effective amount of a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are as defined herein.
1. A method for treating a cough in a patient, wherein the cough is selected from the group consisting of chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough, the method comprising administering to the patient in need thereof an effective amount of a compound of Formula (I):
or a pharmaceutically acceptable salt thereof,
wherein:
R 1 is hydrogen or C 1 -C 6 alkyl, wherein C 1 -C 6 alkyl is optionally substituted with at least one substituent selected from the group consisting of cycloalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, monoalkylamino, dialkylamino, haloalkoxy, heteroalkyl, —COR, —(CR′R″) n —COOR and —(CR′R″) n —CONR a R b , wherein:
in COR, R is hydrogen, alkyl, phenyl or phenylalkyl;
in (CR′R″) n —COOR, R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl;
each n is independently 0, 1, 2, 3, 4 or 5;
each R′ is independently hydrogen or alkyl;
each R″ is independently hydrogen or alkyl;
R a is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl;
R b is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl; and
R 2 R is alkyl, alkenyl, alkynyl, amino, aminosulfonyl, halo, amido, haloalkyl, alkoxy, hydroxy, haloalkoxy, nitro, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkynylalkoxy, alkylsulfonyl, arylsulfonyl, carboxyalkyl, cyano or alkylcarbonyl.
2. The method of claim 1 , wherein the cough is chronic pathological cough.
3. The method of claim 1 , wherein the cough is neuronal hypersensitivity underlying acute cough.
4. The method of claim 1 , wherein the cough is selected from the group consisting of neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough.
5. The method of claim 1 , wherein about 50 mg of the compound of Formula (I) is administered multiple times daily.
6. The method of claim 1 , wherein about 100 mg of the compound of Formula (I) is administered multiple times daily.
7. The method of claim 1 , wherein about 100-900 mg of the compound of Formula (I) is administered multiple times daily.
8. The method of claim 1 , wherein the cough is reduced by about 75%.
9. The method of claim 1 , wherein R 1 is hydrogen or methyl.
10. The method of claim 1 , wherein R 2 is aminosulfonyl, haloalkyl, alkylsulfonyl, carboxyalkyl or alkylcarbonyl.
11. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
12. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
13. The method of claim 1 , wherein the compound is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
14. A method for treating a cough in a patient, wherein the cough is selected from the group consisting of chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough, the method comprising administering to the patient in need thereof an effective amount of a compound having the formula:
or a pharmaceutically acceptable salt thereof.
15. A method for treating a cough in a patient, wherein the cough is selected from the group consisting of chronic pathological cough, sub-acute pathological cough, acute pathological cough, neuronal hypersensitivity underlying chronic cough, neuronal hypersensitivity underlying sub-acute cough and neuronal hypersensitivity underlying acute cough, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutically acceptable salt of a compound having the formula: