Substituted pyrimidines for treatment of acute cough, chronic cough and urge to 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 chronic cough in a patient in need thereof, the method comprising administering to said patient 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 optionally substituted with cycloalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkoxy, heteroalkyl, —COR wherein R is hydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″) n —COOR wherein n is 0, 1, 2, 3, 4 or 5, R′ and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, or —(CR′R″) n —CONR a R b wherein n is 0, 1, 2, 3, 4 or 5, R′ and R″ are independently hydrogen or alkyl, and R a and R b are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl; and
R 2 is alkyl, alkenyl, alkynyl, amino, aminosulfonyl, halo, amido, alkoxy, hydroxy, haloalkoxy, nitro, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkynylalkoxy, alkylsulfonyl, arylsulfonyl, carboxyalkyl, cyano or alkylcarbonyl.
2. The method of claim 1 , wherein the chronic cough is idiopathic or treatment resistant cough.
3. The method of claim h wherein the compound of Formula (I) is administered at about 600 mg twice daily.
4. The method of claim 1 , wherein the compound of Formula (I) is administered for about 2 weeks.
5. The method of claim 1 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.
6. The method of claim 1 , wherein the chronic cough is refractory chronic cough.
7. The method of claim 1 , wherein the chronic cough is reduced by about 75%.
8. The method of claim 1 , wherein the chronic cough is daytime chronic cough.
9. The method of claim 1 , wherein R 1 is hydrogen or methyl.
10. The method of claim 1 , wherein R 2 is haloalkyl, aminosulfonyl, alkylsulfonyl, alkylcarbonyl or carboxyalkyl.
11. The method of claim 1 , wherein the compound is
12. A method for treating neuronal hypersensitivity underlying acute, sub-acute, or chronic cough in a patient in need thereof, the method comprising administering to said patient 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 optionally substituted with cycloalkyl, halo, nitro, cyano, hydroxy, alkoxy, amino, acylamino, mono-alkylamino, di-alkylamino, haloalkoxy, heteroalkyl, —COR wherein R is hydrogen, alkyl, phenyl or phenylalkyl, —(CR′R″) n —COOR wherein n is 0, 1, 2, 3, 4 or 5, R′ and R″ are independently hydrogen or alkyl, and R is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl, —(CR′R″) n —CONR a R b wherein n is 0, 1, 2, 3, 4 or 5, R′ and R″ are independently hydrogen or alkyl, and R a and R b are independently hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, phenyl or phenylalkyl; and
R 2 is alkyla alkenyl, alkynyl, amino, aminosulfonyl, halo, amido, haloalkyl, alkoxy, hydroxy, haloalkoxy, nitro, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkynylalkoxy, alkylsulfonyl, arylsulfonyl, carboxyalkyl, cyano or alkylcarbonyl.
13. The method of claim 12 , wherein the chronic cough is idiopathic or treatment resistant cough.
14. The method of claim 12 , wherein the compound of Formula (I) is administered at about 600 mg twice daily.
15. The method of claim 12 , wherein the compound of Formula (I) is administered for about 2 weeks.
16. The method of claim 12 , wherein the compound of Formula (I) is administered at about 600 mg twice daily for about two weeks.
17. The method of claim 12 , wherein the chronic cough is refractory chronic cough.
18. The method of claim 12 , wherein the chronic cough is reduced by about 75%.
19. The method of claim 12 , wherein the chronic cough is daytime chronic cough.
20. A method for treating chronic cough in a patient in need thereof, the method comprising administering to said patient an effective amount of a compound is selected from: