Substituted pyrimidines for treatment of chronic 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 chronic cough in a patient, 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; and
R 2 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 chronic cough is idiopathic chronic cough or treatment resistant chronic cough.
3. The method of claim 1 , wherein the chronic cough is daytime chronic cough.
4. The method of claim 1 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered for about two weeks.
5. The method of claim 1 , wherein R 1 is hydrogen or methyl; and R 2 is alkyl, aminosulfonyl or alkylsulfonyl.
6. The method of claim 1 , wherein R 2 is aminosulfonyl or alkylsulfonyl.
7. The method of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
or a pharmaceutically acceptable salt thereof.
8. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the compound is:
or a pharmaceutically acceptable salt thereof.
10. A method for treating neuronal hypersensitivity underlying acute cough, neuronal hypersensitivity underlying sub-acute cough, or neuronal hypersensitivity underlying chronic cough in a patient, 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; and
R 2 is alkyl, alkenyl, amino, aminosulfonyl, halo, amido, haloalkyl, alkoxy, hydroxy, haloalkoxy, nitro, hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy, alkynylalkoxy, alkylsulfonyl, arylsulfonyl, carboxyalkyl, cyano or alkylcarbonyl.
11. The method of claim 10 , wherein the chronic cough is idiopathic chronic cough or treatment resistant chronic cough.
12. The method of claim 10 , wherein the chronic cough is daytime chronic cough.
13. The method of claim 10 , wherein the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is administered for about two weeks.
14. The method of claim 10 , wherein the compound is:
15. A method for treating chronic cough in a patient, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutically acceptable salt of the following compound:
16. The method of claim 15 , wherein the chronic cough is refractory chronic cough.
17. The method of claim 15 , wherein the chronic cough is reduced by about 75%.
18. A method for treating neuronal hypersensitivity underlying acute cough, neuronal hypersensitivity underlying sub-acute cough, or neuronal hypersensitivity underlying chronic cough in a patient, the method comprising administering to the patient in need thereof an effective amount of a pharmaceutically acceptable salt of the following compound:
19. The method of claim 18 , wherein the neuronal hypersensitivity underlying chronic cough is refractory chronic cough.
20. The method of claim 18 , wherein the neuronal hypersensitivity underlying chronic cough is reduced by about 75%.