Selective P2X3 modulators
View Patent ↗Provided herein are methods for the treatment of avoiding loss of taste response while treating a chronic cough patient with a selective P2X3 modulator.
1. A method of avoiding loss of taste response while treating a chronic cough patient, the method comprising administering to the patient a therapeutically effective amount of a selective P2X3 antagonist, wherein the selective P2X3 antagonist is at least 10-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism, wherein the selective P2X3 antagonist is a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
wherein:
R 1 is selected from the group consisting of cyano, halogen, methyl, and ethyl;
R 2 is selected from the group consisting of hydrogen, halogen, methyl, and ethyl;
R 3 is selected from the group consisting of halogen, methyl, and ethyl;
R 4 is selected from the group consisting of hydrogen, halogen, methyl, ethyl, and methoxy;
R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1 -C 6 -alkyl, and hydroxy-C 1 -C 6 -alkyl; or
R 5 and R 6 , together with the nitrogen to which they are both attached, form a 5- or 6-member heterocycloalkyl, wherein the heterocycloalkyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, hydroxyl, and C 1 -C 4 -alkyl;
R 7 and R 8 are independently selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
R 9 is selected from the group consisting of C 1 -C 6 -alkyl, C 3 -C 6 -cycloalkyl, C 1 -C 6 -alkyl-C 3 -C 6 -cycloalkyl, halo-C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, halo-C 1 -C 6 -alkoxy, and C 1 -C 6 -alkoxy-C 1 -C 6 -alkyl; and
X is selected from a bond, CH 2 and 0.
2. The method of claim 1 , wherein the selective P2X3 antagonist is at least 20-fold selective, at least 50-fold selective, at least 100-fold selective, at least 500-fold selective, at least 1000-fold selective, at least 2000-fold selective, or at least 2700-fold selective for P2X3 homomeric receptor antagonism versus P2X2/3 heteromeric receptor antagonism.
3. The method of claim 1 , wherein R 1 is methyl.
4. The method of claim 3 , wherein R 2 is hydrogen.
5. The method of claim 4 , wherein R 3 is fluoro.
6. The method of claim 5 , wherein R 4 is fluoro.
7. The method of claim 6 , wherein X is O.
8. The method of claim 7 , wherein the compound corresponds in structure to:
and
R 4 is selected from the group consisting of halogen, methyl, and ethyl.
9. The method of claim 8 , wherein R 5 is hydrogen.
10. The method of claim 9 , wherein R 6 is C 1 -C 6 -alkyl.
11. The method of claim 10 , wherein R 6 is methyl.
12. The method of claim 11 , wherein R 7 is hydrogen and R 8 is hydrogen.
13. The method of claim 12 , wherein R 9 is C 1 -C 6 -alkoxy.
14. The method of claim 13 , wherein R 9 is methoxy.
15. The method of claim 1 , wherein the compound corresponds in structure to:
16. The method of claim 1 , wherein the compound corresponds in structure to:
17. The method of claim 1 , wherein the compound corresponds in structure to:
18. The method of claim 1 , wherein the compound corresponds in structure to:
19. The method of claim 9 , wherein the compound corresponds in structure to: