P2X3 receptor antagonists for treatment of pain
View Patent ↗The subject invention relates to novel P2X3 receptor antagonists that play a critical role in treating disease states associated with pain, in particular peripheral pain, inflammatory pain, or tissue injury pain that can be treated using a P2X3 receptor subunit modulator.
1. A compound of structural formula I:
or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof wherein:
X is N and Y is CR 1 ;
A represents a five membered heterocyclyl selected from the group consisting of (CH 2 ) n isoxazolyl, and (CH 2 ) n dihydro-isoxazolyl;
R 1 represents H, C 1-6 alkyl, halogen, (CH 2 ) n CF 3 , C 3-10 cycloalkyl, CN, (CH 2 ) n O R 2 , (CH 2 ) n C 6-10 aryl, or C 1-6 alkoxy; said alkyl, cycloalkyl, and aryl optionally substituted with 1 to 3 groups of C 1-6 alkyl, halogen, hydroxyl, (CH 2 ) n CF 3 , or CN;
R 2 represents H, C 1-6 alkyl;
R 3 represents CR 2 R 4 R 5 ;
one of R 4 and R 5 represents (CH 2 ) n pyridyl, and the other represents H, (CH 2 ) n OR 2 , CHF 2 , (CH 2 ) n C 6-10 aryl, C 3-10 cycloalkyl, C 1-6 alkoxy, or C 1-6 alkyl; said alkyl, pyridyl, cycloalkyl, and aryl optionally substituted with 1 to 3 groups of R a ;
one of R 6 and R 7 represents (CH 2 ) n pyridyl, and the other represents hydrogen, C 1-6 alkyl, halogen, hydroxyl, (CH 2 ) n CF 3 , C 3-6 cycloalkyl, or (CH 2 ) n C 6-10 aryl, said aryl and pyridyl, optionally substituted with 1 to 3 groups of C 1-6 alkyl, halogen, (CH 2 ) n OR 2 , —C(R 2 ) 2 OR—C(O)R 2 , (CH 2 ) n CF 3 , or CN;
R a represents C 1-6 alkyl, halogen, —OR 2 , hydroxyl, (CH 2 ) n CF 3 , —O—, C 3-6 cycloalkyl, or C 6-10 aryl, said aryl optionally substituted with 1 to 3 groups of C 1-6 alkyl, halogen, hydroxyl, (CH 2 ) n CF 3 , or CN; and
n represents 0 to 4.
2. The compound according to claim 1 wherein A is isoxazolyl.
3. The compound according to claim 1 wherein A is dihydro-isoxazolyl.
4. The compound according to claim 1 wherein the R 2 in R 3 is hydrogen and one of R 4 and R 5 is C 1-6 alkyl and the other is (CH 2 ) n pyridyl, said pyridyl optionally substituted with 1 to 3 groups of R a .
5. The compound according to claim 1 wherein one of R 6 and R 7 is hydrogen and the other is (CH 2 ) n pyridyl, optionally substituted with 1 to 3 groups of R a .
6. The compound according to claim 1 wherein A is isoxazolyl, one of R 6 and R 7 is hydrogen and the other is (CH 2 ) n pyridyl, optionally substituted with 1 to 3 groups of R a , R 3 is CHR 4 R 5 , and one of R 4 and R 5 is C 1-6 alkyl and the other is (CH 2 ) n pyridyl, said pyridyl optionally substituted with 1 to 3 groups of R a .
7. The compound according to claim 1 wherein A is dihydro-isoxazolyl, one of R 6 and R 7 is hydrogen and the other is (CH 2 ) n pyridyl, optionally substituted with 1 to 3 groups of R a , R 3 is CHR 4 R 5 , and one of R 4 and R 5 is C 1-6 alkyl and the other is (CH 2 ) n pyridyl optionally substituted with 1 to 3 groups of R a .
8. The compound according to claim 1 wherein A is
9. A compound of Table 1:
TABLE 1
Example
Structure
4
5
6
7
14
23
36
46
55
79
86
91
92
94
95
97
98
99
101
102
106
107
111
112
115
122
123
132
136
138
142
153
163
168
174
177
179
180
187
196
201
205
212
217
or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof.
10. A compound according to claim 9 which is:
N-[(1R)-1-(5-fluoro-1-oxidopyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
3-(5-methylpyridin-2-yl)-N-{(1R)-1-[1-oxido-6-(trifluoromethyl)pyridin-3-yl]ethyl}-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
N-[(3,5-difluoropyridin-2-yl)methyl]-3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
3-(5-chloropyridin-2-yl)-N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-3-(5-hydroxy-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl)-5-(5-methylpyridin-2-yl)benzamide;
N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide;
N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-[(5R)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide;
3-(5-methylpyridin-2-yl)-5-[(5R)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide;
or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof.
11. A compound according to claim 10 which is 3-(5-chloropyridin-2-yl)-N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof.
12. A compound according to claim 10 which is N-[(1R)-1-(5-fluoropyridin-2-yl)ethyl]-3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]benzamide or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof.
13. A compound according to claim 10 which is 3-(5-methylpyridin-2-yl)-5-[(5S)-5-pyridin-2-yl-4,5-dihydroisoxazol-3-yl]-N-{(1R)-1-[6-(trifluoromethyl)pyridin-3-yl]ethyl}benzamide or a pharmaceutically acceptable salt and individual enantiomers and diastereomers thereof.
14. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .