P2X3, receptor antagonists for treatment of pain
View Patent ↗The subject invention relates to novel P2X 3 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 P2X 3 receptor subunit modulator.
1. A compound represented by structural formula II:
or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof wherein:
A is CH or N;
R b is C 1-6 alkyl, or halogen;
R 2 represents H, C 1-6 alkyl, CF 3 , OH;
R 3 represents (CHR 2 ) n C 5-10 heterocycle,said heterocyclyl substituted with 1 to 3 groups of R a , wherein R 2 in (CHR 2 ) n C 5-10 heterocycle is C 1-6 alkyl which is methyl and n in (CHR 2 ) n C 5-10 heterocycle is 1 ;
R 6 represents C 1-6 alkyl, (CHR 2 ) n C 6-10 aryl, (CHR 2 ) n C 5-10 heterocyclyl, said alkyl, aryl and heterocyclyl optionally substituted with 1 to 3 groups of R a ;
R a represents C 1-6 alkyl, halogen, OR 2 , (CH 2 ) n CF 3 , —O—, C 3-6 cycloalkyl, C(O)N(R 2 )2, C(O)R 2 , CN, N(R 2 )2, C(O)OR 2 , SO 2 R 2 ,(CHR 2 ) n C 5-10 heterocyclyl, or (CHR 2 ) n C 6-10 aryl, said heterocyclyl and 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 R 6 is an optionally substituted phenyl and R 3 is substituted (CHR 2 ) n pyridyl.
3. The compound according to claim 1 wherein R 6 is (CH 2 ) n pyridyl, (CH 2 ) n oxazolyl, (CH 2 ) n pyrimidinyl, or (CH 2 ) n pyrazolyl, wherein the n in (CH 2 ) n pyridyl, (CH 2 ) n oxazolyl, (CH 2 ) n pyrimidinyl, or (CH 2 ) n pyrazolyl, is 0, said pyridyl, oxazolyl, pyrimidinyl, and pyrazolyl are optionally substituted with 1 to 3 groups of R a, and R 3 is substituted (CHR 2 ) n pyridyl.
4. A compound which is represented in Table 1:
TABLE 1
Example
R 3
R 7
R 6
1.1
1.2
1.3
1.4
1.5
1.6
1.7
1.8
1.9
1.10
1.11
1.12
1.13
1.14
1.15
1.16
1.17
1.18
1.19
1.20
1.21
1.22
1.23
1.24
1.25
1.26
1.27
1.28
1.29
1.30
1.31
1.32
1.33
1.34
1.35
1.36
1.37
1.38
1.39
1.40
1.41
1.42
H
1.43
1.44
1.45
1.46
1.47
1.48
1.49
1.50
1.51
1.52
1.53
1.54
1.55
1.56
1.57
1.58
1.59
1.60
1.61
1.62
1.63
1.64
1.65
1.66
1.67
1.68
1.69
1.70
1.71
1.72
1.73
1.74
1.75
1.76
1.77
1.78
1.79
1.80
1.81
1.82
1.83
1.84
1.85
1.86
1.87
1.88
1.89
1.90
1.91
1.92
1.93
1.94
1.95
1.96
1.97
1.98
1.99
1.100
1.101
1.102
1.103
1.104
1.105
1.106
1.107
1.108
1.109
1.110
1.111
1.112
1.113
1.114
1.115
1.116
1.117
1.118
1.119
1.120
1.121
1.122
1.123
1.124
1.125
1.126
1.127
1.128
1.129
1.130
1.131
1.132
1.133
1.134
1.135
1.136
1.137
1.138
1.139
1.140
1.141
1.142
1.143
1.144
1.145
1.146
1.147
1.148
1.149
1.150
or pharmaceutically acceptable salts and individual enantiomers and diastereomers thereof
5. A pharmaceutical composition comprising an inert carrier and an effective amount of a compound according to claim 1 .
6. A method for treating chronic or acute pain in a mammalian patient in need thereof comprising administering to said patient a therapeutically effective amount of a compound according to formula I in claim 1 or a pharmaceutically acceptable salt thereof.