Inhibitors of the microsomal prostaglandin E2 synthase-1
This invention relates to compounds of formula I their use as inhibitors of the microsomal prostaglandin E 2 synthase-1 (mPGES-1), pharmaceutical compositions containing them, and their use as medicaments for the treatment and/or prevention of inflammatory diseases and associated conditions. A, M, W, R 1 , R 2 , R 6 , R 7 have meanings given in the description.
1. A compound of formula I
in which
R 1 represents halo, —C 1-3 alkyl, which latter alkyl group is optionally substituted by one or more fluorine atoms;
R 2 represent hydrogen, halo, —C 1-3 alkyl, which latter alkyl group is optionally substituted by one or more fluorine atoms;
W represents —C(O)—, —C(O)O—, which groups are bound to the nitrogen of the —NH— moiety via the carbon atom;
M represents
—C 1-6 alkyl, —C 3-7 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —NH(C 1-2 alkyl), —N(C 1-2 alkyl) 2 , —OC 1-3 alkyl, —C 1-5 alkyl, —C 3-4 cycloalkyl, in which latter three groups the alkyl or cycloalkyl groups are optionally substituted by one or more fluorine atoms;
or
oxetanyl-, tetrahydrofuranyl-, tetrahydropyranyl-, azetidinyl-, pyrrolidinyl-, piperidinyl-, all of which groups are optionally substituted by one or more substituents selected from fluoro, —CN, —C 1-3 alkyl, which latter alkyl group is optionally substituted by one or more fluorine atoms;
or
phenyl-, pyridyl-, thienyl-, pyrrolyl-, pyrazolyl-, imidazolyl-, thiazolyl-, oxazolyl-, or isoxazolyl-, all of which groups are optionally substituted by one or more substituents selected from halo, —CN or —C 1-3 alkyl, which latter alkyl group is optionally further substituted by one or more fluorine atoms;
R 6 represents —H, —C 1-5 alkyl, —C 0-2 alkyl-C 3-5 cycloalkyl, in which latter two groups the alkyl or cycloalkyl fragments are optionally substituted by one or more fluorine atoms;
R 7 represents C 1-5 alkyl-O—, C 3-7 cycloalkyl-C 0-2 alkyl-O—, 4-7-membered heterocycloalkyl-C 0-2 alkyl-O—, in which latter three groups the alkyl, cycloalkyl or heterocycloalkyl fragments are optionally substituted by one or more substituents selected from —F and —OC 1-3 alkyl which latter alkyl group is optionally further substituted by one or more fluorine atoms;
A represents C 1-8 alkyl-, phenyl-, pyridyl-, thienyl-, pyrrolyl-, pyrazolyl-, thiazolyl-, oxazolyl-, isoxazolyl-, phenyl-C 1-3 alkyl-, thienyl-C 1-3 alkyl-, pyridyl-C 1-3 alkyl-, C 3-7 cycloalkyl-C 0-3 alkyl-, oxetanyl-C 0-3 alkyl-, tetra-hydrofuranyl-C 0-3 alkyl, tetrahydropyranyl-C 0-3 alkyl, in which groups the alkyl-, cycloalkyl- and heterocycloalkyl fragments are optionally substituted by one or more substituents selected from R 9a and the aryl and heteroaryl fragments are optionally substituted by one or more substituents selected from R 9b ;
each R 9a independently represents —F, —Cl, C 1-3 alkyl which is optionally substituted by one or more substituents selected from —F, —OC 1-3 alkyl;
each R 9b represents independently -halo, —CN; —C 1-3 alkyl which is optionally substituted by one or more fluorine atoms;
or a salt thereof.
2. A compound according to claim 1 , wherein
R 6 represents —H, —CH 3 , or —CH 2 CHF 2 ;
or a pharmaceutically acceptable salt thereof.
3. A compound according to claim 1 , wherein
R 1 represents chloro, fluoro or —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 1 , wherein
R 2 represents —H, chloro, -fluoro, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
or a pharmaceutically acceptable salt thereof.
5. A compound according to claim 1 , wherein
R 7 represents fluoro, —OCHF 2 , —OCF 3 , —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OCHF 2 ;
or a pharmaceutically acceptable salt thereof.
6. A compound according to claim 1 , wherein
A represents C 1-4 alkyl-, C 3-6 cycloalkyl-C 0-2 alkyl-, phenyl-, in which groups the alkyl- and cycloalkyl-fragments are optionally substituted by one or more substituents selected from —F, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , and the phenyl fragment is optionally substituted by —F, —Cl, —Br;
or a pharmaceutically acceptable salt thereof.
7. A compound according to claim 1 , wherein
M represents
—C 1-4 alkyl, —C 3-5 cycloalkyl, both of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 , —OCH 3 , —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , cyclopropyl;
or
oxetanyl-, tetrahydrofuranyl- or pyrrolidinyl-, all of which groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
or
phenyl-, thienyl-, pyrrolyl-, pyrazolyl-, imidazolyl-, thiazolyl-, or isoxazolyl-, all of which groups are optionally substituted by one or more substituents selected from —F, —Cl, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
or a pharmaceutically acceptable salt thereof.
8. A compound according to claim 1 , which is a compound of formula Ia
in which
M represents
methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, cyclopropyl, —CH 2 -cyclopropyl, cyclobutyl, cyclopentyl, all of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 ,
—OCH 3 , —CH 3 , —CF 3 ;
or is selected from the following groups
which latter five groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CF 3 ;
or is selected from the following groups
which latter eleven groups are optionally substituted by one or more substituents selected from —F, —Cl, —CH 3 , —CF 3 ; and
A, R 1 , R 2 , R 6 , R 7 have the same meaning as defined in claim 1 ;
or a pharmaceutically acceptable salt thereof.
9. A compound according to claim 8 , wherein
A represents methyl, ethyl, propyl, butyl, which latter four groups are optionally substituted by one or more fluorine atoms,
or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which latter four groups are optionally substituted by one or more substituents selected from —F,
—CH 3 , —CHF 2 , —CF 3 ;
or the group
or phenyl which is optionally substituted by one or more substituents selected from —F, —Cl, —Br;
or a pharmaceutically acceptable salt thereof.
10. A compound according to claim 1 , which is a compound of formula Ia or Ib
in which
R 1 represents chloro, fluoro or —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
R 2 represents —H, chloro, fluoro, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
R 6 represents —H; —CH 3 , —CH 2 CHF 2 ;
R 7 represents fluoro, —OCHF 2 , —OCF 3 , —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 OCHF 2 ;
A represents methyl, ethyl, propyl, butyl, which latter four groups are optionally substituted by one or more fluorine atoms,
or cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, which latter four groups are optionally substituted by one or more substituents selected from —F,
—CH 3 , —CHF 2 , —CF 3 ;
or the group
or phenyl which is optionally substituted by one or more substituents selected from —F, —Cl, —Br;
M represents
methyl, ethyl, propyl, i-propyl, n-butyl, s-butyl, t-butyl, cyclopropyl, —CH 2 — cyclopropyl, cyclobutyl, cyclopentyl, all of which groups are optionally substituted by one or more groups selected from —F, —OH, —CN, —NH 2 ,
—OCH 3 , —CH 3 , —CF 3 ;
or is selected from the following groups
which latter five groups are optionally substituted by one or more substituents selected from —F, —CH 3 , —CF 3 ;
or is selected from the following groups
which latter eleven groups are optionally substituted by one or more substituents selected from —F, —Cl, —CH 3 , —CF 3 ;
or a salt thereof.
11. A compound according to claim 1 , wherein
R 1 and R 2 independently represent chloro, fluoro, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 ;
or a pharmaceutically acceptable salt thereof.
12. A compound according to claim 1 selected from the compounds in the following table, or the pharmaceutically acceptable salts thereof:
Structure
1
2
3
6
7
8
4
5
11
12
9
10
16
17
14
15
21
22
18
19
20
26
27
23
24
25
31
32
28
29
30
37
38
33
34
35
36
43
39
40
41
42
48
44
45
46
47
53
49
50
51
52
59
54
55
56
57
58
60
61
62
63
64
65
66
67
68
69
71
72
73
74
75
70
77
78
79
76
82
83
84
80
81
87
88
85
86
92
93
89
90
91
97
94
95
96
101
98
99
100
105
102
103
104
110
106
107
108
109
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
130
131
132
133
129
135
136
137
134
139
140
141
138
143
144
142
147
148
145
146
151
149
150
155
152
153
154
156
157
13. A pharmaceutical composition comprising at least one compound according to claim 1 , or a pharmaceutically acceptable salt thereof, in admixture with a pharmaceutically acceptable adjuvant, diluent and/or carrier.
14. A method of treating an inflammatory disease in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.
15. A method of treating pain in a patient comprising administering to said patient a therapeutically effective amount of a compound according to claim 1 , or a pharmaceutically acceptable salt thereof.