Bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds represented by Formula I, or pharmaceutically acceptable salts, stereoisomers, solvates, hydrates or combination thereof, The invention also provides pharmaceutical compositions comprising these compounds and methods of using this compounds for treating FXR-mediated or TGR5-mediated diseases or conditions.
1. A compound represented by Formula I or a pharmaceutically acceptable salt thereof:
wherein:
R a is hydrogen or methyl;
R b is selected from the group consisting of:
1) C(O)NR 10 R 11 ;
2) C(O)NHSO 2 R 1 ;
3) —SO 2 R 1 ; and
4) —C(O)R 1 ;
R 1 is selected from the group consisting of:
1) Halogen;
2) Hydroxyl;
3) Substituted or unsubstituted —C 1 -C 8 alkyl;
4) Substituted or unsubstituted —C 2 -C 8 alkenyl;
5) Substituted or unsubstituted —C 2 -C 8 alkynyl;
6) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
7) Substituted or unsubstituted aryl;
8) Substituted or unsubstituted arylalkyl;
9) Substituted or unsubstituted heterocycloalkyl;
10) Substituted or unsubstituted heteroaryl;
11) Substituted or unsubstituted heteroarylalkyl; and
12) —NR 10 R 11 ;
R 2 is hydrogen;
R c is hydrogen;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen or hydroxyl;
R 4 is hydrogen or hydroxyl;
R 5 and R 6 are independently selected from hydrogen and hydroxyl protecting group;
R 7 is selected from the group consisting of:
Hydrogen and substituted or unsubstituted —C 1 -C 8 alkyl;
and
R 10 and R 11 are each independently selected from hydrogen, substituted or unsubstituted —C 1 -C 8 alkyl, substituted or unsubstituted —C 2 -C 8 alkenyl, substituted or unsubstituted —C 2 -C 8 alkynyl, substituted or unsubstituted —C 3 -C 8 cycloalkyl, or R 10 and R 11 are taken together with the nitrogen atom to which they are attached to form a heterocyclic ring.
2. The compound of claim 1 represented by Formula II, or a pharmaceutically acceptable salt thereof:
wherein R a , R b , R c , R 2 , R 3 , R 4 , R 7 and m are as defined in claim 1 .
3. The compound of claim 1 represented by one of formulas (III-4), (III-5), (III-6), (III-10), (III-11), (III-12), (III-16), (III-17) and (III-18), or a pharmaceutically acceptable salt thereof:
wherein R a , R b , R c , R 1 , R 2 , R 7 and m are as defined in claim 1 .
4. The compound of claim 1 represented by Formula IV, or a pharmaceutically acceptable salt thereof:
wherein R a , R b , and m are as defined in claim 1 .
5. A compound, selected from compounds of Formula IV,
wherein R a , R b , and m are delineated for each compound in Table 1, or a pharmaceutically acceptable salt thereof:
TABLE 1
Compound
m
R a
R b
1
0
Methyl
H
2
0
Ethyl
H
3
0
Isopropyl
H
4
0
Butyl
H
5
0
t-Butyl
H
6
0
Propyl
H
7
0
Benzyl
H
8
0
Vinyl
H
9
0
Allyl
H
10
0
CF 3
H
11
0
H
12
0
H
13
0
H
14
0
H
15
0
Methyl
Me
16
0
Ethyl
Me
17
0
Isopropyl
Me
18
0
t-Butyl
Me
19
0
Propyl
Me
20
0
Benzyl
Me
21
0
Vinyl
Me
22
0
Allyl
Me
23
0
CF 3
Me
24
0
Me
25
0
26
0
27
0
28
0
29
0
30
0
31
0
32
0
33
0
34
1
Methyl
H
35
1
Ethyl
H
36
1
Isopropyl
H
37
1
Butyl
H
38
1
t-Butyl
H
39
1
Propyl
H
40
1
Benzyl
H
41
1
Vinyl
H
42
1
Allyl
H
43
1
CF 3
H
44
1
H
45
1
H
46
1
H
47
1
H
48
1
Methyl
Me
49
1
Ethyl
Me
50
1
Isopropyl
Me
51
1
t-Butyl
Me
52
1
Propyl
Me
53
1
Benzyl
Me
54
1
Vinyl
Me
55
1
Allyl
Me
56
1
CF 3
Me
57
1
Me
58
1
Me
59
1
Me
60
1
61
1
62
1
63
1
64
1
65
1
66
1
67
2
Methyl
H
68
2
Ethyl
H
69
2
Isopropyl
H
70
2
Butyl
H
71
2
t-Butyl
H
72
2
Propyl
H
73
2
Benzyl
H
74
2
Vinyl
H
75
2
Allyl
H
76
2
CF 3
H
77
2
H
78
2
H
79
2
H
80
2
H
81
2
Methyl
Me
82
2
Ethyl
Me
83
2
Isopropyl
Me
84
2
t-Butyl
Me
85
2
Propyl
Me
86
2
Benzyl
Me
87
2
Vinyl
Me
88
2
Allyl
Me
89
2
CF 3
Me
90
2
Me
91
2
Me
92
2
Me
93
2
94
2
95
2
96
2
97
2
98
2
99
2
6. The compound according to claim 1 , which is selected from compounds of Formula V, or a pharmaceutically acceptable salt thereof:
wherein R 1 and m are delineated for each compound in Table 2:
TABLE 2
Compound
m
R 1
100
0
Methyl
101
0
Ethyl
102
0
Isopropyl
103
0
Butyl
104
0
t-Butyl
105
0
Propyl
106
0
Benzyl
107
0
Vinyl
108
0
Allyl
109
0
CF 3
110
0
111
0
112
0
113
0
114
0
115
0
116
0
117
0
118
0
NH 2
119
0
120
0
121
0
122
0
123
0
124
0
125
0
126
0
F
127
1
Methyl
128
1
Ethyl
129
1
Isopropyl
130
1
Butyl
131
1
t-Butyl
132
1
Propyl
133
1
Benzyl
134
1
Vinyl
135
1
Allyl
136
1
CF 3
137
1
138
1
139
1
140
1
141
1
142
1
143
1
144
1
145
1
NH 2
146
1
147
1
148
1
149
1
150
1
151
1
152
1
153
1
F
154
2
Methyl
155
2
Ethyl
156
2
Isopropyl
157
2
Butyl
158
2
t-Butyl
159
2
Propyl
160
2
Benzyl
161
2
Vinyl
162
2
Allyl
163
2
CF 3
164
2
165
2
166
2
167
2
168
2
169
2
170
2
171
2
172
2
NH 2
173
2
174
2
175
2
176
2
177
2
178
2
179
2
180
2
F.
7. The compound according to claim 1 , selected from compounds of Formula VI:
wherein R 1 and m for each compound are set forth in Table 3, or a pharmaceutically acceptable salt thereof:
TABLE 3
Compound
m
R 1
181
0
Methyl
182
0
Ethyl
183
0
Isopropyl
184
0
Butyl
185
0
t-Butyl
186
0
Propyl
187
0
Benzyl
188
0
Vinyl
189
0
Allyl
190
0
CF 3
191
0
192
0
193
0
194
0
195
0
196
0
197
0
198
0
199
0
NH 2
200
0
201
0
202
0
203
0
204
0
205
0
206
0
207
0
F
208
1
Methyl
209
1
Ethyl
210
1
Isopropyl
211
1
Butyl
212
1
t-Butyl
213
1
Propyl
214
1
Benzyl
215
1
Vinyl
216
1
Allyl
217
1
CF 3
218
1
219
1
220
1
221
1
222
1
223
1
224
1
225
1
226
1
NH 2
227
1
228
1
229
1
230
1
231
1
232
1
233
1
234
1
F
235
2
Methyl
236
2
Ethyl
237
2
Isopropyl
238
2
Butyl
239
2
t-Butyl
240
2
Propyl
241
2
Benzyl
242
2
Vinyl
243
2
Allyl
244
2
CF 3
245
2
246
2
247
2
248
2
249
2
250
2
251
2
252
2
253
2
NH 2
254
2
255
2
256
2
257
2
258
2
259
2
260
2
261
2
F.
8. A compound selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:
Example #
Structure
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
44-a
44-b
44-c
44-d
44-e
44-f
44-g
44-h
44-i
44-j
44-k
44-l
44-m
44-n
44-o
44-p
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
92
93
94
95
96
97
98
99
100
101
102
103
104
104-a
104-b
104-c
104-d
104-e
104-f
104-g
104-h
104-i
104-j
104-k
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
149
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
209
210
211
212
213
214
215
216
217
218
9. A method for ameliorating a disease or condition selected from the group consisting of primary biliary cirrhosis, cerebrotendinous xanthomatosis, primary sclerosing cholangitis, alcoholic liver disease, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, atherosclerosis, hypercholesterolemia, hypertriglyceridemia, and Type II diabetes, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
10. The method according to claim 9 , wherein the disease or condition is selected from the group consisting of primary biliary cirrhosis, nonalcoholic fatty liver disease, and nonalcoholic steatohepatitis.
11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. The method according to claim 10 , wherein the disease or condition is nonalcoholic steatohepatitis.
13. The method according to claim 10 , wherein the disease or condition is primary biliary cirrhosis.
14. The method according to claim 10 , wherein the disease or condition is nonalcoholic fatty liver disease.
15. The compound of claim 1 , wherein R b is —SO 2 R 1 .
16. The compound of claim 1 , represented by Formula (V),
or a pharmaceutically acceptable salt thereof, wherein m and R 1 are as defined in claim 1 .