Bile acid analogs as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds of Formula I: pharmaceutical compositions comprising these compounds and methods of using these compounds to treat or prevent a disease or disorder mediated by FXR and/or TGR5.
1. A compound represented by Formula I:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
R a , R b , and R c are each independently selected from R 1 ; or R a and R b , or R a and R c , or R b and R c are taken together with the two nitrogen atoms to which they are attached and the intervening carbon atom to form a heterocyclic, heteroaryl or heterocycloalkenyl ring;
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
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 arylalkyl; and
7) Substituted or unsubstituted aryl;
m is 0, 1, 2 or 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —PPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 , or R 3 and R 4 are taken together with the carbons to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are each independently hydrogen or hydroxyl protecting group; and
R 7 is ethyl.
2. The compound of claim 1 represented by Formula II:
or a pharmaceutically acceptable salt, solvate, or ester thereof,
wherein R 1 , 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 Formula III:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 , R a , R b , R c , R 2 , R 3 , R 7 and m are as defined in claim 1 .
4. The compound of claim 1 , represented by one of formulas (III-1) to (III-9),
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 , R a , R b , R c , R 2 , R 3 , R 7 and m are as defined in claim 1 .
5. The compound of claim 1 , represented by Formula IV:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 , R a , R b , R c , and m are as defined in claim 1 .
6. A compound of claim 1 , represented by Formula V:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 and m are as defined in claim 1 .
7. The compound of claim 1 , selected from compounds of Formula V, wherein R 1 and m are delineated for each compound in Table 1:
TABLE 1
(V)
Compound
m
R 1
Compound
M
R 1
Compound
m
R 1
1
0
H
26
1
H
51
2
H
2
0
Methyl
27
1
Methyl
52
2
Methyl
3
0
Ethyl
28
1
Ethyl
53
2
Ethyl
4
0
Isopropyl
29
1
Isopropyl
54
2
Isopropyl
5
0
Butyl
30
1
Butyl
55
2
Butyl
6
0
t-Butyl
31
1
t-Butyl
56
2
t-Butyl
7
0
Propyl
32
1
Propyl
57
2
Propyl
8
0
Benzyl
33
1
Benzyl
58
2
Benzyl
9
0
Allyl
34
1
Allyl
59
2
Allyl
10
0
CF 3
35
1
CF 3
60
2
CF 3
11
0
36
1
61
2
12
0
37
1
62
2
13
0
38
1
63
2
14
0
39
1
64
2
15
0
40
1
65
2
16
0
41
1
66
2
17
0
42
1
67
2
18
0
43
1
68
2
19
0
44
1
69
2
20
0
45
1
70
2
21
0
46
1
71
2
22
0
47
1
72
2
23
0
48
1
73
2
24
0
49
1
74
2
25
0
50
1
75
2
or a pharmaceutically acceptable salt, solvate or ester thereof.
8. The compound of claim 1 , represented by Formula VI:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 and m are as defined in claim 1 .
9. The compound of claim 1 , selected from compounds of Formula VI, wherein R 1 and m are delineated for each compound in Table 2:
TABLE 2
(VI)
Compound
m
R 1
76
0
H
77
0
Methyl
78
0
Ethyl
79
0
Isopropyl
80
0
Butyl
81
0
t-Butyl
82
0
Propyl
83
0
Benzyl
84
0
Allyl
85
0
CF 3
86
0
87
0
88
0
89
0
90
0
91
0
92
0
93
0
94
0
95
0
96
0
97
0
98
0
99
0
100
0
101
1
H
102
1
Methyl
103
1
Ethyl
104
1
Isopropyl
105
1
Butyl
106
1
t-Butyl
107
1
Propyl
108
1
Benzyl
109
1
Allyl
110
1
CF 3
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
2
H
127
2
Methyl
128
2
Ethyl
129
2
Isopropyl
130
2
Butyl
131
2
t-Butyl
132
2
Propyl
133
2
Benzyl
134
2
Allyl
135
2
CF 3
136
2
137
2
138
2
139
2
140
2
141
2
142
2
143
2
144
2
145
2
146
2
147
2
148
2
149
2
150
2
or a pharmaceutically acceptable salt, solvate or ester thereof.
10. The compound of claim 1 , represented by Formula VII:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 and m are as defined in claim 1 .
11. The compound of claim 1 , selected from compounds of Formula VII, wherein R 1 and m are delineated for each compound in Table 3:
TABLE 3
(VII)
Compound
m
R 1
151
0
H
152
0
Methyl
153
0
Ethyl
154
0
Isopropyl
155
0
Butyl
156
0
t-Butyl
157
0
Propyl
158
0
Benzyl
159
0
Allyl
160
0
CF 3
161
0
162
0
163
0
164
0
165
0
166
0
167
0
168
0
169
0
170
0
171
0
172
0
173
0
174
0
175
0
176
1
H
177
1
Methyl
178
1
Ethyl
179
1
Isopropyl
180
1
Butyl
181
1
t-Butyl
182
1
Propyl
183
1
Benzyl
184
1
Allyl
185
1
CF 3
186
1
187
1
188
1
189
1
190
1
191
1
192
1
193
1
194
1
195
1
196
1
197
1
198
1
199
1
200
1
201
2
H
202
2
Methyl
203
2
Ethyl
204
2
Isopropyl
205
2
Butyl
206
2
t-Butyl
207
2
Propyl
208
2
Benzyl
209
2
Allyl
210
2
CF 3
211
2
212
2
213
2
214
2
215
2
216
2
217
2
218
2
219
2
220
2
221
2
222
2
223
2
224
2
225
2
or a pharmaceutically acceptable salt, solvate or ester thereof.
12. The compound of claim 1 , represented by Formula VIII:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein R 1 and m are as defined in claim 1 .
13. The compound of claim 1 , selected from compounds of Formula VIII, wherein R 1 and m are delineated for each compound in Table 4:
TABLE 4
(VIII)
Compound
m
R 1
226
0
H
227
0
Methyl
228
0
Ethyl
229
0
Isopropyl
230
0
Butyl
231
0
t-Butyl
232
0
Propyl
233
0
Benzyl
234
0
Allyl
235
0
CF 3
236
0
237
0
238
0
239
0
240
0
241
0
242
0
243
0
244
0
245
0
246
0
247
0
248
0
249
0
250
0
251
1
H
252
1
Methyl
253
1
Ethyl
254
1
Isopropyl
255
1
Butyl
256
1
t-Butyl
257
1
Propyl
258
1
Benzyl
259
1
Allyl
260
1
CF 3
261
1
262
1
263
1
264
1
265
1
266
1
267
1
268
1
269
1
270
1
271
1
272
1
273
1
274
1
275
1
276
2
H
277
2
Methyl
278
2
Ethyl
279
2
Isopropyl
280
2
Butyl
281
2
t-Butyl
282
2
Propyl
283
2
Benzyl
284
2
Allyl
285
2
CF 3
286
2
287
2
288
2
289
2
290
2
291
2
292
2
293
2
294
2
295
2
296
2
297
2
298
2
299
2
300
2
or a pharmaceutically acceptable salt, solvate or ester thereof.
14. A pharmaceutical composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier.
15. A method for ameliorating an FXR-mediated 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, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound represented by Formula I:
or a pharmaceutically acceptable salt, solvate or ester thereof,
wherein:
R 1 is selected from the group consisting of:
1) Hydrogen;
2) Substituted or unsubstituted —C 1 -C 8 alkyl;
3) Substituted or unsubstituted —C 2 -C 8 alkenyl;
4) Substituted or unsubstituted —C 2 -C 8 alkynyl;
5) Substituted or unsubstituted —C 3 -C 8 cycloalkyl;
6) Substituted or unsubstituted aryl;
7) Substituted or unsubstituted arylalkyl;
8) Substituted or unsubstituted heterocycloalkyl;
9) Substituted or unsubstituted heteroaryl; and
10) Substituted or unsubstituted heteroarylalkyl;
R a , R b , and R c are each independently selected from R 1 ; or R a and R b , or R a and R c , or R b and R c are taken together with the two nitrogen atoms to which they are attached and the intervening carbon atom to form a heterocyclic, heteroaryl or heterocycloalkenyl ring;
R 2 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
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 arylalkyl; and
7) Substituted or unsubstituted aryl;
m is 0, 1, 2 or 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —PPO 3 H 2 or —OPO 3 2− ;
R 4 is hydrogen, halogen, CN, N 3 , hydroxyl, —OSO 3 H, —OSO 3 − , —OAc, —OPO 3 H 2 , —OPO 3 2− , —SR 2 or —NHR 2 , or R 3 and R 4 are taken together with the carbons to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are each independently hydrogen or hydroxyl protecting group; and
R 7 is selected from the group consisting of:
1) Hydrogen;
2) Halogen;
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; and
6) Substituted or unsubstituted —C 2 -C 8 cycloalkyl.
16. A method of ameliorating primary biliary cirrhosis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
17. A method of ameliorating nonalcoholic steatohepatitis in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
18. A method of ameliorating nonalcoholic fatty liver disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of claim 1 .
19. The method of claim 18 , wherein the disease or condition is primary biliary cirrhosis.
20. The method of claim 18 , wherein the disease or condition is nonalcoholic steatohepatitis.
21. The method of claim 18 , wherein the disease or condition is nonalcoholic fatty liver disease.