Deuterated bile acid derivatives as FXR/TGR5 agonists and methods of use thereof
The present invention provides compounds of Formula (I) or Formula (II): 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 II
or a pharmaceutically acceptable salt or ester thereof, wherein:
R a is hydrogen or substituted or unsubstituted —C 1 -C 8 alkyl;
R b is
—C(O)NHSO 2 R 1 ;
R c is H or D;
R d is H or D;
R e is H or D;
D is deuterium;
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 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 arylalkyl; and
6) Substituted or unsubstituted aryl;
m is selected from 0, 1, 2 and 3;
R 3 is hydrogen, hydroxyl, —OSO 3 H, —OSO 3 , —OAc, —OPO 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 ; alternatively R 3 and R 4 are taken together with the carbon atoms to which they are attached to form —CH═CH—, a cycloalkyl ring or a heterocycloalkyl ring;
R 5 and R 6 are independently selected from hydrogen or hydroxyl protecting group;
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, substituted or unsubstituted heterocycloalkyl;
alternatively 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 IV
or a pharmaceutically acceptable salt or ester thereof, wherein R a , R b , R c , R d , R e , R 2 , R 3 , R 4 and m are defined in claim 1 .
3. The compound of claim 1 , represented by Formula VI
or a pharmaceutically acceptable salt or ester thereof, wherein R a , R b , R c , R d , R e , R 3 and m are as defined in claim 1 .
4. The compound of claim 3 , represented by one of formulas (VI-1)˜(VI-6),
or a pharmaceutically acceptable salt or ester thereof, wherein R c , R d , R e , R 1 and m are as defined in claim 3 .
5. The compound of claim 1 , represented by Formula VIII
or a pharmaceutically acceptable salt or ester thereof, wherein R a , R b , R c , R d , R e , and m are as defined in claim 1 .
6. The compound of claim 1 selected from:
compounds of Formula VIII,
wherein R a and R b are as defined in claim 1 , and m, R c , R d and R e are set forth in Table 2:
TABLE 2
Compound
m
R c
R d
R e
1a
0
H
H
H
2a
0
D
H
H
3a
0
D
D
H
4a
0
H
H
D
5a
0
D
H
D
6a
0
D
D
D
7a
1
H
H
H
8a
1
D
H
H
9a
1
D
D
H
10a
1
H
H
D
11a
1
D
H
D
12a
1
D
D
D
13a
2
H
H
H
14a
2
D
H
H
15a
2
D
D
H
16a
2
H
H
D
17a
2
D
H
D
18a
2
D
D
D
or a pharmaceutically acceptable salt or ester thereof.
7. The compound of claim 1 , represented by Formula X
or a pharmaceutically acceptable salt or ester thereof, wherein R a , R b and m are as defined in claim 1 .
8. The compound of claim 1 , represented by Formula (X-A) or (X-B),
or a pharmaceutically acceptable salt or ester thereof, wherein R 1 and m are previously defined in claim 1 .
9. The compound of claim 1 selected from:
(a) compounds of Formula (X-A),
wherein m and R 1 are set forth for each compound in Table 3:
TABLE 3
Example
m
R 1
19
0
Methyl
20
0
Ethyl
21
0
Isopropyl
22
0
Butyl
23
0
t-Butyl
24
0
Propyl
25
0
Benzyl
26
0
Vinyl
27
0
Allyl
28
0
CF 3
29
0
30
0
31
0
32
0
33
0
34
0
35
0
NH 2
36
0
37
0
38
0
39
0
40
0
41
0
42
0
43
0
F
44
1
Methyl
45
1
Ethyl
46
1
Isopropyl
47
1
Butyl
48
1
t-Butyl
49
1
Propyl
50
1
Benzyl
51
1
Vinyl
52
1
Allyl
53
1
CF 3
54
1
55
1
56
1
57
1
58
1
59
1
60
1
NH 2
61
1
62
1
63
1
64
1
65
1
66
1
67
1
68
1
F
69
2
Methyl
70
2
Ethyl
71
2
Isopropyl
72
2
Butyl
73
2
t-Butyl
74
2
Propyl
75
2
Benzyl
76
2
Vinyl
77
2
Allyl
78
2
CF 3
79
2
80
2
81
2
82
2
83
2
84
2
85
2
NH 2
86
2
87
2
88
2
89
2
90
2
91
2
92
2
93
2
F
and
(b) compounds of Formula (X-B),
wherein m and R 1 are set forth for each compound in Table 4:
TABLE 4
Example
m
R 1
94
0
Methyl
95
0
Ethyl
96
0
Isopropyl
97
0
Butyl
98
0
t-Butyl
99
0
Propyl
100
0
Benzyl
101
0
Vinyl
102
0
Allyl
103
0
CF 3
104
0
105
0
106
0
107
0
108
0
109
0
110
0
NH 2
111
0
112
0
113
0
114
0
115
0
116
0
117
0
118
0
F
119
1
Methyl
120
1
Ethyl
121
1
Isopropyl
122
1
Butyl
123
1
t-Butyl
124
1
Propyl
125
1
Benzyl
126
1
Vinyl
127
1
Allyl
128
1
CF 3
129
1
130
1
131
1
132
1
133
1
134
1
135
1
NH 2
136
1
137
1
138
1
139
1
140
1
141
1
142
1
143
1
F
144
2
Methyl
145
2
Ethyl
146
2
Isopropyl
147
2
Butyl
148
2
t-Butyl
149
2
Propyl
150
2
Benzyl
151
2
Vinyl
152
2
Allyl
153
2
CF 3
154
2
155
2
156
2
157
2
158
2
159
2
160
2
NH 2
161
2
162
2
163
2
164
2
165
2
166
2
167
2
168
2
F
or a pharmaceutically acceptable salt or ester thereof.
10. The compound of claim 1 , represented by Formula (X-A) or Formula (X-B),
or a pharmaceutically acceptable salt or ester thereof, wherein R 1 is selected from the groups set forth below:
11. A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable carrier.
12. 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, Type II diabetes, and hepatocellular carcinoma in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound according to claim 1 .
13. The method of claim 12 , wherein the disease or condition is primary biliary cirrhosis.
14. The method of claim 12 , wherein the disease or condition is nonalcoholic steatohepatitis.
15. The method of claim 12 , wherein the disease or condition is nonalcoholic fatty liver disease.