Deuterated GFT-505
This invention relates to novel deuterated forms of GFT-505, and pharmaceutically acceptable salts thereof. This invention also provides compositions comprising a compound of this invention and the use of such compositions in methods of treating diseases and conditions that are characterized by reduced PPAR-alpha and/or PPAR-delta activity.
1. A compound of Formula I:
or a pharmaceutically acceptable salt thereof, wherein:
each of R 1 , R 2 , R 3 , R 4a and R 4b is independently selected from —CH 3 , —CH 2 D, —CHD 2 and —CD 3 ;
each of Y 1 and Y 2 is independently selected from hydrogen and deuterium; and
when each of R 1 , R 2 , R 3 , R 4a and R 4b is —CH 3 , then at least one of Y 1 and Y 2 is deuterium,
wherein each position in Formula I that is designed as containing deuterium has at least 50.1% deuterium incorporation at that position.
2. The compound of claim 1 , wherein each of R 1 , R 2 , R 3 , R 4a and R 4b is independently selected from —CH 3 and —CD 3 .
3. The compound of claim 2 , wherein at least one of R 1 , R 2 , or R 3 is —CD 3 .
4. The compound of claim 3 , wherein at least one of R 1 , R 2 , or R 3 is —CH 3 .
5. The compound of claim 2 , wherein at least two of R 1 , R 2 , or R 3 is —CD 3 .
6. The compound of claim 2 , wherein each of R 1 , R 2 and R 3 is —CD 3 .
7. The compound of any one of claims 1 , wherein R 4a and R 4b are the same.
8. The compound of claim 7 , wherein R 4a and R 4b are both —CD 3 .
9. The compound of claim 7 , wherein R 4a and R 4b are both —CH 3 .
10. The compound of any one of claims 1 , wherein each of Y 1 and Y 2 are the same.
11. The compound of claim 10 , wherein Y 1 and Y 2 are both hydrogen.
12. The compound of claim 1 , wherein R 4a and R 4b are the same; Y 1 and Y 2 are the same; and the compound is selected from any one of the compounds set forth below:
Compound
R 1
R 2
R 3
R 4a /R 4b
Y 1 /Y 2
101
CH 3
CH 3
CD 3
CH 3
H
102
CH 3
CD 3
CH 3
CH 3
H
103
CD 3
CH 3
CH 3
CH 3
H
104
CD 3
CH 3
CD 3
CH 3
H
105
CD 3
CD 3
CH 3
CH 3
H
106
CH 3
CD 3
CD 3
CH 3
H
107
CD 3
CD 3
CD 3
CH 3
H
108
CH 3
CH 3
CD 3
CD 3
H
109
CH 3
CD 3
CH 3
CD 3
H
110
CD 3
CH 3
CH 3
CD 3
H
111
CD 3
CH 3
CD 3
CD 3
H
112
CD 3
CD 3
CH 3
CD 3
H
113
CH 3
CD 3
CD 3
CD 3
H
114
CD 3
CD 3
CD 3
CD 3
H
115
CH 3
CH 3
CD 3
CH 3
D
116
CH 3
CD 3
CH 3
CH 3
D
117
CD 3
CH 3
CH 3
CH 3
D
118
CD 3
CH 3
CD 3
CH 3
D
119
CD 3
CD 3
CH 3
CH 3
D
120
CH 3
CD 3
CD 3
CH 3
D
121
CD 3
CD 3
CD 3
CH 3
D
122
CH 3
CH 3
CD 3
CD 3
D
123
CH 3
CD 3
CH 3
CD 3
D
124
CD 3
CH 3
CH 3
CD 3
D
125
CD 3
CH 3
CD 3
CD 3
D
126
CD 3
CD 3
CH 3
CD 3
D
127
CH 3
CD 3
CD 3
CD 3
D
128
CD 3
CD 3
CD 3
CD 3
D
129
CH 3
CH 3
CH 3
CH 3
D
130
CH 3
CH 3
CH 3
CD 3
H
or a pharmaceutically acceptable salt thereof.
13. The compound of any one of claims 1 , wherein each position in Formula I that is designated as containing deuterium has at least 90% deuterium incorporation at that position.
14. The compound of any one of claims 1 , wherein any atom not designated as deuterium is present at its natural isotopic abundance.
15. A pharmaceutical composition comprising a compound of claim 1 ; and a pharmaceutically acceptable carrier.
16. A method of agonizing PPAR-α and/or PPAR-δ in a mammalian cell comprising the step of contacting the cell with a compound of claim 1 .
17. A method of treating a liver disorder characterized by the pathological disruption, inflammation, degeneration, and/or proliferation of liver cells, wherein the plasma level of Alanine aminotransferase (ALAT), Aspartate aminotransfersase (ASAT), Alkaline Phosphatase (AP), Gamma Glutamyl transpeptidase (GGT), Cytokeratin-18 (CK-18), Resistin or a combination thereof is elevated when compared to normal plasma levels comprising the step of administering to a subject in need thereof the composition of claim 15 .
18. A method of treating a disease or condition selected from fatty liver disease, atherosclerosis, type 2 diabetes, dyslipidemia, insulin resistance, impaired glucose tolerance, non-alcoholic steatohepatitis, liver cancer, cirrhosis, and hepatic fibrosis comprising the step of administering to a subject in need thereof the composition of claim 15 .
19. The method of claim 18 , wherein the disease or condition is selected from type 2 diabetes, atherogenic dyslipidemia, insulin resistance, impaired glucose tolerance, non-alcoholic steatohepatitis, and non-alcoholic fatty liver disease.
20. A method of agonizing PPAR-α and/or PPAR-δ in a mammalian cell comprising the step of contacting the cell with pharmaceutical composition of claim 15 .
21. The compound of claim 1 , wherein each position in Formula I that is designated as containing deuterium has at least 95% deuterium incorporation at that position.
22. The compound of claim 1 , wherein each position in Formula I that is designated as containing deuterium has at least 97% deuterium incorporation at that position.
23. The compound of claim 1 , wherein R 4a and R 4b are the same; Y 1 and Y 2 are the same; and the compound is selected from any one of the compounds set forth below:
Compound
R 1
R 2
R 3
R 4a /R 4b
Y 1 /Y 2
103
CD 3
CH 3
CH 3
CH 3
H
106
CH 3
CD 3
CD 3
CH 3
H
107
CD 3
CD 3
CD 3
CH 3
H
110
CD 3
CH 3
CH 3
CD 3
H
113
CH 3
CD 3
CD 3
CD 3
H
114
CD 3
CD 3
CD 3
CD 3
H
130
CH 3
CH 3
CH 3
CD 3
H
or a pharmaceutically acceptable salt thereof.