Phosphorus-containing thyromimetics
The present invention relates to compounds of phosphonic acid-containing T3 mimetics and monoesters thereof, stereoisomers, pharmaceutically acceptable salts, co-crystals, and prodrugs thereof and pharmaceutically acceptable salts and co-crystals of the prodrugs, as well as their preparation and uses for preventing and/or treating metabolic diseases such as obesity, NASH, hypercholesterolemia and hyperlipidemia, as well as associated conditions such as atherosclerosis, coronary heart disease, impaired glucose tolerance, metabolic syndrome x and diabetes.
1. A compound of Formula VIII:
wherein:
G is —CH 2 —;
T is —OCH 2 —;
R 1 and R 2 are each independently selected from the group consisting of —Cl, —Br, —I, —CH 3 , —CF 3 , and CN;
R 4 , R 7 , R 8 , and R 9 are hydrogen;
R 6 is hydrogen or —CH 3 ;
R 3 is selected from the group consisting of —C 1 -C 6 alkyl, —C 3 -C 6 cycloalkyl and —CH 2 -phenyl optionally substituted on phenyl by halogen;
R 5 is —OH;
X is P(O)YR 11 Y′R 11 ;
Y and Y′ are —O— or —NH—;
when Y and Y′ are —O—, R 11 attached to —O— is independently selected from the group consisting of —H, —C(R z ) 2 —OC(O)R y , —C(R z ) 2 —O—C(O)OR y , and optionally substituted CH 2 heterocycloalkyl
when Y and Y′ are —NH— R 11 attached to —NH— is independently selected from the group consisting of H and —C(R x ) 2 —COOR y ;
each R z is independently —H or C 1 -C 4 alkyl;
R y is C 1 -C 4 alkyl;
each R x is independently —H or C 1 -C 4 alkyl;
or a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein R 1 and R 2 are each —CH 3 .
3. The compound of claim 1 , wherein Y and Y′ are each —NH—.
4. The compound of claim 3 , wherein R 11 attached to —NH— is —C(R x ) 2 —COOR y .
5. The compound of claim 1 , wherein Y and Y′ are —O—.
6. The compound of claim 5 , wherein R 11 attached to —O— is —H or a pharmaceutically acceptable salt thereof.
7. The compound of claim 5 , wherein R 11 attached to —O— is selected from the group consisting of —C(R z ) 2 —OC(O)R y and —C(R z ) 2 —O—C(O)OR y .
8. A compound selected from the group consisting of:
9. A compound:
10. A compound:
11. A compound selected from the group consisting of:
12. A compound selected from the group consisting of:
13. A pharmaceutical composition comprising a compound of any one of claims 1 - 12 and a pharmaceutically acceptable excipient, carrier, or diluent.
14. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition in a form selected from the group consisting of a controlled release composition, transdermal patch, tablet, hard capsule, and soft capsule.
15. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition comprises a crystalline form of said compound.
16. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition comprises a salt form of said compound.
17. The pharmaceutical composition of claim 13 wherein said pharmaceutical composition is administered orally in a unit dose of about 0.375 μg/kg to 3.75 mg/kg.
18. The new pharamaceutical compostion of claim 13 wherein said pharmaceutical composition is administered orally in a total daily dose of about 0.375 μg/kg/day to about 3.75 mg/kg/day, equivalent of the free acid.