Thyromimetics with a biphenylmethane scaffold and their use
The invention concerns a compound of Formula (I) or a salt thereof, wherein R 1 is H, (C 1 -C 3 )alkyl or CF 3 ; R 2 is H, (C 1 -C 3 )alkyl or CF 3 ; A is CH 2 COOH, XCH 2 COOCH 2 CH 3 , XCH 2 COOH, XCH 2 CH 2 NH 2 , where X is nitrogen or oxygen atom; Ar is an aromatic fragment selected from the group consisting of (Ar1), (Ar2) and (Ar3); where R 3 is H, —CH 3 , —CH 2 CH 3 or CH 3 CO—, R 4 is H or —CH 3 , R5 is H or —CH 3 , and R 6 is H or —CH 3 . The compounds of Formula (I) can be used in the treatment of diseases modulated by thyroid hormone receptor-beta (TRb or TRβ).
1. A compound of Formula (I) or a salt thereof:
Wherein
R 1 is H, (C 1 -C 3 )alkyl or CF 3 ;
R 2 is H, (C 1 -C 3 )alkyl or CF 3 ;
A is CH 2 COOH, XCH 2 COOCH 2 CH 3 , XCH 2 COOH, XCH 2 CH 2 NH 2 , where X is nitrogen or oxygen atom;
Ar is an aromatic fragment selected from the group consisting of
where
R 3 is H, —CH 3 , —CH 2 CH 3 or CH 3 CO—,
R 4 is H or —CH 3 ,
R 5 is H or —CH 3 , and
R 6 is H or —CH 3 .
2. The compound of claim 1 wherein R 1 is (C 1 -C 3 )alkyl.
3. The compound of claim 1 , wherein R 2 is (C 1 -C 3 )alkyl.
4. The compound of claim 1 , wherein A is XCH 2 COOH.
5. The compound of claim 4 , wherein X is oxygen.
6. The compound of claim 1 , wherein Ar è Ar1.
7. The compound of claim 6 , wherein R 3 is CH 3 CO—.
8. The compound of claim 1 , wherein Ar is Ar2 or Ar3.
9. The compound of claim 8 , wherein R 6 and R 4 are independently from each other —CH 3 .
10. The compound of claim 1 , wherein the compound of Formula (I) is selected from the group consisting of:
2-(4-(4-amino-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (IS25),
4-(4-(2-aminoethoxy)-2,6-dimethylbenzyl)-N-ethyl-2-isopropylaniline (IS62),
2-(4-(4-amino-3-isopropylbenzyl)-3-methylphenoxy)acetic acid (TR29)
(4-(4-acetamido-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (TG68),
4-(4-(2-aminoethoxy)-2-(trifluoromethyl)benzyl)-N-ethyl-2-isopropylaniline hydrochloride (EP54),
2-(4-(4-amino-3-isopropylbenzyl)-3-(trifluoromethyl)phenoxy)acetic acid (TR30),
2-(4-(4-acetamido-3-isopropylbenzyl)-3-(trifluoromethyl)phenoxy)acetic acid (TR45),
2-(4-(4-acetamido-3-isopropylbenzyl)phenoxy)acetic acid (GM23),
2-(4-(4-amino-3-isopropylbenzyl)phenoxy)acetic acid (GM33),
2-(4-(4-acetamido-3-isopropylbenzyl)-3-methylphenoxy)acetic acid (GM21),
(4-(4-acetamido-3-isopropylbenzyl)phenyl)glycine (PA8),
ethyl (4-(4-acetamido-3-isopropylbenzyl)phenyl)glycinate (PA6),
N 1 -(4((8-methoxy-2-methylquinolin-5-yl)methyl)phenyl)ethane-1,2-diamine (GM10), 2-((4-((8-methoxy-2-methylquinolin-5-yl)methyl)phenyl)amino)acetic acid (GM24),
(4-((1-methyl-1H-indol-5-yl)methyl)phenyl)glycine (TR201), and
2-(4-(4-acetamido-3-isopropylbenzyl)-3-methylphenyl)acetic acid (RM81).
11. The compound of claim 10 , wherein the compound of Formula (I) is selected from the group consisting of 2-(4-(4-acetamido-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (TG68) and 2-(4-(4-amino-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (IS25).
12. A pharmacological composition comprising the compound of Formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 and a carrier.
13. A method for the treatment of diseases modulated by thyroid hormone receptor-beta (TRb or TRβ), wherein the diseases modulated by thyroid hormone receptor-beta (TRb or TRβ) are liver diseases, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), hepatocellular carcinoma (HCC), dyslipidemia, neurodegenerative diseases, multiple sclerosis, Alzheimer's disease and Parkinson's disease (PD), comprising the step of administering the compound of formula (I) or a pharmaceutically acceptable salt thereof according to claim 1 .
14. The compound of claim 1 , wherein R 1 is methyl.
15. The compound of claim 1 , wherein R 2 is methyl.
16. The pharmaceutical composition according to claim 12 , wherein the compound of Formula (I) or a pharmaceutically salt thereof is a selective modulator of thyroid hormone receptor-beta (TRβ).