Thyroid hormone receptor ligand, medicinal compositions containing the same and use thereof
The present invention provides a compound represented by general formula (I): or pharmaceutically acceptable salts thereof, wherein W is O, S(O) m , CH 2 and the like; R 1 is halogen, lower alkyl, halo-lower alkyl, CN and the like; R 3 is hydrogen and the like; R 4 is hydrogen, halogen, alkyl, halo-lower alkyl, substituted alkyl, aryl, aralkyl, alkoxy, substituted alkoxy, alkanoyl, aroyl, —CONR 7 (R 8 ), —S(O) m R 9 , —SO 2 NR 7 (R 8 ) and the like; R 5 is hydrogen, halogen, alkyl, substituted alkyl and the like; A is —N(R 6 )CO—A 1 —COR 10 and the like; pharmaceutical compositions containing them and their uses, which have a high affinity to human thyroid hormone receptors, in particular human thyroid hormone receptor β.
1. A compound represented by general formula (I):
wherein
W is —O—;
R 1 is a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group or —CN;
R 2 is a hydrogen atom;
R 3 is a hydroxy group or an acyloxy group;
R 4 is a hydrogen atom, a halogen atom, an alkyl group, a halo-lower alkyl group, a substituted alkyl group, an aryl group, an aralkyl group, an alkoxy group, a substituted alkoxy group, an alkanoyl group, an aroyl group, —CONR 7 (R 8 ), —S(O) m R 9 or —SO 2 NR 7 (R 8 ), or R 3 and R 4 are bonded together to form —NH—CH═(R 9 )—;
R 5 is a hydrogen atom, a halogen atom, an alkyl group, a substituted alkyl group, a hydroxy group, an alkoxy group, a substituted alkoxy group or an aralkyloxy group; m is 0 or an integer of 1 or 2;
R 6 is a hydrogen atom or a lower alkyl group;
each of R 7 and R 8 is independently a hydrogen atom, an alkyl group, a substituted alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group, or R 7 and R 8 , together with the nitrogen atom to which they are bonded, form a cyclic amine;
R 9 is an alkyl group, a substituted alkyl group, a cycloalkyl group, an aryl group or a heteroaryl group;
A represents
—N(R 6 )CO—A 1 —COR 10 ,
R 10 is a hydroxy group, a lower alikoxy group or —NR 11 (R 12 );
each of R 11 and R 12 is independently a hydrogen atom, a lower alkyl group or a substituted lower alkyl group, or R 11 and R 12 , together with the nitrogen atom to which they are bonded, form a cyclic amine;
A 1 is an alkylene group, an alkenylene group or a bond;
a prodrug thereof, or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 , wherein R 1 is a halogen atom or a lower alkyl group, or a pharmaceutically acceptable salt thereof.
3. The compound according to claim 1 , wherein R 4 is an alkyl group, a substituted alkyl group, an aralkyl group, an alkanoyl group or an aroyl group, or a pharmaceutically acceptable salt thereof.
4. The compound according to claim 1 , wherein R 1 is a halogen atom or a lower alkyl group; and R 4 is an alkyl group, a substituted alkyl group, an aralkyl group, an alkanoyl group or an aroyl group, or a pharmaceutically acceptable salt thereof.
5. The compound according to claim 1 , selected from the group consisting of
ethyl N-[6-bromo-7-(4-hydroxy-3-isopropylphenoxy)indan-4-yl]oxamate;
N-[6-bromo-7-(4-hydroxy-3-isopropylphenoxy)indan-4-yl]malonamic acid;
ethyl N-[7-(4-hydroxy-3-isopropylphenoxy)-6-methyl-indan-4-yl]oxamate;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-methylindan-4-yl]malonamic acid;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-methylindan-4-yl]oxamic acid;
N-(7-{3-[(4-fluorophenyl)hydroxymethyl]-4-hydroxy-phenoxy}-6-methylindan-4-yl)malonamic acid;
N-[6-bromo-7-(4-hydroxy-3-isopropylphenoxy)indan-4-yl]oxamic acid;
N-(7-{3-[2-(4-fluorophenyl)ethyl]-4-hydroxyphenoxy}-6-methylindan-4-yl)oxamic acid;
N-(7-{3-[2-(3,4-difluorophenyl)ethyl]-4-hydroxy-phenoxy}-6-methylindan-4-yl)malonamic acid;
N-(7-{3-[2-(4-fluorophenyl)ethyl]-4-hydroxyphenoxy}-6-methylindan-4-yl)malonamic acid;
N-{7-[3-(2-cyclohexylethyl)-4-hydroxyphenoxy]-6-methylindan-4-yl}oxamic acid;
N-{7-[3-ethyl-4-hydroxy-2-(pyridin-3-ylmethoxy)phenoxy]-6-methylindan-4-yl}malonamic acid;
N-[7-(3-ethyl-4-hydroxy-2-phenethyloxyphenoxy)-6-methylindan-4-yl]malonamic acid;
N-(7-{4-hydroxy-3-[2-(3-oxocyclopentyl)ethyl]phenoxy}-6-methylindan-4-yl)oxamic acid;
N-(7-{4-hydroxy-3-[2-(4-hydroxyphenyl)ethyl]phenoxy}-6-methylindan-4-yl)malonamic acid;
N-(7-{4-hydroxy-3-[2-(2-hydroxyphenyl)ethyl]phenoxy}-6-methylindan-4-yl)malonamic acid;
ethyl N-{7-[4-hydroxy-3-(6-oxo-1,6-dihydropyridazin-3-ylmethyl)phenoxy]-6-methylindan-4-yl}oxamate;
N-{7-[4-hydroxy-3-(6-oxo-1,6-dihydropyridazin-3-yl-methyl)phenoxy]-6-methylindan-4-yl}oxamic acid;
ethyl N-[7-(4-hydroxy-3-isopropyl-2-methoxyphenoxy)-6-methylindan-4-yl]oxamate;
N-(7-[4-hydroxy-3-[2-(tetrahydro furan-3-yl)ethyl]phenoxy}-6-methylindan-4-yl)oxamic acid;
N-(7-{3-[2-(3-fluoro-4-hydroxyphenyl)ethyl]-4-hydroxyphenoxy}-6-methylindan-4-yl)oxamic acid;
ethyl N-(7-{4-hydroxy-3-[2-(3-oxocyclopentyl)ethyl]phenoxy}-6-methylindan-4-yl)oxamate;
ethyl N-[7-(4-hydroxy-3-iodophenoxy)-6-methylindan-4-yl]oxamate;
N-[7-(4-hydroxy-3-iodophenoxy)-6-methylindan-4-yl]oxamic acid;
N-[7-(4-hydroxy-3-iodophenoxy)-6-methylindan-4-yl]malonamic acid;
ethyl N-{7-[3-(4-fluorobenzyl)-4-hydroxyphenoxy]-6-methylindan-4-yl}oxamate;
N-{7-[3-(4-fluorobenzyl)-4-hydroxyphenoxy]-6-methyl-indan-4-yl}oxamic acid;
N-{7-[3-(4-fluorobenzyl)-4-hydroxyphenoxy]-6-methyl-indan-4-yl}malonamic acid;
N-{7-[4-hydroxy-3-(tetrahydropyran-4-ylmethyl)phenoxy]-6-methylindan-4-yl}oxamic acid;
N-[7-(4-hydroxy-3-isopropyl-2-methoxyphenoxy)-6-methylindan-4-yl]oxamic acid;
ethyl N-[7-(4-hydroxy-3-trifluoromethylphenoxy)-6-methylindan-4-yl]oxamate;
N-[7-(4-hydroxy-3-trifluoromethylphenoxy)-6-methyl-indan-4-yl]oxamic acid;
ethyl N-[7-(4-hydroxy-3-isopropylphenoxy)-6-trifluoromethylindan-4-yl]oxamate;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-trifluoromethylindan-4-yl]oxamic acid;
ethyl N-[7-(4-hydroxy-3-isopropylphenoxy)-6-iodoindan-4-yl]oxamate;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-iodoindan-4-yl]oxamic acid;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-trifluoromethylindan-4-yl]malonamic acid;
N-[7-(4-hydroxy-3-isopropylphenoxy)-6-iodoindan-4-yl]malonamic acid;
or a pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition which comprises, as an active ingredient, a compound according to claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
7. A pharmaceutical combination comprising a compound according to claim 1 or a pharmaceutically acceptable salt thereof and at least one member selected from the group consisting of an antihyperlipidemic agent, an antiobesity agent, an antidiabetic agent and an antihypertensive agent other than a thyroid hormone receptor ligand.
8. A method for treating hyperlipidemia, atherosclerosis, obesity, diabetes mellitus, or hypothyroidism, which comprises administering an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof.