3-benzoyl benzofuran derivatives as thyroid hormone antagonists

Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...

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549468, 549469, A61K 3134

Patent

active

058542825

DESCRIPTION:

BRIEF SUMMARY
BACKGROUND OF THE INVENTION

1. Field of the Invention
This invention relates to organic compounds which function as nuclear receptor ligands and particularly as thyroid hormone antagonists.
2. Description of the Prior Art
Thyroid hormones have various effects on metabolism and oxygen consumption and in particular affect the heart. Thyroid hormones bind to nuclear thyroid hormone receptors. The complex formed by the thyroid hormone and the nuclear receptor binds to particular DNA patterns, termed "thyroid responsive elements" (TRE) in the promoter region of 3,5,3'-triiodothyronine (T-3)-regulated genes. The genes may be positively or negatively regulated.
In our International patent application no. PCT/SE92/00307, published as W092/20331, we disclose a selection of organic compounds which can function as receptor ligands for T3 that is to say as thyroid hormone antagonists.


SUMMARY OF THE INVENTION

It is an object of the present invention to provide new and improved compounds and in particular compounds which can act as thyroid hormone antagonists.
According to one aspect of the present application there are provided compounds with the following general formula: ##STR2## in which: Ha=I or Br
For example, the compound may be selected from 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulphona midobenzofuran; 2-n-butyl-3,5-diiodo-4-carboxymethoxybenzoyl)-5-isopropylamidobenzofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)ben zofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)ben zofuran; 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzyl)-5-trifluoromethylsulphon amidobenzofuran; 2-isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-trifluoromethylsulpho namidobenzofuran; 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)b enzofuran; 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)b enzofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-fluorobenzamido)benz ofuran; 2-Isopropyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-nitrobenzamido)ben zofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxyphenylureido) benzofuran; 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxyphenylureido) benzofuran; 2-n-Butyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido)be nzofuran; 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)- 5-(4-methoxybenzamido)benzofuran; 2-Isopropyl-3-(3,5-dibromo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido) benzofuran.
The compound is preferably 2-n-Butyl-3-(3,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-methoxybenzamido)ben zofuran; or 2-n-Butyl-3-(3 ,5-diiodo-4-carboxymethoxybenzoyl)-5-(4-hydroxybenzamido) benzofuran.
The compounds of the present invention have an equal or better receptor binding affinity than the thyroid hormone antagonist compounds known in the prior art. The compounds of the present invention have not been described in the literature.
The compounds of the present invention may be used in the treatment of disorders which are dependent on the expression of T-3-regulated genes for example, heart arrhythymia, heart failure and hyperthyroidism.
According to another aspect of the present invention there is provided a pharmaceutical composition comprising an effective amount of a compound according to the present invention or a pharmaceutically effective salt thereof together with, if necessary, a suitable carrier.
According to another aspect of the present invention there is provided a method of treating a patient with a T-3-regulated gene disorder, comprising administering a compound according to the present invention or a pharmaceutically acceptable salt thereof, if necessary, in a suitable carrier, to the patient. The disorder may be for example, heart arrhythmia, heart failure, or hyperthyroidism.


DESCRIPTION OF THE FIGURES

The preparations of compounds in accordance with the present invention and tests on their activity will now be described, by way of example only, with reference to the following exam

REFERENCES:
patent: 4255585 (1981-03-01), Thuillier nee Nachmias et al.
patent: 4851554 (1989-07-01), Kennedy et al.

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