Receptor ligands

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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Details

549462, 549468, 549471, A61K 3134, C07D30780

Patent

active

055677282

DESCRIPTION:

BRIEF SUMMARY
This application is the national phase of PCT SE 92/00307 filed on May 12, 1992.
The present invention relates to receptor ligands. More specifically it relates to the use of 3,5,3'-triiodothyronine (T-3) receptor ligands, and some new T-3 receptor ligands, which are T-3 antagonists.


BACKGROUND

Thyroid hormones have widespread effect on the rate of metabolism and oxygen consumption. They have notably profound effects on the heart, both on the strength and rate of the contractions. Marked changes in cardiac function occur in patients with hyper- or hypothyroidism. Cardiac contractility is increased in the hyperthyroid state and decreased in hypothyroidism and changes in specific proteins accompany these alterations.
The effect of thyroid hormone is mediated through binding of the hormone to thyroid hormone receptors which are nuclear proteins. The ligand-receptor complex binds to specific DNA motifs so called thyroid responsive elements (TRE) located in the promoter region of 3,5,3'-triiodothyronine (T-3) regulated genes. Through interaction with the transcriptional machinery of the cell, composed of ubiquitous and cell specific factors, the expression of the gene is positively or negatively regulated. Examples of genes of importance for cardiac function which are regulated by T-3 are the myosin heavy chains, .beta. adrenergic receptors and Na+K+ATPase.
Amiodarone, which for long has been used in therapy against many types of arrhythmias, acts as a competitive antagonist to thyroid action as defined by its dose dependent ability to 1) compete with T-3 binding to the thyroid hormone receptor and 2) inhibit T-3 induced increase in rat growth hormone (rGH) mRNA levels in cultured rat pituitary cells (Latham et al., J. Am. Coll. Cardiol Vol 9 (1987) pp 872-6; Norman and Lavin, J. Clin. Invest Vol 83 (1989) pp.)
The chemical structures of the T-3 receptor ligands disclosed herein are similar to that of amiodarone. Further, said ligands are T-3 antagonists. Thus, they are useful in the treatment of disorders which depend on the expression of T-3 regulated genes, such as heart arrhythmia and hyperthyroidism.


DESCRIPTION OF THE INVENTION

One aspect of the invention is directed to the use of a compound selected from the group consisting of


______________________________________ 3,5-diiodo-4-(2-N,N-diethylaminoethoxy)phenyl- (001) (2-butylbenzofur-3-yl)methanol hydrochloride 2-methyl-3-(3,5-diiodo-4-(2-N,N-diethylamino- (003) ethoxy)-benzoyl)benzofuran hydrochloride 2-n-butyl-3-(3,5-diiodo-4-carboxymethoxy- (005) benzoyl)benzofuran 2-methyl-3-(3,5-diiodo-4-hydroxy-benzoyl)benzofuran (011) 2-methyl-3-(3,5-diiodo-4-carboxymethoxy- (015) benzyl)benzofuran 4'-hydroxy-3'-iodo-3,5 diiodo-4-(2-N,N-dimethylamino- (024) ethoxy)benzophenon hydrochloride 2-butyl-3-(3-iodo-4-hydroxybenzoyl)benzofuran (029) 4',4-dihydroxy-3'3,5-triiodo-diphenylmethan (032) ______________________________________ preparation of a medicament for the therapeutic or prophylactic treatment of a disorder which depends on the expression of T-3 regulated genes.
The above compound (011) has been previously published and e.g. reported (Compt. Rend. 253 (1961) p. 1075-1076; CA 57:10497c) to have spasmolytic activity on isolated intestine of the guinea-pig and some dilatory effects on the coronary vessels of the heart of the rabbit.
Disorders which are believed to be dependent on the expression of T-3 regulated genes are i.a. heart arrhythmia and hyperthyroidism. In one embodiment of this aspect of the invention the above listed compounds are used for the treatment of at least one of, heart arrhythmia and hyperthyroidism.
Another aspect of the invention is directed to a method of prophylactically or therapeutically treating a patient having a disorder which depends on the expression of 3,5,3'-triiodothyronine (T-3) regulated genes, which method comprises administering to said patient a pharmacologically effective amount of a compound selected from the group consisting of


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REFERENCES:
patent: 3248401 (1966-04-01), Tondeur
Lazav, MA, Chin WW. `Nuclear Thyroid Hormone Receptor` J. Clin. Invest. 86 pp. 1777-80, 1990.
Drug Facts and Comparisons, 1994, edition.
Facts and Comparisons, St. Louis, Woltens Kluwen Co. pp. 701-707.
Kabalka GW, Kennedy TP, Gondgaon N M. Varma R S. Org. Prep. Proced. Int. 21(3) 348-351 (1989).

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