Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2000-03-20
2002-10-15
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C562S474000, C562S008000, C562S023000, C560S055000, C560S065000, C558S070000, C558S177000, C558S202000, C558S207000, C558S388000, C558S402000, C568S635000, C568S636000, C568S639000
Reexamination Certificate
active
06465687
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to novel compounds which are thyroid receptor ligands, and are preferably selective for the thyroid hormone receptor &bgr;, to methods of preparing such compounds and to methods for using such compounds such as in the regulation of metabolism.
2. Brief Description of the Prior Art
While the extensive role of thyroid hormones in regulating metabolism in humans is well recognized, the discovery and development of new specific drugs for improving the treatment of hyperthyroidism and hypothyroidism has been slow. This has also limited the development of thyroid hormone agonists and antagonists for treatment of other important clinical indications, such as hypercholesterolemia, obesity and cardiac arrhythmias.
Thyroid hormones affect the metabolism of virtually every cell of the body. At normal levels, these hormones maintain body weight, the metabolic rate, body temperature, and mood, and influence serum low density lipoprotein (LDL) levels. Thus, in hypothyroidism there are weight gain, high levels of LDL cholesterol, and depression. In excess with hyperthyroidism, these hormones lead to weight loss, hypermetabolism, lowering of serum LDL levels, cardiac arrhythmias, heart failure, muscle weakness, bone loss in postmenopausal women, and anxiety.
Thyroid hormones are currently used primarily as replacement therapy for patients with hypothyroidism. Therapy with L-thyroxine returns metabolic functions to normal and can easily be monitored with routine serum measurements of levels of thyroid-stimulating hormone (TSH), thyroxine (3,5,3′,5′-tetraiodo-L-thyronine, or T4) and triiodothyronine (3,5,3′-triiodo-L-thyronine, or T3). However, the rapidity with which replacement therapy can be given and in some circumstances, particularly in older individuals, even replacement therapy, is limited by certain of the deleterious effects of thyroid hormones.
In addition, some effects of thyroid hormones may be therapeutically useful in non-thyroid disorders if adverse effects can be minimized or eliminated. These potentially useful influences include weight reduction, lowering of serum LDL levels, amelioration of depression and stimulation of bone formation. Prior attempts to utilize thyroid hormones pharmacologically to treat these disorders have been limited by manifestations of hyperthyroidism, and in particular by cardiovascular toxicity.
Development of specific and selective thyroid hormone receptor agonists could lead to specific therapies for these common disorders while avoiding the cardiovascular and other toxicities of native thyroid hormones. Tissue-selective thyroid hormone agonist may be obtained by selective tissue uptake or extrusion, topical or local delivery, targeting to cells through other ligands attached to the agonist and targeting receptor subtypes. Thyroid hormone receptor agonists that interact selectively with the &bgr;-form of the thyroid hormone receptor offers an especially attractive method for avoiding cardio-toxicity.
Thyroid hormone receptors (TRs) are, like other nuclear receptors, single polypeptide chains. The various receptor forms appear to be products of two different genes &agr; and &bgr;. Further isoform differences are due to the fact that differential RNA processing results in at least two isoforms from each gene. The TR&agr;1, TR&bgr;1 and TR&bgr;2 isoforms bind thyroid hormone and act as ligand-regulated transcription factors. In adults, the TR&bgr;1 isoform is the most prevalent form in most tissues, especially in the liver and muscle. The TR&agr;2 isoform is prevalent in the pituitary and other parts of the central nervous system, does not bind thyroid hormones, and acts in many contexts as a transcriptional repressor. The TR&agr;1 isoform is also widely distributed, although its levels are generally lower than those of the TR&bgr;1 isoform. This isoform may be especially important for development. Whereas many mutations in the TR&bgr; gene have been found and lead to the syndrome of generalized resistance to thyroid hormone, mutations leading to impaired TR&agr; function have not been found.
A growing body of data suggest that many or most effects of thyroid hormones on the heart, and in particular on the heart rate and rhythm, are mediated through the &agr;-form of the TR&agr;1 isoform, whereas most actions of the hormone such as on the liver, muscle and other tissues are mediated more through the &bgr;-forms of the receptor. Thus, a TR&bgr;-selective agonist might not elicit the rhythm and rate influences of the hormones but would elicit many other actions of the hormones. It is believed that the &agr;-form of the receptor is the major drive to heart rate for the following reasons:
1) tachycardia is very common in the syndrome of generalized resistance to thyroid hormone in which there are defective TR&bgr;-forms, and high circulating levels of T4 and T3;
2) there was a tachycardia in the only described patient with a double deletion of the TR&bgr; gene (Takeda et al, J. Clin. Endrocrinol. & Metab. 1992, Vol. 74, p. 49);
3) a double knockout TR&agr; gene (but not &bgr;-gene) in the mouse has a slower pulse than control mice; and,
4) western blot analysis of human myocardial TR's show presence of the TR&agr;1, TR&agr;2 and TR&bgr;2 proteins, but not TR&bgr;1.
If these indications are correct, then a TR&bgr;-selective agonist could be used to mimic a number of thyroid hormone actions, while having a lesser effect on the heart. Such a compound may be used for: (1) replacement therapy in elderly subjects with hypothyroidism who are at risk for cardiovascular complications; (2) replacement therapy in elderly subjects with subclinical hypothyroidism who are at risk for cardiovascular complications; (3) obesity; (4) hypercholesterolemia due to elevations of plasma LDL levels; (5) depression; and, (6) osteoporosis in combination with a bone resorption inhibitor.
SUMMARY OF THE INVENTION
In accordance with the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I:
in which:
R
1
is alkyl of 1 to 6 carbons or cycloalkyl of 3 to 7 carbons;
R
2
and R
3
are the same or different and are hydrogen, halogen, alkyl of 1 to 4 carbons or cycloalkyl of 3 to 5 carbons, at least one of R
2
and R
3
being other than hydrogen;
n is an integer from 0 to 4;
R
4
is an aliphatic hydrocarbon, an aromatic hydrocarbon, carboxylic acid or ester thereof, alkenyl carboxylic acid or ester thereof, hydroxy, halogen, cyano, or a phosphonic acid or ester thereof, or a pharmaceutically acceptable salt thereof, and all stereoisomers thereof.
In addition, in accordance with the present invention, a method for preventing, inhibiting or treating a disease associated with metabolism dysfunction or which is dependent upon the expression of a T3 regulated gene is provided, wherein a compound of formula I is administered in a therapeutically effective amount. The compound of formula I is preferably an agonist that is preferably selective for the thyroid hormone receptor-beta. Examples of such diseases associated with metabolism dysfunction or are dependent upon the expression of a T3 regulated gene are set out hereinafter and include obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer as well as glaucoma and congestive heart failure.
DETAILED DESCRIPTION OF THE INVENTION
The following definitions apply to the terms as used throughout this specification, unless otherwise limited in specific instances.
The term “thyroid receptor ligand” as used herein is intended to cover any moiety which binds to a thyroid receptor. The ligand may act as an agonist, an antagonist, a partial agonist or a partial antagonist.
The term “aliphatic hydrocarbon(s) as used herein refers to acyclic straight or branched chain groups which include alkyl, alkenyl or alkynyl groups.
The term “aromatic hydrocarbon(s) as used herein refers to groups including aryl groups as defined herein
Hedfors Asa
Li Yi-Lin
Liu Ye
Malm Johan
Mellin Charlotta
Garabedian Todd E.
Karo Bio AB
Wiggin & Dana
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