Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Ester doai
Reexamination Certificate
2002-12-06
2004-12-14
Raymond, Richard L. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Ester doai
C514S534000, C514S535000, C514S563000, C514S569000, C560S027000, C560S029000, C560S030000, C560S045000, C560S047000, C560S048000, C562S455000, C562S456000, C562S457000
Reexamination Certificate
active
06831102
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to novel phenyl naphthol compounds which are thyroid receptor ligands and are preferably selective for the thyroid hormone receptor &bgr;. Further, the present invention relates to methods for using such compounds and to pharmaceutical compositions containing such compounds.
BACKGROUND OF THE INVENTION
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 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, metabolic rate, body temperature and mood, and influence blood levels of serum low density lipoprotein (LDL). Thus, in hypothyroidism there is weight gain, high levels of LDL cholesterol, and depression. In 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 T
4
) and triiodothyronine (3,5,3′-triiodo-L-thyronine, or T
3
). However, replacement therapy, particularly in older individuals, may be restricted by certain detrimental effects from 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 ligands, particularly agonists of the thyroid hormone receptor could lead to specific therapies for these common disorders, while avoiding the cardiovascular and other toxicity of native thyroid hormones. Tissue-selective thyroid hormone agonists 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. 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 suggests 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 cardiac rhythm and rate influences of the hormones, but would elicit many other actions of the hormones. Applicants believe that the &agr;-form of the receptor is primarily associated with heart rate function 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 T
4
and T
3
;
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 mice resulted in a slower mouse heart rate, as compared to control mice; and
4) western blot analysis of human myocardial TRs 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 it may be possible that 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 illustrative embodiments and demonstrating features of the present invention, compounds are provided which are thyroid receptor ligands, and have the general formula I:
wherein;
R
1
is halogen, trifluoromethyl, substituted or unsubstituted aryl, substituted or unsubstituted C
1-6
alkyl, or substituted or unsubstituted C
3-7
cycloalkyl;
R
2
and R
3
are each independently hydrogen, halogen, substituted or unsubstituted C
1-4
alkyl, or substituted or unsubstituted C
3-6
cycloalkyl, wherein at least one of R
2
and R
3
is other than hydrogen;
R
4
is a carboxylic acid, or an ester thereof, selected from the group consisting of (CH
2
)
n
COOH, (CH)
2
COOH, NHCO(CH
2
)
n
COOH, CONH(CH
2
)
n
COOH and NH(CH
2
)
m
COOH;
n is an integer from 0 to 4; and
m is an integer from 1 to 4,
including all prodrug-esters, stereoisomers and pharmaceutically acceptable salts of formula I.
The compounds of formula I are thyroid hormone receptor ligands, and include compounds which are, for example, selective agonists, partial agonists, antagonists or partial antagonists of the thyroid receptor. Preferably the compounds of formula I possess activity as agonists of the thyroid receptor, preferably selective agonists of the thyroid receptor-beta, and may be used in the treatment of diseases or disorders associated with thyroid receptor activity. In particular, the compounds of formula I may be used in the treatment of diseases or disorders associated with metabolism dysfunction or which are dependent upon the expression of a T
3
regulated gene, such as obesity, hypercholesterolemia, atherosclerosis, cardiac arrhythmias, depression, osteoporosis, hypothyroidism, goiter, thyroid cancer, glaucoma, skin disorders or diseases and congestive heart failure.
The present invention provides for compounds of formula I, pharmaceutical compositions employing such compounds and for methods of using such compounds. In particular, the present invention provides for a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, alone or in combinatio
Bristol--Myers Squibb Company
O'Brien Maureen P.
Provoost Jonathan N.
Raymond Richard L.
Tucker Zachary C.
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