Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-04-17
2003-09-16
Gerstl, Robert (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S183000
Reexamination Certificate
active
06620830
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to certain thiazolidinedione, oxadiazolidinedione, and triazolone compounds which are thyroid receptor ligands.
The invention further relates to pharmaceutical compositions and kits comprising such thiazolidinedione, oxadiazolidinedione, and triazolone compounds and to methods of using such compounds in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis.
BACKGROUND OF THE INVENTION
Thyroid hormones are critical for normal development and for the maintenance of metabolic homeostasis. As such, thyroid hormones are known to stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones further affect cardiac function both directly and indirectly, e.g., by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance and increased pulse pressure are all observed in patients with hyperthyroidism.
Disorders of the thyroid gland resulting in decreased levels of thyroid hormones are normally treated by administering either naturally occurring thyroid hormones or analogues thereof that mimic the effects of thyroid hormones. Such analogues are known generically as thyromimetics or thyroid receptor ligands.
Two naturally occurring thyroid hormones, 3,5,3′-triiodo-L-thyronine (also referred to as “T
3
”), and 3,5,3′,5′-tetraiodo-L-thyronine (also referred to as “T
4
” or thyroxine), are depicted hereinbelow:
Generally, T
3
is more biologically active than T
4
, and differs therefrom by the absence of an iodine atom in the 5′ position. T
3
may be produced directly, in either the thyroid gland or in peripheral tissues, by removal of the 5′ iodine of T
4
by deiodinase enzymes. Synthetic thyroid receptor ligands can be designed to be structurally similar to T
3
. In addition, naturally occurring metabolites of T
3
are known.
As discussed hereinabove, thyroid hormones may affect cardiac functioning, for example, by causing an increase in heart rate and, accordingly, an increase in oxygen consumption. While the increase in oxygen consumption can result in certain desirable metabolic effects, such increase places additional burden on the heart which, in many situations, results in detrimental side effects. Consequently, efforts have been made to synthesize thyroid hormone analogs/mimetics that function to lower lipids and serum cholesterol, but which have reduced adverse cardiac effects.
A variety of thyroid hormone analogs/mimetics are described and referenced hereinbelow, however, additional agents will be known to one of ordinary skill in the art. For example, U.S. Pat. Nos. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose thyroid hormone mimetics, namely, 3,5-dibromo-3′-[6-oxo-3(1H)-pyridazinylmethyl]-thyronines, while U.S. Pat. No. 5,284,971 discloses thyromimetic cholesterol lowering agents, namely, 4-(3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl)-3,5 dibromo-phenylacetic compounds. Furthermore, U.S. Pat. Nos. 5,654,468 and 5,569,674 disclose certain lipid lowering agents, namely, heteroacetic acid derivatives, which compete with radiolabeled T
3
in binding assays using rat liver nuclei and plasma membrane preparations. Still further, certain oxamic acids and derivatives thereof are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of oxamic acids in preventing immediate type hypersensitivity reactions, U.S. Pat. No. 4,554,290 describes the use of oxamic acids to control pests on animals and plants, U.S. Pat. No. 5,232,947 describes the use of oxamic acids to improve damaged cerebral functions of the brain, and European Application Publication No. EP 0 580 550 (also U.S. Pat. No. 5,401,772) discloses oxamic acid derivatives as hypocholesterolemic agents. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. See, for example, Yokoyama et al.,
J. Med. Chem.,
38 (4), 695-707 (1995), Steele et al., International Congressional Service (Atherosclerosis X) 106, 321-324 (1995), and Stephan et al., Atherosclerosis, 126, 53-63 (1996).
Obesity is a major health risk that leads to increased mortality and incidence of Type 2 diabetes mellitus, hypertension, and dyslipidemia. In the United States, more than 50% of the adult population is overweight, and almost ¼ of the population is considered to be obese. The incidence of obesity is increasing in the United States at a three-percent cumulative annual growth rate. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. The prevalence of obesity in adults is 10-20% in most countries of western Europe. Furthermore, obesity is a devastating disease which can also wreak havoc on an individual's mental health and self-esteem, which can ultimately affect a person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and societal stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Because of the impact of obesity on society in general, much effort has been expended in efforts to treat obesity, however, success in the long-term treatment and/or prevention thereof remains elusive.
The thyroid receptor ligands of the present invention can be used to treat obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias (including atrial and ventricular arrhythmias), skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis.
The diabetic disease state is characterized by an impaired glucose metabolism that manifests itself in, inter alia, elevated glucose levels in patients suffering therefrom. Generally, diabetes is classified into two distinct subgroups:
(1) Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which arises when patients lack &bgr;-cells producing insulin in their pancreatic glands, and
(2) Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients with, inter alia, impaired &bgr;-cell function.
At present, Type 1 diabetic patients are treated with insulin, while the majority of Type 2 diabetic patients are treated with hypoglycemic agents, such as sulfonylureas that stimulate &bgr;-cell function, with other agents that enhance the tissue selectivity of the patients towards insulin, or with insulin itself. Unfortunately, the use of insulin currently requires multiple daily doses, normally administered by self-injection, with determination of the proper dosage of insulin requiring frequent estimations of the sugar in urine or blood, performed either by the patient or the administering physician. The unintended administration of an excess dose of insulin can result in hypoglycemia, with adverse effects ranging from mild abnormalities in blood glucose to coma, or even death. Although hypoglycemic agents agents such as sulfonylureas have been employed widely in the treatment of NIDDM, this treatment is, in many instances, not completely satisfactory. In a large number of NIDDM patients, sulfonylureas have proven ineffective in normalizing blood sugar levels of patients, thereby leading to an increased risk of acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment with sulfonylureas and are thus gradually forced into insulin treatment. Since many extant forms of diabetic therapy have proven ineffective achieving satisfactory glycemic control, there continues to be a great demand for novel
Gerstl Robert
Pfizer Inc.
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