Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
2001-01-23
2002-08-27
Higel, Floyd (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C548S250000, C548S251000, C548S253000, C548S254000, C514S382000
Reexamination Certificate
active
06441015
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to tetrazole compounds that are thyroid receptor ligands. The invention also relates to compositions and kits comprising the tetrazole compounds and to methods of treatment of obesity, diabetes, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias, congestive heart failure, and osteoporosis using the tetrazole compounds.
BACKGROUND OF THE INVENTION
Thyroid hormones are important in normal development and in maintaining metabolic homeostasis. For example, thyroid hormones stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones.
Thyroid hormones also 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 observed in patients with hyperthyroidism.
Disorders of the thyroid gland are generally treated by administering either naturally occurring thyroid hormones or analogues that mimic the effects of thyroid hormones. Such analogues are called thyromimetics or thyroid receptor ligands.
Two naturally occurring thyroid hormones, 3,5,3′,5′-tetraiodo-L-thyronine (also referred to as “T
4
” or thyroxine) and 3,5,3′-triiodo-L-thyronine (also referred to as “T
3
”), are shown below:
T
3
is more biologically active than T
4
, and differs from T
4
by the absence of the 5′ iodine. T
3
may be produced directly in the thyroid gland, or in peripheral tissues, by the removal of the 5′ iodine of T
4
by deiodinase enzymes. 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 above, thyroid hormones 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 desired metabolic effects, nonetheless, it does place an extra burden on the heart, which in some situations, may give rise to damaging side effects. Consequently, efforts have been made to synthesize thyroid hormone analogs that function to lower lipids and serum cholesterol, but which have reduced adverse cardiac effects.
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.
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.
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.
Certain oxamic acids and derivatives thereof are known in the art, e.g., U.S. Pat. No. 4,069,343 describes the use of certain oxamic acids to prevent immediate type hypersensitivity reactions; U.S. Pat. No. 4,554,290 describes the use of certain oxamic acids to control pests on animals and plants; U.S. Pat. No. 5,232,947 describes the use of certain oxamic acids to improve damaged cerebral functions of the brain; and European Patent Specification published as EP 580,550 (also U.S. Pat. No. 5,401,772) discloses certain oxamic acid derivatives as hypocholesterolemic agents.
In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama et al. in an article published in the
Journal of Medicinal Chemistry,
38 (4): 695-707 (1995) describe replacing a —CH
2
group in a naturally occurring metabolite of T
3
with an —NH group resulting in —HNCOCO
2
H. Likewise, R. E. Steele et al. in an article published in International Congressional Service (
Atherosclerosis
X) 106: 321-324 (1995) and Z. F. Stephan et al. in an article published in
Atherosclerosis,
126: 53-63 (1996), describe certain oxamic acid derivatives useful as lipid-lowering thyromimetic agents that have reduced adverse cardiac activities.
European Patent Application EP 276,064 discloses some tetrazole compounds that are leukotriene antagonists as anti-inflammatory agents. Similarly, U.S. Pat. No. 5,347,036 discloses some tetrazole compounds that are leukotriene inhibitors. The tetrazole compounds disclosed in EP 276,064 and U.S. Pat. No. 5,347,036 are structurally different from the compounds of the present invention.
Obesity is a devastating disease. In addition to harming physical health, obesity can wreak havoc on mental health because obesity affects self-esteem, which ultimately can affect a person's ability to interact socially with others. Unfortunately, obesity is not well 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 individuals and society, much effort has been expended to find ways to treat obesity, but little success has been achieved in the long-term treatment and/or prevention of obesity. The present invention provides methods of treating obesity by administering to an obese patient or a patient at risk of becoming obese a therapeutically effective amount of a thyromimetic of the present invention. It is believed that the thyromimetics of the present invention act to treat obesity by increasing energy expenditure, and thus promoting weight loss.
The thyromimetics of the present invention can also be used to treat diabetes, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, hyperlipidemia, thyroid disease, thyroid cancer, hypothyroidism, depression, glaucoma, cardiac arrhythmias, congestive heart failure, and osteoporosis.
In spite of the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosiglitazone or pioglitazone, as oral hypoglycemic agents, the treatment of diabetes remains less than satisfactory.
The use of insulin currently requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of the sugar in urine or blood. The administration of an excess dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. Treatment of non-insulin dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycemic agents, e.g., thiazolidenediones, and, in more severe cases, insulin. However, the clinically available hypoglycemic agents can have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin dependent diabetes mellitus (Type I), insulin is usually the primary course of therapy. Hypoglycemic agents that have fewer side effects or succeed where others fail are needed.
Atherosclerosis, a disease of the arteries, is recognized to be a leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerosis and occlusive heart disease is well known. The earliest stage in this sequence is the formation of “fatty streaks” in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow in color due to the presence of lipid deposits found principally within smooth-muscle cells and in macrophages of the intima layer of the arteries and aorta. Further, it is postulated that most of the cholesterol found within the fatty streaks, in turn, give rise to development of “fibrous plaques,” which consist of accumulated intimal smooth muscle cells laden with lipid and are surrounded by extra-cellular lipid, collagen,
Aspnes Gary E.
Chiang Yuan-Ching P.
Benson Gregg C.
Crissey Todd M.
Higel Floyd
Pfizer Inc.
Richardson Peter C.
LandOfFree
Tetrazole compounds as thyroid receptor ligands does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Tetrazole compounds as thyroid receptor ligands, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Tetrazole compounds as thyroid receptor ligands will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2970886