Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2001-10-23
2003-01-21
Owens, Amelia (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S525000, C560S126000, C562S510000, C562S511000
Reexamination Certificate
active
06509480
ABSTRACT:
The present invention relates to methods of reducing hyperlipidemia and hyperglycemia, as well as to certain compounds and compositions.
The adverse complications of hyperlipidemia are prevalent worldwide, manifest by the high incidence of serious atherosclerotic disease including heart attack and stroke. Cardiovascular and cerebrovascular disease are slowly progressive conditions, often undetected in their early stages of pathophysiology, that are typified by elevated circulating levels of lipids and demonstrable by the accumulating deposition of fatty substances in the macrovasculature over years to decades. Only when sufficient vascular damage and accumulated thrombotic material is present to occlude a major vessel or become detached and create a vascular obstruction, does this disease wreak its high incidence of morbidity and mortality.
Underlying factors both within and beyond an individual's control contribute to the disease process, including genetic predisposition, co-morbidity with diseases such as diabetes mellitus, or lifestyle factors including diet, smoking, and exercise, among other factors. While genetic components have only recently become potential direct targets for therapeutic intervention, and alterations in lifestyle are difficult to achieve and often difficult to maintain, therapies directed toward pharmacologically lowering circulating lipid levels have been clinically successful at reducing the incidence of cardiovascular and cerebrovascular disease. Elevated circulating lipids and their markers indicative of a pathological state include free fatty acids, glycerol, triglycerides, cholesterol, and low-density lipoprotein. Reduction or control of each of these components can have a positive impact upon other abnormal circulating analytes, including glucose and insulin.
Diabetes mellitus is a disease of multifactorial origins involving disorders of metabolism associated with insulin-producing as well as insulin-regulated tissues. In addition to being a disease of hyperglycemia, some forms of the disease are associated with abnormally elevated circulating lipid levels, Therefore, lowering the circulating levels of lipids and glucose is beneficial for the treatment of patients with diabetes mellitus. In type II diabetes, while genetic mutations can cause certain subsets of the disease (e.g., maturity-onset diabetes of the young, or MODY), the most common form of the disease involves resistance to the action of insulin on insulin-target tissues, and is associated with obesity, predominately of abdominal origin. In addition to elevated glucose levels, circulating levels of triglycerides, cholesterol and non-esterified fatty acids (NEFA) are elevated during a fasting period. Persons afflicted with diabetes are predisposed to the development of cardiovascular disorders, which is the main cause of morbidity and mortality for this disease. Resistance to insulin action occurs not only in hyperglycemic states but also in Syndrome X, an insulin-resistant disorder characterized by hyperinsulinemia and dyslipidemia. (Reaven GM, Syndrome X, Clinical Diabetes, March/April 1994:32-36). In this state, normoglycemia can be maintained due to an increase in the secretion of insulin. However, when the insulin-resistance cannot be sustained by the compensatory activity of the pancreas, glucose-intolerance supervenes. Thus, lipid abnormalities, coupled either with overt hyperglycemia or with the normoglycemic Syndrome X phenotype, are believed to contribute to the severity of diabetic complications, such as cardiovascular complications (Olefsky, JM, Current Approaches to the Management of Type 2 Diabetes: A Practical Monograph, National Diabetes Education Initiative, 1997).
Oral antihyperglycemic agents, such as the sulfonylureas and biguanides, promote improvements in elevated lipid levels through overcoming the associated state of insulin-resistance, either by potentiating the endogenous release of insulin from the &bgr; cells of the pancreas, as in the case of the sulphonylureas, or by enhancing glucose disposal and reducing gluconeogenesis, as in the case of biguanides. Other approaches to controlling the elevated lipids and glucose have involved the use of broad acting oral antihyperglycemics such as the thiazolidinedione class of agents which lower fatty acids and improve the insulin-resistant state of insulin responsive tissues. The compound 4,7,8&agr;H-eudesma-5(6),11(13)-dien-8,12-olide, also known as helenin and alantolactone, has been reported to induce hyperglycemia in rabbits at high dose, to induce hypoglycemia at a moderate dose, and to inhibit hyperglycemia induced by food (1986, Handbook of Effective Ingredients of Medicinal Plants, Beijing, China).
Numerous, diverse therapeutic strategies have been developed for treating the hyperlipidemia and associated hyperglycemia of type II diabetes. The aim of lowering of circulating lipids has been to reduce the cardiovascular morbidity and/or improving the overall diabetic state, Examples of classes of agents acting directly on plasma triglyceride and cholesterol content include the HMG-CoA reductase inhibitors, fibric acids, and bile-salt resins. Whereas these classes are effective in lowering triglyceride and cholesterol content, they have little impact on plasma fatty acids.
Of the lipid classes, non-esterified fatty acids appear to play a role in promoting the diabetic and/or the hyperlipidemic, insulin-resistant, state. Elevated free fatty acids arise from either the excess body burden of adipose tissue in the obese state or from uncontrolled breakdown of triglycerides in adipose tissue, a major insulin-target tissue, or both. In addition, elevated levels of free fatty acids have been shown to acutely induce insulin resistance in muscle, the major glucose utilizing tissue of the body, where a direct effect on glucose transport in muscle is observed. In addition, fatty acids affect liver metabolism to increase hepatic glucose output. Furthermore, elevated fatty acids induce impaired &agr;-cell functioning by lessening the secretion of insulin from &agr;-cells in response to a glucose stimulus. Attempts to reduce fatty acid levels have included the development of thermogenic agents (?3 agonists) which are believed to function by stimulating brown adipose tissue to oxidize fatty acids and thus clear them from the circulation. Alternatively, removing fatty acids from their influence in the liver was attempted by developing inhibitors of fatty acid oxidation by the enzyme carnitine palmitoyl transferase I (CPTI).
In particular, resistance to the action of insulin in adipose tissue appears to plays a significant role in the elevation of fatty acids. Agents that inhibit adipose tissue breakdown of triglycerides are known as lipolytic inhibitors. It is toward the development of new methods and agents for lowering circulating lipids to treat hyperlipidemic disorders or for lowering circulatory glucose to treat hyperglycemia, diabetes and associated disorders that the present invention is directed.
SUMMARY OF THE INVENTION
The invention relates to lipid-lowering or glucose-lowering methods and compounds, particularly lipid-lowering or glucose-lowering compounds, with an A-B ring structure of the following Formula I:
wherein the dotted line between carbons 5 and 6, the dotted line between carbon 4 and R
2
, and the dotted line between carbon 11 and R
3
each independently represent an optional double bond from the respective numbered carbon to a linked carbon.
The present invention to provides, among other things: methods for lowering lipid levels in a mammal to treat or prevent the development of pathology associated with elevated lipid levels; compounds which inhibit the enzyme hormone-sensitive lipase and inhibit lipolysis; agents and methods for the treatment of insulin resistance and Syndrome X; methods for lowering glucose levels in a mammal in order to treat or prevent the development of pathology associated with hyperglycemia; methods for treating impaired glucose tolerance associated with fasting or pran
Egan John J.
Fang Sheng Ding
Resek John
Terleckyj Ihor
Wagle Dilip R.
Alteon Inc.
Dechert
Owens Amelia
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