Antidiabetic 4-hydroxy-2-furoic acids

Details Antidiabetic 4-hydroxy-2-furoic acids Antidiabetic 4-hydroxy-2-furoic acids

2002-10-18

2003-07-22

McKane, Joseph K. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C435S017000, C548S455000

Reexamination Certificate

active

06596760

ABSTRACT:

FIELD OF THE INVENTION
The instant application is concerned with 4-hydroxy-2-furoic acids, which are obtained by the bioconversion of asterriquinones. These products may be useful as therapeutic compounds for the treatment of diabetes.
BACKGROUND OF THE INVENTION
Diabetes refers to a disease process derived from multiple causative factors and characterized by elevated levels of plasma glucose or hyperglycemia in the fasting state or after administration of glucose during an oral glucose tolerance test. Persistent or uncontrolled hyperglycemia is associated with increased and premature morbidity and mortality. Often abnormal glucose homeostasis is associated both directly and indirectly with alterations of the lipid, lipoprotein and apolipoprotein metabolism and other metabolic and hemodynamic disease. Patients with Type 2 diabetes mellitus are at an especially increased risk of macrovascular and microvascular complications, including coronary heart disease, stroke, peripheral vascular disease, hypertension, nephropathy, neuropathy, and retinopathy. Therefore, therapeutic control of glucose homeostasis, lipid metabolism and hypertension are critically important in the clinical management and treatment of diabetes mellitus.
There are two generally recognized forms of diabetes. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone which regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are the same or even elevated compared to nondiabetic subjects; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, which are muscle, liver and adipose tissues, and the plasma insulin levels, while elevated, are insufficient to overcome the pronounced insulin resistance.
Insulin resistance in Type 2 diabetes is not primarily due to a diminished number of insulin receptors but to a post-insulin receptor binding defect that is not yet understood. This resistance to insulin responsiveness results in insufficient insulin activation of glucose uptake, oxidation and storage in muscle and inadequate insulin repression of lipolysis in adipose tissue and of glucose production and secretion in the liver. Insulin resistance can result in dyslipidemias, such as high LDL levels, low RDL levels, and hypercholesterolemia. Insulin resistance can be a contributing factor in atherosclerosis, hypertension, lipid disorders, and polycystic ovarian syndrome.
Type 1 diabetes is treated primarily by injections of insulin to control blood glucose levels. There are several available treatments for type 2 diabetes, all of which have recognized limitations. Physical exercise and reductions in dietary intake of calories have been shown to dramatically improve the diabetic condition. However, compliance with this treatment is very poor because of well-entrenched sedentary lifestyles and excess food consumption, especially of foods containing high amounts of saturated fat. Increasing the plasma level of insulin by administration of sulfonylureas (e.g. tolbutamide and glipizide), which stimulate the pancreatic &bgr;-cells to secrete more insulin, and/or by injection of insulin after the response to sulfonylureas fails, will result in insulin concentrations that are high enough to stimulate the very insulin-resistant tissues. However, dangerously low levels of plasma glucose can result from treatment with a sulfonylurea or insulin, and insulin resistance can increase due to the even higher plasma insulin levels that occur. The biguanides increase insulin sensitivity resulting in some correction of hyperglycemia. However, the two biguanides, phenformin and metformin, can induce lactic acidosis and nausea/diarrhea, respectively.
The glitazones (i.e. 5-benzylthiazolidine-2,4-diones) are a newer class of compounds used for the treatment of NIDDM. These compounds substantially increase insulin sensitivity in muscle, liver and adipose tissue in several animal models of type 2 diabetes resulting in partial or complete correction of the elevated plasma levels of glucose without occurrence of hypoglycemia. Two glitazones, rosiglitazone and pioglitazone, are currently available. The first glitazone that was marketed, troglitazone, was withdrawn by the manufacturer due to serious adverse events, resulting primarily from liver toxicity. The glitazones are agonists of peroxisome proliferator activated receptors (PPAR's). Three PPAR sub-types have been discovered and described. Agonists of the three PPAR sub-types (alpha, gamma and delta), including compounds that are mixed sub-types or are partial agonists or antagonists of some of the PPAR sub-types, are under active investigation and development in a number of laboratories.
Given the complexity of the disease, it is extremely unlikely that a new generation of PPAR agonists or any other class of drugs will be developed that can ameliorate all of the symptoms of type 2 diabetes in all patients. Accordingly, there exists a continuing need for novel therapeutic agents, including agents having new biological mechanisms, for controlling the symptoms of type 2 diabetes mellitus.
Insulin is necessary for normal carbohydrate, protein, and fat metabolism in mammals. All known actions of insulin are initiated by binding of the hormone to the extracellular domain (&agr;-subunits) of the insulin receptor. Following insulin binding, conformational changes in the insulin receptor lead to autophosphorylation of the intracellular &bgr;-subunits of the insulin receptor, followed by stimulation of the receptor's intrinsic tyrosine kinase activity and activation of the insulin signal transduction pathway. Considerable evidence suggests that insulin receptor tyrosine kinase activity is essential for many, if not all of the biological effects of insulin. The precise biochemical mechanisms linking receptor kinase-mediated tyrosine phosphorylation to the regulation of cellular metabolic pathways are not completely defined.
The activated tyrosine kinase in the activated insulin receptor phosphorylates several immediate substrates (e.g. IRS-1 and SHC). These proximal events lead to activation of additional signaling intermediates, such as PI-3-kinase and MAP kinase. Through an unknown series of additional steps, modulation of key cellular components (e.g. glucose transporter translocation, activation of glycogen synthase, inhibition of gluconeogenic enzymes) coordinate stimulation of glucose disposal and inhibition of hepatic glucose output.
Compounds Ia to Id below, which are natural products having a 2,5-dioxy-3,6-bis(indolyl)quinone structure, belong to a class of compounds generally known as asterriquinones. These compounds were recently reported to be useful in the treatment of diabetes. (See B. Zhang et al., Science, Vol. 284, pp. 974-977, May 7, 1999 and U.S. Pat. No. 6,051,597). A series of structurally similar synthetic quinones was also found to have anti-diabetic activity (U.S. Pat. No. 6,077,849). These two structurally related classes of compounds are believed to act by a mechanism involving activation of the insulin receptor tyrosine kinase.
I

Compound
R
1
R
2
R
3
Ia
methyl
—CH═CH
2
—CH
2
—CH═C(CH
3
)
2
Ib
H
—CH═CH
2
—CH
2
—CH═C(CH
3
)
2
Ic
methyl
—CH
2
CH
3
—CH
2
—CH
2
—CH(CH
3
)
2
Id
H
—CH
2
CH
3
—CH
2
—CH
2
—CH(CH
3
)
2
SUMMARY OF THE INVENTION
The present invention provides novel compounds IIa, IIb and IIc, and pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutical compositions containing these compounds, for the treatment, control or prevention of diabetes mellitus and related conditions. More generally, the compounds disclosed herein may be useful for treating, controlling, preventing or delaying the onset of diseases or conditions in which the production of endogenous insulin, the biological activity of insulin, or insulin sensitivity, or a combination thereof, are impaired. This i

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