Diabetes mellitus refers to a durable hyperglycemic condition attributable to the absolute or relative shortage of intrinsic insulin. Diabetes mellitus may be classified as insulin dependent diabetes mellitus (IDDM), that is type 1 diabetes mellitus, for treatment of which insulin administration is absolutely necessary, non insulin-dependent diabetes mellitus (NIDDM), that is type 2 diabetes mellitus, and other diabetes mellitus (secondary diabetes mellitus; diabetes mellitus occurring as one symptom of other diseases). In type 1 diabetes or IDDM, patients produce little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes or NIDDM, patients often have plasma insulin levels that are the same or even elevated compared to non-diabetic 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.
The 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.
Metabolic syndrome refers to a cluster of manifestations including insulin resistance with accompanying hyperinsulinemia, type 2 diabetes mellitus, arterial hypertension, central (visceral) obesity, dyslipidemia observed as deranged lipoprotein levels typically characterized by elevated VLDL (very low density lipoprotein) and LDL (low density lipoprotein) and reduced HDL (high density lipoprotein) concentrations and reduced fibrinolysis.
Recent epidemiological research has documented that individuals with insulin resistance run a greatly increased risk of cardiovascular morbidity and mortality, notably suffering from myocardial infarction and stroke. In type 2 diabetes mellitus, atherosclerosis related conditions cause up to 80% of all deaths.
In clinical medicine there is awareness of the need to increase the insulin sensitivity in patients with metabolic syndrome and thus to correct the dyslipidemia which is considered to cause the accelerated progress of atherosclerosis.
The available treatments for type 2 diabetes have recognized limitations. While physical exercise and reductions in dietary intake of calories will dramatically improve the diabetic condition, 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.
For the treatment of NIDDM, sulfonylurea drugs such as tolbutamide, chlorpropamide and tolazamide, and biguanides such as metformin hydrochloride and buformin have been used as oral blood glucose lowering agents. The morbid state of NIDDM is characterized by insulin deficiency and insulin resistance, and the sulfonylureas stimulating insulin secretion from pancreatic β cells may not be very effective therapeutic medicines for patients with NIDDM condition, where the insulin secretion potential is present, but adequate blood glucose control is not achieved in target organs due to insulin resistance, thus permitting hyperglycemia. The biguanide medicines may permit the onset of lactic acid acidosis, limiting the use of such medicines. Further, these chemicals often cause severe hypoglycemia as a side effect. To address these problems, compounds with a new working mechanism were developed, such as the thiazolidinedione (TZD) derivatives, pioglitazone and rosiglitazone. These TZDs are insulin sensitizers and can ameliorate insulin resistance (or enhance the action of insulin) and lower blood glucose without promoting secretion of insulin from the pancreas. It has been revealed that these TZD-type chemicals induce differentiation of adipocytes, and exhibit their action via an intranuclear receptor PPARγ (peroxisome proliferator-activated receptor gamma: a transcriptional factor important for differentiation of adipocytes) (J. Biol. Chem., 270, 12953-12956, (1995)). By the differentiation of preadipocytes, immature and small adipocytes with less secretion of Tumor Necrosis Factor alpha (TNFα), Free Fatty Acid (FFA) and leptin are increased thus resulting in amelioration of insulin resistance. TZD derivatives also act as agonists for PPARγ, to exhibit the effect of ameliorating insulin resistance.
However, from recent clinical findings using TZD derivatives, conventional synthetic ligands that have PPARγ agonistic activity not only have the activity to improve insulin resistance but also cause disorders of the liver and additionally increase circulating plasma volume in vivo to trigger edema. Since the disorders of liver functions induced by the synthetic PPARγ agonists are serious side effects and the triggering of edema is a very serious side effect causing cardiomegaly, detachment of the main activity, namely insulin-resistance improvement, from such serious side effects is strongly desired.
It is believed that the toxicity of PPARγ agonists described above is derived from the thiazolidinedione moiety, and efforts are being made to design bioisosteres of the TZDs which may retain their useful functions while eliminating the undesired effects. In order to avoid side effects associated with potent PPARγ agonists, partial PPAR agonists are being developed.
Besides PPARγ, PPAR subtypes such as α and δ have been found. PPARγ is located substantially in adipose tissue while PPARα occurs mainly in the liver, heart and kidney, and therefore it was considered that each sub-type has an independent function. In recent years, it has been revealed that PPARγ mainly mediates lipid anabolism by promoting expression of a group of genes for Lipoprotein Lipase (LPL), acyl-CoA carboxylase, Glycerol 3 Phosphate Dehydrogenase (GPDH) etc. to convert glucose into lipid and storing the lipid, while PPARα mediates lipid catabolism by regulating expression of a gene group involved in intake of fatty acids into cells and oxidation thereof to decompose lipid. Moreover, research concerning relationships between particular subtypes of PPAR and various diseases have been widely conducted in recent years (J. Med. Chem., 43(4), 527-550, (2000)).
Compounds having a carboxylic acid moiety in their structure which act as dual agonists of PPARγ and α have also been disclosed.
Many of these dual PPAR α and γ agonists are still in clinical trials and several have been dropped from development due to insufficient efficacy or adverse effects seen in advanced-stage development such as edema, raised levels of hepatic enzymes, renal toxicity, and cancers in animal studies.
Accordingly, there is a need for alternative compounds which are effective in treating insulin resistance without showing the toxic effects of currently available compounds.
U.S. Pat. No. 6,489,322 discloses benzoxazepines having an amidine side chain; the disclosed compounds are inhibitors of Nitric Oxide Synthase. International patent publication no. WO 02/051838 discloses novel benzoxazepine derivatives which are useful as orexin receptor antagonists.
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