Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2003-01-16
2004-02-24
McKane, Joseph K. (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S467000
Reexamination Certificate
active
06696574
ABSTRACT:
FIELD OF THE INVENTION
The instant invention provides novel processes and intermediates useful in the preparation of certain N-(indole-2-carbonyl)-&bgr;-alaninamide compounds, which compounds are glycogen phosphorylase inhibitors useful in the treatment of diseases such as hypercholesterolemia, hyperglycemia, hyperinsulinemia, hyperlipidemia, hypertension, atherosclerosis, diabetes, diabetic cardiomyopathy, infection, tissue ischemia, myocardial ischemia, and in inhibiting tumor growth.
BACKGROUND OF THE INVENTION
Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the later discovery of, and use of, sulfonylureas (e.g. Chlorpropamide™ (Pfizer), Tolbutamide™ (Upjohn), Acetohexamide™ (E. I. Lilly), Tolazamide™ (Upjohn), and biguanides (e.g. Phenformin™ (Ciba Geigy), and Mefformin™ (G. D. Searle)) as oral hypoglycemic agents, therapeutic regimens for the treatment of diabetes remain less than satisfactory. The use of insulin, necessary in about 10% of diabetic patients in which synthetic hypoglycemic agents are not effective (Type 1 diabetes, insulin dependent diabetes mellitus), requires multiple daily doses, usually by self-injection. Determination of the proper dosage of insulin requires frequent estimations of sugar levels in the 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 2 diabetes) usually consists of a combination of diet, exercise, oral agents, e.g., sulfonylureas, and, in more severe cases, insulin. However, clinically available hypoglycemic agents can have other side effects that limit their use. In any event, where one of these agents may fail in an individual case, another may succeed. A continuing need for hypoglycemic agents, which may have fewer side effects or succeed where others fail, is clearly evident.
Atherosclerosis, a disease of the arteries, is recognized to be the leading cause of death in the United States and Western Europe. The pathological sequence leading to atherosclerotic development 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. It is further postulated that most of the cholesterol found within the fatty streaks, in turn, gives rise to development of the so-called “fibrous plaque”, which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extra-cellular lipid, collagen, elastin, and proteoglycans. These cells, plus matrix, form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular lipid, which comprises primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the so-called “complicated lesion” which accounts for the arterial occlusion and tendency toward mural thrombosis and arterial muscle spasm that characterize advanced atherosclerosis.
Epidemiological evidence has firmly established hyperlipidemia as a primary risk factor in causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, medical professionals have placed renewed emphasis on lowering plasma cholesterol levels, and low density lipoprotein cholesterol in particular, as an essential step in prevention of CVD. The upper limits of so-called “normal” cholesterol are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now recognized to be at particular high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being male. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part because of the existence of multiple independent risk factors in this population. Successful treatment of hyperlipidemia in the general population, and in diabetic subjects in particular, is therefore of exceptional medical importance.
Hypertension (high blood pressure) is a condition that occurs in the human population as a secondary symptom to various other disorders such as renal artery stenosis, pheochromocytoma, or endocrine disorders. However, hypertension is also evidenced in many patients in whom the causative agent, or disorder, is unknown. While such essential hypertension is often associated with disorders such as obesity, diabetes, and hypertriglyceridemia, the relationship between these disorders has not been elucidated. Additionally, many patients present with symptoms of high blood pressure in the complete absence of any other signs of disease, or disorder.
It is known that hypertension can directly lead to heart failure, renal failure, and stroke, which conditions are all capable of causing short-term death. Hypertension also contributes to the development of atherosclerosis, and coronary disease, which conditions gradually weaken a patient and can lead, in long-term, to death.
The precise etiology of essential hypertension is unknown, although a number of factors are believed to contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, unregulated hormone release (the renin, angiotensin, aldosterone system), excessive salt and water due to kidney malfunction, wall thickening and hypertrophy of the vasculature resulting in vascular constriction, and genetic pre-disposition.
The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of &bgr;-blockers, vasoconstrictors, angiotensin converting enzyme (ACE) inhibitors, and the like have been developed and marketed as antihypertensive agents. The treatment of hypertension utilizing such agents has proven beneficial in the prevention of short-interval deaths such as heart failure, renal failure, and brain hemorrhaging (stroke). However, the development of atherosclerosis, or heart disease due to hypertension over a long period of time, remains a problem. This implies that, although high blood pressure is being reduced, the underlying cause of essential hypertension remains unresponsive to this treatment.
Hypertension has further been associated with elevated blood insulin levels, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose primary actions are to promote glucose utilization, protein synthesis, and the formation and storage of neutral lipids, also acts, inter alia, to promote vascular cell growth and increase renal sodium retention. These latter functions can be accomplished without affecting glucose levels and are known causes of hypertension. Peripheral vasculature growth, for example, can cause constriction of peripheral capillaries; while sodium retention increases blood volume. Thus, the lowering of insulin levels in hyperinsulinemics can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and thereby alleviate hypertension.
Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction, and congestive heart failure. These cardiac events are due, at least in part, to increased susceptibility to myocardial injury after ischemia and reperfusion which can occur in both out-patient and perioperative settings. There is currently an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both cardiac and non-cardiac surgery are associated with substantial risks for myocardial infarction or death, and some 7 million patients undergoing non-cardiac surgery are considered to be at risk, with incidences of perioperative death and serious cardiac complications as high as 20-25% in some instances. In addition, o
Barrila Mark T.
Busch Frank R.
Couturier Michel A.
Orrill Susan L.
Rose Peter R.
Benson Gregg C.
Goddard Carl J.
McKane Joseph K.
Pfizer Inc.
Richardson Peter C.
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