| PATENT NUMBER | This data is not available for free |
| PATENT GRANT DATE | December 7, 1999 |
| PATENT TITLE |
Glycogen phosphorylase inhibitors |
| PATENT ABSTRACT | This invention relates to certain 5-acyl-2-oxo-indole-3-carboxamides useful as inhibitors of glycogen phosphorylase, methods of treating glycogen phosphorylase dependent diseases or conditions with such compounds and pharmaceutical compositions comprising such compounds. This invention also relates to pharmaceutical compositions comprising those 5-acyl-2-oxo-indole-3-carboxamides in combination with antidiabetes agents and methods of treating glycogen phosphorylase dependent diseases or conditions with such compositions |
| PATENT INVENTORS | This data is not available for free |
| PATENT ASSIGNEE | This data is not available for free |
| PATENT FILE DATE | February 16, 1999 |
| PATENT PARENT CASE TEXT | This data is not available for free |
| PATENT CLAIMS |
Claims -------------------------------------------------------------------------------- We claim: 1. A compound of Formula I ##STR28## a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug wherein: R.sup.1 is (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, phenyl or phenyl independently substituted with up to three (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or halogen; R.sup.2 is (C.sub.1 -C.sub.4)alkyl optionally substituted with up to three fluoro atoms; and R.sup.3 is (C.sub.3 -C.sub.7)cycloalkyl; phenyl; phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl; phenyl substituted at the meta position with fluoro; or phenyl substituted at the ortho position with fluoro. 2. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R.sup.1 is phenyl, R.sup.2 is ethyl; and R.sup.3 is phenyl, phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl, phenyl substituted at the meta position with fluoro, or phenyl substituted at the ortho position with fluoro. 3. A compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R.sup.1 is methyl and R.sup.2 is ethyl. 4. A compound of claim 3, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein R.sup.3 is phenyl, phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl, phenyl substituted at the meta position with fluoro, or phenyl substituted at the ortho position with fluoro. 5. A compound of claim 4 selected from 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-p-tolylcarbamoyl-phenyl)-amide; 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-(4-bromophenylcarbamoyl-phenyl)-amide; and 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-phenylcarbamoyl-phenyl)-amide. 6. The compound of claim 4 wherein R.sup.3 is p-tolyl. 7. The compound of claim 4 wherein R.sup.3 is 4-bromophenyl. 8. The compound of claim 4 wherein R.sup.3 is phenyl. 9. A method for treating a glycogen phosphorylase dependent disease or condition in an animal, which comprises administering to said animal suffering from a glycogen phosphorylase dependent disease or condition a glycogen phosphorylase dependent disease or condition treating amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 10. The method as recited in claim 9 wherein the glycogen phorphorylase dependent disease or condition is hyperglycemia which comprises administering to said animal suffering from hyperglycemia a hyperglycemia treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 11. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is diabetes in an animal, which comprises administering to said animal suffering from diabetes a diabetes treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 12. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is hypercholesterolemia in an animal, which comprises administering to said animal suffering from hypercholesterolemia a hypercholesterolemia treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 13. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is atherosclerosis in an animal, which comprises administering to said animal suffering from or susceptible to atherosclerosis an atherosclerosis treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 14. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is hyperinsulinemia in an animal, which comprises administering to said animal suffering from hyperinsulinemia a hyperinsulinemia treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 15. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is hypertension in an animal, which comprises administering to said animal suffering from hypertension a hypertension treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 16. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is hyperlipidemia in an animal, which comprises administering to said animal suffering from hyperlipidemia a hyperlipidemia treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 17. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is tissue ischemic injury in an animal, which comprises administering to said animal at risk for tissue ischemic injury a tissue ischemic injury preventing amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 18. The method of claim 9 wherein the glycogen phosphorylase dependent disease or condition is myocardial ischemic injury in an animal, which comprises administering to said animal at risk for myocardial ischemic injury a myocardial ischemic injury treating or preventing amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. 19. The method of claim 18 wherein said myocardial ischemic injury is perioperative myocardial ischemic injury. 20. A pharmaceutical composition which comprises a therapeutically effective amount of a compound of claim 1, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier of diluent. 21. The pharmaceutical composition of claim 20 for the treatment of glycogen phosphorylase dependent diseases or conditions in animals, which comprises a glycogen phosphorylase dependent disease or condition treating amount of said compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. 22. A pharmaceutical composition which comprises a therapeutically effective amount of a) a glycogen phosphorylase inhibitor as recited in claim 1; b) an antidiabetic agent selected from insulin and insulin analogs; insulinotropin; sulfonylureas and analogs; biguanides; .alpha..sub.2 -antagonists and imidazolines; insulin secretagogues; glitazones; aldose reductase inhibitors; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors; .alpha.-glucosidase inhibitors; .beta.-agonists; phosphodiesterase inhibitors; lipid-lowering agents; antiobesity agents; vanadate and vanadiumn complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors; somatostatin analogs; antilipotic agents; prodrugs of said antidiabetic agents and pharmaceutically acceptable salts of said antidiabetic agents and said prodrugs; and c) a pharmaceutically acceptable carrier or diluent. 23. A method for treating a glycogen phosphorylase dependent disease or condition in an animal, particularly a mammal, which comprises administering to said animal suffering from a glycogen phosphorylase dependent disease or condition a glycogen phosphorylase dependent disease or condition treating amount of a composition of claim 1. -------------------------------------------------------------------------------- |
| PATENT DESCRIPTION |
BACKGROUND OF THE INVENTION This invention relates to glycogen phosphorylase inhibitors, pharmaceutical compositions containing such inhibitors and the use of such inhibitors to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, myocardial ischemia and other tissue ischemias in animals, particularly mammals. In particular, this invention relates to certain 5-acyl-2-oxo-indole-3-carboxamides having such glycogen phosphorylase inhibitor activity. 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 (e.g., Chlorpropamide.TM. Pfizer), Tolbutamide.TM. (Upjohn), Acetohexamide.TM. (E. I. Lilly), Tolazamide.TM. (Upjohn)) and biguanides (e.g., Phenformin.TM. (Ciba Geigy), Metformin.TM. (G. D. Searle)), alpha-glucosidase inhibitors (e.g., glucophage) and insulin sensitizing agents (e.g., troglitazone) as oral hypoglycemic agents, there is still a need for improved diabetes therapies. The use of insulin, necessary in about 10% of diabetic subjects in which synthetic hypoglycemic agents are not effective (Type I diabetes, insulin dependent diabetes mellitus), 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 2 diabetes, NIDDM) usually consists of a combination of diet, exercise, oral agents, e.g. sulfonylureas, and in more severe cases, insulin. However, the clinically available hypoglycemics can have other side effects which 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 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 the "fibrous plaque", which consists of accumulated intimal smooth muscle cells laden with lipid and surrounded by extracellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extracellular lipid. The lipid is primarily free and esterified cholesterol. The fibrous plaque forms slowly, and is likely in time to become calcified and necrotic, advancing to the "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, leaders of the medical profession 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 "normal" are now known to be significantly lower than heretofore appreciated. As a result, large segments of Western populations are now realized to be at particular high risk. Other independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, and being of the male sex. 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 (or high blood pressure) is a condition which 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 subjects 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 subjects display the 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 (brain hemorrhaging). These conditions are capable of causing rapid death in a subject. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a subject, leading to eventual death due to cardiovascular failure. The exact cause of essential hypertension is unknown, though 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 constricted blood vessels and genetic factors. The treatment of essential hypertension has been undertaken bearing the foregoing factors in mind. Thus, a broad range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and the like have been developed and marketed as antihypertensives. The treatment of hypertension utilizing these compounds has proven beneficial in the prevention of deaths resulting from little or no periods of illness such as heart failure, renal failure and brain hemorrhaging. 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 is not responding to this treatment. Hypertension has 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 to promote vascular cell growth and increase renal sodium retention, among other things. 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 out-subject as well as perioperative settings. There is an unmet medical need to prevent or minimize adverse myocardial perioperative outcomes, particularly perioperative myocardial infarction. Both non-cardiac and cardiac surgery are associated with substantial risks for myocardial infarction or death. Some 7 million subjects 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 series. In addition, of the 400,000 subjects undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently a need for improved drug therapy which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. If such a therapy were found, it would be expected to reduce hospitalizations, enhance quality and length of life and reduce overall health care costs of high risk subjects. Hepatic glucose production is an important target for Type 2 therapy. The liver is the major regulator of plasma glucose levels in the post absorptive (fasted) state, and the rate of hepatic glucose production in Type 2 diabetic subjects is significantly elevated relative to normal individuals. Likewise, in the postprandial or fed state, where the liver has a proportionately smaller role in the total plasma glucose supply, hepatic glucose production is abnormally high in Type 2 diabetic subjects. Glycogenolysis is an important target for interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (breakdown of the glucose polymer glycogen) and gluconeogenesis (synthesis of glucose from 2- and 3-carbon precursors). Several lines of evidence indicate that glycogenolysis may make an important contribution to hepatic glucose output in Type 2 diabetes. First, in normal post absorptive humans, up to 75% of hepatic glucose production is estimated to result from glycogenolysis. Second, subjects having liver glycogen storage diseases, including Hers' disease (glycogen phosphorylase deficiency), display episodic hypoglycemia. These observations suggest that glycogenolysis may be a significant process for hepatic glucose production. Glycogenolysis is catalyzed in liver, muscle, and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme cleaves the glycogen macromolecule to release glucose-1-phosphate and a new shortened glycogen macromolecule. Two types of glycogen phosphorylase inhibitors have been reported to date: glucose and glucose analogs [Martin, J. L. et al. Biochemistry, 1991, 30, 10101] and caffeine and other purine analogs [Kasvinsky, P. J. et al. J. Biol. Chem., 1978, 253, 3343-3351 and 9102-9106]. These compounds, and glycogen phosphorylase inhibitors in general, have been postulated to be of potential use for the treatment of Type 2 diabetes by decreasing hepatic glucose production and lowering glycemia. [Blundell, T. B. et al. Diabetologia, 1992, 35, Suppl. 2, 569-576 and Martin et al. Biochemistry 1991, 30, 10101]. WO96/39385 discloses certain substituted N-(indole-2-carbonyl)-B-alanimamides and derivatives as antidiabetic agents. WO96/39384 discloses certain substituted N-(indole-2-carbonyl)-glycinamides and derivatives as antidiabetic agents. The mechanism(s) responsible for the myocardial or other tissue injury observed after ischemia and reperfusion is not fully understood. It has been reported (M. F. Allard, et al. Am. J. Physiol. 267, H66-H74, 1994) that "pre ischemic glycogen reduction . . . is associated with improved post ischemic left ventricular functional recovery in hypertrophied rat hearts". Thus, although there are a variety of hyperglycemia, hypercholesterolemia, hypertension, hyperlipidemia, atherosclerosis and myocardial ischemia therapies, there is a continuing need and a continuing search in this field of art for alternative therapies. SUMMARY OF THE INVENTION This invention is directed to glycogen phosphorylase inhibitor compounds of Formula I which are useful for the treatment of diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial or other tissue ischemia. This invention is particularly directed to compounds of Formula I ##STR1## prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein: R.sup.1 is (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, phenyl or phenyl independently substituted with up to three (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or halogen; R.sup.2 is (C.sub.1 -C.sub.4)alkyl optionally substituted with up to three fluoro atoms; and R.sup.3 is (C.sub.3 -C.sub.7)cycloalkyl; phenyl; phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl; phenyl substituted at the meta position with fluoro; or phenyl substituted at the ortho position with fluoro. A first group of preferred compounds of Formula I are the compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein R.sup.1 is phenyl; R.sup.2 is ethyl; and R.sup.3 is phenyl, phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl, phenyl substituted at the meta position with fluoro, or phenyl substituted at the ortho position with fluoro. A second group of preferred compounds of Formula I are the compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein R.sup.1 is methyl and R.sup.2 is ethyl. A more preferred group of compounds, hereinafter termed the third group of preferred compounds, within the second preferred group of compounds are those compounds of the second group of preferred compounds of Formula I, prodrugs thereof and pharmaceutically acceptable salts of said compounds and said prodrugs wherein R.sup.3 is phenyl, phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl, phenyl substituted at the meta position with fluoro, or phenyl substituted at the ortho position with fluoro. An especially preferred group of compounds within the third preferred group of compounds are 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-p-tolylcarbamoyl-phenyl)-amide; 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-(4-bromophenylcarbamoyl-phenyl)-amide; and 5-acetyl-1-ethyl-2-oxo-2,3-dihydro-1H-indole-3-carboxylic acid (3-phenylcarbamoyl-phenyl)-amide. A particularly preferred compound within the third group of compounds is the compound wherein R.sup.3 is p-tolyl. Another particularly preferred compound within the third group of compounds is the compound wherein R.sup.3 is 4-bromophenyl. Yet another particularly preferred compound within the third group of compounds is the compound wherein R.sup.3 is phenyl. Yet another aspect of this invention is directed to a method for treating a glycogen phosphorylase dependent disease or condition in an animal, particularly a mammal, by administering to said animal suffering from a glycogen phosphorylase dependent disease or condition a glycogen phosphorylase dependent disease or condition treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating hyperglycemia in an animal, particularly a mammal, by administering to said animal suffering from hyperglycemia a hyperglycemia treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating diabetes in an animal, particularly a mammal, by administering to said animal suffering from diabetes a diabetes treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Included in the treatment of diabetes is the prevention or attenuation of long term complications such as, but not limited to, neuropathy, nephropathy, retinopathy or cataracts. Yet another aspect of this invention is directed to a method for treating hypercholesterolemia in an animal, particularly a mammal, by administering to said animal suffering from hypercholesterolemia a hypercholesterolemia treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating atherosclerosis in an animal, particularly a mammal, by administering to said animal suffering from or susceptible to atherosclerosis an atherosclerosis treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating hyperinsulinemia in an animal, particularly a mammal, by administering to said animal suffering from hyperinsulinemia a hyperinsulinemia treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating hypertension in an animal, particularly a mammal, by administering to said animal suffering from hypertension a hypertension treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating hyperlipidemia in an animal, particularly a mammal, by administering to said animal suffering from hyperlipidemia a hyperlipidemia treating amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Included in the treatment of hyperlipidemia is the lowering of triglycerides and free fatty acids. Yet another aspect of this invention is directed to a method for treating or preventing a tissue ischemic injury in an animal, particularly a mammal, by administering to said animal a tissue ischemic injury preventing amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Included within tissue ischemic injury is ischemic injury due to organ transplant. Yet another aspect of this invention is directed to a method for treating or preventing a myocardial ischemic injury in an animal, particularly a mammal, by administering to said animal at risk for myocardial ischemic injury a myocardial ischemic injury treating or preventing amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. Yet another aspect of this invention is directed to a method for treating or preventing a perioperative myocardial ischemic injury in an animal, particularly a mammal, by administering to said animal at risk for perioperative myocardial ischemic injury a perioperative myocardial ischemic injury treating or preventing effective amount of a Formula I compound, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug. This invention is also directed to pharmaceutical compositions which comprise a therapeutically effective amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. Preferred compositions include pharmaceutical compositions for the treatment of glycogen phosphorylase dependent diseases or conditions in animals, particularly mammals, which comprise a glycogen phosphorylase dependent disease or condition treating amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug and a pharmaceutically acceptable carrier or diluent. Preferred pharmaceutical compositions within the immediately preceding group are those compositions wherein the glycogen phosphorylase inhibitor is a compound of Formula I. Another aspect of this invention is directed to pharmaceutical compositions for the treatment of diabetes which comprise a therapeutically effective amount of a glycogen phosphorylase inhibitor of Formula I; one or more antidiabetic agents such as insulin and insulin analogs (e.g. LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH.sub.2 ; sulfonylureas and analogs such as chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide and meglitinide; biguanides such as mefformin, phenformin and buformin; .alpha..sub.2 -antagonists and imidazolines such as midaglizole, isaglidole, deriglidole, idazoxan, efaroxan and fluparoxan; other insulin secretagogues such as linogliride and A-4166; glitazones such as ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone and BRL49653; aldose reductase inhibitors such as epalrestat, sorbinil, tolrestat and zopolrestat; sorbitol dehydrogenase inhibitors; fatty acid oxidation inhibitors such as clomoxir and etomoxir; .alpha.-glucosidase inhibitors such as acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose and MDL-73,945; .beta.-agonists such as (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and BRL 35135, BRL 37344, Ro 16-8714, ICI D7114 and CL 316,243; phosphodiesterase inhibitors such as L-386,398; lipid-lowering agents such as benfluorex; antiobesity agents such as fenfiluramine, sibutramine and bromocriptine; vanadate and vanadium complexes (e.g. naglivan) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors such as glucose-6-phosphatase inhibitors; somatostatin analogs; antilipolytic agents such as nicotinic acid, acipimox and WAG 994; prodrugs thereof or pharmaceutically acceptable salts of said antidiabetic agents or said prodrugs and a pharmaceutically acceptable carrier or diluent. Another aspect of this invention is directed to a method for treating glycogen phosphorylase dependent diseases or conditions in an animal, particularly a mammal, which comprises administering to said animal suffering from a glycogen phosphorylase dependent disease or condition a glycogen phosphorylase dependent disease or condition treating amount of a composition set forth in the immediately preceding paragraph. Another aspect of this invention is a method of treating diabetes in an animal, particularly a mammal, with the above described combination compositions. Another aspect of this invention is directed to a kit comprising a. an amount of a compound of Formula I, a prodrug thereof or a pharmaceutically acceptable salt of said compound or said salt in a first unit dosage form; b. an amount of an antidiabetic agent such as insulin and insulin analogs (e.g. LysPro insulin); GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36)-NH.sub.2 ; sulfonylureas and analogs such as chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide and meglitinide; biguanides such as metformin, phenformin and buformin; .alpha..sub.2 -antagonists and imidazolines such as midaglizole, isaglidole, deriglidole, idazoxan, efaroxan and fluparoxan; other insulin secretagogues such as linogliride and A4166; glitazones such as ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone and BRL49653; aldose reductase inhibitors such as epalrestat, sorbinil, tolrestat and zopolrestat; fatty acid oxidation inhibitors such as clomoxir and etomoxir; .alpha.-glucosidase inhibitors such as acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose and MDL-73,945; .beta.-agonists such as (4-(2-(2-(6-aminopyridin-3-yl)-2(R)-hydroxyethylamino)ethoxy)phenyl)acetic acid and BRL 35135, BRL 37344, Ro 16-8714, ICI D7114 and CL 316,243; phosphodiesterase inhibitors such as L-386,398; lipid-lowering agents such as benfluorex; antiobesity agents such as fenfluramine, sibutramine and bromocriptine; vanadate and vanadium complexes (e.g. naglivan) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; growth hormone secretagogues; gluconeogenesis inhibitors such as glucose-6-phosphatase inhibitors; somatostatin analogs; antilipolytic agents such as nicotinic acid, acipimox and WAG 994; prodrugs thereof or pharmaceutically acceptable salts of said antidiabetic agents or said prodrugs and a pharmaceutically acceptable carrier or diluent in a second unit dosage form; and c. a container. Another aspect of this invention is directed to a compound of formula II, ##STR2## wherein: R.sup.1 is (C.sub.1 -C.sub.4)alkyl, (C.sub.3 -C.sub.7)cycloalkyl, phenyl or phenyl independently substituted with up to three (C.sub.1 -C.sub.4)alkyl, (C.sub.1 -C.sub.4)alkoxy or halogen; R.sup.2 is (C.sub.1 -C.sub.4)alkyl optionally substituted with up to three fluoro atoms; and R.sup.3 is (C.sub.3 -C.sub.7)cycloalkyl; phenyl; phenyl substituted at the para position with (C.sub.1 -C.sub.4)alkyl, halo or trifluoromethyl; phenyl substituted at the meta position with fluoro; or phenyl substituted at the ortho position with fluoro. Glycogen phosphorylase dependent diseases or conditions refers to disorders which are mediated, initiated or maintained, in whole or in part, by the cleavage of the glycogen macromolecule by glycogen phosphorylase enzymes to release glucose-1-phosphate and a new shortened glycogen molecule. These disorders are ameliorated by reduction of or characterized by an elevation of glycogen phosphorylase activity. Examples include diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and myocardial ischemia. The term glycogen phosphorylase inhibitor refers to any substance or agent or any combination of substances and/or agents which reduces, retards, or restrains the enzymatic action of glycogen phosphorylase. The currently known enzymatic action of glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a glycogen macromolecule and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule which is one glucosyl residue shorter than the original glycogen macromolecule (forward direction of glycogenolysis). The term "treating" as used herein includes preventative (e.g., prophylactic), palliative and curative treatment. By halo is meant chloro, bromo, iodo, or fluoro. By alkyl is meant straight chain or branched saturated hydrocarbon. Exemplary of such alkyl groups (assuming the designated length encompasses the particular example) are methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tertiary butyl, pentyl, isopentyl, hexyl and isohexyl. By alkoxy is meant straight chain or branched saturated alkyl bonded through an oxy. Exemplary of such alkoxy groups (assuming the designated length encompasses the particular example) are methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tertiary butoxy, pentoxy, isopentoxy, hexoxy and isohexoxy. The expression "prodrug" refers to compounds that are drug precursors, which, following administration, release the drug in vivo via a chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form). As used herein, the expressions "reaction-inert solvent" and "inert solvent" refers to a solvent or mixture of solvents which does not interact with starting materials, reagents, intermediates or products in a manner which adversely affects the yield of the desired product. The chemist of ordinary skill will recognize that certain compounds of this invention will contain one or more atoms which may be in a particular stereochemical or geometric configuration, giving rise to stereoisomers and configurational isomers. All such isomers and mixtures thereof are included in this invention. Hydrates and solvates of the compounds of this invention, of the produgs of the compounds of this invention, and pharmaceutically acceptable salts of said hydrates and solvates are also included. Other features and advantages will be apparent from the specification and claims which describe the invention. |
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