AP911A

AP911A - Combinatin of aldose reductase inhibitor and a glycogen phosphorylase inhibitor.

Info

Publication number: AP911A
Application number: APAP/P/1998/001401A
Authority: AP
Inventors: Banavara L Mylari; Denis Jay Hoover; Bernard Hulin; Judith Lee Treadway
Original assignee: Pfizer Prod Inc
Priority date: 1997-11-21
Filing date: 1998-11-19
Publication date: 2000-12-07
Also published as: NO20002164L; ES2161548T3; UY25258A1; KR20010032300A; NO20002164D0; ATE205403T1; HRP20000327A2; HUP0100272A2; IL135713A0; UA57811C2; PT1032424E; IS5453A; AR016423A1; OA11379A; PA8462301A1; MA26568A1; TR200001451T2; WO1999026659A1; PE135399A1; EP1032424B1

Abstract

Pharmaceutical combination compositions and methods including aldose reductase inhibitors and glycogen phosphorylase inhibitors. The compositions and methods are useful for the treatment insulin resistant conditions such as diabetes and in reducing tissue damage due to ischemia.

Description

COMBINATION OF AN ALDOSE REDUCTASE INHIBITOR AND A GLYCOGEN PHOSPHORYLASE INHIBITOR BACKGROUND OF INVENTION

This invention relates to pharmaceutical combination of an aldose reductase inhibitor and a glycogen phosphorylase inhibitor, kits containing such combinations and the use of such combinations to treat diabetes, hyperglycemia, hypercholesterolemia, hypertension, hyperinsuiinemia, hyperlipidemia, atherosclerosis and tissue ischemia in mammals. 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™ (Pfizer), Tolbutamide™ (Upjohn), Acetohexamide™ (E.l. Lilly), Tolazamide™ (Upjohn)), biguanides (e.g. Phenformin™ (Ciba Geigy), Metformin™ (G. D. Searle)), alpha-glucosidase inhibitors (e.g., Precose™ (Bayer)) and insulin sensitizers (e.g., Rezulin™ (Parke Davis)) as oral hypoglycemic agents, there is a continuing need for treatments of diabetes. The use of insulin, necessary in about 10 % of diabetic patients 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 II 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.

Aldose reductase inhibitors constitute a class of compounds which have become widely known for their utility in preventing and treating conditions arising from complications of diabetes such as diabetic neuropathy and nephropathy. Such compounds are well known to those skilled in the art and are readily identified by standard biological tests.

For example, the compound zopolrestat, 1 -phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-(trifIuoromethyl)-2-benzothiazolyl]methyl]-, is known, for example from commonly assigned U.S. patent 4,939,140 to Larson et al., (the disclosure of which is hereby incorporated by reference) together with a number of compounds related thereto, to have utility as aldose reductase inhibitors. Zopolrestat has the structure

and, as an aldose reductase inhibitor, is useful in the treatment of the above-mentioned complications arising from diabetes mellitus.

Certain aldose reductase inhibitors have been taught for use in lowering lipid levels in mammals. See, for example, U. S. patent 4,492,706 (the disclosure of which is hereby incorporated by reference) to Kallai-sanfacon and EP 0 310 931 A2 (Ethyl Corporation).

Commonly assigned U. S. patent 5,064,830 (the disclosure of which is hereby incorporated by reference) to Going discloses the use of certain oxophthalazinyl acetic acids, including zopolrestat, for lowering of blood uric acid levels.

Commonly assigned U.S. patent application No. 08/059,688 discloses the use of certain aldose reductase inhibitors, including zopolrestat, for lowering blood lipid levels in humans. The disclosure notes that therapeutic utilities derive from the treatment of diseases caused by an increased level of triglycerides in the blood, such diseases include cardiovascular disorders such as thrombosis, arteriosclerosis, myocardial infarction, and angina pectoris.

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 extra-cellular lipid, collagen, elastin and proteoglycans. The cells plus matrix form a fibrous cap that covers a deeper deposit of cell debris and more extra cellular 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. Such 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 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 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 short-term death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary disease. These conditions gradually weaken a patient and can led to long-term death.

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 short-interval deaths 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 hyperinsuiinemics 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-patient 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 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 series. In addition, of the 400,000 patients undergoing coronary by-pass surgery annually, perioperative myocardial infarction is estimated to occur in 5% and death in 1-2%. There is currently no marketed drug therapy in this area which reduces damage to cardiac tissue from perioperative myocardial ischemia or enhances cardiac resistance to ischemic episodes. Such a therapy is anticipated to be life-saving and reduce hospitalizations, enhance quality of life and reduce overall health care costs of high risk patients.

Hepatic glucose production is an important target for NIDDM 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 NIDDM patients is significantly elevated relative to normal individuals. Likewise, in the postprandial (fed) state, where the liver has a proportionately smaller role in the totdl plasma glucose supply, hepatic glucose production is abnormally high in NIDDM patients.

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 NIDDM. First, in normal post absorptive humans, up to 75% of hepatic glucose production is estimated to result from glycogenolysis. Second, patients 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 NIDDM by decreasing hepatic glucose production and lowering glycemia. [Blundell, T.B. et al. Diabetologia 1992,25, Suppi. 2, 569-576 and Martin et al. Biochemistry 1991, 30,10101].

The mechanism(s) responsible for the myocardial 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, hyperinsuiinemia, hyperlipidemia, atherosclerosis and ischemic 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 pharmaceutical compositions comprising aldose reductase inhibitors and glycogen phosphorylase inhibitors and for the use of such compositions for the treatment of insulin resistant conditions, including diabetes in mammals (e.g., humans either male or female) or for the use of such compositions for reducing tissue damage (e.g., substantially preventing tissue damage, inducing tissue protection) resulting from ischemia.

The combinations comprise therapeutically effective amounts of an aldose reductase inhibitor and a glycogen phosphorylase inhibitor. A preferred amount of aldose reductase inhibitor is about 0.1 mg/kg to about 20 mg/kg and a preferred amount of glycogen phosphorylase inhibitor is about 0.1 mg/kg to about 15 mg/kg.

An especially preferred aldose reductase inhibitor is 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3-[[5-trifluoromethyl)-2-benzothiazolyl]methyl]-.

Preferred glycogen phosphorylase inhibitors include compounds having the Formula I

Formula I and the pharmaceutically acceptable salts and prodrugs thereof wherein the dotted line (—) is an optional bond; A is -C(H)=, -C((C1-C4)alkyl)= or -C(halo)= when the dotted line (—) is a bond, or A is methylene or -CH((C1-C4)alkyl)- when the dotted line (—) is not a bond; R-j, R1o or R31 are each independently H, halo, 4-, 6- or 7-nitro, cyano, (C-|-C4)alkyl, (CrC4)alkoxy, fluoromethyl, difluoromethyl or trifluoromethyl; R2 is H; R3 is H or (CrC5)alkyl; R4 is H, methyl, ethyl, n-propyl, hydroxyiCrCaJalkyl, (C-rCsjalkoxyfCr C3)alkyl, phenyl(C-|-C4)alkyl, phenylhydroxy(CrC4)alkyl, phenyKCrC^alkoxyiCr C4)alkyl, thien-2- or -3-yl(C1-C4)alkyl or fur-2- or -3-yl(CrC4)alkyl wherein said R4 rings are mono-, di- or tri-substituted independently on carbon with H, halo, (Cr C4)alkyl, (C-|-C4)alkoxy, trifluoromethyl, hydroxy, amino or cyano; or is pyrid-2-, -3- or -4-yl(CrC4)alkyl, thiazol-2-, -4- or -5-yl(CrC4)alkyl, imidazol -1-, -2-, -4- or -5-yl(CrC4)alkyl, pyrrol-2- or -3-yl(CrC4)alkyl, oxazol-2-, -4- or -5-yl-(C-i-C4)alkyl, pyrazol-3-, -4- or -S-yKCrC^alkyl, isoxazol-3-, -4- or -5-yl(Cr C4)alkyl, isothiazoi-3-, -4- or -5-yl(Ci-C4)alkyl, pyridazin-3- or -4-yl-(Ci-C4)alkyl, pyrimidin-2-, -4-, -5- or -6-yl(CrC4)alkyl, pyrazin-2- or -3-yl(CrC4)alkyl or 1,3,5-

triazin-2-yl(CrC4)alkyI, wherein said preceding R4 heterocycles are optionally mono-or di-substituted independently with halo, trifluoromethyl, (C1-C4)alkyl, (CrC4)alkoxy, amino or hydroxy and said mono-or di-substituents are bonded to carbon; R5 is H, hydroxy, fluoro, (CrC5)alkyl, (Ci-C5)alkoxy, (C^Cgjalkanoyl, aminoiCrCJalkoxy, mono-N- or di-N,N-(CrC4)alkylamino(Ci-C4)aIkoxy, carboxy(Cr C4)alkoxy, (Ci-C5)alkoxy-carbonyl(Ci-C4)alkoxy, benzyloxycarbonyKC-rC^alkoxy, or carbonyloxy wherein said carbonyloxy is carbon-carbon linked with phenyl, thiazolyl, imidazolyl, 1 H-indolyl, furyl, pyrrolyl, oxazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl or 1,3,5-triazinyl and wherein said preceding R5 rings are optionally mono-substituted with halo, (CrC4)alkyl, (CrC4)alkoxy, hydroxy, amino or trifluoromethyl and said mono-substituents are bonded to carbon; R7 is H, fluoro or (CrC5)alkyl; or R5 and R7 can be taken together to be oxo;

Re is carboxy, (C^CgJalkoxycarbonyl, C(O)NR8Rg or C(O)R12, wherein R8 is H, (CrCsJalkyl, hydroxy or (C^^jalkoxy; and

Rg is H, (CrC8)alkyl, hydroxy, (CrCgjalkoxy, methylene-perfluorinated(C·,-C8)alkyl, phenyl, pyridyl, thienyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl or 1,3,5-triazinyl wherein said preceding Rg rings are carbon-nitrogen linked; or

Rg is mono-, di- or tri-substituted (CrC5)alkyl, wherein said substituents are independently H, hydroxy, amino, mono-N- or di-N,N-(CrC5)aIkylamino; or

Rg is mono- or di-substituted (CrC5)alkyl, wherein said substituents are independently phenyl, pyridyl, furyl, pyrrolyl, pyrrolidinyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, pyranyl, pyridinyl, piperidinyl, morpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl or 1,3,5-triazinyl wherein the nonaromatic nitrogen-containing R9 rings are optionally monosubstituted on nitrogen with (CrC6)alkyl, benzyl, benzoyl or (CrC6)alkoxycarbonyl and wherein the Rg rings are optionally mono-substituted on carbon with halo, (Cr C4)alkyl, (CrC4)alkoxy, hydroxy, amino, or mono-N- and di-N,N (C^CsJalkylamino provided that no quatemized nitrogen is included and there are no nitrogen-oxygen, nitrogen-nitrogen or nitrogen-halo bonds;

Ri2 is piperazin-1-yi, 4-(Ci-C4)alkyipiperazin-1-yl, 4-formylpiperazin-l-yl, morpholino, thiomorpholino, 1-oxothiomorpholino, 1,1-dioxo-thiomorpholino, thiazolidin-3-yl, 1-oxo-thiazoiidin-3-yl, 1,1-dioxo-thiazolidin-3-yl, 2-(Cr C6)alkoxycarbonylpyrrolidin-1-yl, oxazoIidin-3-yl or 2(R)-hydroxymethylpyrrolidin-1-yl; or R-12 is 3- and/or 4-mono-or di-substituted oxazetidin-2-yi, 2-, 4-, and/or 5-mono- or di-substituted oxazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted thiazolidin-3-yi, 2-, 4-, and/or 5- mono- or di- substituted 1-oxothiazolidin-3-yl, 2-, 4-, and/or 5- mono- or di- substituted 1,1-dioxothiazolidin-3-yl, 3- and/or 4-, mono- or di-substituted pyrrolidin-1-yl, 3-, 4- and/or 5-, mono-, di- or tri-substituted piperidin-1-yl, 3- , 4-, and/or 5- mono-, di-, or tri-substituted piperazin-1-yl, 3-substituted azetidin-1-yl, 4- and/or 5-, mono- or di-substituted 1,2-oxazinan-2-yi, 3-and/or 4-mono- or di-substituted pyrazolidin-1-yi, 4- and/or 5-, mono- or di-substituted isoxazolidin-2-yl, 4-and/or 5-, mono- and/or di-substituted isothiazolidin-2-yl wherein said R12 substituents are independently H, halo, (CrC5)-alkyl, hydroxy, amino, mono-N- or di-N,N-(Ci-C5)alkylamino, formyl, oxo, hydroxyimino, (CrC5)aikoxy, carboxy, carbamoyl, mono-N-or di-N,N-(Ci-C4)alkylcarbamoyl, (Ci-C4)aikoxyimino, (Cr C4)aikoxymethoxy, (Ci-C6)alkoxycarbonyl, carboxy^-C5)alkyI or hydroxy(Cr C5)alkyl; with the proviso that if R| is H, methyl, ethyl or n-propyl R5 is OH; with the proviso that if R5 and R7 are H, then R4 is not H, methyl, ethyl, n-propyl, hydroxy(Ci-C3)aikyl or (CrCsjalkoxyiCi-Cyalkyl and R6 is C(O)NR8R9, C(O)Ri2 °r (CrC4)alkoxycarbonyl. A first group of preferred compounds of Formula I consists of those compounds wherein R-ι is 5-H, 5-halo, 5-methyl or 5-cyano; R10 and R31 are each independently H or halo; A is -C(H)=; R2 and R3 are H; R4 is phenyl(C-|-C2)a!kyl wherein said phenyl groups are mono-, di- or tri-substituted independently with H or halo or mono- or di- substituted independently with H, halo, (CrC4)alkyl, (CrC4)aikoxy, trifluoromethyl, hydroxy, amino or cyano; or

Claims

Original document published without claims.