MXPA01004055A - Thyroid receptor ligands - Google Patents

Abstract

The invention provides thiazolidinedione, oxadiazolidinedione, and triazolone compounds of Formula (I) which compounds are thyroid receptor ligands. The invention further provides pharmaceutical compositions and kits comprising such compounds and methods of treating obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis using such compounds.

Description

LIGANDS OF THYROID RECEIVERS FIELD OF THE INVENTION The present invention relates to certain thiazolidinadone, oxadiazolidinedione, and triazolonal compounds which are thyroid receptor ligands. The invention further relates to pharmaceutical compositions and kits comprising such thiazolidinedione, oxadiazolidinedione, and triazolone compounds and to methods for using such compounds in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease , hypothyroidism, cancer of the gland, thyroid, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis.

BACKGROUND OF THE INVENTION Thyroid hormones are critical for the normal development and maintenance of metabolic homoestasis. As such, thyroid hormones are known to stimulate the metabolism of cholesterol in bile acids and by increasing the lipolytic responses of fat cells to other hormones.

Thyroid hormones also affect cardiac function both directly and indirectly, for example by increasing the metabolic rate. For example, tachycardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure are all observed in patients with hyperthyroidism. Disorders of the thyroid gland that result in decreased levels of thyroid hormones are usually treated by administration of either naturally occurring thyroid hormones or their analogs that mimic the effects of thyroid hormones. Such analogs are known generically as thyromimetics or ligands of thyroid receptors. Two thyroid hormones of natural occurrence, 3,5,3'-triyodo-L-thyronine (also known as "T3"), and 3, 5, 3 ', 5'-tetra-L-thyronine (also known as " T "or thyroxine) are illustrated here below: T3 Generally, T is biologically more active than T4, and differs from it by the absence of an iodine atom in the 5 'position. T, can be produced directly, both in the thyroid gland and in peripheral tissues, by removing the 5 'iodine from T4 by means of enzymes of deiodinase. Ligands of synthetic thyroid receptors can be designed to be structurally similar to T3. In addition, metabolites of natural occurrence of T3 are known. As discussed above, thyroid hormones can affect cardiac function, for example, by causing an increase in heart rate and, consequently, an increase in oxygen consumption. While the increase in oxygen consumption can produce certain desirable metabolic effects, such an increase places additional burden on the heart which in many situations, results in harmful side effects. Consequently, efforts have been made to synthesize thioride hormone analogs / mimetics that function to reduce serum lipids or cholesterol, but which have reduced adverse cardiac effects. A variety of analogs / mimetics of thyroid hormones are described and cited below, however, additional agents will be known to one of skill common in the state of the art. For example, the patents of E.U.A. No. 4,766,121; 4,826,876; 4,910,305; and 5,061,798 disclose thyroid hormone mimetics, namely 3,5-dibromo-3 '- [6-oxo-3 (1 H) -pyridazinylmethyl] -thironines, while the U.S. Do not.

No. 5,284,971 discloses thyromimetic cholesterol reducing agents, namely, 4- (3-cyclohexyl-4-hydroxyl or methoxy-phenylsulfonyl) -3,5-dibromo-phenylacetic compounds. In addition, the patents of E.U.A. No. 5,654,468 and 5,569,674 disclose certain lipid-reducing agents, namely, hertoacetic acid derivatives, which compete with the T, radio-labeled in binding assays using rat liver nuclei and plasma membrane preparations. In addition, certain oxamic acids and derivatives thereof are known in the art, eg, the US patent. No. 4,069,343 describes the use of oxamic acids to prevent immediate type hypersensitivity reactions, the U.S. patent. No. 4,554,290 describes the use of oxamic acids to control pests in animals and plants, the patent of E.U.A. No. 5,232,947 describes the use of oxamic acids to improve damaged brain functions, and European application publication No. EP 0 580 550 (also U.S. Patent No. 5,401,772) discloses oxamic acid derivatives as hypocholesterolemic agents. In addition certain derivatives of oxamic acid of thyroid hormones are known in the state of the art. See, for example, Yokoyama, J. Med Chem., 38 (4), 698-707 (1995), Steele, International Congressiponal Service (Atherosclerosis X) 106, 231-324 (1995), and Stephan, Atherosclerosis, 126 53 -63 (1996). Obesity is a major health risk that leads to increased mortality and incidence of type 2 diabetes mellitus, hypertension and dyslipidemia. In the United States, more than 50% of the adult population suffers from overweight, and almost the population is considered obese. The incidence of obesity is increasing in the United States at a cumulative annual growth rate of 3%. While the vast majority of obesity occurs in the United States and Europe, the prevalence of obesity is also increasing in Japan. The prevalence of obesity in adults is 10-20% in most Western European countries. In addition, obesity is a devastating disease which can also wreak havoc on the mental salience and self-esteem of an individual, ultimately affecting the person's ability to interact socially with others. Unfortunately, the precise etiology of obesity is complex and poorly understood, and social stereotypes and presumptions regarding obesity only tend to exacerbate the psychological effects of the disease. Due to the impact of obesity on society in general, much effort has been made to treat obesity, however, success in long-term treatment and / or prevention remains elusive. The thyroid receptor ligands of the present invention can be used to treat obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias (including atrial and ventricular arrhythmias), skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and ostoeoporosis.

The state of diabetic disease is characterized by impaired glucose metabolism that manifests itself in, inter alia, elevated glucose levels in patients suffering from it. Generally, diabetes is classified into two different groups: (1) Type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), which increases when patients lack β-cells that produce insulin in pancreatic glands, and (2) Type 2 diabetes, or non-insulin dependent diabetes mellitus (NIDDM), which occurs in patients , inter alia , impaired function of β-cells. Currently, type 1 diabetic patients are treated insulin, while the majority of type 2 diabetic patients are treated hypoglycemic agents, such as sulfonylureas that stimulate the function of the β-cells, other agents that increase the selectivity of patients towards insulin, or the same insulin. Unfortunately, the use of insulin currently requires multiple daily doses, usually administered by self injection, determination of the appropriate dosage of insulin requiring frequent estimates of sugar in the urine or blood, made by both the patient and the doctor who formulates. The unintentional administration of an excessive dose of insulin can produce hypoglycemia, adverse effects ranging from mild abnormalities in blood glucose to coma, or even death. Although hypoglycemic agents such as sulfonylureas have been widely used in the treatment of NIDDM, this treatment in many instances is not considered satisfactory. In a large number of NIDDM patients, sulfonylureas have been shown to be ineffective in normalizing blood sugar levels, thus leading to an increased risk of acquiring diabetic complications. Also, many patients gradually lose the ability to respond to treatment sulfonylureas and are therefore gradually forced to treatment sulfonylureas and therefore are gradually forced to treatment insulin. Since many existing forms of diabetic therapy have proven inefficient in achieving acceptable glycemic control, there remains a great demand for approximately therapeutic novel ones. Atherosclerosis, a disease of the arteries, is recognized as a significant risk factor in the causes of death in the United States and Western Europe. The pathological sequence that leads to atherosclerosis and occlusive heart disease is well established. The first stage in this sequence is the formation of the known "fatty streaks" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow due to the presence of lipid deposits found mainly in smooth muscle cells and in macrophages of the intima layer of the arteries and the aorta. In addition, it was postulated that most of the cholesterol found in fatty streaks, in turn, leads to the development of the known "fibrous plaques" that consist of accumulated internal smooth muscle cells loaded lipids which are surrounded by extra lipid -cellular, collagen, elastin and proteoglycans. The cells together their matrix form a fibrous layer that covers a deeper deposit of cellular waste and extra cellular extra lipid, comprising mainly free and esterified cholesterol. The fibrous plaque gradually accumulates, and over time it is likely to calcify and become necrotic, progressing to a "complicated lesion", which is responsible for arterial occlusion and a tendency for mural thrombosis and arterial muscle spasm characterizing the condition of advanced atherosclerosis . Epidemiological evidence has firmly established hyperlipidemia as a major risk factor in the production of cardiovascular disease (CDV) due to atherosclerosis. In recent years, medical professionals have placed renewed emphasis on reducing plasma cholesterol levels, particularly low density lipoprotein cholesterol, as an essential step in the prevention of CVD. The upper limits of normal levels of plasma cholesterol are known to be significantly lower than those appreciated up to now. As a result, large segments of accidental populations are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension, particularly affecting members of the male population. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part due to the experience of multiple independent risk factors in this population. The successful treatment of hyperlipidemia in the general population and, in particular, in diabetic individuals, is therefore of exceptional medical importance. Hypertension, or high blood pressure, is a condition that occurs in the human population as a condition subordinated to 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 clarified yet. Additionally, many patients present symptoms of high blood pressure in the total absence of any other signs of disease or disorder. It is known that hypertension can directly lead to heart failure, renal failure and stroke, that is, cerebral hemorrhage, such conditions, capable of producing immediate death in a patient. Hypertension can also contribute to the development of atherosclerosis and coronary heart disease, conditions that can weaken a patient and also lead to death. The exact cause of essential hypertension is unknown, although it is believed that a number of factors contribute to the onset of the disease. Among such factors are stress, uncontrolled emotions, uncontrolled release of hormones, especially those that affect renin, angiotensin, and aldosterone systems, salt and excessive water due to kidney malfunction, thickening of walls and hypertrophy of the vasculature producing narrow blood vessels, and certain genetic factors. The treatment of essential hypertension has been undertaken bearing in mind the above factors. Thus, a wide range of β-blockers, vasconstrictors, angiotensin-converting enzyme (ACE) inhibitors and the like have been developed and commercially as anti-hypertensive. The treatment of hypertension using these compounds has been shown to be beneficial in the prevention of short-interval deaths such as heart failure, renal failure and cerebral hemorrhage. Hypertension has been associated with elevated levels of insulin in the blood, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose main actions are to promote the use of glucose, protein synthesis and the formation and storage of neutral lipids, also acts, inter alia, to promote muscle cell growth and increase renal sodium retention. These latter functions, which are known causes of hypertension, can be performed without affecting glucose levels. Peripheral vascular development, for example, can produce constriction of peripheral capillaries while sodium retention increases blood volume. Thus, the reduction of insulin levels in hyperinsulinemic drugs can prevent abnormal vascular development and renal sodium retention caused by high insulin levels, thus relieving hypertension.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides certain thiazolindinadione, oxadiazolidinedione, and triazolone compounds of the structural formula (i), the stereoisomers and prodrugs of the compounds, stereoisomers, and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, prodrugs, which are thyroid receptor ligands, wherein R1, R2, R3, R4, R5, R6, W, and X are as defined below.

The invention further provides pharmaceutical compositions and kits comprising such compounds and methods of using such compounds, pharmaceutical compositions, and kits in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias (including atrial and ventricular arrhythmias), skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, arteriosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis.

DETAILED DESCRIPTION OF THE INVENTION The present invention supplies compounds of the structural formula (I) the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein: W is oxygen, sulfur, -SO-, -S (0) 2, -CH 2 -, CFZ-, - CHF-, -C (O) -, -CH (OH) -, -NR3, or -C (= CH2) -; R1, R2, R3, and R8 are each independently hydrogen, halogen, -alkyl (C1-C8), CF3, -OCF3, -O-alkyl (C1-C8), or -CN; R 4 is hydrogen, (C 1 -C 12) -alkyl substituted with 0 to 3 substituents independently selected from the group V, alkenyl (C2-C12), alkynyl (C2-C12), halogen, CN, ORb, -SRC -S (0) Rc, aryl, heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, -S (0) 2NRcRd, - C (0) NRcRd, -C (0) ORc, - -NRaC (0) R, -NRaS (0) 2Rd, or -C (0) Rc; or R3 and R4 are taken together with the carbon atoms to which they are attached to form a carboxylic ring of the formula - (CH2) - or a heterocyclic ring of the formula - (CH2) kQ- (CH2)? - in where Q is oxygen, sulfur, or -NRe-; i is 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, or 5; and 1 is 0, 1, 2, 3, 4, or 5; and wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (C1-C4) alkyl -ORb, oxo, -CN, phenyl, or -NRaR9; R5 is hydroxy, alkyl-0 (C1-C6), -OC (0) Rf, fluorine, or -C (0) ORc; or R4 and R5 are taken together with the carbon atoms to which they are attached to form a heterocyclic ring selected from the group consisting of CR = CRa-NH-, -N = CRa-NH-, -CR6 = CRa-0-, CRc = CRa-S-, -CRc = CRa-NH-, and -CRa = CRa-CRa = N-; Ra for each occurrence is independently hydrogen, or - (C 1 -C 6) alkyl substituted with zero or a-C 3 -C 6 cycloalkyl or methoxy; Rb for each occurrence is independently hydrogen, -alkyl (C2-C12) with zero to three substituents independently selected from the group V, aryl, heteroaryl, cycloalkyl (C3-C10), heterocycloalkyl -C (0) NRcRd, or -C ( 0) Rf; Rc and Rd for each occurrence are each independently hydrogen, (C1-C12) alkyl-substituted with zero to three substituents independently selected from group VI, -alkenyl (C2-C12), alkynyl (C2-C12), aryl, heteroaryl , -cycloalkyl (C3-C10), or heterocycloalkyl; as long as R4 is the fraction -SRC, -S (0) Rc, or -S (0) 2RcRc will be different from hydrogen; or Rc and Rd are taken together with the atoms to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from oxygen, -NRC-, or sulfur; and wherein the heterocyclic ring is substituted with zero or four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, -CN, phenyl, or -NRaR9; Re for each occurrence hydrogen, -CN, (C1-C10) alkyl substituted with zero to three substituents independently selected from the group V, -alkenyl (C2-C10), alkoxy (C2-C10), cycloalkyl (C8-C10), aryl, heteroaryl, -C (0) Rf, -C (0) ORf, -C (0) NRaRf or -S (0) 2Rf; Rf for each occurrence independently (C1-C10) alkyl substituted with zero to three substituents independently selected from group VI, (C2-C12) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, aryl, heteroaryl , or heterocycloalkyl; R9 for each occurrence hydrogen (C1-C6) alkyl, alkenyl (C2-C6), aryl, C (0) Rf, C (0) Rf, -C (0) ORf, -C (0) NR3Rf or -S (0) 2Rf; or (C3-C8) cycloalkyl. The group V is halogen, -CF3, -OCF3, -OH, oxo, -alkoxy (C1-C6), -CN, aryl, heteroaryl, cycloalkyl (C3-C8), heterocycloalkyl, -SRf, -S (0) Rf , -S (0) 2Rf, -S (0) 2NRaRf, -NRaR9, -C (0) NRaRf; Group VI is halogen, hydroxyl, oxo, -alkoxy (C1-C6), aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, -CN, or -OCF3; provided that R4 is (C2-C12) alkyl substituted with zero to three substituents independently selected from the group V wherein the substituent of group V is oxo, the oxo group is substituted on a carbon atom different from the carbon atom C1 in the alkyl (C2-C12); aryl for each occurrence independently phenyl or naphthyl substituted with zero to four substituents independently selected from halogen, (C1-C6) alkyl, -CN, -SRf, -S (0) Rf, -S (0) 2Rf, -cycloalkyl (C3 -C6), -S (0) 2NRaRf, -NRaR9, -C (0) NRaRf; -ORb, -perfluoro-alkyl (C1-C4), or COORf; as long as the substituents on aryl are -SRf, -S (0) Rf, -S (0) 2Rf, -S (0) 2NRaRf, -NRaR9, -C (0) NRaRf; -ORb, or COORf, the substituents R, Rf, and R9, are different from aryl or heteroaryl; heteroaryl for each occurrence is independently a monocyclic or bicyclic ring of 5, 6, 7, 8, 9 members having from one to after heteroatoms selected from O, N, or S; wherein in the bicyclic ring, a monocyclic heteroaryl ring is fused with a benzene ring or with another heteroaryl ring, and having zero to three substituents independently selected from halogen, -alkyl (C1-C4), -CF3, -ORb, -NRaR9, or -COORf; as long as the substituents on heteroaryl are -NRaR9, -ORb, or COORf, the substituents Rb, Rf, and Rc, are different from aryl or heteroaryl; heterocycloalkyl for each occurrence is independently a monocyclic or bicyclic cycloalkyl ring of 4, 5, 6, 7, 8 or 9 members having between one to three heteroatoms selected from oxygen, -NRa, or sulfur, and having zero to four substituents independently selected from -alkyl (C1-C4), -ORb, oxo, -CN, phenyl, or -NRaR9; and X is Preferably, the invention provides compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein W is oxygen. More preferably, the invention provides compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein: R1 is located at position 3 and R2 is located at position 5, where R1 and R2 are each independently hydrogen, (C1-C6) alkyl, halogen, or -CN; R3 is hydrogen, (C1-C4) alkyl or halogen; R4 is (C1-C10) alkyl substituted with zero to three substituents independently selected from fluoro, hydroxyl, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) 2NRGRd, -C (0) NRcRd , -S (0) 2RC, (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) Rc, -ORb, -SRC, -S (0) Rc, -NRaC (0) Rd, -NR3C (0) NRcRd , or -NRaS (0) 2Rd; or R ° and Rd are taken together with the atoms to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from oxygen, -NR-, or sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, phenyl, or -NRaRg; or R3 and R4 are taken together with the carbon atoms to which they are attached to form a carbocyclic ring of the formula - (CH2) or a heterocyclic ring of the formula - (CH2) kQ- (CH2) -? - wherein Q is -O-, -S- or -NRC-; i is 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, or 5; and is 0, 1, 2, 3, 4, or 5; and wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (C1-C4) alkyl, ORb, oxo, -CN, phenyl, or -NRaRg; as long as R 4 is (C 1 -C 10) alkyl substituted with zero to three substituents, the oxo group is substituted on a carbon atom different from the carbon atom Hundred (C 1 -C 10) alkyl; R5 is -OH, -OC (0) Rf, -C (0) ORc, or -F; wherein Rf is (C1-C10) alkyl substituted with zero to three substituents independently selected from group VI; R6 is hydrogen, halogen or (C1-C4) alkyl; and X is More preferably, the invention provides compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein: R1 and R2 are each independently hydrogen, alkyl- (C1-C6), halogen, or -CN; R3 is hydrogen; R4 is (C1-C10) alkyl substituted with zero to three substituents independently selected from fluoro, hydroxyl, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) 2NRcRd, -C (0) NRcRd , -S (0) 2RC, (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) Rc, -ORb, -SRC, -S (0) Rc, -NRaC (0) Rd, -NR3C (0) NR ° Rd, or -NRaS (0) 2Rd; or Rc and Rd are taken together with the atoms (s) to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second hetero group selected from oxygen, -NR-, sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, phenyl, or -NRaRg; or R5 is -OH, fluoro, or -OC (0) Rf wherein Rf is (C1-C10) alkyl substituted with zero to three substituents independently selected from group VI; R6 is hydrogen. More preferably, the invention provides compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, wherein: R1 and R2 are both methyl, bromine, or chlorine; R4 is (C1-C10) alkyl, substituted with zero to 2 substituents independently selected from fluoro, hydroxyl, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) 2NRcRd, -S (O) 2R0, (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) Rc, -ORb, -SRC, -S (0) Rc, NRaC (0) Rd, -NRaC (0) NRcRd, or -NRaS (0) 2Rd, or R ° and Rd are taken together with the atom (s) to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second hetero group selected from oxygen, NRC-, sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, ORb, oxo, -CN, phenyl, or -NRaR9; and R5 is -OH. The following compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, are especially preferred in the practice of the pharmaceutical compositions, methods, and kits herein. invention as pharmaceutical compositions, methods, and kits are described in more detail below; 5- [3,5-dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzyl] -thiazolidine-2,4-dione; 5- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-benzyl-deno] -thiazolidine-2,4-dione; 5- [4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-d-methyl-benzyl-thiazolidin-2,4-dione; N-cyclopropyl-5- [2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-ylmethyl] -phenoxy] -2-hydroxy-benzenesulfonamide; N-cyclobutyl-5- [2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-methylmethyl] -phenoxy] -2-hydroxy-N-methyl-benzamide; 2- [3,5- dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzyl] - [1,4] oxadiazolidine-3,5-dione; 2- [4- (3-isopropyl-4-methoxy-phenoxy) -3,5-dimethyl-benzyl] - [1, 2,4] oxadiazolidine-3,5-dione; 2- [4- (4- (hydroxy-4-isopropyl-phenoxy) -3,5-dimethy] l-benzyl] - [1, 2,4] oxadiazolidine-3,5-dione; and 5- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -2, 4-dihydro- [1, 2,4] triazol-3-one The invention further provides pharmaceutical compositions and kits comprising the compounds of the formula (I), the stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, and methods of using the compounds, stereoisomers, and prodrugs, and pharmaceutically acceptable salts thereof, in the treatment of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias (including atrial and ventricular arrhythmias), skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression, and osteoporosis. In particular, the present invention provides methods for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension. , coronary heart disease, hypercholesterolemia, depression, and osteoporosis, in a mammal comprising administering to said mammal a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt thereof. compound, stereoisomer or prodrug. More preferably, the present invention provides such methods wherein the condition is obesity. More preferably, the present invention provides such methods wherein the condition is diabetes. In addition, the present invention provides methods for inducing weight loss in a mammal, such methods comprise administering to said mammal a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable of the compound, stereoisomer or prodrug. The present invention also provides methods for increasing energy consumption in a mammal such methods comprise administering to said mammal a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug.

In addition, the present invention provides methods for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, thyroid cancer, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis, such methods comprise administration to a patient with or at risk of having a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, disorders of skin, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis, a therapeutically effective amount of: 1) a compound of the formula (I) , a stereoisomer or prof of the same, a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined above; and 2) an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension , coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis. More preferably, the present invention provides such methods wherein the condition is obesity. More preferably, the present invention provides such methods wherein the additional compound is a lipase inhibitor. Most preferably, the present invention provides such methods wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastine, ebelactone. A, ebelactone B and RHC 80267, stereoisomers thereof and pharmaceutically acceptable salts of said compounds and stereoisomers. Also, more preferably, the present invention provides such methods wherein the additional compound is an anorectic agent. More preferably, the present invention provides such methods wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine. In another aspect, the present invention provides pharmaceutical compositions comprising a compound of the formula (I). A stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug. In another aspect, the invention provides kits for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis, such kits comprise: a) a first pharmaceutical composition comprising a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined above; b) a second pharmaceutically composition comprising an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis; and c) a container. In yet another aspect, the present invention provides pharmaceutical compositions comprising a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined above.; and an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, disease coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis.

More preferably, the present invention provides such compositions wherein the condition is obesity. More preferably, the present invention provides such compositions wherein the additional compound is a lipase inhibitor. Most preferably, the present invention provides such compositions wherein the lipase inhibitor is selected from the group consisting of lipstatin, tetrahydroipstatin (orlistat), FL-386, WAY-121898, Bay-N-3176, valilactone, esterastine, ebelactone A, ebelactone B and RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers. In addition, more preferably, the present invention provides such compositions wherein the additional compound is an anorectic agent. More preferably, the present invention provides such compositions wherein the anorectic agent is selected from the group consisting of phentermine, sibutramine fenfluramine, dexfenfluramine and bromocriptine. Methods for the treatment of diabetes are also provided, such methods comprising administration to patients with or at risk of suffering from diabetes, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. In a preferred embodiment of the methods for treating diabetes, diabetes is type I diabetes.

In another preferred embodiment of the methods for treating diabetes, diabetes is type II diabetes. Methods for treating atherosclerosis are also provided, such methods comprise administration to patients with or at risk of suffering from atherosclerosis, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable of the compound, stereoisomer, or prodrug. Methods for treating hypertension are also provided, such methods comprising administration to patients with or at risk of suffering from hypertension, a therapeutically effective amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable thereof, stereoisomer, or prodrug. Methods for treating coronary heart disease are also provided, such methods comprise administration to patients with or at risk of suffering from coronary heart disease, a therapeutically effective amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. Methods for treating hypercholesterolemia are also provided, such methods comprising administering to patients with or at risk of suffering from hypercholesterolemia, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable of the compound, stereoisomer, or prodrug. Methods for treating hyperlipidemia are also provided, such methods comprise administration to patients with or at risk of suffering from hyperlipidemia, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable of the compound, stereoisomer, or prodrug. Methods for treating thyroid disease are also provided, such methods comprising administering to patients with or at risk of suffering from thyroid disease, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a salt thereof. pharmaceutically acceptable of the compound, stereoisomer, or prodrug. Methods for treating hypothyroidism are also provided, such methods comprise administration to patients with or at risk of suffering from hypothyroidism, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. Methods for treating depression are also provided, such methods comprising administration to patients with or at risk of suffering from depression, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically salt acceptable of the compound, stereoisomer, or prodrug. Methods for obesity are also provided, such methods comprise administration to patients with or at risk of suffering from obesity, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. Methods for treating osteoporosis are also provided, such methods comprise administration to patients with or at risk of suffering from osteoporosis, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt. of the compound, sterecisomer, or prodrug. Methods for treating hypothyroidism are also provided, such methods comprising administering to patients with or at risk of suffering from hypothyroidism, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt thereof. compound, stereoisomer, or prodrug. Methods for treating thyroid gland cancer are also provided, such methods comprising administration to patients with or at risk of suffering from thyroid cancer, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or a prodrug thereof. , or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug.

Methods for treating glaucoma are also provided, such methods comprising administration to patients with or at risk of suffering from glaucoma, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. Methods for treating cardiac arrhythmias are also provided, such methods comprising administering to patients with or at risk of suffering from cardiac arrhythmias, a therapeutically effective amount of a compound of formula (I), a stereoisomer or prodrug thereof, or a salt pharmaceutically acceptable of the compound, stereoisomer, or prodrug. Methods for treating congestive heart failure are also provided, such methods comprising administration to patients with or at risk of congestive heart failure, a therapeutically effective amount of a compound of the formula (I), a stereoisomer or prodraga thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. The compounds of the invention can be named according to the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. In a preferred form of naming the compounds of the present invention, the carbon atoms in the respective rings are listed as illustrated in the following structure (II): The carbon atom content of the different hydrocarbon-containing radicals is indicated by a prefix designating the minimum and maximum number of carbon atoms in the fraction, that is, the prefix (Cj-Cj) indicates a fraction of the integer " i "a" j "carbon atoms, inclusive. Thus, for example (C1-C3) alkyl refers to alkyl of 1 to 3 carbon atoms inclusive, or methyl, ethyl, propyl, isopropyl, and all sub- stituted forms, and linear and branched forms thereof. The term "alkyl" denotes a straight or branched chain hydrocarbon. Representative examples of alkyl groups comprise methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl, pentyl, and hexyl. Alkyl groups generally preferred are (C1-C12) alkyl. The term "alkoxy" denotes an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, tert-butoxy, propoxy, and isobutoxy. Preferred alkoxy groups are (C1-C12) alkoxy. The term "halogen" or "halo" denotes a radical derived from chlorine, fluorine, bromine, or iodine.

The term "alkenyl" denotes a straight or branched chain hydrocarbon having one or more carbon-carbon double bonds. The term "cycloalkyl" denotes a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. Preferred cycloalkyl groups are (C3-C10) cycloalkyl. It is also possible that the cycloalkyl group has one or more double bonds or triple bonds, or a combination of double bonds and triple bonds, but is not aromatic. Examples of cycloalkyl groups having a double or triple bond include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl, and the like. It is also noted that the term "cycloalkyl" includes polycyclic compounds such as bicyclic or tricyclic compounds. Cycloalkyl groups can be substituted or unsubstituted with one to four substituents. The term "perfluoroalkyl" denotes an alkyl group in which all hydrogen atoms have been replaced with fluorine atoms. The term "acyl" denotes a group derived from an organic acid (-COOH) by removal of the hydroxyl group (-OH). The term "aryl" denotes an aromatic cyclic hydrocarbon. Examples of aryl groups include phenyl, naphthyl and biphenyl. The aryl group can be unsubstituted or substituted. The term "heteroatom" includes oxygen, nitrogen, sulfur and phosphorus.

The term "heteroaryl" denotes a cyclic, aromatic hydrocarbon in which one or more carbon atoms have been replaced with heteroatoms. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heteroaryl groups include pyridyl, pyrimidinyl, imidazolyl, thienyl, furyl, pyrazinyl, pyrrolyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, indolyl, isoindolyl, indolizinyl, triazolyl, pyridazinyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl. , naphthyridinyl, quinoxalinyl, isothiazolyl, and benzo [b] thienyl. Preferred heteroaryl groups are 5 and 6 membered rings containing from 1 to 3 heteroatoms independently selected from O, N, and S. The heteroaryl group, which includes each heteroatom, can be unsubstituted or substituted with one to four substituents, depending on be chemically feasible. For example, the heteroatom S can be substituted by one or two oxo groups, which can be shown as = 0. The term "heterocycloalkyl" denotes a cycloalkyl group in which one or more of the carbon atoms have been replaced with heteroatoms. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydronyl, morpholinyl, piperazinyl, piperazinyl, piperinidyl, and pyrrolidinyl. Preferred heterocycloalkyl groups are five and six membered rings and contain one to three heteroatoms independently selected from O, N, and S. It is also possible that the heterocycloalkyl group has one or more double bonds or triple bonds or a combination of double bonds and Triple bonds, but do not be aromatic.

Examples of heterocycloalkyl groups containing double bonds or triple bonds include dihydrofuran and the like. A heterocycloalkyl group, including each heteroatom, can be unsubstituted or substituted with one to four substituents, as chemically feasible. For example, the heteroatom S can be substituted with one or two oxo groups, which can be shown as = 0. It was also noted that the cyclic groups, ie, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, may comprise more than one ring. For example, the naphtyl group is a fused bicyclic ring system.

It is also desired that the present invention includes cyclic groups having bridging atoms, or cyclic groups having a spiral orientation. For example, "spirocycloalkyl" means a cycloalkyl ring having a spiral bond (the bond formed by a single atom which is the only common member of the rings). Furthermore, it is understood that unless specifically specified otherwise, all appropriate isomers of the cyclic groups are included herein. Representative examples of five to six membered aromatic rings, optionally having one or two heteroatoms, are phenyl, furyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothioazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Representative examples of five to eight partially saturated, fully saturated or completely unsaturated members, optionally having one to three heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Exemplary five-membered example rings are furyl, thienyl, pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl, oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl, imidazolidinyl, pyrazolyl, 2- pyrazolinyl, pyrazolidinyl, isoxazolyl, isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl, 1,2,3-oxadizazolyl, 1,4-oxadiazolyl, 1, 2.5- oxadiazolyl, 1,4-oxadiazolyl, 1,2,3-triazolyl, 1,4-trizazolyl, 1,4-thiadiazolyl, 3H-1, 2,3-dioxazolyl, 1, 2, 4-dioxazolyl, 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl, and 1,3-oxathiolyl. Rings of six additional example members are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperiddinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl, morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, 1, 3.5- triazinyl, 1,4-triazinyl, 1, 3,5-tritylanyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl, 6H-1,3-oxazinyl, 6H-1,2-ozazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, 1,4-oxazinyl, o -sozazinyl, p-isoazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl, and 1,2,2-oxadiazinyl. Rings of seven additional example members are azepinyl, oxepinyl, thiepinyl and 1,2,4-triazepinyl. Rings of eight additional example members are cyclooctyl, cyclooctenyl and cyclooctadienyl. Exemplary bicyclic rings consisting of two rings of five and / or six fused members, partially saturated, fully saturated or completely unsaturated, taken independently, optionally with one to four heteroatoms are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyran 83,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c), thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl, benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinolinyl , phthalazinyl, quinazolyl, quinoxalinyl, 1,8-naphthyridinyl, teridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b) -pyridinyl, pyrido (3,2-b) -pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl, 1 H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1 , 2-benzoxazinyl and 4H-1,4-benzoxazinyl. A cyclic group may be linked to another cyclic group in more than one way. Without any particular binding configuration is specified, then all possible configurations are appropriate. For example, the term "pyridyl" includes 2-, 3-, or 4-pyridyl, and the term "thienyl" includes 2-, or 3-thienyl. The term "substituted" means that a hydrogen atom in a molecule has been replaced with a different molecule or atom. The atom or molecule that replaces the hydrogen atom is called a substituent. The symbol "-" represents a covalent bond. The term "radical" denotes a group of atoms that behave like a simple atom in a chemical reaction, for example, an organic radical is a group of atoms that confers characteristic properties on the compounds that contain it, or that remains stable during a series of reactions. The phrase "therapeutically effective amount" means an amount of a compound thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, or a combination of a compound of the formula (I), a stereoisomer, or a prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, and another compound to be described in detail below, the amount of which alleviates, attenuates, or eliminates one or more symptoms of a particular disease or condition, or prevents or delays the onset of one or more symptoms of a particular condition or disease. The term "patient" means animals, such as dogs, cats, cows, horses, sheep, and humans. Preferred patients are mammals, especially humans, both male and female. The phrase "pharmaceutically acceptable" indicates that the substance or composition must be chemically and / or toxicologically compatible, with another ingredient comprising a formulation, and / or the patient treated. The phrase "reaction inert solvent" or "inert solvent" refers to a solvent or mixture of solvents that does not interact with the starting materials, reagents, intermediates or products in a manner that adversely affects the desired product.

The terms "treating", "treating", or "treatment" include preventive treatment, ie prophylactic, and palliative treatment. The characteristics of patients at risk of suffering from atherosclerosis are known to someone of common skill in the state of the art and include patients who have a family history of cardiovascular disease., including hypercholesterolemia, hyperlipidemia and / or hypertriglyceridemia, high levels of low density lipoproteins (LDL) or lipoprotein (a) (Lp (a)), low levels of high density lipoproteins (HDL), and the like. In one aspect, the present invention relates to the treatment of diabetes, including impaired glucose tolerance, insulin resistance, insulin dependent diabetes mellitus (Type I), and non-insulin dependent diabetes mellitus (NIDDM or Type II). Also included in the treatment of diabetes are diabetic complications related to it, including neuropathy, nephropathy, retinopathy, cataracts, and the like. The preferred type of diabetes to be treated by the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereisomers, or prodrugs, is diabetes mellitus not insulin-dependent, i.e. , NIDDM. Diabetes can be treated by administration to a patient with diabetes (type I and type II), insulin resistance, impaired glucose tolerance, or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, an amount Therapeutically effective of a compound of the formula (I), a stereoisomer, or a prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug. It is also desired that patients can be treated by administration of a compound of the formula (I), a stereoisomer, a prodrug thereof, a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug together with one or more anti-diabetic agents. . Representative agents that can be used to treat diabetes in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereisomers, and prodrugs, include insulin and insulin analogs ( eg, LysPro insulin), inhaled insulin; GLP-1 (7-37) (insulinotropin) and GLP-1 (7 ~ 36) -NH2; sulfonylureas and analogs: chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide, meglitinide; biguanides: metformin, phenformin, buformin; antagonist-a2 and imidazolines: midaglizole, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other insulin secretagogues; linogliride, A-4166; glitazones: cyglitazone, pioglitazone, englitazon, troglitazon, darglitazon, BRL49653, inhibitors of fatty acid oxidation: clomoxir, ethomoxir; α-glucosidase inhibitors: acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MDL-73,945; β-agonists: BRL 35135, BRL 37344, RO 16-8714, ICI D7114, CL 316,243; Phosphodiesterase inhibitors: L-386,398; lipid-reducing agents: benfluorex; anti-obesity agents: fenfluramine; vanadate and vanadium complexes (eg Naglivan) and peroxovanadium complexes; amylin antagonists; glucagon antagonists; inhibitors of gluconeogenesis; analogues of somatostatin; antilipotic agents; nicotinic acid, acipimox, WAG 994. Also designed to be used in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, are pramiintide ( symlin), Ac 2993 and nateglinide. Any agent, or combination of agents, can be administered as described above. In addition, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, can be used in combination with one or more aldose reductase inhibitors, inhibitors of glycogen phosphorylase, sorbitol dehydrogenase inhibitors, NHE-1 inhibitors and / or glucocorticoid receptor antagonists. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers and prodrugs, can be used in combination with an aldose reductase inhibitor, which term refers to compounds which inhibit the bioconversion of glucose to sorbitol, a reaction catalyzed by the enzyme aldose reductase. Accordingly, aldose reductase inhibitors constitute a class of compounds well known for their utility in preventing and treating conditions that arise from complications of diabetes including, for example, diabetic neuropathy and nephropathy. Such compounds are well known to someone of common skill in the art state and are easily identified by standard biological tests. For example, the inhibitor of aldose reductase zopolrestat, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] -1-phthalazine acetic acid, and related compounds are described in the patent E.U.A. No. 4,939,140. Aldose reductase inhibitors are known to be useful in reducing lipid levels in mammals. See, for example, patent E.U.A. No. 4,492,706 and European application publication No. EP 0 310 931. The patent of E.U.A. No. 5,064,830 discloses the use of certain inhibitors of aldose reductase of! Oxophthalazinyl-acetic acid, including zopolrestat, to reduce the levels of uric acid in the blood. The patent E.U.A. No. 5,391, 551 discloses the use of certain inhibitors of aldose reductase, including zopolrestat, to reduce blood lipid levels in humans. The disclosure teaches that diabetic utilities are derived 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. A preferred aldose reductase inhibitor disclosed herein is zopolrestat. Any inhibitor of aldose reductase can be used in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs. The inhibition of aldose reductase is easily determined by those with experience in the state of the art according to standard tests (J. Malone, diabetes, 29, 861-864 (1980) "Sorbitol of Red Blood Cells, an indicator of diabetic control") . A variety of aldose reductase inhibitors are described herein, however, other aldose reductase inhibitors useful in the compositions and methods of this invention will be known to one of skill common in the art. The activity of an aldose reductase inhibitor on a particular tissue substrate can be determined by testing the amount of aldose reductase inhibitor that is required to reduce tissue sorbitol (ie, by inhibiting the additional production of sorbitol consequent to blockade of the aldose reductase and consequently the production of fructose) or to reduce tissue fructose (inhibiting the production of sorbitol consequently to the blockade of aldose reductase and consequently the production of fructose).

Accordingly, additional examples of aldose reductase inhibitors useful in the practice of the pharmaceutical compositions, combinations, methods, and kits of the present invention may comprise: (1) 3- (4-bromo-2-fluorobenzyl) -3 acid , 4-dihydro-4-oxo-1-phthalazine acetic acid (Ponalrestat, US Patent No. 4,251, 528); (2) N - [[(5-trifluoromethyl) -6-methoxy-1-naphthalenyl] thioxomethyl] -N-methylglycine (tolrestat, U.S. Patent 4,600,724); (3) 5 - [(Z, E) -β-methylcinnamylidene] -4-oxo-2-thioxo-3-thiazolideneacetic acid (epalrestat, U.S. Patent Nos. 4,464,382, 4,791, 126 and 4,831, 045); (4) 3- (4-bromo-2-fluorobenzyl) -7-chloro-3,4-dihydro-2,4-dioxo-1 (2H) -quinazoline-acetic acid (zenarestat, U.S. Patent Nos. 4,734,419 and 4,883,800); (5) 2R, 4R-6,7-dichloro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Patent No. 4,771,050); (6) 2R, 4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methylchroman-4-acetic acid (U.S. Patent No. 4,883,410); (7) 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazine-4-acetic acid (U.S. Patent No. 4,771,050); (8) 3,4-dihydro-3-oxo-4 - [(4,5,7-trifluoro-2-benzothiazolyl) methyl] -2H-1,4-benzothiazine-2-acetic acid (SPR-210 , U.S. Patent No. 5,252,572); (9) N- [3,5-dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -2-methyl-benzeneacetamide (ZD5522, U.S. Patent Nos. 5,270,342 and 5,430,060), (10) (S) -d-fluorospiro [chroman-4,4'-imidazolidine] -2,5'-dione (sorbinyl, U.S. Patent No. 4,130,714); (11) d-2-methyl-6-fluoro-spiro (chroman-4'-4'-imidazolidine) -2 ', 50-dione (U.S. Patent No. 4,540,704); (12) 2-fluoro-spiro (9H-fluorene-9,4'-imidazolidine) 2 ', 5'-dione (U.S. Patent No. 4,438,272); (13) 2,7-di-fluoro-spiro (9H-fluorene-9,4'-imidazolidine) 2 ', 5'-dione (U.S. Patent Nos. 4,436,745 and 4,438,272); (14) 2,7-di-fluoro-5-methoxy-spiro (9H-fluorene-9,4'-imidazolidine) 2 ', 5'-dione (U.S. Patent Nos. 4,436,745 and 4,438,272); (15) 7-fluoro-spiro (5H-indenol [1,2-b] pyridine-5,3'-pyrrolidine) 2,5'-dione (US Patents Nos. 4,436,745 and 4,438,272); (16) d-cis-6'-chloro-2'-3'-dihydro-2'-methy1-spyr- (imidazolidine-4,4'-4'-H-pyran (2,3- b) pyridine) -2,5-dione (U.S. Patent No. 4,980,357); (17) spiro [imidazolidin-4,5 '- (6H) -quinoline] 2,5-dione-3'-chloro-7', 8'-dihydro-7'-methyl- (5, -cis) (U.S. Patent No. 5,066,659); (18) (2S, 4S) -6-fluoro-2'-5'-dioxospiro (chroman-4,4'-imidazolidine) -2-carboxamide (U.S. Patent No. 5,447,946); and (19) 2 - [(4-bromo-2-fluorophenyl) methyl] -6-fluorospiro [isoquinoline-4 (1 H), 3, -pyrrolidine] -1, 2 ', 3,5' (2H) - Tetrona (ARI-509, U.S. Patent No. 5,037,831).

Other aldose reductase inhibitors useful in the practice of the pharmaceutical compositions, combinations, methods, and kits of the invention comprise compounds of the structural formula (Ia): (la) and the pharmaceutically acceptable salts and prodrugs thereof, wherein Z is O or S; R1 is hydroxyl or a group capable of being removed in vivo to produce a compound of the formula (Ia) wherein R1 is OH; and X and Y are the same or different and are selected from hydrogen, trifluoromethyl, fluoro and chloro. - A preferred substrate within the above group of aldose reductase inhibitors includes compounds numbered 1, 2, 3, 4, 5, 6, 9, 10 and 17, and the following compounds of the formula (Ia): 3,4 acid -dihydro-3- (5-fluorobenzothiazol-2-ylmethyl) -4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = F; Y = H]; 3- (5,7-difluorobenzoflazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = F]; 3- (5-Chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy]; X = CI; Y = H]; 3- (5,7-Chlorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = CI]; 3,4-dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) phthalazin-1-ylacetic acid [R1 = hydroxy; X = CF3; Y = H]; 3,4-dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy]; X = F; Y = H]; 3- (5,7-difluorobenzoxazol-2-ylmethyl-3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy]; X = Y = F]; 3- (5,7-Dichlorobenzoxazol-2-ylmethyl) -3,4-dydrohydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = CI; Y = H]; 3- (5,7-dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Y = CI]; and - zpolresttat, 1-phthalazine acetic acid, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] - [R1 = hydroxy; X = trifluoromethyl; Y = H]. Methods for preparing the aldose reductase inhibitors of the formula (Ia) can be found in International Application Publication No. WO 99/26659. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with a glucocorticoid receptor antagonist.

The glucocorticoid receptor (GR) is present in glucocorticoid-responsive cells where it resides in the cytosol in an inactive state until stimulation by an antagonist. Upon stimulation, the glucocorticoid receptor moves to the cell nucleus where it specifically interacts with the DNA and / or proteins and regulates transcription in a glucocorticoid-responsive manner. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFK-β. Such interactions produce the inhibition of transcription mediated by API and NFk-β and are considered responsible for the anti-inflammatory activity of endogenously administered glucocorticoids. In addition, glucocorticoids can also exert physiological effects independent of nuclear transcription. Agonists of biologically relevant glucocorticoid receptors include cortisol and corticosterone. There are many synthetic glucocorticoid receptor agonists including dexamethasone, prednisone and prednisilone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding together and producing GR-mediated events, including transcription. RU-486 is an example of a non-selective glucocorticoid receptor antagonist. Antagonists of a GR can be used in the treatment of diseases associated with an excess, or deficiency of glucocorticoids in the body. As such, they can be used to treat the following conditions; obesity, diabetes, cardiovascular disease, hypertension, syndrome X, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration (for example, Alzheimer's disease and Parkinson's disease), an increase in Cognition, Cushing's syndrome, Addison's disease, osteoporosis, weakness, inflammatory diseases (such as osteoarthritis, rheumatoid arthritis, asthma and rhinitis), adrenal function tests, viral infection, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing , compulsive behavior, resistance to multiple drugs, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism and prevention of muscle weakness. Examples of preferred GR antagonists useful in the pharmaceutical compositions, combinations, methods, and kits of the invention may, inter alia, comprise those compounds disclosed in the provisional application E.U.A. No. 60 / 132,130, which is incorporated herein by reference. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts thereof, stereoisomers, and prodrugs, may also be used in combination with an inhibitor of sorbitol dehydrogenase. Inhibitors of sorbitol dehydrogenase reduce fructose levels and have been used to treat or prevent diabetic complications such as neuropathy, retinopathy, nephropathy, cardiomyopathy, microangiopathy, and macroamyopathy. The patents of E.U.A. Nos. 5,728,704 and 5,866,578 disclose compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with inhibitors of sodium-hydrogen type-1 exchange (NHE -1 ). Examples of such NHE-1 inhibitors may comprise, inter alia, those compounds disclosed in International Application Publication No. WO 99/43663. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with an inhibitor of glycogen phosphorylase. Any glycogen phosphorylase inhibitor can be used in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs. The inhibition of glycogen phosphorylase is easily determined by one of skill in the state of the art according to standard assays (see, for example, Pesce, Clinical Chemistry, 23, 1711-1717). A variety of glycogen phosphorylase inhibitors will be known to those of skill in the art (eg, International Application Publication No. WO 95/24391 and those inhibitors disclosed in US Patent No. 5,952,363). The following publications also disclose glycogen phosphorylase inhibitors which can be used according to the method of the present invention: patent E.U.A. No. 5,998,463; Oikanomakos, Science of Proteins, 8 (10), 190-1945 (1999), which in particular discloses the compound 3-isopropyl-4- (2-chlorophenyl) -1,4-dihydro-1-ethyl-2-methylpyridine; International Application Publication No. WO 9524391; WO 9709040; WO 9840353; WO 0850359; and WO 9731091; European application publication No. EP 0 884 050; and Hoover, J. Med. Chem., 41, 2934-2938 (1998). A class of generally preferred glycogen phosphorylase inhibitors useful in such combinations comprises, for example, the compounds disclosed in the provisional application E.U.A. No. 60 / 157,140, filed September 30, 1999, and in international application publication No. WO 96/39384 and WO 96/39385. In addition, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be administered in combination with other pharmaceutically active agents, such as inhibitors of the cholesterol biosynthesis or cholesterol absorption inhibitors, especially inhibitors of HMG-CoA reductase, inhibitors of HMG-CoA synthetase, inhibitors of the genetic expression of HMG-CoA reductase or synthetase, CETP inhibitors, bile acid sequestrants, fibrates , ACAT inhibitors, squalene synthetase inhibitors, antioxidants, or niacin. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be administered in combination with naturally occurring compounds that act to reduce cholesterol levels in plasma. Such naturally occurring compounds are commonly known to be nutraceuticals and may comprise, for example, garlic extract, niacin, and the like. In addition, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with an inhibitor of alipoprotein secretion and / or inhibitor of microsomal triglyceride transfer proteins (MTP). Some inhibitors of the secretion of preferred alipoproteins B and / or MTP inhibitors are disclosed in the patent of E.U.A. No. 5,919,795. A variety of MTP inhibitors and apo B secretion will be known to one of skill common in the state of the art. Although any MTP inhibitor or apo B secretion may be used in the practice of the pharmaceutical compositions, combinations, methods, and kits of the present invention, generally preferred MTP inhibitors or apo B secretion comprise those compounds that are disclosed in, for example, the application publication eurpoea No. EP 0 643 057, EP 0 719 763, EP 0 719 763, EP 0 753 517, EP 0 764 647, EP 0 765 878, EP 0 779 276, EP 0 779 279, EP 0 799 828, EP 0 799 829, EP 0 802 186, EP 0 802 188, EP 0 802 192, and EP 0 802 197; International Application Publication No. WO 96/13499, WO 96/33193, WO 96/40640, WO 97/26240, WO 97/43255, WO 97/43257, WO 98/16526 and W30 98/23593; and patent E.U.A. No. 5,595,872; 5,646,162; 5,684,014; 5,712,279, 5,739,135 and 5,789,197. Particularly preferred apo-B / MPT secretion inhibitors are those tetrahydroisoquinino-6-yl derivatives of biphenyl-2-carboxylic acid disclosed in International Application Publication No. WO 96/40640 and No. WO 98/23593. Especially preferred MTP inhibitors or secretion of apo B disclosed in International Application Publication No. WO 96/40640 and WO 98/23593, and useful in the pharmaceutical compositions, combinations, methods, and kits of the present invention, are [2- (1H- [1, 2,4] triazol-3-ylmethyl) -1,2,3,4-tetrahydroisoquin-6-yl] -amide of 4'-trifluoromethyl-biphe2-carboxylic acid and [ 2- (Acetylaminoethyl) -1,2,3,4-tetrahydroisoquinolin-6-yl] -amide of 4'-trifluoromethyl-biphe2-carboxylic acid. Another especially preferred class of MTP inhibitors or secretion of apo B disclosed in the U.S.A. 5,595,872; 5,721, 279; 5,739,135 and 5,789,197 and useful in the pharmaceutical compositions, combinations, methods, and kits of the present invention, are the (2,2,2-trifluoroethyl) -amide of 9- (4-. {4- [4 '-trifluoromethyl-biphe2-carbo amino] -piperidin-1-yl} -butyl-9H-fluorene-9-carboxylic acid and (2,2,2-trifluoroethyl) -amide of 9- acid. { 4- [4- (2-Benzothiazol-2-yl-benzoylamino) -piperidin-1-yl] -butyl-9H-fluorene-9-carboxylic acid. Another class of especially preferred MTP inhibitors or secretion of apo B is disclosed in International Application Publication No. WO 98/16526, and useful in the pharmaceutical compositions, combinations, methods, and kits of the present invention are [ 11 aR] -8 - [(4-cyanophe methoxy] -2-cyclopentyl-7- (prop-2-e -2,3,11, 11a-tetrahydro-6H-pyrazolo [1, 2b] isoquinoline-1 , 4-dione and [11 aR] -cyclopentyl-7- (prop-2-e -8 - [(pyridin-2-yl) methoxy] -2,3,11, 11a-tetrahydro-6H-pyrazino [1 , 2b] isoquinoline-1,4-dione. Another especially preferred class of MTP inhibitors or secretion of apo B is disclosed in the US patent. No. 5,684,014. An especially preferred MTP inhibitor or apo B secretion disclosed in the U.S.A. No. 5,584,014, and useful in the pharmaceutical compositions, combinations, methods, and kits of the present invention, is 2-cyclopentyl-2- [4- (2,4-dimethyl-pyrid [2,3-b] indol-9-ylmethyl) -phe -N- (2-hydroxy-1-pheethyl-acetamide.) Still another class of especially preferred inhibitors of MTP or secretion of apo B is disclosed in U.S. Patent No. 5,646,162 An especially preferred inhibitor of MTP or apo B secretion disclosed in U.S. Patent No. 5,646,162 and useful in the pharmaceutical compositions, combinations, methods, and kits of the present invention, is 2-cyclopentyl-N- (2- hydroxy-1-phethyl) -2- [4- (quinolin-2-ylmethoxy) -phe -acetamide Further inhibitors of MTP or apo B which can be used in combination with the compounds of the Formula (I), the stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, are disclosed in the provisional application U.S. No. 60 / 164,803, filed November 11, 1999. Examples of specific inhibitors of MTP or apo B secretion are disclosed in the aforementioned provisional application, which is incorporated herein by reference. Specific inhibitors of cholesterol absorption and inhibitors of cholesterol biosynthesis are described in more detail below. Additional inhibitors of cholesterol absorption will be known to one of skill in the art and are described, for example, in International Application Publication No. WO 94/00480. Any HMG-CoA reductase inhibitor can be employed as an additional compound in the combination therapy aspect of the present invention. The term "HMG-CoA reductase inhibitor" refers to a compound that inhibits the biotransformation of the coenzyme hydroxymethylglutaryl A into mevalonic acid when catalyzed by the enzyme HMG-CoA reductase. Such inhibition can easily be determined by one of skill in the art according to standard tests (eg, Enzymology Method *, 71, 455-509 (1981), and references cited here). A variety of these ñí). A variety of these compounds are described and referenced below. The patent E.U.A. No. 4,231, 938 discloses certain isolated compounds after culturing a microorganism belonging to the genus Aspergillus, such as lovastatin. As well, the patent E.U.A. No. 4,444,784 discloses synthetic derivatives of the aforementioned compounds, such as simvastatin. Additionally, the E.U.A patent. No. 4,739,073 discloses certain substituted Índles, such as fluvastatin. In addition, the patent E.U.A. No. 4,346,227 discloses derivatives of ML-236B, such as prevastatin. Additionally, European application publication No. EP 0 491,226 teaches certain pyridyldihydroxyheptonoic acids, such as rivastatin. Also, patent of E.U.A. No. 4,647,576 discloses certain 6- [2- (pyrrol-1-yl-substuted) -alkyl] -pyran-2-ones such as atorvastatin. Other inhibitors of HMG-- CoA reductase will be known to those skilled in the art. Examples of marketed products containing HMG-CoA reductase inhibitors include Baycol®, Lescol®, Lipitor®, Mevacor®, Pravachol® and Zocor®. Any inhibitor of HMG-CoA synthetase can be used as an additional compound in the combination therapy aspect of this invention. The term "HMG-CoA synthetase inhibitor" refers to a compound that inhibits the biosynthesis of hydroxymethylglutaryl-coenzyme A from acetyl-coenzyme A and acetoacetyl-coenzyme A, catalyzed by the enzyme HMG-CoA synthetase. Such inhibition can be determined by someone of skill in the state of the art according to standard tests (eg, Methods of Enzimotología, 35 ^ 155-160 (1975); y7 Enzymology Methods, 110, 19-26 (1985); and the references cited there. A variety of these compounds are described and referenced below. The patent E.U.A. No. 5,120,729 discloses certain β-lactam derivatives. The patent E.U.A. No. 5,064,856 discloses certain spiro-lactone derivatives prepared by culturing the microorganism MF5253. The patent E.U.A. No. 4,847,271 discloses certain oxetane compounds such as 11- (3-hydroxymethyl-4-oxo-2-oxetail) -3,5,7-trimethyl-2,4-undecadienoic acid derivatives. Other inhibitors of HMG-CoA synthetase useful in the methods, compositions and kits of the present invention will be known to one of skill in the art. Any compound is decreased gene expression of HMG-CoA reductase can be used as an additional compound in the combination therapy aspect of this invention. These agents can be transcription inhibitors of HMG-CoA reductase that block transcription of DNA or translational inhibitors that prevent the translation of mRNA encoding HMG-CoA reductase into protein. Such inhibitors can affect both transcription and translation directly, or can be biotransformed into compounds having the above-mentioned attributes by one or more enzymes on the cholesterol biosynthetic scale or can lead to accumulation of an isoprene metabolite having the above activities mentioned. Such regulation is easily determined by those of skill in the state of the art according to standard tests (Methods of Enzymology, 110, 9-19 1985). Several of these compounds are described and cited below; however, other inhibitors of the genetic expression of HMG-CoA reductase will be known to those of skill in the state of the art, for example, the patent of E.U.A. 5,041, 432 discloses certain lanosterol derivatives that are inhibitors of the genetic expression of HMG-CoA reductase. Other oxygenated sterols that suppress the biosynthesis of HMG-CoA reductase are discussed by E.l. Mercer (Prog. Lip. Res., 32, 357-416 1993). Any compound having activity as a CEPT inhibitor can serve as a second compound in the combination therapy aspect of the present invention. The term "CEPT inhibitor" refers to compounds that inhibit the transport mediated by cholesteryl ester transfer proteins (CEPT) of various cholesteryl esters and triglycerides of HDL to LDL and VLDL. A variety of these compounds are described and cited below: however, other inhibitors of CEPTs will be known to those of skill in the state of the art. The patent of E.U.A. No. 5,512,548 discloses certain polypeptide derivatives having activity as CEPT inhibitors, while certain inhibitory CEPT resenonolactone derivatives and cholesteryl ester phosphate-containing analogs are disclosed in J. Atibiol, 49 (8), 815-816 (1996), and Bioorg. Med. Chem. Lett, 6, 1951-1954 (1996). respectively, the preferred CEPT inhibitors which can be used in combination with the compounds of the formula (I), the stereoisomers and prodogates thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodograms, can comprise those compounds described in the EUA application serial No. 09/391, 152, filed September 7, 1999. Any ACAT inhibitor can serve as an additional compound in the combination therapy aspect of this invention. The term "ACAT inhibitor" refers to a compound that inhibits the intracellular esterification of dietary cholesterol by the enzyme acyl CoA: cholesterol acyltransferase. Such inhibition can easily be determined by one of skill in the art according to standard tests, such as the Heider method described in the Lipid Research Journal, 24 1127 (1963). A variety of these compounds are described and cited below; however, other ACAT inhibitors will be known by someone of common skill in the state of the art. For example, the patent E.U.A. No. 5,510,379 discloses certain carboxysulfonates, while publications of international applications No. WO 96/26948 and WO 96/10559 disclose urea derivatives having ACAT inhibitory activity. Any compound having activity as an inhibitor of squalene synthetase can serve as an additional compound in the aspect of combination therapy of the present invention.

The term squalene synthetase inhibitor refers to the two compounds that inhibit the condensation of the two molecules of farnesylpyrrophosphate to form squalene, a reaction that is catalyzed by the enzyme squalene synthetase. Such inhibition is easily determined by those of skill in the state of the art according to standard methodology (Methods of Enzymology, 15, 393-454 (1969), and enzymology methods, 110, 359-373 (1985), and references cited in the present). A summary of inhibitors of squalene synthetase has been compiled in Curr. Op. Ther. Patents, 861-4, (1993). European application publication No. 0 567 026 discloses certain 4,1-benzoxazepine derivatives as inhibitors of the -skeleno synthetase and its use in the treatment of hypercholesterolemin and as fungicides. European application publication No. 0 645 378 discloses certain heterocycles of seven and eight members as squalene synthetase inhibitors and their use in the prevention treatment of hypercholesterolemin and fungal infections. European application publication No. 0 645 377 discloses certain benzoxazepine derivatives as squalene synthetase inhibitors useful for the treatment of hypercholesterolemia or coronary sclerosis. European application publication No. 0 611 749 discloses certain substituted amic acid derivatives useful for the treatment of arteriosclerosis. European application publication No. 0 705 607 discloses certain seven or eight member condensed heterocyclic compounds useful as antihypertriglyceridemic agents. International application publication WO 96/09827 discloses certain combinations of cholesterol absorption inhibitors and inhibitors of cholesterol biosynthesis including benzoxazepine derivatives and benzothiazepine derivatives. European application publication No. 0 701 725 discloses a process for preparing certain optically active compounds, including benzoxazepine derivatives, with plasma triglyceride and cholesterol reduction activities. Other compounds that are marketed to treat hyperlipidemia, including hypercholesterolemia, and that are designed to help prevent or treat atherosclerosis, including bile acid sequestrants, such as Colestid®, LoCholest®, and Questran®; and fibric acid derivatives, such as Atromid®, Lopid®, Tricor®. These compounds can also be used in combination with the compounds of the formula (I), the stereoisomers and prodogates thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodogas. The compounds of the formula (I), the stereoisomers and prodogates thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and the prodogas, may also be administered together with a lipase inhibitor and / or glucosidase inhibitor. , which are typically used in the treatment of conditions resulting from the presence of excessive triglycerides, free fatty acids, cholesterol, cholesterol or glucose esters including, inter alia, obesity, hyperlipidemia, hyperlipoproteinemia, syndrome X, and the like.

Any lipase inhibitor or glucosidase inhibitor can be used in combination with the compounds of the formula (I), the stereoisomers and pro-drugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and pro-drugs. Preferred lipase inhibitors comprise gastric or pancreatic lipase inhibitors. Generally preferred glucosidase inhibitors comprise amylase inhibitors. A lipase inhibitor inhibits the breakdown of dietary triglycerides into free fatty acids and monoglycerides. Under normal physiological conditions, lipolysis occurs through a discrete two-step process involving the acylation of an activated serine fraction of the lipase enzyme. This leads to the production of a hemiacetal intermediate of lipase-fatty acid, which is then divided to release a diglyceride. After further deacylation, the fatty acid-lipase intermediate is decomposed, yielding free lipase, a monoglyceride and a fatty acid. The resulting monoglycerides and free fatty acids are incorporated into phospholipid-bile acid micelles, which are subsequently absorbed at the level of the brush border of the small intestine. The micelles eventually enter the peripheral circulation as chylomicrons. Accordingly, compounds, including lipase inhibitors, that selectively limit or inhibit the absorption of ingested fatty precursors, are useful in the treatment of conditions including obesity, hyperlipidemia, hyperlipoproteinemia, syndrome X, and the like.

Pancreatic lipase mediates the metabolic breakdown of fatty acids from triglycerides at positions 1 and 3 of carbons. The main site of the metabolism of ingested fats is in the duodenum and nearby jejunum by pancreatic lipase, which is usually secreted in vast excess of the amounts necessary for the breakdown of fats in the upper small intestine. Since pancreatic lipase is the main enzyme required for the absorption of triglycerides from the diet, the inhibitors have utility in the treatment of obesity and the other related conditions. Gastric lipase is an immunologically distinct lipase that is responsible for approximately .10 to 40% of dietary fat intake. Gastric lipase is secreted in response to mechanical stimulation, ingestion of food, the presence of a fatty food, or by sympathetic agents. Gastric lipolysis of ingested fats is of physiological importance, in the provision of fatty acids necessary to activate the activity of pancreatic lipase in the intestine and is also of importance for fat absorption in a variety of physiological and pathological conditions associated with pancreatic insufficiency . See, for example, C.K. Abrams, Gastroenterology, 92, 125 (1987). A variety of lipase inhibitors will be known to one of skill common in the state of the art. However, in the practice of the pharmaceutical compositions, combinations, methods, and kits of the present invention, generally preferred lipase inhibitors comprise those inhibitors that are selected from the group consisting of lipstatin, tetrahydrolipstatin (orlistat), FL-386 , WAY-121898, Bay-N-3176, valilactone, esterastine, ebelactone A, ebelactone B and RHC 80267. The tetrahydrolipstatin compound is especially preferred. Inhibitors of pancreatic lipase lipstatin, 2S, 3S, 5S, 7Z, 10Z) -5 - [(s) -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-7 lactone, 10-hexadecanoic, and tetrahydrolipstatin (orlistat), 2S, 3S, 5S) -5 - [(s)] -2-formamido-4-methyl-valeryloxy] -2-hexyl-3-hydroxy-hexadecanoic acid lactone, and the virulently substituted N-formileucine derivatives and stereoisomers thereof are disclosed in the US patent No. 4,598,089. The pancreatic lipase inhibitor FL-386, 1- [4- (2-methylpropyl) cyclohexyl] -2 - [(phenylsulfonyl) oxy] -ethanone, and the variously substituted sulfonate derivatives related thereto, are disclosed in the US patent No. 4,452,813. The pancreatic lipase inhibitor WAY-121898, 4-phenoxyphenyl-4-methylpiperidin-1-α-carboxylate, and the different carbamate esters and pharmaceutically acceptable salts related thereto, are disclosed in US Pat. No. 5,512,565; 5,391, 571 and 5,602,151. The lipase inhibitor Bay-N-3176, N ^ -trifluoromethylphenyl-N'-3-chloro-4'-trifluoromethylphenylurea, and the various urea derivatives related thereto, are disclosed in the patent E.U.A. No. 4,405,644.

The pancreatic valilactone inhibitor, and a process for the preparation thereof by the microbial culture of Actinomycetes strain MG147-CF2, are disclosed in Kitahara, J. Antibiotics, 40 (11), 1647-1650 (1987). The lipase inhibitor steracein, and certain processes for the preparation thereof by the microbial culture of Streptomyces strain ATCC 31336, are disclosed in the U.S. Patents. 4,189,438 and 4,242,453. The pancreatic lipase inhibitors ebelactone A and ebelactone B, and a process for the preparation thereof by the microbial culture of Actinomycetes strain MG7-G1, are disclosed in Umezawa, J. Antibiotics, 33, 1594-1596 (1980). The use of ebelactones A and B in the suppression of the formation of monoglycerides is disclosed in Japanese kokai 08-143457, published on June 4, 1996. The lipase inhibitor RHC 80267, cyclo-0,0 '- [( 1,6-hexanediyl) -bis- (iminocarbonyl)] dioxime, and the various bis (iminocarbonyl) -dimeimides related thereto can be prepared as described in Peterse, Liebis' Annalen, 562, 205-229 (1949). The ability of RHC 80267 to inhibit the activity of myocardial lipoprotein lipase is disclosed in Carroll, Lipidos, 27 pp. 305-307 (1992) and Chuang J. Mol Cell Cardiol., 22, 1009-1016 (1990). Any suitable dosage of a lipase inhibitor is used in aspects of the present invention comprising such inhibitors. The dosage of the lipase inhibitor is generally in the range between about 0.01 and 50 mg / kg of the subject's body weight per day, preferably between about 0.05 and 10 mg / kg of the subject's body weight per day, administered in a single dose or as a divided dose. For example, where the lipase inhibitor is tetrahydrolipstatin, the dosage of tetrahydrolipstatin preferably ranges from about 0.05 to 2 mg / kg of body weight of the subject per day. In practice, the physician will determine the actual dosage of the lipase inhibitor that will be most appropriate for the individual patient and which will vary with, eg, age, weight, response of the patient itself, previous dosages of lipase inhibitors are by way of example, but there can naturally be instances where higher or lower dosage ranges of such lipase inhibitors are appropriate, and such dosages have the purpose thereof; within the scope of the present invention. A glucosidase inhibitor inhibits the enzymatic hydrolysis of complex carbohydrates by glycoside hydrolases, for example amylase or maltase, in simple bioavailable sugars, for example, glucose. The rapid metabolic action of glucosidase, particularly after the uptake of high levels of carbohydrates, produces a state of alimentary hyperglycide that in adipose or diabetic subjects, leads to increased insulin secretion, increased synthesis of fats and a reduction of fat degradation . After such hyperglycemia, hypoglycemia frequently occurs, due to the increased levels of insulin present. Additionally, it is known that both the hypoglycemia and the chyme that remain in the stomach promote the production of gastric juice, which initiates or favors the development of gastritis or duodenal ulcers. Accordingly, glucosidase inhibitors are known to be useful in accelerating the passage of carbohydrates through the stomach and inhibiting the absorption of glucose from the intestine. In addition, the conversion of carbohydrates into fatty tissue lipids and the subsequent incorporation of dietary fat into fatty tissue deposits is therefore reduced or delayed, with the concomitant benefit of reducing or avoiding the deleterious abnormalities resulting therefrom. Any glucosidase inhibitor can be used in combination with the compounds of the formula (I), the same, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodogas, however, generally preferred glucosidase inhibitors comprise amylase inhibitors. An amylase inhibitor is a glucosidase inhibitor that inhibits the enzymatic degradation of starch or glycogen in maltose. The inhibition of such enzymatic degradation is beneficial in reducing amounts of bioavailable sugars, including glucose and maltose, and the concomitant detrimental conditions resulting therefrom. A variety of glucosidase and amylase inhibitors will be known to one of skill common in the state of the art. However, in the practice of the pharmaceutical compositions, combinations, methods, and kits of the present invention, generally preferred glucosidase inhibitors are those inhibitors selected from the group consisting of acarbose, adiposine, voglyose, miglitol, emiglitate, MDL- 25637, camiglibose, tendamistate, AI-3688, trestatin, pradimicin-Q and salbostatin. The glucosidase inhibitor acarbose, 0-4, 6-dideoxy-4 - [[(1s, 4R, 5S, 6S) -, 5,6-trihydroxy-3- (hydroxymethyl) -2-cyclohexen-1-yl] amino] -a-glucopuranosyl- (1 ->) -0-aD-glucopyranosyl - (1 ->) -D-glucose, the different amino sugar derivatives related thereto and a process for the preparation thereof by the microbial culture of Actinoplanes strains SE 50 (CBS 961.70), SB18 (CBS 957.70), Se 82 (CBS 615.71), SE 50/13 (614.71) and SE 50/110 (674.73) are disclosed in US Pat. No. 4,062,950 and 4,174,439 respectively. The glucosidase inhibitor, adiposity, which consists of forms of adipsin 1 and 2, is disclosed in U.S. Pat. No. 4,254,256. Additionally, a process for the preparation and purification of adiposine is disclosed in Namiki, J. Antibiotics 35, 1234-1236 (1982). The glucosidase inhibitor, voglibose, 3,4-dideoxy-4 - [[2-hydroxy-1 - (hydroxylmethyl) ethyl] amino] -2-C- (hydroxyethyl) -D-epi-inositol, and the different N-substituted pseudo-amino sugars related thereto, are disclosed in the US Pat. No. 4,701, 559. The glucosidase inhibitor, miglitol, (2R, 3R, 4R, 5S) -1- (2-hydroxyethyl) -2- (hydroxymethyl) -3,4,5- piperidinetriol, and the various 3,4,5-trihydroxypiperidines related thereto, are disclosed in the US Pat. No. 4,639,436. The glucosidase inhibitor, emiglitato, p- [2 - [(2R, 3R, 4R, 5S) - 3,4,5-trihydroxy-2- (hydroxymethyl) piperidino] ethoxy] -benzoic acid ethyl ester, the various derivatives related thereto and the pharmaceutically acceptable acid addition salts thereof are disclosed in the US Pat.

No. 5,192,772. The glucosidase inhibitor, MDL-25637, 2,6-dideoxy-7-0-β-D-glucopyranosyl-2,6-imino-D-glycerol-L-gluco-heptitol, the different homodisaccharides related to the same and the pharmaceutically acceptable acid addition salts thereof, are disclosed in the US Pat.

No. 4,634,765. The glucosidase inhibitor, camiglibose, methyl-6-deoxy-6 - [(2R, 3R, 4R, 5S) -3,4,5-tri- hydroxy-2- (hydroxymethyl) piperidine] -a -glucopuranoside sesquihydrate, the deoxy-nojirimycin derivatives related thereto, the various pharmaceutically acceptable salts thereof and the synthetic methods for the preparation thereof, are disclosed in US Pat. No. 5,157,116 and 5,504,078. The amylase inhibitor, tendamistat, the various cyclic peptides related thereto and processes for the preparation thereof by the microbial culture of Streptomyces tendae strains 4158 or HAG 1226, are disclosed in U.S. Pat. No. 4,451, 455.

The amylase inhibitor AI-3688, the different cyclic polypeptides related thereto, and a process for the preparation thereof by the microbial culture of Streptomyces aureofaciens strain FH 1656, are disclosed in U.S. Pat. No. 4,623,714. The amylase inhibitor, trestatin, which consists of a mixture of trestatin A, trestatin B and trestatin C, the different amino sugars containing trehalose related thereto and a process for the preparation thereof by the microbial culture of Streptomyces dimophogenes strains NR -320-OM7HB and NR-320-OM7HBS, are disclosed in the US patent No. 4,273,765. The glucosidase inhibitor, pradimicin-Q and a method for the preparation thereof by the microbial culture of Actinomadura verrucospora strains R103-3 or A10102, are disclosed in U.S. Pat. do not. 5,091, 418 and 5,217,877 respectively. The glycosidase inhibitor, salvostatin, the various pseudosaccharides related thereto, the various pharmaceutically acceptable salts thereof and a process for the preparation thereof by the microbial culture of Streptomyces albus strain ATCC 21838, are disclosed in U.S. Pat. No. 5,091, 524. Preferred lipase inhibitors comprise compounds selected from the group consisting of lipastatin, tetrahydrolipstatin, FL-386. WAY-121898, Bay-n-3176, valilactone, sterazine, ebelactone A, ebelactone B, RHC 80267, stereoisomers thereof, and pharmaceutically acceptable salts of said compounds and stereoisomers. The tetrahydrolipstatin compound is especially preferred. Preferred glucosidase inhibitors comprise compounds selected from the group consisting of acarbose, adiposine, voglibose, miglitol, emiglitate, MDL-26637, camiglibose, pradimicin-Q, and salbostatin. A particularly preferred glucosidase inhibitor is acarbose. Especially preferred glycosidase inhibitors further comprise amylase inhibitors which are selected from the group consisting of tendamistate, AI-3688 and trestatin. In another aspect of the invention, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may be used in combination with an anti-obesity agent. The anti-obesity agent preferably selected from! group consisting of a β3-adrenergic receptor agonist, a cholecystokinin-A agonist, a monoamine reuptake inhibitor, a sympathomimetic agent, a serotonergic agent, a dopamine agonist, an agonist or a receptor-mimic the stimulating melanocyte hormone, an analogue of the stimulating melanocyte hormone receptor, a cannabinoid receptor antagonist, a melanin-concentrating hormone antagonist, leptin, a leptin analogue, a leptin receptor agonist, an antagonist of the galanin, a lipase inhibitor, a bombesin agonist, a neuropeptide-Y antagonist, a thyromimetic agent, dehydropiandrosterone or analogue thereof, a glucocorticoid receptor agonist or antagonist, an orexin receptor antagonist, an antagonist of the binding protein of urocortin, a glucagon-like peptide-1 receptor agonist, and a ciliary neurotrophic factor. Especially preferred anti-obesity agents comprise those compounds selected from the group consisting of sibutramine, fenfluramine, dexfenfluramine, bromocriptine, phentermine, ephedrine, leptin, phenylpropanolamine, pseudoephedrine, acid. { 4- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} acetic, acid. { 4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamine) ethoxy] phenol} benzoic, acid. { 4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenyl} Propionic, and acid. { 4- [2- (2- [6-aminopyridin-3-yl] -2 (R) -hydroxyethylamino) ethoxy] phenoxy} acetic. Anorectic agents suitable for the compositions, methods and kits of the present invention can be prepared using methods known to those of skill in the art, for example, the phentermine can be prepared as described in U.S. Pat. No. 2,408,345; Sibutramine can be prepared as described in U.S. Pat. No. 4,929,629; fenfluramine and dexfenfluramine can be prepared as described in U.S. Pat. No. 3,198,834; and bromocriptine can be prepared as described in U.S. Patent Nos. 3,752,814 and 3,752,888. Any suitable dosage of an anorectic agent can be used in aspects of the present invention comprising such agents. The dose of the anorectic agent is generally in the range between approximately 0.01 and 50 mg / kg of body weight of the subject per day, preferably between 0.1 and 10 mg / kg of body weight approximately of the subject per day, administered in single dose or as a divided dose. For example, where the anorectic agent is phentermine, the dose of phentermine is between about 0.01 and 50 mg / kg of body weight of the subject per day. In addition, the anorectic agent is sibutramine, the dosage range being between 0.01 and 50 mg / kg of body weight approximately of the subject per day, preferably between 0.1 and 1 mg / kg of body weight approximately of the subject per day; wherein the anorectic agent is dexfenfluramine or fenfluramine, the dosage range is between about 0.01 and 50 mg / kg of body weight of the subject per day, preferably between 0.1 and 1 mg / kg of body weight approximately of the subject per day; and wherein the anorectic agent is bromocriptine, the dosage range is between about 0.01 and 10 mg kg of body weight of the subject per day, preferably between about 0.1 and 1 mg / kg of body weight of the subject per day. In practice, the physician will determine the current dosage of the anorectic agent that will be most appropriate for an individual patient and which will vary with, eg, age, weight and response of the particular patient. The above dosages of anorectic agents are exemplary, but naturally there may be individual instances where higher or lower dosage ranges of such anorectic agents are appropriate, and such dosages are within the scope of the present invention. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with an antihypertensive agent. Examples of currently marketed products containing antihypertensive agents include calcium channel blockers, such as Cardizem®, Adalat®, Calan®, Cardene®, Covera®, Dilacor®, DynaCirc®, Procardia XL®, Sular®, Tiazac®, Vascor®, Verelan®, Isoptin®, Ni otop®, Norvasc®, and Plendil®: angiotensin converting enzyme (ACE) inhibitors, such as Accupril®, Altace®, Captopril®, Lotesina®, Mavik®, Monoprii®, Privinil®, Univasc®, Vasotec® and Zestril®. In addition, diuretics and combinations of the above hypertensive agents have been employed and are contemplated as used in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used in combination with an anti-depressant.

Examples of commercialized antidepressants that can be used in combination with a compound of the present invention include monoamine oxidase inhibitors such as Nardil® and Parnato®; selective serotonin reuptake inhibitors, such as Paxil®, Prozac®, and Zoloft®; tricycles, such as Asendin®, Elavil®, Etrafon®, Limbitrol®, Norpramin®, Pamelor®, Sinecuan®, Surmontil®, Tofranil®, Triavil®, and Vivactil®. Additional anti-depressants which are useful in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may comprise Desyrel®, Effexcr®, Remeron ®, Serzone®, and Wellbutrin®. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, may also be used with a compound useful in the treatment of osteroporosis. Examples of marketed products containing active agents useful in the treatment of osteoporosis and which may be used in combination with a compound of the present invention include bisphosphonates such as Fosamax® and hormonal agents such as calcitonin and estrogens. In addition, Evista® can be used in combination with the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs.

The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts, stereoisomers, and prodrugs, are administered to a patient in need of treatment therewith, in therapeutically effective amounts. The compounds can be administered alone or preferably, as part of a pharmaceutically acceptable composition. In addition, the compounds or compositions can be administered all at once, such as, for example, by bolus injection, multiple times, such as by a series of tablets, or released substantially uniformly over a period of time, as for example, using transdermal delivery . It is also indicated that the dose of the compound can be varied with the passage of time. In addition, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, can be administered alone, in combination with other compounds of the present invention, or with other pharmaceutically active compounds. The other pharmaceutically active compounds can be designed to treat the same disease or condition as the compounds of the present invention or a different disease or condition. If the patient is going to receive or is receiving multiple pharmaceutically active compounds, the compounds must be administered simultaneously, or sequentially in any order. For example, in the case of tablets, the active compounds can be found in a tablet or in separate tablets, which can be administered at the same time or sequentially. In addition, it should be recognized that the compositions may comprise different forms. For example, one or more compounds can be released through a tablet, while another is administered by injection or orally as a syrup. All compositions, methods of delivery and administration sequences are intended to be included within the scope of the invention. Since one aspect of the present invention comprises the treatment of diseases / conditions with a combination of pharmaceutically active agents that can be administered separately, the invention furthermore relates to the combination of pharmaceutical compositions in the form of a kit. The kit according to the invention comprises two separate pharmaceutical compositions: a compound of the formula (I), or an stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug and a further pharmaceutically active compound. The kit further comprises a container for containing the separate compositions such as a divided bottle or a divided sheet pack. Additional examples of containers include syringes, boxes, bags, and the like. Typically, the kit comprises instructions for the administration of the separate components. The form of kit is particularly advantageous when the separate components are preferably administered in different dosage forms (eg, oral and parenteral), are administered at different dosing intervals, or when the titration of the individual components of the combination is desired by the doctor who formulates An example of such a kit comprises the known blister pack. The blister packs. Blister packs are well known in the packaging industry and are widely used for packaging pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally comprise a sheet of relatively rigid material covered with a sheet of preferably transparent plastic material. During the packaging process, depressions form in the plastic sheet. The depressions generally conform to the size and shape of the tablets or capsules to be contained therein. Then / the tablets or capsules are placed in the depressions and the sheet of relatively rigid material is sealed against the plastic sheet on the face of the sheet that is opposite from the direction G? which depressions were formed. As a result, the tablets or capsules are sealed in the depressions between the plastic sheet and the sheet. Preferably, the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by applying manual pressure on the depressions whereby an opening is formed in the sheet at the depression site. The tablet or capsule can then be removed through said opening.

It may be desirable to provide a memory aid on the package, eg, in the form of number or similar indications adjacent to the tablets or capsules, such indications correspond to the days of the regime in which the dosage form thus specified is going to be swallowed Another additional example of such memory aid is a heating printed on the card, eg, as follows "First Week, Monday, Tuesday etc ... Second Week, Monday, Tuesday ... "etc. Other variations of memory aids will be easily manifested.A" daily dose "can be a single tablet or capsule or several pills or capsules to be taken on any given day. Each day of the compound identified by the present invention can consist of a tablet or capsule while a daily dose of the second compound can consist of several tablets or capsules and vice versa.The memory aid should reflect this and aid in the correct administration of the active agents. In another specific embodiment of the invention, a dispenser designed to dispense daily doses one at a time in the order of its future use is provided, preferably, the dispenser is equipped with a memory aid, to further facilitate compliance with the regimen. example of such memory aid is a mechanical counter that indicates the number of daily doses that have been dispensed.Other example of such help from memory is a battery-powered microchip memory coupled with a liquid crystal read display, or audible reminder signal which, for example, reads the date on which the last daily dose has been taken and / or reminds the patient when it is going to be taken the next dose. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, and other pharmaceutically active agents, if desired, can be administered to a patient orally. , rectal, parenteral, (eg, intravenously, intramuscularly, or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally (eg, powders, ointments, or drops), or as a buccal or nasal spray. The compositions suitable for parenteral injection may comprise physiologically acceptable sterile aqueous or non-aqueous solutions, dispersions, suspensions, or emulsions, and sterile powders for reconstitution into sterile injectable solutions or dispersions. Examples of suitable carriers, diluents, solvents, or aqueous and non-aqueous vehicles include ethanol. Polyols (propylene glycol, polyethylene glycol, glycerol, and the like), appropriate mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of a cover such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preserving agents, humectants, emulsifiers, and dispersants. The prevention of microorganism contamination of the compositions can be achieved with various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like. It may also be desirable to include isotonic agents, for example sugars, sodium chloride, and the like. Prolonged absorption of injectable pharmaceutical compositions can be caused by the use of agents capable of delaying absorption, for example, aluminum monostearate and gelatin. Solid dosage forms for oral administration include capsules, tablets, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one usual inert (or carrier) pharmaceutical excipient such as sodium citrate or dicalcium phosphate or (a) fillers or diluents, such as, for example, starches, lactose, sucrose , amnitol, and silicic acid; (b) binders such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar, calcium carbonate, potato starch or tapioca, alginic acid, certain complex silicates, and sodium carbonate; (e) solution retardants, such as paraffin; (f) absorption accelerators, such as, for example, quaternary ammonium compounds; (g) wetting agents, such as, for example, cetyl alcohol and glycerol monostearate; (h) adsorbents, such as, for example, kaolin and bentonite; and / or (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, or mixtures thereof. In the case of capsules and tablets, the dosage forms may also comprise buffering agents. Solid compositions of a similar type can also be used as fillers in gelatin capsules as gelatin capsule fillings with soft or hard fillings using excipient such as lactose or lactin, as well as high molecular weight polyethylene glycols, and the like. Solid dosage forms such as tablets, dragees, capsules and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the state of the art. These may contain opacifying agents, and may also be of such composition that they release the active compound or compound in a delayed manner. Examples of encrusting compositions that can be used are polymeric substances and waxes. The active compounds may also be in micro-encapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable elixirs, syrups, suspensions, solutions, and emulsions. In addition to the active compounds, the liquid form of agitation may contain inert diluents commonly used in the state of the art, such as water or other solvents, solubilizing agents and emulsifiers, such as, for example, ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils, in particular, cottonseed oil, peanut oil, corn germ oil, olive oil, castor oil, sesame seed oil, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and sorbitan esters of fatty acids, or mixtures of these substances, and the like. In addition to such inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfume agents. In addition to the active compound, the suspensions may additionally comprise suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxy, bentonite, agar, and tragacanth, or mixtures of these substances , and similar. Compositions for rectal or vaginal administration preferably comprise suppositories, which can be prepared by mixing a compound of the present invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at temperature common environment, but liquid at body temperature, and therefore, melt in the rectum or vaginal cavity thus releasing the active component.

Dosage forms for topical administration of the compounds of the formula (I), the stereoiss and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoiss, and prodrugs, may comprise ointments, powders, sprays and inhalants. The active agent or agents are mixed under sterile condition with a physiologically acceptable carrier, and any condom, buffer, or propellant that may be required. Ophthalmic formulations, eye ointments, powders, and solutions are also desired to be within the scope of the present invention. The compounds of the formula (I), the stereoiss and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoiss, and prodrugs, can be administered to a patient at dosage levels in the range between about 0.7 and about 7,000 mg. day. Typically, for a normal adult human with a body weight of approximately 70 kg, a dosage in the range between 0.01 and 100 mg per kilogram of body weight is typically sufficient. The specific dosage and dosage range that can be used depend on a number of factors, including the requirements of the patient, the severity of the condition or disease being treated, and the pharmacological activity of the compound administered. The determination of dosage range and optimal dosages for a particular patient is within the capacity of sne with common skill in the state of the art who has the benefit of the present disclosure. It is also noted that the compounds of the present invention can be used with formulations of sustained release, controlled release, and delayed release, which forms are also well known to one of skill common in the state of the art. The following paragraphs describe dosages, example formulations, etc., useful for non-human animals. The administration of the compounds of the formula (I), the stereoiss and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoiss, and prodrugs, can be carried out orally or non-orally, for example, by injection. An amount of a compound of the formula (I), or a stereois or prodrug thereof,? a pharmaceutically acceptable salt of the compound, stereois, or prodrug, is administered such that an effective dose is received, generally a daily dose which when administered orally to an animal is usually between about 0.01 and 100 mg / kg of body weight , preferably between 0.1 and 50 mg / kg of body weight approximately. Conveniently, the compound can be carried in drinking water so that a therapeutic dose of the compound is ingested with the daily water supply. The compound can be directly melted in the drinking water, preferably in the form of a water-soluble, liquid concentrate (such as an aqueous solution of a water-soluble salt).

Conveniently, the compound can also be added directly to the food, as such, or in the form of an animal food supplement, also known as a premix or concentrate. A premix or concentrate of the compound in a carrier is most commonly employed for the inclusion of the agent in the food. Suitable carriers are liquids or solids, as desired, such as water, various flours such as alfalfa meal, soybean meal, cotton meal, linseed meal, corn meal and cornmeal, melase, urea, bone meal , and mineral mixtures such as those commonly used in chicken feed. A particularly effective carrier is the same animal feed; that is, a small portion of ta! food. The carrier facilitates the uniform distribution of the compound in the finished food with which the premix is mixed. It is important that the compound be completely mixed in the premix and, subsequently, the food. In this regard, the compound can be dispersed or dissolved in an appropriate oily vehicle such as soybean oil, corn oil, cottonseed oil, and the like, or in a volatile organic solvent and then mixed with the carrier. It will be appreciated that the proportions of the compound in the concentrate are capable of wide variation since the amount of the active compound in the finished food can be adjusted by mixing the appropriate ratio of the premix with the food to obtain a desired level of the compound.

High potency concentrates can be mixed by the food manufacturer with proteinaceous carriers such as soybean meal and other flours, as described above, to produce concentrated supplements, which are suitable for direct feeding to animals. In such instances, animals are allowed to consume the usual diet. Alternatively, such concentrated supplements can be added directly to the food to produce a nutritionally balanced finished food containing a therapeutically effective level of a compound of the present invention. The mixtures are completely mixed by standard procedures, such as in a double shell mixer, to ensure homogeneity. If the supplement is used as a fertilizer for the feed, it also helps ensure uniformity of compound distribution through the top of the feed. Preferred foods for poultry and domestic pets usually contain between about 1 and 400 grams and preferably between 10 and 400 grams of a compound of the formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound , stereoisomer, or prodrug, per ton of food. For parenteral administration in animals, the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, can be prepared in the form of a paste or a pill and administered as an implant, usually under the skin of the head or ear of the animal. In general, parenteral administration of the pharmaceutical compositions involves injection of a sufficient amount of a compound of the formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer, or prodrug, to animal between 0.01 and 100 mg per kilogram of body weight per day of the active ingredient. The preferred dosage for poultry, pigs, cows, sheep, goats and domestic pets is in the range between 0.1 and 50 mg / kg / day. . The paste formulations can be prepared by dispersing a compound of the present invention in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pills containing effective amounts of the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, can be prepared by mixing a compound with a diluent such as carbocera, Carnauba wax, and the like, and a lubricant, such as calcium or magnesium stearate, can be added to improve the process of forming pills.

Naturally, it is recognized that more than one pill can be administered to the animal to achieve the desired dosage level. Furthermore, it has been found that implants can also be made periodically during the treatment period of the animal in order to maintain the level of the active agent in the body of the animal. The terms "pharmaceutically acceptable salts, esters, amides, or prodrugs" mean the dicarboxylate salts, amino acid addition salts, esters, amides, and prodrugs of a compound that are within the purview of sound medical judgment, suitable for use with patients without undue toxicity. irritation, allergic response, and the like, of measure equal to a reasonable benefit / risk ratio, and effective for their intended use, as well as zwitterionic forms, where possible. The term "salts" refers to inorganic and organic salts of a compound of the formula (I), or a stereoisomer or prodrug thereof. These salts can be prepared in situ during the final separation and purification of a compound, or by reacting separately a compound of the formula (I)or a stereoisomer or prodrug thereof with an appropriate organic or inorganic acid and thus isolating the salt thus formed include hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate salts, lactate, phosphate, tosylate, besylate, esylate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate, and lauryl sulphonate, and the like. These may include cations based on alkali and alkaline earth metals, such as sodium, potassium, lithium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium, and amine cations including, but not limited to, ammonium, tetramethylammonium , tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, trimethylamine, triethylamine, ethylamine, and the like. See, for example, Berge, "Pharmaceutical Sales," J Pharm Sci, 66: 1-19 (1977). The term "prodrug" means a compound that is transformed in vivo to produce a compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer. The transformation can occur through various meconisms, such as through hydrolysis in the blood. Unite - Discussion of the use of prodrugs is provided by T. Higuchí and W. Stella, "Pro-drugs as Innovative Systems of Liberation", Vol. 14 of the symposium series A.C.S., and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche. American Pharmaceutical Association and Pergamon Press, 1987. For example, if a compound of the formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt of the compound or stereoisomer, contains a functional group of the carboxylic acid, a prodrug may comprise a ester formed by the replacement of the hydrogen atom in the acid group with a group such as alkyl (Ci-Cs), alkanoyloxymethyl (Q2-C12), 1- (alkanoyloxy) ethyl having from 4 to 9 carbon atoms, 1-methyl -1- (alkanoyloxy) -ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) and having from 4 to 7 carbon atoms, 1-methyl-1 - (alkoxycarbonyloxy) ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl having from 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl having from 4 to 10 carbon atoms, -phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N-alkylam no (CrC2) alkyl (C2_3) (such as b-dimethylaminoethyl), carbamoyl-alkyl (C? -C2), NN-di-alkylcarbamoyl (C? -C2) -alkyl (C? -C2) and piperidino- , pyrrolidino- or mofolino-C2-C3 alkyl. Similarly, if a compound of the formula (I), or a stereoisomer thereof, comprises a functional group of alcohol, a prodrug can be formed by the replacement of the hydrogen atom of! alcohol group with a group such as alkanoyloxymethyl (Ci-Cß), 1- (alkanoyloxy (CrC8) ethyl, 1-methyl-a - ((C 1-6 alkanoyloxy), alkoxycarbonyloxymethyl (C? -C6) , N-alkoxycarbonylaminomethyl (C C6), N-alkoxycarbonylaminomethyl (CrC6), succinoyl, alkanoyl (Ci-Cß), a-amino-alkanoyl (C? -C), arylacyl and a-aminoacyl, or a-aminoacyl-a- aminoacyl, wherein each a-aminoacyl group is independently selected from naturally occurring L-amino acid groups, P (O) (OH) 2, -P (O) (0-alkyl (C? -C6) 2 or glycosyl (the radical resulting from the removal of a hydroxyl group from the hemiacetal form of a carbohydrate.) If a compound of the formula (I), or a stereoisomer thereof, incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl wherein R and R 'are each independently alkyl (CrC? o), cycloalkyl (C3-C7), benc ilo, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl natural a-aminoacyl, -C (OH) C (OY where (Y is H, alkyl (CV Cß) or benzyl); -C (OY0) Y? wherein Y0 is alkyl (CC) and Yi is alkyl (Ci-Cß), carboxy-alkyl (C? -C6), amino-alkyl (C? -C) or mono-N or di-N, N-alkylaminalkyl ( C? -C6), -C (Y2) Y3 wherein Y2 is H or methyl and Y3 is mono-N- or di-N, N-alkylamino (C? .C6), morpholino, piperidin-1-yl or pyrrolidine -1-ilo. The compounds of the formula (I) may contain asymmetric or chiral centers, and therefore, exist in different stereoisomeric forms. It is contemplated that all stereoisomeric forms of the compounds of the formula (I), as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention contemplates all geometric and positional isomers. For example, if a compound of the formula (I) incorporates a double bond, both the cis form and the trans form, as well as mixtures, are contemplated within the scope of the present invention. Diasteromic mixtures can be separated into their individual isomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as chromatography and / or fractional crystallization. The enantiomers can be separated by converting the eantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (ex., alcohol), separating the diastereomers and converting (eg, hydrolyzing) the individual diastereomers into corresponding pure enantiomers. Also, some of the compounds of the formula (I) can be atropisomers (eg, substituted biaryl and are considered as part of this invention) The compounds of the formula (I) can exist in unsolvated and solvated forms with pharmaceutically acceptable solvents such such as water, ethanol, and the like The present invention contemplates and includes the solvated and unsolvated forms It is also possible that the compounds of the formula (I) may exist in different tautomeric forms, and all these forms are contemplated within the scope of For example, all tautomeric forms of the imidazole moiety are included in the invention, and also, for example, all forms of ceo-enol or imine-enamine of the compounds included in the invention. in the state of the art it will recognize that the names of compounds which refer to the compounds of formula (I) disclosed herein can be based on n a particular tautomer of a compound. While the name can be used only for a particular tautomer, it is intended that all tautomers be included by the name of the particular tautomer and all tautomers are considered part of the present invention.

It is also intended that the invention disclosed herein encompass compounds of formula (I) that can be synthesized in vitro using laboratory techniques, such as those well known to synthetic organic chemists of common skill; or synthesized using in vivo techniques, such as through metabolism, fermentation, digestion, and the like. It is also contemplated that the compounds can be synthesized using a combination of in vitro and in vivo techniques. The present invention also includes isotopically labeled compounds of the formula (I), which are identical to those cited herein, but bearing in mind that one or more atoms are replaced by an atom having an atomic mass or mass number other than the Atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the present invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 180, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. The compounds of the formula (I), the stereoisomers and prodrugs thereof, and pharmaceutically acceptable salts of the compounds, stereoisomers, or prodrugs which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. invention. Certain isotopically labeled compounds of the formula (I), for example those in which the radioactive isotopes such as 3H and 14C are incorporated, are useful in tests of distribution of compounds and / or substrates in tissue. Trio isotopes, ie, 3H and carbon-14 are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, can provide certain therapeutic advantages that result in greater metabolic stability, for example increased half-life in vivo or reduced dosage requirements and, therefore, can be preferred in some circumstances. Isotopically labeled compounds of the formula (I) can generally be prepared by carrying out the procedures analogous to those disclosed in the schemes and / or in the examples below, substituting an isotopically labeled reagent readily available for a non-isotopically labeled reagent. The compounds of the structural formula (I) can generally be prepared according to the synthetic methodologies established in schemes 1 to 5.

SCHEME 1 1-1 1-2 1-3 1 -4 The preparation of the thiazolidinedione derivatives 1-6 and 1-7 is illustrated in Scheme 1. The key intermediate diaryl ether 1-3 can be synthesized by 1,2-bis-arylyl-iododonium tetrafluoroborate with p-hydroxybenzonate 1-2 at room temperature in an appropriate organic solvent such as dichloromethane, in the presence of a copper catalyst and an appropriate base, for example, triethylamine (TEA). The preparation of bis-aryl iodonium tetrafluoroborate 1-1 can be made from the corresponding anisole derivative known according to the method disclosed in J. Med. Chem., 38, 695-707 (1995). The reduction of ester 1-3 to benzaldehyde 1-4 can be carried out according to methods which will be known to one of skill common in the state of the art. For example, the ester 1-3 can be reduced to the corresponding alcohol by reaction with an appropriate reducing agent for example, diisobutalaluminum hydride (DIBAL), followed by oxidation to aldehyde 1-4 by manganese dioxide. The aldehyde reaction product thus produced can then be released through a Knoevengel condition with thiazolidinedione in the presence of a catalytic amount of piperidinium acetate to produce benzylidene thiazolidinedione 1-5. Demethylation of the condensation product 1-5 with boron tribromide gives phenol 1-6. Hydrogenation of 1-5 provides saturated benzyl thiazolidine which reacts with boron tribromide to produce phenol 1-7.

SCHEME 2 2-6 The sulfonamide derivatives 2-5 and 2-6 are prepared as illustrated in scheme 2. The bis-aryiodonium tetrafluoroborate 2-1 is coupled with 4-hydroxybenzoate 1-2 at room temperature in dichloromethane in the presence copper bronze and an appropriate base such as triethylamine (TEA) to produce diaryl ether 2-2. The reduction of ether 2-2 with DIBAL supplies the corresponding alcohol which is oxidized to benzaldehyde 2-3 with manganese dioxide. Condensation of aldehyde 2-3 with thiazolidinedione provides an intermediate benzylidene thiazolidinedione which is hydrogenated to provide benzyl thiazolidinedione 2-4. A subsequent chlorosulfonylation reaction provides a 3'-sulfonyl chloride which is then reacted with a primary or secondary amine to produce 3'-sulfonyl amide 2-5. Demethylation of 2-5 with boron tribromide provides hydroxylsulfonamide 2-6.

SCHEME 3 3-8 The formation of amide derivatives 3-8 and 3-9 is carried out as shown in Scheme 3. The ester 2-2 can be reduced to the corresponding alcohol 3-1 according to methods that will be well known by someone of common skill in the state of the technique, for example DIBAL reduction. The protection of benzyl alcohol 3-1 by reaction with methyl iodide in the presence of sodium hydride in dimethylformamide (DMF) provides methylbenzyl ether 3-2. The ether formulation 3-2 for supplying aldehyde 3-3 can be carried out according to known methods, for example, by treating ether 3-2 with hexamethylenetetramine at 65 ° C in trifluoroacetic acid. The oxidation of 3-3 to the corresponding carboxylic acid 3-4 can also be carried out according to conventional methods. Generally preferred oxidation methods include the use of the Jones reagent, ie, crustamatic acid / aqueous sulfuric acid, or, alternatively, those methods employing sodium hypochlorite, for example, buffered aqueous NaCl and 2-methyl-2-butene in tert-butanol / tetrahydrofuran. The carboxylic acid 3-4 can be converted to carboxamide 3-5 according to known methods, for example, by reacting the acid chloride or the mixed anhydride of carboxylic acid 3-4 with a primary or secondary amine in dry aprotic solvent such as dichloromethane , tetrahydrofuran (THF), dimethoxyethane (DME), or diethoxyethane (DEE) in the presence of a base such as TEA, dimethylaminopyridine (DMAP), or pyridine. Alternatively, carboxylic acid 3-4 can be reacted with N-hydroxysuccinimide, dicyclohexylcarbodiimide, and an amine in the presence of a base such as TEA in 1,2-dimethoxyethane. Demethylation of 3-5 with boron tribromide provides benzyl bromide 3-6. Oxidation of benzyl bromide 3-6 with N-methylmorpholine N-oxide in acetonitrile provides benzadehyde 3-7 which is converted to benzyl 3-9 thiazolidinedione by Knoevenagel condensation followed by hydrogenation.

SCHEME 4 4-3 4-4 The preparation of oxydiazolidinadione derivatives 4-4 can be carried out as described in Scheme 4. The reduction of the compound 1-3 with DIBAL provides benzyl alcohol 4-2. Treatment of 4-2 with boron tribromide in dichloromethane provides benzyl bromide 4-3. The reaction of benzyl bromide 4-3 with oxadiazolindinedione in the presence of sodium carbonate in DMF yields oxazolidinedione benzyl 4-4.

SCHEME 5 H2NNHCONH2 HCl NaOAc, EtOH -2 H -3 H -4 The formation of triazolone derivatives 5-4 is illustrated in Scheme 5. Treatment of benzaldehyde 1-4 with semicarbazide in the presence of sodium acetate provides the corresponding semicarbazone 5-2. Cyclization of semicarbazone 5-2 with sulfur monochloride in a mixture of ethyl acetate and acetic acid provides triazolone 5-3 which is subsequently demethylated with boron tribromide to provide hydroxyl compound 5-4. The present invention is illustrated by the following Examples. However, it should be understood that the Examples are presented by way of illustrations of the invention and are not intended to be considered as limitations thereof.

EXPERIMENTAL Chemical Synthesis In the present description, the following abbreviations or acronyms are used with the meanings indicated: AcOH acetic acid APCI + chemical ionization at atmospheric pressure, positive ion mode APCI- chemical ionization at atmospheric pressure, negative ion mode Calculated CAL DEETethoxyethane DME dimethoxyethane DMF N, N-dimethylformamide DMSO dimethyl sulfoxide ES + ionization by electroatomization, positive ion mode Et ethyl EtOAc ethyl acetate EtOH ethanol Equiv equivalent (s) Hex hexanes KHMDS bis (trimethylsilyl) potassium amide Me methyl MeOH methanol MS mass spectrometry MSA methanesulfonic acid NMP 1-methylpyrrolidone NMR nuclear magnetic resonance RT ambient temperature TEA triethylamine TES triethyl silane TFA trifluoroacetic acid THF tetrahydrofuran TLC thin layer chromatography The following synthetic examples are illustrated from those procedures shown and described here the sequential preparation of compounds 1-3 to 1-7 illustrated generically in scheme 1.

EXAMPLE 1 5- [3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzyl-1-thiazolidin-2,4-dione Step A: 3,5-Dichloro-4- (3-isopropyl-4-methoxy-phenoxy) -benzoic acid ethyl ester The title compound was prepared from bis- (3-isopropyl-4-methoxy tetrafluoroborate -phenyl) -iodonium and 3,5-dichloro-4-hydroxy-benzoic acid ethyl ester in the presence of copper bronze and triethylamine by the methodologies described in Med. Chem., 38, 695-707 (1995). MS (APCI +). Calc: 383.01. Found: 383.0 (M + 1).

Step B: 3,5-Dichloro-4- (3-isopropyl-4-methoxy-phenoxy) -benzaldehyde To a solution of the product from Step A (100 mg, 0.26 mmol) in dichloromethane (3 mL) at 0 ° C under dry nitrogen was added diisobutylaluminum hydride (1 M in hexanes, 0.6 ml, 0.6 mmol) slowly over a period of about one minute with stirring. The reaction mixture was allowed to warm to room temperature and stirred for one hour. The reaction was quenched with methanol, followed by the addition of potassium tartrate (5 mL, 0.5 N) and the mixture was extracted with methylene chloride (3x10 mL). The combined extracts were dried, filtered, and concentrated to deliver the crude intermediate alcohol as an oil. To a solution of the crude alcohol in methylene chloride (5 ml) was added manganese dioxide (450 mg). After stirring at room temperature for 2.5 hours, the reaction mixture was filtered through diatomaceous earth, and the filter cake was heated with hot methylene chloride (3x10 ml). The filtrates were combined and concentrated to deliver the title product as a solid which was used in the next step without purification. MS (APCI). Cale: 338.0. Found: 336.9 (M-1) Step C: 5-F3,5-Dichloro-4- (3-isopropyl-4-methoxy-phenoxy) -benzylidene-1-thiazolidine-2,4-dione To a suspension of the above compound from step B (60) mg, 0.18 mmol) and thiazolidinedione (21 mg, 0.18 mmol) in dry toluene (2 mL) was added a catalytic amount of piperidium acetate which was generated by the addition of piperidine (1.5 mg, 0.018 mmol) and acetic acid ( 1.1 mg, 0.018 mmol). The mixture was heated to reflux under nitrogen for two hours. The solution was cooled, diluted with ethyl acetate (15 mL), washed with 1 N HCl (3x10 mL) and brine (10 mL), dried, filtered, and concentrated. The residue was purified by preparative TLC (5% methanol in dichloromethane) to give the title compound (26.1 mg) as a yellow solid. MS (APCI) Cale: 437-0, Found: 436.1 (M-1).

Step D: 5-r3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzylidene-1-thiazolidino-2,4-dione To a solution of the title compound from step C (26 mg, 0.060 mg, 0.060 mmol) in dichloromethane (1 ml) at room temperature was added boron tribromide (1 M in dichloromethane, 0.12 ml, 0.12 mmol). After the addition, a brown solution was obtained which was stirred at room temperature for about three hours. An additional 4 equivalents of boron tribromide was added and the mixture was stirred for 15 minutes at room temperature. A brown precipitation formed. The reaction was quenched with water (5 ml) and extracted with dichloromethane (3x10 ml). The combined extracts were dried, filtered, and concentrated, and the residue was purified by preparative TLC (7% methanol in dichloromethane) to yield the title compound (13 mg) as an off-white solid. MS 8APCI) Calculated: 423.0, Found: 422.0 (M-1).

Step E: 5- [3,5-Dichloro-4- (3-isopropyl-4-methoxyl-phenoxy) -benzyl] -thiazolidine-2,4-dione A solution of the title compound from step D (31 mg, 0.072 mmol) was dissolved in ethyl acetate / methanol (1 ml / 1 ml) and placed in a hydrogenation bottle with 10% patadic on carbon (90 mg). The mixture was placed on a Parr shaker for two hours under 50 p.s.i. of hydrogen, then filtered through diatomite, and the filter cake was washed with ethyl acetate / ethanol. The combined filtrate was concentrated to yield the title compound (26 mg) as a clear viscous agent which was used in the next step without purification. MS (APCI) Cal: 439.0, Found: 438.1 (m-1).

Step F 5- [3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzopy-thiazolidine-2,4-dione To a solution of the title compound from Step E (26 mg, 0.058 mmol) in dichloromethane (1 ml) at room temperature was added boron tribromide (1 M in dichloromethane 0.12, 0.12 mmole), A tan precipitate was immediately formed. After stirring at room temperature for about 30 minutes, the mixture was quenched with water (5 ml), and extracted with dichloromethane (3x10) mi). The combined extracts were dried, filtered and concentrated. The residue was purified by preparative TLC (7% methanol in dichloromethane) to yield the title compound (19 mg) as a solid. MS (APCI) Cale: 425.0, Found: 424.0 (M-1). Using the appropriate starting materials, examples 2 and 3 were prepared in a manner analogous to the sequence of reactions described for example 1.

EXAMPLE 2 5- [4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-benzylidene] -thiazolidino-2,4-dione; MS (APCI) Cale: 383.1, Found: 382.3 (M-1) EXAMPLE 3 5-r4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-d-methyl-benzyl-thiazolamidine-2,4-dione; MS (APCI) Cale: 385.1, Found: 384.2 (M-1) The following synthetic examples are illustrative of those procedures shown and described hereinbefore for the sequential preparation of compounds 2-3 to 2-6 illustrated generically in Table 2. .

EXAMPLE 4 N-Cyclopropyl-5-r2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-ylmethyl) -phenoxy-1-benzenesulfonamide Step A: 3,5-Dichloro-4 (4-methoxy-phenoxy) -benzoic acid ethyl ester To a solution of bil- (4-methoxyphenyl) iodonium tetrafluoroborate (15 g, 35 mmol) and copper bronze (3.0 g, 46.7 mmole) in methylene chloride (30 ml) at 0 ° C was added dropwise a solution of 3,5-dichloro-4-hydroxy-benzoic acid ethyl ester (5.50 g, 23 mmol) and triethylamine (3 m 6). mi, 26 mmol) in dichloromethane (30 ml). The resulting mixture was stirred in the dark at room temperature for approximately five days and then filtered through a short pad of silica gel eluting with 3% ethyl acetate to remove the reference material. The filtrate was concentrated and the residue was dissolved in ether 830 ml). The product was crystallized to give the title compound as a solid (4.8 g). The filtrate was concentrated and purified by chromatography to give an additional 1.57 g of the product. The total yield for the reaction was 81%. MS (APCI +) Cale: 340.0, Found: 314: 8 (m + 1, -Et).

Step B: 3,5-Dichloro-4- (4-methoxy-phenoxy) -benzaldehyde The title compound was prepared from 3,5-dichloro-4- (4-methoxy-phenoxy) ethyl ester -benzoic acid according to the procedure described in Example 1, Step B. MS (APCI-) Cale: 297.1, Found: 296.0 (M-1) Step C: 5- 3,5-Dichloro-4- (4-methoxy-phenoxy) -benzylidene] -thiazolidine-2,4-dione) To a solution of the compound from step B (284 mg, 0.96 mmol) is toluene (16 ml) was added 2,4-thiazolidinedione (140 mg, 1.2 mmol), a catalytic amount of piperidinium acetate which was generated from piperidine (five drops) and acetic acid (five drops) and molecular sieves from 4 Á. The mixtures were stirred under reflux for about four hours, cooled to room temperature, filtered and concentrated. The product was purified by preparative TLC (4% methanol in dichloromethane) to yield the title compound (153 mg). MS (APCI-). Cale: 395.0. Found: 394.0 (M-1).

Step D: 5r3,5-Dichloro-4- (4-methoxy-phenoxy) -benzyl-1-thiazlidine-2,4-dione The title compound from step C (93 mg) was dissolved in ethyl acetate / methanol (4 ml / 2 ml) and then 10% palladium on carbon (70 mg) was added. The reaction mixture was placed on Parr shaker for four hours under 50 psi hydrogen at room temperature. The solution was filtered through diatomite, and concentrated. The residue was purified by preparative TLC (3% methanol in dichloromethane) to give the title compound (52 mg) as a solid. MS (APCI). Cale: 397.0 (M.1). Found: 396.0 (M-1) Step E: 5-r2,6-Dichloro-4- (2,4-dioxo-thiazolidin-5-ymethyl) -phenoxy-1-2-methoxy-benzenesulfonyl chloride The title compound of step D (52 mg, 0.13 mmoles) was cooled to 0 ° C and chlorosulfonic acid (0.5 ml) was added. The mixture was warmed to room temperature and stirred for 1.5 hours. The solution was poured onto ice (75 g), stirred until the ice melted, and then extracted with ethyl acetate (3x25 ml). The combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated to yield the title compound (38 mg) as a brown solid which was used in the next step without purification.

Step F: NC-Cyclopropyl-5-r2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-ylmethyl) -phenoxy-2-methoxy-benzenesulfonamide To the compound of step E (38 mg, 0.08 mmoles) in dry tetrahydrofuran (1 mL) at room temperature was added cyclopropylamide (8.0 mL, 0.12 mmol) and N-methylmorpholine (17 mL, 0.15 mmol). The reaction mixture was stirred at room temperature for a few hours, cooled with 1 N HCl (15 mL), and extracted with ethyl acetate (3x15 mL). The combined extracts were washed with 1 N HC1 (2x15 mL), brine (15 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (8% methanol in dichloromethane) to yield the title compound (16 mg, 41% yield). MS (APCI) Cale: 516.0. Found: 516.9 (M + 1).

Step G: NC-Chloropropyl-5-r2,6-dichloro-4- (2,4-dioxo-triazolidin-5-ylmethyl) -phenoxyl-2-hydroxy-benzenesulfonamide To a solution of the title compound of Step F (16 mg, 0.032 mmol) in dichloromethane (0.5 ml) at 0 ° C was added boron tribromide (1 M in dichloromethane, 0.06 ml, 0.06 mmol). The reaction mixture was stirred at room temperature for one hour, then cooled by the addition of 1 N HCl (5 ml). The resulting solution was extracted with dichloromethane (3x5 ml). The combined extracts were dried over sodium sulfate, filtered, and concentrated. The residue was purified by preparative TLC (7% methanol in dichloromethane) to give the title compound (11 mg, 68% yield) as a white solid. MS (APCI). Cale: 502.0. Found: 501.2 (M-1). The following synthetic examples are illustrative of those prures shown and described above for the sequential preparation of the 3-1 to 3-9 compounds generically illustrated in Table 3.

EXAMPLE 5 N-Cyclobutyl-5-r2.6-dichloro-4- (2,4-d-oxo-thiazolidin-5-ylmethyl) -phenoxyl-2-hydroxy-N-methyl-benzamide Step A: [3,5-Dichloro-4- (4-methoxy-phenoxy) -fenip-methanol To a solution of 3,5-dichloro-4- (4-methoxy-phenoxy) -benzoic acid ethyl ester ( 1.36 g, 4.01 mmol) in dichloromethane (35 ml) at 0 ° C was added diisobutylaluminum hydride (1 M in toluene, 12 ml, 12 mmol) and the mixture was stirred for 2.5 hours at 0 ° C. The reaction mixture was cooled with potassium sodium tartrate tetrahydrate (0.5 M aqueous solution, 50 ml), stirred for 20 minutes at room temperature and then filtered through diatomaceous earth. The filtrate was concentrated and then collected in water (60 ml). The aqueous solution was extracted with ethyl acetate (4x60 ml). The combined extracts were dried, filtered, and concentrated. The residue was purified by flash column chromatography (ethyl acetate 2% in dichloromethane) to yield the title compound (871 mg). NMR (400 MHz, CDC13) d 7.39 (s, 2H), 6.74-6.82 (m, 4H), 4.69 (d, 2H), 3.76 (s, 3H), 1.83 (t, 1 H).

Step B: 4- (2,6-dichloro-4-methoxymethyl-phenoxy) -anisole To a solution of the title compound from step A (400 mg, 1.34 mmol) in dry dimethylformamide (13 ml) at 0 ° C under nitrogen was added NaH (60% dispersion in mineral oil, 134 mg, 3.3 mmol). After stirring for 30 minutes at 0 ° C until the evolution of hydrogen ended, methyl iodine (949 mg, 6.61 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The solution was poured into water (100 ml) and extracted with ethyl acetate (3 x 100 ml). The combined extracts were washed with 1 M HCl (3 x 100 mL), brine (100 mL), dried, filtered, and concentrated. The crude product was purified by preparative TLC (30% hexane in dichloromethane) to yield the title compound (410 mg). NMR (400 MHz, CDCl 3) d 7.36 (s, 2H), 6.75-6.83 (m, 4H), 4.40 (s, 2H), 3.75 (s, 3H), 3.43 (s, 3H).

Step C: 5- (2,6-D-Chloro-4-methoxymethyl-phenoxy) - 2-methoxy-benzaldehyde A mixture of the title compound from Step B (410 mg, 1.31 mmol), hexamethylenetetramine (256 mg, 2.0 mmoles) and trifluoroacetyl acid (2.5 ml) under nitrogen was heated to 75 ° C and stirred for about three hours. The solution was concentrated in vacuo to give a yellow viscous oil. Water was added to the yellow oil and the mixture was stirred for about 30 minutes at room temperature. The aqueous solution was neutralized with saturated sodium bicarbonate and extracted with ethyl acetate (3 x 30). The combined organic extracts were washed with saturated sodium bicarbonate (2 x 50 mL), brine, (50 mL), dried, filtered and concentrated to give the title compound (440 mg) as a crude product which was used in the next step without further purification. NMR (400 MHz, CDCl 3) d 10.36 (s, 1 H), 7.33 (s, 2 H), 7.11-7.16 (m, 2 H), 6.93 (d, 1 H), 4.39 / s, 2 H), 3.86 (s) , 3H), 3.40 (s, 3H).

Step D: 5- (2,6-Dichloro-4-methoxymethyl-phenoxy) -2-methoxy-benzoic acid To a solution of the title compound of step C (228 mg, 0.67 mmol) and 2-methyl-2-butene (2M in tetrahydrofuran, 5 mL, 10.0 mmol) in tert-butanol / tetrahydrofuran (1 mL / 3 mL) was slowly added to a solution of sodium hypochlorite (543 mg, 6.0 mmol) in aqueous potassium dihydrogen phosphate solution ( 0.6 M, 8 mi). The reaction mixture was stirred for one hour at room temperature. The mixture was acidified with 1 N HCl and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with 1 N HCl (2 x 40 mL), brine (40 mL), dried, filtered, and concentrated to give the title compound (241 mg) as a viscous oil which was used in the following step without further purification.

MS (APCI-) Cale: 356.0 Found: 355.0 (M-1).

Step E: N-Cyclobutyl-5- (2,6-dichloro-4-methoxymethyl-phenoxy) -2-methoxy-benzamide To a solution of the title compound from step D (238 mg, 0.67 mmol) in tetrahydrofuran (7 ml. ) at 0 ° C under nitrogen, isobutylchlorofomate (0.13 ml, 1 mmol) and N-methylmorpholino (0.15 ml, 1.3 mmol) were added. After stirring for approximately 30 minutes at 0 ° C, cyclobutylamine (0.11 ml, 1.3 mmol) was added. The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction solution was diluted with 1 N HCl (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with 1 N HCl (2 x 50 mL), brine (50 mL), dried, filtered and concentrated. The crude product was purified by preparative TLC (50% ethyl acetate in hexanes) to give the title compound (170 mg) as a viscous oil. MS (ACPI +) Cale: 409.1 Found: 409.7 (M + 1).

Step F: N-Cyclobutyl-5- (2,6-dichloro-4-methoxymethyl-phenoxy) -2-methoxy-N-methyl-benzamide To a solution of the title compound from step E (170 mg, 0.41 mmol) in dimethylformamide (4 mL) at 0 ° C under nitrogen was added sodium hydride (60% dispersion in mineral oil, 41 mg, 1 mmol). The resulting slurry mixture was stirred at 0 ° C for about 30 minutes and gradually turned into a brown-yellow solution.

To this solution at 0 ° C was added methyl iodide (0.13 ml, 2 mmol). The resulting solution was warmed to room temperature and stirred for about 19 hours. The solution was diluted with 1 N HCl (30 mL) and extracted with ethyl acetate (3 x 15 mL). The combined organic extracts were washed with 1 N HCl (3 x 50 mL), brine, dried, filtered and concentrated. The residue was purified by preparative TLC (50% ethyl acetate in hexanes) to give the title compound (155 mg). MS (APCI +) Cale: 423.1 Found: 424.0 (M + 1).

Step G: 5- (4-Bromomethyl-2,6-dichloro-phenoxy) -N-cyclobutyl-2-hydroxy-N-methyl-benzamide To a solution of the title compound from step F in dichloromethane (2.2 ml) at room temperature, boron tribromide (1 M in dichloromethane, 1.5 ml, 1.5 mmol) was added. The reaction mixture was stirred at room temperature for about two hours, and cooled with water (20 ml). After stirring for approximately 15 minutes, the solution was extracted with dichloromethane (3 x 15 mL). The combined organic extracts were washed with brine (50 ml), treated with activated carbon, filtered through diatomaceous earth, dried and concentrated to give the title compound (163 mg) as a whitish solid which was used in the next step without additional purification. MS (APCI) Cale: 457.0 Found: 456.0 (M + 1).

Step H: N-Cyclobutyl-5- (2,6-dichloro-4-formyl-phenoxy) -2-2-hydroxy-N-methyl-benzamide To a solution of the title compound of step G (130 mg, 0.28 mmol) ) in dry acetonitrile (6 ml) at room temperature under nitrogen was added molecular sieves (4 A, 50 mg). After stirring for about 15 minutes at room temperature, N-methylmorpholine N-oxide (66 mg, 0.57 mmol) was added. The resulting mixture was stirred at room temperature for about 18 hours, then filtered through a short pad of silica gel with an acetonitrile wash. The filtrate was concentrated to give the title compound (88 mg) as a whitish foam which was used in the next step without further purification. MS (APCI-) Cale: 393.1 E Found: 392.1 (M-1).

Step N-Cyclobutyl-5-r2,6-dichloro-4- (2,4-d-oxo-thiazolidin-5-yldenomethyl) -phenoxy-2-hydroxy-N-methyl-benzamide To a solution of the compound from step H (40 mg, 0.10 mmol) and thiazolidinedione (13 mg, 0.11 mmol) in toluene (2 ml) was added acetic acid (1.5 μl, 0.025 mmol), piperidine (2.5 μl, 0.025 mmol) and powdered 3 A molecular sieves. The reaction mixture was heated to reflux and stirred at reflux for about 18 hours. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate (10 ml) and water (10 ml). The organic layer was washed with 1 N HCl (2 x 10 mL), brine (10 mL), dried, filtered, and concentrated. The crude product was purified by preparative TLC (7% MeOH in dichloromethane) to give the title compound (37 mg). MS (APCI-) Cale: 492.0 Found: 491.0 (M-1).

Step J: N-Cyclobutyl-5- [2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-ylmethyl) -phenoxyl-2-hydroxy-N-methyl-benzamide To one solution of the title compound from step I (35 mg, 0.073 mrnol) in ethyl acetate / methanol (4 ml / 1 ml) in a hydrogenation bottle was added 10% palladium on carbon (70 mg). The solution was placed on a Parr shaker for one hour under 55 psi of hydrogen at room temperature, then filtered through diatomite. The filtrate was concentrated to deliver the compound of! title (13 mg) as a yellow solid. MS (APCI) Cale: 494.0 Found (M-1). The following synthetic examples are illustrative of those procedures shown and described above for the sequential preparation of compounds 4-2 to 4-4 generically illustrated in scheme 4.

EXAMPLE 6 2-r3,5-Dichloro-4- 4-hydroxy-3-isopropyl-phenoxy) -benzyl-1, 2,4-oxadiazolidene-3,5-dione Step A [3,5-Dichloro-4- (3-isopropyl-4-methoxy-phenoxy) -phenyl] -methanol To a solution of 3,5-dichloro-4- (3-ethyl) ethyl ester Sodium propyl-4-methoxy-phenoxy) -benzoic acid (prepared as described in Example 1, step A) (100 mg, 0.26 mmol) in methylene chloride (3 mL) at -78 ° C under nitrogen was added hydride. diisobutylaluminum (1 M in hexane, 0.6 ml, 0.6 mmole). The reaction mixture was warmed to room temperature and stirred for about 19 hours. The reaction was quenched with methanol (1 ml) and potassium sodium tartrate (0.5 M aqueous solution, 2 ml). After stirring for approximately 15 minutes, the solution was extracted with methylene chloride (3 x 10 mL). The combined organic extracts were washed with saturated sodium bicarbonate and brine, dried, filtered and concentrated. The crude product was purified by preparative TLC (methylene chloride) to give the title compound (75 mg) as a solid. NMR (400 MHz, CDCl 3) d 7.39 (s, 2H), 6.85 (d, 1 H), 6.69 (d, 1 H), 6. 43-6.46 (dd, 1 H), 4.68 (s, 2H), 3.77 (s, 3H), 3.26-3.30 (Sept. 1 H), 2.03 (bs.1H), 1.18 (d, 6H).

Step B: 4 (4-Bromomethyl-2,6-dichloro-phenoxy) -2-isopropyl-phenol To a solution of the title compound from step A (75 mg, 0.22 mmol) in dry methylene chloride (2 ml) Room temperature under nitrogen was added boron tribromide (1 M in methylene chloride, 0.44 ml, 0.44 mmol). The reaction mixture was stirred at room temperature for about 1 hour, quenched with water (5 ml) and extracted with methylene chloride (3 x 5 ml). The combined organic extracts were dried, filtered and concentrated. The crude product was purified by preparative TLC (methylene chloride) to give the title compound 59 mg) as an oil. MS (APCI) Cale: 388.0 Found: 386.9 (M-1).

Step C: (2- [3,5-Dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzin- [1, 2,4] oxadiazolidine-3,5-dione The title compound was prepared according to the methodology described in Synthesis, 265-266 (1991) To a solution of the title compound of step B (59 mg, 0.15 mmol) and [1, 2,4] oxadiazolidine-3,5-dione (16 mg , 0.15 mmole) in DMF (1.5 ml) at room temperature was added sodium carbonate (32 mg, 0.30 mmol) After stirring at room temperature for about two hours, the solution was diluted with 0.5 N HCl (10 ml). and extracted with ethyl acetate (3 x 10 mL) .The combined organic extracts were washed with water (3 x 15 mL), brine (15 mL), dried, filtered and concentrated.The crude product was purified by preparative TLC (methanol). 22% / 3.5% water / 4.5% chloroform) to provide the title compound (61 mg) MS (APCI-) Cale: 410.0 Found: 409.1 (M-1) Using appropriate starting materials, the examples 7 and 8 was were prepared in a manner analogous to the sequence of reactions described for Example 6.

EXAMPLE 7 2-r4- (3-lsopropyl-4-methoxy-phenoxy) -3,5-d.methyl-benzyl-1-f1,2,4] oxadiazole-dina-3,5 -diona MS (APCI-) Cale: 384.2 Found: 383.2 (M-2) EXAMPLE 8 2-r4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-benzyl-M, 2,41-oxadiazolidine, 3,5-dione MS (APCI-) Cale: 370.2 Found: 369.2 (M-1) The following synthetic examples are illustrative of those procedures shown and described above for the sequential preparation of compounds 5-2 to 5-4 generically polished in scheme 5 .

EXAMPLE 9 5-r4- (4-Hydroxy-3-isopropyl-phenoxy) -3,5-d-methyl-phenyl-2,4-dihydroH, 2,4-Uriazol-3-one Step A: 3,5-Dimethyl-4- (3-isopropyl-4-methoxy-phenoxy) -benzaldehyde-semicarbazone To a solution of 4- (3-isopropyl-4-methoxy-phenoxy) 3 , 5-dimethyl-benzaldehydro (19 mg, 0.063 mmol) in ethanol (1 ml) at room temperature was added semicarbazide (7.7 mg, 0.69 mmol) and sodium acetate (5.1 mg, 0.063 mmol). After stirring at room temperature for about 1 hour, the solvent was removed under vacuum, and the residue was dissolved in ethyl acetate (5 ml). The ethyl acetate solution was washed with water (3 x 5 mL), brine (5 mL), dried, filtered and concentrated to give the title compound (20 mg) as a yellow solid which was used directly in the next step without further purification. MS (APCI) Cale: 355.2 Found: 354.3 (M + 1).

Step B: 5-í4- (3-lsopropyl-4-methoxy-phenoxy) -3,5-d-methyl-phenylene-2,4-dihydro-f1, 2,41-triazol-3-one To one solution of the title compound from Step B (4.7 mg, 0.013 mmol) in chloroform (0.5 mL) was added boron tribromide (1 M in dichloromethane, 0.26 mL, 0.26 mmol) and the mixture was stirred at room temperature for about one hour. The reaction was quenched with water (5 mL), acidified with 1 N HCl (1 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried, filtered, and concentrated to give the title compound (4.2 mg). MS (APCI) Cale: 339.2 Found: 338.3 (M-1).

Step C: To a solution of the title compound from Step B (4.7 mg, 0.013 mmol) in chloroform (0.5 mL) was added boron tribromide (1 M in dichloromethane, 0.26 mL, 0.26 mmol) and the mixture was stirred at room temperature. room temperature for about an hour. The reaction was quenched with water (5 mL), acidified with 1 N HCl (1 mL), and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were dried, filtered, and concentrated to provide the title compound (4.2 mg). MS (APCI) Cale: 339.2 Found: 338.3 (M-1).

BIOLOGICAL TESTING The utility of the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs in the practice of the present invention can be evidenced by activity in at least one of the tests described below.

TEST 1 Oxygen consumption As will be well known to one of skill common in the state of the art, during increased energy consumption, animals generally consume increased amounts of oxygen. In addition, metabolic fuels such as, for example, glucose and fatty acids, are oxidized to C02 and H0 with the concomitant evolution of heat, an effect commonly known in the art as thermogenesis. Therefore, the measurement of oxygen consumption in animals, including humans and companion animals, is an indirect measure of thermogenesis, and indirect calorimetry can be commonly used in animals for example, humans, by someone of common ability in the state of the technique to measure such energy consumption. Someone of common skill in the state of the art will appreciate that the increased energy consumption and the concomitant burning of metabolic fuels resulting in the production of heat can be effective with respect to the exemplary treatment, obesity. As will be well known to one of skill in the art, thyroid hormones affect cardiac function, for example, by producing an increase in heart rate and, consequently, an increase in oxygen consumption with concomitant production of hot.

The ability of the compounds of the formula (I), the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of the compounds, stereoisomers, and prodrugs, to generate a thermogenic response can be demonstrated according to the following protocol.

A. Experimental. This in vivo protocol is designed to evaluate the efficacy and cardiac effects of compounds that are selective thyroid hormone agonists at the tissue level. The measured endpoints of efficacy are whole-body oxygen consumption and the activity of mitochondrial hepatic-glycerophosphate dehydrogenase ("mGPDH"). The cardiac end points that are measured are cardiac weight and cardiac mGPDH activity. The protocol involves: (a) dosing of Zucker rats fattened for approximately 6 days, (b) measurement of energy consumption and (c) harvesting of mitochondria preparation tissue and subsequent assay of enzymatic activity by it.

B. Preparation of rats Male Zucker rats fattened with body weight between 400 and Approximately 500 g are housed for 3 and 7 days in individual cages under standard laboratory conditions before the initiation of the study.

A compound of the formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug; vehicle; or sodium salt T3, is administered by oral priming between 3 p.m. and 6 p.m. approximately, for approximately six days. A compound of the formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug; vehicle; or sodium salt of T3, is dissolved in an approximately small volume of approximately 1 N of NaOH and then absorbed at an appropriate volume with approximately 0 01 N of NaOH containing approximately 0.25% methyl cellulose (10: 1, 0.1 N NaOH / 1 N NaOH MC). The dosage volume is approximately 1 ml.

C. Oxygen consumption. Approximately the day after the last dose of the compound is administered, oxygen consumption is measured using an open-circuit indirect calorimeter (Oxymax, Columbus Instruments, Columbus, OH 43204). Oxymax gas sensors are calibrated with N2 gas and a gas mixture (approximately 0.5% C02, approximately 20.5% of 02, approximately 79% N2 before each experiment.) Rats are removed from their cages and their weights recorded The rats are placed in sealed chambers (43 x 43 x 10 cm) the Oxymax calorimeter, the chambers are placed in the activity monitors, and the rate of air flow through the chambers is then placed between 1.6 1 /? min and approximately 1.7 1 / min The Oxymax software then calculates the oxygen consumption (ml / kg / hour) of the rats based on the rate of air flow through the chambers and the difference in oxygen content in the The input and output ports The activity monitors have 15 light rays separated by 2.54 cm on each axis, and the ambulatory activity is recorded when two consecutive rays are interrupted, and the results are recorded as counts. and the a Ambulatory activity is measured approximately every 10 minutes for 5 to 6.5 hours approximately. Resting oxygen consumption is calculated on individual rats averaging the values excluding the first 5 values obtained during periods of time where the ambulatory activity exceeds 100. approximately counts.

ASSAY 2 Union with thyroid hormone receptors The ability of a compound of the formula (I), or a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the stereoisomer or prodrug, to bind to thyroid hormone receptors can be demonstrated in the following protocol.

A. Preparation of insect cell nuclear extracts High Five cell pellets (BTC-TN-5B1-4, catalog number B855-02, Invitrogen, Carlsbad, California) obtained approximately 48 hours after infection with baculovirus (GibcoBRL, Gaithersburg, Maryland) expressing each other TRβ or human TR2 are suspended in cold sample buffer (10 mM Tris, pH 8.0; 1 mM MgCl 2, 1 mM DTT, 0.05% Tween 20, 1 mM 4- (2-aminoethyl) -benzenesulfonyl fluoride, 25 ug / ml e leupeptin). After approximately 10 minutes of ice incubation, the suspension is homogenized by 20 strokes with a Dounce homogenizer (VWR Scientific Products, West Chester, Pennsylvania) and centrifuged at 800 x g for approximately 15 minutes at 4 ° C. The pellet (core) suspended in a hypertonic buffer (0.4 M KCl, 10 mM Tris, pH 8.0, 1 mM MgCl 2, 1 mM DTT, 0.05% Tween 20) and incubated for about 30 minutes on ice. The suspension is centrifuged at 100,000 x g for approximately 30 minutes at 4 ° C. The supernatant (nuclear extract) is stored in 0.5 ml aliquots at -80 ° C.

B. Binding Assay Competition binding assays for measuring the integration of compounds of formula (I) with thyroid hormone receptor a1 and β1 (TRa and TRβ) are carried out according to the following protocol. Solutions of the compounds of the formula (I), or the stereoisomers or prodrugs thereof, or the pharmaceutically acceptable salts of the stereoisomers or prodrugs (final compound concentration of 20 mM) are prepared using 100% DMSO as a solvent. The compound is serially diluted in a test buffer (5 mM Tris-HCl, pH 8.0; 50 mM NaCl; 2 mM EDTA; 10% glycerol (v / v); 1 mM DTT, "assay buffer") containing 0.4 nm 125 I-T3 (specific activity of approximately 2200 Ci / mmole) to produce solutions varying in compound concentration between about 10 uM and about 0.1 nM. A nuclear extract of High Five insect cells containing each other TRa or TRβ is diluted to a total protein concentration of 0.0075 mg / ml using the assay buffer as a diluent. One volume (100 μl) of each dilution of compounds of the formula (I) (containing 0.4 nM 125 I-T3) is combined with an equal volume (100 μl) of diluted nuclear extract containing TRa1 or TRβ1, and incubating at RT for approximately 90 min. a 150 ml sample of the binding reaction is removed and placed in a 96-well filter plate (Millipor, Bedford, Massachusetts) that has been pre-washed with cold assay buffer. The plate is subjected to vacuum filtration using a collector (Millipore®). Each well is washed five times by the addition of 200 μl of cold assay buffer and subsequent vacuum filtration. The plate is removed from the vacuum filtration collector, the bottom of the plate is briefly dried on paper towels, then 25 μl of the Wallac Optiphase Supermix scintillation cocktail (EG &G Wallac, Gaithersburg, Maryland) is added to each well. and the top of the plate is covered with a plastic sealing tape (Microplate Press-on Adhesive sealing Film, Packard Instrument Co., Inc., Downers grove, Illinois) and the radioactivity is quantified using a 96-plate scintillation counter. Wells Wallac Microbeta.

Claims (21)

NOVELTY OF THE INVENTION CLAIMS 1 .- A compound of the formula (I): (1) the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers, and prodrugs wherein:
1. W is oxygen, sulfur, -SO-, -S (0) 2, -CH2-, CF2-, -CHF-, -C (O) -, -CH (OH) -, - NR3, or -C (= CH2) -; R1, R2, R3 and R6 are each independently hydrogen, halogen, (C1-C12) alkyl, CF3, -OCF3, -O-alkyl (C? -8), or -CN; R4 is hydrogen, (C1-C12) alkyl- substituted with 0 to 3 substituents independently selected from the group V, (C2-C12) alkenyl, (C2-C12) alkynyl, halogen, CN, ORb, -SRC, -S ( 0) Rc, aryl, heteroaryl, (C3-C10) cycloalkyl, heterocycloalkyl, -S (0) 2 NRcRd, -C (0) NRcRd, -C (0) ORC, -NRaC (0) Rd, -NRaS (0) 2Rd, or -C (0) Rc; or R and R are taken together with the carbon atoms to which they are attached to form a carboxylic ring of the formula - (CH2) 1- or a heterocyclic ring of the formula (CH2) k-Q- (CH2) 1-where q is oxygen, sulfur, or -NRe-; i is 3, 4, 5, or 6; k is 0, 1, 2, 3, 4, or 5; and 1 is 0, 1, 2, 3, 4, or 5; and wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, -CN, phenyl, or -NR3R9; R5 is hydroxyl, alkyl-0 (C? -Cβ), -OC (0) Rf, fluorine, or -C (0) ORc, or R and R are taken together with the carbon atoms to which they are attached to form a heterocyclic ring selected from the group consisting of CR = CRa-NH-, -N = CRa-NH, -CR6-CRa-0-, -CRcCRa-S-, -CRC = N-NH-, and -CRa = CRa -CRa = N-; Ra for each occurrence is independently hydrogen, or -alkyl (Ci-Cß) substituted with zero to one -cycloalkyl (C3-C6) or methoxy; Rb for each occurrence is independently hydrogen, -alkyl (C2-C12) with zero to three substituents independently selected from the group V, aryl, heteroaryl, cycloalkyl (C3-C10), heterocycloalkyl, -C (0) NRcRd, or -C (0) Rf; R and R for each occurrence are each independently hydrogen, alkyl (C? -Ci2) -substituted with zero to three substituents independently selected from group VI, -alkenyl (C2-C12), alkynyl (C2-C12), aryl, heteroaryl, -cycloalkyl (C3-C10), or heterocycloalkyl; as long as R4 is the -SRC, -S (0) Rc, or -S (0) 2RC, Rc is different from hydrogen; or Rc and Rd are taken together with the atoms to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from oxygen, -NRC-, or sulfur, and wherein the heterocyclic ring selected of oxygen, -NRC-, or sulfur, and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, -CN, phenyl, or -NRaRg; Re for each occurrence is hydrogen, -CN, (C1-C10) alkyl substituted with zero to three substituents independently selected from the group V, alkenyl- (C2-C10), alkoxy (C2-C10), cycloalkyl (Ce-Cio) , aryl, heteroaryl, -C (0) Rf, -C (0) NRaRf, or -S (0) 2f; Rf for each occurrence is independently (C1-C10) alkyl substituted with zero to three substituents independently selected from the group VI, (C2-C12) alkenyl, (C2-C10) alkynyl, (C3-C10) cycloalkyl, aryl, heteroaryl, or heterocycloalkyl; R for each occurrence is independently hydrogen, alkyl (C Cß), alkenyl (C2-C6), aryl, -C (0) Rf, -C (0) Rf, -C (0) ORf, -C (0) NR3Rf , -S (0) 2Rf, or -cycloalkyl (C3-C8); the group V is halogen, -CF3, -OCF3, -OH, oxo, (C? -C6) alkoxy, -CN, aryl, heteroaryl, cycloalkyl (C3-C? o), heterocycloalkyl, -SR1, -S (0 ) Rf, -S (0) 2Rf, S (0) 2NRaRf, -NRaRg, or -C (0) NRaRf; Group VI is halogen, hydroxyl, oxo, -alkoxy (Ci-Ce), aryl, heteroaryl, (C3-C8) cycloalkyl, heterocycloalkyl, -CN, -OCF3; provided that R is (C1-C12) alkyl substituted with zero to three substituents independently selected from the group V wherein the substituent of group V is oxo, the oxo group is substituted on a carbon atom different from the carbon atom C1 in alkyl (C1-C12); aryl for each occurrence is independently phenyl or naphthyl substituted with zero to four substituents independently selected from halogen, (C? -C6) alkyl, -CN, -SRf, -S (0) Rf, -S (0) 2Rf, -cycloalkyl (C3-C6), S (0) 2NRaRf, -NRaR9, -C (0) NRaRf, -0Rb, prefluoro-C 1 -C 4 alkyl, or COORf; provided that the substituents on aryl are -SRf, -S (0) Rf, -S (0) 2Rf, -S (0) 2NRaRf, -NRaRg, -C (0) NRaRf, -ORb, or -COORf, substituents Rb, Rf and R9, are different from aryl or heteroaryl; heteroaryl for each occurrence independently a monocyclic or bicyclic ring of 5, 6, 7, 8, 9 members having from one to three heteroatoms selected from O, N, or S; wherein the bicyclic ring, a monocyclic heteroaryl ring is fused with a benzene ring or with another heteroaryl ring, and having zero to three substituents independently selected from halogen, - (C4) alkyl, -CF3, -ORb, -NRaR9 , or -COORf; so long as the substituents on heteroaryl on heteroaryl are -NRaR9, -ORb 'or -COORf, the substituents Rb, Rf, and Rc, are different from aryl or heteroaryl; 'heterocycloalkyl for each occurrence is independently a monocyclic or bicyclic cycloalkyl ring of 4,5,6,7,8, or 9, members having from one to three heteroatoms selected from oxygen, -NRa, or sulfur, and having zero to four substituents independently selected from -alkyl (C1-C4), -ORb, oxo, -CN, phenyl, or -NRaRg; and X is
2. 2. - A compound according to claim 1 wherein W is oxygen. 3. A compound according to claim 1 wherein: R1 is located in the 3-position and R2 are each independently hydrogen, alkyl- (C1-C6), halogen, or CN; R3 is hydrogen, (C1-C4) alkyl or halogen; R4 is (C1-C10) alkyl substituted with zero to three substituents independently selected from fluoro, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) 2NRcRd, -C (0) NRcRd, - S (0) 2RC, (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) Rc, -ORb, -SRC, S (0) Rc, -NRaC (0) Rd, NR3C (0) NRcRd, or -NRaS (0) 2Rd; or Rc and Rd are taken together with the atoms to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second selected heterogroup of oxygen, -NR-, or sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -ORb, oxo, -CN, phenyl, or -NRaRg; or R3 and R4 are taken together with the carbon atoms to which they are attached to form a carbocyclic ring of the formula - (CH2) - or a heterocyclic ring of the formula (CH2) kQ- (CH2) i- wherein Q is -O-, -S- or -NRC-; i is 3,4,5, or 6; k is 0.1, 2.
3. 3.4 or 5; and 1, 2,3,4, or 5; and wherein the carbocyclic ring and the heterocyclic ring are each substituted with zero to four substituents independently selected from -alkyl (C1-C4), -ORb, oxo, -CN, phenyl, or -NRaRg; provided that R 4 is (C 1 -C 10) alkyl substituted with zero to three substituents, the oxo group is substituted on a carbon atom other than the C 1 carbon atom in (C 1 -C 10) alkyl; R5 is -OC (0) Rf, -C (0) ORc, or -F; wherein RF is (C1-C10) alkyl substituted with zero to three substituents independently selected from Group VI; R6 is hydrogen, halogen or (C1-C4) alkyl; and X is
4. 4. - A compound according to claim 3 wherein, R1 and R2 are each independently hydrogen, (C1-C6) alkyl, halogen, or -CN; R3 is hydrogen; R4 is (C1-C10) alkyl substituted with zero to three substituents independently selected from fluoro, hydroxyl, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) NRcRd, -C (0) NRcRd , S (0) 2RC, (C3-C8) cycloalkyl, heterocycloalkyl, -C (0) Ra, -ORb, -SRC, -S (0) Rc, -NRaC (0) Rd, or -NRaS (0) 2Rd; or Rc and Rd are taken together with the atom (s) at which! they are joined to form a 3-10 membered heterocyclic ring which may optionally contain a second selected heterogroup of oxygen, NRC, sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -OR, oxo, -CN, phenyl, or -NRaRg; R5 is -OH, fluoro, or -OC (0) Rf wherein Rf is (C1-C10) alkyl substituted with zero to three substituents independently selected from group VI; and Rd is hydrogen,
5. 5. A compound according to claim 4 wherein, R1 and R2 are both methyl, bromo, or chloro; R4 is (C1-C10) alkyl, substituted with zero to 2 substituents independently selected from fluoro, hydroxide, oxo, aryl, heteroaryl, (C3-C8) cycloalkyl, or heterocycloalkyl, -S (0) 2RC, cycloalkyl (C3-C8) ), heterocycloalkyl, -C (0) Rc, -0Rb, -SRC, -NRaC (0) Rd, -NRaC (0) NRcRd, or -NRaS (0) 2Rd; or Rc and Rd are taken together with the atom (s) to which they are attached to form a 3-10 membered heterocyclic ring which may optionally contain a second heterogroup selected from oxygen, NRC-, or sulfur; and wherein the heterocyclic ring is substituted with zero to four substituents independently selected from (C1-C4) alkyl, -0R, oxo, -CN, phenyl, or -NRaRg; and R5 is -OH.
6. 6. A compound selected from the group consisting of: 5- [3,5-dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) -benzyl] -thiazole-2,4-dione; 5- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-benzylidene] -thiazolidine-2,4-dione 5- [4- (4-hydroxy-3-isopropyl-phenoxy !) -3,5-dimethyl-benzyl-thiazole-2,4-dione; N-cyclopropyl! -5- [2,6-dichloro-4- (2,4-dioxo-thiazolidin-5-ylmethyl] -phenoxy] -2-hydroxy-benzenesulfonamide; N-cyclobutyl-5- [2,6-dichloro- 4- (2,4-dioxo-thiazolidin-5-ylmethyl) -phenoxy] -2-hydroxy-N-methyl-benzamide; 2- [3,5-dichloro-4- (4-hydroxy-3-isopropyl-phenoxy) - benzyl] - [1, 2,4] oxadiazolidine-3,5-dione; 2- [4- (3-isopropyl-4-methoxy-phenoxy) -3,5-dimethyl-benzyl] - [1, 2.4 ] oxadiazolidine-3,5-dione; 2- [4- (4- (hydroxy-3-ysopropyl-phenoxy) -3,5-dimethyl-benzyl] - [1,4] oxadiazolidine-3 , 5-dione, and 5- [4- (4-hydroxy-3-isopropyl-phenoxy) -3,5-dimethyl-phenyl] -2,4-dihydro- [1,4] triazole-3-ion , the stereoisomers and prodrugs thereof, and the pharmaceutically acceptable salts of said compounds, stereoisomers, and prodrugs
7. 7. The use of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt. of said compound, stereoisomer or prodrug, as defined in claim 1 for the manufacture of a medicament for treating a on condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, hypercholesterolemia, depression and osteoporosis , in a mammal.
8. 8. The use of a compound as claimed in claim 7 wherein said condition is obesity.
9. 9. The use of a compound as claimed in claim 7 wherein said condition is diabetes.
10. 10. The use of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined in claim 1 for the manufacture of a medicament for inducing Weight loss in a mammal.
11. 11. - The use of a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined in claim 1 for the manufacture of a medicament for increasing consumption of energy in a mammal.
12. 12. The use of: 1) a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined in claim 1; and 2) an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension , coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis for the manufacture of a medicament for treating a patient who has, or at risk of having, a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis.
13. 13. The use of a compound as claimed in claim 12 wherein said condition is obesity. 4
14. 14. - The use of a compound as claimed in claim 12 wherein said additional compound is a lipid inhibitor.
15. 15. The use of a compound as claimed in claim 14 wherein said lipase inhibitor is selected from the group consisting of lipstatin, tetrahydrolipstatin, FL-386, WAY-121898, Bay-N-3176, valilactone , esterastine, ebelactone A, ebelactone B and RHC 80267
16. 16. The use of a compound as claimed in claim 12 wherein said additional compound is an anorectic agent.
17. 17. The use of a compound as claimed in claim 16 wherein said anorectic agent is selected from the group consisting of phentermine, sibutramine, fenfluramine, dexfenfluramine and bromocriptine.
18. 18. A pharmaceutical composition comprising a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, as defined in claim 1.
19. 19. A kit to treat a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, coronary heart disease, heart failure congestive, hypercholesterolemia, depression and osteoporosis, wherein said kit comprises: a) a first pharmaceutical composition comprising a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of the compound, stereoisomer or prodrug, as defined in claim 1; b) a second pharmaceutical composition comprising an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes , atherosclerosis, hypertension, coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis; and c) a container.
20. 20. A pharmaceutical composition comprising a compound of the formula (I), a stereoisomer or prodrug thereof, or a pharmaceutically acceptable salt of said compound, stereoisomer or prodrug, as defined in claim 1; and an additional compound useful for treating a condition selected from the group consisting of obesity, overweight condition, hyperlipidemia, glaucoma, cardiac arrhythmias, skin disorders, thyroid disease, hypothyroidism, cancer of the thyroid gland, diabetes, atherosclerosis, hypertension, disease coronary heart disease, congestive heart failure, hypercholesterolemia, depression and osteoporosis.
21. 21. A composition according to claim 20 wherein said condition is obesity.