MXPA00009622A - Bicyclic pyrrolyl amides as glycogen phosphorylase inhibitors - Google Patents

Abstract

This invention relates to compounds of Formula I or stereoisomers, pharmaceutically acceptable salts or prodrugs thereof or pharmaceutically acceptable salts of the prodrugs. This invention also relates to pharmaceutical compositions comprising a compound of Formula I, and to methods of treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hyperglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis, or tissue ischemia.

Description

BIOLOGICAL PYROLYLAMIDES AS INHIBITORS OF GLUCOGEN PHOSPHORYLASE FIELD OF THE INVENTION This invention relates to bicyclic pyrrolylamides and pharmaceutical compositions comprising bicyclic pyrrolylamides. This invention also relates to the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiukaemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis and tissue ischemia, in particular myocardial ischemia, using the bicyclic pyrrolyl amides.

BACKGROUND OF THE INVENTION Despite the early discovery of insulin and its subsequent widespread use in the treatment of diabetes, and the subsequent discovery and use of sulfonylureas, biguanides and thiazolidenediones, such as troglitazone, rosglitazone or pioglitazone, as hypoglycaemic oral agents, the treatment of diabetes continues to be unsatisfactory. The use of insulin requires several daily doses, usually by autoinjection. The determination of the correct dose of insulin requires frequent estimates of sugar in urine or blood. The administration of an excessive dose of insulin causes hypoglycemia, with effects ranging from mild abnormalities in blood glucose to coma, or even death. The treatment of non-insulin-dependent diabetes mellitus (Type II diabetes, NIDDM) usually consists of a combination of diet, exercise, oral hypoglycaemic agents, for example, thiazolidenediones and, in the most severe cases, insulin. However, clinically available hypoglycemic agents may have side effects that limit their use, or an agent may not be effective with a particular patient. In the case of insulin-dependent diabetes mellitus (Type I), insulin is usually the main course of therapy. Hypoglycemic agents that have fewer side effects or that are successful when others do not have it are necessary. Atherosclerosis, a disease of the arteries, is known to be the leading cause of death in the United States and Western Europe. The pathological sequence that leads to atherosclerosis and occlusive heart disease is well known. The first stage in this sequence is the formation of "fatty deposits" in the carotid, coronary and cerebral arteries and in the aorta. These lesions are yellow due to the presence of lipid deposits found mainly within the smooth muscle cells and in the macrophages of the intima of the arteries and the aorta. Furthermore, it is believed that most of the cholesterol found in fatty deposits, in turn leads to the development of the "fibrous plaque" which is composed of accumulated smooth muscle cells of the intimate lipid-laden and surrounded by extracellular lipid, Collagen, elastin and proteoglycans. The cells plus the matrix form a fibrous plug that covers a deeper deposit of cellular debris and more extracellular lipids. Lipids are essentially free cholesterol and esterified. The fibrous plaque forms slowly, and probably with time it calcifies and undergoes necrosis, advancing to the so-called "complicated lesion", which justifies the arterial occlusion and the tendency towards mural thrombosis and the spasm of the muscle of the arteries that characterizes the advanced atherosclerosis. Epidemiological evidence has strongly established hyperlipidemia as a primary risk factor causing cardiovascular disease (CVD) due to atherosclerosis. In recent years, the leaders of the medical profession have placed a renewed emphasis on lowering plasma cholesterol levels and, in particular, cholesterol associated with low density lipoproteins, as a fundamental step in the prevention of CVD. There are now known "normal" upper limits that are significantly lower than those previously known. As a result, large segments of the Western population are realizing that they are at particularly high risk. Such independent risk factors include glucose intolerance, left ventricular hypertrophy, hypertension and being male. Cardiovascular disease is especially prevalent among diabetic subjects, at least in part due to the existence of several independent risk factors in this population. The treatment of hyperlipidemia is of exceptional medical importance in the general population and, in particular, in diabetic subjects. Hypertension (or high blood pressure) is a disorder that occurs in the human population as a secondary symptom to other disorders such as renal artery stenosis, pheochromocytoma or endocrine disorders. However, hypertension is also evident in many patients in whom the causative agent or disorder is unknown. Although said "essential" hypertension is frequently associated with disorders such as obesity, diabetes and hypertriglyceridemia, the relationship between these disorders has not been determined. In addition, many patients have symptoms of high blood pressure in a total absence of any other sign of disease or disorder. It is known that hypertension can lead directly to heart failure, to renal failure and to stroke (cerebral hemorrhage). These disorders can cause death in a patient. Hypertension also contributes to the development of atherosclerosis and coronary heart disease. These disorders gradually weaken a patient and can 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, unregulated hormonal release (renin, angiotensin, aldosterone system), excessive salts and water due to renal dysfunction, hardening and hypertrophy of the vasculature wall causing clogged blood vessels and genetic factors. The treatment of essential hypertension has been carried out taking into account the above factors. Thus, a wide range of beta-blockers, vasoconstrictors, angiotensin converting enzyme inhibitors and similar agents have been developed and marketed as antihypertensives. The treatment of hypertension using these compounds has been shown to be beneficial in the prevention of short-term death such as heart failure, kidney failure and cerebral hemorrhage. However, the development of atherosclerosis or heart disease due to hypertension for a long period of time remains a problem. This implies that although high blood pressure is reduced, the underlying cause of essential hypertension does not respond to this treatment. Hypertension has been associated with high levels of insulin in the blood, a condition known as hyperinsulinemia. Insulin, a peptide hormone whose main functions are to promote the use of glucose, protein synthesis and the formation and storage of neutral lipids, also acts to promote vascular cell growth and increases renal sodium retention, among other things. These latter functions can be carried out without affecting glucose levels and are known causes of hypertension. The growth of the peripheral vasculature, for example, can cause the constriction of the peripheral capillaries while the retention of sodium increases the volume of blood. Thus, the decrease in insulin levels in hyperinsulinemic drugs can prevent abnormal vascular growth and renal sodium retention caused by high insulin levels and, therefore, relieve hypertension. Cardiac hypertrophy is a significant risk factor in the development of sudden death, myocardial infarction and congestive heart failure. These cardiac events are due, at least in part, to an increased susceptibility to myocardial injury after ischemia and reperfusion that may occur in outpatients, as well as in perioperative situations. There is a medical need not covered to prevent or minimize adverse myocardial perioperative events, in particular, perioperative myocardial infarction. Both noncardiac and cardiac surgery are associated with substantial risks of myocardial infarction or death. Approximately 7 million patients who undergo non-cardiac surgery are considered at-risk population, with incidences of perioperative death and serious cardiac complications of up to 20-25% in some series. In addition, of the 400,000 patients who undergo coronary bypass surgery each year, it is estimated that perioperative myocardial infarction occurs in 5% and death in 1 to 2%. There is currently a drug therapy not marketed in this area that reduces damage to cardiac tissue due to perioperative myocardial ischemia or that improves resistance to ischemic episodes. It is believed that such therapy will save lives and reduce hospitalizations, improving the quality of life and reducing the overall costs of care for high-risk patients. The mechanism (s) responsible for the myocardial injury observed after ischemia and reperfusion is not fully understood. It has been described (MF Allard, et al., Am. J. Physiol., 267: H66-H74 (1994)) that "the reduction of glycogen prior to ischemia ... is associated with a functional recovery of the ventricle. left after improved ischemia in hypertrophic rat hearts. " In addition to myocardial ischemia, other tissues may suffer ischemia and be damaged, causing serious problems for the patient. Examples of such tissues include cardiac, cerebral, hepatic, pulmonary, intestinal, skeletal muscle, spleen, pancreatic, nervous, spinal cord, retinal tissue, vasculature or intestinal tissue. Hepatic glucose production is an important target for NIDDM therapy (Non-Insulin Dependent Diabetes Mellitus). The liver is the main regulator of plasma glucose levels in the postabsorbent state (fasting) and the rate of hepatic glucose production in NIDDM patients is significantly elevated with respect to normal individuals. Likewise, in the postprandial (fed) state, when the liver performs a proportionally lower function in the total plasma glucose supply, the hepatic glucose production is abnormally high in NIDDM patients. Glycogenolysis is an important goal for the interruption of hepatic glucose production. The liver produces glucose by glycogenolysis (decomposition of the glycogen polymer into glucose) and gluconeogenesis (synthesis of glucose from 2 and 3 carbons precursors). Some lines of evidence indicate that glucogenolisis may have an important contribution in the production of hepatic glucose in NIDDM. First, it is estimated that in men in normal post-absorbent state, up to 75% of the production of hepatic glucose originates from glycogenolysis. Secondly, patients suffering from diseases related to hepatic glycogen storage, including Hert's disease (deficiency of glycogen phosphorylase), present episodes of hypoglycaemia. These observations suggest that glycogenolysis may be a significant process for the production of hepatic glucose. Glycogenolysis is catalyzed in the liver, muscle and brain by tissue-specific isoforms of the enzyme glycogen phosphorylase. This enzyme breaks the glycogen macromolecule by releasing glucose-1-phosphate and a new shorter glycogen macromolecule. To date, several types of glycogen phosphorylase inhibitors have been described: glucose and glucose analogues [Martin, J. L et al., Biochemistry, 30: 10101 (1991)]; caffeine and other purine analogs [Kasvinsky, P. J ef al., J. Biol. Chem., 253: 3343-3351 and 9102-9106 (1978)]; N- (indol-2-carbonyl) -amides substituted [PCT publication number WO 96/39385]; and N- (indole-2-carbonyl) -substituted glycinamide (PCT publication number WO96 / 39384) These compounds and glycogen phosphorylase inhibitors in general have been described as being useful for the treatment of NIDDM by reducing the production of hepatic glucose and lowering blood glucose [Blundell, TB et al., Diabetologia, 35, Suppl 2, 569-576 (1992) and Martin et al., Biochemistry, 30, 10101 (1991)]. The myocardial ischemic lesion It can occur in outpatients as well as in perioperative situations and can lead to the development of sudden death, myocardial infarction or congestive heart failure.There is an unmet medical need to prevent or minimize ischemic injury in the myocardium, in particular, Perioperative myocardial infarction.This therapy is expected to save lives and reduce hospitalizations, improving the quality of life and reducing the total costs of patient care and treatment. High-risk patients Although there are a variety of therapies for hyperglycemia, hypercholesterolemia, hypertension, hyperlipidemia, atherosclerosis and ischemia of tissues, there is a continuing need and a continuous search in this field for the technique of alternative therapies.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides compounds of its stereoisomers, pharmaceutically acceptable salts and prodrugs, and pharmaceutically acceptable salts of the prodrugs, wherein Q is aryl, substituted aryl, heteroaryl or substituted heteroaryl; each of Z and X is independently (C, CH or CH2), N, O or S; X1 is NRa, -CH2-, O or S; each - is, independently, a link or is not present, with the proviso that both - are not simultaneously links; R1 is hydrogen, halogen, -O (Ci-Cß alkyl), -S (C?-C_ alkyl) - (C?-C 8 alkyl), -CF 3, -NH 2, -NH (CrC 8 alkyl), -N- ( C? -C8 alkyl) 2, -NO2, -CN, -CO2H, -CO2 (C8 alkyl), - (C2-C8 alkenyl) or (C2-C8 alkynyl); each of Ra and R is independently hydrogen or-CrC8 alkyl; And it is and C- 0H or it is not present; H R2 and R3 are independently hydrogen, halogen,-C8 alkyl, -CN, -C = C-Si (CH3) 3, -O (C8 alkyl), -S (C8 alkyl), -CF3, -NH2 , -NH (C8 alkyl, -N (CrC8 alkyl) 2, -NO2, -CO2H, -CO2 (C8 alkyl), - (C2-C8 alkenyl) or - (C2-C8 alkynyl), or R2 and R3 together with the atoms on the ring to which they are attached form a five or six member ring containing 0 to 3 heteroatoms and 0 to 2 double bonds: R4 is -C (= O) A; A is -NRdRd, -NRaCH2CH2ORa, every R > d is independently hydrogen, CrC8 alkyl, C?-C8 alkoxy, aryl, substituted aryl, heteroaryl or substituted heteroaryl; each Rc is independently hydrogen, -C (= O) ORa, -ORa, -SRa or -NRaRa;; and each n is independently from 1 to 3. In a preferred embodiment of the compounds of Formula I, Rb and R1 are hydrogen. In another preferred embodiment of the compounds of Formula I, R is hydrogen; R1 is hydrogen; and A is In another preferred embodiment of the compounds of Formula I, R is hydrogen; R1 is hydrogen; And it is not present; and A is In another preferred embodiment of the compounds of Formula I, Rb is hydrogen; R1 is hydrogen; Z is C; X is O or S; And it is not present; A is R2 is hydrogen; and R3 is hydrogen; halogen or methyl. In another preferred embodiment of the compounds of Formula I, Q is phenyl and A is In another preferred embodiment, the invention provides compounds of Formula I the stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and the pharmaceutically acceptable salts of the prodrugs, wherein Q is phenyl; (Z is S and X is C), (Z is C and X is S) or (Z is C and X is O); each - is, independently, a link or is not present, with the proviso that both - are not simultaneously links; R1 is hydrogen or halogen; each of Ra and Rb is independently hydrogen or alkyl of C? -C8; And it is and C- 0H or it is not present; H R2 and R3 are independently hydrogen, halogen, -alkyl C C8, -CN, -C = CSi (CH3) 3 or - (C2-C8 alkynyl), or R2 and R3 together with the atoms on the ring to which they are joined they form a ring of five or six members containing from 0 to 3 heteroatoms and from 0 to 2 double bonds; R 4 is -C (= O) -A; A is -NRdRd, each Rd is independently C 8 alkyl; each Rc is independently hydrogen, -OH or -C (= O) - O (CrC8 alkyl); each n is independently from 1 to 3.

In another preferred embodiment of the compounds of Formula I, Also provided are pharmaceutical compositions comprising a compound of Formula I, the stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. Also provided are methods for treating or preventing atherosclerosis, the methods comprising the step of administering to a patient suffering from atherosclerosis or having a risk of atherosclerosis, a therapeutically effective amount of a compound of Formula I, the stereoisomers, pharmaceutically acceptable salts, prodrugs. thereof and pharmaceutically acceptable salts of the prodrugs. Procedures are also provided to treat diabetes, the methods comprising the step of administering to a patient suffering from diabetes, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and the pharmaceutically acceptable salts of the prodrugs. In a preferred embodiment of the methods for treating diabetes, diabetes is non-insulin-dependent diabetes mellitus (Type II). In a preferred embodiment of the methods for treating diabetes, diabetes is insulin-dependent diabetes mellitus (Type I). Methods for treating insulin resistance are also provided, the methods comprising the step of administering to a patient suffering from insulin resistance, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and the prodrugs of the invention. same and the pharmaceutically acceptable salts of the prodrugs. Methods for treating diabetic neuropathy are also provided, the methods comprising the step of administering to a patient suffering from diabetic neuropathy, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and the prodrugs thereof. pharmaceutically acceptable salts of the prodrugs. Methods for treating diabetic nephropathy are also provided, the methods comprising the step of administering to a patient suffering from diabetic nephropathy, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and the prodrugs thereof. pharmaceutically acceptable salts of the prodrugs. Methods for treating diabetic retinopathy are also provided, the methods comprising the step of administering to a patient suffering from diabetic retinopathy, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and the pharmaceutically acceptable salts of the prodrugs. Methods for treating cataracts are also provided, the methods comprising the step of administering to a patient suffering from cataracts, a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically salts acceptable of the prodrugs. Methods for treating or preventing hypercholesterolemia are also provided, the methods comprising the step of administering to a patient suffering from hypercholesterolemia or having a risk of suffering from hypercholesterolemia, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs.

Methods for treating or preventing hypertriglyceridemia are also provided, the methods comprising the step of administering to a patient suffering from hypertriglyceridemia or having a risk of suffering from hypertriglyceridemia, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. Methods for treating or preventing hyperlipidemia are also provided, the methods comprising the step of administering to a patient suffering from hyperlipidemia or at risk of suffering from hyperlipidemia, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. Methods for treating or preventing hypergiukaemia are also provided, the methods comprising the step of administering to a patient suffering from hypergiukaemia or having a risk of suffering from hypergiukaemia, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. Methods for treating hypertension are also provided, the methods comprising the step of administering to a patient suffering from hypertension or having a risk of hypertension, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and the prodrugs thereof and the pharmaceutically acceptable salts of the prodrugs. Methods for treating or preventing tissue ischemia are also provided, the methods comprising the step of administering to a patient suffering from ischemia of tissues or at risk of ischemia of tissues, a therapeutically effective amount of a compound of Formula I, the stereoisomers, the pharmaceutically acceptable salts and the prodrugs thereof and the pharmaceutically acceptable salts of the prodrugs. Methods for treating or preventing myocardial ischemia are also provided, the methods comprising the step of administering to a patient suffering from myocardial ischemia or at risk of myocardial ischemia, a therapeutically effective amount of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and prodrugs thereof and pharmaceutically acceptable salts of the prodrugs. Methods for inhibiting glycogen phosphorylase are also provided, the methods comprising the step of administering to a patient in need of inhibition of glycogen phosphorylase, an amount which inhibits glycogen phosphorylase of a compound of Formula I, stereoisomers, pharmaceutically acceptable salts and the prodrugs thereof and the pharmaceutically acceptable salts of the prodrugs. The present invention provides the compounds: [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxo-propyl] -amide of 6H-thieno acid [ 2,3-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl-amide of 2-bromo-6H-thieno [2,3-b] pyrrol- 5-carboxylic; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - 2-methyl-6H-thieno [2,3-b] - (2R) -hydroxy-3-oxopropyl] -amide ] pyrrole-5-carboxylic acid; [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] amide of (±) -2-methyl-6H-thieno [2,3-b] pyrrol- 5-carboxylic; 2-bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl-amide of 2-chloro-6H-thieno [2,3-b] pyrrole -5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] 2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl-amide of 2,4-dichloro-6H-thieno [2,3] -b] pyrrole-5-carboxylic acid; (1) -4H-thieno [3,2-b] pyrrole-5-carboxylic acid [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxo-ethyl] -amide; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-bromo-4H-thieno [3,2-b] ] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 4 H -thieno [3,2-b] pyrrole-5 -carboxylic; [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] amide of (±) -2-bromo-4H-furo [3,2-b] pyrrol- 5-carboxylic; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl-amide of 2-bromo-4H-furo [3,2-b] pyrrole -5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 6-H-thieno [2,3-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide-2-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2,4-dichloro-6H-thieno [2,3-b] pyrrole-5 -carboxylic; 2-Cyano-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1 S) -benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -dimethylcarbamoyl-2-phenylethyl] -amide; [(1S) -Benzyl-2- (1, 1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide of 2-chloro-6H-thieno [2,3-b] pyrrole -5-carboxylic acid; Ethyl ester of acid 1-. { (2S) - [(2-chloro-6H-thieno [2, 3-b] pyrrole-5-carbonyl) amino] -3-phenylpropionyl} piperidine-4-carboxylic acid; 2-bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyazetin-1-yl] -2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide-2-methyl-4H-furo [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide of 2-trimethylsilanylethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid; 2-ethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] 2-fluoro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; 2-Cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxy-azetidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-chloro-4H-furo [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl-jamide of 2-chloro-4H-furo [3,2-b] pyrrole -5-carboxylic acid; Acid 1-. { (2S) - [(2-chloro-6H-thieno [2,3-b] pyrrole-5-carbonyl) amino] -3-phenylpropionyl} -piperidine-4-carboxylic acid; 3-Chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-3 - ((3R, 4S) -Dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 3-chloro-4H-thieno [3,2-] b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 3-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -Dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 3-bromo-4H-thieno [3,2-b] ] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl-amide of 2-chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-chloro-4H-thieno [3,2-b] pyrrole-5-acid -carboxylic; [(1 S) -Benzyl-2 - ((3R, 4S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 3-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid : [(1S) -Benzyl-3 - ((3R, 4S) -Dihydroxypyrrolidol-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide 3-methyl-4H -thien [3,2-b] pyrrole-5-carboxylic acid; 2-cyano-4H-thieno [3,2-b] -5-carboxylic acid [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-cyano-4H-furo [3,2-] b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 3-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid co; [(1 S) -Benzyl-3 - ((3R, 4S) -Dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 3-bromo-4H-furo [3,2-] b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 4H-1,7-dithia-4-azacyclopenta [ a] pentalen-5-carboxylic; [(1 S) -Benzyl-2 - ((3R, 4S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 4 H -1,7-dithia-4-azacyclopenta [a] pentalene-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-chloro-3-methyl-4H-thieno [3,2-b] pyrrole -5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -Dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-chloro-3-methyl-4H-thieno [ 3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -Dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide-2-methylsulfanyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2- (1, 1-dioxo-1-thiazolidin-3-yl) -2-oxoethyl] -amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; 2-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; 2-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1 S) -Benzyl-2 - ((3S, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide; and [(1S) -Benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5 acid -carboxylic acid, and stereoisomers, pharmaceutically acceptable salts and prodrugs thereof, and pharmaceutically acceptable salts of prodrugs. Cases are also provided for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy or cataracts in a patient suffering from diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, retinopathy diabetic or cataracts, the kits comprising: a) a first pharmaceutical composition comprising a compound of formula I, the stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of the prodrugs; b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy or cataracts; and c) a container for containing the first and second compositions. In a preferred embodiment of the kits, the second compound is selected from: insulin and insulin analogues; GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) -NH2; sulfonylureas and the like; biguanides; a2-antagonists; imidazolines; glitazones (thiazolidenediones); PPAR-gamma agonists; inhibitors of fatty acid oxidation; a-glucosidase inhibitors; β-agonists; Phosphodiesterase inhibitors; agents that reduce lipid levels; anti-obesity agents; vanadate, vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; inhibitors of gluconeogenesis; analogues and antagonists of somatostatin; and antilipolytic agents. In another preferred embodiment of the kits, the second compound is selected from insulin LysPro, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36) -NH2, chlorpropamide, glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide, meglitinide, metformin, phenformin, buformin, midaglizol, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir, etomoxir, acarbose, miglitol, emiglitato, voglibosa, MDL-25,637, camiglibosa, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, L-386,393; benfluorex, fefluramine, Naglivan®, acipimox, WAG 994, Symlim ™, AC2993 and nateglinide. In another preferred embodiment of the kits, the second compound is selected from insulin, sulfonylureas, biguanides and thiazolidinediones. Cases are also provided for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia in a patient suffering from diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycaemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia, the kits comprising: a ) a first pharmaceutical composition comprising a compound of formula I, the stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of the prodrugs; b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia; and c) a container for containing the first and second compositions. Procedures are also provided to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia. of the tissues, the method comprising the step of administering to a patient suffering from diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia of tissues , an effective amount of a compound of formula I, the stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of the prodrugs, combined with at least one other compound useful for the treatment of diabetes, resistance to insulin, neuropa diabetic aunt, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia. Also provided are pharmaceutical compositions comprising a compound of formula I, the stereoisomers, pharmaceutically acceptable salts and prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of the prodrugs and at least one other compound useful for treating diabetes, resistance to insulin, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycaemia, hypercholesterolemia, hypertension, hyperinsulinism, hyperlipidemia, atherosclerosis or tissue ischemia.

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to compounds of formula I, to the stereoisomers of the compounds of formula I, the pharmaceutically acceptable salts of the compounds of formula I and the prodrugs of the compounds of formula I and the pharmaceutically acceptable salts of the prodrugs of the compounds of formula I. The invention also relates to methods for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypoglycaemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia, in particular, myocardial ischemia, and pharmaceutically acceptable compositions comprising a compound of formula I, the stereoisomers of compounds of formula I, the pharmaceutically acceptable salts of the compounds of formula I and the prodrugs of the compounds of formula I and pharmaceutically acceptable salts of the prodrugs of the compounds of formula I.

Here are some terms that are used in this application. The term "alkyl" means a straight or branched chain hydrocarbon. Representative examples of alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, urea-butyl, sec-butyl, pentyl and hexyl. Preferred alkyl groups are C?-C8 alkyl. The term "alkoxy" means an alkyl group attached to an oxygen atom. Representative examples of alkoxy groups include methoxy, ethoxy, urea-butoxy, propoxy and isobutoxy. Preferred alkoxy groups are Cr Cß alkoxy. The term "halogen" means chlorine, fluorine, bromine or iodine. The term "alkenyl" means a straight or branched chain hydrocarbon having one or more carbon-carbon double bonds. The term "alkynyl" means a straight or branched chain hydrocarbon having one or more triple carbon-carbon bonds. The term "cycloalkyl" means a cyclic hydrocarbon. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and cycloheptyl. Preferred cycloalkyl groups are C3-C8 cycloalkyl. It is also possible for the cycloalkyl group to have one or more double bonds, but it is not aromatic. Examples of cycloalkyl groups having double bonds include cyclopentenyl, cyclohexenyl, cyclohexadienyl, cyclobutadienyl and similar groups.

The term "perfluoroalkyl" means an alkyl group in which all the hydrogen atoms have been replaced by fluorine atoms. The term "acyl" means a group derived from an organic acid (-COOH) by the elimination of a hydroxy group (-OH). The term "aryl" means a cyclic aromatic hydrocarbon.

Examples of aryl groups include phenyl and naphthyl. The term "heteroatom" includes oxygen, nitrogen, sulfur and phosphorus. The term "heteroaryl" means a cyclic aromatic hydrocarbon in which one or more carbon atoms have been replaced by a heteroatom. If the heteroaryl group contains more than one heteroatom, the heteroatoms may be identical 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 the five- or six-membered rings and contain from one to three heteroatoms. The term "heterocycloalkyl" means a cycloalkyl group in which one or more of the carbon atoms have been replaced by a heteroatom. If the heterocycloalkyl group contains more than one heteroatom, the heteroatoms may be the same or different. Examples of heterocycloalkyl groups include tetrahydrofuryl, morpholinyl, piperazinyl, piperadyl and pyrrolidinyl. Preferred heterocycloalkyl groups are the five or six membered rings and contain from one to three heteroatoms. It is also possible that the heterocycloalkyl group has one or more double bonds, but not aromatics. Examples of herocycloalkyl groups containing double bonds include dihydrofuran and the like. It will be appreciated that the cyclic ring, i.e., aryl, heteroaryl, cycloalkyl, heterocycloalkyl groups may comprise more than one ring. For example, the naphthyl group is a fused bicyclic ring system. It is also intended that the present invention include groups of rings having bridged atoms, or groups of rings having a spiro orientation. 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, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl and pyrazinyl. Representative examples of five to eight partially saturated, fully saturated or fully unsaturated members having one to three heteroatoms are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and phenyl. Other example five-membered 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-oxadiazolyl, 1,4-oxadiazolyl, 1, 2,5-oxadioazolyl 1, 3,4-oxadiazolyl, 1, 2,3-triazolyl, 1,4-triazolyl, 1,4-thiadiazolyl, 3H-1, 2,3-dioxazolyl, 1,4-dioxazolyl , 1,2-dioxazolyl, 1,4-dioxazolyl, 5H-1, 2,5-oxathiazolyl and 1,3-oxathiolyl. Other example rings of six members are 2H-pyranyl, 4H-pyranyl, pyridinyl, piperidinyl, 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, 2,3-triazinyl, 1, 3,5-trityanyl, 4H-1,2-oxazinyl, 2H-1, 3 -oxazinyl, 6H-1, 3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl, 4H-1,4-oxazinyl, 1, 2,5-oxathiazinyl, , 4-oxazinyl, o-isoxazinyl, p-isoxazinyl, 1, 2,5-oxathiazinyl, 1, 2,6-oxathiazinyl and 1,4,2-oxadiazinyl. Other example rings of seven members are azepinyl, oxepinyl, thiepinyl and 1,4-triazepinyl. Other example rings of eight members are cyclooctyl, cyclooctenyl and cyclooctadienyl. Example bicyclic rings comprising two rings of five and / or six condensed partially saturated, fully saturated or totally unsaturated, taken independently, optionally having from one to four heteroatoms are indolizinyl, indolyl, isoindolyl, indolinyl, cyclopenta (b) pyridinyl, pyran (3,4-b) pyrrolyl, benzofuryl, isobenzofuryl, benzo (b) thienyl, benzo (c) thienyl, 1 H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzoimidazolyl, benzothiazolyl, purinyl, quinolinyl, isoquinolinyl, cinolinyl, phthalazinyl , quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl, 2H-1-benzopyranyl, pyrido (3,4-b) -pyridinyl, pyrid (3,2-b) pyridinyl, pyrido (4,3-b) -pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl and 4H-1,4-benzoxazinyl. A cyclic ring group may be linked to another group in various ways. If the particular binding arrangement is not specified, then all possible arrangements are contemplated. 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 or an organic molecule has been replaced by a different atom or molecule. The atom or molecule that replaces the hydrogen atom is called a substituent. Examples of suitable substituents include halogens, -O- (CrC8 alkyl), - (CrC8 alkyl), -CF3, NH2, -NH (C8 alkyl), -N (C -? - C8 alkyl) 2, -NO2, -CN, -CO2H, - CO2 (C -? - C8 alkyl) and similar groups. The symbol "-" represents a covalent bond. The term "therapeutically effective amount" means an amount of compound that alleviates, attenuates or eliminates one or more symptoms of a particular disease or disorder or prevents or delays the onset of one or more symptoms of a particular disease or disorder. The term "patient" means animals, such as dogs, cats, cows, horses, sheep and humans. Particularly preferred patients are mammals. The term patient includes both sexes.

The term "pharmaceutically acceptable" means that the carrier, diluent, excipients and / or salt should be compatible with the other ingredients of the formulation and not be detrimental to the patient. The terms "a compound of the present invention, compounds of the present invention, a compound of formula I, or a compound according to formula I" and similar expressions, include the stereoisomers of the compound (s), prodrugs of the compound (s) and pharmaceutically acceptable salts of the prodrugs. The terms "solvent inert to the reaction" or "inert solvent" refer to a solvent or mixture of solvents that do not interact with the starting materials, reactants, intermediates or products in a manner that adversely affects the desired product. The terms "treat", "treatment" or "treatment" include preventive (for example, prophylactic) and palliative treatment. The term "glycogen phosphorylase inhibitor" refers to any substance or agent or any combination of substances and / or agents that reduces, delays or eliminates the enzymatic action of glycogen phosphorylase. The enzymatic action currently known for glycogen phosphorylase is the degradation of glycogen by catalysis of the reversible reaction of a macromolecule of glycogen and inorganic phosphate to glucose-1-phosphate and a glycogen macromolecule which is a glucosyl residue lower than the macromolecule of original glycogen (in the direction of advancement of gluconeogenesis).

A patient in need of inhibition of glycogen phosphorylase is a patient suffering from a disease or disorder in which glycogen phosphorylase plays a role in the disease or disorder. Example of patients who need inhibition of glycogen phosphorylase include patients suffering from diabetes (including type I diabetes, type II, reduced glucose tolerance, insulin resistance and diabetic complications such as nephropathy, hypertension, hyperinsulinemia , Hyperlipidemia, Atherosclerosis and Ischemia of the Tissues The characteristics of patients at risk of atherosclerosis are well known to those skilled in the art and include patients who have a family history of cardiovascular disease, including hypertension and atherosclerosis. , patients who are obese, patients who do little exercise, patients with hypercholesterolemia, patients who have high levels of low density lipoproteins (LDL), patients who have reduced levels of high density lipoproteins (HDL) and the like. myocardial ischemia and other ischemia in tissues also They are well known to those skilled in the art and include patients who undergo or have undergone surgery, trauma or great stress. The compounds of the present invention are administered to a patient in a therapeutically effective amount. The compounds can be administered alone or as part of a pharmaceutically acceptable composition or formulation. In addition, the compounds or compositions can be administered at one time, such as by a large injection, several times, such as by a series of tablets or released substantially uniformly over a period of time, as for example, using transdermal release. It will be appreciated that the dose of the compound can be varied over time. In addition, the compounds of the present invention can be administered alone, combined with other compounds of the present invention or with other pharmaceutically active compounds. The other pharmaceutically active compounds can be used to treat the same disease or disorder as the compounds of the present invention or a different disease or disorder. If the patient is going to receive or is receiving several pharmaceutically active compounds, the compounds can be administered simultaneously or sequentially. For example, in the case of tablets, the active compounds can be in a tablet or in separate tablets, which can be administered at the same time or sequentially in any order. In addition, it will be appreciated that the compositions may be different shapes. For example, one or more compounds can be administered by one tablet that another is administered by injection or orally as a syrup. All combinations, release procedures and administration sequences are contemplated.

Since one aspect of the present invention contemplates the treatment of diseases / disorders with a combination of pharmaceutically active agents that can be administered separately, the invention further relates to combining separate pharmaceutical compositions in the form of a kit. The kit comprises two separate pharmaceutical compositions: a compound of the present invention and a second pharmaceutical compound. The kit comprises a package for containing the separate compositions such as a divided bottle or a divided metal foil pack. Other examples of packages include syringes, boxes, bags and the like. Typically, the kit comprises instructions for administration of the separate components. The case form is particularly advantageous when the separate components are preferably administered in different dosage forms (e.g., oral and parenteral), administered at different dosage intervals, or when the attending physician wishes to increase or decrease the individual components. . An example of such a case is the so-called blister pack. Blister packs are well known in the packaging industry and are widely used for packaging dosage unit dosage forms (tablets, capsules and the like). The blister packs are generally formed by a sheet of relatively rigid material covered with a thin sheet of a plastic material, preferably transparent. During the packaging process, alveoli are formed in the thin sheet of plastic. The alveoli have the size and shape of the tablets or capsules to be packaged. Next, the tablets or capsules are placed in the alveoli and the sheet of relatively rigid material is sealed to the thin sheet of plastic on the face of the sheet opposite the direction in which the alveoli have been formed. As a result, the tablets or capsules are hermetically sealed in the alveoli between the thin sheet of plastic 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 a manual pressure on the cells, by means of which an opening is made in the sheet in the position where the socket is located. The tablet or capsule can then be extracted through said opening. It would be desirable to provide a memory aid in the case, for example, in the form of numbers near the tablets or capsules, so that the numbers correspond to the days of the administration schedule in which the tablets should be ingested or specified capsules. Another example of such means of memory aid is a calendar printed on the card, for example, as follows "First week, Monday, Tuesday, and so on, second week, Monday, Tuesday, and so on". Other variations of memory aids will be apparent. A "daily dose" may be a single tablet or capsule or several pills or capsules that must be taken on a given day. In addition, a daily dose of compound of formula I may consist of a tablet or capsule, while a daily dose of the second compound may consist of several tablets or capsules and vice versa. The means of memory aid should reflect this and help the correct administration of active agents. In another preferred embodiment of the invention, there is provided a dispenser designed to dispense the doses daily at each time in the order of their intended use. Preferably, the dispenser is provided with a means of memory aid, to facilitate compliance with the dosing schedule. An example of said memory aid means is a mechanical counter that indicates the number of daily doses that have been dispensed. Another example of said memory aid means is a battery operated microprocessor memory coupled to a liquid crystal display, or an audible reminder signal that, for example, shows the date on which the last dose was taken and / or remember when the next dose should be taken. If desired, the compounds of the present invention and other pharmaceutically active agents can be administered to a patient orally, rectally, parenterally (eg, intravenously, intramuscularly or subcutaneously), intracisternally, intravaginally, intraperitoneally, intravesically, locally ( for example, powders, ointments or drops) or as an oral or nasal spray. Compositions suitable for parenteral injection may comprise sterile physiologically acceptable solutions, dispersions, suspensions or emulsions, aqueous or non-aqueous, and sterile powders for their reconstitution into sterile injectable solutions or dispersions. Examples of suitable aqueous or non-aqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (propylene glycol, polyethylene glycol, glycerol and the like), their suitable mixtures, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by using a coating such as lecithin, maintaining the desired particle size in the case of dispersions and using surfactants. These compositions may also contain adjuvants such as preservatives, humectants, emulsifiers and dispersing agents. Contamination by microorganisms can be avoided by adding various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid and the like. It may also be desirable to include isotonicity agents, for example, sugars, sodium chloride and the like. Prolonged absorption of injectable pharmaceutical compositions can be achieved by the use of agents that delay absorption, for example, aluminum monostearate or 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 conventional inert excipient (or vehicle) such as sodium citrate or dicalcium phosphate or (a) fillers or extenders, such as, for example, starches, lactose, sucrose, mannitol and silicic acid; (b) binders, such as, for example, carboxymethyl cellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and gum arabic; (c) humectants, such as, for example, glycerol; (d) disintegrating agents, such as, for example, agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain complex silicates and sodium carbonate; (e) solution retarders, 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 or bentonite; e (i) lubricants, such as, for example, talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulphate or mixtures of the same. In the case of capsules and tablets, the dosage forms may further comprise buffering agents. In solid and soft filled gelatin capsules, solid compositions of a similar type can also be used using excipients such as lactose or milk sugar, as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, dragees, capsules, lozenges and granules can be prepared with coatings and shells, such as enteric coatings and others well known in the art. These can also contain opacifying agents and can also be constituted of such a composition. which releases the active compound (s) in a certain part of the intestinal tract in a delayed manner. Examples of embedded compositions that can be used are polymeric substances or waxes. The active compounds may be in microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage form may contain inert diluents commonly used in the art, such as water or other solvents, solubilizing and emulsifying agents, 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 seed oil, olive oil, castor oil, and oil of sesame seed, glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and esters of sorbitan fatty acids or mixtures of these substances and the like. In addition to the inert diluents, the composition may also include adjuvants, such as wetting agents, emulsifying and suspending agents, sweetening agents, flavors and perfumes. The suspensions, in addition to the active compound, may contain suspending agents, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth or mixtures of these substances and the like.

Compositions for rectal administration are preferably suppositories, which can be prepared by mixing the compounds of the present invention with suitable non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol or a suppository wax, which are solid at the usual room temperature but liquids to body temperature and, therefore, melt in the rectum or vaginal cavity and release the active component. Dosage forms for topical administration of a compound of the present invention include ointments, powders, sprays and inhalers. The active compound (s) are mixed under sterile conditions with a physiologically acceptable carrier and any preservatives, buffers or propellants that may be necessary. Ophthalmic formulations, eye ointments, powders and solutions are also contemplated within the scope of the present invention. The compounds of the present invention can be administered to a patient at dosage levels ranging from about 0.1 to about 3000 mg per day. For a normal adult human having a weight of about 70 kg, a dosage in the range of about 0.01 to about 100 mg per kilogram of weight is usually sufficient. The specific dosage and dosage range that can be used depends on a number of factors including the patient's needs, the intensity of the disease or disorder being treated and the pharmacological activity of the compound being administered. The determination of dosing ranges and optimum dosages for a particular patient are within the knowledge of one of ordinary skill in the art. The following paragraphs describe example formulations, dosages, etc., useful for non-human animals. The administration of a compound of the present invention can be effected orally or non-orally, such as by injection. An amount of a compound of the present invention is administered such that an effective dose is received, usually a daily dose which, when orally administered to an animal, normally ranges from 0.01 to 100 mg / kg of weight, preferably 0.1 at 50 mg / kg of weight. For convenience, the medication can be carried out in the proper water so that the therapeutic dosage of the agent is ingested with the daily water supply. The agent can be dosed directly into the water of due, preferably in the form of a concentrate soluble in liquid water (such as an aqueous solution of a water-soluble salt). Conveniently, the active ingredient can also be added directly to the food, as such, or in the form of a food supplement for the animal, also called supplement or concentrate. A supplement or concentrate of therapeutic agent in a vehicle is more commonly employed for the inclusion of the agent in the food. Suitable vehicles are liquid or solid, as desired, such as water, various flours such as alfalfa meal, soybean meal, cottonseed meal, linseed oil meal, cornmeal meal and cornmeal, molasses, urea, bone meal and mineral mixtures such as those commonly used in poultry feed. A particularly effective vehicle is the animal's own food; that is, a small part of that food. The vehicle facilitates the uniform distribution of the active materials in the final food with which the supplement is mixed. It is important that the compound is mixed uniformly in the supplement and, therefore, in the food. In this regard, the agent can be dispersed or dissolved in a suitable oil vehicle such as soybean oil, corn oil, cottonseed oil and the like, or in a volatile organic solvent and then mixed with the vehicle. It will be appreciated that the proportions of active material in the concentrate can vary widely since the amount of agent in the final food can be adjusted by mixing the appropriate proportion of supplement with the food to obtain a desired level of therapeutic agent. High potency concentrates can be mixed by the food manufacturer with a proteinaceous carrier such as soybean oil meal and other flours as described above, to produce concentrated supplements that are suitable for the direct feeding of animals. In such cases, animals are allowed to consume their usual diet. Alternatively, such concentrated supplements can be added directly to the food producing a nutritionally balanced final food containing a therapeutically effective level of a compound according to the invention. The blends are uniformly blended by conventional methods, such as a double shell mixer, to ensure homogeneity. If the supplement is used as a superficially added dressing for the food, it can also help to ensure the uniformity of the distribution of the active material throughout the upper part of the seasoned food. The water of due and the food effective to increase the deposition of lean meat and to improve the ratio of lean meat to fat are usually prepared by mixing a compound of the invention with a sufficient amount of animal feed, providing about 10" 3 to about 500 ppm of the compound in the feed or water The preferred medicated feed for pigs, sheep and goats generally contains from about 1 to about 400 grains of active ingredient per tonne of feed, the optimum amount being normally for these animals of about 50 to about 300 grams per tonne of feed The preferred foods for poultry and domestic pets typically contain from about 1 to about 400 g per tonne of feed For parenteral administration to animals, the compounds of the present invention are can be prepared in the form of a thick ointment or a pellet and administrars e as an implant, usually under the skin of the neck or ear of the animal. In general, parenteral administration involves the injection of a sufficient amount of a compound of the present invention to provide the animal from about 0.01 to about 100 mg / kg / day of body weight of the active ingredient. The preferred dosage for poultry, pigs, cows, sheep and goats and domestic animals varies in the range of about 0.1 to about 50 mg / kg / day. Formulations of thick ointments can be prepared by dispersing the active compound in a pharmaceutically acceptable oil such as peanut oil, sesame oil, corn oil or the like. Pellets containing an effective amount of a compound of the present invention can be prepared by mixing a compound of the present invention with a diluent such as Carbowax, carnauba wax and the like, and a lubricant such as magnesium stearate or calcium can be added for improve the conditions of the pelleting process. Of course, it is known that more than one pellet can be administered to an animal to achieve the desired dose level. Furthermore, it has been found that implants can be performed periodically during the treatment period of the animal in order to maintain the correct active agent level in the body of the animal.

The terms pharmaceutically acceptable salts, esters, amides or prodrugs refer to carboxylate salts, amino acid addition salts, esters, amides and prodrugs of the compounds of the present invention which are all within the scope of medical judgment, suitable for use with patients no toxicity, irritation, undue allergic responses, or similar effects, in a balanced manner with the benefit / risk ratio and effective for their intended use, as well as the hybrid forms, when possible, of the compounds of the present invention. The term "salts" refers to the inorganic and organic salts of the compounds of the present invention. The salts can be prepared in situ during the final phase of isolation and purification of the compound, or a purified compound in its free base form can be separately reacted with an organic or inorganic acid by isolating the salt thus formed. Representative salts include the salts hydrobromide, hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate, palmitate, stearate, laurate, borate, benzoate, lactate, phosphate, toluenesulfonate, citrate, maleate, fumarate, succinate, tartrate, naphthylate, mesylate, glucoheptonate, lactobionate and lauryl sulphonate, and similar salts. The salts may include cations based on alkali and alkaline earth metals, such as sodium, lithium, potassium, 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, ethylamine and the like. For example, see S. M. Berge, et al., "Pharmaceutical Salts", J. Pharm. Sci. 66: 1-19 (1977). Examples of non-toxic, pharmaceutically acceptable esters of the compounds of the present invention, if any, include CrC8 alkyl esters. Acceptable esters also include C5-C cycloalkyl esters, as well as arylalkyl esters such as benzyl. C 1 -C 4 alkyl esters are preferred. The esters of the compounds of the present invention can be prepared according to procedures that are well known in the art. Examples of non-toxic, pharmaceutically acceptable amides of the compounds of the present invention include the amides derived from ammonia, (CrC8 alkyl) primary amines and (dialkyl CrC8) secondary amines. In the case of secondary amines, the amine can also be in the form of a 5- or 6-membered heterocycloalkyl group containing at least one nitrogen atom. Amides derived from ammonia, (alkyl dC3) primary amines and (C1-C2 dialkyl) secondary amines are preferred.

The amides of the compounds of the present invention can be prepared according to procedures well known to those skilled in the art. The term "prodrug" means compounds that are transformed in vivo to provide a compound of formula I. Transformation can occur by various mechanisms, such as by hydrolysis in the blood. In T. Higuchi and W. Stella, "Pro-Drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987 can be found a description of the use of prodrugs. For example, if the compound of the invention contains a carboxylic acid functional group, a prodrug may comprise an ester formed by the substitution of the hydrogen atom of the acid group with a group such as CrC8 alkyl, (C2-C12 alkanoyloxy) methyl, - (alkanoyloxy) ethyl with 4 to 9 carbon atoms, 1-methyl-1- (alkanoyloxy) ethyl with 5 to 10 carbon atoms, alkoxycarbonyloxymethyl with 3 to 6 carbon atoms, 1- (alkoxycarbonyloxy) ethyl with 4 to 7 carbon atoms, 1-methyl-1 - (alkoxycarbonyloxy) ethyl with 5 to 8 carbon atoms, N- (alkoxycarbonyl) aminomethyl with 3 to 9 carbon atoms, 1- (N- (alkoxycarbonyl) amino) ethyl with 4 a 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N, N- (alkyl CrC2) amino (C2-C3 alkyl) (such as β-dimethylaminoethyl), carbamoyl- (C -? - alkyl) C2), N, N-di (C 1 -C 2 alkyl) carbamoyl- (C 2 -C 2 alkyl) and piperidino-, pyrrolidino- or morpholino (C 2 -C 3 alkyl). Similarly, if the compound of the present invention comprises an alcohol functional group, a prodrug can be formed by replacing the hydrogen atom of the alcohol group with a group such as (C 1 -Cymethyloxy) alkanoyloxy, 1- (C 1 -C 6 alkanoyloxy) ) et1lo, 1-methyl-1 - (Ci-Cβ-Jethyl alkanoyloxy, C (-C6-alkoxy) carbonyloxymethyl, N- (C alco-alkoxy) Carbonylaminomethyl, succinoyl, (C-pCß alkanoyl), a-amino (C4 alkanoyl), arylacyl and a-aminoacyl, or -aminoacyl-a-aminoacyl, each not being of the a-aminoacyl groups independently selected from the L-amino acids natural, P (O) (OH) 2, -P (O) - (O (C 6 alkyl)) 2 or glycosyl (the radical resulting from the removal of the hydroxy group from the hemiacetal being a carbohydrate). If the compound of the present invention comprises an amine functional group, a prodrug can be formed by the substitution of the hydrogen atom of the amine group for a group such as R-carbonyl, RO-carbonyl, NRR'-carbonyl, where R and R are 'independently C 1 -C 10 alkyl, C 3 -C 6 cycloalkyl) benzyl, or R-carbonyl is a natural a-aminoacyl or natural a-aminoacyl natural-a-aminoacyl, -C- (OH) C (O) OY, being Y, H, C? -C6 alkyl, carboxy (C? -C6 alkyl, amino (C1-C4 alkyl) or mono-N- or di-N, N- (C-pC? Alkyl) aminoalkyl, -C (Y2 Y 3, where Y 2 H or methyl and Y 3 are mono-N- or di-N, N- (Ci-C 1 J alkyl, morpholino, piperidin-1-yl or pyrrolidin-1-yl) The compounds of the present invention may contain asymmetric or chiral and, therefore, exist in different stereoisomeric forms It is contemplated that all stereoisomeric forms of the compounds, 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 the compound contains a double bond, both cis and trans forms, as well as mixtures thereof, are contemplated.

Mixtures of diastereoisomers can be separated into their individual stereochemical components based on their physicochemical differences by methods known per se, for example, by chromatography and / or fractional crystallization. The enantiomers can be separated by converting the mixture of enantiomers into a mixture of diastereomers by reaction with a suitable optically active compound (e.g., an alcohol), separating the diastereoisomers and converting (e.g., by hydrolysis) into the corresponding pure enantiomers. In addition, some of the compounds of this invention can be atropoisomers (e.g., substituted biaryls) and are considered part of this invention. The compounds of the present invention may exist in solvated and unsolvated form with pharmaceutically acceptable solvents such as water, ethanol and the like. The present invention contemplates and includes solvated and unsolvated forms. It is also possible that the compounds of the present invention may exist in different tautomeric forms. All tautomers of the compounds of the present invention are contemplated. For example, all tautomers of the imidazole moiety are included in this invention. Further, for example, all keto-enol or ir-enamine forms of the compounds are included in this invention. Those skilled in the art will recognize that the names of the compounds contained herein may be based on a particular tautomer of a compound . Although the name can be used for a single particular tautomer, it is intended that all tautomers be included in the name of the particular tautomer and are included as part of the invention. It is also intended that the invention described herein encompass compounds that are synthesized in vitro using laboratory techniques, such as those well-known to the synthetic chemical; or they are synthesized using in vitro techniques such as by metabolism, fermentation, digestion and the like. It is also contemplated that the compounds of the present invention can be synthesized using a combination of in vivo and in vitro techniques. The present invention also includes compounds labeled with radioisotopes, which are identical to those mentioned herein, except for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or Mass number found normally in nature. Examples of isotopes that can be incorporated into the compounds of the invention include hydrogen isotopes, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 8O, 17O, 31P, 32P, 35S, 18F and 36CI respectively. The compounds of the present invention which contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of this invention. Certain radioisotope-labeled compounds of the present invention, for example, those in which radioactive isotopes such as 3H and 14C have been incorporated, are useful in drug and / or tissue substrate distribution assays. The isotopes of tritiated H, ie, 3 H, and carbon 14, ie, 14 C, are particularly preferred for their ease of preparation and detection. In addition, replacement with heavier isotopes such as deuterium, ie, 2H, may provide certain therapeutic advantages caused by increased metabolic stability, for example, a greater half-life in vivo or the need for lower doses and, therefore, may be preferred in some circumstances. In general, the isotope-labeled compounds of formula I of this invention and their prodrugs can be prepared by carrying out the procedures described in the schemes and / or the following examples, substituting a reagent without an isotopic label for an isotope-labeled reagent. available. In general, the compounds of this invention can be prepared by methods which include procedures analogous to those known in the chemical art, in particular, in light of the description contained herein. In another aspect, the present invention relates to the treatment of diabetes, including reduced glucose tolerance, insulin resistance, insulin-dependent diabetes mellitus (type I) and non-insulin-dependent diabetes mellitus (NIDDM or type II). The treatment of diabetic complications such as neuropathy, nephropathy and diabetic retinopathy or cataracts are also included in the treatment of diabetes.

Diabetes can be treated by administering to a patient suffering from diabetes (type I or type II), insulin resistance, reduced glucose tolerance or any of the diabetic complications such as neuropathy, nephropathy, retinopathy or cataracts, an amount Therapeutically effective of a compound of the present invention. It is also contemplated that diabetes is treated by administering a compound of the present invention or a glycogen phosphorylase inhibitor combined with another agent that can be used to treat diabetes and / or obesity. Preferred glycogen phosphorylase inhibitors which are useful in combination with other agents useful for treating diabetes and / or obesity include those of formula I. Additional preferred glycogen phosphorylase inhibitors are described in PCT publications WO 98/39384 and WO 96/39385. Representative agents that can be used to treat diabetes include insulin and insulin analogs (e.g., LysPro insulin, inhalation formulations comprising 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; α2 antagonists and imidazolines: midaglizole, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan; other insulin secretagogues: linogliride, insulinotropin, exendin-4, BTS-67582, A-4166; glitazones: ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone; PPAR-gamma agonists, RXR agonists: JTT-501, MCC-555, MX-6054, DRF-2593, Gl-282570, KPR-297, LG 100268; inhibitors of fatty acid oxidation: clomoxir, etomoxir; a-glucosidase inhibitors: pracose, acarbose, miglitol, emiglitate, voglibose, MDL-25,637, camiglibose, MLD-73,945; β-agonists: BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316.243, TAK-667, AZ40140; cAMP and cGMP type phosphodiesterase inhibitors: sildenafil, L686398, L-386,393; agents to reduce lipid levels: benfluorex, atorvastatin; antiobesity agents: fenfluramine, orlistat, sibutramine; vanadate and vanadium complexes (eg, Naglivan®) and peroxovanadium complexes; amylin antagonists: pramlintide, AC-137; lipoxygenase inhibitors: masoprocal; Somatostatin analogues: BM-23014, saglitide, octreotide; glucagon antagonists: BAY 278-9965, insulin signaling agonists, insulin emulators, PTB1 inhibitors B: L-783281, TER17411, TER17529; gluconeogenesis inhibitors: GP3034; Somatostatin analogues and somatostatin antagonists; antilipolytic agents: nicotinic acid, acipimox, WAG 994; stimulators of glucose transport: BM-130795; inhibitors of glucose synthase kinase: lithium chloride, CT98014, CT98023; Galanin receptor agonists; MTP inhibitors such as those described in U.S. Provisional Patent Application No. 60 / 164,803; growth hormone secretagogues such as those described in PCT publications nrs WO97 / 24369 and WO 98/58947; NPY antagonists: PD-160170, BW-383, BW1229, CGP-71683A, NGD 95-1, L-152804; anorectic agents including antagonists and / or emulators of 5-HT and 5-HT2C receptors: dexfenfluramine, Prozac (R), Zoloft (R); CCK receptor agonists: SR-278978; Galatin receptor antagonists; MCR-4 agonists: HP-228; leptin or leptin emulators: inhibitors of 11-beta-hydroxysteroid dehydrogenase type I; urocortin emulators, CRF antagonists, and CRF binding proteins: RU-488, urocortin. Other antidiabetic agents that can be used in combination with a glycogen phosphorylase inhibitor include ergoset and D-chiroinositol. Any combination of agents of those described above can be administered. In addition to the categories and compounds mentioned above, the compounds of the present invention can be administered in combination with thiometamyl compounds, aldose reductase inhibitors, glucocorticoid receptor antagonists, NHE-1 inhibitors or sorbitol dehydrogenase inhibitors, or combinations thereof, to treat or prevent diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia of tissues, in particular, myocardial ischemia. It is generally accepted that thyroid hormones, especially biologically active iodothyronines, are critical for normal development and for maintaining metabolic homeostasis. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and potentiate the lipolytic response of fat cells to other hormones. U.S. Patent Nos. 4,766,121, 4,826,876, 4,910,305 and 5,061,798 disclose certain mimetics of thyroid hormones (thyromimetics), namely 3,5-dibromo-3 '- [6-oxo-3 (1 H) -p Ridazinylmethyl] -thironins. U.S. Patent No. 5,284,971 discloses certain thyromimetic agents that reduce cholesterol levels, namely, 4- (3-cyclohexyl-4-hydroxy or -methoxy phenylsulfonyl) -3,5-dibromo-phenylacetic compounds. U.S. Patent Nos. 5,401, 772, 5,654,468 and 5,569,674 disclose certain thyromimetics which are agents that reduce lipid levels, namely, heteroacetic acid derivatives. In addition, certain oxamic acid derivatives of thyroid hormones are known in the art. For example, N. Yokoyama, et al., In an article published in the Journal of Medicinal Chemistry, 38 (4): 695-707 (1995) describe replacing a -CH2 group in a natural metabolite of T2 by a -NH group. , resulting in -HNCOCO2H. Likewise, R.E. Steele et al., In an article published in the International Cogressional Service (Atherosclerosis X) 1066: 321-324 (1995) and Z.F. Stephan et al., In an article published in Atherosclerosis, 126: 53-63 (1996) describe certain derivatives of oxamic acids useful as thyromimetic agents that reduce lipid levels, free of undesirable cardiac activity. Each of the above mentioned thyromimetic compounds and other thyromimetic compounds can be used in combination with the compounds of the present invention to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia. The compounds of the present invention can also be used in combination with aldose reductase inhibitors. Aldose reductase inhibitors are a class of compounds that are increasingly known for their usefulness in preventing and treating disorders derived from complications of diabetes such as diabetic neuropathy and nephropathy. Such compounds are well known to those skilled in the art and are easily identified by conventional biological assays. For example, the inhibitors of aldose reductase zopolrestat, 1-phthalazine acetic acid, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzothiazolyl] methyl] - and the related compounds are described in U.S. Patent 4,939,140 to Larson et al. Aldose reductase inhibitors have been described for their use to reduce lipid levels in mammals. See, for example, U.S. Patent 4,492,706 to Kallai-sanfacon and EP 0 310 931 A2 (Ethyl Corporation). United States Patent 5,064,830 to Going describes the use of certain aldose reductase inhibitors based on oxophthalazinyl acetic acid, including zopolrestat, to reduce levels of uric acid in blood.

U.S. Patent 5,391, 551, commonly assigned, discloses the use of certain aldose reductase inhibitors, including zopolrestat, to reduce blood lipid levels in humans. The description sets out what therapeutic utilities are derived from the treatment of diseases caused by an elevated level of triglycerides in the blood, including such diseases cardiovascular disorders such as thrombosis, arteriosclerosis, myocardial infarction and angina pectoris. A preferred aldose reductase inhibitor is 1-phthalazine acetic acid, 3,4-dihydro-4-oxo-3 - [[(5-trifluoromethyl) -2-benzothiazolyl] methyl] -, also known as zopolrestat. The term "aldose reductase inhibitor" refers to compounds that inhibit glucose bioconversion in sorbitol, which is catalyzed by the enzyme aldose reductase. Any aldose reductase inhibitor combined with a compound of the present invention can be used. The inhibition of aldose reductase is easily determined by those skilled in the art according to conventional assays (J. Malone, Diabetes, 29: 861-864 (1980). "Red Cell Sorbiol, an Indicator of Diabetic Control"). In the present specification a series of inhibitors of aldose reductase are described; however, other aldose reductase inhibitors useful in the compositions and methods of this invention will be well known to those skilled in the art. The activity of an aldose reductase inhibitor in a tissue can be determined by assaying an amount of aldose reductase inhibitor that is necessary to reduce tissue sorbitol (ie, by inhibiting the additional production of sorbitol after blocking aldose reductase) or reduce the fructose in the tissue (inhibiting the production of sorbitol after blocking the aldose reductase and, consequently, the production of fructose). Accordingly, examples of aldose reductase inhibitors that are useful in the compositions, combinations and methods of the present invention include: 1- 3- (4-bromo-2-fluorobenzyl) -3,4-dihydro-4- acid oxo-1-phthalazine acetic acid (ponalrestat, US Patent 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) -? - methylcinnamylidene] -4-oxo-2-thioxo-3-thiazolidenacetic acid (epalrestat, U.S. Patent 4,464,382, U.A. 4,791, 126 and U.A. 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. Patents 4,734,419 and 4,883,800); 5.- 2R, 4R-6,7-dichloro-4-hydroxy-2-methyl-chroman-4-acetic acid (US patent 4,883,410); 6.- 2R, 4R-6,7-dichloro-6-fluoro-4-hydroxy-2-methyl-chroman-4-acetic acid (U.S. Patent 4,883,410); 7.- 3,4-dihydro-2,8-diisopropyl-3-oxo-2H-1,4-benzoxazin-4-acetic acid (U.S. Patent 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, US Patent 5,252,572); 9.- N- [3,5- dimethyl-4 - [(nitromethyl) sulfonyl] phenyl] -2-methyl-benzeneacetamide (ZD5522, patents E.U.A. 5,270,342 and E.U.A. 5,430,060); 10.- (S) -6-fluorospiro [chroman-4,4'-midazolidine] -2,5'done (sorbinyl, patent E.U.A. 4,130,714); 11.- d ^ -methyl-d-fluoro-spirochroman ^ '^' - imidazolidine ^ '. S'-dione (patent E.U.A. 4,540,704); 12- 2-fluoro-spiro (9H-fluorene-9,4, -imidazolidine) 2 ', 5, -dione (patent US Pat. No. 4,438,272); 13.- 2,7-difluoro-spiro (9H-fluorene-9,4'-imidazolidine) -2, 5'-dione (patents E.U.A. 4,436,745 and E.U.A. 4,438,272); 14.- 2,7-difluoro-5-methoxy-spiro (9H-fluorene-9,4'-amidazolidine) -2, 5'-dione (US Patents 4,436,745 and E.U.A. 4,438,272); 15.- 7-fluoro-spiro (5H-indenol [1,2-b] pyridine-5,3'-pyrrolidine) -2,5'-dione (US Patents 4,436,745 and E.U.A. 4,438,272); 16.- d-cis-d-chloro ^ '. S'-dihydro ^' - methyl-spiroyimidazolidine-4,4 ', 4'-H-pyran (2,3-b) pyridine) -2,5- diona (US Patent 4,980,357); 17. Spiro [imidazolidine-4,5 '(6H) quinoline] 2,5-dione-3'-chloro-7', 8, -dihydro-7, -methyl- (5, -cis) (US patent 5,066,659 ); 18. (2S, 4S) -6-fluoro-2 ', 5, -dixospiro (chroman-4, -4, -imidazolidin) -2-carboxamide (US patent 5,447,946); and 19.- 2 - [(4-Bromo-2-fluorophenyl) methyl] -6-fluorospiro [isoquinoline-4] (I HJ.S'-pyrrolidinal-1 '' S.d '(2H) -tetrone (ARI-509, U.S. Patent 5,037,831) Other inhibitors of aldose reductase include the compounds of the formula or one of its pharmaceutically acceptable salts, wherein Z is O or S; R1 is hydroxy or a group capable of being removed in vivo to produce a compound of formula I, wherein R1 is OH; and X and Y are identical or different and are selected from hydrogen, trifluoromethyl, fluoro and chloro. A subgroup within the above group of compounds includes the compounds numbered 1, 2, 3, 4, 5, 6, 9, 10 and 17 and the following compounds of the formula: - 3,4-dihydric acid 3- (5-flurobenzothiazol-2-ylmethyl) -4-oxophthalazin-1-yl acetic acid [R1 = hydroxy; X = F; Y = H]; 21. 3- (5,7-difluorobenzothiazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = Y = F]; 22.- 3- (5-Chlorobenzothiazol-2-yl] methyl) -3,4-dihydro-4-oxophthalazin-1-yl-acetic acid [R1 = hydroxy; X = Cl; Y = H]; 23. - 3- (5,7-Dichlorobenzothiazol-2-methylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = Y = Cl]; 24.- 3,4-Dihydro-4-oxo-3- (5-trifluoromethylbenzoxazol-2-ylmethyl) phthalazin-1-yl acetic acid [R 1 = hydroxy; X = CF3; Y = H]; 25.- 3,4-dihydro-3- (5-fluorobenzoxazol-2-ylmethyl) -4-oxophthalazin-1-yl acetic acid [R1 = hydroxy; X = F; Y = H]; 26.- 3- (5,7-difluorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-ylacetic acid [R1 = hydroxy; X = Y = F]; 27.- 3- (5-Chlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxophthalazin-1-yl acetic acid [R1 = hydroxy; X = Cl; Y = H]; 28.- 3- (5,7-Dichlorobenzoxazol-2-ylmethyl) -3,4-dihydro-4-oxaphthalazin-1-ylacetic acid [R1 = hydroxy; X = Y = Cl]; 29.- zopolrestat; 1-phthalazineacetic acid, 3,4-dihydro-4-oxo-3 - [[5- (trifluoromethyl) -2-benzozothiazolyl] methyl] -, [R1 = hydroxy; X = trifluoromethyl; Y = H]. In compounds 20 to 23 and 29, Z is S. in compounds 24 a 28, Z is O. Of the above subgroup, compounds 20 to 29 are most preferred, 29 being especially preferred. Methods for preparing the aldose reductase inhibitors of formula la can be found in PCT publication number WO 99/26659. Each of the aldose reductase inhibitors mentioned above and other aldose reductase inhibitors can be used in combination with the compounds of the present invention to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia. The compounds of the present invention can also be used in combination with glucocorticoid receptor antagonists. The glucocorticoid receptor (GR) is present in the glucocorticoid-responsive cells where it resides in the cytosol in an inactive state until it is stimulated by an agonist. After stimulation, the glucocorticoid receptor moves the nucleus of the cell in which it interacts specifically with the DNA and / or proteins and regulates the transcription of a sensitive form of glucocorticoids. Two examples of proteins that interact with the glucocorticoid receptor are the transcription factors, API and NFR-B. Such interactions result in the inhibition of transcription measured by API and NFk-B and is believed to be responsible for the anti-inflammatory activity of glucocorticoids administered endogenously. In addition, glucocorticoids can also exert physiological effects independent of nuclear transcription. The biologically important glucocorticoid receptor agonists include cortisol and corticosterone. There are many synthetic glucocorticoid receptor agonists, including dexamethasone, prednisone, and prednisolone. By definition, glucocorticoid receptor antagonists bind to the receptor and prevent glucocorticoid receptor agonists from binding and triggering events mediated by the GR, including transcription.

RU486 is an example of a non-selective glucocorticoid receptor antagonist. GR antagonists can be used in the treatment of diseases associated with an excess or deficiency of glucocorticoids in the body. As such, they can also be used to treat the following disorders: obesity, diabetes, cardiovascular disease, hypertension, x syndrome, depression, anxiety, glaucoma, human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), neurodegeneration ( for example, Alzheimer's or Parkinson's disease), cognition enhancement, Cushing's syndrome, Addison's disease, osteoporosis, bone fragility, inflammatory diseases (such as osteoarthritis, rheumatoid arthritis, asthma and rhinitis), adrenal function tests, infection viral, immunodeficiency, immunomodulation, autoimmune diseases, allergies, wound healing, compulsive behavior, resistance to various drugs, addiction, psychosis, anorexia, cachexia, post-traumatic stress syndrome, post-surgical bone fracture, medical catabolism and prevention of muscle fragility. Examples or antagonists of the GR that can be used in combination with a compound of the present invention include compounds of formula Ib below: Ib and an isomer thereof, a prodrug of said compound or isomer, or a pharmaceutically acceptable salt of said compound, isomer or prodrug; where m is 1 or 2; - represents an optional link; A is selected from the group formed by A-1 A-2 A-3 AA A-5 D is CR7, CR7R? E, N, NR7 or O; E is C, CR6 or N; G, H and I together with 2 carbon atoms of ring A or 2 carbon atoms of ring B form a 5-membered heterocyclic ring comprising one or more N, O or S atoms; with the proviso that there is at least one of O and S per ring; J, K, L and M together with 2 carbon atoms of the B ring form a 6-membered heterocyclic ring comprising 1 or more N atoms; X is a) not present, b) -CH2-, c) -CH (OH) - or d) -C (O) -.

R is a) -H), -Z-CF3) c) - (C6 alkyl), d) - (C2-C6 alkenyl), e) - (C2-C6 alkynyl), f) -CHO, g) -CH = N * OR12, h) -ZC (O) OR12, i) -ZC (O) -NR12R13, j) -ZC (O) -NR12-Z-het, k) -Z-NR12R? 3 ,. I) -Z-NR12het, m) -Z-het, n) -ZO-het, o) -Z-aryl ', p) -ZO-aryl', q) -CHOH-aryl 'or) -C- ( O) -aryl ', the aryl being in the substituents o) ar) independently substituted with 0, 1 or 2 of the following: -Z-OH, -Z-NR12R? 3, -Z-NR12het, -C (O ) NR12R13, -C- (O) O (CrC6 alkyl), -C (O) OH, -C (O) het, -NR12-C (O) - (C6 alkyl), -NR12-C (O) (C2-C6 alkenyl), -NR12-C (O) (C2-C6 alkynyl), -NR12-C (O) -Z-het, -CN, -Z-het, -O- (C3 alkyl) - C (O) -NR 12 R 3, -O- (C 3 alkyl) -C (O) O (d-C 6 alkyl), -NRi 2 -ZC (O) O (C 6 alkyl), -N (ZC (O ) O (C? -C6 alkyl)) 2, -NR12-ZC (O) -NR12R13, -Z-NR12-SO2-Ri3, -NR12-SO -het. -C (O) H, -Z-NR12-ZO- (C6 alkyl), -Z-NR12-Z-NR12Ri3, -Z-NR12 (C3-C6 cycloalkyl), -ZN (ZO (CrC6 alkyl)) 2 , -SO2R12, -SOR12, -SR12, -SO2NR12R13, -OC (O) - (C1-C4 alkyl), -O-SO2- (C1-C4 alkyl), -halo or -CF3; Z in each occurrence is independently a) - (alkyl Co-Cß), b) - (C2-C6 alkenyl), or c) - (C2-C6 alkynyl); R2 is a) -H, b) -halo, c) -OH, d) - (CrC6 alkyl) substituted with 0 or 1 -OH, e) -NR12Ri3, f) -ZC (O) O (C6 alkyl) , g) -ZC (O) NR12R? 3, h), -O- (C6 alkyl), i) -ZOC (O) - (C6 alkyl), j) -ZO- (CrC3 alkyl) -C ( O) -NR12R13, k) -ZO- (C 1 -C 3 alkyl) -C (O) -O (C 1 -C 6 alkyl), I) -O- (C -C 6 alkenyl), m) -O - ( C2-C6 alkynyl), n) -OZ-het, o) COOH, p) -C (OH) R12R-? 3 or q) -Z-CN; R3 is a) -H, b) - (C1-C10 alkyl), wherein 1 or 2 carbon atoms other than the carbon atoms of the bond, can optionally be replaced by 1 or 2 heteroatoms independently selected from S, O and N and wherein each of the carbon atoms is substituted with 0, 1 or 2 Ry, c) - (C2-C10 alkenyl) substituted with 0, 1 or 2 Ry, d) - (C2-C10 alkynyl) wherein 1 carbon atom, other than the bonding carbon atom, can optionally be replaced by 1 oxygen atom and wherein each of the carbon atoms is substituted with 0, 1 or 2 Ry, e) -CH = C = CH2, f) -CN, g) - (C3-C6 cycloalkyl), h) -Z.aril, i) -Z-het, j) -C- (O) O (C6 alkyl), k ) -O (C6 alkyl), I) -ZS-R12, m) -ZS (O) -Ri2, n) -ZS (O) 2-Ri2, o) -CF3, p) -NR12-O- ( C6 alkyl) or q) -CH2OR?; with the proviso that one of R2 and R3 is not present when there is a double bond between CR2R3 (position 7) and the remainder F (position 8) of ring C; Ry is for each occurrence independently, a) -OH, b) -halo, c) -Z-CF3, d) -Z-CF (C3 alkyl) 2, e) -CN, f) -NR? 2R? 3 , g) - (C3-C6 cycloalkyl), h) (C3-C6 cycloalkenyl), i) - (C0-C3 alkyl) -arillo, j) -het ok) -N3; or R2 and R3 are taken together forming a) = CHRn, b) f) oxiranyl or g) 1,2-dioxolan-4-yl; R4 and R5 are for each occurrence, independently a) -H, b) -CN, c) - (Ci-Cß alkyl) substituted with 0 to 3 halo, d) - (C2-Cß alkenyl) substituted with 0 to 3 halo , g) -O- (C2-C6 alkenyl) substituted with 0 to 3 halo, h) -O- (C2-C6 alkynyl) substituted with 0 to 3 halo, i) halo, j) -OH, k) (cycloalkyl) C3-C6) or I) - (C3-C6 cycloalkenyl); or R4 and R5 are taken together forming = 0; R6 is a) -H, b) -CN, c) - (C6 alkyl) substituted with O to 3 halo, d) - (C2-C6 alkenyl) substituted with O to 3 halo, e) - (C2- alkynyl) C6) substituted with O to 3 halo of) -OH; R7 and R6 are for each occurrence independently a) -H, b) -halo, c) -CN, d) - (CrC6 alkyl) substituted with O to 3 halo, e) - (C2-C6 alkenyl) substituted with O to 3 halo, of) - (C2-Cß alkynyl) substituted with O to 3 halo; with the proviso that R is different from -CH or -halo when D is NR7; or R7 and R16 are taken together formed = 0; Re. R9, H and R15 are for each occurrence a) -H, b) -halo, c) C-i-Cß alkyl substituted with 0 to 3 halo; d) - (C2-C6 alkenyl) substituted with 0 to 3 halo, e) - (C2-C6 alkynyl) substituted with 0 to 3 halo, f) -CN, g) - (cycloalkyl) C3-C6), h) - (C2-C6 cycloalkenyl), i) -OH, j) -O- (C Ce alkyl), k) -O- (CrC6 alkenyl), I) -O- (C alkynyl C ), m) -NR12R13, n) C (O) ORi2 uo) -C (O) NR? 2R? 3; or R8 and Rg are taken together on the ring of C forming = O; with the proviso that when m is 2, only one group of R8 and Rg are taken together forming = O; or Ru and R15 are taken together forming = O; with the proviso that when R14 and R15 are taken together forming = O, D is different from CR7 and E is different from C; R-to is a) - (C1-C10 alkyl) substituted with 0 to 3 substituents independently selected from -halo, -OH and -N3, b) - (C2-C10 alkenyl) substituted with 0 to 3 substituents independently selected from - halo, -OH and N3, c) - (C2-C10 alkynyl) substituted with 0 to 3 substituents independently selected from -halo, -OH and N3, d) -halo, e) -Z-CN, f) -OH, g) -Z-het, h) -Z-NR12R? 3, i) -ZC (O) -het, j) -ZC (O) - (C? -C6 alkyl), k) -ZC (O) - NR12R? 3, 1) -ZC (O) -NR12-Z-CN, m) -ZC (O) -NR12-Z-het, n) -ZC (O) -NR12-Z-aryl, o) -ZC - (O) -NR12-Z-NR12R? 3 > p) -ZC (O) -NR12-ZO (C6 alkyl), q) - (CrC6 alkyl) -C (O) OH, r) -ZC (O) O (alkyl d-Ce), s) -ZO - (C0-C6 alkyl) -het, t) -ZO - (C0-C6 alkyl) -aryl, u) -ZO - (C6 alkyl) substituted with 0 to 2 Rx, v) -ZO - (C6 alkyl) ) -CH (O), w) -ZO- (alkyl CrC6) -NR12-het, x) -ZOZ-het-Z-het, and) -ZOZ-het-Z-NR12R? 3, z) -ZOZ- het-C (O) -het, a1) -ZOZC (O) -het, b1) -ZOZC (O) -het-het, d) -ZOZC (O) - (CrC6 alkyl), d1) -ZOZC (S) ) -NR12R13, e1) -ZOZC (O) -NR12Ri3, f1) -ZOZ- (C3 alkyl) -C (O) -NR12R13, g1) -ZOZC (O) -O (C6 alkyl), h1) - ZOZC (O) -OH, 1) -ZOZC (O) -NR12-O (d-Cß alkyl), j1) -ZOZC (O) -NR12-OH, k1) -ZOZC (O) - NR12-Z- NR12R? 3, H) -ZOZC (O) - NR12-Z-het, m1) -ZOZC (O) - NR12-SO2 - (alkyl d-Ce), n1) -ZOZC (= NR12) (NR12R? 3) , o1) -ZOZC (= NOR12) (NR12R13), p1) -Z- NR12-C (O) -OZ- NR12R13, q1) -ZSC (O) -NR12R13, r1) -ZO-SO2 - (C -Cß alkyl) ), s1) -ZO-SO2-aryl, t1) -ZO-SO2- NR12R13, u1) -ZO-SO2-CF3, v1) -Z-NR12C (O) OR13 or w1) -Z- NR12C (O) R13; or Rg and R10 are taken together on the remainder of formula A-5 to form a) = O or b) = NOR? 2; R11 is a) -H, b) - (CrC5 alkyl), c) - (C3-C6 cycloalkyl) or d) - (Co-C3 alkyl) aryl; R12 and R13 for each case are independently a) -H, b) - (CrC6 alkyl), wherein 1 or 2 carbon atoms, other than the carbon atoms, can optionally be replaced by 1 or 2 heteroatoms selected independently of S, O and N and wherein each carbon atom is substituted with 0 to 6 halo, c) - (C2-C6 alkenyl) substituted with 0 to 6 halo od) - (CrCß alkynyl) in which 1 atom of carbon, other than the carbon atom, can optionally be replaced by 1 oxygen atom and wherein each carbon atom is substituted with 0 to 6 halo; or R12 and R3 are taken together with N forming het; or Re and Ru or R15 are taken together to form 1,3-dioxolanyl; aryl is a) phenyl substituted with 0 to 3 Rx, b) naphthyl substituted with 0 to 3 Rx or c) biphenyl substituted with 0 to 3 Rx; het is a 5, 6 or 7 membered saturated, partially saturated or unsaturated ring containing one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and includes any bicyclic group in which any of the above heterocyclic rings is fused with a benzene ring or other heterocycle; and the nitrogen may be in the oxidation state which gives the N-oxide form; and is substituted with 0 to 3 Rx; Rx is, for each occurrence, independently a) -halo, b) -OH, c) - (alkyl CrCe), d) - (alkenyl C2-C6), e) - (alkynyl C2-Ce), f) -O (Cr C6 alkyl), g) -O (C2-C6 alkenyl), h) -O (C2-C6 alkynyl), i) - (Co-C6 alkyl) -NR12R? 3, j) -C (O) - NR12R? 3, k) -Z-SO2R2, I) -Z-SOR12, m) -Z-SR12, n) -NR12-SO2R? 3, o) -NR12-C (O) -R13, p) -NR12 -OR13, q) -SO2-NR12R13, r) -CN, s) -CF3, t) -C (O) (CrC6 alkyl), u) = O, v) -Z-SO2-phenyl or) -Z- SO2het '; aryl is phenyl, naphthyl or biphenyl; het 'is a saturated, partially saturated or unsaturated 5, 6 or 7 membered ring containing from one (1) to three (3) heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur; and which includes any bicyclic group in which any of the above heterocyclic rings is fused with a benzene ring or other heterocycle; with the proviso that: 1) X-R1 is other than hydrogen or methyl; 2) when Rg and R-io are substituents on ring A, these are different from mono- or di-methoxy; 3) when R2 and R3 are taken together to form = CHRn u = O, where Rn is -O (CrCß alkyl), then -X-R1 is other than C1-C4 alkyl; 4) when R2 and R3 taken together are C = O and Rg is hydrogen on ring A; or when R2 is hydroxy, R3 is hydrogen and Rg is hydrogen on ring A, then R10 is other than -O- (alkyl CrCe) or -O-CH2-phenyl in position 2 of ring A; ) when X-Ri is C1-C4 alkyl, C2-C4 alkenyl or C2-C4 alkynyl, Rg and R10 are other than monohydroxy u = O, including its diol form, when taken together, and 6) when X is not present, R1 is other than a moiety containing a heteroatom independently selected from N, O or S, directly attached to the junction of ring B and ring C. (See U.S. Provisional Patent Application number 60 / 132,130) . Each of the glucocorticoid receptor antagonists cited above and other glucocorticoid receptor antagonists can be used in combination with the compounds of the present invention to treat or prevent diabetes, hypergiukaemia, hypercholesterolemia, hypertension, hyperinsulinemia, atherosclerosis or ischemia of tissues. The compounds of the present invention can also be used in combination with inhibitors of sorbitol dehydrogenase. Inhibitors of sorbitol dehydrogenase reduce fructose levels and have been used to treat or prevent diabetic complications such as neuropathy, nephropathy, retinopathy, cardiomyopathy, microangiopathy, and macroangiopathy. U.S. Patent Nos. 5,728,704 and 5,866,578 describe compounds and a method for treating or preventing diabetic complications by inhibiting the enzyme sorbitol dehydrogenase. Each of the sorbitol dehydrogenase inhibitors mentioned above and other inhibitors of sorbitol dehydrogenase can be used in combination with the compounds of the present invention to treat diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsuliemia, hyperlipidemia, atherosclerosis or tissue ischemia. The compounds of the present invention can also be used in combination with type I inhibitors of the sodium-hydrogen exchanger (NHE-1). NHE-1 inhibitors can be used to reduce tissue damage caused by ischemia. Tissue damage that occurs as a result of ischemia of the cardiac, cerebral, hepatic, renal, pulmonary, stomach, skeletal, splenic, pancreatic, nervous, spinal or retinal tissues in the vasculature or in the intestinal tissue is of great importance. NHE-1 inhibitors can also be administered to prevent perioperative myocardial ischemic injury. Examples of NHE-1 inhibitors include a compound having the formula Formula is a prodrug thereof or a pharmaceutically acceptable salt of said compound or said prodrug, wherein Z is a diaza, di-saturated five-member ring connected through a carbon, having two contiguous nitrogens, said ring being optionally mono , di or trisubstituted with up to three substituents independently selected from R1, R2 and R3; or Z is a triaza, diunsaturated five-membered ring connected through a carbon, said ring optionally mono- or di-substituted with up to two substituents independently selected from R 4 and R 5; each of R1, R2, R3, R4 and R5 being independently hydrogen, hydroxy (C1-C4 alkyl), C1-C4 alkyl, (CrC4 alkyl) thio, C3-C4 cycloalkyl, (C3-C cycloalkyl) (alkyl C1-C4), C1-C4 alkoxy, (CrC4 alkoxy) (C1-C4 alkyl), mono-N- or di-N, N- (C1-C4 alkyl) carbamoyl, M or M (C1-C4 alkyl), having any of the above C1-C4 alkyl moieties of one to nine fluorine atoms; said C 1 -C 4 alkyl or C 3 -C 4 cycloalkyl optionally mono- or disubstituted independently with hydroxy, C 1 -C 4 alkoxy, (CrC 4 alkyl) thio, (C 1 -C 4 alkyl) sulfinyl, (C 1 -C 4 alkyl) sulfonyl, C 1 -C 4 alkyl, mono-N- or di-N, N- (C 1 -C 4 alkyl) carbamoyl or mono-N, or di-N, N- (C 1 -C 4 alkyl) aminosulfonyl; and said C3-C4 cycloalkyl optionally having from one to seven fluorine atoms; M being a five to eight member ring partially saturated, fully saturated or totally unsaturated which optionally has one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, or bicyclic ring comprising two rings of three to six condensed partially saturated members, fully saturated or totally unsaturated, taken independently, which optionally have from one to four heteroatoms independently selected from nitrogen, sulfur and oxygen; said M being optionally substituted, on a ring if the moiety is monocyclic, or on one or both rings if the moiety is bicyclic, on a carbon or nitrogen with up to three substituents independently selected from R6, R7 and R8, where R6, R7 and R8 optionally a three to seven member ring partially saturated, fully saturated or fully unsaturated optionally having one to three heteroatoms independently selected from oxygen, sulfur and nitrogen, optionally substituted with CrC4 alkyl and further, R6, R7 and R8 are optionally hydroxy, nitro, halo, C 1 -C 4 alkoxy, (CrC 4 alkoxy) carbonyl, C 1 -C 4 alkyl, formyl, C 4 alkanoyl, C 1 -C 4 alkanoyloxy, (Cr C 4 alkanoyl) amino, (CrC 4 alkoxy) carbonylamino, sulfonamido, (CrC4 alkyl) sulfonamido, amino, mono-N- or di-N, N- (CrC4 alkyl) amino, carbamoyl, mono-N- or di-N, N- (CrC4 alkyl) carbamoyl, cyano, thiol, (alkyl CrC4) thio, (CrC4 alkyl) sulfinyl, (CrC4 alkyl) sulfonyl, mono-N- or di-N, N- (CrC4 alkyl) aminosulfonyl, C2-C4 alkenyl, Q2-C4 alkynyl or Cs-C cycloalkenyl, said substituents R6, R7 and R8 being C1-C4 alkoxy, C1-C4 alkyl, alkanoyl of CrC7, (CrC4 alkyl) thio, mono-N- or di-N, N- (C4 alkyl) amino or C3-C7 cycloalkyl optionally independently monosubstituted with hydroxy, (CrC4 alkoxy) carbonyl, C3-C7 cycloalkyl, C1 alkanoyl -C4, (CrC4 alkanoyl) amino, (C1-C4 alkanoyloxy), (CrC4 alkoxy) carbonylamino, sulfonamido, (CrC4 alkyl) sulfonamido, amino, mono-N- or di-N, N- (CrC4 alkyl) amino, carbamoyl, mono-N- or di-N, N- (C 1 -C 4 alkyl) carbamoyl, cyano, thiol, nitro, (CrC 4 alkyl) t, (CrC 4 alkyl) sulfinyl, (C 4 alkyl) sulfonyl, or mono -N- or di-N, N- (CrC4 alkyl) aminosulfonyl or optionally substituted with one to nine fluorine atoms. (See PCT patent application number PCT / IB99 / 00206). Each of the above-mentioned NHE-1 inhibitors and other NHE-1 inhibitors can be used in combination with the compounds of the present invention to treat or prevent diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy , diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia. The examples presented below are to illustrate particular embodiments of the invention and are not intended to limit the scope of the specification, including the claims in any way. All patents, patent applications and other references cited herein are incorporated herein by reference.

EXAMPLES CHEMICAL EXAMPLES The following are exemplary procedures for the manufacture of the compounds of the invention and are illustrated in the reaction schemes. These procedures can be carried out in sequential or convergent synthesis routes. Purification procedures include crystallization and normal phase or reverse phase chromatography. As a general rule, the preparation of the compounds described herein may require protection of a remote functional group (eg, primary amine, secondary amine, carboxyl). The need for such protection will vary depending on the nature of the remote functional group and the conditions of the preparation procedures. The need for such protection will be readily determined by one skilled in the art. The use of such protection / deprotection procedures is also within the reach of those skilled in the art. In T.W Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, New York 1991 can be found a general description of protective groups and their use. In the present specification the following abbreviations are used.

Et Ethyl DMF Dimethylformamide BOC urea-butyloxycarbonyl CBz benzyloxycarbonyl Ph Phenyl H Hours D Days Min Minutes Equiv Equivalents DMSO Dimethylsulfoxide Desc Decomposition p.f. Melting point CIMS Chemical ionization mass spectrometry SCHEME I ientos H SCHEME I (continued) Procedures A-C (free amine or HCl or trifluoroacetate salt) H 8 SCHEME II SCHEME 20 SCHEME III (continued) SCHEME IV A B C D SCHEME V SCHEME VI SCHEME Vil alkyl J K L M N or p . ^^^^^^ SCHEME VIII T The bicyclic pyrroly lacids of formula 5 can be prepared by various synthesis methods. With reference to scheme I, a preferred process (Hemetsberger, H. et al., Monatshefte fur Chemie, 103: 194-204 (1972)) begins with the condensation of an alkylester of azidoacetic acid with an aldehyde of formula 2 in a alcohol-based solvent in the presence of an alkoxide. The preferred alcohol and alkoxide are the alkyl ester derivatives to avoid transesterification problems. The reaction is carried out at a temperature from about -20 ° C to about 25 ° C, for about 1 to 24 hours, usually employing 3 to 8 equivalents of the alkoxide and an equimolar amount of the alkylester of azidoacetic acid . The resulting azides are then heated to reflux in an inert solvent such as xylenes, yielding the heterocyclopyrrole esters of formula 3. An example of a suitable preparation is shown by the following procedure H. The aldehydes of formula 2 can be prepared by conventional procedures known to those skilled in the art or the methods for their preparation can be determined from the literature (see, for example, Ortiz, JA et al., Eur. J. Med. Chem., 23: 477-482 (1988)). Regarding the scheme, example preparations include the formylation of Villsmeyer-Haack heterocycles (R "= H) of formula I (see O. Meth-Cohn and SP Stanforth in Comprehensive Organic Synthesis: Selectivity, Strategy &Efficiency in Modern Organic Chemistry , Vol. 2 Pergamon, New York, 1991, CH Heathcock, Ed. P. 777), metal-halogen exchange of bromine or iodoheterocycles (R "= Br, I) of formula I or lithiation of heterocycles of formula I (R "= H), followed by the treatment of aryl lithium of formula 11 with a formylating agent such as dimethylformamide (Ortiz, JA et al., Eur. J. Med. Chem., 23: 477-482 (1988)) O N-methyl formailide (See D. Comins &SP Joseph in Encyclopedia of Reagents for Organic Synthesis, Vol 5, Wiley, New York 1995, LA Paquette, Ed., P.3503), reduction of heterocyclic esters of formula 12 (R = alkyl) or acids (R = H) to alcohols of formula 13 or aldehydes of formula 2 (Nicolaou, KC et al., Angew. Chem. Int. E d. Engl., 36: 166-7 (1997)) with reducing agents (Comprehensive Organic Synthesis: Selectivity, Strategy &; Efficiency in Modern Organic Chemistry, Vol. 8, I. Fleming, Ed. Pergamon, 1991, New York) such as lithium aluminum hydride, diisobutylaluminum hydride or borane and the subsequent oxidation of alcohols of formula 13 to aldehydes of formula 2 using oxidizing agents (Comprehensive Organic Synthesis: Selectivity, Strategy &Efficiency in Modern Organic Chemistry, Vol. 7, SV Law, Ed. Pergamon, 1991, New York) such as pyridinium chlorochromate, manganese dioxide, Swern reagent and oxide of barium or halogenation of the aldehydes of formula 14 using electrophilic halide sources such as N-halosuccinimide (RM Kellogg et al., J. Org. Chem., 33: 2092-2909 (1968)), N-fluoropyridinium salts ( Umemoto, T. et al., J. Am. Chem. Soc, 112: 8563-75 (1990)) or elemental halogen (Ortiz, JA et al., Eur. J. Med. Chem., 23: 477-482. (1988)). Alternatively substitution of the heterocyclopyrroles of formula 3 can be carried out by conventional analogous methods known to those skilled in the art or substitution procedures can be easily determined from the literature. For example, with reference to scheme III, mono- and bis-halide substitution can be carried out by treatment with an electrophilic halide source such as N-halosuccinimide, salts of N-fluoropyridinium or elemental halogen (Gale, WW et al. ., J. Org. Chem., 29: 2160-2165 (1964)) producing heterocyclopyrroles of formula 4 (R "= H and / or halide) Methyl substitution can be carried out by formylation of Villsmeyer- Haack to aldehydes of formula 4 (R "'= CHO), followed by complete reduction of the formyl group under various reducing conditions such as sodium cyanoborohydride in the presence of zinc iodide in dichloroethane (CK Lau et al., J. Org. Chem. ., 51: 3038-3043 (1964)). The substitution of methyl and other alkyls can be carried out by coupling bromo- or iodoheterocyclopyrroles of formula 3 (R = Br, I) with alkyl metal reagents as alkyl-copper reagents (Corey EJ et al., J. Am. Chem. Soc.:89:3911-12 (1967)). They can also be coupled with the bromo- or iodoheterocyclopyrroles of formula 3 (R = Br, I) in the presence of a catalyst such as palladium alkenes and alkynes, in the presence of copper salts such as copper iodide (JM Tour et al., J. Org Chem 61: 6906-6921 (1996), GM Whitesides et al J. Org Chem, 53: 2489-2496 (1988)), and alkenyl and alkynyl stannanes (Stille, JK Angew, Chem. Int. Ed. Engl., 25: 508-524 (1986)). Palladium catalysts include, but are not limited to, palladium chloride, dichlorobis (triphenylphosphine) palladium (II), tetrakis (triphenylphosphine) palladium (0), and palladium acetate. Other useful example conditions for forming carbon bonds with aromatic rings are described by K. Tamao, D.W. Knight, and K. Sonogashira in Comprehensive Organic Synthesis: Selectivity, Strategy & Efficiency in Modern Organic Chemistry, Vol. 3 (Pergamon, New York, 1991, G. Pattenden, Ed., Pages 435-551). The condensation of hydroxylamine with formylated esters of formula 3 (R "-CHO) or acids of formula 5 (R = CHO) can be carried out directly (Ford, RE et al., J. Med. Chem., 29: 538-549 ( 1986)) or after a second hydration step (Malicome, G. et al., Eur. J. Med. Chem. Chim. Ther., 26: 3-11 (1991) providing nitriles. nitriles can be carried out by coupling cuprous cyanide with the bromo- or iodoheterocyclopyrroles of formula 3 (R = Br, I) in dimethylformamide (Klemm, LH et al., J. Heterocyclic Chem., 21: 785-9 (1984 ).) Other useful example conditions for forming nitriles are described by R. Grashey in Comprehensive Organic Synthesis: Selectivity, Strategy &Efficiency in Modern Organic Chemistry, Vol. 6 (Pergamon, New York, 1991, Ed. Winterfeldt, Ed., page 225) An example of the preparation of nitriles is the following procedure G. As an alternative, the aforementioned procedures of substitution The heterocyclopyrroles of formula 3 can also be applied to the amides of formulas 6 and 7. The coupling of an acid of formula 5 (scheme I) with an amine of formula A (scheme IV) or P (scheme VII) for preparing a compound of the present invention can be carried out in various ways, which are analogous to those well known to those skilled in the art. In a typical coupling procedure, the acid and the amine are combined with a suitable coupling agent. A suitable coupling agent is an agent that transforms the carboxylic acid group into a reactive species so that an amide bond is formed between the carboxylic acid and the amine.

The coupling agent may provide the coupling in a single-step process or several steps may be required to achieve coupling. Examples of suitable coupling agents include 1- (3-dimethylaminopropyl) -3-ethylcarbodiomide-hydroxybenzotriazole hydrochloride (DEC / HBT), carbonyldiimidazole, dicyclohexylcarbodiimide / hydroxybenzotriazole, 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (EEDQ), carbonyldiimidazole / HBT, propanophosphonic anhydride (propanophosphonic acid anhydride, PAA) and diethylphosphoryl cyanide. The coupling reaction is generally carried out in an inert solvent, preferably in an aprotic solvent at a temperature from about -20 ° C to about 50 ° C for about 1 to about 48 hours, optionally in the presence of a tertiary amine as triethylamine. Suitable solvents include acetonitrile, dichloromethane, ethyl acetate, dimethylformamide and chloroform, or mixtures thereof. In an example of a multi-stage coupling process, the carboxylic acid group is reacted with the coupling agent to form an activated intermediate, which can be isolated in the first stage of the process. In a second step, the activated intermediate is then reacted with the amine to form the amide. Examples of coupling agents that convert an acid to an activated intermediate include thionyl chloride, oxalyl chloride, which form acid chlorides, cyanuric fluoride, which forms acid fluorides, or an alkyl chloroformate such as isobutyl chloroformate or isopropenyl (with a tertiary amine base), which forms a mixed anhydride of the carboxylic acid. If the coupling agent is oxalyl chloride, it is advantageous to employ a small amount of dimethylformamide as a cooperating solvent with another solvent such as dichloromethane, to catalyze the formation of the acid chloride. The acid chloride can be coupled with the amine in an appropriate solvent and a suitable base. Acceptable solvent / base combinations include dichloromethane, dimethylformamide or acetonitrile, or mixtures thereof in the presence of a tertiary amine base such as triethylamine. Other suitable solvent / base combinations include water or a C1-C5 alcohol, or mixtures thereof, together with a cooperating solvent such as dichloromethane, tetrahydrofuran or dioxane, and a base such as sodium or potassium carbonate, sodium, potassium or lithium hydroxide. or sodium bicarbonate, in sufficient quantity to consume the acid released in the reaction. The use of a phase transfer catalyst (typically from 1 to 10 mol%) such as a quaternary ammonium halide (for example, tetrabutylammonium bromide or methyl trioctylammonium chloride) is advantageous when a mixture of solvents is employed cooperators only partially miscible (for example, dichloromethane-water or dichloromethane-methanol). The use of these coupling agents and the proper selection of solvents and temperatures are known to those skilled in the art and can be readily determined from the literature. These and other example conditions useful for coupling carboxylic acids with amines are described in Houben-Weyl, Vol. XV, part II, E. Wunsch, Ed., G. Thieme Verlag, 1974, Stuttgart and M. Bodansky, Principies of Peptide Synthesis. , Springer Verlag Berlin, 1984 and The Peptides: Analysis, Synthesis and Biology (Ed. E. Gross and J. Meienhofer) Vol. 1 to 5 (Academic Press, NY 1979-1983). The amines that are reacted with the carboxylic acid functional group to prepare an amide of the present invention can be synthesized in a number of ways. With reference to scheme IV, an alpha amino acid of formula A can be protected in the nitrogen of the amine with an appropriate protecting group (Pr) by forming a protected amino acid of formula B. One skilled in the art can easily select an amino protecting group suitable. For example, two common protecting groups are BOC, which is introduced by treating the amino acid with di-ert-butyldicarbonate, preferably in a protic solvent or in a mixture of solvents at a high pH, and CBZ, which is introduced by treatment of the amino acid with chloroformate of benzyl, preferably in a protic solvent or a mixture of solvents, and a base. The amino acid compound protected in the amino of formula B is then coupled with an appropriate amine of formula HNRR (in which the R groups are consistent with the compounds of the present invention) in a procedure analogous to the coupling reaction discussed above to form a protected amide compound of formula C. The protected amide of formula C can then be deprotected to form an amide of formula D. If the protecting group is BOC, deprotection is typically carried out by treating the compound protected with an acid in a solvent aprotic. Suitable acids include HCl, CH3SO3H and trifluoroacetic acid. It may be desired to prepare esters of the compounds of formulas A or B. With reference to scheme V, the esters of compounds A and B can be prepared by reacting the compound with an appropriate alcohol and an acid catalyst such as concentrated sulfuric acid or by treatment with alkyl halide such as methyl iodide and a base such as potassium carbonate. The compounds of formula E can also be prepared by protecting a compound of formula A and then forming the ester. Alternatively, compounds of formula E can be prepared starting with a compound of formula A, forming an ester and then protecting the amine group. Analogous methods for forming and separating esters and protecting amine groups are well known to those skilled in the art. According to scheme VI, compounds of formula A in which Rb is not hydrogen can be prepared as follows. The amino acid of formula B can be prepared by N-alkylation of a compound of formula G, which is an alpha-amino acid protected at the amino group. N-alkylation is well known in the art and can be carried out using an appropriate alkylating agent and a suitable base. In Benoiton, Can. J. Chem., 55: 906-910 (1985) and Hansen, J. Org. Chem., 50: 945-950 (1977) describes specific procedures for alkylation. For example, when Rb is methyl, and Pr is BOC, sodium hydride and methyl iodide in tetrahydrofuran can be used. Deprotection of the compound of formula B produces a compound of formula A. Alternatively, a compound of formula H can be N-alkylated by a three-step sequence involving reductive benzylation, such as with benzaldehyde followed by Pd / catalyzed hydrogenation. C, giving the mono-N-benzyl derivative and the reductive amination with an appropriate carbonyl compound, for example, formaldehyde and sodium cyanoborohydride to introduce Rb as methyl, giving the amino acid substituted with N-benzyl. The N-benzyl protecting group is conveniently removed, for example, by hydrogenation with an appropriate catalyst to provide a compound of formula A. Reinhold et al., J. Med. Chem., 11: 258-260 (1968) describe specific conditions for the alkylation process in three stages. Although many of the starting materials based on alpha-amino acids are known, these can be synthesized by a series of procedures that are well known in the art. For example, the Strecker synthesis or variations thereof can be used. Accordingly, an aldehyde, sodium or potassium cyanide and ammonium chloride react to form an aminonitrile. It will be appreciated that the selected aldehyde is determined by the desired amino acid. The aminonitrile is then hydrolyzed with a mineral acid to form the desired amino acid. Alternatively, the Bucherer-Berg procedure in which hydantoin is formed by heating an aldehyde with ammonium carbonate and potassium cyanide can be used., followed by hydrolysis, for example, with barium hydroxide in refluxing dioxane, with acid or base, forming the desired compounds. In reviews of Duthaler, Tetrahedron, 50: 1539-1650 (1994) or of Williams, Synthesis of Optically Active Amino Acids, Pergamon, Oxford, UK, 1989, suitable methods are found for the synthesis and / or resolution of compounds of formula H ( Scheme VI) (alpha-amino acids). Another procedure is presented in Corey and Link, J. Am. Chem. Soc, 114: 1906-1908 (1992). The synthesis of the compounds of the present invention in which Y is it is carried out by coupling an amide compound of formula P (Scheme VII) with a bicyclic pyrrolyl carboxylic acid of formula 5. The coupling process can be carried out as described above. The synthesis of the amides of formula P is illustrated by scheme VII. To begin, an aminoaldehyde is treated with the protected nitrogen of formula J with sodium or potassium cyanide in an aqueous solution with a common solvent such as dioxane or ethyl acetate at a temperature from about 0 ° C to about 50 ° C, providing a compound of formula K which is a cyanohydrin. The cyanohydrin of formula K is then reacted with an alcohol such as methanol and a strong acid-based catalyst such as HCl at a temperature from about 0 ° C to about 50 ° C, followed by the addition of water, if necessary. The protecting group is then removed, if still present, by an appropriate deprotection procedure, to provide a compound of formula L. For example, if the protecting group is BOC, the compound of formula L is formed directly from the compound of formula K, and the addition of water is not necessary. The compound of formula L can be protected on nitrogen by forming a compound of formula M followed by hydrolysis of the ester with aqueous alkali at a temperature from about 0 ° C to about 50 ° C in an inert reaction solvent, giving rise to the hydroxy acid corresponding to the formula N. The hydroxy acid of formula N is coupled with a suitable amine to form the protected aminoamide of formula O, which is subsequently deprotected to form a compound of formula P. In PCT publication WO / 9325574, example 1a, it is provided an analogous example of the conversion of the compound of formula K to the corresponding compound of formula L. Further analogous examples in which a cyanohydrin is converted to a compound of formula M can be found in U.S. Patent No. 4,814,342 and in the publication EPO 0438233. It may be desirable to have a certain stoichiometry at the alpha and beta positions of the compounds of formula P. (The alpha position is the carbon atom that contains the hydroxyl group). The desired stereochemistry can be obtained by the use of a single stereoisomer aldehyde of formula J. The cyanohydrin of formula K can be prepared from the stereochemically pure aldehyde by treatment with sodium or potassium cyanide as described above, maintaining the carbon stereochemistry chiral of the aldehyde, giving rise to a mixture of separable stereoisomers, as is well known to those skilled in the art. technique, by crystallization. See, for example, Biochemistry, 31: 8125-8141 (1992). Alternatively, the separation of the isomers can be effected by chromatography or recrystallization techniques after conversion of a compound of formula K to a compound of formula L, M, N, O or P, by methods described herein and the like to those well known in the art. With reference to scheme VIII, aminoaldehydes of formula J can be prepared from the corresponding alpha-amino acid of formula Q. In one process, the alpha-amino acid of formula Q is protected in nitrogen and esterified to form a compound of formula R The compound of formula R is reduced, for example, with diisobutylaluminum hydride in hexane or toluene, or in a mixture of both, at a temperature from about -78 ° C to about -50 ° C, followed by the quenching with methanol. at -78 ° C, as described in J. Med. Chem., 28: 1779-1790 (1995), forming the aldehyde of formula J. Alternatively, the aldehydes of formula J can be prepared by oxidation of alcohols of formula T; for example, with pyridine-SO 3 at a temperature of about -10 ° C to about 40 ° C in an inert reaction solvent, preferably dimethisulfoxide. Protected aminoalcohols of formula T, if not commercially available, can be prepared by protecting aminoalcohols of formula S. The aminoalcohols of formula S are prepared by reducing amino acids of formula Q. The reduction can be carried out by treating the amino acids of Formula Q with lithium aluminum hydride according to the procedure described by Dickman et al., Organic Synthesis; Wiley, New York, 1990; Collect. Vol. VIII, p. 530, or with sulfuric acid-sodium borohydride by the method of Abiko and Masamune, Tetrahedron Lett., 333: 5517-5518 (1992) or with sodium borohydride-iodine according to the method of McKennon and Myers, J. Org. Chem., 58: 3568-3571 (1993), in which other procedures are also reviewed. The preparation of the alpha-amino acid and N-alkylated amino acids has been described above. In addition, PCT publications WO96 / 3985, published December 12, 1996, and WO96 / 39384, published December 12, 1996, contain additional details and examples of the methods of synthesis aspects of the present compounds. These publications are incorporated herein by reference.

Equipment and general procedures The NMR spectra were recorded on a Bruker AM300 or Varian XL-400 spectrometer at approximately 23 ° C, at 300 or 400 MHz, respectively, for the proton nuclei. Unless otherwise stated, NMR spectrum data is recorded for a 400 MHz spectrometer. Routine mass spectrum data were obtained using a VG / Fisons Instruments Platform II spectrometer that operated with an APCI source (chemical ionization at atmospheric pressure). The melting points are uncorrected and determined in a Thomas Hoover melting point apparatus. Unless indicated otherwise, the reagents were used as obtained from commercial suppliers. The term "concentrate" refers to the removal of the solvent in a rotary evaporator. The exceptions in the use of the A-H procedures are noted in particular in parentheses, followed by the mention of the procedure.

General synthesis procedures PROCEDURE A (Formation of amide using 1-hydroxybenzotriazole hydrate and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride A mixture of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride was treated with a 0.1-0.7M mixture at 0 ° C of the primary amine (1 equivalent, or a salt of the primary amine and 1 equivalent of triethylamine per equivalent of HCl), 1 equivalent of the specified carboxylic acid and 1 equivalent of 1-hydroxybenzotriazole hydrate (1 equivalent to the carboxylic acid) in dichloromethane: dimethylformamide 3: 1. The mixture was allowed to warm to room temperature for several hours, stirred overnight, concentrated to remove dichloromethane and partitioned between ethyl acetate and 1-2N HCl. The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHC 3, dried over MgSO and concentrated to give a crude product which was purified by chromatography on silica gel and / or recrystallization.

PROCEDURE B (Formation of amide using hydrated 1-hydroxy-7-azabenzotriazole and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride It was treated with 1 equivalent (corresponding to the molar ratio to carboxylic acid) of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide hydrochloride a 0.1-0.3M mixture at 0 ° C of the primary amine or a salt of the primary amine (1 equivalent), 1 equivalent of triethylamine, 1 equivalent of the specified carboxylic acid and 1 equivalent of hydrated 1-hydroxybenzotriazole (1 equivalent to the carboxylic acid). The mixture was allowed to warm to room temperature for several hours, stirred overnight and partitioned between ethyl acetate and HCl 1-2N. The organic phase was washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated to give a crude product which was purified by chromatography on silica gel.

PROCEDURE C (Formation of amide using hydrated 1-hydroxy-7-azabenzotriazole and 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide metvodide It was treated with 1.2 equivalents of 1- (3-dimethylamino-propyl) -3-ethylcarbodiimide methiodide a 0.3M mixture of the primary amine hydrochloride (1 equivalent), 1.2 equivalents of triethylamine, 1 equivalent of the specified carboxylic acid and 1.2 equivalents of 1-hydroxybenzotriazole hydrated in dimethylformamide. The mixture was stirred overnight and partitioned between ethyl acetate and 1 N HCl. The organic phase was washed sequentially with 1 N HCl and water, dried over MgSO 4 and concentrated to give a crude product.

PROCEDURE D (Hydrolysis of ethyl ester with potassium hydroxide) A 0.1-0.8M suspension of the ethyl ester (1 equivalent) and KOH (2 equivalents) in water was heated to reflux for 1 to 7 hours, allowed to cool to room temperature, stirred overnight and extracted with ethyl acetate. ethyl. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO4 and concentrated to give a crude product which was purified by chromatography and / or washing with solvent.

PROCEDURE E (Hydrolysis of ethyl ester with sodium hydroxide) A 0.1-0.8 M suspension of ethyl ester (1 equivalent) and NaOH (10 equivalents) in methanol was heated at 65 ° C for 2 hours, allowed to cool to room temperature, concentrated to remove methanol, diluted with water and it was extracted with ethyl acetate. The aqueous phase was acidified with 2N HCl and extracted with ethyl acetate. The combined organic phases were dried over MgSO 4 and concentrated to give a crude product which was purified by recrystallization.

PROCEDURE F (Hydrolysis of ethyl ester with lithium hydroxide) A 0.1-0.3 M solution of the ethyl ester (1 equivalent) and LiOH-H 2 O (4-6 equivalents) in tetrahydrofuran: methanol: water 3: 2: 1 was heated at 60-65 ° C overnight, allowed to cool to room temperature, concentrated to remove tetrahydrofuran and methanol, and acidified with 1-2N HCl. The resulting precipitate was filtered, washed with water and dried in vacuo to give the product.

PROCEDURE G (Formation of nitrile with hydroxylamine hydrochloride) A mixture 0.1-0.2 M of the aldehyde (1 equivalent) and hydroxylamine hydrochloride (2.2-4 equivalents) in dimethylformamide was heated overnight at 125 ° C, allowed to cool to room temperature and partitioned between ethyl acetate and water. . The aqueous phase was extracted with ethyl acetate. The combined organic phases were washed with water, dried over MgSO 4 and concentrated to give the crude product which was purified by chromatography on silica gel.

PROCEDURE H (Cancellation with azidoacetic acid ethyl ester) A 0.6-1.2M solution at 0 ° C of sodium (3-4 equivalents) in ethanol was treated with a mixture of the aldehyde (1 equivalent) and azidoacetic acid ethyl ester (1 equivalent to sodium), dropwise so that the temperature of the reaction was maintained at 5-10 ° C. The reaction mixture was stirred for 1-2 hours, quenched with cold saturated aqueous NH CI and extracted with ether. The combined organic phases were dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel. A 0.1-0.2M solution of the resulting acrylate in xylenes was heated at reflux for 20 to 60 minutes and allowed to cool to room temperature. The reaction solution was further cooled to induce crystallization of the product or concentrated to give the crude product which was purified by washing with hexanes and / or by chromatography on silica gel.

EXAMPLE 1 Fd S) -Benzyl-3 - ((3R. 4S) -dihydroxypyrrolidin-1-l) - 6H-thieno r2,3-blpyrrole-5-carboxylic acid (2R) -hydroxy-3-oxo-propylamide 6H-Thieno [2,3-b] pyrrole-5-carboxylic acid (Soth, S. et al., Bull. Soc. Chim. Fr., 2511-2515 (1975)) and (3S) -amino- were coupled. 1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1-one according to the procedure A (4- (dimethylamino) pyridine (0.1 eq.) Was also added to the reaction mixture). P.f .: 137-145 ° C, CIMS m / e 430.2 (MH +). 1 H NMR (DMSO-de) d 11.67 (br s, 1 H), 7.74 (d, J = 8.9 Hz, 1 H), 7. 21 (m, 4H), 7.11 (m, 1 H), 6.96 (s, 3H), 5.03 (dd, J = 2.9, 7.5 Hz, 0.5 H), 4.93 (m, 1 H), 4.87 (m, 0.5 H), 4.80 (dd, J = 2.9, 7.5 Hz, 0.5 H), 4.74 (br s, 0.5 H), 4.40 (br s, 1 H), 4.19 (m, 1 H), 4.06 (dq, J = 3.2, 5.3 Hz, 0.5H), 3.99-3.87 (m, 1.5H), 3.54 (m, 1 H), 3.38 (m, 0.5H), 3.25-3.06 (m, 2.5H), 2.94-2.81 (m , 2H).

EXAMPLE 1A Benzyl ester of r (1S) -benzyl-3 - ((3R.4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxo-propyl carbamic acid (2R, 3S) -3-benzyloxycarbonylamino-2-hydroxy-4-phenylbutyric acid (Takita, T. et al., J. Med. Chem., 20: 510-515 (1977) and pyrrolidin- hydrochloride) were coupled. 3S, 4S) -diol according to procedure A (dimethylformamide as the solvent of the reaction concentrated to half volume before the procedure) CIMS m / e 415.2 (MH +). 1H NMR (DMSO-de) d 7.28-7.15 (m , 10H), 7.07-7.01 (m, 1 H), 4.94-4.75 (m, 4.5H), 4.65 (d, J = 7.7 Hz, 0.5H), 4.09-3.88 (m, 4H), 3.51-3.38 ( m, 1 H), 3.27-3.07 (m, 3H), 2.83-2.63 (m, 2H).

EXAMPLE 1 B (3S) -Amino-1 - ((3R.4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-4-phenylbutan-1-one According to a procedure of Takita, T. et al. (J. Med. Chem., 20: 510-515 (1977)), a mixture of [(1S) -benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) benzyl ester was stirred - (2R) -hydroxy-3-oxopropyl] carbamic (1.2 g, 2.9 mmol) and 10% palladium on carbon (120 mg) in methanol (20 ml) under a hydrogen atmosphere (2.72-3.01 atm) in a Parr device overnight, was filtered through Celite ( R) and concentrated. The product was obtained in the form of a sticky solid (1.0 g, 100%). CIMS m / e 281.2 (MH +). 1 H NMR (DMSO-d 6) d 7.27-7.13 (m, 5H), 4.95-4.80 (m, 3H), 3.93 (br s, 2H), 3.83 (dd, J = 3.3, 9.1 Hz, 1 H), 3.45 -3.05 (m, 6H), 2.99 (dq, J = 3.5, 6.3 Hz, 1 H), 2.65 (m, 1 H), 2.50 (m, 1 H).

EXAMPLE 2 r (1S) -Benzyl-3 - ((3R.4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropylamide of 2-bromo-6H-thienor-2,3-b1pyrrole -5-carboxylic 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydrox- were coupled. -4-phenylbutan-1-one according to the APf procedure: 143-145 ° C, CIMS m / e 508.0 / 510.0 (MH +). 1 H NMR (DMSO-de) d 11.72 (br s, 1 H), 7.84 (d, J = 9.1 Hz, 1 H), 7. 22 (m, 5H), 7.11 (m, 1 H), 6.99 (s, 1 H), 5.04 (d, J = 7.3 Hz, 0.5H), 4.95 (m, 1 H), 4.89 (d, J = 5.0 Hz, 0.5H), 4.80 (d, J = 7.7 Hz, 0.5H), 4.75 (d, J = 4.4 Hz, 0. 5H), 4.40 (m, 1 H), 4.19 (m, 1 H), 4.00-3.85 (m, 2H), 3.54 (m, 1 H), 3.39 (dd, J = 4.9, 12.6 Hz, 0.5H) , 3.22 (m, 1.5H), 3.16-3.06 (m, 1 H), 2.94-2.81 (m, 2H).

EXAMPLE 2A 2-Bromo-6H-thienor-2,3-b1pyrrole-5-carboxylic acid 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester was hydrolysed (Eras, J., Gálvez, C, García F., J. Heterocycl. Chem., 21: 215 -217 (1984)) according to the procedure F. CIMS m / e 244.0 / 246.0 ((MH) +). 1 H NMR (DMSO-de) 12.66 (br s, 1 H), 12.10 (br s, 1 H), 7.22 (s, 1 H), 6.87 (d, J = 2.1 Hz, 1 H).

EXAMPLE 3 r (1S) -Benzyl-3 - ((3R.4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropylamide of 2-methyl-6H-thienoyl-2,3-bliroprol 5-carboxylic 2-Methyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (3S) -amio-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) hydrochloride were coupled. -hydroxy-4-phenylbutan-1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 15: 1 dichloromethane: dimethylformamide, phases combined organic washed with water before saturated aqueous NaHCOs). P.f .: 154-157 ° C, CIMS m / e 442.2 ((M-H) +). 1 H NMR (DMSO-d 6) d 11.58 (m, 1 H), 7.66 (d, J = 8.5 Hz, 1 H), 7. 22-7.10 (m, 5H), 6.86 (s, 1 H), 6.64 (s, 1 H), 6.64 (s, 1 H), 5.03-4.73 (m, 3H), 4.38 (br s, 1 H) , 4.18 (m, 1 H), 3.98-3.88 (m, 2H), 3.53 (m, 1 H), 3.39-3.05 (m, 3H), 2.90-2.83 (m, 2H), 2.38 (s, 3H) .

EXAMPLE 3A 2-Methyl-6H-thienor-2,3-b] pyrrole-5-carboxylic acid ethyl ester Using a procedure of C.K. Lau et al. (J. Org. Chem., 51: 3038-3043 (1986)), a mixture of 2-formyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester (Soth, S) was stirred. et al., Bull. Soc. Chim. Fr., 2511-2515 (1975), 500 mg, 2.24 mmol), Znl 2 (1.08 g, 3.36 mmol) and NaBH 3 CN (1.06 g, 16.8 mmol) in dichloroethane (25 ml. ) for 7 days and quenched with saturated aqueous NH4CI (25 ml). The resulting biphasic mixture was stirred for another 30 minutes, extracted with ethyl acetate, dried over Na2SO4 and concentrated. The product was purified by chromatography Chromatotron (3: 2 hexanes: ether) and obtained as a white foam (233 mg, 50%). P.f .: 107-109 ° C, CIMS m / e 208.3 (MH +). 1 H NMR (CDCl 3) d 9.13 (br s, 1 H), 6.94 (s, 1 H), 6.61 (s, 1 H), 4.33 (q, J = 7.1 Hz, 2 H), 2.48 (s, 3 H), 1.36 (t, J = 7.1 Hz, 3H).

EXAMPLE 3B 2-Methyl-6H-thienor-2,3-b] pyrrole-5-carboxylic acid 2-Methyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to the procedure E.P.F .: 180-182 ° C dec., CIMS m / e 180.1 ((M-H) +). 1 H NMR (DMSO-de) d 12.36 (s, 1 H), 11.93 (s, 1 H), 6.77 (s, 1 H), 6.66 (s, 1 H), 2.40 (s, 3 H), 1.36 (t , J = 7.1 Hz, 3H).

EXAMPLE 3C r (1S) -benzyl-3 - ((3R.4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropylcarbamic acid tert-butyl ester (2R, -3S) -3-tert-butoxycarbonylamino-2-hydroxy-4-phenylbutyric acid and pyrrolidin- (3R, 4S) -diol hydrochloride were coupled according to procedure A (1.05 eq of triethylamine, 1.1 eq. carboxylic acid, 1.5 eq of 1-hydroxybenzotriazole hydrate and 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, after removal of dichloromethane, the residue was partitioned between ethyl acetate and 2N NaOH, the combined organic phases were washed sequentially with 2N HCl and saturated NaCl). CIMS m / e 381 (MH +).

EXAMPLE 3D ((3S) -amino-1 - ((3R.4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1 -one hydrochloride It was added to a solution at 0 ° C of tert-butyl acid ester [(1 S) -benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] carbamic acid (1.1 g, 2.9 mmol) in methanol (4 ml), HCl 4N in dioxane (7.2 ml, 28.9 mmol). The solution was allowed to warm slowly to room temperature and stirred overnight. The reaction mixture was concentrated and the residue was washed with methanol and dried in vacuo. The product was obtained as a white solid (1.03 g, 113%). CIMS m / e 281.2 (MH +).

EXAMPLE 4 p-Benzyl-2 - ((3R, 4S) -dih -droxypyrrolidin-1-yl) -2-oxoethylamide of (±) - 2-methyl-6H-thienor-2,3-b1pyrrole-5 carboxylic 2-Methyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (+) - 2-amino-1 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl hydrochloride) were coupled -3-phenylpropan-1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 15: 1 dichloromethane: dimethylformamide, combined organic phases washed with water before saturated aqueous NaHCO3).

P.f .: 134-136 ° C, CIMS m / e 412.0 ((M-H) +). 1 H NMR (DMSO-de) d 11.60 (s, 1 H), 8.37 (m, 1 H), 7.27-6.98 (m, 6H), 6.65 (s, 1 H), 4.99-4.73 (m, 3H), 4.05-3.82 (m, 2.5H), 3.40-2.87 (m, 5.5H), 2.38 (s, 3H).

EXAMPLE 4A (±) -H-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoetipcarbamic acid tert-butyl ester Boc-DL-phenylalanine and pyrroline-hydrochloride (3R, 4S) -diol according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, dichloromethane, reaction time 3 days). CIMS m / e 351.2 (MH +). 1 H NMR (CDCl 3) d 7.28-7.19 (m, 5H), 5.35 (m, 1 H), 4.52 (m, 1 H), 4. 14-3.99 (m, 1.5H), 3.78-3.63 (m, 1.5H), 3.46-3.34 (m, 2H), 3.00-2.65 (m, 3H), 1.40 (s, 9H).

EXAMPLE 4B (±) -2-amino-1 - ((3R. 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan-1-one hydrochloride It was added to a solution at 0 ° C of tert-butyl acid ester (±) - [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] carbamic acid (6.5 g, 20 mmol) in methanol (8 ml), 4N HCl in dioxane (50 g) ml, 200 mmol). The solution was allowed to warm slowly to room temperature and stirred overnight. The resulting white reaction mixture was diluted with ether and the precipitate was filtered, washed with ether and dried in vacuo. The product was obtained as a white solid (5 g, 87%). CIMS m / e 251.2 (MH +). 1 H NMR (300 MHz, DMSO-d 6) d 8.28 (br s, 3 H), 7.38-7.21 (m, 5 H), 5.11-4.93 (m, 2 H), 4.34-4.22 (m, 1 H), 3.96 (m , 1 H), 3.81-3.70 (m, 1 H), 3.89 (m, 0.5H), 3.47 (m, 0.5H), 3.33-2.85 (m, 4H), 2.63 (m, 1 H).

EXAMPLE 5 r (1S) -benzyl-2 - ((3R, 4S) -d-hydroxypyrrolidin-1-yl) -2-oxoetinamide of 2-bromo-6H-thienor-2,3-b1pyrrole-5-carboxylic acid 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide, organic phases washed with water before saturated aqueous NaHCO3). P.f .: 140,142 ° C, CIMS m / e 477.9 / 479.9 (MH +). 1 H NMR (DMSO-de) d 11.73 (s, 1 H), 8.55 (d, J = 8.1 Hz, 1 H), 7. 26-7.09 (m, 7H), 5.00 (br s, 0.5H), 4.91-4.85 (m, 1.5H), 4.77 (m, 1 H), 4.07-3.93 (m, 1.5H), 3.83 (m, 1.5H), 3.41-3.25 (m, 1 H), 3.13 (m, 2H), 3.00-2.87 (m, 2H).

EXAMPLE 5A r (1S) -benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethenacarbamic acid tert-butyl ester Boc-L-phenylalanine and pyrrolidin- (3R, 4S) -diol hydrochloride were coupled according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, dichloromethane, reaction mixture diluted with ethyl acetate and washed sequentially with NaOH 1 N, 1 N HCl and saturated sodium chloride before drying), CIMS m / e 351.2 (MH +). 1 H NMR (DMSO-de) d 7.25-7.13 (m, 5H), 7.06 (dd, J = 8.4, 13.6 Hz, 1 H), 4.98 (d, J = 5.4 Hz, 0.5H), 4.91 (d, J = 5.0 Hz, 0.5H), 4.84 (m, 1 H), 4.25 (dd, J = 8.5, 14.3 Hz ), 4.02 (m, 0.5H), 3.94 (m, 0.5H), 3.79 (m, 1 H), 3.68 (dd, J = 5.9, 10.1 Hz, 0.5H), 3.38 (dd, J = 5.3, 12.2 Hz, 0.5H), 3.27-3.10 (m, 3H), 2.83-2.67 (m, 2H), 1.27 (s, 5H), 1.25 (s, 4H).

EXAMPLE 5B (2S) -amino - ((3R.4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan-1-one hydrochloride It was added to 1 N HCl in dioxane (120 mL, 480 mmol), [(1S) -benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] teramic acid tert-butyl ester. (27 g, 77 mmol). The solution was stirred for 2.5 hours and concentrated. The product was obtained as a white solid (21.5 g, 98%). CIMS m / e 251.0 (MH +). 1 H NMR (DMSO-de) d 8.33 (br s, 3 H), 7.32-7.16 (m, 5 H), 5.10-4.86 (m, 2 H), 4.25-4.13 (m, 1 H), 3.93 (m, 1 H ), 3.73-3.66 (m, 1 H), 3.54 (m, 0.5H), 3.46-3.23 (m, 1.5H), 3.18-3.05 (m, 2H), 3.00 (m, 0.5H), 2.91-2.79 (m, 1 H), 2.57 (dd, J = 5.6 10.0 Hz, 0.5H).

EXAMPLE 6 T (1 S) -Benzyl-3 - ((3R. 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 2-chloro-6H-thienof2,3-b1pyrrole-5 -carboxylic 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) hydrochloride were coupled. -hydroxy-4-phenylbutan-1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide , combined organic phases washed with water before saturated aqueous NaHCO3). P.f .: 148-152 ° C, CIMS m / e 464.0 / 465.9 (MH +). 1 H NMR (DMSO-de) d 11.71 (m, 1 H), 7.84 (d, J = 8.9 Hz, 1 H), 7.23-6.98 (m, 7H), 5.05-4.74 (m, 3H), 4.39 (m , 1 H), 4.20 (m, 1 H), 4.02-3.88 (m, 2H), 3.54 (m, 0.5H), 3.41-3.06 (m, 3.5H), 2.94-2.83 (m, 2H).

EXAMPLE 6A 2-Chloro-6H-thieno-2,3-bupropyl-5-carboxylic acid ethyl ester Using a modified procedure of R.M. Kellogg et al. (J. Org. Chem., 33: 2902-290) (1968), was added to a 0 ° C solution of 6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester (Eras, J., Gálvez, C, García, F., J. Heterocycl. Chem., 21: 215-217 (1984), 1.45 g, 7.44 mmol) in acetic acid (15 ml) and CHCl3 (15 ml), N-chlorosuccinimide (1.04 g, 7.81 mmol) for 2 hours. The reaction mixture was allowed to warm slowly to room temperature for several hours, stirred overnight, concentrated to remove chloroform, diluted with water, made basic with 5N NaOH and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4, and concentrated. The product was purified by Chromatron chromatography (radial) using 90:10 hexanes / diethyl ether (90:10). Finally, the recrystallization product was further purified by flash column chromatography using 90:10 petroleum ether / isopropyl ether. The resulting product was obtained as a white solid (824 mg, 48%). CIMS m / e 228.2 / 230.2 ((M-H) +). 1 H NMR (CDCl 3) d 9.28 (br s, 1 H), 6.98 (d, J = 1.9 Hz, 1 H), 6.88 (s, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 1.35 ( t, J = 7.2 Hz, 3H).

EXAMPLE 6B 2-Chloro-6H-thieno r2,3-b] pyrrole-5-carboxylic acid 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to procedure D (reaction heated to 85 ° C). CIMS m / e 200.1 / 202.1 ((M-H) +). 1 H NMR (DMSO-de) d 12.66 (br s, 1 H), 12.08 (s, 1 H), 7.11 (d, J = 1.9 Hz, 1 H), 6.86 (t, J = 2.1 Hz, 1 H) .

EXAMPLE 7 r (1S) -Benzyl-2 - ((3R.4S) -dihydroxypyrrolidin-1-yl) -2-oxoetinamide of 2-chloro-6H-thienoF2,3-blpyrrole-5-carboxylic acid 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide, washed combined organic phases with water before saturated aqueous NaHCO3). P.f .: 142-145 ° C, CIMS m / e 432.1 / 434.2 ((M-H) +). 1 H NMR (DMSO-de) d 11.72 (m, 1 H), 8.55 (d, J = 8.5 Hz, 1 H), 7.28-7.10 (m, 7H), 5.00 (d, J = 5.2 Hz, 0.5H) , 4.99-4.70 (m, 2.5H), 4.09-3.76 (m, 2.5H), 3.41-3.24 (m, 2H), 3.13 (m, 1.5H), 3.02-2.87 (m, 2H).

EXAMPLE 8 (1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide 2,4-dichloro-6H-thienoyl 2,3 -b1pyrrole-5-carboxylic acid 2,4-Dichloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin 1- hydrochloride were coupled. il) - (2R) -hydroxy-4-phenylbutan-1-one according to process A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, : 1 dichloromethane: dimethylformamide, 0.06 M). P.f. : 130-134 ° C (dec.), CIMS m / e 496.2 / 498.2 ((M-H) +). 1 H NMR (DMSO-de) d 12.13 (br s, 1 H), 7.40-7.15 (m, 7H), 5.51 (d, J = 5.8 Hz, 0.5H), 5.38 (d, J = 6.3 Hz, 0.5H ), 4.99 (d, J = 4.9 Hz, 1 H), 4.92 (d, J = 4.8 Hz, 0.5H), 4.85 (d, J = 4.1 Hz, 0.5H), 4.55-4.40 (m, 1 H) , 4.26 (m, 1 H), 4.08-3.90 (m, 2H), 3.56-2.89 (m, 6H).

EXAMPLE 8A 2,4-dichloro-6H-thienol-2,3-b] pyrrole-5-carboxylic acid ethyl ester To a 0 ° C solution of 6H-thieno [2,3-b] pyrrole-5-carboxylic acid ethyl ester (180 mg, 0.92 mmol) in acetic acid (2 ml) and CHCl3 (2 ml) was added, N-chlorosuccinimide (294 mg, 2.2 mmol) for 30 minutes for 30 minutes. The reaction mixture was allowed to warm slowly to room temperature for several hours, stirred overnight, concentrated to remove chloroform, diluted with water, made basic with 5N NaOH and extracted with ethyl acetate. The combined organic phases were washed with saturated aqueous NaHCO3, dried over MgSO4 and concentrated. The product was purified by Chromatron chromatography (4: 1 hexanes: ether) and obtained as a white solid (180 mg, 74%). P.f .: 166-167 ° C, CIMS m / e 262.1 / 264.1 ((M-H) +). 1 H NMR (300 MHz, CDCl 3) d 9.21 (br s, 1 H), 6.90 (s, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.39 (t, J = 7.2 Hz, 3 H).

EXAMPLE 8B 214-dichloro-6H-thienor-2,3-blpyrrole-5-carboxylic acid The ethyl ester of 2,4-dichloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure E (reflux for 12 hours before allowing to cool to room temperature, acidification with concentrated HCl, without purification). CIMS m / e 234.0 / 236.0 ((M-H) +). 1 H NMR (DMSO-de) d 12.28 (br s, 1 H), 7.17 (s, 1 H).

EXAMPLE 9 (±) - 4H-Thienor3,2-blpyrrole-5-carboxylic acid (-) - Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxo-ethynamide 4H-Thieno [3,2-b] pyrrole-5-carboxylic acid was coupled (Soth, S., Farnier, M, Paulmier, C, Can. C. Chem., 56, 1429-34 (1978)) and (±) -2-amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan-1-one hydrochloride according to Procedure A (9: 1 dichloromethane: dimethylformamide, 0.06M, combined organic phases washed with 2N NaOH, dried over Na 2 S 4).

P.f .: 212 ° C, CIMS m / e 400.1 (MH +). 1 H NMR (DMSO-de) d 11.59 (m, 1 H), 8.51 (d, J = 8.5 Hz, 1 H), 7.36 (d, J = 5.2 Hz, 1 H), 7.30-7.11 (m, 5H) , 6.92 (m, 1 H), 5.01 (d, J = 5.0 Hz, 0.5H), 4.92 (d, J = 4.8 Hz, 0.5H), 4.87-4.76 (m, 2H), 4.04-3.93 (m, 1 H), 3.83 (m, 1.5H), 3.43-3.25 (m, 2.5H), 3.13 (m, 1 H), 3.03-2.86 (m, 2H).

EXAMPLE 10 T (1 S) -Benzyl-3 - ((3R. 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 2-bromo-4H-tienof3.2-b1-5 acid -pyrrolcarboxyl 2-Bromo-4H-thieno [2,3-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R) hydrochloride were coupled., 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1-one according to process B (1.5 eq of 1-hydroxy-7-azabenzotriazole hydrate, 1.1 eq. of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide before the procedure, combined organic phases washed with water before saturated NaHCO 3 saturated). P.f .: 138-143 ° C, CIMS m / e 508.0 / 510.0 (MH +). 1 H NMR (DMSO-de) d 11.68 (m, 1 H), 7.86 (d, J = 9.1 Hz, 1 H), 7.25-7.18 (m, 4H), 7.12-7.08 (m, 2H), 7.02 (s) , 1 H), 5.05 (d, J = 7.5 Hz, 0.5H), 4. 95 (m, 1 H), 4.88 (d, J = 5.0 Hz, 0.5H), 4.81 (d, J = 7.5 Hz, 0.5H), 4.75 (d, J = 3. 5 Hz, 0.5H), 4.46-4.37 (m, 1 H), 4.20 (m, 1 H), 4.08-3.85 (m, 2H), 3.54 (m, 1 H), 3.40-3.05 (m, 3H), 2.95-2.81 (m, 2H).

EXAMPLE 10A 2-Bromo-4H-thienor3,2-b1pyrrole-5-carboxylic acid 2-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid ethyl ester was hydrolysed (Eras, J., Gálvez, C, García, F., J. Heterocycl. Chem., 21: 215 -217 (1984)) according to procedure D (after cooling to room temperature, acidification with 2N HCl, filtration of the resulting precipitate, suspension in toluene, concentration, without purification). CIMS m / e 244.0 / 246.0 ((M-H) +). 1 H NMR (DMSO-de) d 12.63 (s, 1 H), 12.04 (s, 1 H), 7.13 (s, 1 H), 6. 97 (s, 1 H).

EXAMPLE 11 r (1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropylamide of 4H-thienor-3,2-b] pyrrole-5-carboxylic acid 4H-Thieno [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4 hydrochloride were coupled. phenylbutan-1-one according to procedure A (combined organic phases washed with 2N NaOH, dried over Na 2 SO 4). P.f .: 185-190 ° C, CIMS m / e 430.1 (MH +). H NMR (DMSO-de) d 11.57 (s, 0.5H), 11.53 (s, 0.5H), 7.80 (d, J = 8.9 Hz, 1 H), 7.32 (dd, J = 0.9, 5.3 Hz, 1 H ), 7.23 (m, 4H), 7.12 (m, 1 H), 7.07 (s, 1 H), 6.91 (m, 1 H), 5.06 (d, J = 7.3 Hz, 0.5H), 4.96 (m, 1 H), 4.89 (d, J = 5.2 Hz, 0.5H), 4.82 (d, J = 7.5 Hz, 0.5H), 4.76 (d, J = 4.2 Hz, 0.5H), 4.45-4.38 (m, 1 H), 4.21 (m, 1 H), 4.01-3.86 (m, 2H), 3.55 (m, 1 H), 3.40 (dd, J = 4.9, 12.6 Hz, 0.5H), 3.23 (m, 1.5H) , 3.17-3.07 (m, 1 H), 2.97-2.83 (m, 2H).

EXAMPLE 12 M-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoetipamide of (±) - 2-bromo-4H-furor3,2-b1pyrrole-5-carboxylic acid 2-Bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (±) -2-amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) hydrochloride were coupled. 3-phenylpropan-1-one according to procedure A (1: 1 dichloromethane: dimethylformamide, stirred reaction mixture for 3 days, combined organic phases washed with 2N NaOH, dried over Na 2 SO 4). P.f .: 100-101 ° C (dec.), CIMS m / e 462.2 / 464.1 (MH +). 1 H NMR (DMSO-de) d 11.33 (m, 1 H), 8.41 (dd, J = 2.8, 8.2 Hz, 1 H), 7.27-7.18 (m, 4H), 7.13 (m, 1 H), 6.93 ( d, J = 5.8 Hz, 1 H), 6.69 (d, J = 0.8 Hz, 1H), 4.98-4.75 (m, 3H), 3.99 (m, 0.5H), 3.93 (m, 0.5H), 3.81 ( m, 1.5H), 3.41-3.21 (m, 2.5H), 3.12 (m, 1 H), 3.00-2.82 (m, 2H).

EXAMPLE 12A 2-Bromo-4H-furor3,2-blpyrrole-5-carboxylic acid The ethyl ester of 2-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid was hydrolysed (Krutosikova, A., Kovac, J. Dandarova, M, Lesko, J, Ferik, S., Collect Chem. Commun., 46: 2564-2573 (1981)) according to procedure E (4 eq of 2N NaOH, ethanol, reflux for 5 hours, at room temperature overnight, after concentration to remove the Ethanol, partition of the residue between ethyl acetate and 2N HCl, combined organic phases dried over Na2SO4, without purification). 1 H NMR (DMSO-de) d 12.47 (br s, 1 H), 11.67 (s, 1 H), 6.76 (d, J = 0.8 Hz, 1 H), 6.67 (t, J = 0.8 Hz, 1 H) .

EXAMPLE 13 fd s) -Benzyl-3 - ((3R. 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 2-bromo-4H-furor3.2-bloterrol-5 -carboxylic 2-Bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) hydrochloride were coupled. -hydroxy-4-phenylbutan-1-one according to procedure A (2: 1 dichloromethane: dimethylformamide, stirred reaction mixture for 3 days, combined organic phases washed with 2N NaOH, dried over Na 2 SO 4, Mp: 112-123 ° C ( desc.), CIMS m / e 492.1 / 494.1 (MH +). 1 H NMR (DMSO-de) d 11.31 (s, 0.5H), 11.27 (s, 0.5H), 7.71 (d, J = 8.7 Hz, 1 H), 7.25-7.18 (m, 4H), 7.11 (m, 1 H), 6.81 (s, 1 H), 6.68 (d, J = 2.9 Hz, 1 H), 5.05-4.73 (m, 3H), 4.44-4.34 (m, 1 H), 4.17 (br s, 1 H), 3.98-3.85 (m, 2H), 3.56-3.48 (m, 1 H), 3.40-3.06 (m, 3H), 2.94-2.80 (m, 2H).

EXAMPLE 14 r (1S) -Benzyl-2 - ((3R.4S) -dihydroxypyrrolidin-1-yl) -2-oxoethenamide of 6H-thienor-2,3-b] pyrrole-5-carboxylic acid 6H-Thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan-1-one hydrochloride were coupled. according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 15: 1 dichloromethane: dimethylformamide, stirred reaction mixture for 3 days, then saturated aqueous NaHCO3, combined organic phases washed with water, dried over Na2S? 4). MP: 179-184 ° C, CIMS m / e 400.1 (MH +), 398.2 ((M-H) +). 1 H NMR (300 MHz, DMSO-d 6) d 11.79 (br s, 1 H), 8.52 (d, J = 8.3 Hz, 1 H), 7.34-7.16 (m, 6H), 7.04 (m, 2H), 5.04 (d, J = 5.1 Hz, 0.5H), 4.96 (d, J = 4.9 Hz, 0.5H), 4.90-4.80 (m, 2H), 4.09-3.98 (m, 1 H), 3.89 (m, 1.5H) ), 3.49-3.29 (m, 2.5H), 3.19 (m, 1 H), 3.08-2.91 (m, 2H).

EXAMPLE 15 r (1S) -Benzyl-2 - ((3R.4S) -dihydroxypyrrolidin-1-yl) -2-oxoetinamide of 2-bromo-4H-thienor3.2-blpyrroxy-5-carboxylic acid 2-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide, the reaction mixture was stirred for 3 days, the combined organic phases were washed with water before saturated aqueous NaHCO3, dried over Na2S4). P.f .: 140-143 ° C, CIMS m / e 476.1 / 478.0 ((M-H) +). 1 H NMR (300 MHz, DMSO-d 6) d 11.73 (m, 1 H), 8.61 (d, J = 8.3 Hz, 1 H), 7.34-7.15 (m, 6H), 5.05-4.84 (m, 3H), 4.15-3.85 (m, 2.5H), 3.48-2.95 (m, 5.5H).

EXAMPLE 16 f (1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxo-ethyl-2-methyl-4H-thienor3,2-blpyrrole-5-carboxylic acid 2-Methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1 -one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide, stirred reaction mixture for 3 days , organic phases combined with water before saturated aqueous NaHCO3, dried over Na2SO4). P.f .: 128-130 ° C, CIMS m / e 412.2 ((M-H) +), 414.1 (MH +). 1 H NMR (DMSO-de) d 11.40 (m, 1 H), 8.38 (m, 1 H), 7.37-7.05 (m, 6H), 6.65 (s, 1 H), 4.97 (d, J = 5.2 Hz, 0.5H), 4.90-4.76 (m, 2.5H), 4.07-3.82 (m, 2.5H), 3.42-3.25 (m, 2H), 3.13 (m, 1.5H), 3.01-2.87 (m, 2H), 2.44 (d, J = 1 Hz, 3H).

EXAMPLE 16A 2-Methyl-4H-thienor3,2-blpyrrole-5-carboxylic acid ethyl ester A ring was formed with 5-methyl-2-thiophenecarboxaldehyde according to procedure H (organic acrylate phases dried over Na 2 SO 4). P.f .: 129-130 ° C, CIMS m / e 208.2 ((M-H) +). 1 H NMR (CDCl 3) d 8.90 (br s, 1 H), 7.04 (s, 1 H), 6.63 (s, 1 H), 4.33 (q, J = 7.1 Hz, 1 H), 2.54 (s, 3 H) , 1.36 (t, J = 7.2 Hz, 3H).

EXAMPLE 16B 2-Methyl-4H-thienor3,2-blpyrrole-5-carboxylic acid The ethyl ester of 2-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure D (after cooling to room temperature, acidification with 2N HCl, extraction with ethyl acetate, phases organic extracts dried over Na2SO4, without purification). CIMS m / e 180.2 ((M-H) +). 1 H NMR (300 MHz, DMSO-d 6) d 12.35 (br s, 1 H), 11.72 (s, 1 H), 6.95 (s, 1 H), 6.73 (s, 1 H), 2.51 (s, 3 H) .

EXAMPLE 17 T (1 S-Benzyl-2 - ((3R.4S) -dihydroxypyrrolidin-1-yl) -2-oxoetipamide of 2,4-dichloro-6H-thieno [2,3-blpyrrole-5- carboxylic 2,4-Dichloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3 hydrochloride were coupled. -phenylpropan-1-one according to procedure A (1.5 eq of 1-hydroxybenzotriazole hydrate, 1.1 eq of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride, 25: 1 dichloromethane: dimethylformamide, reaction time 2 days , combined organic phases washed with water before saturated aqueous NaHCO3, dried over Na2S? 4). P.f .: 203-204 ° C, CIMS m / e 468.1 / 470.1 (MH +). 1 H NMR (DMSO-d 6) d 12.20 (s, 1 H), 7.65-7.58 (m, 1 H), 7.28-7.08 (m, 6H), 5.04 (d, J = 3.3 Hz, 1 H), 4.98- 4.80 (m, 3H), 4.08-3.95 (m, 1 H), 3.91-3.74 (m, 2H), 3.26-3.10 (m, 2H), 3.10-2.88 (m, 2H).

EXAMPLE 18 r (1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethinamide of 2-cyano-6H-thieno [2,3-b1pyrrole-5-carboxylic acid 2-Cyano-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1- (3-hydroxyazetidin-1-yl) -3-phenylpropan-1-one hydrochloride were coupled. according to procedure B. CIMS m / e 395.1 (MH +) 1 H NMR (DMSO-d6) d 12.09 (s, 1 H), 8.74 (d, J = 8.5 Hz, 1 H), 7.99 (s, 1 H), 7.29-7.12 (m, 6H), 5.68 (m, 1 H), 4.58 (m, 1 H), 4.41 (m, 1 H), 4.28 (m, 0.5H), 4.11- 3.90 (m, 2H), 3.69 (m, 0.5H), 3.57-3.49 (m, 1 H), 3.01-2.88 (m, 2H).

EXAMPLE 18A 2-Cyano-6H-thienoyl-2,3-blpyrrole-5-carboxylic acid 2-Formyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid (Soth et al., Bull. Soc. Chim. Fr., 2511-2515 (1975)) was treated with hydroxylamine hydrochloride. according to procedure G (temperature of 100 ° C for 13 hours, 125 ° C for 7 hours, after cooling to room temperature, the concentration gave the crude product). CIMS m / e 190.9 ((M-H) +). 1 H NMR (DMSO-de) d 13.03 (br s, 1 H), 12.39 (br s, 1 H), 7.97 (s, 1 H), 7.04 (s, 1 H).

EXAMPLE 19 r (1S) -Benzyl-2-morpholin-4-yl-2-oxoetinamide of 2-chloro-6H-thienof2.3-blpyrrole-5-carboxylic acid 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1-morpholin-4-yl-3-phenylpropan-1-one hydrochloride were attached (See, for example, example, Suzuki, K, Fujita, H., Sasaki, Y, Shiratori, M., Sakurada, S., Kisara, K., Chem. Pharm. Bull., 36, 4834-40 (1998)) according to procedure C (dissolution of the product in ethyl acetate, washing with water, drying over MgSO 4, concentrated). P.f .: 108-110X, CIMS m / e 416.3 / 418.2 ((M-H) +). 1 H NMR (DMSO-de) d 11.84 (m, 1 H), 8.65 (d, J = 8.2 Hz, 1 H), 7.39-7.13 (m, 7H), 5.08 (q, J = 7.6 Hz, 1 H) , 3.60-3.30 (m, 7H), 3.23 (m, 1 H), 3.09-2.95 (m, 2H).

EXAMPLE 20 f (1S) -Dimethylcarbomoyl-2-phenylethylamide of 2-chloro-6H-thienor2.3-blpyrrole-5-carboxylic acid 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-N, N-dimethyl-3-phenylpropioamide trifluoroacetate were added (See, for example, Holladay, N. et al., J. Med. Chem., 37, 630-5 (1994)) according to procedure C (washed product with ethyl acetate). P.f .: 234-235 ° C, CIMS m / e 374.2 / 376.2 ((M-H) +). 1 H NMR (DMSO-de) d 11.72 (s, 1 H), 8.53 (d, J = 8.1 Hz, 1 H), 7.23 (m, 4H), 7.13 (m, 3H), 5.01 (m, 1 H), 3.01-2.88 (m, 5H), 2.78 (s, 3H).

EXAMPLE 21 r (1S) -Benzyl-2- (1,1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethynamide of 2-chloro-6H-thienor-2,3-b1pyrrole-5-carboxylic acid 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1- (1,1-dioxo-1-thiazolidin-3-yl) -3 hydrochloride were coupled. -phenylpropan-1-one (WO96 / 39384, example 40a) according to procedure C (dissolution of the product in ethyl acetate, washing with water, drying over MgSO4, concentrated). P.f .: 125-129 ° C, CIMS m / e 450.2 / 452.2 ((M-H) +). 1 H NMR (300 MHz, DMSO-d 6) d 11.80 (m, 1 H), 8.75 (dd, J = 8.1, 12.9, 1 H), 7.36 (m, 2 H), 7.26-7.14 (m, 5 H), 5.08 -4.97 (m, 1 H), 4.81 (m, 0.5H), 4.63 (d, J = 11.4, 0.5H), 4.55 (d, J = 12.5, 0.5H), 4.45 (d, J = 12.4, 0.5 H), 4.25 (m, 1 H), 3.90-3.75 (m, 1 H), 3.55-3.35 (m, 2H), 3.05 (m, 2H).

EXAMPLE 22 Ethyl ester of (2S) -r (2-chloro-6H-thieno.2,3-blpyrrole-5-carbonyl) amino-3-phenylpropionyl > piperidin-4-carboxylic 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and 1 - [(2S) -amino-3-phenylpropionyl] piperidine-4-carboxylic acid ethyl ester hydrochloride were coupled according to the procedure C (dissolution of the product in ethyl acetate, washing with water, drying over MgSO, concentrated). P.f .: 104-105 ° C, CIMS m / e 486.2 / 488.2 ((M-H) +). 1 H NMR (300 MHz, DMSO-de) d 11.84 (m, 1 H), 8.64 (t, J = 8.8 Hz, 1 H), 7.32-7.14 (m, 7H), 5.10 (m, 1 H), 4.30-3.89 (m, 4H), 3.15-2.92 (m, 3H), 2.80-2.50 (m, 2H), 1.83- 1.69 (m, 2H), 1.52-0.94 (m, 5H).

EXAMPLE 22A 1 - ((2S) -tert-Butoxycarbonylamino-3-phenylpropionyl) piperidine-4-carboxylic acid ethyl ester Boc-L-phenylalanine (1.1 eq.) And the ethyl ester of piperidine-4-carboxylic acid were coupled according to procedure A (1.5 eq. Of 1-hydroxybenzotriazole hydrate, 1.3 eq. Of 1- (3-dimethylaminopropyl hydrochloride ) -3-ethylcarbodiimide, room temperature, dichloromethane, reaction mixture poured into water, acidified "with 1 N HCl, resulting precipitate filtrate, filtrate extracted with CHCl 3, organic phase washed sequentially with water and brine, dried over MgSO 4 before concentration) CIMS m / e 405.2 (MH +). 1 H NMR (CDCl 3) d 7.26-7.14 (m, 5H), 5.40 (dd, J = 8.9, 19.3 Hz, 1 H), 4.82 (m, 1 H), 4.34- 4.24 (m, 1 H), 4.09 (dq, J = 2.0, 7.1 Hz, 2H), 3.57 (m, 1 H), 2.99-2.88 (m, 2.5H), 2.72 (m, 1 H), 2.45- 2.32 (m, 1.5H), 1.95-1.79 (m, 1.5H), 1.58 (m, 2H), 1.40 (d, J = 2.1 Hz, 9H), 1.23 (m, 3H), 0.68 (m, 0.5H) ).

EXAMPLE 22B 1 - ((2S) -amino-3-phenylpropionyl) piperidine-4-carboxylic acid ethyl ester hydrochloride HCl gas was circulated through a solution of 1 - ((2S) -tert-butoxycarbonylamino-3-phenylpropionyl) piperidine-4-carboxylic acid ethyl ester (11 g, 27.20 mmoles) in ethyl acetate (150 ml) for 10 minutes. The reaction mixture was stirred overnight, concentrated, redissolved in ethyl acetate and ether, and concentrated. The crude product was precipitated with hexanes, filtered and dried under vacuum to provide the title compound (9.1 mg, 98%). CIMS m / e 305.1 (MH +). 1 H NMR (CDCl 3) d 8.56 (br s, 2 H), 7.29-7.18 (m, 5 H), 4.94-4.82 (m, 1 H), 4.22-3.97 (m, 4H), 3.53 (dt, J = 4.5, 12.7 Hz, 1 H), 3.41-3.27 (m, 1 H), 3. 12 (m, 1 H), 2.95 (m, 0.5H), 2.76 (t, J = 10.9 Hz, 0.5H), 2.66 (m, 0.5H), 2.27 (m, 1 H), 2.07 (m, 0.5 H), 1.79-1.51 (m, 2H), 1.38-1.11 (m, 3.5H), 0.41 (m, 0. 5H).

EXAMPLE 23 s) -Benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxoetiHamide of 2-bromo-6H-t-inor-2,3-blpyrrole-5-carboxylic acid 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid and (2S) -amino-1- (3-hydroxyazetidon-1-yl) -3-phenylpropan-1-one hydrochloride were coupled. according to procedure B. CIMS m / e 448.1 / 450.0 (MH +). 1 H NMR (DMSO-de) d 11.77 (s, 1 H), 8.55 (d, J = 8.1 Hz, 1 H), 7.26-7.10 (m, 7H), 5.00-4.76 (m, 3H), 4.07-3.94 (m, 1.5H), 3.83 (m, 1.5H), 3.40-3.22 (m, 1 H), 3.13 (m, 2H), 2.93 (m, 2H).

EXAMPLE 24 r (1s) -Benzyl-2 - ((3R.4S) -dihydroxypyrrolidin-1-yl) -2-oxoetnamide of 2-methyl-4H-furor3,2-blpyrrole-5-carboxylic acid 2-Methyl-4H-furo [3,2-b] pyrrole-5-carboxylic acid was coupled (Krutosikova, A., Kovac, J., Dandarova, M., Lesko, J., Ferik, S., Collect, Czech, Chem. Commun., 46: 2564-2573 (1981)) and (2S) hydrochloride. amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan-1-one according to process B (aqueous acid phase extracted with ethyl acetate, organic phases combined before the basic procedure). CIMS m / e 396.3 ((M-H) +). 1 H NMR (DMSO-de) d 10.96 (m, 1 H), 8.23 (m, 1 H), 7.27-7.19 (m, 4H), 7.14 (m, 1 H), 6.83 (d, J = 5.4 Hz, 1 H), 6.15 (s, 1 H), 4.97 (d, J = 5.2 Hz, 0. 5H), 4.89 (d, J = 4.6 Hz, 0.5H), 4.80 (m, 2H), 3.99 (m, 0.5H), 3.93 (m, 0.5H), 3.82 (m, 1.5H), 3.38 (m , 1 H), 3.25 (m, 1 H), 3.13 (m, 1.5H), 3.00-2.85 (m, 2H), 2. 31 (s, 3H).

EXAMPLE 25 r (1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoetinamide of 2-trimethylsilanylethynyl-6H-thienof2,3-blpyrrole-5-carboxylic acid Using a modified procedure of J.M. Tour et al., (J. Org. Chem., 61, 6906-6921 (1996)), were added sequentially to a degassed solution of [(1S) -benzyl-2- (3-hydroxyazetidin-1-yl) - 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid 2-oxoethyl] -oxoethyl] (106 mg, 0.24 mmol) in tetrahydrofuran (5 ml), diisopropylamine (36 μl, 0.26 mmol), a mixture of copper iodide (I) (9 mg, 0.05 mmol), dichlorobis (triphenylphosphine) palladium (II) (68 mg, 0.1 mmol) and (trimethylsilyl) acetylene (41 μl, 0.29 mmol). The mixture was stirred overnight, poured into water and extracted with dichloromethane. The combined organic phases were washed with saturated NaCl, dried over MgSO4 and concentrated. The product was purified by chromatography Chromatotron (dichloromethane, 20: 1 dichloromethane: methanol) to give the title compound (4.5 mg, 4%). CIMS m / e 464.3 ((M-H) +). 1 H NMR (DMSO-de) d 11.86 (s, 1 H), 8.54 (t, J = 8.9 Hz, 1 H), 7.31 (s, 1 H), 7.23 (m, 4 H), 7.13 (m, 2 H) , 5.66 (m, 1 H), 4.56 (m, 1 H), 4.41 (m, 1 H), 4.28 (m, 0.5H), 4.11-3.89 (m, 2H), 3.66 (m, 0.5H), 3.57-3.46 (m, 1 H), 2.99-2.85 (m, 2H), 0.23 (s, 9H).

EXAMPLE 26 f (1S) -Benzyl-2- (3-hydroxyzetidin-1-yn-2-oxoethinamide of 2-ethynyl-6H-thienor-2,3-blpyrrole-5-carboxylic acid Using a procedure analogous to that of G.M. Whitesides et al., (J. Org. Chem., 53: 2489-2496 (1988)), was added to a solution of [(1S) -benzyl-2- (3-hydroxy] azetin-1-yl. 2-oxoethyl] amide of 2-trimethylsilanylethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid (110 mg, 0.02 mmol) in methanol (0.5 ml), a 5% aqueous solution of hydroxide of potassium (7 μl, 0.06 mmol). The reaction mixture was stirred for 3 hours, concentrated to remove methane, diluted with water and extracted with dichloromethane. The organic phase was dried over MgSO 4 and concentrated to give the title compound (7 mg, 77%). CIMS m / e 392.1 ((M-H) +). 1 H NMR (CDCl 3) d 7.32-7.16 (m, 7 H), 7.03 (m, 2 H), 4.66 (m, 1 H), 4.47 (m, 1 H), 4.17 (m, 1 H), 4.00 (m, 1 H), 3.75-3.56 (m, 3H), 3.35 (m, 1 H), 3.04 (m, 2H).

EXAMPLE 27 r (1S) -Benzyl-2 - ((3R. 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethenamide of 2-fluoro-4H-thienor3,2-b] pyrrol- 5-carboxylic 2-Fluoro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure B (reaction time 4 days). P.f .: 128-132 ° C, CIMS m / e 416.1 ((M-H) +), 418.2 (MH +). 1 H NMR (DMSO-d 6) d 11.72 (m, 1 H), 8.49 (d, J = 8.5 Hz, 1 H), 7. 28-7.13 (m, 6H), 6.71 (s, 1 H), 4.99 (d, J = 5.2 Hz, 0.5H), 4.91 (d, J = 4.8 Hz, 0.5H), 4.86 (d, J = 3.7 Hz, 1 H), 4.79 (m, 1 H), 4.01 (m, 0.5H), 3.94 (m, 0.5H), 3.83 (m, 1.5H), 3.42-3.24 (m, 2.5H), 3.14 ( m, 1 H), 3.01-2.84 (m, 2H) EXAMPLE 27A 2-fluoro-4H-thienor3,2-blpyrrole-5-carboxylic acid ethyl ester A ring was formed with 5-fluorothiophene-2-carbaldehyde (see, for example, Schuetz, RD and Nilles, GP, J. Org. Chem., 36: 2188-90 (1971)) according to procedure H (aldehyde and ester) of azidoacetic acid added in the form of ethanolic solution (0.6M ester), organic phase acrylate washed with saturated aqueous NaCl before drying, non-purified acrylate). CIMS m / e 212.1 ((M-H) +). 1 H NMR (CDCl 3) d 9.16 (br s, 1 H), 7.03 (s, 1 H), 6.51 (s, 1 H), 4.33 (q, J = 7.2 Hz, 2 H), 1.36 (t, J = 7.2 Hz, 3H).

EXAMPLE 27B 2-Fluoro-4H-thienor3,2-blpyrrole-5-carboxylic acid The ethyl ester of 2-fluoro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated). CIMS m / e 184.1 ((M-H) +). 1 H NMR (DMSO-de) d 12.47 (br s, 1 H), 12.03 (s, 1 H), 6.96 (s, 1 H), 6.73 (s, 1 H).

EXAMPLE 28 r (1S) -Benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxoetnamide of 2-cyano-4H-furo [3,2-b1pyrrole-5-carboxylic acid 2-Cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1- (3-hydroxyazetidin-1-yl) 3-phenylpropan-1-one hydrochloride were coupled Procedure B (reaction mixture partitioned between ethyl acetate and water before the acid wash). CIMS m / e 377.1 ((M-H) +), 379.1 (MH +). 1 H NMR (DMSO-de) d 11.78 (s, 1 H), 8.68 (t, J = 8.2 Hz, 1 H), 7.67 (s, 1 H), 7.22 (m, 4H), 7.15 (m, 1 H), 7.01 (d, J = 3.1 Hz, 1 H), 5.68 (m, 1 H), 4.59 (m, 1 H) , 4.40 (m, 1 H), 4.26 (m, 0.5H), 4.05 (m, 1 H), 3.92 (m, 1 H), 3.65 (m, 0.5H), 3.53 (m, 1 H), 3.00 -2.88 (m, 2H).

EXAMPLE 28A 2-Cyano-4H-furor3,2-blpyrro-5-carboxylic acid 2-Formyl-4H-furo [3,2-d] pyrrole-5-carboxylic acid was treated (see, for example, Krutosikova, A. Dandarova, M., Alfodi, J., J Chem. Pap., 48: 268-73 (1994)) with hydroxylamine hydrochloride according to procedure G. CIMS m / e 174.9 ((MH) +). 1 H NMR (DMSO-de) d 13.10-12.60 (br s, 1 H), 12.05 (s, 1 H), 7.73 (s, 1 H), 6.75 (s, 1 H).

EXAMPLE 29 r (1S) -Benzyl-2 - ((3R, 4S) -d-hydroxypyrrolidin-1-yl) -2-chloro-4H-furor3,2-blpyrrole-5-carboxylic acid 2-oxoethylamide 2-Chloro-4H-furo- [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3- hydrochloride were coupled. phenylpropan-1-one according to process B (reaction time 3 days, reaction mixture partitioned between ethyl acetate and water before acid washing). CIMS m / e 418.1 / 420.1 (MH +). 1 H NMR (DMSO-de) d 11.36 (s, 1 H), 8.42 (dd, 2.9, 8.3 Hz, 1 H), 7. 27-7.10 (m, 5H), 6.94 (d, J = 6.0 Hz, 1 H), 6.63 (m, 1 H), 4.99 (d, J = 5.2 Hz, 0.5H), 4.91 (d, J = 5.0 Hz, 0.5H), 4.86-4.77 (m, 2H), 4.00 (m, 0.5H), 3.94 (m, 0.5H), 3.81 (m, 1.5H), 3.43-3.21 (m, 2.5H), 3.13 (m, 1 H), 3.00-2.85 (m, 2H).

EXAMPLE 29A 2-Chloro-4H-furo-r3,2-b1pyrrole-5-carboxylic acid ethyl ester A ring was formed with 4-chlorofuran-2-carbaldehyde (Snyder, HR, Jr., Seehausen, PH, J. Heterocycl, Chem., 10: 385-6 (1973)) according to procedure H (8 eq. , aldehyde and ethyl ester of azidoacetic acid are added in the form of ethanolic solution (0.9 M ester), the condensation of the reaction mixture is allowed to warm to room temperature, stirred for a period of 1 hour, inactivated at -40 ° C, diluted with water and extracted with ether, unpurified acrylate, filtered furanopyrrole before concentration). CIMS m / e 212.0 / 214.1 ((M-H) +). 1 H NMR (CDCl 3) d 8.69 (br s, 1 H), 6.74 (dd, J = 0.8, 1.7 Hz, 1 H) 6.31 (d, J = 0.6 Hz, 1 H), 4.33 (q, J = 7.1 Hz , 2H), 1.36 (t, J = 7.1 Hz, 3H).

EXAMPLE 29B 2-Chloro-4H-furor3,2-blpyrrole-5-carboxylic acid 2-Chloro-4H-furo [3,2-b] pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to procedure F (room temperature overnight, temperature 50 ° C for 4 hours, acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated). CIMS m / e 183.8 / 185.8 ((M-H) +). 1 H NMR (DMSO-de) d 12.47 (br s, 1 H), 11.70 (s, 1 H), 6.70 (s, 1 H), 6.67 (s, 1 H).

EXAMPLE 30 id S) -Benzyl-3 - (((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropinamide of 2-chloro-4H-furor3,2-blpyrrole-5-carboxylic acid 2-Chloro-4H-furo [3,2-b] pyrrole-5-carboxylic acid was coupled and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1-one-according to procedure B (reaction time 3 days, mixing of reaction partitioned between ethyl acetate and water before acid washing). CIMS m / e 448.1 / 450.1 (MH +). 1 H NMR (DMSO-de) d 11.33 (m, 1 H), 7.72 (d, J = 8.7 Hz, 1 H), 7. 25-7.09 (m, 5H), 6.82 (s, 1 H), 6.61 (dd, J = 0.7, 3.0 Hz, 1 H), 5.04 (d, J = 7.3 Hz, 0.5H), 4.94 (m, 1 H), 4.89 (d, J = 5.0 Hz, 0.5H), 4.80 (d, J = 7.5 Hz, 0.5H), 4.75 (d, J = 4.2 Hz, 0.5H), 4.45-4.35 (m, 1 H) ), 4.18 (m, 1 H), 4.00-3.88 (m, 2H), 3.57-3.49 (m, 1 H), 3.39 (m, 0.5H), 3.26-3.06 (m, 2.5H), 2.95-2.80 (m, 2H).

EXAMPLE 31 1 - ^ (2S) -r2-Chloro-6H-thienoyl-2,3-blpyrrole-5-carbonyl) amino-3-phenylpropionyl) piperidine-4-carboxylic acid The ethyl ester of acid 1- was hydrolysed. { (2S) - [(2-chloro-6H-t-ene [2,3-b] pyrrole-5-carbonyl) amino] -3-phenylpropionyl} piperidin-4-carboxylic acid according to procedure F (room temperature, after the residue concentration of the reaction partitioned between ethyl acetate and 1-2N NaOH, aqueous phase acidified with 2N HCl, extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated, crude product washed with ether). Mp: 145-150 ° C 1 H NMR (DMSO-de) d 12.21 (s, 1 H), 11.83 (s, 0.5 H), 11.77 (s, 0.5 H), 8.58 (m, 1 H), 7.26-7.11 (m, 7H), 5.05 (m, 1 H), 4.23 (d, 13.3 Hz, 0.5H), 4.10 (d, J = 12.5 Hz, 0.5H), 3.93 (d, J = 12.7 Hz, 0.5H) , 3.85 (d, J = 13.5 Hz, 0.5H), 3.11-2.90 (m, 3H), 2.77-2.61 (m, 1 H), 2.49-2.39 (m, 1 H), 1.75-1.65 (m, 2H ), 1.43-1.17 (m, 1.5H), 1.07-0.97 (m, 0.5H).

EXAMPLE 32 T (1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethenamide of 3-chloro-4H-thienor3,2-b] pyrrole-5-carboxylic acid co 3-Chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure B (split reaction mixture between ethyl acetate and water before the acid wash). CIMS m / e 434.0 / 436.0 (MH +). 1 H NMR (DMSO-de) d 12.09 (m, 1 H), 8.57 (d, J = 8.3 Hz, 1 H), 7.40 (m, 0.5H), 7.28-7.10 (m, 6.5H), 5.00 (d, J = 5.2 Hz, 0.5H), 4.92 (d, J = 5.0 Hz, 0.5H), 4.84 (m, 2H), 4.10-3.93 (m, 1 H), 3.82 (m, 1.5H), 3.44-3.23 (m, 2.5H), 3.13 (m, 1H), 3.02-2.87 (m, 2H).

EXAMPLE 32A 3-Chloro-4H-thienor3,2-blopyrrole-5-carboxylic acid ethyl ester A ring was formed with 4-chlorothiophen-2-carbaldehyde (Iriarte, J., Martinez, E., Muchowski, JM, J. Heterocycl. Chem., 13: 393-4 (1976)) according to procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1.2 M ester), so that the reaction temperature was maintained at 0 ° C, the reaction mixture was allowed to warm to 10 ° C, stirred for 1.5 hours, it was poured onto saturated aqueous NH4CI, after extracting with ether, the combined organic phases of acrylate were washed with water until neutralizing the aqueous phase, unpurified acrylate). CIMS m / e 228.0 ((M-H) +). 1 H NMR (CDCl 3) d 9.02 (br s, 1 H), 7.24 (s, 1 H), 7.10 (s, 1 H), 4.37 (q, J = 7.1 Hz, 2 H), 1.38 (t, J = 7.1 Hz, 3H).

EXAMPLE 32B 3-Chloro-4H-thienof3,2-b] pyrrole-5-carboxylic acid The ethyl ester of 3-chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (7 equivalents of LiOH »H2O, room temperature overnight, then temperature of 50 ° C. overnight, acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated).

CIMS m / e 199.9 / 201.8 ((M-H) +). 1 H NMR (DMSO-de) d 12.71 (br s, 1 H), 12.40 (s, 1 H), 7.48 (s, 1 H), 7.06 (d, J = 1.9 Hz, 1 H).

EXAMPLE 33 T (1 s) -Benzyl-3 - ((3R. 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropipamide of 3-chloro-4H-thienor-3-blpyrrole-5 -carboxylic 3-Chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy were coupled. -4-phenylbutan-1 -one according to process B (reaction mixture partitioned between ethyl acetate and water before acid washing). CIMS m / e 464.0 / 466.0 (MH +). 1 H NMR (DMSO-de) d 12.4 (m, 1 H), 7.89 (d, J = 8.9 Hz, 1 H), 7.38 (s, 0.5H), 7.26-7.10 (m, 5.5H), 7.05 (d , J = 3.1 Hz, 1 H), 5.08 (d, J = 7.1 Hz, 0.5H), 4. 97-4.84 (m, 2H), 4.76 (d, J = 4.2 Hz, 0.5H), 4.44 (m, 1 H), 4.20 (m, 1 H), 4.09-3.88 (m, 2H), 3.53 (m , 1 H), 3.38 (m, 0.5H), 3.25-3.06 (m, 2.5H), 2.97-2.82 (m, 2H).

EXAMPLE 34 r (1S) -Benzyl-2 - ((3R. 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl-amide of 3-bromo-4H-thieno r3,2-blpyrrole-5-carboxylic acid 3-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1-one according to procedure B (reaction mixture partitioned between ethyl acetate and acid wash water). CIMS m / e 475.9 / 478.2 ((M-H) +). 1 H NMR (DMSO-de) d 11.99 (m, 1 H), 8.56 (d, J = 8.3 Hz, 1 H), 7.48 (d, J = 1.2 Hz, 0.5H), 7.27-7.12 (m, 6.5H), 4.99 (d, J = 5.2, 0.5H), 4.91 (d, J = 5.2 Hz, 0.5H), 4.84 (m , 2H), 4.09-3.92 (m, 1.5H), 3.78 (m, 1.5H), 3.43-3.22 (m, 2H), 3.13 (m, 1 H), 2.99-2.85 (m, 2H).

EXAMPLE 34A 3-Bromo-4H-thienor3.2-blpyrrole-5-carboxylic acid A ring was formed with 4-bromothiophen-3-carbaldehyde according to procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1.2 M ester), so that the reaction temperature was maintained at 0 ° C, the reaction mixture was allowed to warm to 10 ° C, stirred for 1 hour, poured onto saturated aqueous NH 4 Cl, after extracting with ether, the combined organic phases of acrylate were washed with water until neutralizing the aqueous phase, unpurified acrylate) + CIMS m / e 272.0 / 273.9 ((MH) +). 1 H NMR (CDCl 3) d 8.99 (br s, 1 H), 7.21 (s, 1 H), 7.13 (d, J = 1.9 Hz, 1 H), 4.37 (q, J = 7.2 Hz, 2 H), 1.38 ( t, J = 7.2 Hz, 3H).

EXAMPLE 34B 3-Bromo-4H-thieno [3,2-blpyrrole-5-carboxylic acid The ethyl ester of 3-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolysed according to procedure F (7 equivalents of LiOH »H2O, room temperature overnight, then temperature of 50 ° C. overnight, acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated). CIMS m / e 243.9 / 245.9 ((M-H) +). 1 H NMR (DMSO-de) d 12.69 (br s, 1 H), 12.33 (s, 1 H), 7.56 (s, 1 H), 7.08 (s, 1 H).

EXAMPLE 35 id S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 3-bromo-4H-thienor3.2, -blpyrrol-5- acid carboxylic 3-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was coupled and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1-one according to process B (reaction mixture distributed between ethyl acetate and water before the acid wash). CIMS m / e 508.1 / 501.0 (MH +). 1 H NMR (DMSO-de) d 11.96 (s, 0.5H), 11.91 (s, 0.5H), 7.90 (d, J = 9. 3 Hz, 1 H), 7.46 (s, 0.5H), 7.22 (m, 4.5H), 7.12 (m, 1 H), 7.04 (m, 1 H), 5.08 (d, J = 6.9 Hz, 0.5H ), 4.94 (m, 1 H), 4.89 (d, J = 5.0 Hz, 0.5H), 4.85 (d, J = 7.1 Hz, 0.5H), 4.75 (d, J = 4.4 Hz, 0.5H), 4.45 (m, 1 H), 4.20 (m, 1 H), 4.08-3.87 (m, 2H), 3.53 (m, 1 H), 3.40-3.30 (m, 0.5H), 3.22 (m, 1 H), 3.15-3.05 (m, 1.5H), 2.98-2.82 (m, 2H).

EXAMPLE 36 T (1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 2-chloro-4H-thienor-3,2-blpyrrole-5 -carboxylic 2-Chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was coupled and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1 -one according to process B (reaction mixture distributed between ethyl acetate and water before the acid wash). CIMS m / e 464.0 / 466.0 (MH +). 1 H NMR (DMSO-de) d 11.72 (s, 0.5H), 11.67 (s, 0.5H), 7.85 (d, J = 9.1 Hz, 1 H), 7.21 (m, 4H), 7.12 (m, 1 H ), 7.00 (m, 2H), 5.05 (d, J = 7.1 Hz, 0. 5H), 4.95 (m, 1 H), 4.89 (d, J = 4.8 Hz, 0.5H), 4.81 (d, J = 7.5 Hz, 0.5H), 4.75 (d, J = 3.9 Hz, 0.5H), 4.41 (m, 1 H), 4.20 (m, 1 H), 4.00-3.87 (m, 2H), 3.54 (m, 1 H), 3. 40 (m, 0.5H), 3.22 (m, 1.5H), 3.15-3.06 (m, 1 H), 2.94-2.80 (m, 2H).

EXAMPLE 36A 2-Chloro-4H-thienoyl-3,2-blopyrrole-5-carboxylic acid ethyl ester A ring was formed with 5-chlorothiophen-2-carbaldehyde according to procedure H (aldehyde and ethyl ester of azidoacetic acid added as an ethanolic solution (1.2M ester), so that the reaction was maintained at 0-5 °. C, the reaction mixture was allowed to warm to room temperature, stirred for 2 hours, poured onto saturated aqueous cold NH4CI, after extracting with ether, the combined organic phases of acrylate were washed with water until neutralizing the aqueous phase, the 0.5M crude acrylate solution was heated for 1.5 hours). CIMS m / e 228.0 / 229.9 ((M-H) +). 1 H NMR (CDCl 3) d 9.04 (br s, 1 H), 7.02 (m, 1 H), 6.88 (m, 1 H), 4.34 (q, J = 7.2 Hz, 2 H), 1.37 (t, J = 7.2 , 3H).

EXAMPLE 36B 2-Chloro-4H-Tiemor3,2-b1pyrrole-5-carboxylic acid The ethyl ester of 2-chloro-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (temperature of 50 ° C for 9 hours). CIMS m / e 199.9 / 201.8 ((M-H) +). 1 H NMR (DMSO-de) d 12.62 (s, 1 H), 12.04 (s, 1 H), 7.05 (s, 1 H), 6.97 (s, 1 H).

EXAMPLE 37 r (1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethenamide of 2-chloro-4H-thienor3,2-b] pyrrole-5-carboxylic acid 2-Chloro-4H-thieno [3,2b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxy-1-yl) -3-phenolpropane hydrochloride were coupled. -1-one according to procedure B (reaction mixture partitioned between ethyl acetate and water before the acid wash). CIMS m / e 434.0 / 436.0 (MH) +). 1 H NMR (DMSO-de) d 11.73 (m, 1 H), 8.57 (d, J = 7.9 Hz, 1 H), 7. 28-7.19 (m, 4H), 7.13 (m, 2H), 7.01 (d, J = 2.7 Hz, 1 H), 5.00 (d, J = 5.2 Hz, 0.5H), 4.92 (d, J = 5.2 Hz , 0.5H), 4.86 (m, 1 H), 4.79 (m, 1 H), 4.08-3.94 (m, 1 H), 3.82 (m, 1.5H), 3.42-3.24 (m, 2H), 3.14 ( m, 1.5H), 3.01-2.87 (m, 2H).

EXAMPLE 38 r (1S) -Benzyl-2 - ((3R. 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl-amide of 3-methyl-4H-thienor-3-blpyrrole-5-carboxylic acid 3-Methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1 -one according to process B (reaction mixture partitioned between ethyl acetate and water before the acid wash). CIMS m / e 412.1 ((M-H) +), 414.0 (MH +). 1 H NMR (DMSO-de) d 11.69 (m, 1 H), 8.45 (m, 1 H), 7.28-7.18 (m, 4H), 7.12 (m, 2H), 6.93 (d, J = 1.0 Hz, 1 H), 4.98 (d, J = 5.2 Hz, 0.5H), 4.90 (d, J = 5.0 Hz, 0.5H), 4.83 (m, 2H), 4.03-3.92 (m, 1 H), 3.83 (m, 1.5H), 3.42-3.23 (m, 2.5H), 3.14 (m, 1 H), 3.03-2.88 (m, 2H) , 2.24 (s, 3H).

EXAMPLE 38A 3-Methyl-4H-thienoyl-3,2-b1pyrrole-5-carboxylic acid ethyl ester A ring was formed with 4-methylthiophen-2-carbaldehyde (Detty, M.R., Hays, DS, Heterocycles, 40: 925-37 (1995)) according to the procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1.1 M ester), the reaction was poured onto saturated aqueous NH4CI , after extracting with ether, the combined organic phases of acrylate were washed with water until neutralizing the aqueous phase, unpurified acrylate). CIMS m / e 207.9 ((M-H) +), 209.9 (MH +). 1 H NMR (CDCl 3) d 9.02 (br s, 1 H), 7.09 (d, J = 1.9 Hz, 1 H), 6.91 (d, J = 1.0 Hz, 1 H), 4.35 (quart, J = 7.3 Hz, 1 H), 2.32 (d, J = 1.2 Hz, 3H), 1.38 (t, J = 7.2 Hz, 3H).

EXAMPLE 38B 3-Methyl-4H-thienor-3,2,2-pyrrole-5-carboxylic acid The ethyl ester of 3-methyl-4H-thieno [3,2b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (temperature of 50 ° C for 13 hours, acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO4, concentrated). CIMS m / e 179.9 ((M-H) +), 181.8 (MH +). 1 H NMR (DMSO-de) d 12.45 (br s, 1 H), 11.99 (s, 1 H), 7.02 (m, 1 H), 6.96 (m, 1 H), 2.25 (s, 3 H).

EXAMPLE 39 f (1 S) -Benzyl-3 - ((3R.sub.4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropinamide of 3-methyl-4H-thienor-3,2-blpyrrole-5 -carboxylic 3-Methyl-4H-thieno [3,2b] pyrrole-5-carboxylic acid was coupled and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-4-phenylbutan-1-one according to process B (reaction mixture distributed between ethyl acetate and water before the acid wash). CIMS m / e 442.1 ((M-H) +), 444.0 (MH +). 1 H NMR (DMSO-de) 11.66 (s, 0.5H), 11.62 (s, 0.5H), 7.76 (d, J = 8.9 Hz, 1 H), 7.22 (m, 4 H), 7.11 (m, 1 H), 7.01 (d, J = 1.7 Hz, 1 H), 6.91 (s, 1 H), 5.06 (d, J) = 7.3Hz, 0.5H), 4.95 (m, 1 H), 4.90 (d, J = 5.0 Hz, 0.5H), 4.82 (d, J = 7.5 Hz, 0.5H), 4.77 (d, J = 4.4 Hz , 0.5H), 4.44 (m, 1 H), 4.21 (m, 1 H), 4.01-3.87 (m, 2H), 3.55 (m, 1 H), 3.40 (dd, J = 5.0, 12.6 Hz, 0.5 H), 3.24 (m, 1.5H), 3.16-3.06 (m, 1 H), 2.97-2.83 (m, 2H), 2.23 (s, 3H).

EXAMPLE 40 r (1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethylamide of 2-cyano-4H-thienor3,2-bl-5-carboxylic acid 2-Cyano-4H-thieno [3,2b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled. -1- Ona according to procedure B (reaction mixture partitioned between ethyl acetate and water before the acid wash). CIMS m / e 423.1 ((M-H) +), 425.1 (MH +). 1 H NMR (DMSO-de) d 12.15 (m, 1 H), 8.85 (d, J = 8.3 Hz, 1 H), 7.79 (m, 1 H), 7.29-7.11 (m, 6H), 5.00 (m, 0.5H), 4.93-4.78 (m, 2.5H), 4.04-3.93 (m, 1 H), 3.81 (m, 1.5H), 3.43-3.25 (m, 2.5H), 3.15 (m, 1 H), 3.03-2.89 (m, 2H).

EXAMPLE 40A 2-formyl-4H-thienor3.2-b1pyrrole-5-carboxylic acid The ethyl ester of 2-formyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolysed (see, for example, Gale, W.W. et al., J. Org. Chem., 29: 2160-2165 (1964)) according to procedure F (temperature of 50 ° C overnight, acidified aqueous phase extracted with ethyl acetate, combined organic phases dried over MgSO, concentrated). CIMS m / e 193.9 ((M-H) +), 195.8 (MH +). 1 H NMR (DMSO-de) d 13.38-12.78 (br s, 1 H), 12.43 (s, 1 H), 9.90 (s, 1 H), 7.92 (s, 1 H). 7.08 (s, 1 H).

EXAMPLE 40B 2-Cyano-4H-thienor-3,2-pyrrole-5-carboxylic acid 2-Formyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was treated with hydroxylamine hydrochloride according to procedure G. CIMS m / e 190.9 ((M-H) +). 1 H NMR (DMSO-de) d 13.06 (br s, 1 H), 12.45 (s, 1 H), 7.84 (s, 1 H), 7.09 (s, 1 H).

EXAMPLE 41 T (1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropinamide of 2-cyano-4H-furor3,2-blpyrrol- 5-carboxylic 2-Cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -4 were coupled phenylbutan-1-one according to process A (1 eq of triethylamine, dimethylformamide, reaction time of 4 days, reaction mixture partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHCOs). P.f .: 137-140 ° C. CIMS m / e 437.1 ((M-H) +), 439.0 MH +). 1 H NMR (DMSO-de) d 11.70 (m, 1 H), 7.99 (d, J = 8.9 Hz, 1 H), 7.65 (m, 1 H), 7.22 (m, 4H), 7.12 (m, 1 H), 6.91 (s, 1 H), 5.09 (d, J = 7.2 Hz, 0.5H), 4.95 (m, 1 H) , 4.89 (d, J = 5.2 Hz, 0.5H), 4.83 (d, J = 7.3 Hz, 0.5H), 4.76 (d, J = 3.9 Hz, 0.5H), 4.42 (m, 1 H), 4.21 ( m, 1 H), 4.08-3.89 (m, 2H), 3.61-3.50 (m, 1 H), 3.40 (m, 0.5H), 3.24 (m, 1.5H), 3.13 (m, 1 H), 2.95 -2.80 (m, 2H).

EXAMPLE 42 r (1S) -Benzyl-2 - ((3R.sub.4S) -d-hydroxy-pyrrolidin-1-yl) -2-oxyethylene-3-bromo-4H-furor3. 2-blpirrol-5-carboxylic acid 3-Bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3 hydrochloride were coupled. phenylpropan-1 -one according to process A (dimethylformamide, reaction mixture partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHC 3). P.f .: 140 ° C (dec.), CIMS m / e 461.9 / 463.9 (MH +). 1 H NMR (300 MHz, DMSO-d 6) d 11.75 (m, 1 H), 8.47 (d, J = 8.6 Hz, 1 H), 7.90 (d, J = 0.8 Hz, 1 H), 7.33-7.15 (m , 5H), 6.98 (dd, J = 1.5, 3.4 Hz, 1 H), 5.03 (d, J = 5.3 Hz, 0.5H), 4.95 (d, J = 5.1 Hz, 0.5H), 4.91-4.83 (m, 2H), 4. 13-3.97 (m, 1 H), 3.86 (m, 1.5H), 3.48-3.25 (m, 2.5H), 3.18 (m, 1 H), 3.08-2.92 (m, 2H).

EXAMPLE 42A 3-Bromo-4H-furor3,2-b1pyrrole-5-carboxylic acid ethyl ester A ring was formed with 4-bromo-2-furaldehyde according to process H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1 M ester) to an ethoxide solution at -20 ° C, minutes at a temperature of -20 ° C, period of 1.5 hours at a temperature of -5 ° C, period of 15 minutes at a temperature of ° C, the reaction was poured onto saturated cold aqueous NH4CI, after extraction with ether the organic acrylate phase was washed with water until the aqueous phase was neutralized, the crude acrylate solution 0.5M) was heated. CIMS m / e 257.8 / 259.8 (MH +). 1 H NMR (300 MHz, CDCl 3) d 8.81 (br s, 1 H), 7.48 (s, 1 H), 6.79 (d, J = 1.8 Hz, 1 H), 4.35 (q, J = 7.1 Hz, 2 H) , 1.36 (t, J = 7.1 Hz, 3H).

EXAMPLE 42B 3-Bromo-4H-furor3.2-blpyrrole-5-carboxylic acid 3-Bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid ethyl ester was hydrolyzed according to procedure F (temperature of 50 ° C for a period of 14 hours, acidified aqueous phase extracted with ethyl acetate organic phase dried over MgSO4, concentrated). CIMS m / e 228.0 / 230.0 ((M-H +). 1 H NMR (300 MHz, DMSO-d 6) d 12.60 (br s, 1 H), 12.06 (br s, 1 H), 7.98 (s, 1 H), 6.77 (d, J = 1.8 Hz, 1 H).

EXAMPLE 43 fd S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 3-bromo-4H-furor3,2-bliroprol-5-carboxylic acid 3-Bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy were coupled. -4-phenylbutan-1 -one according to procedure A (1 eq of triethylamine, dimethylformamide, reaction mixture partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHCO3). P.f .: 140 ° C (dec.), CIMS m / e 492.0 / 494.0 (MH +). 1 H NMR (300 MHz, DMSO-d 6) d 11.73 (s, 0.5H), 11.68 (s, 0.5H), 7.88 (d, J = 0.7 Hz, 1 H), 7.79 (d, J = 8.9 Hz, 1 H), 7.27 (m, 4H), 7.17 (m, 1 H), 6.87 (s, 1 H), 5.18-4.74 (m, 3H), 4.56-4.40 (m, 1 H), 4.24 (s, 1 H), 4.05-3.94 (m, 1.5H), 3.64-3.11 (m, 4.5H), 3.02-2.85 (m, 2H).

EXAMPLE 44 f (1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropinamide of 4H-1,7-dithia-4-azacyclopentaralpentalene-5 - carboxylic 4H-1,7-dithia-4-azacyclopenta [a] pentalen-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy were coupled -4-phenylbutan-1-one according to process B (2: 1 dichloromethane: dimethylformamide, reaction mixture partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHCO3). CIMS m / e 484.0 ((M-H) +), 486.0 (MH +). 1 H NMR (DMSO-de) d 12.00 (s, 0.5H), 11.95 (s, 0.5H), 7.83 (m, 1 H), 7.55 (dd, J = 0.8, 5.2 Hz, 1 H), 7.35 (dd) , J = 1.2, 5.2 Hz, 1 H), 7.23 (m, 4 H), 7.12 (m, 2 H), 5.07 (d, J = 7.3 Hz, 0.5 H), 4.96 (m, 1 H), 4.90 (d , J = 5.0 Hz, 0.5H), 4.81 (d, J = 7.5 Hz, 0.5H), 4.76 (d, J = 4.2 Hz, 0.5H), 4.44 (m, 1 H), 4.20 (m, 1 H ), 4.08-3.88 (m, 1.5H), 3.57 (m, 1 H), 3.40 (m, 0.5H), 3.26 (m, 1.5H), 3.17-3.07 (m, 1.5H), 2.97-2.84 ( m, 2H).

EXAMPLE 44A 4H-1,7-Dithia-4-azacyclopentara1 pentalen-5-carboxylic acid ethyl ester A ring was formed with thieno [2,3-b] thiophen-2-carbaldehyde (Dopper, JH et al., J. Am. Chem. Soc, 95: 3692-8 (1973)) according to procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1 M ester) to a solution of ethoxide at -20 ° C, period of 30 minutes at a temperature of -20 ° C, temperature of -20 ° C to room for a period of 2.5 hours, the reaction was poured onto saturated cold aqueous NH4CI, after ether extraction, the organic acrylate phase was washed with water until the aqueous phase was neutralized, the crude acrylate solution 0.35M was heated). CIMS m / e 250.1 ((M-H) +), 251.9 (MH +). 1 H NMR (CDCl 3) d 9.46 (br s, 1 H), 7.35 (d, J = 5.3 Hz, 1 H), 7.29 (d, J = 5.3 Hz, 1 H), 7.14 (d, J = 2.0 Hz, 1 H), 4.38 (q, J = 7.1 Hz, 2 H), 1.39 (t, J = 7.1 Hz, 3 H).

EXAMPLE 44B 4H-1-Dithia-4-azacyclopenaralpentalene-5-carboxylic acid The ethyl ester of 4H-1, 7-dithia-4-azacyclopenta [a] pentalen-5-carboxylic acid was hydrolysed according to procedure F (temperature of 50 ° C for 11 hours). CIMS m / e 222.0 ((M-H +). 1 H NMR (DMSO-de) d 12.51 (s, 1 H), 12.32 (s, 1 H), 7.59 (d, J = 5.3 Hz, 1 H), 7.38 (J = 5.3 Hz, 1 H), 7.05 (d, J = 1.9 Hz, 1 H).

EXAMPLE 45 r (1S) -benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoetinamide acid 4H-1.7-dithia-4-azacyclopentara1pentalene-5-carboxylic acid 4H-1, 7-dithia-4-azacyclopenta [a] pentalen-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -3-phenylpropan hydrochloride were coupled -1-one according to procedure B (1: 1 dichloromethane: dimethylformamide, reaction mixture partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHCO3). CIMS m / e 454.0 ((M-H) +), 456.0 (MH +). 1 H NMR (DMSO-de) d 12.03 (m, 1 H), 8.53 (d, J = 8.1 Hz, 1 H), 7.55 (dd, J = 0.8, 5.2 Hz, 1 H), 7.34 (dd, J = 2.7, 5.2 Hz, 1 H), 7.29-7.19 (m, 5H), 7.12 (m, 1 H), 4.99 (d, J = 5.2 Hz, 0.5H), 4.91 (d, J = 5.0 Hz, 0.5H ), 4.84 (m, 2H), 3.98 (m, 1 H), 3.83 (m, 2H), 3.41-3.29 (m, 3H), 3.13 (m, 1 H), 2.95 (m, 2H).

EXAMPLE 46 r (1S) -Benzyl-2 - ((3R.4S) -dihydroxy-pyrrolidin-1-yl) -2-oxoethylamide of 2-chloro-3-methyl-4H-thienor3.2-b1pyrrol- 5-carboxylic 2-Chloro-3-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidine hydrochloride were coupled. 1-yl) -3-phenylpropan-1-one according to procedure B (1: 1 dichloromethane: dimethylformamide, reaction time 2 days, concentrated reaction mixture to remove dichloromethane, partitioned between ethyl acetate and water, washed organic phase with 2N HCl before saturated aqueous NaHCO3). P.f .: 139-141 ° C, CIMS m / e 448.1 / 450.1 (MH +). 1 H NMR (DMSO-de) d 11.95 (m, 1 H), 8.54 (d, J = 7.9 Hz, 1 H), 7.28-7.18 (m, 4H), 7.13 (m, 2H), 4.98 (d, J = 5.2 Hz, 0.5H), 4.90 (d, J = 4.6 Hz, 0.5H), 4.83 (m, 2H), 4.02-3.92 (m, 1 H), 3.82 (m, 1.5H), 3.41-3.22 ( m, 2.5H), 3.14 (m, 1 H), 3.01-2.90 (m, 2H), 2.20 (d, J = 2.5 Hz, 3H).

EXAMPLE 46A 5-Chloro-4-methylthiophen-2 -carbaldehyde Using a modified procedure of Silverstein et al. (Organic Synthesis Coil, Vol 4, Wiley, New York, 1963, N. Rabjohn, Ed. Page 831), was added dropwise to a pale yellow solution at 80 ° C of 2-chloro-3-methylthiophene ( Crast. LB, Jr., US Patent 3290291, Example 2, 70 g, 0.53 mol) in dimethylformamide (48.3 g, 0.66 mol), phosphorus oxychloride (101.5 g, 0.66 mol) for 45 minutes maintaining the temperature at 80-97 ° C. The dark brown solution was stirred at 90 ° C for 3 hours and poured slowly into water (500 ml) at a temperature of 90 ° C. The resulting mixture was fractionally distilled and the distillate was cooled to 0 ° C, providing white crystals. The first 500 ml of distillate were extracted with chloroform, concentrated and the residue was recrystallized with hexane (100 ml) and the insoluble material was filtered. The filtrate was diluted with hexane (50 ml), stirred with Norit (R) (2 g) and concentrated. The product was purified by recrystallization with hexane (50 ml) at a temperature of -40 ° C and obtained as white crystals (7.5 g., 13%). The remaining distillate from the fractional distillation was extracted with chloroform (2 x 250 ml) and the white crystals were dissolved in chloroform (1.5 I). The combined organic phases were dried over MgSO4, filtered, shaken with Norit (R) (30 g) for 15 minutes and concentrated. The residue was dissolved in hexane (350 ml), the insoluble material was filtered, the filtrate was stirred at -15 ° C for 10 minutes and the resulting precipitate was filtered. The title product was obtained in the form of pale yellow crystals (48.6 g, 83%). P.f .: 39-40 ° C.

EXAMPLE 46B 2-Chloro-3-methyl-4H-thienor3,2-b1pyrrole-5-carboxylic acid ethyl ester A ring was formed with 5-chloro-4-methylthiophen-2-carbaldehyde according to the procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1 M ester) to an ethoxide solution at a temperature of - 20 ° C, allowed to warm to 10 ° C for 2 hours, maintained at a temperature of 10 ° C for 2 hours, the reaction was poured onto saturated cold aqueous NH 4 Cl, after extraction with ether, the organic phase was washed of acrylate with water until the aqueous phase was neutralized, the crude acrylate solution was added to xylenes under reflux for 5 minutes and then heated to reflux). CIMS m / e 243.8 / 245.9 (MH +). 1 H NMR (CDCl 3) d 9.25 (br s, 1 H), 7.02 (d, J = 1.9 Hz, 1 H), 4.36 (q, J = 7.1 Hz, 2 H), 2.28 (s, 3 H), 1.38 (t , J = 7.1 Hz, 3H).

EXAMPLE 46C 2-Chloro-3-methyl-4H-thienor3,2-blpyrrole-5-carboxylic acid The ethyl ester of 2-chloro-3-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (temperature of 50 ° C for 14 hours). CIMS m / e 213.8 / 215.8 ((M-H +). 1 H NMR (DMSO-de) d 12.61 (br s, 1 H), 12.25 (s, 1 H), 6.96 (dd, J = 0.5, 2.0 Hz, 1 H), 2.23 (s, 1 H).

EXAMPLE 47 f (1 S) -Benzyl-3 - ((3R, 4S) -dihydrox? Pyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropylamide of 2-chloro-3-methyl-4H-thienor3 .2-blpirrol-5-carboxylic 2-Chloro-3-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid and (3S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - ( 2R) -hydroxy-4-phenylbutan-1-one according to process B (4: 5 dichloromethane: dimethylformamide, reaction time 2 days, concentrated reaction mixture to remove dichloromethane, partitioned between ethyl acetate and water, washed organic phase with 2N HCl before saturated aqueous NaHCO 3). P. f .: 150-153 ° C, CIMS m / e 478.1 / 480.1 (MH +). 1 H NMR (DMSO-de) d 11.91 (s, 0.5 H), 11.86 (s, 0.5 H), 7.82 (d, J = 8.7, 1 H), 7.22 (m, 4 H), 7.11 (m, 1 H), 7.01 (m, 1 H), 5.07 (d, J = 6.8 Hz, 0.5 H), 4.95 (m, 1 H), 4.90 (d, J = 5.0 Hz, 0.5 H), 4.82 (d, J = 6.8 Hz , 0.5 H), 4.77 (d, J = 3.7 Hz, 0.5 H), 4.44 (m, 1 H), 4.21 (m, 1 H), 4.08-3.88 (m, 1.5 H), 3.56 (m, 1 H ), 3.40 (m, 0.5 H), 3.24 (m, 1.5H), 3.14 (m, 1 H), 3.08 (m, 0.5H), 2.95-2.82 (m, 2H).

EXAMPLE 48 r (1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl-1-amide of 2-methylsulfanyl-4H-thienor-3-blpyrrole-5-carboxylic acid 2-Methylsulfanyl-4H-t-ene [3,2-b] pyrrol-5-carboxylic acid and (2S) -amino-1 - ((3R, 4S) -dihydroxypyrrolidin-1-yl hydrochloride) were coupled. -3-phenylpropan-1-one according to procedure B (1: 1 dichloromethane: dimethylformamide, concentrated reaction mixture to remove dichloromethane, partitioned between ethyl acetate and water, organic phase washed with 2N HCl before saturated aqueous NaHCO3. f .: 104-110 ° C, 444.0 ((MH) +), 445.9 (MH +). 1 H NMR (DMSO-de) d 11.61 (m, 1 H), 8.52 (d, J = 8.6 Hz, 1 H ), 7.28-7.12 (m, 6H), 6.97 (d, J = 3.9 Hz, 1 H), 4.99 (d, J = 5.1 Hz, 0.5H), 4.91 (d, J = 5.1 Hz, 0.5H), 4.83 (m, 2H), 4.06-3.94 (m, 1 H), 3.80 (m, 2H), 3.43-3.24 (m, 2H), 3.14 (m, 1 H), 3.02-2.87 (m, 2H), 2.46 (s, 3H).

EXAMPLE 48A 2-Methylsulfanyl-4H-thienor3.2-blpyrrole-5-carboxylic acid ethyl ester A ring was formed with 5-methylsulfanylthiophen-2-carbaldehyde according to the procedure H (aldehyde and ethyl ester of azidoacetic acid added in the form of ethanolic solution (1 M ester) to an ethoxide solution at a temperature of -20 ° C, it was allowed to warm for 4 hours at 10 ° C, the reaction was poured into saturated cold aqueous NH4CI, after extraction with ether the organic phase of acrylate was washed with water until neutralizing the aqueous phase, the crude acrylate solution was heated to reflux for 2 hours, it was allowed to cool to room temperature and stirred overnight). CIMS m / e 240.0 ((M-H +), 242.0 (MH +). 1 H NMR (CDCl 3) d 9.05 (br s, 1 H), 7.04 (m, 1 H), 6.97 (s, 1 H), 4.35 ( q, J = 7.1 Hz, 2H), 2.53 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H).

EXAMPLE 48B 2-Methylsulfanyl-4H-thienor3,2-blopyrrole-5-carboxylic acid The ethyl ester of 2-methylsulfanyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid was hydrolyzed according to procedure F (temperature of 40 ° C overnight). CIMS m / e 211.9 ((M-H) +). 1 H NMR (DMSO-de) d 12.56 (s, 1 H), 11.90 (s, 1 H), 6.97 (s, 1 H), 6.94 (s, 1 H), 2.47 (s, 1 H). The following compounds can also be prepared as indicated above: 2-bromo-4H-thieno [(1S) -Benzyl-2- (3-hydroxyazetidin-1-yl) -2-oxoethyl] -amide [3,2-b] ] pyrrole-5-carboxylic acid, [(1S) -Benzyl-2- (1, 1-dioxo-1-thiazolidin-3-yl) -2-oxoethyl] -amide of 2-bromo-4H-thieno acid [3,2 -b] pyrrole-5-carboxylic acid, [2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -benzyl-2-morpholin-4-yl-2-oxoethyl] -amide] , [(1S) -Benzyl-2 - ((3S, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxoethyl] -amide of 2-bromo-4H-thieno [3,2-b] pyrrole -5-carboxylic acid, [(1 S) -Benzyl-2 - ((3R, 4R) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid, [(1 S) -Benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] -amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5 -carboxylic Biological protocols The utility of the compounds of the present invention as medical agents in the treatment or prevention of diseases (such as those described herein) in animals, in particular in mammals (eg, humans) is demonstrated by the activity of the compounds of this invention in conventional assays and in the in vivo and in vivo assays described below. Such assays are further provided as a means by which the activities of the compounds of this invention can be compared to the activities of other known compounds. The results of these comparisons are useful for determining dosage levels in animals, in particular, in mammals, including humans, for the treatment of such diseases.

Production and testing of glycogen phosphorylase The three different isoenzymes of purified glycogen phosphorylase (GP), in which glycogen phosphorylase is in the activated state 'a' (referred to as glycogen phosphorylase a, or abbreviated as Gpa), and referred to herein as hepatic to human glycogen phosphorylase (HLGPa), human muscle glycogen phosphorylase a (HMGPa) and human brain glycogen phosphorylase a (HBGPa), can be obtained by the following procedures.

Expression and fermentation The HLGP cDNAs (obtained as described in Newgard et al., Proc. Nati, Acad. Sci., 83: 8132-8136 (1986) and Newgard et al., Proc. Nati. Acad. Sci., 263: 3850-3857 (1988), respectively) and the HMGP cDNAs (obtained by screening a human muscle cDNA library from Stratagene (Stratagene Cloning Systems, La Jolla, CA) with a cDNA fragment generated by chain reaction with polymerase (PCR) based on the information and methodology described to isolate the human skeletal muscle glycogen phosphorylase gene and the partial cDNA sequence of Kubish et al., Center for Molecular Neurobiology, University of Hamburg, Martinistrasse 85, Hamburg , 20246, Germany, Genbank (National Center for Biotechnology Information, National Institutes of Health, USA), accession numbers U94774, U94775, U94776 and U94777, filed March 20, 1997, Burke et al., Proteins, 2: 177- 187 (1987) and Hwang et al., Eur. J. Biochem., 152: 267-274 (1985)) are xpresan from plasmid pKK233-2 (Pharmacia Biotech. Inc., Piscataway, New Jersey) in the E. coli strain XL-1 Blue (Stratagene Cloning Systems, La Jolla, CA). The strain is inoculated in LB medium (consisting of 10 g of tryptone, 5 g of yeast extract, 5 g of NaCl and 1 ml of 1 N NaOH per liter) plus 100 mg / l of ampicillin, 100 mg / l of pyridoxine and 600 mg / l of MnCl2, and allowed to grow at 37 ° C to a cell density of OD550 = 1.0. At this time, the cells are induced with 1 mM isopropyl-1-thio-β-D-galactoside (IPTG). Three hours after induction, the cells are harvested by centrifugation and the cell pellets are frozen at -70 ° C until they are needed for purification. The HBGP cDNA can be expressed by several methodologies, for example, by the procedure described by Crerar et al., (J. Biol. Chem. 270: 13748-13756 (1995)). The procedure described by Crerar et al., (J. Biol. Chem. 270: 13748-13756 (1995)) for the expression of HBGP is as follows: the HBGP cDNA can be expressed in plasmid pTACTAC in strain 25A6 of E coli. The strain is inoculated in LB medium (consisting of 10 g of tryptone, 5 g of yeast extract, 5 g of NaCl and 1 ml of 1 N NaOH per liter) plus 50 mg / l of ampicillin, developed overnight , then resuspended in a new LB medium plus 50 mg / l of ampicillin, it is re-inoculated in a volume 40 times of medium LB / amp containing isoprqpil-1-thio-β-D-galactoside (IPTG) 250 μM, 0.5 mM pyridoxine and 3 mM MgCl2 and develops at 22 ° C for 48-50 hours. The cells can then be harvested by centrifugation and the cell pellets are frozen at -70 ° C until they are needed for purification. The HLGP cDNA is expressed in the plasmid pBlueBac III (Invitrogen Corp. San Diego, CA) which is used to co-transfect with the BaculoGold Viral Linear DNA (Pharmingen, San Diego, CA) in Sf9 cells. Subsequently, the recombinant viruses are purified on plates. For protein purification, Sf9 cells grown in a serum-free medium are infected (SF 900-II Gibco BRL Life Technologies, Grand Island, NY) with a multiplicity of infection (moi) of 0.5 and a cell density of 2 x 106 cells / ml. After being grown for 72 hours at 27 ° C, the cells are centrifuged and the cell pellets are frozen at -70 ° C until they are needed for purification.

Purification of glycogen phosphorylase expressed in E. coli The E. coli cells in the sediments, described above, are resuspended in 25 mM β-glycerophosphate (pH 7.0) with 0.2 mM DTT, 1 mM MgCl 2, plus the following protease inhibitors: 0.7 μg / ml Pepstatin A 0.5 μg / ml Leupeptin 0.2 mM Phenylmethylsulfonyl fluoride (PMSF), and 0.5 mM EDTA are lysed by pretreatment with 200 μg / ml lysozyme and 3 μg / ml DNase, followed by sonication in 250 ml batches for 5 x 1.5 minutes on ice, using a Branson Model 450 Ultrasonic Cell Breaker (Branson Sonic Power Co. Danbury CT). The lysates of E. coli cells are then rinsed by centrifugation at 35,000 X g for 1 hour, followed by filtration through 0.45 μm filters. The GP in the soluble fraction of the lysates (estimated to be less than 1% of the total protein) is purified by controlling the enzymatic activity (as described in the GPa Activity Assay section shown below) in a series of chromatographic steps detailed below.

Metal-immobilized affinity chromatography (IMAC) This step is based on the procedure of Luong et al. (Luong et al, Journal of Chromatography (1992) 584: 77-84). 500 ml of the filtered soluble fraction from the cell lysates (prepared from approximately 160-250 g of original cell pellet) are introduced into a 130 ml column of IMAC Chelating-Sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey) which had been loaded with 50 mM CuCI2 and 25 mM β-glycerophosphate, 250 mM NaCl and 1 mM imidazole in an equilibrium buffer at pH 7. The column is washed with equilibration buffer until the A28o returns to the baseline. Then, the sample is eluted from the column with the same buffer containing 100 mM imidazole to remove the bound GP and other bound proteins. Fractions containing GP activity are pooled (approximately 600 ml) and ethylenediaminetetraacetic acid (EDTA), DL-dithiothreitol (DTT), phenylmethylsulfonyl fluoride (PMSF), leupeptin and pepstatin A are added to obtain concentrations 0.3 mM, 0.2 mM, 0.2 mM, 0.5 μg / ml and 0.7 μg / ml, respectively. The pooled GP is desalted on a Sephadex G-25 column (Sigma Chemical Co., St. Louis, Missouri) equilibrated with 25 mM Tris-HCl (pH 7.3) and 3 mM DTT buffer (Buffer A) to remove the imidazole and store on ice until the second chromatographic stage (next) if necessary.

Chromatography in 5'-AMP-Sepharose The pooled and desalted GP sample (approximately 600 ml) is then mixed with 70 ml of 5'-AMP Sepharose (Pharmacia LKB Biotechnology, Piscataway, New Jersey) which has been equilibrated with Buffer A ( see above). The mixture is gently stirred for 1 hour at 22 ° C and then introduced into a column and washed with Buffer A until the A28o returns to the baseline. The GP and other proteins are eluted from the column with 25 mM Tris-HCl, 0.2 mM DTT and 10 mM adenosine-5'-monophosphate (AMP) at pH 7.3 (Buffer B). Fractions containing GP are pooled after identification, determining enzymatic activity and visualizing the GP protein band of approximately 97 Kdaltons Mr by polyacrylamide gel electrophoresis and sodium dodecyl sulfate (SDS-PAGE) followed by silver staining (2D- Silver Stain II "Daiichi Kit", Daiichi Puré Chemicals Co., LTD., Tokyo, Japan) and then meet. The pooled GP is dialyzed into 25 mM β-glycerophosphate, 0.2 mM DTT, 0.3 mM EDTA, 200 mM NaCl, pH 7.0 buffer (Buffer C) and stored on ice until used. Before the use of the GP enzyme, the enzyme is converted, from the inactive form that is expressed in the XL-1 Blue strain of E. coli (named GPb) (Stratagene Cloning Systems, La Jolla, California), in the active form (named GPa) by the procedure described in section (A) Activation of GP, shown below.

Purification of glycogen phosphorylase expressed in Sf9 cells The Sf9 cells from the sediments described above are resuspended in 25 mM β-glycerol phosphate (pH 7.0) with 0.2 mM DTT and 1 mM MgCl 2., plus the following protease inhibitors: 0.7 μg / ml Pepstatin A 0.5 μg / ml Leupeptin 0.2 mM Phenylmethylsulfonyl fluoride (PMSF), and 0.5 mM EDTA are lysed by pretreatment with 3 μg / ml DNase followed by sonication in batches, during 3 x 1 minutes on ice, using a Branson Model 450 ultrasonic cell breaker (Branson Sonic Power Co. Danbury CT). The Sf9 cell lysates are then rinsed by centrifugation at 35,000 x g for 1 hour, followed by filtration through 0.45 μm filters. The GP in the soluble fraction of the lysates (estimated to be 1.5% of the total protein) is purified by controlling the enzymatic activity (as described in the section on GPa activity assay shown below) in a series of chromatographic steps detailed below.

Metal-immobilized affinity chromatography (IMAC) Affinity chromatography immobilized on metal is performed as described in the previous section. The assembled and misaligned GP is then stored on ice until it is processed later.

Activation of GP Before performing another chromatography, the fraction of the inactive enzyme, as expressed in the Sf9 cells (called GPb), is converted into the active form (called GPa) by the following procedure described in section (A) Activation of GP shown below.

Anion exchange chromatography After activation of the GPb purified by IMAC to GPa by reaction with the immobilized phosphorylase kinase, as described below, the pooled GPa fractions are dialyzed against 25 mM Tris-HCl, pH 7.5 containing DTT 0.5 mM, 0.2 mM EDTA, 1.0 mM phenylmethylsulfonyl fluoride (PMSF), 1.0 μg / ml leupeptin and 1.0 μg / ml pepstatin. The sample is then introduced into a monoQ anion exchange chromatography column (Pharmacia Biotech, Inc., Piscataway, New Jersey). The column is washed with equilibration buffer until the A28o returns to the baseline. Then, the sample is eluted from the column with a linear gradient of 0-0.25 M NaCl to remove the bound GP and other bound proteins. Fractions containing GP elute within the NaCl range of 0.1-0.2 M, as detected by controlling the eluent with respect to the absorbance of protein peaks at A28o- The GP protein is then identified by visualizing the GP protein band of GP. of approximately 97 kdaltons by polyacrylamide and sodium dodecyl sulfate gel electrophoresis (SDS-PAGE), followed by silver staining (2D-silver Stain II 'Daiichi Kit', Daiichi Pure Chemicals Co., LTD., Tokyo, Japan) and Then it meets. The pooled GP is dialyzed into 25 mM N, N-bis [2-hydroxyethyl] -2-aminoethanesulfonic acid, 1.0 mM DTT, 0.5 mM EDTA, 5 mM NaCl, pH 6.8 buffer and stored on ice until use.

Determination of the enzymatic activity of GP A) Activation of GP: Conversion of GPb into GPa Prior to the determination of the enzymatic activity of GP, the enzyme is converted from the inactive form, as expressed in the XL-1 Blue strain of E. coli (designated GPb) ( Stratagene Cloning Systems, La Jolla, California), in the active form (designated GPa) by phosphorylation of Gp using the phosphorylase kinase as indicated below. The fraction of the inactive enzyme as expressed in Sf9 cells (referred to as GPb) is also converted to the active form (termed GPa) by the following procedure.

Gp Reaction with Immobilized Phosphorylase Kinase Phosphorylase kinase (Sigma Chemical Company, St. Louis, MO) is immobilized in Affi-Gel® 10 (BioRad Corp., Melville, NY) following the manufacturer's instructions. Briefly, the enzyme phosphorylase kinase (10 mg) is incubated with washed Affi-Gel® beads (1 ml) in 2.5 ml of 100 mM HEPES and 80 mM CaCl2 at pH 7.4, for 4 hours at 4 ° C. The Affi-Gel® beads are then washed once with the same buffer before blocking with 50 mM HEPES and 1 M glycine methyl ester at pH 8.0, for one hour at room temperature. The blocking buffer is removed and replaced with 50 mM HEPES (pH 7.4), 1 mM β-mercaptoethanol and 0.2% NaN 3 for storage. Before use to convert GPb to GPa, the Affi gel® beads with the immobilized phosphorylase kinase are equilibrated by washing them in the buffer used to perform the kinase reaction, which consists of 25 mM β-glycerophosphate, 0.3 mM DTT and EDTA 0.3 mM at pH 7.8 (kinase assay buffer). The inactive and partially purified GP obtained from the chromatography on the above d'AMP-Sepharose (from E. coli) or the mixture of GPa and GPb obtained from the above IMAC (from Sf9 cells) is diluted 1: 10 with the kinase assay buffer and then mixed with the aforementioned phosphorylase kinase enzyme immobilized on Affi-Gel® beads. NaATP is added at a concentration of 5 mM and MgCl2 at a concentration of 6 mM. The resulting mixture is mixed gently at 25 ° C for 30-60 minutes. The sample is removed from the beads and the percentage of activation of GPb is estimated by conversion to GPa determining the enzymatic activity of GP in the presence and absence of 3.3 mM AMP. The percentage of total GP enzymatic activity is then calculated due to the activity of the GPa enzyme (independent of AMP) as follows: Total HLGPa% = HLGP activity - AMP activity of HLGP + AMP Alternatively, the conversion of GPb to Gpa can be controlled by isoelectric focusing, based on the displacement of electrophoretic mobility that is detected after the conversion of GPb to GPa. The GP samples are analyzed by isoelectric focusing (IEF) using the Pharmacia PfastGel system (Pharmacia Biotech, Inc., Piscataway, New Jersey), using previously melted gels (interval pl 4-6.5) and the procedure recommended by the manufacturer. The resolved bands of GPa and GPb are then visualized on the gels by silver staining (2D-silver Stain II 'Daiichi Kit', Daiichi Pure Chemicals Co., LTD., Tokyo, Japan). The identification of GPa and GPb is carried out by comparison with the GPa and GPb standards derived from E. coli that are tested in parallel on the same gels as the experimental samples.

B) GPa activity assay The disease / condition treatment / prevention activities described herein of the glycogen phosphorylase inhibitor compounds of this invention can be determined indirectly by evaluating the effect of the compounds of this invention on the activity of the activated form of glycogen phosphorylase (GPa) by one of two procedures; the activity of glycogen phosphorylase a is measured in the forward direction by controlling the production of glucose-1-phosphate from glycogen, or following the reverse reaction, measuring the synthesis of glycogen from glucose-1-phosphate by the release of inorganic phosphate. All reactions can be performed in triplicate in 96-well microtiter plates and the change in absorbance due to the formation of the reaction product at the wavelength specified below is measured in an MCC / 340 MKII Elisa Reader (Lab Systems, Finland) connected to a Titertech Microplate Stacker (ICN Biomedical Co., Huntsville, Alabama). To measure the enzymatic activity of GPa in the forward direction, the production of glucose-1-phosphate from glycogen is controlled by the general multienzyme coupled procedure of Pesce et al. [Pesce, MA, Bodourian, SH, Harris, RC and Nicholson, JF (1977) Clinical Chemistry 23: 1711-1717] modified as follows: diluted from 1 to 100 μg of GPa, 10 units of phosphoglucomutase and 15 glucose-6-phosphate dehydrogenase units (Boehringer Mannheim Biochemicals, Indianapolis, IN) at 1 ml, in buffer D, at pH 7.2 and contains 50 mM HEPES, 100 mM KCl, 2.5 mM ethylene glycoltetraacetic acid (EGTA), 2.5 mM MgCl 2, 3.5 mM KH2PO4 and 0.5 mM dithiothreitol. 20 μl of this stock solution is added to 80 μl of buffer D containing 0.47 mg / ml of glycogen, glucose 9.4 mM and 0.63 mM of the oxidized form of nucleotide phosphate of nicotinamide adenine (NADP +). The compounds to be tested are added in the form of 5 μl of solution in 14% dimethylsulfoxide (DMSO) before the addition of the enzymes. The basal rate of enzymatic activity of GPa in the absence of inhibitors, for example, a compound of this invention, is determined by adding 5 μl of 14% DMSO and a completely inhibited proportion of the GPa enzyme activity is obtained by adding 20 μl of the positive control test substance, caffeine, at 50 mM. The reaction is followed at room temperature by measuring the conversion of oxidized NADP + to reduced NADPH at 340 nm.

To measure the enzymatic activity of GPa in the reverse direction, the conversion of glucose-1-phosphate to glycogen + inorganic phosphate is measured by the general procedure described by Engers et al. [Engers, H. D., Shechosky, S. and Madsen, N. B. Can J. Biochem. 48: 746-754 (1970)], modified as follows: dilute from 1 to 100 ug of GPa in 1 ml of Buffer E (pH 7.2, 50 mM HEPES, 100 mM KCl, 2.5 mM EGTA, MgCl22. 5 mM and 0.5 mM dithiothreitol). 20 μl of this stock solution is added to 80 μl of Buffer E with 1.25 mg / ml of glycogen, glucose 9.4 mM and glucose-1-phosphate 0.63 mM. The compounds to be tested are added in the form of 5 μl of solution in 14% DMSO before the addition of the enzyme. The basal proportion of the GPa enzyme activity in the absence of added inhibitors is determined by adding 5 μl of 14% DMSO and the fully inhibited proportion of the GPa enzyme activity is obtained by adding 20 μl of 50 mM caffeine. This mixture is incubated at room temperature for 1 hour and the inorganic phosphate released from glucose-1-phosphate is measured by the general procedure of Lanzetta et al. [Lanzetta, P.A., Alvarez, L.J., Reinach, P.S. and Candia, O.A.A., Biochem. 100: 95-97 (1979)] modified as follows: 150 ml of 10 mg / ml ammonium molybdate and 0.38 mg / ml malachite green in 1 N HCl are added to 100 μl of the enzyme mixture. After an incubation period of 20 minutes at room temperature, the absorbance at 620 nm is measured. The above tests carried out with a range of concentrations of test compounds allow the determination of a CI5o value (concentration of the test compound necessary for a 50% inhibition) for the in vitro inhibition of the enzymatic activity of GPa by that compound of test. The compounds of this invention readily adapt to clinical use as hypoglycaemic agents. The hypoglycaemic activity of the combinations of this invention can be determined by the amount of test compound that reduces glucose levels relative to a vehicle without test compound, in male ob / ob mice. The assay also allows the determination of an approximate minimum effective dose (MED) value for the in vivo reduction of the plasma glucose concentration in such mice for such test compounds. Since the concentration of blood glucose is closely related to the development of diabetic disorders, the compounds of the present invention, by virtue of their hypoglycaemic action, prevent, stop and / or reverse diabetic disorders. Five male mice aged 5 to 8 weeks, C57BL / 6J-ob / ob (obtained from Jackson Laboratory, Bar Harbor, ME) are enclosed per cage, under conventional animal care practices. After a one-week acclimatization period, the animals are weighed and 25 μl of retroorbital sinus blood is removed before any treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin and kept on ice for analysis of metabolites. Animals are assigned to treatment groups so that each group has a similar average for plasma glucose concentration. After the allocation of the groups, the animals receive orally, every day, for 4 days, the vehicle consisting of: 1) 0.25% p / v of hypromellose in water without adjusting the pH; or 2) 0.1% Pluronic® P105 Block Copolymer Sufactant (BASF Corporation, Parsippany, NJ) in 0.1% saline without pH adjustment. On day 5, the animals are weighed again and then orally receive the test compound or the vehicle alone. All compounds are administered in a vehicle consisting of: 1) 0.25% w / v of hypromellose in water without pH adjustment; or 2) 10% DMSO / 0.1% Pluronic® P105 in 0.1% saline without pH adjustment; or 3) Pure PEG400 without pH adjustment. Three hours later, blood is drawn from the animals through the retro-orbital sinus to determine the levels of the metabolites in the blood. The freshly collected samples are centrifuged for two minutes at 10,000 x g at room temperature. In the supernatant glucose is analyzed, for example, by the Abbott VP ™ system (Abbott Laboratories, Diagnostics Division, Irving, TX) and VP Super System® Autoanalizer (Abbott Laboratories, Irving, TX) or the Abbott Spectrum CCX ™ Autoanalizer ( Abbott Laboratories, Irving, TX) using the A-Gent ™ Glucose-UV reagent system (Abbott Laboratories, Irving, TX) (a modification of the Richterich and Dauwaider procedure, Schweizerische Medizinische Wochenschrift, 101: 860 (1971)) (procedure of hexokinase), using a 100 mg / dl standard. The plasma glucose is then calculated by the equation: Plasma glucose (mg / dl) = sample value x 8.14 where 8.14 is the dilution factor, adjusted for the plasma hematocrit (assuming the hematocrit is 44%). The animals that received the vehicle maintained substantially unchanged hyperglycemic glucose levels (eg, greater than or equal to 250 mg / dl), the animals treated with the test compounds at appropriate doses have significantly reduced glucose levels. The hypoglycaemic activity of the test compounds is determined by statistical analysis (unpaired t test) of the mean plasma glucose concentration between the group treated with test compounds and the group treated with vehicles on day 5. The previous test carried out with a range of doses of test compounds, allows the determination of an approximate value of the minimum effective dose (MED) for in vivo reduction of plasma glucose concentration. The compounds of this invention readily adapt to clinical use as agents to reverse hyperinsulinemia, as agents to reduce triglycerides and as hypocholesterolemic agents. Such activity can be determined by the amount of test compound that reduces the levels of insulin, triglycerides or cholesterol with respect to a control vehicle without test compound in male ob / ob mice. Since the concentration of cholesterol in the blood is closely related to the development of cardiovascular, cerebrovascular or peripheral vascular disorders, the compounds of this invention, by virtue of their hypocholesterolemic action, prevent, arrest and / or reverse atherosclerosis. Since the concentration of insulin in blood is closely related to the promotion of vascular cell growth and the increase in sodium retention by the kidney, (in addition to other actions, for example, the promotion of glucose utilization) and these functions are known causes of hypertension, the compounds of this invention, by virtue of their hypoinsulinemic action, prevent, stop and / or reverse hypertension. Since the concentration of triglycerides and free fatty acids in the blood contributes to the overall levels of blood lipids, the compounds of this invention, by virtue of their triglyceride and fatty acid reducing activity, prevent, stop and / or reverse hyperlipidemia. Free fatty acids contribute to the overall level of blood lipids and, independently, have been negatively correlated with insulin sensitivity in a variety of physiological and pathological states. Five male mice aged 5 to 8 weeks are enclosed, C57BL / 6J-ob / ob (obtained from Jackson Laboratory, Bar Harbor, ME) per cage, under conventional animal care practices and fed ad libitum with a conventional diet for rodents. After a one-week acclimation period, the animals are weighed and 25 μl of retroorbital sinus blood is removed before any treatment. The blood sample is immediately diluted 1: 5 with saline containing 0.025% sodium heparin and kept on ice for a plasma glucose analysis. Animals are assigned to treatment groups so that each group has a similar average for plasma glucose concentration. The compound to be tested is administered via a nasogastric tube as a solution of about 0.02% to 2.0% (w / v (w / v)) in (1) 10% DMSO / 0.1% Pluronic® P105 Block Copolymer Surfactant ( BASF Corporation, Parsippany, NJ) in 0.1% saline without pH adjustment or (2) 0.25% w / v of hypromellose in water without pH adjustment. Alternatively, the compounds can be tested by administering them by nasogastric tube dissolved or suspended in PEG400. A dosing once a day (s.i.d) or dosing twice a day (b.i.d) is maintained for 1 a, for example, 15 days. Control mice receive only 10% DMSO / 0.1% Pluronic® P105 in 0.1% saline without pH adjustment or 0.25% w / v hypromellose in water without pH adjustment. Three hours after the last dose is administered, the animals are sacrificed by decapitation and blood is collected from the trunk in 0.5 ml serum separator tubes containing 3.6 mg of a 1: 1 weight / weight mixture of sodium fluoride: potassium oxalate. Freshly collected samples are centrifuged for 2 minutes at 10,000 x g at room temperature and the serum supernatant is transferred and diluted 1: 1 volume / volume with a solution of ITIU / ml aprotinin in 0.1% saline without pH adjustment. The diluted serum samples are then stored at -80 ° C until analysis. The diluted and thawed serum samples are analyzed with respect to insulin, triglycerides, free fatty acids and cholesterol levels. Serum insulin concentration is determined using Equate® RIA INSULIN kits (double antibody procedure, as specified by the manufacturer), purchased from Binax, South Portland, ME. The coefficient of variation between tests is <; 10% Serum tiglycerides are determined using the Abbott VP ™ system and VP Super System® Autoanalyzer (Abbott Laboratories, Irving, TX) or the Abbott Spectrum CCX ™ (Abbott Laboratories, Irving, TX), using the A-Gent ™ Triglycerides reagent system Test (Abbott Laboratories, Diagnostics Division Irving, TX) (enzyme procedure coupled to lipase, a modification of the procedure of Sampson et al., Clinical Chemistry 21: 1983 (1975)). Total serum cholesterol levels are determined using the Abbott VP ™ and VP Super System® Autoanalizer (Abbott Laboratories, Irving, TX) and the A-Gent ™ Cholesterol Test reagent system (cholesterol esterase-coupled enzyme procedure). procedure of Allain, et al., Clinical Chemistry 20: 470 (1974)) using 100 and 300 mg / dl standards. The concentration of free acids in serum is determined using a kit from Amano International Enzyme Co., Inc., adapted for use with the Abbott VP ™ and VP Super System® Autoanalyzer (Abbott Laboratories, Irving, TX) or the Abbott Spectrum CCX ™ (Abbott Laboratories, Irving, TX). Then calculate the levels of insulin, triglycerides, free fatty acids and total cholesterol in serum by the equations, Insulin in serum (μU / ml) = Sample value x 2 Triglycerides in serum (mg / dl) = Sample value x 2 Total serum cholesterol (mg / dL) = Sample value x 2 Free fatty acids in serum (μEq / l) = Sample value x 2 where 2 is the dilution factor. The animals that received the vehicle maintained substantially unchanged and high levels of serum insulin (e.g., 275 μU / ml), serum triglycerides (e.g., 235 mg / dl), free fatty acids in serum (e.g. , 1500 μEq / ml) and total serum cholesterol (for example, 190 mg / dl), while the animals treated with the compounds of the present invention, generally have lower levels of insulin, triglycerides, free fatty acids and total cholesterol in serum. The activity of reducing the insulin, triglycerides, free fatty acids and total cholesterol in serum of the test compounds is determined by statistical analyzes (unpaired t tests) of the mean concentration of insulin, triglycerides, free fatty acids or total cholesterol in serum, between the group treated with the test compound and the control group treated with vehicle.

Claims (15)

NOVELTY OF THE INVENTION CLAIMS

1. A compound of formula a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof, or a pharmaceutically acceptable salt of the prodrug, wherein Q is aryl, substituted aryl, heteroaryl or substituted heteroaryl; each of Z and X is independently (C, CH or CH2), N, O or S; X1 is NRa, -CH2-, O or S; each is, independently, a link or is not present, with the condition that both are not simultaneously links; R1 is hydrogen, halogen, -O (CrCß alkyl), -S (CrCß alkyl) - (CrCß alkyl), -CF3, -NH2, -NH (C8 alkyl), -N- (CrC8 alkyl) 2, -NO2 , -CN, -C02H, -C? 2 (CrC8 alkyl), - (C2-C8 alkenyl) or (C2-C8 alkynyl); each of Ra and R is independently hydrogen or-CrC8 alkyl;

And it is or is not present; R2 and R3 are independently hydrogen, halogen, -alkyl d-C8, -CN, -C = C-Si (CH3) 3, -O (C8 alkyl), -S (CrC8 alkyl), -CF3, -NH2, -NH (C8 alkyl), -N (C8 alkyl) 2, -NO2, -CO2H, -C02 (CrC8 alkyl), - (C2-C8 alkenyl) or - (C2-C8 alkynyl), or R2 and R3 together with the atoms on the ring to which they are attached, they form a ring of five or six members containing from 0 to 3 heteroatoms and from 0 to 2 double bonds; R4 is -C (= O) A; A is -NRdRd, -NRaCH2CH2OR4, each Rd is independently hydrogen, CrC8 alkyl, CrC8 alkoxy, aryl, substituted aryl, heteroaryl or substituted heteroaryl; each Rc is independently hydrogen, -C (= O) ORa, -ORa, -SRa or -NRaRa; and each n is independently from 1 to 3. 2. A compound, according to claim 1, further characterized in that Rb and R1 are hydrogen.

3. A compound, according to claim 1, further characterized in that Rb is hydrogen; R1 are hydrogen; and A is

4. - A compound, according to claim 1, further characterized in that Rb is hydrogen; R1 is hydrogen; And it is not present; and A is

5. - A compound, according to claim 1, further characterized in that Rb is hydrogen; R1 is hydrogen; Z is C; X is O or S; And it is not present; A is

R2 is hydrogen; and R3 is hydrogen, halogen or methyl. 6. A compound, according to claim 1, further characterized in that Q is phenyl and A is .

7. - A pharmaceutical composition comprising a compound, according to claim 1, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutically acceptable salt of the prodrug.

8. A method for treating or preventing atherosclerosis, diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypergiukaemia, hypertension, tissue ischemia or myocardial ischemia, comprising procedure the step of administering to a patient suffering from or at risk of suffering from atherosclerosis, diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, hypergiukaemia, hypertension, ischemia of tissues or myocardial ischemia a therapeutically effective amount of a compound according to claim 1, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutically acceptable salt of said prodrug.

9. A method for inhibiting glycogen phosphorylase, the method comprising the step of administering to a patient in need of inhibition of glycogen phosphorylase an amount that inhibits the glycogen phosphorylase of a compound, according to claim 1, a stereoisomer, a pharmaceutically acceptable salt or a prodrug thereof or a pharmaceutically acceptable salt of the prodrug.

10. The compound: 6H-Thieno [(1S) -Benzyl-3 - ((3R, 4S) -dih! Droxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxo-propyl] [2.3 -b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-bromo-6H-thieno [2,3-b] acid pyrrole-5-carboxylic; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxo-propyl] -amide of 2-methyl-6H-thieno [2, 3-b] pyrrole-5-carboxylic acid; [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of (±) -2-methyl-6H-thieno [2,3-b] pyrrole-5-acid carboxylic; [(1 S) -benzyl-2 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxoethyl] -amide of 2-bromo-6H-thieno [2,3-b] pyrrole-5-acid -carboxylic; [(1S) -Benzyl-3 - ((3R, 4S) -dih -droxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-chloro-6H-thieno [2,3] -b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] 2-chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2,4-dichloro-6H-thieno [2,3] b] pyrrole-5-carboxylic acid; [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxo-ethyl] -amide of (+) - 4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-bromo-4H-thieno [3,2-b] ] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 4 H -thieno [3,2-b] pyrrole-5- carboxylic; [1-Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of (±) -2-bromo-4H-furo [3,2-b] pyrrole-5 -carboxylic; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxo-propyl] -amide of 2-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 6-H-thieno [2,3-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide-2-methyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2,4-dichloro-6H-thieno [2,3-b] pyrrole-5 -carboxylic; 2-Cyano-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; 2-Chloro-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Dimethylcarbamoyl-2-phenylethyl] -amide; [(1S) -Benzyl-2- (1, 1-dioxo-1-thiazolidin-3-yl) -2-oxo-ethyl] -amide of 2-chloro-6H-thieno [2,3-b] pyrrol- 5-carboxylic; Ethyl ester of acid 1-. { (2S) - [(2-chloro-6H-thieno [2,3-b] pyrrole-5-carbonyl) amino] -3-phenylpropionyl} piperidine-4-carboxylic acid; 2-Bromo-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidn-1-yl) -2-oxoethyl] -amide of 2-methyl-4H-furo [3,2-b] pyrrol- 5-carboxylic; [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide of 2-trimethylsilanylethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid; 2-ethynyl-6H-thieno [2,3-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] amide of 2-fluoro-4H-thieno [3,2-b] pyrrole-5 -carboxylic; 2-Cyano-4H-furo [3,2-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] 2-chloro.4H-furo [3,2-b] pyrrole-5-carboxylic acid amide; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxo-3-oxopropyl-2-chloro-4H-furo [3,2-b] ] pyrrole-5-carboxylic acid; Acid 1-. { (2S) - [(2-chloro-6H-thieno [2,3-b] pyrrole-5-carbonyl) amino] -3-phenylpropionl} -piperidine-4-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 3-chloro-4H-thieno [3,2-b] pyrrole-5-amide -carboxylic; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide 3-chloro-4H-thieno [3,2-b] ] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-3-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl-amide of 3-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxy-pyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-chloro-4H-thieno [3,2] -b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-chloro-4H-thieno [3,2-b] pyrrole-5 -carboxylic; [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl] -2-oxoetyl] -amide 3-methyl-4H-thieno [3,2-b] pyrrole-5 -carboxylic; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide 3-methyl-4H-thieno [3, 2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-2-cyano-4H-thieno [3,2-b] -5-carboxylic acid; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - (2R) -hydroxy-3-oxopropyl] -amide of 2-cyano-4H-furo [3,2-b] ] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-3-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 3-bromo-4H-furo [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) - (2R) -hydroxy-3-oxopropyl] -amide of 4H-1.7-dithia-4-azacyclopenta [a] pentalen- 5-carboxylic; [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxy-pyrrolidin-1-yl) -2-oxoethyl] -amide of 4H-1, 7-dithia-4-azacyclopenta [a] pentalen- 5-carboxylic; [(1S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide of 2-chloro-3-methyl-4H-thieno [3,2-b] pyrrol- 5-carboxylic; [(1 S) -Benzyl-3 - ((3R, 4S) -dihydroxypyrrolidin-1 -yl) - 2-chloro-3-methyl-4H-thieno [3-S] -3-oxo-propyl] -amide [3]; , 2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amide-2-methylsulfanyl-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2- (3-hydroxyzetidin-1-yl) -2-oxoethyl] amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1S) -Benzyl-2- (1, 1-dioxo-1-thiazolidin-3-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-amide carboxylic; 2-Bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid [(1S) -Benzyl-2-morpholin-4-yl-2-oxoethyl] -amide; [(1 S) -Benzyl-2 - ((3S, 4S) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid; [(1 S) -Benzyl-2 - ((3R, 4R) -dihydroxypyrrolidin-1-yl) -2-oxoethyl] -amino-2-bromo-4H-thieno [3,2-b] pyrrole-5-amide -carboxylic; or [(1S) -Benzyl-2- (4-hydroxypiperidin-1-yl) -2-oxoethyl] amide of 2-bromo-4H-thieno [3,2-b] pyrrole-5-carboxylic acid , or a stereoisomer, a pharmaceutically acceptable salt or prodrug of the compound, or a pharmaceutically acceptable salt of the prodrug.

11. - A kit for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia in a patient suffering from diabetes, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia of the tissues, the kit comprising: a) a first pharmaceutical composition comprising a compound, according to claim 1, or a stereoisomer, pharmaceutically acceptable salt or prodrug of the compound or a pharmaceutically acceptable salt of the prodrug; b) a second pharmaceutical composition comprising a second compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or ischemia of the tissues; and c) a container for containing the first and second compositions.

12. A method for treating diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia, the method comprising the step of administering a patient suffering from diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia, a therapeutically effective amount of a compound, according to claim 1, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutically acceptable salt of a prodrug, combined with at least one additional compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, nefropat a diabetic, diabetic retinopathy, cataracts, hipergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia.

13. A pharmaceutical composition comprising a compound, according to claim 1, a stereoisomer, a pharmaceutically acceptable salt or prodrug thereof or a pharmaceutically acceptable salt of a prodrug and at least one additional compound useful for the treatment of diabetes, insulin resistance, diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, cataracts, hypergiucemia, hypercholesterolemia, hypertension, hyperinsulinemia, hyperlipidemia, atherosclerosis or tissue ischemia.

14. The pharmaceutical composition according to claim 13, wherein the second compound is selected from: insulin and insulin analogs; GLP-1 (7-37) (insulinotropin) and GLP-1 (7-36) -NH2; sulfonylureas and the like; biguanides; 2-antagonists; imidazolines; glitazones (thiazolidinediones); PPAR-gamma agonists; inhibitors of fatty acid oxidation; a-glucosidase inhibitors; β-agonists; Phosphodiesterase inhibitors; agents that reduce lipid levels; anti-obesity agents; vanadate, vanadium complexes and peroxovanadium complexes; amylin antagonists; glucagon antagonists; inhibitors of gluconeogenesis; analogues and antagonists of somatostatin; and antilipolytic agents.

15. The pharmaceutical composition according to claim 13, wherein the second compound is selected from insulin LysPro, GLP-1 (7-37) (insulinotropin), GLP-1 (7-36) -NH2, chlorpropamide , glibenclamide, tolbutamide, tolazamide, acetohexamide, glipizide, glimepiride, repaglinide, meglitinide, metformin, phenformin, buformin, midaglizole, isaglidol, deriglidol, idazoxan, efaroxan, fluparoxan, linogliride, ciglitazone, pioglitazone, englitazone, troglitazone, darglitazone, rosiglitazone, clomoxir , etomoxir, acarbose, miglitol, emiglytate, voglibose, MDL-25,637, camiglibose, MDL-73,945, BRL 35135, BRL 37344, Ro 16-8714, ICI D7114, CL 316,243, L-386,393; benfluorex, fenfluramine, Naglivan®, acipimox, WAG 994, Symlim ™, AC2993 and nateglinide.