MX2008000849A - Methods for preventing and treating metabolic disorders and new pyrazole-o-glycoside derivatives - Google Patents

Abstract

The invention relates to methods for preventing or treating metabolic disorders, for improving glycemic control, for preventing progression from impaired glucose tolerance, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus, for preventing or treating of complications of diabetes mellitus, for reducing the weight, for preventing or treating the degeneration of pancreatic beta cells, for treating hyperinsulinemia and insulin resistance and diabetes type 1, in patients in need thereof by administering a pharmaceutical composition comprising a pyrazole-O-glycoside as defined in claim 1 , or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

Description

METHODS FOR PREVENTING AND TREATING METABOLIC DISORDERS AND NEW DERIVATIVES OF PIRAZOL-O-GLUCOSIDE TECHNICAL FIELD OF THE INVENTION The invention relates to methods - to prevent, slow the progression, delay or treat a metabolic disorder, - to improve glycemic control and / or to reduce fasting plasma glucose, postprandial plasma glucose and / or glycosylated HbA1c hemoglobin, - to prevent, slow down, delay or reverse progression from impaired glucose tolerance, resistance to insulin and / or from the metabolic syndrome to type 2 diabetes mellitus, - to prevent, slow the progression, delay or treat a disorder or condition selected from the group consisting of complications of diabetes mellitus; - to reduce weight or prevent weight gain or to facilitate weight reduction, - to prevent or treat the degeneration of pancreatic beta cells and / or to improve and / or restore pancreatic beta cell functionality and / or restore functionality of pancreatic insulin secretion, - maintaining and / or improving insulin sensitivity and / or to treat or prevent hyperinsulinemia and / or insulin resistance, in patients who need it, by administering a pharmaceutical composition that it comprises a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), as defined below, or its prodrug, or its pharmaceutically acceptable salt. In addition, the present invention relates to the use of a pyrazole-O-glucoside derivative according to invention, to prepare a pharmaceutical composition, and to these medicaments and pharmaceutical compositions. In addition, the present invention relates to novel pyrazole-O-glucoside derivatives, as defined below, or their prodrugs, or their pharmaceutically acceptable salts. The present invention also relates to pharmaceutical compositions comprising at least one of the pyrazole-O-glucoside derivatives, as defined below, or their prodrugs, or their pharmaceutically acceptable salts. BACKGROUND OF THE INVENTION European patent application EP 1338603 A1 describes novel pyrazole-O-glucoside derivatives. The pyrazole-O-glucoside derivatives are proposed as inducers of urinary sugar secretion and as drugs in the treatment of diabetes. The renal filtration and the reuptake of glucose contribute, among other mechanisms, to maintaining the concentration of plasma glucose in a stable state and, therefore, can serve as an antidiabetic target. The reuptake of glucose filtered through the epithelial cells of the kidney is carried out by means of sodium-dependent glucose cotransporters (SGLT) which are found in the hairy border membranes in the proximal tubules along the sodium gradient (1). There are at least three isoforms of SGLT that differ in their expression pattern, as well as in their physico-chemical properties (2). SGLT2 is expressed exclusively in the kidney (3), whereas SGLT1 is expressed in other tissues, such as the intestine, colon, skeletal muscle and heart (4: 5). It has been discovered that SGLT3 is a glucose detector in interstitial cells of the intestine, without any transport function (6). Potentially, other genes that are related, but not yet characterized, can also contribute to the renal reuptake of glucose (7, 8 '9). In normoglycemia, glucose is completely absorbed by the SGLT in the kidney, while the reuptake capacity of the kidney is saturated at a glucose concentration greater than 10 mM, resulting in glucosuria ("diabetes mellitus"). This threshold concentration can be decreased by the inhibition of SGLT2. It has been demonstrated in experiments with the inhibitor of SGLT florizine that the inhibition of SGLT partially inhibits the reuptake of glucose from the glomerular filtrate into the blood, leading to a decrease in blood glucose concentration and glucosuria. (10; 11) (1) Wright, E.M. (2001), Am. J. Renal Physiol., 280, F10-F18; (2) Wright, E.M. et al. (2004), Pflugers Arch., 447 (5): 510-518; (3) You, G. et al. (1995), J. Biol. Chem., 270 (49), 29365-29371; (4) Pajor A.M., Wright E.M. (1992), J. Biol. Chem., 267 (6): 3557-3560; (5) Zhou, L. et al. (2003), J. Cell. Biochem., 90: 339-346; (6) Diez-Sampedro, A. et al. (2003), Proc. Nati Acad. Sci. USA, 100 (20), 11753-11758; (7) Tabatabai, N.M. (2003), Kidney Int., 64, 1320-1330; (8) Curtís, R.A.J. (2003), US patent application 2003/0054453; (9) Bruss, M. and Bonisch, H. (2001), Cloning and functional characterization of a new human sugar transporter in kidney (Genbank registration number AJ305237); (10) Rossetti, L et al. (1987), J. Clin. Invest., 79, 1510-1515; (11) Gouvea, W.L (1989), Kidney Int., 35 (4): 1041 -1048.

Type 2 diabetes is a disease with an increasing incidence that, due to the high frequency of complications, leads to a significant reduction in life expectancy. Due to the microvascular complications associated with diabetes, type 2 diabetes is currently the most frequent cause of vision loss in adult life, renal failure, and amputation in the industrialized world. In addition, the presence of type 2 diabetes is associated with a two to five-fold increase in the risk of cardiovascular disease. After suffering from the disease for a long time, most patients with type 2 diabetes do not respond to oral therapy and become insulin dependent, requiring daily injections and multiple daily measurements of glucose. The UKPDS (United Kingdom Prospective Diabetes Study) showed that intensive treatment with metformin, sulphonylureas or insulin produced only a limited improvement in glycemic control (difference in HbA1c of approximately 0.9%). Furthermore, even in patients under intensive treatment, glycemic control deteriorates significantly over time, and this was attributed to the deterioration of ß cell function. Importantly, intensive treatment was not associated with a significant reduction in macrovascular complications, ie, cardiovascular events. Therefore, there is a medical need not covered by drugs with good efficacy with respect to glycemic control, with respect to the disease modifying properties, and with respect to the reduction of cardiovascular morbidity and mortality, while at the same time showing an improved security profile. OBJECT OF THE INVENTION The objective of the present invention is to provide a method for preventing, slowing the progression, delaying or treating a metabolic disease. Another objective of the present invention is to provide a method for improving glycemic control in a patient in need thereof. Another objective of the present invention is to provide a method for preventing, slowing or delaying progression from altered glucose tolerance, insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus. Another objective of this invention is to provide a method for preventing, slowing the progression, delaying or treating a disorder or condition of the group consisting of complications of diabetes mellitus. Another objective of the present invention is to provide a method for reducing weight or preventing weight gain or facilitating a weight reduction in a patient in need thereof. Other objects of the present invention relate to new uses of pyrazole-O-glucoside derivatives according to this invention, including their prodrugs and pharmaceutically acceptable salts. Another object of the present invention is to provide novel pyrazole-O-glucoside derivatives and novel prodrugs of the pyrazole-O-glucoside derivatives which have a good to very good inhibitory effect on the sodium-dependent glucose cotransporter SGLT, in particular SGLT2, in vitro and / or in vivo and / or having pharmacological and / or pharmacokinetic and / or physicochemical properties from good to very good. Other objects of the present invention will be obvious to the experts in the art from the previous and subsequent description and from the examples. SUMMARY OF THE INVENTION Within the scope of the present invention, it has now been surprisingly discovered that a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or their prodrugs, or their salts Pharmaceutically acceptable, as defined below, can be used, advantageously, to prevent, slow the progression, delay or treat a metabolic disorder, in particular to improve glycemic control in patients. This opens up new therapeutic possibilities in the treatment and prevention of type 2 diabetes mellitus, overweight, obesity, complications of diabetes mellitus and nearby disease states. Therefore, in a first aspect, the present invention provides a method for preventing, slowing the progression, delaying or treating a metabolic disorder selected from the group consisting of diabetes mellitus type 1, diabetes mellitus type 2, impaired glucose tolerance , hyperglycemia, postprandial hyperglycemia, overweight, obesity, including class I obesity, class II obesity, class III obesity, visceral obesity and abdominal obesity, and metabolic syndrome in a patient who needs it, which is characterized by a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), which consists of (1) 4- (2,3-D-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (2) 4- (2,5-D-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (3) 4- ( 2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (4) 4- (3,5-difluoro-4-) methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (5) 1-cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5- methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (6) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3-β-D- glucopyranos-1-yloxy-1 H-pyrazole, (7) 1-cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole , (8) 4- (3-chloro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (9) 4- (2-chloro) -4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (10) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl- 5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (11) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β- D-glucopyranos-1-yloxy-1H-pyrazole, (12) 4- (2-flu) gold-4-methylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (13) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl -5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (14) I 4- (4-ethylenebenzyl) -1-isopropyl-5-methyl-3-β- D-glucopyranos-1-yloxy-1 H-pyrazole, (15) [4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole, (16) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (17) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3-β-D-glucopyranosyl-1-yloxy-1 H-pyrazole, (18) 4- (4-bromo-2-fluorobenzyl) - 1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (19) 4- (2-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- β-D-glucopyranos-1-yloxy-1 H-pyrazole, (20) 4- (2-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1- iloxy-1 H-pyrazole, (21) 4- (4-etl-benzyl) -1-isopropyl-5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (22) 4- (4-bromobenzyl) -1-isopropyl-5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (23) 4- (4-ethylbenzyl) -1-cyclobutyl-5-trifluoromethyl- 3-ß-D-glucopyranos-1-yloxy-1 H-pyrazole, (24) 4- (4-ethylbenzyl) -1 - (2-fluoro-1-fluoro-methyl-ethyl) -5-trifluoromethyl-3-β-D- glucopyranos-1-yloxy-1 H-pyrazole, (25) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3-β-D-glucopyranos-1- Ilyloxy-1 H-pyrazole, (26) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (27) 4- (2,3-difluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, 28L 4- (3-fluoro-4-methoxybenzyl) ) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H- pyrazole, (29) | 4- (4-ethylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, or its prodrug, in which one or more hydroxyl groups of the group β-D -glucopyranosyl are acylated with selected groups of (C-M-alkylcarbonyl, (C 1 -8 alkyl) oxycarbonyl, phenylcarbonyl, phenyl- (alkyl) phenyloxycarbonyl, and phenyl- (C 1 -C 3 alkyl) -oxocarbonyl, or its pharmaceutically acceptable salt, is administered. According to another aspect of the invention, there is provided a method for improving glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated HbA1c hemoglobin in a patient in need thereof, characterized in that administering a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and below. As through the use of a compound according to this invention an improvement of the glycemic control is obtained in patients who need it, those disorders and / or diseases related or caused by an increase in the blood glucose level can also be treated. Therefore, in another aspect, the invention provides a method for preventing, slowing the progression, delaying or treating a disorder or condition selected from the group consisting of complications of diabetes mellitus, such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction, cerebrovascular accidents and peripheral arterial occlusive disease, in a patient who needs it, which is characterized by the administration of A pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and below. The term "tissue ischemia" comprises, in particular, diabetic macroangiopathy, diabetic microangiopathy, difficult wound healing and diabetic ulcer. The compounds according to this invention can also have valuable disease modifying properties with respect to diseases or disorders related to impaired glucose tolerance, insulin resistance and / or metabolic syndrome. Therefore, in another aspect of the present invention, a method is provided for preventing, slowing, delaying or reversing the progression from altered glucose tolerance, insulin resistance and / or metabolic syndrome to diabetes mellitus of type 2 in a patient in need thereof, characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt is administered, defined as before and after. By administering a compound according to the invention, excessive levels of blood glucose are not converted into insoluble storage forms, such as fat, but are excreted through the patient's urine. Therefore, weight is not gained, and even a weight reduction is obtained as a result. After this, another aspect of the invention provides a method for reducing weight or preventing weight gain or facilitating a Weight reduction in a patient in need thereof, characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically salt is administered acceptable, defined as before and after. The pharmacological effect of the compounds according to the invention is independent of insulin. Therefore, an improvement in glycemic control is possible without an additional effort of the pancreatic beta cells. By administering a compound according to this invention the degeneration of the beta cells and the decrease in the functionality of the beta cells can be delayed or prevented as, for example, apoptosis or necrosis of pancreatic beta cells. In addition, the functionality of pancreatic cells can be improved or restored, and can increase the number and size of pancreatic beta cells. It can be shown that the state of differentiation and hyperplasia of the pancreatic beta cells altered by hyperglycemia can be normalized by a treatment with a compound according to the invention. Therefore, another aspect of the present invention provides a method for preventing, slowing, delaying or treating degeneration of pancreatic beta cells and / or decreased functionality of pancreatic beta cells and / or for improving and / or restoring functionality. of pancreatic beta cells and / or restoring the functionality of pancreatic insulin secretion in a patient in need thereof, characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds is administered (1 ) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and subsequently. As a result of this, another aspect of the invention provides a method for maintaining and / or improving insulin sensitivity and / or for treating or preventing hyperinsulinemia and / or insulin resistance in a patient in need thereof, characterized in that a pharmaceutical composition comprising a derivative is administered of pyrazole-O-glucoside selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and subsequently. Other aspects of the present invention relate to the use of a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and subsequently, in the treatment or prophylaxis of diseases or disorders as described above and subsequently. Other aspects of the present invention relate to the use of a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and subsequently, for the manufacture of a medicament for a therapeutic method as described above and subsequently. In addition, another aspect of the present invention relates to a medicament or pharmaceutical composition comprising a therapeutically or prophylactically effective amount of a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, defined as above and subsequently, for the treatment or prophylaxis of diseases or disorders, described above and subsequently. Another aspect of the present invention relates to novel pyrazole-O-glucoside derivatives selected from the group consisting of: pyrazole, IJ l 4- (4-ethynylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (15) 4- (3-fluoro-4-isopropoxybenzyl) ) -1-isopropyl-5-methyl-3-β-D-glucopyranosyl-1-yloxy-1 H -pyrazole, (17) 4- (2-fluoro-4-methoxybenzyl) -1-ylpropyl-5-trifluoromethyl -3-ß-D-glucopyranos-1-yloxy-1 H-pyrazole, (18) 4- (4-bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1 -iloxy- 1 H-pyrazole, (19) 4- (2-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranosyl-1-yloxy-1 H-pyrazole, (20) ) 4- (2-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, or its prodrug, in which one or more hydroxyl groups of the ß-D-glucopyranosyl group are acylated with selected groups of (C C-alkyl) i8) carbonyl, (C 1 -sycloxycarbonyl, phenylcarbonyl, phenyl- (C C-3 alkyl) -carbonyl, phenyloxycarbonyl, and phenyl- (alkyl or its pharmaceutically acceptable salt. Another aspect of the present invention relates to novel prodrugs of pyrazole-O-glucoside derivatives selected from the group consisting of: (46) 4- (3-fluoro-4-methylbenzyl) -1-ylpropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole, (47) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D- glucopyranos-1-yloxy) -1 H-pyrazole, (48) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-isobutyl) loxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-hex-1-yloxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4 - (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-phenoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (2-fluoro) -4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-benzyloxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (2-fluoro-4-methoxy) Benzyl) -1-isopropyl-5-methyl-3- (6-O-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (2-fluoro-4) -methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-propylcarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole, 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-isopropylcarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (2-fluoro-4-methoxybenzyl) -1- sopropil-5-methyl-3- (6-O-benzylcarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (4-ethylbenzyl) -1-isopropyl-5-tr Fluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole4- (4-bromobenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole; - (4-ethylbenzyl) -1-cyclobutyl-5-trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (4-ethylbenzyl) -1- (2-Fluoro-1-fluoromethylethyl) -5-trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4- (4-isopropoxybenzyl) -1-isopropyl-5-methyl- 3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (62) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (63) 4- (4-ethylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, or their pharmaceutically acceptable salts. Another aspect of the present invention relates to pharmaceutical compositions comprising at least one pyrazole-O-glucoside derivative according to this invention, or its pharmaceutically acceptable salt. Definitions The expression "body mass index" or "BMI" of a human patient is defined as the weight in kilograms divided by the square of the height in meters, so that the BMI has units of kg / m2. The term "overweight" is defined as the disorder in which the individual has a BMI of 25 kg / m2 or greater, and less than 30 kg / m2. The terms "overweight" and "preobeso" are used interchangeably. The term "obesity" is defined as the disorder in which the individual has a BMI equal to or greater than 30 kg / m2. According to a WHO definition, the term obesity can be classified as follows: the expression "class I obesity" is the disorder in which the BMI is equal to or greater than 30 kg / m2, but less than 35 kg / m2; the expression "class II obesity" is the disorder in which the BMI is equal to or greater than 35 kg / m2, but less than 40 kg / m2; the term "class III obesity" is the disorder in which the BMI is equal to or greater than 40 kg / m2. The term "visceral obesity" is defined as the disorder in which a waist to hip ratio greater than or equal to 1.0 is measured in men and 0.8 in women. It defines the risk of insulin resistance and the development of prediabetes. The term "abdominal obesity" is usually defined as the disorder in which the waist circumference is > 102 cm in men, and it is > 94 cm in women. With regard to Japanese ethnicity or to Japanese patients, abdominal obesity can be defined as a waist circumference > 85 cm in men and = 90 cm in women (see, for example, the research committee for the diagnosis of metabolic syndrome in Japan). The term "euglycemia" is defined as the disorder in which a subject has a fasting blood glucose concentration within the normal range, greater than 70 mg / dL (3.89 mmol / L) and less than 110 mg / dL (6.11 mmol). / l). The expression "fasting" has the normal meaning as a medical term. The term "hyperglycemia" is defined as the disorder in which a subject has a fasting blood glucose concentration above the normal range, greater than 110 mg / dl (6.11 mmol / L). The expression "fasting" has the normal meaning as a medical term. The term "postprandial hyperglycemia" is defined as the disorder in which a subject has a blood glucose concentration or postprandial serum glucose concentration at 2 hours greater than 200 mg / dl (11.11 mmol / l). The term "impaired glucose tolerance" or "IGT" is defined as the disorder in which a subject has a fasting blood glucose concentration or a fasting serum glucose level greater than 110 mg / dl and less than 126 mg / dl (7.00 mmol / l), or a blood concentration glucose or postprandial serum glucose concentration at 2 hours greater than 140 mg / dl (7.78 mmol / l) and less than 200 mg / dl (11.11 mmol / l). It is also intended that the expression impaired glucose tolerance be applied to impaired fasting glucose disorder. Abnormal glucose tolerance, ie blood glucose concentration or postprandial serum glucose concentration at 2 hours can be measured as the blood sugar level in mg of glucose per day of plasma 2 hours after ingesting 75 g of glucose after the fast. The term "hyperinsulinemia" is defined as the disorder in which a subject has insulin resistance, with or without euglycemia, in which the serum or plasma concentration of fasting or postprandial insulin rises above that of thin individuals normal, without insulin resistance, which have a waist-to-hip ratio <; 1.0 (for men) or < 0.8 (for women). The terms "insulin sensitization", "improvement of insulin resistance" or "decrease in insulin resistance" are synonymous and are used interchangeably. The term "insulin resistance" is defined as a state in which insulin levels in the circulation in excess of the normal response to a glucose load are required to maintain the euglycemic state (Ford ES, et al., JAMA., (2002), 287: 356-359). One method to determine insulin resistance is the euglycemic-hyperinsulinemic clamp test. The ratio of insulin to glucose is determined within the scope of a combined technique of insulin-glucose infusion. It is determined that there is an insulin resistance if the absorption of glucose is below 25 ° percentile of the background population investigated (WHO definition). A little less laborious than the pincer test are the so-called minimum models, in which during an intravenous glucose tolerance test, the concentrations of insulin and glucose in the blood are measured at fixed time intervals and, from these , insulin resistance is calculated. In this method it is not possible to distinguish between hepatic and peripheral insulin resistance. In addition to insulin resistance, the response to therapy of a patient with insulin resistance, insulin sensitivity and hyperinsulinemia can be quantified by evaluating the score of the "evaluation of insulin resistance in a model of homeostasis (HOMA-IR) ", a reliable indicator of insulin resistance (Katsuki A., er al., Diabetes Care, 2001, 24: 362-365). Reference is also made to methods for determining the HOMA index for insulin sensitivity (Matthews et al., Diabetologia, 1985, 28: 412-419), for the ratio of intact proinsulin to insulin (Forst et al., Diabetes , 2003, 52 (suppl.1): A459) and a study of euglycemic pincers. In addition, plasma adiponectin levels can be controlled as a potential substitute for insulin sensitivity. The estimation of the insulin resistance by means of the score of the homeostasis evaluation model (HOMA) -IR is calculated with the formula (Galvin P., et al., Diabet Med., 1992, 9: 921-928) : HOMA-IR = [fasting serum insulin (μU / ml)] x [fasting plasma glucose (mmol / l) /22.5] As a rule, other parameters are used in daily clinical practice to evaluate insulin resistance. Preferably, the concentration of triglycerides of the patient, for example, since higher levels of triglycerides correlate significantly with the presence of insulin resistance. Patients with a predisposition for the development of IGT or type 2 diabetes are those with euglycemia with hyperinsulinemia and are, by definition, resistant to insulin. A typical patient with insulin resistance is usually overweight or obese. If insulin resistance can be detected, this is a particularly strong indication of the presence of prediabetes. Therefore, in order to maintain glucose homoeostasis, a person may need 2-3 times more insulin than another person, without this having any direct pathological importance. Methods to investigate the function of pancreatic beta cells are similar to previous methods with respect to insulin sensitivity, hyperinsulinemia or insulin resistance: An improvement in beta cell function can be measured, for example, by determining a HOMA index for the function of beta cells (Matthews et al., Diabetologia, 1985, 28: 412-419), of the ratio of intact proinsulin to insulin (Forst er al., Diabetes, 2003, 52 (suppl.1) : A459), of insulin secretion / C-peptide after an oral glucose tolerance test or a food tolerance test, or using a hyperglycemic pincer study and / or a minimum model after a tolerance test intravenous glucose with frequent sampling (Stumvoll et al., Eur. J. Clin. Invest., 2001, 31: 380-381). The term "prediabetes" is the disorder in which an individual is predisposed to the development of type 2 diabetes. Pre-diabetes extends the definition of impaired glucose tolerance to include individuals with a fasting blood glucose within the high normal range = 100 mg / dL (J.B. Meigs, er al., Diabetes, 2003, 52: 1475-1484) and fasting hyperinsulinemia (high plasma insulin concentration). The scientific and medical basis for identifying prediabetes as a serious threat to health is set forth in an opinion report entitled "The Prevention or Delay of Type 2 Diabetes" issued jointly by the American Diabetes Association and the National Institute of Diabetes and Digestive and Kidney Diseases (Diabetes Care, 2002, 25: 742-749). Individuals likely to have insulin resistance are those who have two or more of the following attributes: 1) overweight or obese, 2) high blood pressure, 3) hyperlipidemia, 4) one or more first-degree relatives with a diagnosis of IGT or type 2 diabetes. Insulin resistance can be confirmed in these individuals by calculating the HOMA-IR score. For the purposes of this invention, insulin resistance is defined as the clinical disorder in which the individual has a HOMA-IR >score.; 4.0, or an HOMA-IR score above the normal upper limit, according to the laboratory definition that performs the glucose and insulin tests. The term "type 2 diabetes" is defined as the disorder in which a subject has a blood glucose concentration or fasting serum glucose level greater than 125 mg / dl (6.94 mmol / l). The measurement of blood glucose values is a conventional procedure in routine medical tests. If a glucose tolerance test is performed, the blood sugar level of a diabetic will be greater than 200 mg of glucose per day of plasma 2 hours after ingesting 75 g of glucose on an empty stomach. In a glucose tolerance test, 75 g of glucose are administered orally to the patient being tested after 10-12 hours of fasting, and the blood sugar level is registered immediately before eating glucose, and 1 and 2 hours after ingesting it. In a healthy subject, the blood sugar level before ingesting glucose will be between 60 and 110 mg per day of plasma, less than 200 mg per day 1 hour after ingesting glucose, and less than 140 mg per day after 2. hours. If after 2 hours the value is between 140 and 200 mg, this is considered an abnormal tolerance to glucose. The term "late stage of type 2 diabetes mellitus" includes grandal patients with a failure to secondary drugs, an indication for insulin therapy, and a progression to micro- and macrovascular complications, eg, diabetic nephropathy, coronary heart disease (CHD). The term "HbA1c" refers to the product of a nonenzymatic glycation of the B chain of hemoglobin. His determination is well known to those skilled in the art. In the control of the treatment of diabetes mellitus, the HbA1c value is of exceptional importance. Since its production essentially depends on the blood sugar level and the life of the erythrocytes, HbA1c, in the sense of a "blood sugar memory", reflects the average blood sugar levels of the previous 4-6 weeks. Diabetic patients whose HbA1c value is consistently well adjusted by intensive diabetes management (ie, <6.5% of total hemoglobin in the sample), are significantly better protected against diabetic microangiopathy. For example, metformin, by itself, achieves an average improvement in the HbA1 c value in diabetics of the order of 1.0-1.5%. This reduction of the HbA1C value is not sufficient in all diabetics to achieve the desired target range of < 6.5% and preferably < 6% of HbA1c. The "metabolic syndrome", also called "syndrome X" (when used in the context of a metabolic disorder), also called "dysmetabolic syndrome" is a complex syndrome with the cardinal characteristic of presenting insulin resistance (Laaksonen DE, et al. al., Am. J. Epidemiol., 2002,156: 1070-1077). According to the ATP III / NCEP guidelines (Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III), JAMA: Journal of the American Medical Association (2001), 285: 2486-2497), a diagnosis of metabolic syndrome is made when three or more of the following risk factors are present: 1. Abdominal obesity, defined as a waist circumference > 102 cm in men, and > 94 cm in women; or with respect to Japanese ethnicity or Japanese patients, it is defined as a waist circumference = 85 cm in men, and = 90 cm in women; 2. Triglycerides: > 150 mg / dl 3. HDL cholesterol < 40 mg / dl in men 4. Blood pressure > 130/85 mm Hg (SBP> 130 or DBP> 85) 5. Fasting blood glucose > 110 mg / dl The definitions of NCEP have been validated (Laaksonen D.E., ef al., Am. J. Epidemiol. (2002), 156: 1070-1077). Triglycerides and HDL cholesterol in blood can also be determined by conventional methods in medical analysis and are described, for example, in Thomas L. (editor): "Labor und Diagnose", TH-Books Verlagsgesellschaft mbH, Frankfurt / Main, 2000 According to a commonly used definition, hypertension is diagnosed if the systolic blood pressure (SBP) is greater than 140 mm Hg, and the diastolic blood pressure (DBP) is greater than 90 mm Hg. If a patient suffers from overt diabetes, it is currently recommended to reduce the systolic blood pressure to a level lower than 130 mm Hg, and reduce the diastolic blood pressure to a level below 80 mm Hg. The expression "treat prophylactically" and the term "prevent" are used interchangeably. DETAILED DESCRIPTION The aspects according to the present invention, in particular the methods and uses, refer to pyrazole-O-glucoside derivatives selected from the group of compounds (1) to (29) as defined above and subsequently herein, or their prodrugs, or pharmaceutically acceptable salts thereof. Preferably, all hydroxyl groups are unsubstituted, or only the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted as defined. Preferred substituents are selected from (Ci.sub.β alkyl) carbonyl, (C 1-6 alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl. Even more preferred substituents are selected from acetyl, methoxycarbonyl and ethoxycarbonyl, in particular ethoxycarbonyl. Preferred prodrugs are selected from the group consisting of (30a) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (30b) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pirazol, (31 a) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, ( 31b) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (32a) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H- pyrazole, (32b) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole, (33a) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole, (33b) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1) -iloxy) -1 H-pyrazole, (34a) 4- (2-fluoro-4-ylpropoxybenzyl) -1-ylpropyl-5-methyl-3- (6-O-methoxycarbonyl) - D-glucopyranos-1-yloxy) -1 H-pyrazole, (34b) 4- (2-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6- O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy! -1 H-pyrazole, (35a) 4- ( 2-fluoro-4-ethoxybenzyl) -1-ylpropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (35b) 4- (2-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (36a) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (36b) 4- (2 -fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (37a) 4- (2,6 -difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- ( 3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 4- (3, 5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 1-cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 1-cyclobutyl-4- (3-fluoro- 4-methylbenzyl) -5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) - 5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3 - (6-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole, 1-cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (6-O-methoxycarbonyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 1-cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (6-O-ethoxycarbonyl- ß-D -glucopyranos-1-ylox) -1 H-pyrazole, 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos -1-yloxy) -1 H-pyrazole, 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazol, (43b) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pirazol, (44a) 4- (4-Bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole, (44b) 4- (4-bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl) -D-glucopyranos-1-yloxy ) -1 H-pyrazole, (45a) 4- (2-fluoro-4-methylbenzN) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1 - iloxy) -1 H-pyrazole, (45b) 4- (2-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl) -D-glucopyranos-1-yloxy) -1 H-pyrazole, or their pharmaceutically acceptable salts. In addition, other preferred prodrugs are selected from the group consisting of compounds (46) to (63), or pharmaceutically acceptable salts thereof, as defined above and subsequently herein. Other preferred prodrugs are selected from the group consisting of compounds (64) to (73) (64) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O) -methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole(65) 4- (4-ethylbenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole (66) 4- (4-bromobenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole (67) 4- (4-ethylbenzyl) -1-cyclobutyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (68) 4- (4-ethylbenzyl) ) -1- (2-Fluoro-1-fluoromethylethyl) -5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (69) 4- (3 -fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (70) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, ( 71) 4- (4-iopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (72) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole, (73 ) 4- (4-ethylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, or its pharmaceutically acceptable salt. According to a first preferred embodiment, the aspects according to the invention, in particular the methods and uses, relate to (1) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkylcarbonyl, C 1 -C 6 alkyl) oxycarbonyl , phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, the compound (30a) and (30b). According to a second preferred embodiment, the aspects according to the invention, in particular the methods and uses, refer to or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (alkyl) (C, 6 alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, the compound (43a) and (43b). According to a third preferred embodiment, the aspects according to the invention, in particular the methods and uses, refer to or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkylcarbonyl, C 1 -C 6 alkyl) oxycarbonyl , phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, the compound (45a) and (45b). According to a fourth preferred embodiment, the aspects according to the invention, in particular the methods and uses, refer to or its prodrug, in which the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkylcarbonyl, C 1 -C 6 alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, compound (47) and (72). According to a fifth preferred embodiment, the aspects according to the invention, in particular the methods and uses, relate to or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkylcarbonyl, C 1 -C 6 alkyl) oxycarbonyl , phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, the compound (35a) and (35b). According to a sixth preferred embodiment, the aspects according to the invention, in particular the methods and uses, refer to or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkylcarbonyl, C 1 -C 6 alkyl) oxycarbonyl , phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, compound (46) and (70).

According to a seventh preferred embodiment, the aspects according to the invention, in particular the methods and uses, relate to or its prodrug, wherein the hydroxyl group connected to the carbon atom in the 6th position of the β-D-glucopyranosyl group is substituted with a substituent selected from (C 1 -C 3 alkyl) carbonyl, (C 1 -C 6 alkyl) ox Carbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, in particular selected from acetyl, methoxycarbonyl and ethoxycarbonyl; for example, compound (62) and (64). When this invention relates to patients who require treatment or prevention, it relates primarily to treatment and prevention in humans, but the active substance can also be used in compliance in veterinary medicine with mammals. Within the scope of the present invention, the pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds (1) to (29), or its prodrug, or its pharmaceutically acceptable salt, is preferably administered orally. . Other forms of administration are possible and are described below. In addition to treatment and / or prophylaxis, the therapy mentioned below according to this invention is preferably a monotherapy, that is, during the course of therapy preferably no other antidiabetic drug other than the compound of this invention is administered to the patient. As described above, by administering a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, the excess blood glucose is excreted through the patient's urine, so that there is no weight gain and the weight can even be reduced . Therefore, a treatment or prophylaxis according to the invention is advantageously suitable for those patients who need this treatment or prophylaxis, who are diagnosed with one or more disorders selected from the group consisting of overweight, class I obesity, class II obesity, obesity of class III, visceral obesity and abdominal obesity, or for those individuals in whom weight gain is contraindicated. It has been found that a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, shows very good efficacy with respect to glycemic control, in particular in view of a reduction of fasting plasma glucose, postprandial plasma glucose and / or glycosylated hemoglobin (HbA1c). By administering a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, a HbA1c reduction equal to or greater than preferably 0.5%, even more preferably equal to or greater than 1.0%, and the reduction is found, in particular, in the range of 1.0% to 1.5%. In addition, the method according to this invention is advantageously applied to those patients who show one, two or more of the following disorders: (a) a fasting blood glucose or serum glucose concentration greater than 110 mg / dl, in particular greater than 125 mg / dl, (b) a postprandial plasma glucose concentration equal to or greater than 140 mg / dl, (c) an HbA1c value equal to or greater than 6.5%, in particular equal to or greater than 8. 0% The present invention also describes the use of a pharmaceutical composition to improve glycemic control in patients who have type 2 diabetes, or who show the first signs of prediabetes. Therefore, the invention also includes the prevention of diabetes. Thus, if a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is used immediately to improve glycemic control as soon as one of the prediabetes signals mentioned above is present, the onset of diabetes manifest type 2 mellitus may be delayed or prevented. In addition, the pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is particularly suitable in the treatment of patients with insulin dependence, i.e., in patients who are treated, or would otherwise be treated or in need of treatment, with insulin or an insulin derivative or a substitute for insulin or a formulation comprising insulin or its derivative or substitute. These patients include patients with type 2 diabetes and patients with type 1 diabetes. It can be discovered that when a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is used, an improvement in glycemic control can be achieved. even in those patients who have insufficient glycemic control, in particular despite treatment with one or more antidiabetic drugs, for example, despite a maximum tolerated dose of an oral monotherapy with metformin or an antidiabetic of the sulphonylureas class. A maximum tolerated dose with respect to metformin is, for example, 850 mg three times daily or any equivalent thereto. In the scope of the present invention, the expression "insufficient glycemic control" means a disorder in which patients show HbA1c values greater than 6.5%, in individuals greater than 8%. Thus, according to a preferred embodiment of the present invention, a method is provided for improving glycemic control and / or for reducing fasting plasma glucose., postprandial plasma glucose and / or hemoglobin glycosalated HbA1c in a patient who needs it, who is diagnosed with impaired glucose tolerance, with insulin resistance, with metabolic syndrome and / or with diabetes mellitus type 1 or of type 2, characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt is administered. It has been found that the decrease in blood glucose level by the administration of a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is insulin-independent. Thus, a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is particularly suitable in the treatment of patients diagnosed with one or more of the following disorders - insulin resistance, - hyperinsulinemia, - prediabetes, - diabetes mellitus type 2, in particular having a late stage of type 2 diabetes mellitus, - type 1 diabetes mellitus. In addition, a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt , is particularly suitable in the treatment of patients diagnosed with one or more of the following disorders (a) obesity (including class I, II and / or III obesity), visceral obesity and / or abdominal obesity, (b) blood level of triglycerides > 150 mg / dl, (c) HDL cholesterol blood level < 40 mg / dl in female patients, and < 50 mg / dl in male patients, (d) systolic blood pressure > 130 mm Hg, and a diastolic blood pressure = 85 mm Hg, (e) a fasting blood glucose level = 110 mg / dl. It is assumed that patients diagnosed with impaired glucose tolerance, insulin resistance and / or metabolic syndrome suffer from a higher risk of developing cardiovascular disease such as, for example, myocardial infarction, coronary heart disease, cardiac, thromboembolic events. A glycemic control according to this invention can produce a reduction of cardiovascular risks. The pyrazole-O-glucoside derivatives according to this invention, or their prodrugs or pharmaceutically acceptable salts, show a good safety profile. Therefore, a treatment or prophylaxis according to this invention is advantageously possible in those patients for whom the treatment with Other antidiabetic drugs, such as metformin, are contraindicated and / or present intolerance before these drugs in therapeutic doses. In particular, a treatment or prophylaxis according to this invention is advantageously possible in those patients who show or have a higher risk of one or more of the following disorders: renal insufficiency or diseases, heart diseases, heart failure, liver diseases, lung diseases, conditions catabolites and / or danger of lactate acidosis, or female patients who are pregnant or breast-feeding. Furthermore, it can be discovered that the administration of a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, does not produce, or produces a low risk of hypoglycemia. Therefore, a treatment or prophylaxis according to this invention is also advantageously possible in those patients who show or have a higher risk of hypoglycemia. The pyrazole-O-glucoside derivatives according to this invention, or their prodrugs or pharmaceutically acceptable salts, are particularly suitable in the long-term treatment or prophylaxis of the diseases and / or disorders described above and subsequently herein, in particular in the long-term glycemic control of patients with type 2 diabetes mellitus. The term "long term" as used above and subsequently, indicates a treatment or administration to a patient within a period of time greater than 12 weeks, preferably longer than 25 weeks, even more preferably more than a year. Therefore, a particularly preferred embodiment of the present invention provides a method for oral therapy, preferably the oral monotherapy, for improvement, especially the long-term improvement of glycemic control in patients with type 2 diabetes mellitus, especially in patients with a late stage of type 2 diabetes mellitus, particularly in patients who are also diagnosed overweight, obesity (including class I, class II and / or class III obesity), visceral obesity and / or abdominal obesity. It will be appreciated that the amount of pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, to be administered to the patient and required for use in the treatment or prophylaxis according to the present invention will vary according to the route of administration, the nature and severity of the disorder for which the treatment or prophylaxis is required, the age, weight and disorder of the patient, the concomitant medication and, ultimately, will be at the discretion of the attending physician. However, in general, the pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, is included in the pharmaceutical composition or dosage form in an amount sufficient to improve glycemic control in the patient being treated. is trying. The pharmaceutical composition to be administered to the patient according to a method described above and subsequently herein preferably comprises an amount in the range of 1 mg to 1000 mg, even more preferably 10 to 500 mg, most preferably 50 to 500 mg. mg per day of a pyrazole-O-glucoside derivative according to this invention, or its prodrug or pharmaceutically acceptable salt, with respect to an adult patient. The amounts specified above are especially preferred for oral administration. An example of a suitable pharmaceutical composition according to this invention is a tablet for oral administration comprising 200 mg of 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole. The desired dose of the pharmaceutical composition according to this invention may conveniently be presented in a single dose once a day, or as a divided dose administered at appropriate intervals, for example as two, three or more daily doses. The pharmaceutical composition can be formulated for oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration in a liquid or solid form, or in a form suitable for administration by inhalation or insufflation. Where appropriate, the formulations can conveniently be prepared in discrete dosage units, and can be prepared by any of the methods well known in the art of pharmacy. All methods include the step of bringing the active compound into association with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product to produce the desired formulation. The pharmaceutical composition can be formulated in the form of tablets, granules, fine granules, powders, capsules, oblong tablets, soft capsules, pills, oral solutions, syrups, dry syrups, chewable tablets, troches, effervescent tablets, drops, suspensions, dissolution tablets fast, oral rapid dispersion tablets, etc. The pharmaceutical composition preferably comprises one or more acceptable pharmaceutical carriers that must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient. Pharmaceutical compositions suitable for oral administration may conveniently be presented as discrete units such as capsules, including white gelatin capsules, stamps or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution, a suspension or an emulsion, for example, as syrups, elixirs or self-emulsifying delivery systems (SEDDS). The active ingredient may also be presented as a bolus, electuary or paste injection. Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricants, disintegrants or wetting agents. The tablets may be coated according to methods well known in the art. Oral liquid preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. These liquid preparations may contain conventional additives, such as suspending agents, emulsifying agents, non-aqueous vehicles (which may include edible oils), or preservatives. The pharmaceutical composition according to the invention can also be formulated for parenteral administration (for example, by injection, for example, bolus injection or continuous infusion) and can be presented in a unit dosage form in ampoules, pre-filled syringes, infusion small volume and in multi-dose containers with an added preservative. The compositions may take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents, such as suspending, stabilizing and / or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of the sterile solid, or by lyophilization from a solution, for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use . Pharmaceutical compositions suitable for rectal administration, in which the vehicle is a solid, are most preferably presented as unit dose suppositories. Suitable carriers include cocoa butter and other materials commonly used in the art, and suppositories can be formed, conveniently, by mixing the active compound (s) with a carrier (s). softened (s) or melted (s), followed by a cooling and introduction in molds to give the form. Examples of pharmaceutically acceptable carriers are known to those skilled in the art. The methods for the manufacture of pyrazole-O-glucoside derivatives according to this invention and their prodrugs are known to those skilled in the art. Advantageously, the compounds according to this invention can be prepared using synthetic methods as described in the literature, in particular as described in EP 1338603 A1, EP 1389621 A1, WO 04/014932, WO 04/018491, WO 04 / 019958, WO 04/031203, WO 04/050122 and WO 03/020737. Preferred methods for the synthesis of the compounds according to this invention are described in the examples.

When the compounds according to this invention can form salts, the salts should be pharmaceutically acceptable. The pharmaceutically acceptable salts include salts of inorganic acids, such as hydrochloric acid, sulfuric acid and phosphoric acid; salts of organic carboxylic acids, such as oxalic acid, acetic acid, citric acid, malic acid, benzoic acid, maleic acid, fumaric acid, tartaric acid, succinic acid and glutamic acid, and salts of organic sulfonic acids, such as methanesulfonic acid and p -toluenesulfonic. The salts can be formed by combining the compounds of this invention and an acid in the appropriate amount and proportion in a solvent and decompose. They can also be obtained by an exchange of the cation or anion from the form of other salts. Compounds according to this invention include solvates, such as hydrates and alcohol adducts. The biological properties of the new compounds can be investigated as described, for example, in EP 1338603 A1, in particular with respect to the inhibitory activity on the reuptake of glucose in the renal hairy membrane, and to the activity on excretion. of sugar in urine in rats. In addition, the following assays can be applied: The ability of substances to inhibit SGLT-2 activity can be demonstrated in a test structure in which a CHO-K1 cell line (ATCC No. CCL 61) or, alternatively, a line Cell HEK293 (ATCC No. CRL-1573), which is stably transfected with a pZeoSV expression vector (Invitrogen, EMBL registration no L36849), containing the cDNA for the coding sequence of the human glucose and sodium cotransporter 2 (Genbank registration no. NM_003041) (CHO-hSGLT2 or HEK-hSGLT2). These cell lines transport 14C-labeled alpha-methyl-glucopyranoside (1 C-AMG, Amersham) into the cell in a sodium-dependent manner. The SGLT-2 assay is performed as follows. CHO-hSGLT2 cells are cultured in Ham's F12 medium (BioWhittaker) with 10% fetal calf serum and 250 μg / ml zeocin (Invitrogen), and HEK293-hSGLT2 cells are cultured in DMEM medium with 10% fetal calf serum and 250 μg / ml zeocin (Invitrogen). The cells are detached from the culture flasks by washing twice with PBS and subsequently treating with trypsin / EDTA. After addition of the cell culture medium, the cells are centrifuged, resuspended in culture medium, and counted in a Casy cell counter. Then 40,000 cells are seeded per well in a white 96-well plate coated with poly-D-lysine and incubated overnight at 37 ° C, 5% C02. Cells are washed twice with 250 μl of assay buffer (Hanks balanced salt solution, 137 mM NaCl, 5.4 mM KCl, 2.8 mM CaCl2, 1.2 mM MgSO4 and 10 mM HEPES (pH 7.4), 50 μg / ml gentamicin ). Then 250 μl of assay buffer and 5 μl of test compound were added to each well and the plate was incubated for an additional 15 minutes in the incubator. 5 μl of 10% DMSO was used as negative control. The reaction begins by adding 5 μl of 1 C-AMG (0.05 μCi) to each well. After 2 hours of incubation at 37 ° C, 5% C02, the cells were washed again with 250 μl of PBS (20 ° C) and then used by the addition of 25 μl of 0.1 N NaOH (5 min 37 ° C). 200 μl of MicroScint20 (Packard) was added to each well and incubation continued for a further 20 min at 37 ° C. After this incubation the radioactivity of 14C-AMG is measured absorbed in a Topcount (Packard) using a 14C scintillation program. To determine the selectivity with respect to human SGLT1, an analogous assay is mounted in which the hSGLTI cDNA (Genbank registration no. NM000343) is expressed in place of the hSGLT2 cDNA in the CHO-K1 or HEK293 cells. In the previous and following text, the H atoms of the hydroxyl groups are not explicitly shown in each case in the structural formulas. The following examples are intended to illustrate the present invention without restricting it. EXAMPLES Previous and subsequently the following abbreviations are used: Bn benzyl Bu butyl DCM dichloromethane DMF dimethylformamide Et ethyl EtOAc ethyl acetate Pr isopropyl i. empty vacuum Methyl Phosphine Ph at room temperature (approx 20 ° C) THF tetrahydrofuran Preparation of starting materials: Example I 2-fluoro-4-hydroxybenzaldehyde To a solution at -70 ° C of 2-fluoro-4-methoxybenzaldehyde (19.1 g, 120 mmol) in CH 2 Cl 2 (100 mL) was added boron tribromide in CH 2 Cl 2 (1 M, 160 mL, 160 mmol). After stirring the reaction solution at -68 ° C for 45 min, the cooling bath was removed, and the solution was stirred again at room temperature overnight. The reaction solution was poured into ice water and stirred for 30 min. The formed precipitate was separated, washed with CH2Cl2, and dissolved in EtOAc. The resulting EtOAc phase was washed with water and dried over MgSO. After evaporation of the solvent, the residue was washed with a little CH2Cl2 and dried under vacuum to produce the product as a beige solid. Yield: 14.5 g (86%). ESI-MS: m / z = 139 [M-H] - Example II 4-benzyloxy-3-fluorobenzaldehyde To a suspension of 4-hydroxy-3-fluorobenzaldehyde (10.0 g, 70 mmol) and potassium carbonate (10.2 g, 74 mmol) in DMF (60 ml) was added drop by drop benzyl bromide (8.7 ml, 74 mmol). The mixture was stirred at room temperature for 48 hours and then quenched with ice water. The mixture was further diluted with water and the precipitate was separated by filtration. The precipitate was washed with water and dissolved in ethyl acetate. The organic solution was washed with brine, dried over sodium sulfate, and the solvent was removed in vacuo. Yield: 16.0 g (99%). ESI-MS: m / z = 231 [M + H] + In an analogous manner, the following compounds can be obtained: (1) 4-benzyloxy-2-fluorobenzaldehyde ESI-MS: m / z = 253 [M + Na] + (2) 2-chloro-4-methoxy-1-methylbenzene The above procedure was followed, except that methyl iodide was used in place of benzyl bromide as an electrophile. ESI-MS: m / z = 156/158 [M] + (chloro) Example III 2,5-difluoro-4-methoxybenzaldehyde To a solution at -65 ° C of 1-bromo-2,5-difluoro-4-methoxybenzene (25.0 g, 0.11 mol) in THF (150 ml) and Et20 (250 ml) under an Ar atmosphere was added dropwise n-BuLi in hexane (1.6 M, 70 ml, 0.11 mol). After stirring the solution at -65 ° C for 45 min, DMF (10 ml, 0. 13 mol). The solution was heated in the cooling bath to room temperature overnight and then diluted with Et2O (500 mL).

The resulting organic solution was washed with brine, dried over MgSO4, and the solvent removed in vacuo. The residue was recrystallized from iPr20 to produce the product as yellow crystals. Yield: 6.7 g (35%). Rf 0.63 (silica gel, petroleum ether / EtOAc 1: 1) In an analogous manner, the following compounds can be obtained: (1) 2,6-difluoro-4-methoxybenzaldehyde ESI-MS: m / z = 173 [M + H] + (2) 3,5-Difluoro-4-methoxybenzoic acid The above procedure was followed, except that the extinction of the aryl-lithium compound was carried out with crushed dry ice (CO2) instead of DMF.

ESI-MS: m / z = 187 [M-H] - Example IV (4-benzyloxy-3-fluorophenyl) methanol To a suspension of sodium borohydride (3.4 g, 90 mmol) in THF (60 ml) was added a solution of 4-benzyloxy-3-fluorobenzaldehyde (16.1 g, 70 mmol) in THF (60 ml). After stirring at room temperature overnight, the reaction mixture was quenched by the addition of ice water. The mixture was acidified with aqueous HCl (4 M) and extracted with Et20. The combined organic phases were washed with an aqueous solution of NaHCO 3 and dried over sodium sulfate. After removal of the solvent, the product was obtained. Yield: 16.2 g (100%). ESI-MS: m / z = 215 [M-OH] + In an analogous manner, the following compounds can be prepared: (1) (2,5-difluoro-4-methoxyphenyl) methanol ESI-MS: m / z = 215 [M-OH] + (2) (4-benzyloxy-2-fluorophenyl) methanol ESI-MS: m / z = 232 [M] + (3) (2-fluoro-4-methoxyphenyl) methanol ESI-MS: m / z = 139 [M-OH] + (4) (2,6-difluoro-4-methoxyphenyl) methanol ESI-MS: m / z = 157 [M-OH + H] + Example V (3,5-difluoro-4-methoxyphenyl) methanol A solution of 3,5-difluoro-4-methoxybenzoic acid (2.9 g, 15 mmol) in THF (20 ml). After stirring the reaction mixture at room temperature overnight, water was added The resulting mixture was acidified with 2N sulfuric acid. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic phases were washed with an aqueous solution of NaHCO 3 and brine, and dried over MgSO 4. After removal of the solvent, the residue was purified by chromatography on silica gel (petroleum ether / EtOAc 2: 1).

Yield: 1.6 g (60%). Rf 0.7 (silica gel, petroleum ether / EtOAc 1: 1) Example VI 1-benzyloxy-4-bromomethyl-2-fluorobenzene To an ice cooled solution of (4-benzyloxy-3-fluorophenyl) methanol (16.7 g, 72 mmol) in diethyl ether (130 mL) was added phosphorus tribromide (2.8 mL, 30 mmol) at a rate such that the The temperature of the solution did not increase above 8 ° C. After stirring at room temperature for 2 h, the reaction mixture was cooled in an ice bath and quenched by the addition of ice water, ethyl acetate and Et2O. The organic layer was separated, and washed with an aqueous solution of NaHCO3 and brine. After evaporation of the solvent, the product was obtained. Yield: 20.5 g (97%). ESI-MS: m / z = 294/296 [M] + (bromine) In an analogous manner, the following compounds were prepared: (1) 1-bromomethyl-2,5-difluoro-4-methoxybenzene ESI-MS: m / z = 236/238 [M] + (bromo) (2) 4-benzyloxy-1-bromomethyl-2-fluorobenzene ESI-MS: m / z = 294/296 [M] + (bromo) (3) 1-bromomethyl-2-fluoro-4-methoxybenzene Rf 0.8 (silica gel, petroleum ether / EtOAc 1: 1) (4) 2-bromomethyl-1,3-difluoro-5-methoxybenzene ESI-MS: m / z = 236/238 [M] + (bromine) (5) 5-bromomethyl-1,3-difluoro-2-methoxybenzene ESI-MS: m / z = 236/238 [M] + (bromine) EXAMPLE VII 2.3-Difluoro-1-methoxy-4-methylbenzene To a solution at 20 ° C of sodium hydroxide (14.4 g, 0.36 mol) and 2,3-difluoro-4-methylphenol (50.0 g, 0.35 mol) in water (160 ml) was added dropwise to dimethyl sulfate (34 ml, 0.36 mol). After stirring at room temperature overnight, the reaction solution was extracted with Et20. The ether phase was washed with a 2 N NaOH solution, water and brine, and then dried over MgSO4. After removal of the solvent under reduced pressure, the product was obtained as a colorless oil. Yield: 49.0 g (89%). ESI-MS: m / z = 158 [Mf Example VIII 1-bromomethyl-2,3-difluoro-4-methoxybenzene] A solution of 2,3-difluoro-1-methoxy-4-methylbenzene (39.5 g, 0.25 mol), N-bromosuccinimide (44.5 g, 0.25 mol) and azobisisobutyronitrile (0.41 g, 2.5 mmol) in CCI4 (300 ml) were added. stirred at reflux for 3.5 h. Then the formed succinimide was removed by filtration, and the filtrate was concentrated in vacuo. The residue was dissolved in Et20 (200 ml) and concentrated to approximately 100 ml. After cooling in an ice bath the precipitate The residue was filtered off, washed with cold Et2O, and dried in vacuo to yield the product as a white solid. Yield: 36.0 g (61%). Rf 0.3 (silica gel, petroleum ether / EtOAc 20: 1) The following compounds can be obtained by analogy with the procedure described above: (1) 4-bromomethyl-2-chloro-1-methoxybenzene Rf 0.4 (silica gel, petroleum ether / EtOAc 20: 1) (2) 1-bromomethyl-2-chloro-4-methoxybenzene Rf 0.5 (silica gel, petroleum ether / EtOAc 20: 1) Example IX 2- (2,3-Dfluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester To an ice-cooled suspension of sodium hydride (4.8 g, 120 mmol, 60% in mineral oil, oil-free with pentane) in THF (140 ml) was added 3-oxobutyric acid ethyl ester (17.2 g). , 132 mmol) in THF (50 ml). After removing the ice bath and stirring the solution at room temperature At room temperature for 0.5 h, a solution of 1-methoxy-4-bromomethyl-2,3-difluorobenzene (28.4 g, 120 mmol) in THF (60 ml) was added dropwise. After stirring the reaction mixture at reflux overnight, the solvent was removed in vacuo and the residue was triturated with Et20 (300 ml). The ether phase was washed with water and brine and dried over MgSO4. The product was obtained as a yellow oil after evaporation of the solvent. Yield: 35.5 g (with a purity of about 80%). ESI-MS: m / z = 285 [M-H] "In an analogous manner the following compounds can be obtained: (1) 2- (4-benzyloxy-3-fluorobenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 345 [M + H] + (2) 2- (4-iodobenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 345 [M-H] '(3) 2- (2,5-Difluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester Rf 0.27 (silica gel, petroleum ether / EtOAc 4: 1) (4) 2- (4-Benzyloxy-2-fluorobenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 343 [M-H] "(5) 2- (2,6-Difluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester O O ESI-MS: m / z = 287 [M + H] + (6) 2- (3,5-Difluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 287 [M + H] + (7) 2- (3-Fluoro-4-methylbenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 253 [M + H] + (8) 2- (2-Fluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 269 [M + H] + (9) 2- (3-Chloro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 283/285 [M-HV (chlorine) (10) 2- (2-Chloro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester ESI-MS: m / z = 285/287 [M + H] + (chloro) (11) 4,4,4-Trifluoro-2- (2-fluoro-4-methoxybenzyl) -3-ethyl ester -oxobutyric ESI-MS: m / z = 321 [M-H] "Example X 2- (2,3-D-Fluoro-4-methylbenzyl) -3-oxobutyric acid ethyl ester To an ice-cooled solution of the ethyl ester of 3-oxobutyric acid (4.17 g, 32.1 mmol) and sodium iodide (23.9 g, 160 mmol) under an atmosphere of Ar in acetonitrile (220 mL) was added throughout the 3 min trimethylsilyl chloride (20.2 ml, 160 mmol), followed by 2,3-difluoro-4-methylbenzaldehyde (5.0 g, 32.1 mmol). The ice bath was removed, and the reaction mixture was stirred at room temperature for 8 h and subsequently at 60 ° C for 15 h. After cooling to room temperature, the reaction mixture was poured into a mixture of EtOAc (300 ml) and water (200 ml). The organic phase was separated and washed with an aqueous solution of Na 2 S 2 O 3 and brine, and dried over Na 2 SO 4. The solvent was removed under reduced pressure, and the residue was purified by chromatography on silica gel (hexane / EtOAc, 1: 6) to yield the product as a colorless oil. Yield: 8.4 g (97%). Rf 0.35 (silica gel, hexane / EtOAc 5: 1) In an analogous manner, the following compounds can be obtained: (1) Ethyl 2- (4-bromo-3-fluorobenzyl) -3-oxobutyric acid ethyl ester (2) 2- (4-Bromo-2-fluorobenzyl) -3-oxobutyric acid ethyl ester Rf 0.42 (silica gel, hexane / EtOAc 4: 1) (3) 2- (2-Fluoro-4-methylbenzyl) -3-oxobutyric acid ethyl ester Example XI Ethyl ester of 4.4.4-trifluoro-2- (2-fluoro-4-methoxybenzyl) -3-methoxybut-2-enoic acid ethyl ester To a mixture at 20 ° C of 4,4,4-trifluoro-2- (2-fluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester (6.35 g, 19.7 mmol) and cesium carbonate (9.5 g, 28.9 mmol) in DMF (50 ml) was added dropwise a solution of toluene-4-sulfonic acid methyl ester (4.5 g, 23.7 mmol) in DMF (20 ml). The reaction mixture was stirred at room temperature overnight and subsequently at 60 ° C for 1.5 h. After cooling to room temperature, dilute phosphoric acid was added, and the resulting solution was extracted with Et20. The combined organic phases were washed with brine and dried over Na2SO4. After removal of the solvent, the residue was purified by chromatography on aluminum oxide (cyclohexane / EtOAc 99: 1-> 70:30).

Yield: 6.6 g (100%). ESI-MS: m / z = 337 [M + H] + Example XII 4- (2,3-difluoro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol A solution of 2- (2,3-difluoro-4-methoxybenzyl) -3-oxobutyric acid ethyl ester (33.0 g, 0.115 mol) and hydrazine hydrate (80%, 8.0 g, 128 mmol) in EtOH (300 ml) was stirred at reflux for 2 h. After cooling in an ice bath, the precipitate was collected, washed with cold EtOH, and dried in vacuo to yield the product as a white solid. Yield: 22.5 g (70%). ESI-MS: m / z = 255 [M + H] + The following compounds can be obtained in a similar manner: (1) 4- (4-benzyloxy-3-fluorobenzyl) -5-methyl-1 H-pyrazole-3 -ol ESI-MS: m / z = 313 [M + H] + (2) 4- (4-iodobenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 315 [M + H] + (3) 4- (2,5-difluoro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 255 [M + H] + (4) 4- (4-benzyloxy-2-fluorobenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 313 [M + H] + (5) 4- (2,6-difluoro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 255 [M + H] + (6) 4- (3,5-difluoro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 255 [M + H] + (7) 4- (3-fluoro-4-methylbenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 221 [M + H] + (8) 4- (2-fluoro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 237 [M + H] + (9) 4- (3-chloro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 253/255 [M + H] + (chloro) (10) 4- (2-chloro-4-methoxybenzyl) -5-methyl-1 H-pyrazole-3-ol ESI-MS: m / z = 253/255 [M + H] + (chloro) (11) 4- (2-fluoro-4-methoxybenzyl) -5-trifluoromethyl-1 H-pyrazole-3-ol The product was prepared following the above procedure, starting from the ethyl ester of 4,4,4-trifluoro-2- (2-fluoro-4-methoxybenzyl) -3-methoxybut-2-enoic ESI-MS: m / z = 289 [MH] "(12) 4- (4-bromo-3-fluorobenzyl) -5-methyl-1 H-pyrazole-3-ol (13) 4- (2,3-difluoro-4-methylbenzyl) -5-methyl-1 H-pyrazole-3-ol Rf 0.05 (silica gel, hexane / EtOAc 5: 1) (14) 4- (4-bromo-2-fluorobenzyl) -5-methyl-1 H-pyrazole-3-ol Rf 0.15 (silica gel, hexane / EtOAc 1: 1) (15) 4- (2-fluoro-4-methylbenzyl) -5-methyl-1 H-pyrazole-3-ol Rf 0.11 (silica gel, hexane / EtOAc 1: 1) Example XIII 3- (tert-Butyldimethylsilyloxy) -4- (2-fluoro-4-methoxybenzyl) -5-trifluoromethyl-1H-pyrazole To a solution of 4- (2-fluoro-4-methoxybenzyl) -5-trifluoromethyl-1H-pyrazol-3-ol (0.21 g, 0.72 mmol) and imidazole (8.0 g, 128 mmol) in DMF (2 mL) tert-butyldimethylsilyl chloride (0.13 g, 0.86 mmol) was added. After stirring at room temperature for 4 h, the solution was diluted with EtOAc and washed with water and brine. The organic phase was dried and the solvent was removed. Yield: 0.34 g (with a purity of about 80%).

ESI-MS: m / z = 405 [M + H] + Example XIV 3- (tert-butyldimethylsilyloxy) -4- (2-fluoro-4-methoxybenzyl) -1-ylpropyl-5-trifluoromethyl-1 H- pyrazole To a suspension of 3- (tert-butyldimethylsilyloxy) -4- (2-fluoro-4-methoxybenzyl) -5-trifluoromethyl-1 H-pyrazole (0.27 g, 0.67 mmol) and Ph3P (0.20 g, 0.76 mmol) in isopropanol (2 ml) was added diethyl azodicarboxylate in toluene (40%, 0.35 ml, 0.76 mmol). The solution was stirred for 1 h at room temperature and then diluted with Et20. The resulting solution was washed with water and an aqueous solution of NaOH (2 N), dried over Na 2 SO, and the solvent was removed. The residue was purified by chromatography on silica gel (cyclohexane / EtOAc 99: 1-> 4: 1) to produce the product as a colorless oil. Yield: 0.14 g (47%). ESI-MS: m / z = 447 [M + H] + Example XV 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-1 H -pyrazole-3-ol A solution of 3- (tert-butyldimethylsilyloxy) -4- (2-fluoro-4-) methoxybenzyl) -1-isopropyl-5-trifluoromethyl-1 H-pyrazole (0.27 g, 0.67 mmol), aqueous HCl (1 N, 1 mL, 1 mmol), MeOH (0.5 mL) and THF (12 mL) was stirred at 60 ° C for 2 h. After cooling to room temperature, the solution was diluted with EtOAc and washed with water and brine. The product was obtained as a white solid after drying over Na 2 SO 4 and removal of the solvent in vacuo. Yield: 0.10 g (100%). ESI-MS: m / z = 333 [M + H] + Example XVI 4- (2,3-d.fluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6- tetra-Q-benzyl-β-D-chloropyranos- 1 -loxy) -1 H-pyrazole To a solution at 0 ° C of 4- (2,3-difluoro-4-methoxybenzyl) -5-methyl-1 H -pyrazol-3-ol (2.14 g, 8.4 mmol), 2,3,4,6- tetra-O-benzyl-aD-glucopyranose (4.54 g, 8.4 mmol) and PPh3 (2.20 g, 8.4 mmol) in dry THF (80 mL) was added diethyl azodicarboxylate in toluene (40%, 3.85 mL, 8.4 mmol ) at a rate such that the solution was maintained at 2-6 ° C. After 10 min the cooling bath was removed and the reaction solution was stirred at room temperature for the night. Then the solution was concentrated at 40 ° C under reduced pressure, and the remainder was treated with Et 2 O (50 ml). The ether solution was cooled to -18 ° C, and the precipitate in formation was separated and washed with cold Et2O. The filtrate was diluted with Et2O and washed with an aqueous solution of NaOH (2 N), water and brine.

After drying over MgS? and from evaporation of the solvent, the residue was purified by chromatography on silica gel (hexane / EtOAc 2: 1-> 1: 6 cycle). The purified product was recrystallized from iPr20 to produce the product as a white solid (< 5% of the anomer a). Yield: 3.10 g (48%). ESI-MS: m / z = 777 [M + H] + The following compounds can be obtained in a similar manner: (1) 4- (2,5-difluoro-4-methoxybenzyl) -5-methyl-3- (2 , 3,4,6-tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 777 [M + H] + (2) 4- (2-fluoro-4-benzyloxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 835 [M + H] + (3) 4- (2,6-difluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0 -benzyl-ß-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 777 [M + H] + (4) 4- (3,5-difluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0 -benzyl-ß-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 777 [M + H] + (5) 4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole Bu3P and 1, 1 '- (azodicarbonyl) dipiperidine were used instead of Ph3P and diethyl azodicarboxylate. ESI-MS: m / z = 743 [M + H] + (6) 4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole Bu3P and 1, 1 '- (azodicarbonyl) dipiperidine were used instead of Ph3P and diethyl azodicarboxylate. ESI-MS: m / z = 759 [M + H] + (7) 4- (3-chloro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole Bu3P and 1, 1 '- (azodicarbonyl) dipiperidine were used instead of Ph3P and diethyl azodicarboxylate. ESI-MS: m / z = 775/777 [M + H] + (chloro) (8) 4- (2-chloro-4-methoxybenzyl) -5-methyl-3- (2,3,4, 6-tetra-0-benzyl-β-D-glucopyranos- 1-yloxy) -1 H-pyrazole Bu3P and 1, 1 '- (azodicarbonyl) dipiperidine were used instead of Ph3P and diethyl azodicarboxylate. ESI-MS: m / z = 775/777 [M + H] + (chloro) (9) 4- (4-bromo-3-fluorobenzyl) -5-methyl-3- (2,3,4,6- tetra-O-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole (10) 4- (2,3-difluoro-4-methylbenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.24 (silica gel, hexane / EtOAc 1: 1) (11) 4- (2-fluoro-4-methylbenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl) β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.48 (silica gel, hexane / EtOAc 1: 1) Example XVII 4- (4-Vodobenzyl) -5-methyl-3- (2,3,4,6-tetra-0-acetyl-β-D) -glucopyranos-1-yloxy) -1 H-pyrazole To a solution of 4- (4-iodobenzyl) -5-methyl-1H-pyrazol-3-ol (0.70 g, 2.23 mmol) in dry THF (80 mL) was added Ag2CO3 (0.65 g, 2.36 mmol), followed by 2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yl bromide (1.00 g, 2.43 mmol). The reaction mixture was stirred at reflux in the dark overnight before the addition of another portion of Ag2CO3 (0.75 g, 2.72 mmol) and 2,3,4,6-tetra-O-acetyl-β-D bromide. -glucopyranos-1-yl (1.10 g, 2.68 mmol). The reaction mixture was stirred at reflux for another night and then cooled to room temperature. The mixture was filtered, and the filtrate was concentrated in vacuo. The residue was purified by chromatography on silica gel (CH2Cl2 / MeOH 1: 0-> 10: 1) to produce the product as a white solid. Yield: 0.40 g (28%). ESI-MS: m / z = 645 [M + H] + The following compounds can be obtained in a similar manner: (1) 4- (4-benzyloxy-3-fluorobenzyl) -5-methyl-3- (2,3 , 4,6-tetra-0-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 643 [M + H] + (2) 4- (4-bromo-2-fluorobenzyl) -5-methyl-3- (2,3,4,6-tetra-O-acetyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.46 (silica gel, hexane / EtOAc 1: 1) Example XVIII 4- (2-fluoro-4-methoxybenzyl) -5-trifluoromethyl-3- (2.3.4.6-tetra-0-acetyl-β-D) -alucopyranos-1-yloxy) -1 H-pyrazole To a solution of 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-1H-pyrazol-3-ol (1.84 g, 5.54 mmol), K2C03 (7.5 g, 54.3 mmol) and nBu3BnNCI (0.25 g, 0.8 mmol) in water (5 ml) and CH2Cl2 (25 ml) was added 2,3,4,6-tetra-0-acetyl-β-D-glucopyranos-1-yl bromide (3.80 g). 8.78 mmol). The reaction mixture was stirred vigorously at room temperature in the dark overnight. Then CH2Cl2 was added and the organic layer was separated. After washing with water and 1 M phosphoric acid, the organic phase was dried over Na 2 SO 4, and the solvent was removed. The residue was purified by chromatography on silica gel (cidohexane / EtOAc 3: 2-> 0: 1). Yield: 2.42 g (with a purity of about 50%). ESI-MS: m / z = 663 [M + H] + Example XIX 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2.3.4.6-tetra-Q- benzyl-β-D-chloropyranos-1-yloxy) -1 H-pyrazole To a mixture at 20 ° C of 4- (2,3-difluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra-0-benzyl-β-D-glucopyranos) -1-yloxy) -1H-pyrazole (2.90 g, 3.7 mmol) and Cs2CO3 (12.30 g, 37.8 mmol) in DMF (56 mL) was added isopropyl iodide (1.90 mL, 18.9 mmol). The reaction mixture was stirred at room temperature for 2.5 h. Then the reaction mixture was then poured into water (300 ml), and the resulting solution was extracted with EtOAc. The combined organic extracts were washed with water and brine, and dried over MgSO 4. The organic solution was concentrated at 40 ° C under reduced pressure, and the residue was purified by chromatography on silica gel (cyclohexane / EtOAc 6: 1-> 1: 1). Yield: 2.10 g (69%). ESI-MS: m / z = 459 [M + H] + The following compounds can be obtained in a similar manner: (1) 4- (4-benzyloxy-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 685 [M + H] + (2) 4- (4-iodobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-O-acetyl) -β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 687 [M + H] + (3) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6 -tetra-O-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 819 [M + H] + (4) 4- (2-fluoro-4-benzyloxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra -0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 877 [M + H] + (5) 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4 , 6-tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 819 [M + H] + (6) 4- (3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6 -tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 819 [M + H] + (7) 1-cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (2,3,4,6-tetra -0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Bromocyclobutane was used as an electrophile in place of isopropyl iodide. ESI-MS: m / z = 797 [M + H] + (8) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (2,3,4,6-tetra -0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole It was obtained as a by-product in the preparation of Example XVIII (7). ESI-MS: m / z = 797 [M + H] + (9) 1-cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (2,3,4,6-tetra -0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Bromocyclobutane was used as an electrophile in place of isopropyl iodide. ESI-MS: m / z = 813 [M + H] + (10) 4- (3-chloro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra -0-benzyl-ß-D- glucopyranos-1-yloxy) -1 H-pyrazole The reaction is preferably carried out with potassium hexamethyldisilazide as the base in toluene and THF. ESI-MS: m / z = 817/819 [M + H] + (chloro) (11) 4- (2-chloro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3, 4,6-tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole The reaction is preferably carried out with potassium hexamethyldisilazide as the base in toluene and THF. ESI-MS: m / z = 817/819 [M + H] + (chloro) (12) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole (13) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-benzyl-β-D-glucopyranos- 1-yloxy) -1 H-pyrazole Rf 0.65 (silica gel, hexane / EtOAc 1: 1) (14) 4- (4-bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6- tetra-0-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.50 (silica gel, hexane / EtOAc 1: 1) (15) 4- (2-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra- 0-benzyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.53 (silica gel, hexane / EtOAc 4: 1) Example XX 4- (3-fluoro-4-hydroxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0 -acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole A mixture of 4- (4-benzyloxy-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole (0.26 g, 0.38 mmol) and 10% Pd on carbon (0.05 g) in EtOAc (10 mL) was stirred at room temperature under a hydrogen atmosphere (3 bar). After 3 h the catalyst was removed by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in Et20, filtered over Celite®, and concentrated in vacuo. Yield: 0.22 g (97%). ESI-MS: m / z = 595 [M + H] + Example XXI 4- (3-fluoro-4-ethoxybenzyl) -1-ylpropyl-5-methyl-3- (2,3A6-tetra-O -acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole To a suspension of 4- (3-fluoro-4-hydroxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yloxy) ) -1 H-pyrazole (0.22 g, 0.37 mmol) and cesium carbonate (0.31 g, 0.40 mmol) in DMF (3 mL) was added ethyl bromide (30 μL, 0.40 mmol). After stirring at room temperature for 5 h, the mixture was poured into a mixture of EtOAc and phosphoric acid (0.1 M). The organic phase was separated, washed with an aqueous solution of NaHCO 3 and brine, and dried over Na 2 SO 4. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (petroleum ether / EtOAc 1: 1).

Yield: 0.18 g (78%). ESI-MS: m / z = 623 [M + H] + The following compound can be obtained in a similar manner: (1) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 637 [M + H] + Example XXII 4- (2-fluoro-4-hydroxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole A mixture of 4- (2-fluoro-4-benzyloxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-O-benzyl-β-D-glucopyranos-1- iloxy) -1 H-pyrazole (2.0 g, 2.3 mmol) and 20% Pd on carbon (1.0 g) in EtOH (70 mL) was stirred at room temperature under a hydrogen atmosphere (344,737 kPa). After 2 h the catalyst was removed by filtration, and the solvent was removed under reduced pressure. The residue was purified by chromatography on silica gel (CH2Cl2 / MeOH 10: 1-> 3: 1). Yield: 0.69 g (71%). ESI-MS: m / z = 427 [M + H] + Example XXIII 4- (4-trimethylsilylethynylbenzyl) -1-ylpropyl-5-methyl-3- (2,3,4,6-tetra -Q-acetyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole To a degassed solution of 4- (4-iodobenzyl) -1-isopropyl-5- methyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole (0.31 g, 0.45 mmol) in DMF (5 ml) under one atmosphere of Ar was added, in the indicated order, NEt3 (0.2 ml, 1.43 mmol), Cul (0.02 g, 0.11 mmol), (Ph3P) 2PdCI2 (0.05 g, 0.07 mmol) and trimethylsilylacetylene (0.10 ml, 0.69 mmol). The reaction mixture was stirred at 90 ° C for 3.5 h. After cooling to room temperature, EtOAc was added, and the resulting solution was washed with an aqueous solution of NaHCO3 and dried over Na2SO. The solvent was evaporated, and the residue was purified by chromatography on silica gel (cidohexane / EtOAc, 9: 1 -> 1: 1) to produce the product as a yellow oil. Yield: 0.18 g (64%). ESI-MS: m / z = 657 [M + H] + Preparation of the products Example 1 (1) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β- D-glucopyranos-1-yloxy-1 H-pyrazole A mixture of 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-0-benzyl-β-D-glucopyranos-1- ilox!) -1 H-pyrazole (1.80 g, 2.2 mmol) and 20% Pd on carbon (1 g) in EtOH (50 ml) was stirred at room temperature under a hydrogen atmosphere (344,737 kPa). After 2.5 h the catalyst was removed by filtration, and the solvent was removed under reduced pressure. He The residue was purified by chromatography on silica gel (DCM / MeOH 1: 0-> 4: 1) to produce the product as a white solid. Yield: 0.48 g (48%). ESI-MS: m / z = 459 [M + H] + The following compounds can be obtained in a similar manner: (2) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl- 3-ß-D-glucopyranos-1-yloxy-1 H-pyrazole ESI-MS: m / z = 459 [M + H] + (3) 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1 - iloxy- 1 H-pyrazole ESI-MS: m / z = 459 [M + H] + (4) 4- (3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1 - iloxy- 1 H-pyrazole ESI-MS: m / z = 459 [M + H] + (5) 1 -cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole ESI-MS: m / z = 437 [M + H] + (6) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole ESI-MS: m / z = 437 [M + H] + (7) 1 -cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole ESI-MS: m / z = 453 [M + H] + (8) 4- (3-chloro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy -1 H-pyrazole ESI-MS: m / z = 457/459 [M + H] + (chloro) (9) 4- (2-chloro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos -1-yloxy-1 H-pyrazole ESI-MS: m / z = 457/459 [M + H] + (chloro) (10) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos -1-yloxy-1 H-pyrazole (11) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole Rf 0.24 (silica gel, CHC / MeOH 9: 1) (12) 4- (2-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy -1 H-pyrazole Rf 0.24 (silica gel, CH2Cl2 / MeOH 9: 1) Example 2 (13) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3-β-D-alucopyranos-1-yl -1 H-pyrazole To an ice-cooled solution of 4- (4-ethoxy-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos- 1-yloxy) -1H-pyrazole (0.17 g, 0.27 mmol) in MeOH (1 ml) and THF (1.5 ml) was added an aqueous solution of LiOH (1 M, 1.25 ml). The solution was stirred in the ice bath for 1 h and then diluted with EtOAc and water. The organic phase was separated, washed with water and brine, and dried over Na2SO4. The solvent was removed and the residue dried in vacuo to yield the product as a white foam. Yield: 0.12 g (95%). ESI-MS: m / z = 455 [M + H] + The following compounds can be obtained in a similar manner: (14) 4- (4-ethynylbenzyl) -1-isopropyl-5-methyl-3-β-D- glucopyrans-1-yloxy-1 H-pyrazole 4- (4-trimethylsilylethynylbenzyl) -1-isopropyl-5-methyl-3- (2,3,4,6-tetra-O-acetyl-β-D-glucopyranos-1-yloxy) -1H- Pyrazole was subjected to the reaction conditions described above. ESI-MS: m / z = 417 [M + H] + (15) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole ESI-MS: m / z = 469 [M + H] + (16) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole (17) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole ESI-MS: m / z = 495 [M + H] + (18) 4- (4-bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy- 1 H-pyrazole Rf 0.29 (silica gel, CH2Cl2 / MeOH 9: 1) Example 3 (19) 4- (2-fluoro-4-isopropoxy-benzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos -1-yloxy- 1 H-pyrazole To a suspension of 4- (2-fluoro-4-hydroxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole (0.20 g, 0.47 mmol) and carbonate of cesium (0.16 g, 0.50 mmol) in DMF (3.5 ml) was added isopropyl iodide (52 μl).0.50 mmol). After stirring the mixture at room temperature overnight, another portion of cesium carbonate (0.10 g) and isopropyl iodide (30 μl) was added. After stirring another 24 h at room temperature, the mixture was diluted with EtOAc, phosphoric acid (0.1 M) and brine. The organic phase was separated, washed with brine and dried over Na2SO4. The organic solution was concentrated, and the residue was purified by chromatography on silica gel (DCM / MeOH, 10: 1) to produce the product as a white foam.

Yield: 0.16 g (73%). ESI-MS: m / z = 469 [M + H] + The following compound can be obtained in a similar manner: (20) 4- (2-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- ß-D-glucopyranos-1-yloxy-1 H-pyrazole ESI-MS: m / z = 455 [M + H] + Compounds (21) to (29) can be obtained by methods such as those described in this application or in the literature. Example 4 (30a) 4- (2,3-D-Fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-Q-methoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole To an ice-cooled solution of 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole (0.23 g, 0.50 mmol) in 2,4,6-trimethylpyridine (0.7 ml) was added methyl chloroformate (42 μl, 0.55 mmol). The reaction solution was heated in the ice bath to room temperature and stirred overnight. Then the solution was diluted with Et2O, washed with aqueous HCl (1 M) and brine, and dried over MgSO4. The solvent was evaporated, and the residue was purified by chromatography on silica gel (DCM / MeOH, 25: 1-> 1: 3) to produce the product as a white solid. Yield: 0.15 g (56%). ESI-MS: m / z = 517 [M + H] + The following compounds can be obtained in a similar manner: (31 a) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3 - (6-0-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 513 [M + H] + (32a) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D) -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 527 [M + H] + (33a) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 517 [M + H] + (34a) 4- (2-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-methoxycarbonyl-β-D) -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 527 [M + H] + (35a) 4- (2-fluoro-4-ethoxybenzyl) -1-iopropyl-5-methyl-3- (6-O-methoxycarbonyl) -D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 513 [M + H] + (36a) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 553 [M + H] + (37a) 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-methoxycarbonyl-β - D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 517 [M + H] + (38a) 4- (3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β - D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 517 [M + H] + (39a) 1-Cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole ESI-MS: m / z = 495 [M + H] + (40a) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-methoxycarbonyl-β-D-glucopyranos -1-yloxy) -1 H-pyrazole ESI-MS: m / z = 495 [M + H] + (41a) 1 -cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (6-0-methoxycarbonyl-β-D -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 511 [M + H] + (42a) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-0-methoxycarbonyl-β-D -glucopyranos-1-yloxy) -1 H-pyrazole (43a) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.49 (silica gel, CHCIs / MeOH 10: 1) (44a) 4- (4-bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-0-methoxycarbonyl-β-D- glucopyranos-1-ylox!) -1 H-pyrazole Rf 0.39 (silica gel, CH2Cl2 / MeOH 19: 1) (45a) 4- (2-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D- glucopyranos-1-yloxy) -1 H-pyrazole Rf 0.62 (silica gel, CH2Cl2 / MeOH 9: 1) Compounds (30b), (31b), (32b), (33b), (34b), (35b), (36b), (37b), ( 38b), (39b), (40b), (41b), (42b), (43b), (44b) and (45b) are obtained in an analogous manner. Example 5: (46) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-Q-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole To an ice-cooled solution of 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole (0.30 g, 0.70 mmol) in 2,4,6-trimethylpyridine (1 ml) was added methyl chloroformate (76 μl, 0.80 mmol). The reaction solution was heated in the ice bath to room temperature and stirred overnight. After the solution was diluted with Et20, washed with aqueous HCl (1 M) and brine, and dried over MgSO 4. The solvent was evaporated, and the residue was purified by chromatography on silica gel (DCM / MeOH, 25: 1-> 1: 3) to produce the product as a white solid. Yield: 0.23 g (66%). ESI-MS: m / z = 497 [M + H] + The following compounds can be obtained by analogy with the procedure described above: (47) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl -3- (6-0-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 513 [M + H] + (48) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-isobutyloxycarbonyl-β-D) -glucopyranos-1-yloxy) - 1 H-pyrazole ESI-MS: m / z = 541 [M + H] + (49) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-hex-1-yloxycarbonyl) -ß-D- glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 569 [M + H] + (50) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-phenoxycarbonyl-β-D) -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 561 [M + H] + (51) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-benzyloxycarbonyl-β-D -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 575 [M + H] + (52) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-acetyl) l-ß-D-glucopyranos- 1-yloxy) -1 H-pyrazole ESI-MS: m / z = 483 [M + H] + (53) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-propylcarbonyl-β -D-glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 511 [M + H] + (54) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-0-isopropylcarbonyl-β-D -glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 511 [M + H] + (55) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-benzylcarbonyl-β-D) - glucopyranos-1-yloxy) -1 H-pyrazole ESI-MS: m / z = 559 [M + H] + Compounds (56) to (63) can be obtained by analogy with the procedure described above.

Claims (22)

1. CLAIMS 1.- Method to prevent, slow down the progression, delay or treat a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, hyperglycemia, postprandial hyperglycemia, overweight, obesity and metabolic syndrome in a patient in need, which is characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29 consists of (1) 4- (2,3-Difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (2) 4- (2, 5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (3) 4- (2,6-difluoro-4-) methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (4) 4- (3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5 -methyl-3-ß-D-glucopyranos-1-yloxy-1 H-pyrazole, (5) 1-cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3-β-D-glucopyranos -1-yloxy-1 H-pyrazole, (6) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (7) 1-cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (8) 4- (3-chloro- 4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, pyrazole, (23) 4- (4-ethylbenzyl) -1-cyclobutyl-5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (24) 4- (4-ethylbenzyl) -1 - (2-Fluoro-1-fluoromethylethyl) -5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1H-pyrazole, (25) 4- (3-fluoro-4-methoxybenzyl) -1- isopropyl-5-trifluoromethyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (26) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3-β- D-glucopyranos-1-yloxy-1 H-pyrazole, (27) 4- (2,3-difluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy -1 H-pyrazole, (28) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, (29) | 4- (4-ethylbenzyl) -1-isopropyl-5-methyl-3-β-D-glucopyranos-1-yloxy-1 H-pyrazole, or its prodrug, in which one or more hydroxyl groups of the β-D group -glucopyranosyl are acylated with selected groups of (C 1 -C 8 alkylcarbonyl, C 1 -isioxycarbonyl, phenylcarbonyl, phenyl- (C 1 .3 alkyl) -carbonyl, phenyloxycarbonyl, and phenyl- (C 1 -C 3 alkyl) - oxycarbonyl, or its pharmaceutically acceptable salt, is administered
2. 2.- Method for improving glycemic control and / or for reducing fasting plasma glucose, postprandial plasma glucose and / or glycosylated HbA1c hemoglobin in a patient in need thereof, is characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, as defined in US Pat. claim 1.
3. 3.- Method to prevent, slow down, delay or reverse the progression from impaired tolerance to glucose, insulin resistance and / or metabolic syndrome to type 2 diabetes mellitus in a patient who needs it, which is characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, is defined as defined in claim 1.
4. 4.- Method for prevent, slow the progression, delay or treat a disorder or condition selected from the group consisting of complications of diabetes mellitus, such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischemia, arteriosclerosis, myocardial infarction , cerebrovascular accidents and peripheral arterial occlusive disease, in a patient who needs it, which is characterized because it was administered to a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1.
5. 5.- Method for reducing weight or preventing an increase in weight or facilitate a weight reduction in a patient who needs it, characterized in that a pharmaceutical composition is administered which comprises a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1.
6. 6.- Method to prevent, slow, delay or treat the degeneration of pancreatic beta cells and / or the decrease in the functionality of the cells pancreatic beta and / or to improve and / or restore the functionality of pancreatic beta cells and / or restore the functionality of pancreatic insulin secretion in a patient in need thereof, characterized in that a pharmaceutical composition comprising a derivative is administered of pyrazole-O-glucoside selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1.
7. 7. Method for maintaining and / or improving insulin sensitivity and / or for treating or preventing hyperinsulinemia and / or insulin resistance in a patient in need thereof, characterized in that a pharmaceutical composition comprising a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29 is administered, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1.
8. 8. Method according to one or more of claims 1 to 7, characterized by that a pharmaceutical composition comprising an amount of 1 mg to 1000 mg of a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1, is administered daily with respect to an adult patient.
9. 9. Method according to one or more of claims 1 to 8, wherein the patient is an individual diagnosed with one or more disorders selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity.
10. 10. Method according to one or more of claims 1 to 8, wherein the patient is an individual showing one, two or more of the following disorders: a) a blood glucose or serum glucose concentration in fasting greater than 110 mg / dl, in particular greater than 125 mg / dl, b) a postprandial plasma glucose concentration equal to or greater than 140 mg / dl, c) an HbA1c value equal to or greater than 6.5%, in particular equal or greater than 8.0%.
11. 11. Method according to one or more of claims 1 to 8, wherein the patient is an individual in which one, two, three or more of the following disorders are present: a) obesity, visceral obesity and / or obesity abdominal, b) triglyceride blood level = 150 mg / dl, c) HDL cholesterol blood level < 40 mg / dl in female patients, and < 50 mg / dl in male patients, d) systolic blood pressure > 130 mm Hg, and a diastolic blood pressure = 85 mm Hg, e) a fasting blood glucose level = 110 mg / dl.
12. 12. Method according to one or more of claims 1 to 11, wherein the patient is an individual for whom treatment with metformin is contraindicated and / or has an intolerance to metformin in therapeutic doses.
13. 13. Method according to one or more of claims 1 to 11, wherein the patient is an individual with insufficient glycemic control, despite a treatment with one or more antidiabetic drugs.
14. 14. Method according to one or more of claims 1 to 13, wherein the pyrazole-O-glucoside derivative is a prodrug selected from the group of compounds 1 to 29, as defined in claim 1, wherein the Hydrogen atom of the hydroxyl group in the 6-position of the β-D-glucopyranosyl group is substituted by a group selected from (C 1 -C 3 alkylcarbonyl, (C 6 alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, or its salt pharmaceutically acceptable.
15. 15. - The method according to claim 14, wherein the prodrug of a pyrazole-O-glucoside derivative is selected from the group of compounds 30a to 45a, 30b to 45b, and 46 to 63 defined as in claim 20 and 21, or its pharmaceutically acceptable salt, or of the group of compounds 64 to 73 (64) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, ( 65) 4- (4-ethylbenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole (66) 4- (4-bromobenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pirazol(67) 4- (4-ethylbenzyl) -1-cyclobutyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole (68) 4- (4-ethylbenzyl) -1- (2-fluoro-1-fluoromethylethyl) -5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (69) 4- (3-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (70) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H- pyrazole, (71) 4- (4-iopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole , (72) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl) -D-glucopyranos-1 - iloxy) -1 H-pyrazole, (73) 4- (4-ethylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, or its pharmaceutically acceptable salt.
16. 16. Use of a pyrazole-O-glucoside derivative selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1, for the manufacture of a medicament for a therapeutic method according to one or more of claims 1 to 15.
17. 17. A pharmaceutical composition or composition for use in a method according to one or more of claims 1 to 15, comprising a therapeutically or prophylactically effective amount of a pyrazole-O- derivative. glycoside selected from the group of compounds 1 to 29, or its prodrug, or its pharmaceutically acceptable salt, defined as in claim 1.
18. 18.- Pyrazole-O-glucoside derivative selected from the group consisting of: or its prodrug, in which one or more hydroxyl groups of the β-D-glucopyranosyl group are acylated with selected groups of (C 1.) alkylcarbonyl, (C 1. 8 alkyl) oxycarbonyl, phenylcarbonyl, phenyl- (C 1 -C 3 alkyl) ) -carbonyl, phenyloxycarbonyl, and phenyl- (C 1-3 alkyl) -oxycarbonyl, or its pharmaceutically acceptable salt
19. 19.- Pyrazole-O-glucoside derivative according to claim 18, characterized in that it is a prodrug, wherein the hydrogen atom of the hydroxyl group in the 6-position of the β-D-glucopyranosyl group is substituted by a group selected from (C 1 -C 3 alkylcarbonyl, (C 1 -C 6 alkyl) oxycarbonyl, phenyloxycarbonyl, benzyloxycarbonyl and benzylcarbonyl, or its pharmaceutically acceptable salt
20. 20. Derivative of pyrazole-O-glucoside according to claim 19 selected from the group consisting of (30a) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) ) -1 H-pyrazole, (30b) 4- (2,3-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1) -iloxy) -1 H-pyrazole, (31a) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D) - glucopyranos-1-yloxy) -1 H-pyrazole, (31b) 4- (3-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos -1-yloxy) -1 H-pyrazole, (32a) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl) -D- -glucopyranos-1-yloxy) -1 H-pyrazole, (32b) 4- (3-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl) β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (33a) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl) -D-glucopyranos-1 -iloxy) -1 H-pyrazole, (33b) 4- (2,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1 -iloxy) -1 H-pyrazole, (34a) 4- (2-fluoro-4-isopropoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D- glucopyranos-1-yloxy) -1 H-pyrazole, (34b) 4- (2-fluoro-4-isopropoxybenzyl) -1-ylpropyl-5-methyl-3- (6-O-ethoxycarbonyl) β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (35a) 4- (2-fluoro-4-ethoxy-benzyl) -1-isopropyl-5-methyl-3- (6-O- methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (35b) 4- (2-fluoro-4-ethoxybenzyl) -1-isopropyl-5-methyl-3- (6- O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (36a) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- ( 6-O-methoxycarbonyl- -D-glucopyranos-1-yloxy) -1 H -pyrazole, (36b) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-trifluoromethyl-3- (6-O -ethoxycarbonyl-β-D-glucopyranos-1-yloxy! -1 H-pyrazole, (37a ) 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropN-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H- pyrazole, (37b) 4- (2,6-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H- pyrazole, (38a) 4- (3,5-difluoro-4-methoxybenzyl) -1-ylpropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H -pyrazole, (38b) 4- (3,5-difluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl) -D-glucopyranos-1-yloxy ) -1 H-pyrazole, (39a) 1-cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) - 1 H-pyrazole, (39b) 1-Cyclobutyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole(40a) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (40b) 1-cyclopropylmethyl-4- (3-fluoro-4-methylbenzyl) -5-methyl-3- (6-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (41a) 1 -cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (41 b) ) 1-Cyclobutyl-4- (2-fluoro-4-methoxybenzyl) -5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (42a) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, ( 42b) 4- (4-bromo-3-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, ( 43a) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, ( 43b) 4- (2,3-difluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, ( 44a) 4- (4-bromo-2-fluorob encil) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (44b) 4- (4- bromo-2-fluorobenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (45a) 4- (2-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-methoxycarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (45b) 4- (2 -fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, or their pharmaceutically acceptable salts.
21. 21. Derivative of pyrazole-O-glucoside selected from the group consisting of: (46) 4- (3-fluoro-4-methylbenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (47) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-ethoxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (48) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-isobutyloxycarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, (49 ) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-hex-1-yloxycarbonyl-β-D-glucopyranos-1) -yloxy) -1 H-prazol, (50) 4- (2-fluoro-4-methoxy-benzyl) -1-ylpropyl-5-methyl-3- (6-O-phenoxycarbonyl) D-glucopyranos-1-yloxy) -1 H-pyrazole, (51) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-benzyloxycarbonyl-β-D- glucopyranos-1-yloxy) -1 H-pyrazole, (52) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-acetyl-β-D-glucopyranos- 1-yloxy) -1 H-pyrazole, (53) 4- (2-fluoro-4-methoxybenzyl) -1-isopropyl-5-methyl-3- (6-O-propylcarbon L-ß-D-glucopyranos-1-yloxy) -1 H-pyrazole, (54) 4- (2-fluoro-4-methoxybenzyl) -1-is opropyl-5-methyl-3- (6-O-isopropylcarbonyl-β-D-glucopyranos-1-yloxy) -1 H-pyrazole, (55) 4- (2-fluoro-4-methoxybenzyl) -1- Sopropyl-5-methyl-3- (6-O-benzylcarbonyl-β-D-glucopyranos-1-yloxy) -1H-pyrazole, 156 4- (4-ethylbenzyl) -1-isopropyl-5 -trifluoromethyl-3- (6-O-ethoxycarbonyl-β-D- or their pharmaceutically acceptable salts.
22. 22. Pharmaceutical composition comprising at least one pyrazole-O-glucoside derivative of claim 18, 19, 20 or 21, or its pharmaceutically acceptable salt.