Pharmaceutical composition, methods for treating and uses thereof

Abstract

The invention relates to the treatment or prevention of one or more conditions selected from type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance and hyperglycemia using a SGLT-2 inhibitor. In addition the present invention relates to methods for preventing or treating of metabolic disorders and related conditions.

1 . Method for preventing, slowing the progression of, delaying or treating a metabolic disorder selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, impaired glucose tolerance, impaired fasting blood glucose, hyperglycemia, postprandial hyperglycemia, overweight, obesity, metabolic syndrome, gestational diabetes, new onset diabetes after transplantation (NODAT) and complications associated therewith, and post-transplant metabolic syndrome (PTMS) and complications associated therewith in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         2 . Method according to  claim 1  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         3 . Method according to  claim 1 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         4 . Method according to  claim 1  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         5 . Method for improving glycemic control and/or for reducing of fasting plasma glucose, of postprandial plasma glucose and/or of glycosylated hemoglobin HbA1c in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         6 . Method according to  claim 5  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         7 . Method according to  claim 5 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         8 . Method according to  claim 5  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         9 . Method for preventing, slowing, delaying or reversing progression from impaired glucose tolerance, impaired fasting blood glucose, insulin resistance and/or from metabolic syndrome to type 2 diabetes mellitus in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         10 . Method according to  claim 9  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         11 . Method according to  claim 9 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         12 . Method according to  claim 9  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         13 . Method for preventing, slowing the progression of, delaying or treating of a condition or disorder selected from the group consisting of complications of diabetes mellitus such as cataracts and micro- and macrovascular diseases, such as nephropathy, retinopathy, neuropathy, tissue ischaemia, diabetic foot, arteriosclerosis, myocardial infarction, acute coronary syndrome, unstable angina pectoris, stable angina pectoris, stroke, peripheral arterial occlusive disease, cardiomyopathy, heart failure, heart rhythm disorders and vascular restenosis, in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         14 . Method according to  claim 13  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         15 . Method according to  claim 13 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         16 . Method according to  claim 13  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         17 . Method for reducing body weight and/or body fat, or preventing an increase in body weight and/or body fat, or facilitating a reduction in body weight and/or body fat, in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         18 . Method according to  claim 17  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         19 . Method according to  claim 17 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         20 . Method according to  claim 17  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         21 . Method for preventing, slowing, delaying or treating the degeneration of pancreatic beta cells and/or the decline of the functionality of pancreatic beta cells and/or for improving and/or restoring the 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 an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         22 . Method according to  claim 21  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         23 . Method according to  claim 21 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         24 . Method according to  claim 21  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         25 . Method for preventing, slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of ectopic fat in a patient in need thereof characterized in that a pharmaceutical composition comprising an SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         26 . Method according to  claim 25  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         27 . Method according to  claim 25 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         28 . Method according to  claim 25  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         29 . Method for maintaining and/or improving the 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 SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         30 . Method according to  claim 29  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         31 . Method according to  claim 29 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         32 . Method according to  claim 29  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers. 
     
     
         33 . Method for treating and preventing hyperuricemia and hyperuricemia associated conditions, kidney stones and hyponatremia in a patient in need thereof characterized in that a pharmaceutical composition comprising a SGLT2 inhibitor is administered to the patient, wherein the SGLT2 inhibitor is a glucopyranosyl-substituted benzene derivative of the formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  denotes Cl, methyl or cyano; R 2  denotes H, methyl, methoxy or hydroxy and R 3  denotes ethyl, cyclopropyl, ethynyl, ethoxy, (R)-tetrahydrofuran-3-yloxy or (S)-tetrahydrofuran-3-yloxy; or a prodrug thereof. 
     
     
         34 . Method according to  claim 33  wherein the patient:
 (1) is an individual diagnosed of one or more of the conditions selected from the group consisting of overweight, obesity, visceral obesity and abdominal obesity; or 
 (2) is an individual who shows one, two or more of the following conditions:
 (a) a fasting blood glucose or serum glucose concentration greater than 100 mg/dL, in particular greater than 125 mg/dL; 
 (b) a postprandial plasma glucose 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%; or 
 
 (3) is an individual wherein one, two, three or more of the following conditions are present:
 (a) obesity, visceral obesity and/or abdominal obesity, 
 (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) a systolic blood pressure ≧130 mm Hg and a diastolic blood pressure ≧85 mm Hg, 
 (e) a fasting blood glucose level ≧100 mg/dL. 
 
 
     
     
         35 . Method according to  claim 33 , wherein the SGLT2 inhibitor is selected from the group consisting of the group of compounds (I.1) to (I.11):
 (I.1) 6-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-2-methoxy-benzonitrile,   (I.2) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methoxy-benzonitrile,   (I.3) 1-cyano-2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-methyl-benzene,   (I.4) 2-(4-ethylbenzyl)-4-(β-D-glucopyranos-1-yl)-5-hydroxy-benzonitrile,   (I.5) 2-(4-ethyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.6) 2-(4-cyclopropyl-benzyl)-4-(β-D-glucopyranos-1-yl)-benzonitrile,   (I.7) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-(4-ethynyl-benzyl)-benzene,   (I.8) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.9) 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene,   (I.10) 1-methyl-2-[4-((R)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene, and   (I.11) 1-methyl-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-4-(β-D-glucopyranos-1-yl)-benzene.   
     
     
         36 . Method according to  claim 33  wherein the pharmaceutical composition additionally comprises one or more pharmaceutically acceptable carriers.