Pharmaceutical composition comprising a glucopyranosyl-substituted benzene derivate

1. A phamaceutical composition comprising the glucopyranosyl-substituted benzene derivative 1-chloro-4-( 62 -D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in combination with the DPP IV inhibitor 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, or a pharmaceutically acceptable salt thereof.

2. The pharmaceutical composition according to claim 1 , wherein the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present in a single dosage form.

3. The pharmaceutical composition according to claim 1 , wherein the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present each in a separate dosage form.

4. Method for 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 and metabolic syndrome in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with the DPP IV inhibitor according to claim 1 .

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 comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with the DPP IV inhibitor according to claim 1 .

6. Method for 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 comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

7. Method for slowing the progression of, or delaying a condition or disorder selected from the group consisting of complications of diabetes mellitus consisting of cataracts and micro- and macrovascular diseases consisting of nephropathy, retinopathy, neuropathy, tissue ischaemia, arteriosclerosis, myocardial infarction, stroke and peripheral arterial occlusive disease, in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

8. Method for reducing body weight or facilitating a reduction in body weight in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

9. Method for 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 comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

10. Method for slowing, delaying or treating diseases or conditions attributed to an abnormal accumulation of liver fat in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

11. Method for maintaining and/or improving the insulin sensitivity and/or for treating hyperinsulinemia and/or insulin resistance in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with a DPP IV inhibitor according to claim 1 .

12. Method according to claim 4 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

13. Method according to claim 5 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

14. Method according to claim 6 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

15. Method according to claim 7 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

16. Method according to claim 8 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

17. Method according to claim 9 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

18. Method according to claim 10 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

19. Method according to claim 11 wherein the patient is:

(1) 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) an individual who shows one, two or more of the following conditions:

(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 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) 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 ≧110 mg/dL; or

(4) an individual for whom the monotherapy with metformin is contraindicated and/or who has an intolerance against metformin at therapeutic doses; or

(5) an individual with insufficient glycemic control despite monotherapy with a SGLT2 inhibitor; or

(6) an individual with insufficient glycemic control despite monotherapy with a DPP IV inhibitor.

20. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is formulated for oral administration.

21. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition is formulated for oral administration in solid form.

22. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition comprises an amount of 5 to 50 mg of the glucopyranosyl-substituted benzene derivative.

23. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition comprises an amount of 0.5 to 10 mg of the DPP IV inhibitor.

24. The pharmaceutical composition according to claim 1 , wherein said pharmaceutical composition comprises an amount of 5 to 50 mg of the glucopyranosyl-substituted benzene derivative and an amount of 0.5 to 10 mg of the DPP IV inhibitor.

25. Method for treating type 2 diabetes mellitus in a patient in need thereof comprising administering to the patient the glucopyranosyl-substituted benzene derivative according to claim 1 in combination or alternation with the DPP IV inhibitor according to claim 1 .

26. Method according to claim 25 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 0.5 to 50 mg once daily.

27. Method according to claim 25 , wherein the DPP IV inhibitor is administered in an amount of 0.5 to 10 mg once daily.

28. Method according to claim 25 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 0.5 to 50 mg once daily and the DPP IV inhibitor is administered in an amount of 0.5 to 10 mg once daily.

29. Method according to claim 25 , wherein the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present in a single dosage form.

30. Method according to claim 29 , wherein the single dosage form is administered orally.

31. The pharmaceutical composition according to claim 22 , wherein said pharmaceutical composition comprises an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg of the glucopyranosyl-substituted benzene derivative.

32. The pharmaceutical composition according to claim 22 , wherein said pharmaceutical composition comprises an amount of 10 mg of the glucopyranosyl-substituted benzene derivative.

33. The pharmaceutical composition according to claim 22 , wherein said pharmaceutical composition comprises an amount of 25 mg of the glucopyranosyl-substituted benzene derivative.

34. The pharmaceutical composition according to claim 23 , wherein said pharmaceutical composition comprises an amount of 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10 mg of the DPP IV inhibitor.

35. The pharmaceutical composition according to claim 23 , wherein said pharmaceutical composition comprises an amount of 1 mg, 2.5 mg or 5 mg of the DPP IV inhibitor.

36. The pharmaceutical composition according to claim 23 , wherein said pharmaceutical composition comprises an amount of 5 mg of the DPP IV inhibitor.

37. A pharmaceutical composition comprising the glucopyranosyl-substituted benzene derivative 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in combination with the DPP IV inhibitor 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises an amount of 10 mg of the glucopyranosyl-substituted benzene derivative and an amount of 5 mg of the DPP IV inhibitor.

38. A pharmaceutical composition comprising the glucopyranosyl-substituted benzene derivative 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in combination with the DPP IV inhibitor 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises an amount of 10 mg of the glucopyranosyl-substituted benzene derivative and an amount of 5 mg of the DPP IV inhibitor, wherein the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present in a single dosage form.

39. A pharmaceutical composition comprising the glucopyranosyl-substituted benzene derivative 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in combination with the DPP IV inhibitor 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises an amount of 25 mg of the glucopyranosyl-substituted benzene derivative and an amount of 5 mg of the DPP IV inhibitor.

40. A pharmaceutical composition comprising the glucopyranosyl-substituted benzene derivative 1-chloro-4-(β-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene in combination with the DPP IV inhibitor 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine, or a pharmaceutically acceptable salt thereof, wherein said pharmaceutical composition comprises an amount of 25 mg of the glucopyranosyl-substituted benzene derivative and an amount of 5 mg of the DPP IV inhibitor, wherein the glucopyranosyl-substituted benzene derivative and the DPP IV inhibitor are present in a single dosage form.

41. The method according to claim 26 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 5 mg, 10 mg, 15 mg, 20 mg, 25 mg or 50 mg once daily.

42. The method according to claim 26 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 10 mg once daily.

43. The method according to claim 26 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 25 mg once daily.

44. The method according to claim 27 , wherein the DPP IV inhibitor is administered in an amount of 0.5 mg, 1 mg, 2.5 mg, 5 mg or 10 mg once daily.

45. The method according to claim 27 , wherein the DPP IV inhibitor is administered in an amount of 1 mg, 2.5 mg or 5 mg once daily.

46. The method according to claim 27 , wherein the DPP IV inhibitor is administered in an amount of 5 mg once daily.

47. The method according to claim 28 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 10 mg once daily and the DPP IV inhibitor is administered in an amount of 5 mg once daily.

48. The method according to claim 28 , wherein the glucopyranosyl-substituted benzene derivative is administered in an amount of 25 mg once daily and the DPP IV inhibitor is administered in an amount of 5 mg once daily.