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Claims for Patent: 8,178,541

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Claims for Patent: 8,178,541

Title:8-[3-amino-piperidin-1-yl]-xanthines, the preparation thereof and their use as pharmaceutical compositions
Abstract: The present invention relates to substituted xanthines of general formula ##STR00001## wherein R.sup.1 to R.sup.3 are as defined herein, the tautomers, the stereoisomers, the mixtures, the prodrugs thereof and the salts thereof which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
Inventor(s): Himmelsbach; Frank (Mittelbiberach, DE), Langkopf; Elke (Warthausen, DE), Eckhardt; Matthias (Biberach, DE), Mark; Michael (Biberach, DE), Maier; Roland (Biberach, DE), Lotz; Ralf (Schemmerhofen, DE), Tadayyon; Mohammad (Neu-Ulm, DE)
Assignee: Boehringer Ingelheim Pharma GmbH & Co. KG (Ingelheim am Rhein, DE)
Application Number:12/143,128
Patent Claims: 1. A pharmaceutical composition comprising a first compound of the formula (I): ##STR00006## wherein R.sup.1 denotes: a 4-methyl-2-quinazolinylmethyl group; R.sup.2 denotes a methyl group; and R.sup.3 denotes: a 2-butyn-1-yl group, or an enantiomer, mixture thereof, or a salt thereof; and one or more other therapeutic agents selected from antidiabetics, lipid lowering agents, active substances for the treatment of obesity, and drugs for treating high blood pressure; optionally together with one or more inert carriers and/or diluents.

2. The pharmaceutical composition of claim 1, wherein said composition comprises at least one antidiabetic selected from the group consisting of: metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist or antagonist, a PPAR-gamma/alpha modulator, an alpha-glucosidase inhibitor, another DPPIV inhibitor different from the first compound of formula I, an alpha2 antagonist, insulin, GLP-1, or exendin-4, amylin, an SGLT2 inhibitor, an inhibitor of protein tyrosine phosphatase 1, an inhibitor of glucose-6-phosphatase, an inhibitor of fructose-1,6-bisphosphatase, an inhibitor of glycogen phosphorylase, a glucagon receptor antagonist, an inhibitor of phosphoenolpyruvate carboxykinase, an inhibitor of glycogen synthase kinase, and an inhibitor of pyruvate dehydrokinase.

3. The pharmaceutical composition of claim 2, wherein said composition comprises at least one antidiabetic sulphonylurea selected from glibenclamide, tolbutamide and glimepriride.

4. The pharmaceutical composition of claim 2, wherein said composition comprises at least one antidiabetic thiazolidinedione selected from rosiglitazone and pioglitazone.

5. The pharmaceutical composition of claim 2, wherein said composition comprises at least one antidiabetic alpha-glucosidase inhibitor selected from acarbose and voglibose.

6. The pharmaceutical composition of claim 1, wherein said composition comprises at least one lipid lowering agent selected from the group consisting of: an HMG-CoA-reductase inhibitor, bezafibrate, fenofibrate, nicotinic acid, a PPAR-alpha agonist, a PPAR-delta agonists, an ACAT inhibitor, a cholesterol resorption inhibitor, a bile acid-binding substance, an inhibitor of ileac bile acid transport, an HDL-raising compound, an inhibitor of CETP, and a regulator of ABC1.

7. The pharmaceutical composition of claim 6, wherein said composition comprises at least one HMG-CoA-reductase inhibitor selected from simvastatin and atorvastatin.

8. The pharmaceutical composition of claim 6, wherein said composition comprises at least one lipid lowering agent selected from bezafibrate and fenofibrate.

9. The pharmaceutical composition of claim 6, wherein said composition comprises at least one cholesterol resorption inhibitor which is ezetimibe.

10. The pharmaceutical composition of claim 1, wherein said composition comprises at least one active substance for the treatment of obesity selected from the group consisting of: sibutramine, tetrahydrolipostatin, dexfenfluramine, axokine, an antagonist of the cannabinoid1 receptor, a MCH-1 receptor antagonist, a MC4 receptor agonist, a NPY5 or NPY2 antagonist, a .beta..sub.3-agonist, and an agonist of the 5HT2c receptor.

11. The pharmaceutical composition of claim 1, wherein said composition comprises at least one drug for treating high blood pressure selected from the group consisting of: an AII antagonist, an ACE inhibitor, a diuretic, and a .beta.-blocker.

12. The pharmaceutical composition of claim 1, wherein said first compound of the formula (I) is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine; or a salt thereof.

13. The pharmaceutical composition of claim 1, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.

14. The pharmaceutical composition of claim 12, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid.

15. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound ##STR00007## wherein R.sup.1 denotes: a 4-methyl-2-quinazolinylmethyl group; R.sup.2 denotes a methyl group; and R.sup.3 denotes: a 2-butyn-1-yl group, or an enantiomer, mixture thereof, or a salt thereof; and a pharmaceutically effective amount of one or more other therapeutic agents selected from antidiabetics, lipid lowering agents, active substances for the treatment of obesity, and drugs for treating high blood pressure.

16. The method of claim 15, wherein said other therapeutic agent comprises at least one antidiabetic selected from the group consisting of: metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist or antagonist, a PPAR-gamma/alpha modulator, an alpha-glucosidase inhibitor, another DPPIV inhibitor different from the first compound of formula I, an alpha2 antagonist, insulin, GLP 1, exendin-4, amylin, an SGLT2 inhibitor, an inhibitor of protein tyrosine phosphatase 1, an inhibitor of glucose-6-phosphatase, an inhibitor of fructose-1,6-bisphosphatase, an inhibitor of glycogen phosphorylase, a glucagon receptor antagonist, an inhibitor of phosphoenolpyruvate carboxykinase, an inhibitor of glycogen synthase kinase, and an inhibitor of pyruvate dehydrokinase.

17. The method of claim 16, wherein said other therapeutic agent comprises at least one antidiabetic sulphonylurea selected from glibenclamide, tolbutamide and glimepriride.

18. The method of claim 16, wherein said other therapeutic agent comprises at least one antidiabetic thiazolidinedione selected from rosiglitazone and pioglitazone.

19. The method of claim 16, wherein said other therapeutic agent comprises at least one antidiabetic alpha-glucosidase inhibitor selected from acarbose and voglibose.

20. The method of claim 15, wherein said other therapeutic agent comprises at least one lipid lowering agent selected from the group consisting of: an HMG-CoA-reductase inhibitor, bezafibrate, fenofibrate, nicotinic acid a PPAR-alpha agonist, a PPAR-delta agonists, an ACAT inhibitor, a cholesterol resorption inhibitor, a bile acid-binding substance, an inhibitor of ileac bile acid transport, an HDL-raising compound, an inhibitor of CETP, and a regulator of ABC1.

21. The method of claim 20, wherein said other therapeutic agent comprises at least one HMG-CoA-reductase inhibitor selected from simvastatin and atorvastatin.

22. The method of claim 20, wherein said other therapeutic agent comprises at least one lipid lowering agent is selected from bezafibrate and fenofibrate.

23. The method of claim 20, wherein said other therapeutic agent comprises at least one cholesterol resorption inhibitor which is ezetimibe.

24. The method of claim 15, wherein said other therapeutic agent comprises at least one active substance for the treatment of obesity selected from the group consisting of: sibutramine, tetrahydrolipostatin, dexfenfluramine, axokine, an antagonist of the cannabinoid1 receptor, a MCH-1 receptor antagonist, a MC4 receptor agonist, a NPY5 or NPY2 antagonist, a .beta..sub.3-agonist, and an agonist of the 5HT2c receptor.

25. The method of claim 15, wherein said other therapeutic agent comprises at least one drug for treating high blood pressure selected from the group consisting of: an AII antagonist, an ACE inhibitor, a diuretic, and a .beta.-blocker.

26. The method of claim 15, wherein said first compound is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine; or a salt thereof.

27. The method of claim 15, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.

28. The method of claim 26, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid.

29. The pharmaceutical composition of claim 1, wherein said other therapeutic agent is selected from the group consisting of: metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4, amylin, inhibitors of protein tyrosine phosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, HMG-CoA-reductase inhibitors, bezafibrate, fenofibrate, nicotinic acid, cholesterol resorption inhibitors, bile acid-binding substances, HDL-raising compounds, inhibitors of CETP, regulators of ABC1, sibutramin, tetrahydrolipostatin, .beta..sub.3-agonists, AII antagonists, ACE inhibitors, diuretics, and .beta.-blockers.

30. The method of claim 15, wherein said other therapeutic agent is selected from the group consisting of: metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4, amylin, inhibitors of protein tyrosine phosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, HMG-CoA-reductase inhibitors, bezafibrate, fenofibrate, nicotinic acid, cholesterol resorption inhibitors, bile acid-binding substances, HDL-raising compounds, inhibitors of CETP, regulators of ABC1, sibutramin, tetrahydrolipostatin, .beta..sub.3-agonists, AII antagonists, ACE inhibitors, diuretics, and .beta.-blockers.

31. A pharmaceutical composition comprising a first compound that is selected from the group consisting of the compound of claim 12 or a physiological acceptable salt thereof; and an antidiabetic selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4 and amylin.

32. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound of claim 26 or a physiologically acceptable salt thereof; and a pharmaceutically effective amount of an antidiabetic selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinedione, PPAR-gamma agonists, alpha-glucosidase inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4 and amylin.

33. The pharmaceutical composition of claim 1, wherein said first compound is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine.

34. The method of claim 15, wherein said first compound is 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine.

35. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, and a pharmaceutically effective amount of an other therapeutic agent selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists and antagonists, PPAR-gamma/alpha modulators, alpha-glucosidase inhibitors, other DPPIV inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4, amylin, SGLT2 inhibitors, inhibitors of protein tyrosine phosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxykinase, inhibitors of glycogen synthase kinase, inhibitors of pyruvate dehydrokinase, HMG-CoA-reductase inhibitors, bezafibrate, fenofibrate, nicotinic acid, PPAR-alpha agonists, PPAR-delta agonists, ACAT inhibitors, cholesterol resorption inhibitors, bile acid-binding substances, inhibitors of ileac bile acid transport, inhibitors of CETP, regulators of ABC1, sibutramin, tetrahydrolipostatin, antagonists of the cannabinoid 1 receptor, MCH-1 receptor antagonists, MC4 receptor agonists, NPY5 or NPY2 antagonists, .beta.3-agonists, agonists of the 5HT2c receptor,AII antagonists, ACE inhibitors, diuretics, and .beta.-blockers.

36. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)]-3-methyl-7-(2-butyn-1-yl)-8-(3-(- R)-amino-piperidin-1-yl)-xanthine, in combination with a pharmaceutically effective amount of another therapeutic agent selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, alpha2 antagonists, insulin, GLP-1, exendin-4 and amylin.

37. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, in combination with a pharmaceutically effective amount of an other therapeutic agent selected from inhibitors of protein tyrosine phosphatase 1, inhibitors of glucose-6-phosphatase, inhibitors of fructose-1,6-bisphosphatase, inhibitors of glycogen phosphorylase, glucagon receptor antagonists, inhibitors of phosphoenolpyruvate carboxykinase, glycogen synthase kinase or pyruvate dehydrokinase, HMG-CoA-reductase inhibitors, bezafibrate, fenofibrate, nicotinic acid, cholesterol resorption inhibitors, bile acid-binding substances, inhibitors of CETP, regulators of ABC1, sibutramin, tetrahydrolipostatin, and .beta.3-agonists.

38. A method of treating type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, in combination with a pharmaceutically effective amount of a drug for treating high blood pressure selected from AII antagonists, ACE inhibitors, diuretics, and .beta.-blockers.

39. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, and a pharmaceutically effective amount of an antidiabetic selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, alpha-glucosidase inhibitors, insulin, GLP-1 and exendin-4.

40. A pharmaceutical composition comprising 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine, and an antidiabetic selected from metformin, sulphonylureas, nateglinide, repaglinide, thiazolidinediones, PPAR-gamma agonists, and alpha-glucosidase inhibitors.

41. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, and a pharmaceutically effective amount of an antidiabetic selected from metformin, a sulphonylurea, and a thiazolidinedione.

42. The method according to claim 41, wherein the thiazolidinedione is pioglitazone.

43. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine, and an antidiabetic selected from metformin, a sulphonylurea, nateglinide, repaglinide, a thiazolidinedione, a PPAR-gamma agonist, an alpha-glucosidase inhibitor and insulin.

44. A pharmaceutical composition comprising 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-a- mino-piperidin-1-yl)-xanthine and metformin

45. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine and metformin

46. A pharmaceutical composition comprising 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1 -yl)-8-(3-(R)-amino-piperidin-1 -yl)-xanthine and pioglitazone.

47. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine and pioglitazone.

48. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a pharmaceutically effective amount of 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-- 8-(3-(R)-amino-piperidin-1-yl)-xanthine and a sulphonylurea.
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