8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

US 20080249089A1
Filed: 06/20/2008
Published: 10/09/2008
Est. Priority Date: 08/21/2002
Status: Active Grant

First Claim

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1-22. -22. (canceled)

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Abstract

The present invention relates to substituted xanthines of general formula

wherein R¹to R³are defined as in claims 1 to 16, 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).

Citations

58 Claims

1-22. -22. (canceled)

23. A pharmaceutical composition comprising:
- a first compound of the formula (I);
- View Dependent Claims (24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40)
- - 24. The pharmaceutical composition of claim 23, 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, an alpha2 antagonist, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue, 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.
  - 25. The pharmaceutical composition of claim 24, wherein said composition comprises at least one antidiabetic sulphonylurea selected from glibenclamide, tolbutamide and glimepriride.
  - 26. The pharmaceutical composition of claim 24, wherein said composition comprises at least one antidiabetic thiazolidinedione selected from rosiglitazone and pioglitazone.
  - 27. The pharmaceutical composition of claim 24, wherein said composition comprises at least one antidiabetic alpha-glucosidase inhibitor selected from acarbose and voglibose.
  - 28. The pharmaceutical composition of claim 23, wherein said composition comprises at least one lipid lowering agent selected from the group consisting of:
    - an HMG-CoA-reductase inhibitor, a fibrate, nicotinic acid, a nictonic acid derivative, 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.
  - 29. The pharmaceutical composition of claim 28, wherein said composition comprises at least one HMG-CoA-reductase inhibitor selected from simvastatin and atorvastatin.
  - 30. The pharmaceutical composition of claim 28, wherein said composition comprises at least one fibrate selected from bezafibrate and fenofibrate.
  - 31. The pharmaceutical composition of claim 28, wherein said composition comprises at least one cholesterol resorption inhibitor which is ezetimibe.
  - 32. The pharmaceutical composition of claim 23, 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 β
      
      ₃-agonist, and an agonist of the 5HT2c receptor.
  - 33. The pharmaceutical composition of claim 23, 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, a β
      
      -blocker, and a Ca-antagonist.
  - 34. The pharmaceutical composition of claim 23, wherein said first compound is of formula (I) wherein:
    - R¹denotes;
      
      a 4-methoxy-1-naphthylmethyl group,a 2-quinolinylmethyl, 4-quinolinylmethyl or a 6-quinolinylmethyl group,a 1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1-isoquinolinyl-methyl or a 3-isoquinolinylmethyl group, ora 2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or a 4-quinazolinylmethyl group;
      
      R²denotes a methyl group; and
      
      R³denotes a 2-buten-1-yl or a 2-butyn-1-yl group;
      
      or a tautomer, enantiomer, diastereomer, mixture thereof, or a salt thereof.
  - 35. The pharmaceutical composition of claim 23, wherein said first compound of the formula (I) is chosen from:
    - (1) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(2) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(3) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(4) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(5) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(6) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(7) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(8) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(9) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,(10) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(11) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(12) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(13) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,(14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(19) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(20) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(21)-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(22) 1-[(4-fluoro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(23) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(24) 1-[(3-trifluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(25) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(26) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(27) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(28) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(29) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(30) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine;
      
      or a tautomer, enantiomer, diastereomer, mixture thereof or a salt thereof.
  - 36. The pharmaceutical composition of claim 23, wherein said first compound of the formula (I) is chosen from:
    - 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-3-amino-piperidin-1-yl)-xanthine,1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(S)-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine;
      
      or a tautomer, enantiomer, diastereomer, mixture thereof or a salt thereof.
  - 37. The pharmaceutical composition of claim 23, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 38. The pharmaceutical composition of claim 34, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 39. The pharmaceutical composition of claim 35, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 40. The pharmaceutical composition of claim 36, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.

41. A method of treating type I or type II diabetes mellitus or obesity comprising administering to a patient in need thereof a pharmaceutically effective amount of a first compound of the formula (I):
- View Dependent Claims (42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58)
- - 42. The method of claim 41, 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, an alpha2 antagonist, insulin or an insulin analogue, GLP-1 or a GLP-1 analogue, 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.
  - 43. The method of claim 42, wherein said other therapeutic agent comprises at least one antidiabetic sulphonylurea selected from glibenclamide, tolbutamide and glimepriride.
  - 44. The method of claim 42, wherein said other therapeutic agent comprises at least one antidiabetic thiazolidinedione selected from rosiglitazone and pioglitazone.
  - 45. The method of claim 42, wherein said other therapeutic agent comprises at least one antidiabetic alpha-glucosidase inhibitor selected from acarbose and voglibose.
  - 46. The method of claim 41, wherein said other therapeutic agent comprises at least one lipid lowering agent selected from the group consisting of:
    - an HMG-CoA-reductase inhibitor, a fibrate, nicotinic acid, a nictonic acid derivative, 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.
  - 47. The method of claim 46, wherein said other therapeutic agent comprises at least one HMG-CoA-reductase inhibitor selected from simvastatin and atorvastatin.
  - 48. The method of claim 46, wherein said other therapeutic agent comprises at least one fibrate selected from bezafibrate and fenofibrate.
  - 49. The method of claim 46, wherein said other therapeutic agent comprises at least one cholesterol resorption inhibitor which is ezetimibe.
  - 50. The method of claim 41, 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 β
      
      ₃-agonist, and an agonist of the 5HT2c receptor.
  - 51. The method of claim 41, 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, a β
      
      -blocker, and a Ca-antagonist.
  - 52. The method of claim 41, wherein said first compound is of formula (I) wherein:
    - R¹denotes;
      
      a 4-methoxy-1-naphthylmethyl group,a 2-quinolinylmethyl, 4-quinolinylmethyl or a 6-quinolinylmethyl group,a 1-isoquinolinylmethyl, 3-methyl-1-isoquinolinylmethyl, 4-methyl-1-isoquinolinyl-methyl or a 3-isoquinolinylmethyl group, ora 2-quinazolinylmethyl, 4-methyl-2-quinazolinylmethyl or a 4-quinazolinylmethyl group;
      
      R²denotes a methyl group; and
      
      R³denotes a 2-buten-1-yl or a 2-butyn-1-yl group;
      
      or a tautomer, enantiomer, diastereomer, mixture thereof, or a salt thereof.
  - 53. The method of claim 41, wherein said first compound is a compound of the formula (I) chosen from:
    - (1) 1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(2) 1-(2-{2-[(ethylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(3) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(4) 1-(2-phenyl-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(5) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(6) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(7) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(8) 1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(9) 1-[2-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,(10) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(11) 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(12) 1-[2-(benzo[1,3]dioxol-4-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(13) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,(14) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(15) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(16) 1-(2-{2-[(methylaminocarbonyl)methoxy]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,(17) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(18) 1-(2-{2-[(isopropylcarbonyl)amino]-phenyl}-2-oxo-ethyl)-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(19) 1-[(4-cyano-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(20) 1-[(4-phenyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(21) 1-[(8-methyl-quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(22) 1-[(4-fluoro-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(23) 1-((E)-3-pentafluorophenyl-allyl)-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(24) 1-[(3-trifluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(25) 1-[(3-difluoromethyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(26) 1-[2-(biphenyl-2-yl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(27) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-cyclopropyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(28) 1-[2-(3-methoxy-phenyl)-2-oxo-ethyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(29) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-chloro-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,(30) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-bromo-benzyl)-8-((R)-3-amino-piperidin-1-yl)-xanthine;
      
      or a tautomer, enantiomer, diastereomer, mixture thereof or a salt thereof.
  - 54. The method of claim 41, wherein said first compound is a compound of the formula (I) chosen from:
    - 1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-3-amino-piperidin-1-yl)-xanthine,1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methoxy-naphthalen-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinolin-4-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(quinolin-6-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((S)-3-amino-piperidin-1-yl)-xanthine,1-[(quinazolin-2-yl)methyl]-3-methyl-7-((E)-2-buten-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(S)-amino-piperidin-1-yl)-xanthine,1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-(3-(R)-amino-piperidin-1-yl)-xanthine,or a tautomer, enantiomer, diastereomer, mixture thereof or a salt thereof.
  - 55. The method of claim 41, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 56. The method of claim 41, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 57. The method of claim 41, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.
  - 58. The method of claim 41, wherein said first compound is a physiologically acceptable salt of a compound of formula I, with an inorganic or organic acid or base.

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Current Assignee
Boehringer Ingelheim International GmbH (C.H. Boehringer Sohn AG & Co. KG)
Original Assignee
Boehringer Ingelheim Pharmaceuticals Incorporated (C.H. Boehringer Sohn AG & Co. KG)
Inventors
Himmelsbach, Frank, Langkopf, Elke, Eckhardt, Matthias, Mark, Michael, Maier, Roland, Tadayyon, Mohammad, Lotz, Ralf R.H.

Granted Patent

US 8,178,541 B2
Time in Patent Office

Days
Field of Search
US Class Current

514/234.2
CPC Class Codes

A61P 13/12   of the kidneys

A61P 19/02   for joint disorders, e.g. a...

A61P 25/02   for peripheral neuropathies

A61P 27/02   Ophthalmic agents

A61P 3/04   Anorexiants; Antiobesity ag...

A61P 3/10   for hyperglycaemia, e.g. an...

C07D 473/04   two oxygen atoms

C07D 473/06   with radicals containing on...

C07D 473/08   with methyl radicals in pos...

C07D 519/00   Heterocyclic compounds cont...

8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

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8-[3-AMINO-PIPERIDIN-1-YL]-XANTHINES, THE PREPARATION THEREOF AND THEIR USE AS PHARMACEUTICAL COMPOSITIONS

First Claim

1 Assignment

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0 Petitions

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Accused Products

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Abstract

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58 Claims

Specification

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Solutions

Use Cases

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