8-[3-amino-piperidin-1-yl]-xanthines, their preparation and their use as pharmaceutical compositions
Disclosed are substituted xanthines of the formula wherein R is defined as in claim 1 , the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, which have valuable pharmacological properties, particularly an inhibiting effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
1. A compound of the formula (I):
wherein
R denotes:
a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group,
a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group,
a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group,
a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group,
a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or (5-methoxycarbonyl-furan-2-yl)methyl group,
a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group,
a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or (5-cyano-6-methoxy-pyridin-2-yl)methyl group,
a (6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,
a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2-yl)methyl group, or
a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, or diastereomer thereof, or a mixture thereof, or a salt thereof.
2. A compound of the formula (Ia):
wherein R denotes:
a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group,
a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group,
a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group,
a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group,
a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or (5-methoxycarbonyl-furan-2-yl)methyl group,
a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group,
a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or (5-cyano-6-methoxy-pyridin-2-yl)methyl group,
a (6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,
a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2-yl)methyl group, or
a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, or a tautomer or salt thereof.
3. A compound of the formula (Ib):
wherein R denotes:
a benzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2,6-difluoro-benzyl, 3,4-difluoro-benzyl, 2-chlorobenzyl, 3-chlorobenzyl or 4-chlorobenzyl group,
a 2-trifluoromethyl-benzyl, 3-trifluoromethyl-benzyl or 4-trifluoromethyl-benzyl group,
a 3-trifluoromethoxy-benzyl or 4-trifluoromethoxy-benzyl group,
a 2-cyanobenzyl, 3-cyanobenzyl or 4-cyanobenzyl group,
a 2,6-dicyanobenzyl, 3,4-dicyanobenzyl, 3,5-dicyanobenzyl, 2-trifluoromethyl-4-cyano-benzyl, 3-nitro-4-cyano-benzyl, 2-cyano-3-methoxy-benzyl, 2-cyano-4-methoxy-benzyl, 2-cyano-5-methoxy-benzyl, 2-cyano-4-fluoro-benzyl, 2-cyano-5-fluoro-benzyl, 2-cyano-6-fluoro-benzyl, 3-cyano-4-fluoro-benzyl, 4-cyano-3-fluoro-benzyl, 2-fluoro-4-cyano-benzyl, 2-cyano-3-chlorobenzyl, 2-chloro-4-cyano-benzyl or 2-cyano-4-bromobenzyl group,
a 2-methoxy-benzyl, 3-methoxy-benzyl, 4-methoxy-benzyl, 2-fluoro-3-methoxy-benzyl, 2-fluoro-4-methoxy-benzyl, 2-fluoro-5-methoxy-benzyl, 3-fluoro-4-methoxy-benzyl, 3,4-dimethoxy-benzyl, 3,5-dimethoxybenzyl or 3,4-dimethoxy-6-fluoro-benzyl group,
a (furan-2-yl)methyl, (furan-3-yl)methyl, (5-bromo-furan-2-yl)methyl, (5-methyl-furan-2-yl)methyl, (5-cyano-furan-2-yl)methyl or (5-methoxycarbonyl-furan-2-yl)methyl group,
a (pyridin-2-yl)methyl, (6-fluoro-pyridin-2-yl)methyl or (5-methoxy-pyridin-2-yl)methyl group,
a (3-cyanopyridin-2-yl)methyl, (6-cyanopyridin-2-yl)methyl, (5-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-2-yl)methyl, (4-cyano-pyridin-3-yl)methyl, (3-cyano-pyridin-4-yl)methyl, (2-cyano-pyridin-3-yl)methyl, (2-cyano-pyridin-4-yl)methyl, (5-cyano-pyridin-3-yl)methyl, (6-cyano-pyridin-3-yl)methyl or (5-cyano-6-methoxy-pyridin-2-yl)methyl group,
a (6-phenyl-pyridin-2-yl)methyl or a ([2,2′]bipyridinyl-6-yl)methyl group,
a (pyrimidin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl or (4,6-dimethyl-pyrimidin-2-yl)methyl group, or
a (2-phenyl-pyrimidin-4-yl)methyl or (4-phenyl-pyrimidin-2-yl)methyl group, or a tautomer or salt thereof.
4. A physiologically acceptable salt of the compound according to claim 1 , with inorganic or organic acids.
5. A physiologically acceptable salt of the compound according to claim 2 , with inorganic or organic acids.
6. A physiologically acceptable salt of the compound according to claim 3 , with inorganic or organic acids.
7. A pharmaceutical composition comprising a compound according to claim 1 , with one or more inert carriers or diluents.
8. A pharmaceutical composition comprising a compound according to claim 2 , with one or more inert carriers or diluents.
9. A pharmaceutical composition comprising a compound according to claim 3 , with one or more inert carriers or diluents.
10. A method of treating type II diabetes mellitus or obesity, comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 1 .
11. A method of treating type II diabetes mellitus or obesity, comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 2 .
12. A method of treating type II diabetes mellitus or obesity, comprising administering to a patient a pharmaceutically effective amount of a compound according to claim 3 .
13. A compound of the formula (Ia) or a physiologically acceptable salt thereof with an inorganic or organic acid
wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
14. A pharmaceutical composition comprising one or more inert carriers or diluents and a compound of the formula (Ia) or a physiologically acceptable salt thereof with an inorganic or organic acid
wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
15. A method of treating type II diabetes mellitus or obesity, comprising the step of administering to a patient a pharmaceutically effective amount of a compound of the formula (Ia) or a physiologically acceptable salt thereof with an inorganic or organic acid
wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
16. A method of treating type II diabetes mellitus comprising the step of administering to a patient a pharmaceutically effective amount of a compound of the formula (Ia) or a physiologically acceptable salt thereof with an inorganic or organic acid
wherein R denotes a (3-cyanopyridin-2-yl)methyl group.
17. The compound 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid.
18. A pharmaceutical composition comprising one or more inert carriers or diluents and 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid.
19. A method of treating type II diabetes mellitus or obesity, comprising the step of administering to a patient a pharmaceutically effective amount of 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid.
20. A method of treating type II diabetes mellitus comprising the step of administering to a patient a pharmaceutically effective amount of 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-((R)-3-amino-piperidin-1-yl)-xanthine in a physiologically acceptable salt form with an inorganic or organic acid.