3-methyl-7-butinyl-xanthines, the preparation thereof and their use as pharmaceutical compositions
The present invention relates to new substituted xanthines of general formula wherein R 1 , R 2 and X are defined as in the claims, the tautomers, the enantiomers, the diastereomers, 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 formula
wherein
R 1 denotes an arylmethyl or arylethyl group,
a heteroarylmethyl or heteroarylethyl group,
an arylcarbonylmethyl group,
a heteroarylcarbonylmethyl group or
an arylprop-2—enyl or heteroarylprop-2−enyl group, wherein the propenyl chain may be substituted by 1 to 4 fluorine atoms or a cyano, C 1-3 -alkyloxy-carbonyl or nitro group,
R 2 denotes a C 1-4 -alkyl group, which may be straight-chain or branched, and X denotes a —CH 2 CH 2 group, which may optionally be substituted by one or two C 1-3 -alkyl groups, which may be identical or different,
while, unless otherwise stated, the above-mentioned alkyl, alkenyl and alkynyl groups may be straight-chain or branched, or a tautomer or salt thereof.
2. The compound according to claim 1 , wherein R 2 denotes a methyl or ethyl group and X denotes a —CH 2 CH 2 group, which may optionally be substituted by one or two methyl or ethyl groups, while the substituents may be identical or different, or a tautomer or salt thereof.
3. The compound according to claim 2 , l wherein R 1 denotes a phenylmethyl, phenylcarbonylmethyl, phenylprop-2-enyl, pyridinylmethyl, pyrimidinylmethyl, naphthylmethyl, quinolinylmethyl, quinolinonylmethyl, imidazoquinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinazolinonylmethyl, quinoxalinylmethyl, phenanthridinylmethyl, naphthyridinylmethyl, benzo- naphthiridinylmethyl, imidazopyridinylmethyl or benzotriazolylmethyl group which may be substituted in each case by one or two fluorine, chlorine, or bromine atoms or one or two cyano, nitro, amino, C 1-3 -alkyl, C 1-3 -alkyloxy, phenyl or morpholinyl groups, while the substituents are identical or different,
R 2 denotes a methyl group and
X denotes a —CH 2 CH 2 group, which may optionally be substituted by one or two methyl groups, or
a tautomer or salt thereof.
4. The compound according to claim 3 , wherein R 1 denotes a benzyl group substituted by one or two cyano groups or by a methoxy group and a cyano group or
R 1 denotes a pyridinylmethyl, pyrimidinylmethyl, quinolinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl, naphthyridinylmethyl or naphthylmethyl group, which may be substituted in each case by one or two cyano or methyl groups,
R 2 denotes a methyl group and
X denotes a —CH(CH 3 )—CH 2 group, a —CH 2 —CH(CH 3 ) group or a —CH 2 —C(CH 3 ) 2 group, or
a tautomer or salt thereof.
5. The compound according to claim 4 , wherein
R 1 denotes a benzyl group substituted by a cyano group or a pyridinylmethyl, isoquinolinylmethyl, quinazolinylmethyl, quinoxalinylmethyl or naphthyridinylmethyl group, each of which may be substituted by a cyano or methyl group,
R 2 a methyl group and
X denotes a —CH(CH 3 )—CH 2 group, a —CH 2 —CH(CH 3 ) group or a —CH 2 —C(CH 3 ) 2 group, while in each case the carbon atom on the right is linked to the terminal amino group, or
a tautomer or salt thereof.
6. A compound selected from the group consisting of:
(a) 1-[(3-methyl-isoquinolin- 1 -yl)methyl]-3-methyl-7-(2-butyn- 1 -yl)-8-[(2-amino-ethyl) -methylamino]-xanthine,
(b) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8[(2-amino-ethyl) -methylamino]-xanthine,
(c) 1-[(3-methyl-isoquinolin-1 -yl)methyl]-3-methyl-7(2-butyn-1-yl)-8-[(2-amino-2-methyl -propyl)-methylamino]-xanthine,
(d) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(2-amino-2-methyl -propyl)-methylamino]-xanthine,
(e) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)-8-[(S)-(2-amino -propyl)-methylamino]-xanthine,
(f) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)-8-[(R)-(2-amino-propyl) -methylamino]-xanthine,
(g) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)-8-[(S)-(2-amino-propyl) -methylamino]-xanthine,
(h) 1-[(4-methyl-quinazolin-2-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)-8-[(R)-(2-amino-propyl) -methylamino]-xanthine,
(i) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(R)-(2-amino-1-methyl-ethyl)-methylamino]-]-xanthine,
(j) 1-[(3-methyl-isoquinolin-1-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-1-methyl-ethyl)-methylamino]-]-xanthine,
(k) 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn-1-yl)- 8-[(S)-(2-amino-propyl)-methyl-amino]-xanthine,
(l) (1)-[([1,5]naphthyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)- 8-[(S)-(2-amino-propyl)-methylamino]-xanthine,
(m) 1-[(quinoxalin-6-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)- 8-[(S)-(2-amino-propyl ) -methylamino]-xanthine,
(n) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn-1-yl)-8-[(S)-(2-amino-propyl -methylamino]-xanthine,
(o) 1-[(4-cyano-isoquinolin-3-yl)methyl]-3-methyl-7-(2-butyn- 1-yl )-8-[(S)-(2-amino -propyl)-methylamino]-xanthine,
(p) 1-(2-cyano-benzyl)-3-methyl-7-(2-butyn- 1-yl) 8- [(2-amino-2-methyl-propyl) -methylamino]-xanthine, and
(q) 1-[(3-cyano-pyridin-2-yl)methyl]-3-methyl-7-(2-butyn- 1-yl)- 8-[(2-amino-2-methyl -propyl)-methylamino]-xanthine, or a salt thereof.
7. A physiologically acceptable salt of a compound according to claim 1 with an inorganic or organic acid or base.
8. A pharmaceutical composition comprising a pharmaceutically acceptable amount of a compound according to claim 1 together with one or more inert carriers or diluents.
9. A method of treating type II diabetes mellitus, or obesity, comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
10. A method of treating type II diabetes mellitus comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
11. A method of treating obesity comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to claim 1 .
12. The method of claim 9 , wherein the compound is administered to the patient by intravenous route in an amount of 1 to 100 mg or by oral route in an amount of 1 to 1000 mg, in each case 1 to 4 times a day.
13. The method of claim 9 , wherein the compound is administered to the patient by intravenous route in an amount of 1 to 30 mg, or by oral route in an amount of 1 to 100 mg, in each case 1 to 4 times a day.