Pyrrolo[3,2-D] pyrimidines as DPP-IV inhibitors for the treatment of diabetes mellitus
The present invention relates to substituted pyrrolo[3,2-d]pyrimidines of formula (I), wherein R1 and R2 are defined as in claim 1 , including the tautomers, stereoisomers, mixtures and salts thereof, which have valuable pharmacological properties, particularly an inhibitory effect on the activity of the enzyme dipeptidylpeptidase-IV (DPP-IV).
1. A compound of formula (I)
wherein:
R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl; and
R2 is hydrogen, methyl, hydroxy, methoxy, cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, (2-methoxyethyl)-aminocarbonyl, (2,2,2-trifluoroethyl)aminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, (cyclopropylmethyl)aminocarbonyl, (cyclobutylmethyl)-aminocarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl; or
a tautomer, enantiomer, diastereomer, mixture or salt thereof.
2. The compound according to claim 1 of formula (IA) or (IB)
or (IB)
or a tautomer or salt thereof.
3. A compound of formula (II)
wherein:
R1 is ([1,5]naphthyridin-2-yl)methyl, (quinazolin-2-yl)methyl, (quinoxalin-6-yl)methyl, (4-methyl-quinazolin-2-yl)methyl, 2-cyano-benzyl, (3-cyano-quinolin-2-yl)methyl, (3-cyano-pyridin-2-yl)methyl, (4-methyl-pyrimidin-2-yl)methyl, or (4,6-dimethyl-pyrimidin-2-yl)methyl;
R2 is hydrogen, methyl, hydroxy, methoxy; cyano, carboxy, methoxycarbonyl, aminocarbonyl, methylaminocarbonyl, dimethylaminocarbonyl, (2-methoxyethyl)-aminocarbonyl, (2,2,2-trifluoroethyl)aminocarbonyl, cyclopropylaminocarbonyl, cyclobutylaminocarbonyl, (cyclopropylmethyl)aminocarbonyl, (cyclobutylmethyl)-aminocarbonyl, azetidin-1-ylcarbonyl, pyrrolidin-1-ylcarbonyl, piperidin-1-ylcarbonyl or morpholin-4-ylcarbonyl; and
Ra denotes an amino group protected by a protective group.
4. The compound according to claim 1 , characterised in that the compound is a physiologically acceptable salt with an inorganic or organic acid.
5. A medicament containing a compound according to claim 1 and one or more inert carriers and/or diluents.
6. A process for preparing the compound according to claim 1 or a salt thereof, comprising deprotecting a compound of formula (II)
or a salt thereof, wherein
R1 and R2 are as defined in claim 1 ; and
Ra denotes an amino group protected by a protective group.
7. The process according to claim 6 , characterised in that the compound of formula (I) or salt thereof thus obtained is resolved into an enantiomer or diastereomer thereof.
8. The process according claim 6 , characterised in that the compound of formula (I) or salt thereof thus obtained with an inorganic or organic acid is converted into a physiologically acceptable salt thereof.
9. A process for the treatment of type II diabetes mellitus, comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 or a salt thereof.