Fluoropyrrolidines having dipeptidyl peptidase enzyme inhibitory activity
The present invention relates to new, potent DPP-IV enzyme inhibitors of the general formula (I), which contain fluorine atoms.
1. A compound of formula (I)
wherein—
R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl, tetrazolyl, triazinyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group, amino group or phenyl group; or
thienyl, furyl or benzyl group; or
p-toluenesulfonyl group; or
acyl group of formula R 1a —CO, wherein R 1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
B stands for
a group of formula (6) or (7)
R 2 stands for hydrogen atom or fluorine atom;
R 3 stands for fluorine atom—
and salts, and tautomers thereof.
2. A compound of claim 1
wherein
R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
thienyl or furyl group; or
p-toluenesulfonyl group; or
acyl group of formula R 1a —CO, wherein R 1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
B stands for
a group of formula (6) or (7);
R 2 stands for hydrogen atom or fluorine atom;
R 3 stands for fluorine atom—
and salts, and tautomers thereof.
3. A compound of claim 2
wherein
R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings, preferably a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl ring; which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl groups, C1-4 alkoxy groups, halogen atom, trihalogenomethyl group, methylthio group, nitro group, cyano group; or
a thienyl or furyl group; or
a p-toluenesulfonyl group; or
an acyl group of formula R 1a —CO, wherein R 1a means C1-4 alkyl group, phenyl group; phenyl, pyridyl or phenylethenyl group substituted with one or more alkyl- and/or alkoxy- or nitro-group or halogen atom; phenylethenyl or phenylethyl group substituted with alkylene-dioxy group; piperidin-1-yl, 4-methylpiperazin-1-yl, pyrrolidin-1-yl group,
B stands for
a group of formula (6) or (7);
R 2 stands for hydrogen atom or fluorine atom;
R 3 stands for fluorine atom—
and salts, and tautomers thereof.
4. A compound of claim 2
wherein
R 1 means 2-pyrimidinyl, 2-pyrazinyl, chloro- and cyano-substituted pyridazinyl, cyano-substituted 2-pyridinyl; B stands for a group of formula (6) or (7); R 2 and R 3 stand for fluorine atom.
5. A pharmaceutical formulation comprising a compound of claim 1 or salts, and tautomers thereof.
6. A process for the preparation of a compound of formula (I) in claim 1 , wherein a compound of formula (II),
wherein the meanings of R 1 and B are defined in claim 1 , is reacted with a compound of formula (III),
wherein the meanings of R 2 and R 3 are defined in claim 1 , and a compound of formula (I) in claim 1 or its salt is isolated from the reaction mixture.
7. A method for treating diabetes comprising administering to a patient in need thereof a therapeutically effective amount of the compound of claim 1 .