Fluoropyrrolidines having dipeptidyl peptidase enzyme inhibitory activity

1. A compound of Formula (I)

wherein:

R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings which is, in a given case, independently from each other mono-or disubstituted by one or two of the following groups: C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalogenomethyl, methylthio, nitro, cyano, amino or phenyl;

thienyl, furyl or benzyl;

p-toluenesulfonyl;

acyl group of formula R 1a —CO, wherein R 1a means C1-4 alkyl, phenyl ; phenyl, pyridyl or phenylethenyl substituted with one or more alkyl-and/or alkoxy-or nitro or halogen atom; phenylethenyl or phenylethyl substituted with alkylene-dioxy;

piperidin- 1-yl, 4-methylpiperazin- 1-yl, or pyrrolidin-1-yl;

B stands for a group of formula (4) or (5):

R 2 stands for hydrogen atom or fluorine atom; and

R 3 stands for fluorine atom;

and salts thereof.

2. The compound of claim 1 wherein:

R 1 means a nitrogen-containing aromatic moiety consisting of one or two aromatic rings which is, in a given case, independently from each other mono- or disubstituted by one or two of the following groups: C1-4 alkyl, C1-4 alkoxy, halogen atom, trihalogenomethyl, methylthio, nitro, cyano;

thienyl or furyl;

p-toluenesulfonyl; or

acyl group of formula R 1a —CO, wherein R 1a means C1-4 alkyl, phenyl; phenyl, pyridyl or phenylethenyl substituted with one or more alkyl- and/or alkoxy- or nitro or halogen atom; phenylethenyl or phenylethyl substituted with alkylene-dioxy;

piperidin- 1-yl, 4-methylpiperazin- 1-yl, or pyrrolidin- 1-yl,

B stands for

a group of formula (4) or (5)

R 2 stands for hydrogen atom or fluorine atom; and

R 3 stands for fluorine atom; and salts, thereof.

3. The compound of claim 2 wherein

R 1 means 2-pyrimidinyl, 2-pyrazinyl, chloro- and cyano-substituted pyridazinyl, or cyano-substituted 2-pyridinyl;

B stands for a group of formula (4) or (5)

and

R 2 and R 3 stand for fluorine atom.

4. The compound of claim 1 which is (2S)-4,4-difluoro-1-(2-{[8-(2-pyrimidinyl)-8-azabicyclo[3.2.1 ]oct-3-yl]exo-amino }acetyl)-2-pyrrolidine carbonitrile.

5. The compound of claim 1 which is (2S,4S)-4-fluoro-1-(2-{[8-(2-pyrazinyl)-8-azabicyclo- [3.2.1 ]-oct-3-yl]exo-amino }acetyl)-2-pyrrolidinecarbonitrile.

6. A pharmaceutical formulation comprising a compound of claim 1 or salts thereof.

7. A process for the preparation of the compounds of claim 1 wherein the meanings of R 1 , B, R 2 and R 3 are the same as defined in claim 1 —characterised in that, a compound of the general formula (II)

wherein the meanings of R 1 and B are as defined above—is reacted with a compound of the general formula (III)

wherein the meanings of R 2 and R 3 are as defined above—and the resulting compound is of the general formula (I)

or its salt is isolated from the reaction mixture.

8. The compound according to claim 1 , wherein R 1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl, benzisoxazolyl, tetrazolyl or triazinyl.

9. The compound according to claim 2 , wherein R 1 is pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl, benzoxazolyl or benzisoxazolyl.