The present invention relates to new, potent DPP-IV enzyme inhibitors of the general formula (I), which contain fluorine atoms.
1. A compound having the formula:
wherein
R 1 represents a nitrogen-containing aromatic moiety consisting of one or two aromatic rings; which is optionally mono- or disubstituted by a substituent independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, trihalogenomethyl, methylthio, nitro, cyano, amino, and phenyl group;
B represents a group having the formula
R 2 represents a hydrogen atom or a fluorine atom;
R 3 represents a fluorine atom;
or a salt, isomer, tautomer, solvate, or hydrate thereof with the proviso that R1 cannot be benzoxazolyl.
2. A compound according to claim 1 wherein said nitrogen-containing aromatic moiety consisting of one or two aromatic rings is selected from the group consisting of a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl or benzisoxazolyl, tetrazolyl, and a triazinyl ring.
3. A compound according to claim 1 wherein R 1 represents a nitrogen-containing aromatic moiety consisting of one or two aromatic rings; which is optionally mono- or disubstituted by a substituent independently selected from the group consisting of C1-4 alkyl, C1-4 alkoxy, halogen, trihalogenomethyl, methylthio, nitro, and cyano.
4. A compound according to claim 3 wherein B represents a group having the formula
5. A compound according to claim 3 wherein B represents a group having the formula
6. A compound according to claim 3 wherein said nitrogen-containing aromatic moiety consisting of one or two aromatic rings is selected from a pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, imidazolyl, pirazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, benzimidazolyl, indazolyl, benzothiazolyl, benzisothiazolyl or benzisoxazolyl ring.
7. A compound according to claim 6 wherein B represents a group having the formula
8. A compound according to claim 6 wherein B represents a group having the formula
9. A compound according to claim 4 wherein R 1 represents 2-pyrimidinyl, 2-pyrazinyl, chloro- and cyano-substituted pyridazinyl, or cyano-substituted 2-pyridinyl; and R 2 represents a fluorine atom.
10. A compound according to claim 5 wherein R 1 represents 2-pyrimidinyl, 2-pyrazinyl, chloro- and cyano-substituted pyridazinyl, or cyano-substituted 2-pyridinyl; and R 2 represents a fluorine atom.
11. A compound according to claim 1 selected from the group consisting of
(2S)-4,4-Difluoro-1-(2-{[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile,
(2S)-4,4-Difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile,
(2S)-4,4-Difluoro-1-(2-{[1-(6-chloropyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile, and
(2S)-4,4-Difluoro-1-(2-{[1-(6-cyanopyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile.
12. A pharmaceutical formulation comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.
13. A pharmaceutical formulation comprising a compound according to claim 3 and a pharmaceutically acceptable excipient.
14. A pharmaceutical formulation comprising a compound according to claim 6 and a pharmaceutically acceptable excipient.
15. A pharmaceutical formulation comprising a compound according to claim 7 and a pharmaceutically acceptable excipient.
16. A pharmaceutical formulation comprising a compound according to claim 8 and a pharmaceutically acceptable excipient.
17. A pharmaceutical formulation according to claim 12 wherein the compound is selected from the group consisting of
(2S)-4,4-difluoro-1-(2-{[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile;
(2S)-4,4-difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile;
(2S)-4,4-difluoro-1-(2-{[1-(6-chloropyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile; and
(2S)-4,4-difluoro-1-(2-{[1-(6-cyanopyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile.
18. A process for the preparation of a compound according to claim 1 , wherein a compound having the formula (II):
R 1 —B—NH 2 (II)
is reacted with a compound of the formula (III):
wherein R 1 , B, R 2 and R 3 are as defined in claim 1 .
19. A method for the treatment of type II diabetes comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 1 .
20. A method for the treatment of type II diabetes comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 3 .
21. A method for the treatment of type II diabetes comprising administering to a patient in need of such treatment an effective amount of a compound according to claim 6 .
22. A method according to claim 19 , wherein the compound is selected from the group consisting of:
(2S)-4,4-difluoro-1-(2-{[1-(2-pyrazinyl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile;
(2S)-4,4-difluoro-1-(2-{[1-(5-cyanopyridin-2-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile;
(2S)-4,4-difluoro-1-(2-{[1-(6-chloropyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile; and
(2S)-4,4-difluoro-1-(2-{[1-(6-cyanopyridazin-3-yl)piperidin-4-yl]amino}acetyl)-2-pyrrolidine carbonitrile.