2-oxo-1-pyrrolidinyl imidazothiadiazole derivatives

1. A 2-oxo-1-pyrrolidinyl imidazothiadiazole derivative in the form of formula I or the form of an enantiomer, diastereomer or mixture, or pharmaceutically acceptable salt thereof,

wherein

R 1 is a C 1-4 alkyl containing at least one halogen substituent;

R 2 is either a halogen or a C 1-4 alkyl containing at least one halogen substituent;

R 3 is a C 1-4 alkyl containing at least one hydroxy or alkoxy substituent.

2. The compound according to claim 1 , wherein R 1 is a 2,2-difluoropropyl, a 2-chloro-2,2-difluoroethyl, a 2,2-difluoroethyl, a 2,2,2-trifluoroethyl, a 3,3,3-trifluoropropyl or a 2-fluoroethyl moiety.

3. The compound according to claim 1 , wherein R 2 is either a chloro, a difluoromethyl or a trifluoromethyl moiety.

4. The compound according to claim 1 , wherein R 3 is either a hydroxymethyl, a methoxymethyl, a [( 2 H 3 )methyloxy]methyl, a methoxy( 2 H 2 ) methyl, a (2,2,2-trifluoroethoxy)methyl or a 2-methoxyethyl moiety.

5. The compound according to claim 1 , wherein

R 1 is a 2,2-difluoropropyl, a 2-chloro-2,2-difluoroethyl, a 2,2,2-trifluoroethyl or a 3,3,3-trifluoropropyl moiety;

R 2 is a chloro, a difluoromethyl or a trifluoromethyl moiety; and

R 3 is a methoxymethyl moiety.

6. The compound according to claim 1 selected from the group consisting of:

4-(2,2-difluoropropyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(+)-4-(2,2-difluoropropyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(−)-4-(2,2-difluoropropyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one trifluoroacetate;

(4S)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(4S)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

(4R)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

(4S)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

(4S)- 1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

(4R)- 1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5 -yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

(4S)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

4-(2,2-difluoroethyl)-1- {[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(+)-4-(2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one, isomer A;

(−)-4-(2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one, isomer B;

4-(2-chloro-2,2-difluoroethyl)-1-{[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(−)-4-(2-chloro-2,2-difluoroethyl)-1-{[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(+)-4-(2-chloro-2,2-difluoroethyl)-1-{[6-(difluoromethyl)-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

4-(2-chloro-2,2-difluoroethyl)-1-({6-chloro-2-[(2,2,2-trifluoroethoxy)methyl]imidazo[2,1-b][1,3,4]thiadiazol-5-yl}methyl)pyrrolidin-2-one;

1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

(−)-1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

(+)-1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one;

1-{[6-chloro-2-(methoxymethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2-fluoroethyl)pyrrolidin-2-one;

(4R)-1-{[2-(hydroxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;

(4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-{[( 2 H 3 )methyloxy]methyl}-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

(4R)-4-(2-chloro-2,2-difluoroethyl)-1-({2-[methoxy( 2 H 2 )methyl]-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl}methyl)pyrrolidin-2-one;

(4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl) -imidazo[2,1-b][1,3,4]thiadiazol-5-yl](2H2)methyl}pyrrolidin-2-one

4-(2-chloro-2,2-difluoroethyl)- 1-{[2-(2-methoxyethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one;

1-{[2-(2-methoxyethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one; and

1-{[2-(2-methoxyethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}-4-(3,3,3-trifluoropropyl)pyrrolidin-2-one.

7. A pharmaceutical composition comprising a compound according to claim 1 in combination with a pharmaceutically acceptable diluent or carrier.

8. The compound according to claim 2 , wherein R 2 is a chloro, a difluoromethyl or a trifluoromethyl moiety.

9. The compound according to claim 2 , wherein R 3 is a hydroxymethyl, a methoxymethyl, a [( 2 H 3 )methyloxy]methyl, a methoxy( 2 H 2 ) methyl, a (2,2,2-trifluoroethoxy)methyl or a 2-methoxyethyl moiety.

10. The compound according to claim 8 , wherein R 3 is a hydroxymethyl, a methoxymethyl, a [( 2 H 3 )methyloxy]methyl, a methoxy( 2 H 2 ) methyl, a (2,2,2-trifluoroethoxy)methyl or a 2-methoxyethyl moiety.

11. A pharmaceutical composition comprising a compound according to claim 2 in combination with a pharmaceutically acceptable diluent or carrier.

12. A pharmaceutical composition comprising a compound according to claim 3 in combination with a pharmaceutically acceptable diluent or carrier.

13. A pharmaceutical composition comprising a compound according to claim 5 in combination with a pharmaceutically acceptable diluent or carrier.

14. A pharmaceutical composition comprising a compound according to claim 6 in combination with a pharmaceutically acceptable diluent or carrier.

15. A method of treating a patient with refractory epilepsy, the method comprising administering to the patient an effective amount of a compound according to claim 1 , optionally together with a pharmaceutically acceptable diluent or carrier.

16. A method of treating a patient with refractory epilepsy, the method comprising administering to the patient an effective amount of a compound according to claim 2 , optionally together with a pharmaceutically acceptable diluent or carrier.

17. A method of treating a patient with refractory epilepsy, the method comprising administering to the patient an effective amount of a compound according to claim 3 , optionally together with a pharmaceutically acceptable diluent or carrier.

18. A method of treating a patient with refractory epilepsy, the method comprising administering to the patient an effective amount of a compound according to claim 5 , optionally together with a pharmaceutically acceptable diluent or carrier.

19. A method of treating a patient with refractory epilepsy, the method comprising administering to the patient an effective amount of a compound according to claim 6 , optionally together with a pharmaceutically acceptable diluent or carrier.

20. The compound according to claim 1 which is (4R)-4-(2-chloro-2,2-difluoroethyl)-1-{[2-(methoxymethyl)-6-(trifluoromethyl)imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl}pyrrolidin-2-one.