2-OXO-1-pyrrolidinyl imidazothiadiazole derivatives
View Patent ↗The present invention relates to 2-oxo-1-pyrrolidinyl imidazothiadiazole derivatives, processes for preparing them, pharmaceutical compositions containing them and their use as pharmaceuticals.
1. A compound having formula (I), or a geometrical isomer, enantiomer, diastereomer, isotope or mixture thereof, or a pharmaceutically acceptable salt thereof,
wherein
R 1 is a C 1-4 alkyl optionally substituted by one or more halogen substituents;
R 2 is a C 1-4 alkyl containing at least one hydroxy or alkoxy substituent; and
R 3 is a methyl (including —CD 3 ).
2. A compound according to claim 1 , wherein R 1 is i-butyl, a n-propyl, 2,2-difluoropropyl, 2-chloro-2,2-difluoroethyl, 2,2-difluoroethyl, 2,2,2-trifluoroethyl, or 2-fluoroethyl.
3. A compound according to claim 1 , wherein R 1 is n-propyl, 2-chloro-2,2-difluoroethyl, 2,2-difluoropropyl or 2,2,2-trifluoroethyl.
4. A compound according to claim 1 , wherein R 2 is hydroxymethyl, methoxymethyl, CD 3 O—CH 2 -, CH 3 O-CD 2 - or CD 3 O-CD 2 -.
5. A compound according to claim 1 , wherein R 2 is methoxymethyl, CD 3 O—CH 2 -, CH 3 O-CD 2 - or CD 3 O-CD 2 -.
6. A compound according to claim 1 , wherein
R 1 is a n-propyl, 2-chloro-2,2-difluoroethyl, a 2,2-difluoropropyl or a 2,2,2-trifluoroethyl moiety;
R 2 is a hydroxymethyl, methoxymethyl, CD 3 O—CH 2 -, CH 3 O-CD 2 - or CD 3 O-CD 2 -; and
R 3 is —CH 3 or —CD 3 .
7. A compound according to claim 6 , wherein
R 1 is n-propyl, 2-chloro-2,2-difluoroethyl, 2,2-difluoropropyl or 2,2,2-trifluoroethyl;
R 2 is methoxymethyl, CD 3 O—CH 2 -, CH 3 O-CD 2 - or CD 3 O-CD 2 -; and
R 3 is CH 3 or CD 3 .
8. A compound according to claim 1 which is selected from the group consisting of:
(4R)-4-(2-chloro-2,2-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]pyrrolidin-2-one;
(4S)-4-(2-chloro-2,2-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]pyrrolidin-2-one;
(4S)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-4-propyl-pyrrolidin-2-one;
(4R)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-4-propyl-pyrrolidin-2-one;
(4R)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]-4-(2,2,2-trifluoroethyl)pyrrolidin-2-one;
(4S)-1-[[2-(methoxymethyl)-6-methyl-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-difluoro-ethyl)-1-[[2-(methoxymethyl)-6-(trideuteriomethyl) imidazo[2,1-b][1,3,4]thiadiazol-5-yl]methyl]pyrrolidin-2-one;
(4R)-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methyl]pyrrolidin-2-one; and
(4S)-(2,2-difluoropropyl)-1-[[2-(methoxymethyl)-6-methyl-imidazo[2,1-b][1,3,4]-thiadiazol-5-yl]methyl]pyrrolidin-2-one.
9. A pharmaceutical composition comprising an effective amount of a compound according to claim 1 in combination with a pharmaceutically acceptable diluent or carrier.
10. A method of treating epilepsy, epileptogenesis, seizure disorders, or convulsions comprising administering to a subject in need thereof a compound according to claim 1 .
11. A method of treating refractory seizures comprising administering to a subject in need thereof a compound according to claim 1 .