1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives
View Patent ↗The invention relates to 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the general Formula I wherein R 1 is H, (C 1-6 )alkyl (optionally substituted with oxo, (C 1-3 )alkyloxy, (C 1-3 )alkyloxycarbonyl, halogen or CN), (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl(C 1-3 )alkyl, each cycloalkyl ring optionally comprising a heteroatom selected from O and S; R 2 and R 3 are independently H or (C 1-3 )alkyl; or R 2 and R 3 form together with the carbon atom to which they are bound a (C 3-5 )cycloalkyl group; R 4 is H or 1 to 3 F substituents; R 5 is H or 1 to 4 F substituents; R 6 and R 7 are independently H or F; X represents R 8 , OR 8 , NR 8 R 9 , R 8 is (C 5-7 )cycloalkyl optionally comprising a heteroatom selected from O, S, SO and SO 2 ; R 9 is H or (C 1-4 )alkyl; R 10 represents 1-3 substituents independently selected from H, (C 1-3 )alkyl, halogen, oxo, CN and CF 3 ; Y is CF 2 , O, S, SO or SO 2 ; or a pharmaceutically acceptable salt thereof, to pharmaceutical compositions comprising the same, as well as to the use of said 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivatives in the treatment of pain such as for example peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.
1. A 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative having the Formula I
wherein
R 1 is H, (C 1-6 )alkyl (optionally substituted with oxo, (C 1-3 )alkyloxy, (C 1-3 )-alkyloxycarbonyl, halogen or CN), (C 3-6 )cycloalkyl or (C 3-6 )cycloalkyl(C 1-3 )alkyl, each cycloalkyl ring optionally comprising a heteroatom selected from O and S;
R 2 and R 3 are independently H or (C 1-3 )alkyl; or
R 2 and R 3 form together with the carbon atom to which they are bound a (C 3-5 )cycloalkyl group;
R 4 is H or 1 to 3 F substituents;
R 5 is H or 1 to 4 F substituents;
R 6 and R 7 are independently H or F;
X represents R 8 , OR 8 , NR 8 R 9 ,
R 8 is (C 5-7 )cycloalkyl optionally comprising a heteroatom selected from O, S, SO and SO 2 ;
R 9 is H or (C 1-4 )alkyl;
R 10 represents 1-3 substituents independently selected from H, (C 1-3 )alkyl, halogen, oxo, CN and CF 3 ;
Y is CF 2 , O, S, SO or SO 2 ;
or a pharmaceutically acceptable salt thereof.
2. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 , wherein R 2 , R 3 and R 5 are H.
3. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 , wherein R 1 is (C 1-4 )alkyl.
4. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 , wherein X represents NR 8 R 9 ,
5. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 4 , wherein X is NR 8 R 9 and R 8 is cyclohexyl optionally comprising a heteroatom selected from O and S.
6. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 5 , wherein R 4 is a F substituent at the position ortho to the CR 6 R 7 X group.
7. The 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 which is selected from
3-Isobutyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-isobutyl-1-(4-(6-(morpholinomethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;
1-(4-(6-((1,1-Dioxo-1λ 6 -thiomorpholin-4-yl)methyl)pyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;
1-(4-(6-((1,1-Dioxo-1λ 6 -thiomorpholin-4-yl)methyl)-5-fluoropyridin-2-yl)benzyl)-3-isobutylimidazolidine-2,4-dione;
3-Isobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Ethyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Ethyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;
1-(4-(6-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-ethylimidazolidine-2,4-dione;
1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-propylimidazolidine-2,4-dione;
3-(2,2-Difluoroethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-(2,2-Difluoroethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-(Cyclopropylmethyl)-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-(Cyclopropylmethyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-(2-Oxopropyl)-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
1-(4-(5-Fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-(2-oxopropyl)imidazolidine-2,4-dione;
3-Isopropyl-1-(4-(6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)-3-isopropylimidazolidine-2,4-dione;
3-Cyclopropyl-1-(4-(5-fluoro-6-(piperidin-1-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Cyclopropyl-1-(4-(6-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoro-pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Cyclobutyl-1-(4-(5-fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Cyclobutyl-1-(4-(6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl)imidazolidine-2,4-dione;
3-Cyclobutyl-1-(4-(6-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)pyridin-2-yl)benzyl)imidazolidine-2,4-dione;
1-(4-(6-(Piperidin-1-ylmethyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;
1-(4-(6-(1,1-Dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-5-fluoropyridin-2-yl)benzyl-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;
1-(4-(6-((Tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione; and
1-(4-(5-Fluoro-6-((tetrahydro-2H-pyran-4-ylamino)methyl)pyridin-2-yl)benzyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione; or a pharmaceutically acceptable salt thereof.
8. A pharmaceutical composition comprising a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxilliaries.
9. A pharmaceutical composition comprising a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 7 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxilliaries.
10. A method of treatment of pain comprising administering to a patient in need thereof a therapeutically effective amount of a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 1 or a pharmaceutically acceptable salt thereof.
11. The method of claim 10 wherein the pain is selected from the group consisting of peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.
12. A method of treatment of pain comprising administering to a patient in need thereof a therapeutically effective amount of a 1-(4-(pyridin-2-yl)benzyl)imidazolidine-2,4-dione derivative of claim 7 or a pharmaceutically acceptable salt thereof.
13. The method of claim 12 wherein the pain is selected from the group consisting of peri-operative pain, chronic pain, neuropathic pain, cancer pain and pain and spasticity associated with multiple sclerosis.