1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione

1. A 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative the general Formula I represented by

wherein

R 1 is 1) H, 2) (C 1-6 )alkyl wherein the alkyl is optionally substituted with oxo, OR 4 , COOR 5 , halogen or CN, 3) (C 2-6 )alkenyl, 4) (C 2-6 )alkynyl, 5) (C 3-6 )cycloalkyl or 6) (C 3-6 )cycloalkyl(C 1-3 )alkyl;

R 2 and R 2 ′ are independently H or (C 1-3 )alkyl; or

R 2 and R 2 ′ form together with the carbon atom to which they are bound a (C 3-5 )-cycloalkyl group;

R 3 represents H or 1 to 4 F substituents;

Y represents

 or NR 8 R 9 ;

X represents CHR 6 , CF 2 , O, S, SO or SO 2 ;

R 4 and R 5 are (C 1-6 )alkyl;

R 6 is H, OR 7 or CN;

R 7 is (C 1-3 )alkyl;

R 8 is (C 5-7 )cycloalkyl comprising a heteroatom selected from O, S, SO and SO 2 ;

R 9 is H or (C 1-4 )alkyl;

o and m represent the ortho or meta position of the substituent Y—CH 2 ;

or a pharmaceutically acceptable salt thereof.

2. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 1 , wherein R 3 represent a para-fluoro substituent.

3. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 1 , wherein Y—CH 2 is a meta substituent and wherein Y represents NR 8 R 9 and R 8 is tetrahydropyran-4-yl or tetrahydrofuran-3-yl.

4. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 1 , wherein Y represents

and wherein

R 1 is 1) H, 2) (C 1-6 )alkyl wherein the alkyl is optionally substituted with oxo, OR 4 , COOR 5 , halogen or CN, 3) (C 2-6 )alkenyl, 4) (C 2-6 )alkynyl, 5) (C 3-6 )cycloalkyl or 6) (C 3-6 )cycloalkyl(C 1-3 )alkyl;

R 2 and R 2 ′ are independently H or (C 1-3 )alkyl; or

R 2 and R 2 ′ form together with the carbon atom to which they are bound a (C 3-5 )-cycloalkyl group;

R 3 represents H or 1 to 4 F substituents;

X represents CHR 6 , CF 2 , O, S, SO or SO 2 ;

R 4 and R 5 are (C 1-6 )alkyl;

R 6 is H, OR 7 or CN;

R 7 is (C 1-3 )alkyl;

o and m represent the ortho or meta position of the aminomethylene substituent;

or a pharmaceutically acceptable salt thereof.

5. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 4 , wherein X is CH 2 , CF 2 or O.

6. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 5 , wherein R 1 is 1) (C 1-6 )alkyl wherein the alkyl is optionally substituted with F, 2) (C 3-6 )cycloalkyl or 3) (C 3-6 )cycloalkyl-(C 1-3 )alkyl and R 2 and R 2 ′ are H.

7. The 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 1 which is selected from

1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-propyl-imidazolidine-2,4-dione;

3-isobutyl-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-butyl-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclobutylmethyl-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-allyl-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-prop-2-ynyl-imidazolidine-2,4-dione;

3-(2,2-difluoro-ethyl)-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-(2-fluoro-ethyl)-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-(2-methoxy-ethyl)-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-((2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-2,5-dioxo-imidazolidin-1-yl)-acetic acid methyl ester;

1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-(2-oxo-butyl)imidazolidine-2,4-dione;

3-cyclopropylmethyl-1-(2′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

1-(3′-(4,4-difluoro-piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-allyl-1-(3′-(4,4-difluoro-piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclobutylmethyl-1-(3′-(4,4-difluoro-piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclopropyl-1-(4′-fluoro-3′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

1-(4′-(3-cyclopropylmethyl-2,4-dioxo-imidazolidin-1-ylmethyl)biphenyl-2-yl-methyl)-piperidine-4-carbonitrile;

3-cyclopropylmethyl-1-(2′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclopropyl-1-(3′-(thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclopropyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-isobutyl-1-(3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

1-(4′-fluoro-3′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

1-(2′-fluoro-5′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

1-(2′-fluoro-3′-(morpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

3-cyclobutylmethyl-1-(3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-(2,2-difluoro-ethyl)-1-(3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)-imidazolidine-2,4-dione;

1-(4′-fluoro-3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

3-(2,2-difluoro-ethyl)-1-(2′-fluoro-3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)-imidazolidine-2,4-dione;

1-(2′-fluoro-3′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

1-(3′-fluoro-5′-(piperidin-1-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-4′-fluoro-biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

3-cyclopropylmethyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclopropylmethyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-4′-fluoro-biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)-3-isobutyl-imidazolidine-2,4-dione;

3-cyclobutyl-1-((4′-fluoro-3′-(thiomorpholinomethyl)biphenyl-4-yl)methyl)imidazolidine-2,4-dione;

3-cyclobutyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclobutyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)-4′-fluoro-biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

3-cyclopropyl-1-(3′-(1,1-dioxo-1λ 6 -thiomorpholin-4-ylmethyl)biphenyl-4-ylmethyl)imidazolidine-2,4-dione;

(S)-3-(cyclopropylmethyl)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)-biphenyl-4-yl)methyl)imidazolidine-2,4-dione;

(R)-3-(cyclopropylmethyl)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)biphenyl-4-yl)methyl)imidazolidine-2,4-dione;

3-(cyclopropylmethyl)-1-((4′-fluoro-3′-((tetrahydro-2H-pyran-4-ylamino)methyl)biphenyl-4-yl)methyl)imidazolidine-2,4-dione;

1-((3′-((tetrahydro-2H-pyran-4-ylamino)methyl)biphenyl-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;

(R)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)biphenyl-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;

(S)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)biphenyl-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione;

(R)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)biphenyl-4-yl)methyl)-3-isopropylimidazolidine-2,4-dione;

1-((4′-fluoro-3′-((tetrahydro-2H-pyran-4-ylamino)methyl)biphenyl-4-yl)methyl)-3-isopropylimidazolidine-2,4-dione;

(S)-1-((4′-fluoro-3′-((tetrahydrofuran-3-ylamino)methyl)biphenyl-4-yl)methyl)-3-isopropylimidazolidine-2,4-dione; and

1-((4′-fluoro-3′-((tetrahydro-2H-pyran-4-ylamino)methyl)biphenyl-4-yl)methyl)-3-(2,2,2-trifluoroethyl)imidazolidine-2,4-dione or a pharmaceutically acceptable salt thereof.

8. A pharmaceutical composition comprising a 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 1 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.

9. A pharmaceutical composition comprising a 1-(biphenyl-4-ylmethyl)imidazolidine-2,4-dione derivative of claim 7 or a pharmaceutically acceptable salt thereof in admixture with one or more pharmaceutically acceptable auxiliaries.

10. A method of treatment of pain comprising administering to a patient in need thereof a therapeutically effective amount of a 1-(biphenyl-4-ylmethyl)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, 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-(biphenyl-4-ylmethyl)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, and pain and spasticity associated with multiple sclerosis.