Imidazolidine-2,4-dione derivatives, and use thereof as a cancer drug

1. A compound formula (I)

in racemic or enantiomeric form or any combination thereof, wherein

R 1 and R 2 represent independently a halogen atom, or an alkyl, haloalkyl, alkoxy, cyano, nitro, amino, alkylamino, dialkylamino, —NR 8 —CO—R 5 , —NR 8 —SO 2 —R 5 , —NR 8 —CO—(CH 2 ) n —NR 6 , R 7 , —NR 8 —SO 2 —(CH 2 ) n —NR 6 R 7 , or —CO—NH 2 radical;

n represents an integer chosen from 0, 1, 2, 3, 4, 5, or 6;

R 5 represents an alkyl, aryl, or heteroaryl radical;

R 6 and R 7 represent independently a hydrogen atom, an alkyl, or an alkyloxycarbonyl radical;

R 8 represents a hydrogen atom or an alkyl radical;

R 3 represents an alkyl radical or a hydrogen atom; or the two R 3 radicals form together with the carbon atom to which they are attached a cycloalkyl radical comprising 3 to 6 members;

R 4 represents a haloalkyl radical with 2 to 10 carbon atoms;

Y represents a linear or branched alkylene chain with 2 to 14 carbon atoms, wherein the chain is saturated or unsaturated, and optionally comprising one or more additional —O-members;

X represents —S—, —SO—, —SO 2 —, —S═N(R 9 )— or —S(O)═N(R 9 )—;

R 9 represents a hydrogen atom or a haloalkylcarbonyl radical,

or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1 , wherein R 1 represents a halogen atom, or an alkyl, alkoxy, cyano, nitro, amino, alkylamino, dialkylamino, —NR 8 —CO—R 5 , —NR 8 —SO 2 —R 5 , —NR 8 —CO—(CH 2 ) n —NR 6 R 7 , —NR 8 —SO 2 —(CH 2 ) n —NR 6 R 7 , or —CO—NH 2 radical; R 2 represents a halogen atom, an alkyl, or haloalkyl radical.

3. The compound according to claim 1 , wherein R 5 represents an alkyl radical.

4. The compound according to claim 1 , wherein R 3 represents an alkyl radical.

5. The compound according to claim 1 , wherein R 4 represents a haloalkyl radical comprising 4 to 6 carbon atoms and 3 to 9 fluorine atoms; and Y represents an alkylene chain with 5 to 10 carbon atoms.

6. The compound according to claim 1 , wherein R 1 is in para position.

7. The compound according to one of claim 1 , wherein R 2 is in meta position.

8. The compound according to one of claim 1 , wherein:

R 1 represents a cyano, nitro, amino, —NR 8 —CO—R 5 , —NR 8 —SO 2 —R 5 , —NR 8 —CO—(CH 2 ) n —NR 6 R 7 , —NR 8 —SO 2 —(CH 2 ) n —NR 6 R 7 , or —CO—NH 2 radical;

R 2 represents an alkyl or haloalkyl radical;

R 5 represents an alkyl radical;

R 6 and R 7 represent independently a hydrogen atom, an alkyl, or alkyloxycarbonyl radical;

R 3 represents an alkyl radical or the two R 3 radicals form together with the carbon atom to which they are attached a cycloalkyl radical comprising 3 to 6 members;

R 4 represents a haloalkyl radical comprising 4 to 6 carbon atoms and 3 to 9 fluorine atoms;

n is equal to 0 or 1;

R 9 represents a hydrogen atom or —COCF 3 ;

or a pharmaceutically acceptable salt thereof.

9. The compound according to claim 1 , wherein R 1 represents a cyano, nitro, —NR 8 —CO—R 5 , —NR 8 —SO 2 —R 5 , —NR 8 —CO—(CH 2 ) n NR 6 R 7 , —NR 8 —SO 2 —(CH 2 ) n —NR 6 R 7 , or —CO—NH 2 radical; n is equal to 0 or 1; R 5 represents an alkyl radical, R 6 and R 7 represent independently a hydrogen atom or an alkyl radical, and R 2 represents an alkyl or haloalkyl radical.

10. The compound according to claim 1 , wherein R 1 represents a nitro or —NR 8 —CO—R 5 radical and wherein R 5 represents an alkyl radical.

11. The compound according to claim 1 , wherein the alkyl radical represents a methyl group and/or the haloalkyl radical represents a trifluoromethyl group, or a radical of molecular formula C 5 H 6 F 5 , C 5 H 4 F 7 , C 6 H 8 F 5 , C 6 H 6 F 7 or C 6 H 4 F 9 .

12. The compound according to claim 1 , wherein Y represents an alkylene chain with 9 to 10 carbon atoms.

13. The compound according to claim 1 , wherein the compound is selected from

5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-1-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]nonyl}imidazolidine-2,4-dione;

5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-1-{10-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]decyl}imidazolidine-2,4-dione;

5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-1-{9-[(4,4,4-trifluorobutyl)thio]nonyl}imidazolidine-2,4-dione;

5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]-1-{9-[(4,4,4-trifluorobutyl)sulphinyl]nonyl}imidazolidine-2,4-dione;

N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]-nonyl}imidazolidin-1-yl)-2-(trifluoromethyl)phenyl]acetamide;

N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]nonyl}imidazolidin-1-yl)-2-(trifluoromethyl)phenyl]-N2,N2-dimethylglycinamide; or

N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]nonyl}imidazolidin-1-yl)-2-(trifluoromethyl)phenyl]-N2,N2-dimethylglycinamide hydrochloride;

or a pharmaceutically acceptable salt thereof.

14. The compound according to claim 1 , wherein the compound is N-[4-(4,4-dimethyl-2,5-dioxo-3-{9-[(4,4,5,5,5-pentafluoropentyl)sulphinyl]-nonyl}imidazolidin-1-yl)-2-(trifluoromethyl)phenyl]acetamide or a pharmaceutically acceptable salt thereof.

15. A method of preparing the compound according to claim 1 , comprising

condensing hydantoin derivatives of general formula (II)

in the presence of a strong base, at a temperature range between 25° C. and 60° C., in an anhydrous polar solvent, on mesylate derivatives of general formula (III),

or treating thiobenzoyl derivatives of general formula (V),

with an alcoholate in a polar protic solvent, followed by adding a halogenated derivative of general formula (IV) to the thiobenzoyl derivative,

in solution in a polar solvent solution.

16. A method of preparing a compound of formula I.2

comprising

oxidizing the compounds of formula of claim 1 to obtain a sulphoxide of formula (I.2).

17. A method of preparing a compound of formula (I.3)

comprising oxidizing the compound of formula (I.2) of claim

to obtain a sulphone of formula (I.3).

18. An intermediate compound selected from:

1-(5-iodopentyl)-5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione;

1-(8-iodooctyl)-5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione;

1-(9-bromononyl)-5,5-dimethyl-3-[4-nitro-3-(trifluoromethyl)phenyl]imidazolidine-2,4-dione;

4-[3-(9-bromononyl)-4,4-dimethyl-2,5-dioxoimidazolidin-1-yl]-2-(trifluoromethyl)benzonitrile;

5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidine-2,4-dione; or

1-(9-bromononyl)-5,5-dimethyl-3-(3-methyl-4-nitrophenyl)imidazolidine-2,4-dione.

19. A pharmaceutical composition comprising, as an active ingredient, the compound according to claim 1 , and at least one pharmaceutically acceptable excipient.

20. A method of treating breast or prostate cancer comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to claim 1 .

21. The method according to claim 20 , wherein the cancer is prostate cancer.