Derivatives of triazines and uracils, their preparation and their application in human therapeutics

1. A compound of formula I wherein:

W represents nitrogen

R1 and R2 represent:

a hydrogen or a linear or branched C 1 -C 7 alkyl or alkenyl radical, with the proviso that R1 and R2 are not simultaneously hydrogen, or,

a C 1 -C 3 alkyl radical substituted with groups selected from:

trifluoromethyl, nitrile, hydroxy, C 1 -C 3 alkoxy, C 3 -C 6 alkoxyalkoxy, indolyl, thiophenyl, oxothiophenyl, C 1 -C 3 N-alkyl or N-dialkylcarbamoyl groups or,

phenyl or aroyl or benzyloxy or N-arylcarbamoyl groups, for which the phenyl ring is optionally substituted with one or more groups selected from linear or branched C 1 -C 4 alkyl, nitro groups, or halogen atoms,

a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups selected from halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 3 alkoxy, phenyl, C 1 -C 3 N-mono- or di-alkylcarbamoyl, or C 1 -C 4 alkylcarboxamido groups,

a C 5 -C 6 2-oxocycloalkyl radical optionally fused with a phenyl group,

m and n are equal to 1

V represents CH 2

X—Y represents —N—(C═O)—, —CH—CH 2 —, —CH—O—, —CH—(C═O)—,

Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 3 alkoxy groups.

2. The compound according to claim 1 , corresponding to the formula I wherein:

W represents nitrogen

R1 and R2 represent:

a hydrogen or a linear or branched C 1 -C 7 alkyl radical, with the proviso that R1 and R2 are not simultaneously hydrogen, or,

a C 1 -C 3 alkyl radical substituted with groups selected from trifluoromethyl, nitrile, hydroxy, C 1 -C 3 alkoxy, C 3 -C 6 alkoxyalkoxy, indolyl, oxothiophenyl, C 1 -C 3 N-alkyl or N-dialkylcarbamoyl groups,

a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups selected from halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 3 alkoxy, C 1 -C 3 N-mono- or di-alkylcarbamoyl, or C 1 -C 4 alkylcarboxamido groups,

a C 5 -C 6 2-oxocycloalkyl radical optionally fused with a phenyl group,

m and n are equal to 1

V represents CH 2

X—Y represents —N—(C═O)—, —CH—O—,

Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, or linear or branched C 1 -C 4 alkyl groups.

3. The compound according to claim 1 , corresponding to the formula I wherein:

W represents nitrogen,

R1 represents:

a hydrogen or linear or branched C 1 -C 5 alkyl radical or,

a C 1 -C 3 alkyl radical substituted with groups selected from trifluoromethyl, nitrile, hydroxy, C 1 -C 3 alkoxy, C 3 -C 6 alkoxyalkoxy, indolyl, oxothiophenyl, or C 1 -C 3 N-alkylcarbamoyl groups,

a phenyl or pyridyl or naphthyl or thiophenyl group optionally substituted with one or more groups selected from halogen atoms, nitro, nitrile, trifluoromethyl, vinyl, methylsulfanyl, linear or branched C 1 -C 4 alkyl, linear or branched C 1 -C 3 alkoxy, phenyl, C 1 -C 3 N-mono- or di-alkylcarbamoyl, or C 1 -C 4 alkylcarboxamido groups,

a C 5 -C 6 2-oxocycloalkyl radical,

R2 represents: a linear or branched C 1 -C 7 alkyl radical,

m and n are equal to 1,

V represents CH 2 ,

X—Y represents —N—(C═O)—,—CH—O—,

Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms, or linear C 1 -C 4 alkyl groups.

4. The compound according to claim 1 , corresponding to the formula I wherein:

W represents nitrogen,

R1 represents:

a hydrogen or a linear or branched C 1 -C 5 alkyl radical or,

a C 1 -C 3 alkyl radical substituted with groups selected from trifluoromethyl, nitrile, hydroxy, C 1 -C 3 alkoxy, C 3 -C 6 alkoxyalkoxy, indolyl, oxothiophenyl, or C 1 -C 3 N-alkylcarbamoyl groups,

a phenyl or pyridyl or thiophenyl group possibly substituted with one or more groups selected from halogen atoms, nitrile, linear or branched C 1 -C 4 alky, or linear or branched C 1 -C 3 alkoxygroups,

a C 6 2-oxocycloalkyl radical,

R2 represents a methyl or heptyl,

m and n are equal to 1,

V represents CH 2 ,

X—Y represents —N—(C═O)—,—CH—O—,

Z represents a phenyl group substituted with one or more trifluoromethyl groups, halogen atoms or linear C 1 -C 4 alkyl groups.

5. The compound according to claim 1 , selected from:

4-heptyl-2-methyl-6-[4-(2-trifluoromethyl-benzoyl)-piperazin- 1-yl]-2H-[1,2,4]triazine-3,5-dione,

2-methyl-6-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-(4,4,4-trifluoro-butyl)-6-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-6-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

2,4-dimethyl-6-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

2,4-dimethyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

3-{4-heptyl-3,5-dioxo-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-propionitrile,

2-butyl-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

N-methyl-2-{4-methyl-3,5-dioxo-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-acetamide,

2-(2-ethoxy-ethyl)-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin- 1-yl]-2H-[1,2,4]triazine-3,5-dione,

2-[2-(1H-Indol-3-yl)-ethyl]-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-(4-oxo-4-thiophen-2-yl-butyl)-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

3-{6-[4-(2-chloro-phenoxy)-piperidin-1-yl]-4-methyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-propionitrile,

6-[4-(2-chloro-phenoxy)-piperidin-1-yl]-4-methyl-2-(4,4,4-trifluoro-butyl)-2H-[1,2,4]triazine-3,5-dione,

6-[4-(2-chloro-phenoxy)-piperidin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(2-fluoro-phenoxy)-piperidin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(2-chloro-5-trifluoromethyl-phenoxy)-piperidin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(2-chloro-5-fluoro-phenoxy)-piperidin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

2,4-dimethyl-6-(4-o-tolyloxy-piperidin-1-yl)-2H-[1,2,4]triazine-3,5-dione,

6-[4-(4-fluoro-phenoxy)-piperidin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-2,4-dimethyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-4-methyl-2-(4,4,4-trifluoro-butyl)-2H-[1,2,4]triazine-3,5-dione,

6-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-4-methyl-2-(3-methyl-butyl)-2H-[1,2,4]triazine-3,5-dione,

6-[4-(5-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-4-methyl-2H-[1,2,4]triazine-3,5-dione,

6-[4-(4-fluoro-2-trifluoromethyl-benzoyl)-piperazin-1-yl]-4-methyl-2H-[1,2,4]triazine-3,5-dione,

2-butyl-4-methyl-6-[4-(2-trifluoromethyl-benzoyl)-piperazin- 1-yl]-2H-[1,2,4]triazine-3,5-dione,

6-[4-(2-chloro-phenoxy)-piperidin-1-yl]-4-heptyl-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-o-tolyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

2-(4-fluoro-phenyl)-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-pyridin-3-yl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-thiophen-3-yl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-{4-methyl-3,5-dioxo-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-benzonitrile,

2-(2-methoxy-phenyl)-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

4-methyl-2-(2-oxo-cyclohexyl)-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione,

2[2-(2-ethoxy-ethoxy)-ethyl]-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione, or

2-(2-hydroxy-ethyl)-4-methyl-6-[4-(2-trifluoromethyl-phenoxy)-piperidin-1-yl]-2H-[1,2,4]triazine-3,5-dione.

6. A method for preparing a compound of formula I as defined in claim 1 , wherein a compound of formula II

with W, R1 and R2 being defined in claim 1 , is fused with a compound of formula III

for which m, n, X, Y, V, and Z, are as defined in claim 1 .

7. A method for preparing a compound of formula I as defined in claim 1 , for which X represents a nitrogen, wherein a compound of formula IV

with m, V, W, R1 and R2 being defined in claim 1 , is fused with a compound of general formula V

wherein Hal represents a halogen,

n represents 0 or 1, and

when n=1, Y represents —(C═O)—, —CH 2 —, or —O—(C═O)—,

when n=0, Y represents —CH═CH—(C═O)—, or —C—(CH(CH 3 ) 2 )—(C═O)—

and Z is defined in claim 1 .

8. A method for preparing a compound of formula I as defined in claim 1 , wherein W represents a nitrogen, and wherein a compound of formula VI

with X ,Y, V, Z, m, n and R2 being defined in claim 1 , is alkylated by a halogenated compound of formula R1Hal, wherein Hal represents a halogen and R1 is defined in claim 1 .

9. A method for treating obesity or type-2 diabetes which comprises administering a compound of formula (I) as defined in claim 1 to a patient in need thereof.

10. A pharmaceutical composition comprising a compound of formula (I) as defined according to claim 1 or addition salts with pharmaceutically acceptable bases and acids, in association with any suitable excipient.

11. A method for preparing a compound according to claim 1 , wherein a compound of formula II

with W, R1 and R2 being defined in formula I, is fused with a compound of formula III

for which m, n, X, Y, V, and Z, are defined in claim 1 .

12. A method for preparing a compound according to claim 2 , wherein a compound of formula II

with W, R1 and R2 being defined in claim 2 , is fused with a compound of formula III

for which m, n, X, Y, V, and Z, are as described in claim 2 .

13. A method for preparing compound according to claim 3 , wherein a compound of formula II

with W, R1 and R2 being defined in claim 3 , is fused with a derivative of general formula III

for which m, n, X, Y, V, and Z, are defined in claim 3 .

14. A method for preparing a compound of formula I according to claim 4 , wherein a compound of formula II

with W, R1 and R2 being defined in claim 4 , is fused with a compound of formula III

for which m, n, X, Y, V, and Z, are defined in claim 4 .

15. The method of claim 3 , wherein R2 represents methyl.

16. The method of claim 6 , wherein the reaction is conducted in the presence of triethylamine in n-butanol or toluene or dimethylformamide.

17. The method of claim 7 , wherein the reaction is conducted in the presence of triethylamine in dichloromethane or in toluene when Y is —CH 2 —.

18. The method of claim 8 , wherein the reaction is conducted in the presence of NaH or tBuOK in dimethylformamide.

19. The method of claim 11 , wherein the reaction is conducted in the presence of triethylamine in n-butanol or toluene or dimethylformamide.

20. The method of claim 12 , wherein the reaction is conducted in the presence of triethylamine in n-butanol or toluene or dimethylformamide.

21. The method of claim 13 , wherein the reaction is conducted in the presence of triethylamine in n-butanol or toluene or dimethylformamide.

22. The method of claim 14 , wherein the reaction is conducted in the presence of triethylamine in n-butanol or toluene or dimethylformamide.