1,2,4-triazine derivatives, preparation and use thereof in human therapy
The invention relates to 3,5-dioxo-(2H,4H)-1,2,4-triazine compounds of formula I in which the variables are defined herein, as well as additive salts with pharmaceutically acceptable bases and the various enantiomers of compounds having asymmetrical carbons, as well as their mixtures in all proportions, including racemic mixtures in particular.
1. 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents an oxygen atom or a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5 when Z=C or from 2 to 4 when Z=O,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
or additive salt with pharmaceutically acceptable base thereof.
2. 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I according to claim 1 in which:
R 1 and R 2 represent, independently one from the other, an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 6 , nitrile, or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl,
Z represents an oxygen atom or a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5 when Z=C or from 2 to 4 when Z=O,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
or additive salt with pharmaceutically acceptable base thereof.
3. 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I according to one of the claims 1 and 2 in which:
R 1 and R 2 represent independently one from the other, an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or nitrile,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen or a linear or branched alkyl radical at C 1 -C 7 ,
Z represents a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I,
n can range from 0 to 5,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represents hydrogen or a linear or branched alkyl group at C 1 -C 5 ,
or additive salt with pharmaceutically acceptable base thereof.
4. 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I according to one of the claims 1 and 3 in which:
R 1 and R 2 represent independently one from the other, an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , optionally substituted at the end of the chain by a trifluoromethyl group,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen or a linear or branched alkyl radical at C 1 -C 7 ,
Z represents a methylene group which can be bound in meta or para position on the phenyl group of formula I,
n can range from 1 to 5,
X represents oxygen or sulfur,
R 4 to R 8 represent hydrogen,
R 9 and R 10 represent a methyl radical represents hydrogen or an ethyl radical,
or additive salt with pharmaceutically acceptable base thereof.
5. Compounds of formula I according to claim 1 wherein they are selected among:
1. Ethyl 2-{2-[2-(4-butyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-ethyl]-phenoxy}-2-methyl-propionate
2. Ethyl 2-{3-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-ethyl]-phenoxy}-2-methyl-propionate
3. Ethyl 2-methyl-2-(3-{2-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}phenoxy)-propionate
4. Ethyl 2-methyl-2-(3-{3-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}-phenoxy)-propionate
5. Ethyl 2-{3-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propyl]-phenoxy}-2-methyl-propionate
6. Ethyl 2-methyl-2-(3-{3-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}-phenoxy)-propionate
7. Ethyl 2-{3-[3-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propyl]-phenoxy}-2-methyl-propionate
8. Ethyl 2-(3-{3-[4 heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-propyl}-phenoxy)-2-methyl-propionate
9. Ethyl 2-methyl-2-(3-{5-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-pentyl}-phenoxy)-propionate
10. Ethyl 2-{3-[5-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionate
11. Ethyl 2-{3-[5-(4-butyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionate
12. 2-{3-[5-(4-Butyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionic acid
13. Ethyl 2-{3-[5-(2,4-dibutyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionate
14. Ethyl 2-(3-{5-[4-butyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-pentyl}-phenoxy)-2-methyl-propionate
15. Ethyl 2-{3-[5-(4-butyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionate
16. Ethyl 2-methyl-2-(3-{5-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-pentyl}-phenoxy)-propionate
17. Ethyl 2-{3-[5-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl propionate
18. Ethyl 2-(3-{5-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-pentyl}-phenoxy)-2-methyl-propionate
19. Ethyl 2-{3-[5-(2-benzyl-4-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-pentyl]-phenoxy}-2-methyl-propionate
20. Ethyl 2-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxymethyl)-phenoxy]-2-methyl-propionate
21. Ethyl 2-methyl-2-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxymethyl]-phenoxy}-propionate
22. Ethyl 2-[4-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxymethyl)-phenoxy]-2-methyl-propionate
23. Ethyl 2-{4-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxymethyl]-phenoxy}-2-methyl-propionate
24. Ethyl 2-methyl-2-(4-{2-[4-methyl-3,5-dioxo-2-(4,4,4-trifluorobutyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}-phenoxy)-propionate
25. Ethyl 2-{4-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-ethyl]-phenoxy}-2-methyl-propionate
26. Ethyl 2-{4-[2-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-ethyl]-phenoxy}-2-methyl-propionate
27. Ethyl 2-{4-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propyl]-phenoxy}-2-methyl-propionate
28. Ethyl 2-methyl-2-(4-{4-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}-phenoxy)-propionate
29. Ethyl 2-{4-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-ethyl]-phenoxy}-2-methyl-propionate
30. Ethyl 2-methyl-2-(4-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-ethyl}-phenoxy)-propionate
31. Ethyl 2-(4-{4-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-butyl}-phenoxy)-2-methyl-propionate
32. Ethyl 2-{3-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propyl]-phenylsulfanyl}-2-methyl-propionate
33. Ethyl 2-{3-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propoxy]-phenoxy}-2-methyl-propionate
34. Ethyl 2-{3-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-propoxy]-phenylsulfanyl}-2-methyl-propionate
35. Ethyl 2-(3-{3-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-propoxy}-phenoxy)-2-methyl-propionate
36. Ethyl 2-{3-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-butoxy]-phenoxy}-2-methyl-propionate
37. Ethyl 2-{3-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy)-butoxy]-phenylsulfanyl}-2-methyl-propionate
38. Ethyl 2-{4-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-G-yloxy)-ethoxy]-phenylsulfanyl}-2-methyl-propionate
39. Ethyl 2-(4-{3-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yloxy]-propoxy}-phenoxy)-2-methyl-propionate
40. Ethyl 2-{4-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethoxy]-phenoxy}-2-methyl-propionate
41. Ethyl 2-(4-{2-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethoxy}-phenoxy)-2-methyl-propionate
42. Ethyl 2-{4-[2-(2,4-diheptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethoxy]-phenoxy}-2-methyl-propionate
43. Ethyl 2-(4-{2-[2,4-bis-(3-cyclohexyl-propyl)-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethoxy}-phenoxy)-2-methyl-propionate
44. Ethyl 2-methyl-2-(4-{3-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propoxy}-phenoxy)-propionate
45. Ethyl 2-{4-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propoxy]-phenoxy}-2-methyl-propionate
46. Ethyl 2-methyl-2-(4-{3-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propoxy}-phenoxy)-propionate
47. Ethyl 2-{4-[3-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propoxy]-phenoxy}-2-methyl-propionate
48. Ethyl 2-(4-{3-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propoxy}-phenoxy)-2-methyl-propionate
49. Ethyl 2-{4-[3-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propoxy]-phenylsulfanyl}-2-methyl-propionate
50. Ethyl 2-{4-[4-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butoxy]-phenoxy}-2-methyl-propionate
51. Ethyl 2-(3-{3-[(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-(4,4,4-trifluoro-butyl)-amino]-propoxy}-phenoxy)-2-methyl-propionate
52. Ethyl 2-(3-{3-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-heptyl-amino]-propoxy}-phenylsulfanyl)-2-methyl-propionate
53. Ethyl 2-(4-{3-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-heptyl-amino]-propoxy}-phenylsulfanyl)-2-methyl-propionate
54. Ethyl 2-(3-{4-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-heptyl-amino]-butoxy}-phenylsulfanyl)-2-methyl-propionate
55. Ethyl 2-(2-{2-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-2-methyl-propionate
56. Ethyl 2-methyl-2-(3-{2-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-propionate
57. Ethyl 2-{3-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
58. Ethyl 2-methyl-2-(3-{2-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-propionate
59. Ethyl 2-{3-[2-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
60. Ethyl 2-(3-{2-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-2-methyl-propionate
61. Ethyl 2-{3-[2-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenylsulfanyl}-2-methyl-propionate
62. Ethyl 2-methyl-2-(3-{3-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-propionate
63. Ethyl 2-(3-{3-[3-(2-cyano-ethyl)-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propyl}-phenoxy)-2-methyl-propionate
64. Ethyl 2-{3-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenoxy}-2-methyl-propionate
65. Ethyl 2-methyl-2-(3-{3-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-propionate
66. Ethyl 2-(3-{3-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propyl}-phenoxy)-2-methyl-propionate
67. Ethyl 2-{3-[3-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenoxy}-2-methyl-propionate
68. Ethyl 2-(3-{3-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propyl}-phenoxy)-2-methyl-propionate
69. Ethyl 2-{3-[3-(2,4-diheptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenoxy}-2-methyl-propionate
70. Ethyl 2-{3-[3-(2-benzyl-4-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenoxy}-2-methyl-propionate
71. Ethyl 2-(3-{3-[4-benzyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-propyl}-phenoxy)-2-methyl-propionate
72. Ethyl 2-{3-[3-(4-benzyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenoxy}-2-methyl-propionate
73. Ethyl 2-{3-[3-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenylsulfanyl}-2-methyl-propionate
74. Ethyl 2-methyl-2-(3-{4-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-propionate
75. Ethyl 2-{3-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenoxy}-2-methyl-propionate
76. Ethyl 2-methyl-2-(3-{4-[4-(3-methyl-but-2-enyl)-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-propionate
77. Ethyl 2-methyl-2-(3-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-propionate
78. Tert-butyl 2-methyl-2-(3-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-propionate
79. 2-Methyl-2-(3-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-propionic acid
80. Ethyl 2-(3-{4-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
81. Ethyl 2-(3-{4-[2-(2-cyano-ethyl)-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
82. Ethyl 2-(3-{4-[2-heptyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
83. Tert-butyl 2-(3-{4-[2-heptyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
84. 2-(3-{4-[2-Heptyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionic acid
85. Ethyl 2-(3-{4-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
86. Ethyl 2-(3-{4-[2-(2-cyano-ethyl)-4-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
87. Ethyl 4-(6-{4-[3-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl-]-butylamino}-4-heptyl-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl)-but-2-enonate
88. Ethyl 2-{3-[4-(2,4-diheptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenoxy}-2-methyl-propionate
89. Ethyl 2-{3-[4-(2-benzyl-4-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenoxy}-2-methyl-propionate
90. Ethyl 2-(3-{4-[4-benzyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenoxy)-2-methyl-propionate
91. Ethyl 2-{3-[4-(4-benzyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenoxy}-2-methyl-propionate
92. Ethyl 2-(3-{5-[3,5-dioxo-2,4-bis-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-pentyl}-phenoxy)-2-methyl-propionate
93. Ethyl 2-methyl-2-(3-{4-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenylsulfanyl)-propionate
94. Ethyl 2-{3-[4-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenylsulfanyl}-2-methyl-propionate
95. Ethyl 2-methyl-2-(3-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenylsulfanyl)-propionate
96. 2-Methyl-2-(3-{4-[2-methyl-3,5-dioxo-4-(4,4,4-trifluoro butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenylsulfanyl)-propionic acid
97. Ethyl 2-(3-{4-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenylsulfanyl)-2-methyl-propionate
98. Ethyl 2-{3-[4-(2,4-diheptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenylsulfanyl}-2-methyl-propionate
99. Ethyl 2-{3-[4-(2-benzyl-4-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenylsulfanyl}-2-methyl-propionate
100. Ethyl 2-(3-{4-[4-benzyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-butyl}-phenylsulfanyl)-2-methyl-propionate
101. Ethyl 2-{3-[4-(4-benzyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-butyl]-phenylsulfanyl}-2-methyl-propionate
102. Ethyl 2-methyl-2-(4-{2-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-propionate
103. Ethyl 2-{4-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
104. Ethyl 4-[6-{2-[4-(1-ethoxycarbonyl-1-methyl-ethoxy)-phenyl]-ethylamino}-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-4,5-dihydro-3H-[1,2,4]triazin-2-yl]-but-2-enoate
105. Ethyl 2-(4-{2-[2-(3-cyclohexyl-propyl)-3,5-dioxo-4-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-2-methyl-propionate
106. Ethyl 2-{4-[2-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
107. Ethyl 2-(4-{2-[4-heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenoxy)-2-methyl-propionate
108. Ethyl 2-{4-[2-(2,4-diheptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
109. Ethyl 2-{4-[2-(4-benzyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
110. Ethyl 2-{4-[2-(2,4-bis-benzyloxymethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenoxy}-2-methyl-propionate
111. Ethyl 2-(4-{2-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-(4,4,4-trifluoro-butyl)-amino]-ethyl}-phenoxy)-2-methyl-propionate
112. Ethyl 2-(4-{2-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-heptyl-amino]-ethyl}-phenoxy)-2-methyl-propionate
113. 2-(4-{2-[(2,4-Dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-heptyl-amino]-ethyl}-phenoxy)-2-methyl-propionic acid
114. Ethyl 2-(4-{2-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-phenethyl-amino]-ethyl}-phenoxy)-2-methyl-propionate
115. Ethyl 2-(4-{2-[(2,4-dimethyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-2-methyl-propionate
116. Ethyl 2-(4-{2-[(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-phenethyl-amino]-ethyl}-phenoxy)-2-methyl-propionate
117. Ethyl 2-(4-{2-[(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-yl)-(3-phenyl-propyl)-amino]-ethyl}-phenoxy)-2-methyl-propionate
118. 2-Methyl-2-(4-{2-[4-methyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenylsulfanyl)-propionic acid
119. Ethyl 2-{4-[2-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenylsulfanyl}-2-methyl-propionate
120. 2-{4-[2-(2-Heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenylsulfanyl}-2-methyl-propionic acid
121. 2-{4-[2-(4-Butyl-2-heptyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenylsulfanyl}-2-methyl-propionic acid
122. Ethyl 2-{4-[2-(4-heptyl-2-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-ethyl]-phenylsulfanyl}-2-methyl-propionate
123. 2-(4-{2-[4-Heptyl-3,5-dioxo-2-(4,4,4-trifluoro-butyl)-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino]-ethyl}-phenylsulfanyl)-2-methyl-propionic acid and
124. Ethyl 2-{4-[3-(2-heptyl-4-methyl-3,5-dioxo-2,3,4,5-tetrahydro-[1,2,4]triazin-6-ylamino)-propyl]-phenylsulfanyl}-2-methyl-propionate,
or additive salt with pharmaceutically acceptable base thereof.
6. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents an oxygen atom or a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5 when Z=C or from 2 to 4 when Z=O,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a compound of formula II is condensed
in which R 1 and R 2 represent the groups defined above in formula I with a compounds of formula III
where YR 3 , n, Z, X, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are defined above in formula I, in the presence of a base.
7. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents an oxygen atom which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 2 to 4,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a) a compound of formula II is condensed
in which R 1 and R 2 represent the groups defined above in formula I with a compound of formula IV
in which R 3 Y can be equal to NH or O and n is defined in formula I, in the absence of solvent without adding base if R 3 Y═NH, or in the presence of a base if R 3 Y═O;
b) the compound obtained V is condensed
with a compound of formula VI
where X, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are defined above in formula I.
8. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents an oxygen atom which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 2 to 4,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a) the alcohol function of a compound of formula VII is protected
in which R 1 , R 2 and n are such as described previously in formula I by a protection group
b) the nitrogen of compound VIII previously obtained is alkylated by a halogenated compound R 3 Hal in which the Hal group represents a halogen and R 3 is as described previously in formula I;
c) the compound IX thus obtained is deprotected
d) the compound obtained X is condensed
with a compound of formula VI
where X, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are as described previously in formula I.
9. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a) a compound of formula II is condensed
in which R 1 and R 2 represent the groups as previously described in formula I with a compound of formula XI
in which n, R 3 R 4 , R 5 , R 6 , R 7 and R 8 are defined above in formula I and A can be hydrogen or a methyl group, in the presence of a base;
b) after demethylation, the phenol function of compound XII is alkylated
by a halogenated compound of formula XIII in the presence of a base
in which the Hal group represents a halogen, and R 9 , R 10 and R 11 are defined above in formula I.
10. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a) a compound of formula XIV is alkylated
in which R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , R 8 et n are defined above in formula I with a compound of formula R 3 Hal in which the Hal group represents a halogen and R 3 is defined above in formula I;
b) after demethylation, the phenol function of the compound XII thus obtained is alkylated
by a halogenated compound of formula XIII in the presence of a base
in which the Hal group represents a halogen, and R 9 , R 10 and R 11 are defined above in formula I.
11. Method of preparation of 3,5-Dioxo-(2H,4H)-1,2,4-triazine compounds of formula I
in which
R 1 and R 2 can be identical or different and represent an alkyl or alkenyl radical, linear or branched, at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl, cycloalkyl at C 5 -C 6 , nitrile, alkoxycarbonylvinyl at C 1 -C 4 , hydroxycarbonylvinyl, alkoxycarbonyl at C 1 -C 4 , carboxylate, benzyloxy or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
YR 3 represents oxygen or NR 3 in which R 3 represents hydrogen, an alkyl or alkenyl radical, linear or branched at C 1 -C 7 , an alkyl radical at C 1 -C 6 substituted by trifluoromethyl or phenyl, wherein the core phenyl is optionally substituted by one or more alkyl at C 1 -C 4 , alkoxy at C 1 -C 4 , nitro, halogen or trifluoromethyl,
Z represents an oxygen atom or a methylene group which can be bound in ortho, meta or para position on the phenyl group of formula I
n can range from 0 to 5 when Z=C or from 2 to 4 when Z=O,
X represents oxygen or sulfur,
R 4 , R 5 , R 6 , R 7 and R 8 represent hydrogen or fluorine,
R 9 , R 10 and R 11 represent hydrogen or an alkyl group, linear or branched, at C 1 -C 5 ,
wherein:
a) a compound of formula I is placed
in which R 1 =(CH 2 ) 2 CN and R 2 , R 3 , n, Z, X, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are defined above in formula I or R 2 =(CH 2 ) 2 CN and R 1 , R 3 , n, Z, X, R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are defined above in formula I under operating conditions in the presence of a base;
b) the nitrogen of the triazine of compound XIVa or XIVb thus obtained is then alkylated
by a halogenated compound of formula R 1 Hal in the case of the intermediate XIVa and of formula R 2 Hal in the case of the intermediate XIVb in which the Hal group represents a halogen and R 1 and R 2 are as defined above in formula I.
12. A method for treating diseases selected from the group consisting of diabetic dyslipidemia, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, hyperglycemia, obesity and atherosclerosis, which comprises administering to a person in need thereof a therapeutically effective amount of a compound defined according to claim 1 .
13. Pharmaceutical composition comprising as an active ingredient a compound defined according to one of the claims 1 to 5 in association with a suitable excipient.
14. A method for treating obesity, which comprises administering to a person in need thereof a therapeutically effective amount of a compound according to claim 1 .
15. The method according to claim 6 , wherein the condensation of compounds of formulas II and III is conducted in the presence of triethylamine in n-butanol if YR 3 is NR 3 or in the presence of potassium carbonate in dimethylformamide if YR 3 is oxygen.
16. The method according to claim 7 , wherein the condensation of compounds of formulas V and VI is conducted under conditions of the Mitsunobu reaction in the presence of triphenylphosphine and diethylazodicarboxylate in THF.
17. The method according to claim 8 , wherein the protection group for step (a) is tertbutyldimethylsilane and the protection group is added in the presence of THF using chlorotertbutyldimethylsilane and imidazole; wherein the halogen in step (b) is Cl, Br or I and alkylation is conducted in the presence of NaH or tBuOK in DMF; wherein deprotection step (c) is conducted using tetrabutylammonium fluoride in THF; and wherein the conditions of the condensation step (d) are those of the Mitsunobu reaction in the presence of triphenylphosphine and diethylazodicarboxylate in THF.
18. The method according to claim 9 , wherein condensation step (a) is conducted in the presence of triethylamine in n-butanol; wherein the alkylation in step (b) is conducted in the presence of potassium carbonate; and wherein Hal I step (b) is Cl, Br or I.
19. The method according to claim 10 , wherein the alkylation step (a) is conducted in the presence of NaH or tBuOK in DMF; wherein Hal in step (a) is Cl, Br or I; and wherein the alkylation in step (b) is conducted in the presence of potassium carbonate.
20. The method according to claim 11 , wherein step (a) is conducted in the presence of NaH in DMF; wherein Hal in step (b) is Cl, Br or I; and wherein the alkylation in step (b) is conducted in the presence of NaH or tBuOK in DMF.