Patent EA-003399-B1 (EA)
Title: Substituted imidazo[1,2a]azines as selective inhibitors of cox-2
Inventor: FERNANDEZ GARCIA ANDRES
IPC: A61P35/00
Filed: 1999-07-23
Abstract: 1. A substituted imidazo[1,2a]azine of formula (I), or a pharmaceutically acceptable solvate and acid addition salt thereof, wherein A and B are independently selected from N and CH, with the proviso that when A is N, then B is N too; R<1> is selected from the group consisting of CH3 and NH2; R<2> and R<3> are selected from the group consisting of H, CH3, Cl, Br, COCH3 and OCH3 ; and R<4>, R<5> and R<6> are each independently selected from the group consisting of H, F, Cl, Br, (C1-C3)-alkyl, trifluoromethyl, (C1-C3)-alkoxy and trifluoromethoxy. 2. A compound according to claim 1, wherein A is CH and B is N. 3. A compound according to claim 2, wherein R<4>, R<5>, and R<6> are selected from the group consisting of H, F, Cl, methyl, isopropyl, methoxy and ethoxy. 4. A compound according to claim 3, said compound being selected from the group consisting of: (Ia) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo[1,2a] pyrimidine; (Ib) 2-(4-methylphenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (Ic) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (Id) 2-(4-chlorophenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (Ie) 2- (4-bromophenyl) -3- (4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (If) 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (Ig) 2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyrimidine; (Ih) 2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Ii) 2-(3-methyl-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Ij) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Ik) 2-(3-chloro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Il) 2-(3,4-dimethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Im) 7-methyl-2-(4-methylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (In) 7-methyl-2-(3,4-dimethylphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyrimidine; (Io) 2-(4-methylphenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyrimidine; (Ip) 2-(3-fluoro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyrimidine; (Iq) 2-(2-methylphenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyrimidine; (Ir) 2-(4-fluorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyridine; (Is) 2-(2-chlorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyrimidine; (It) 2- (3-fluorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyrimidine; (Iu) 2-(3-chlorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a]pyrimidine; 5. A compound according to claim 4, said compound being 3-(4-methylsulfonylphenyl)-2-(4-fluorophenyl)imidazo[1,2a]pyrimidine (Ic). 6. A compound according to claim 4, said compound being 3-(4-methylsulfonylphenyl)-2-(4-methoxyphenyl)imidazo[1,2a] pyrimidine (If). 7. A compound according to claim 4, said compound being 3-(4-methylsulfonylphenyl)-2-(4-ethoxyphenyl)imidazo[1, 2a]pyrimidine (Ig). 8. A compound according to claim 1, wherein A is N and B is N. 9. A compound according to claim 8, wherein R<4>, R<5>, and R<6> are selected from the group consisting of H, F, Cl, methyl, isopropyl, methoxy and ethoxy. 10. A compound according to claim 9, said compound being selected from the group consisting of: (Iaa) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo[1,2a] [1,2,4]triazine; (Ibb) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a][1,2,4]triazine; (Icc) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a][1,2,4]triazine; (Idd) 2-phenyl-3-(4-aminosulfonylphenyl)imidazo[1,2a] [1,2,4]triazine; (Iee) 2-(2-fluorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a][1,2,4]triazine; (Iff) 2-(2-chlorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a][1,2,4]triazine; (Igg) 2-(3-methylphenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a][1,2,4]triazine; (Ihh) 2-(3-fluorophenyl)-3-(4-aminosulfonylphenyl) imidazo[1,2a][1,2,4]triazine. 11. A compound according to claim 1, wherein A is CH and B is CH. 12. A compound according to claim 11, wherein R<4>, R<5>, and R<6> are selected from the group consisting of H, F, Cl, methyl, isopropyl, methoxy and ethoxy. 13. A compound according to claim 12, said compound being selected from the group consisting of: (Iaaa) 2-phenyl-3-(4-methylsulfonylphenyl)imidazo [1,2a]pyridine; (Ibbb) 2-(4-fluorophenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyridine; (Iccc) 2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyridine; (Iddd) 2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl) imidazo[1,2a]pyridine; (Ieee) 2-(4-isopropoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Ifff) 2- (3-methyl-4-methoxyphenyl) -3- (4-methylsulfonylphenyl) imidazo [1,2a] pyridine; (Iggg) 2-(3-fluoro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Ihhh) 2-(3-chloro-4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Iiii) 2-(3,4-dimethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Ijjj) 7-methyl-2-(4-methoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Ikkk) 6-methyl-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Illl) 6-chloro-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Immm) 6-bromo-2-(4-ethoxyphenyl)-3-(4-methylsulfonylphenyl)imidazo[1,2a]pyridine; (Innn) 2-(2-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Iooo) 2-(2-fluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Ippp) 2-(3-methylphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Iqqq) 2- (3-fluorophenyl) -3- (4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Irrr) 2-phenyl-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Isss) 2- (4-fluorophenyl) -3- (4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Ittt) 2-(4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Iuuu) 2-(3-methyl-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Ivvv) 2-(3-fluoro-4-methoxyphenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Iwww) 2- (3-chloro-4-methoxyphenyl) -3- (4-aminosulfonylphenyl)imidazo[1,2a]pyridine; (Ixxx) 2-(3,4-difluorophenyl)-3-(4-aminosulfonylphenyl)imidazo[1,2a]pyridine. 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound as defined in any of the claims 1-13, and suitable amounts of pharmaceutically acceptable carriers. 15. A pharmaceutical composition for treating an inflammatory disease, comprising a therapeutically effective amount of a compound as defined in any of the claims 1-13, and suitable amounts of pharmaceutically acceptable carriers. 16. A pharmaceutical composition for treating a cyclooxigenase-mediated disease, comprising a therapeutically effective amount of a compound as defined in any of the claims 1-13, and suitable amounts of pharmaceutically acceptable carriers. 17. A pharmaceutical composition for the selective inhibition of cyclooxigenase 2 (COX-2), comprising a therapeutically effective amount of a compound as defined in any of the claims 1-13, and suitable amounts of pharmaceutically acceptable carriers. 18. Use of a compound as defined in any of the claims 1-13, for the manufacture of a medicament for the treatment of inflammation. 19. Use of a compound as defined in any of the claims 1-13, for the manufacture of a medicament for the treatment of a cyclooxigenase-mediated disease. 20. Use of a compound as defined in any of the claims 1-13, for the manufacture of a medicament for the selective inhibition of cyclooxigenase 2 (COX-2). 21. Use of a compound as defined in any of the claims 1-13, for the manufacture of a medicament for the treatment of cancer. 22. Use according to claim 21, wherein the cancer is colon cancer. 3. A preparation process of a substituted imidazo[1,2a]azine of formula (I), as defined in claim 1, comprising the condensation reaction of a substituted 2-bromo-2-(4-R-sulfonylphenyl)-1-phenylethanone of formula (II) with a substituted aminoazine of formula (III), in a polar solvent.