Patent EA-002755-B1 (EA)
Title: Triazolo-pyridazine derivatives as ligands for gaba receptors
Inventor: CARLING WILLIAM ROBERT
IPC: C07D487/04
Filed: 1999-01-13
Abstract: 1. A compound of formula I, or a pharmaceutically acceptable salt thereof:   wherein  Z represents trifluoromethyl, 2-methylpropyl, 2,2-dimethylpropyl, 3-methylbutyl, 1-fluorobut-3-enyl, cyclobutyl, 1-methylcyclobutyl, 1-fluorocyclobutyl, 3-fluorocyclobutyl, 3,3-difluorocyclobutyl, 3-hydroxycyclobutyl, 3-benzyloxycyclobutyl, 3-oxocyclobutyl, 1-methylcyclohexyl, 4,4-difluoro-1-methylcyclohexyl, cyclopentylmethyl,  4-fluorocyclohex-3-enyl, 3-fluorophenyl, tetrahydrofur-2-yl, pyrrolidin-1-yl, 4-methyltetrahydropyran-4-yl or thien-2-yl; R<1> represents hydrogen or fluoro; and R<2> represents methyl-isoxazolyl, methyl-pyrazolyl, methyl-imidazolyl, benzimidazolyl or methyl-triazolyl; provided that, when Z represents 1-methylcyclobutyl, R1 is hydrogen and R2 represents 1-methyl-1H-1,2,4-triazol-3-yl or 2-methyl-2H-1,2,4-triazol-3-yl, then the fluorine atom is not at the 2-position of the phenyl ring. 2. A compound as claimed in claim 1 wherein Z represents cyclobutyl. 3. A compound as claimed in claim 1 or claim 2 wherein R<2> represents a ring of structure (a), (b), (c), (d), (e), (f) or (g):                 where the asterisk * denotes the point of attachment of the ring to the remainder of the molecule. 4. A compound as claimed in claim 3 wherein R<2> represents a ring of structure (g) as depicted in claim 3. 5. A compound as claimed in claim 1 represented by formula IIA, and pharmaceutically acceptable salts thereof:   wherein R<1> is as defined in claim 1; and R<3> represents hydrogen or fluoro. 6. A compound as claimed in claim 5 represented by formula IIB, and pharmaceutically acceptable salts thereof:   wherein R<1> is as defined in claim 1; and R<3> is as defined in claim 5. 7. A compound as claimed in claim 5 or claim 6 wherein R<3> represents hydrogen. 8. A compound selected from: 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(3-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo [4,3-b]pyridazine; 7-cyclobutyl-3-(4-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo [4,3-b]pyridazine; 7-cyclobutyl-3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(3,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 3-(2,4-difluorophenyl)-7-(1-methylcyclobutyl)-6-(2-methyl-2H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 7-cyclobutyl-3-(3,4-difluorophenyl)-6-(2-methyl-2H-1,2.4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2,3-difluorophenyl}-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 7-cyclobutyl-3-(2,5-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(2-methyl-2H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2,4-difluorophenyl)-7-(1-methylcyclohexyl)-6-(1-methyl-1H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-pyrazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(5-methylisoxazol-3-ylmethoxy}-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H-imidazol-2-ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(4-methyl-4H-1,2,4-triazol-3-ylmethoxy)- 1,2,4-triazolo[4,3-b]pyridazine; 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2.4-triazol-3-ylmethoxy)-7-(thien-2-yl)-1,2,4-triazolo [4,3-b]pyridazine; 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(thien- 2-yl)-1,2,4-triazolo[4,3-b]pyridazine; 6-(1H-benzimidazol-2-ylmethoxy)-7-cyclobutyl-3-(2,4-difluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2,4-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2,4-difluorophenyl)-6-{1-methyl-1H-1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin-1-yl)-1,2,4-triazolo(4,3-b]pyridazine; 3-(2-fluorophenyl)-6-(1-methyl-1H 1,2,4-triazol-3-ylmethoxy)-7-(pyrrolidin- 1-yl)-1,2,4-triazolo(4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(1-methyl-1H imidazol-4-ylmethoxy)- 1,2,4-triazolo(4,3-b]pyridazine; 7-(1-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclobutyl-3-(2-fluorophenyl)-6-(2-methyl-2H-pyrazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; and pharmaceutically acceptable salts thereof. 9. A compound selected from: 7-(2,2-dimethylpropyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine; 3-(2-fluorophenyl)-7-(2-methylpropyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2-fluorophenyl)-7-(3-methylbutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-cyclopentylmethyl-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol- 3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2-fluorophenyl)-7-(3-hydroxycyclobutyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-(1-fluorobut-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo(4,3-b]pyridazine; 7-(3-fluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2-fluorophenyl)-6-(2-methyl-2H 1,2,4-triazol-3-ylmethoxy)-7-trifluoromethyl-1,2,4-triazolo[4,3-b]pyridazine; and pharmaceutically acceptable salts thereof. 10. A compound selected from: 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo(4,3-b]pyridazine; 3-(2-fluorophenyl)-7-(4-methyltetrahydropyran-4-yl)-6-(1-methyl-1H 1,2,4triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-(2-methyl-2H- 1,2,4,-triazol-3-ylmethoxy)-1, 2,4-triazolo [4,3-b]pyr idazine; 7-(4-fluoro-1-methylcyclohex-3-enyl)-3-(2-fluorophenyl)-6-(2-methyl-2H- 1,2,4,-triazol-3-ylmethoxy)-1,2,4,-triazolo (4,3-b]pyridazine; 7-(4,4-difluoro-1-methylcyclohexyl)-3-(2-fluorophenyl)-6-(1-methyl-1H- 1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo[4,3-b]pyridazine; 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-7-(3-oxocyclobutyl)-1,2,4-triazolo(4,3-b]pyridazine; 7-(3,3-difluorocyclobutyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4,-triazolo [4,3-b]pyridazine; 3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4,-triazol-3-ylmethoxy)-7-(tetrahydrofur-2-yl)-1,2,4-triazolo(4,3-b]pyridazine; 7-(3-fluorophenyl)-3-(2-fluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4,-triazolo [4,3-b]pyridazine; and pharmaceutically acceptable salts thereof. 11. A pharmaceutical composition comprising a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof in association with a pharmaceutically acceptable carrier. 12. The use of a compound as claimed in any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of anxiety. 13. The use of a compound as claimed in any one of claims 1 to 10 for the manufacture of a medicament for the treatment and/or prevention of convulsions. 14. A process for the preparation of a compound as claimed in claim 1, which comprises: reacting a compound of formula III with a compound of formula IV:                           wherein Z, R<1> and R<2> are as defined in claim 1, and L<1> represents a suitable leaving group. 15. A method for the treatment and/or prevention of anxiety which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof. 16. A method for the treatment and/or prevention of convulsions which comprises administering to a patient in need of such treatment an effective amount of a compound of formula I as defined in claim 1 or a pharmaceutically acceptable salt thereof. 17. A compound as claimed in claim 1 which is 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine. 18. A pharmaceutical composition as claimed in claim 11 for treating and/or prevention of anxiety wherein comprises 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine as a compound of formula I. 19. Use as claimed in claim 12 wherein a compound of formula I is 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine. 20. A method as claimed in claim 15 wherein 7-cyclobutyl-3-(2,6-difluorophenyl)-6-(2-methyl-2H-1,2,4-triazol-3-ylmethoxy)-1,2,4-triazolo [4,3-b]pyridazine is administered as a compound of formula I.