Patent EA-002775-B1 (EA)
Title: 2,3-diaryl-purazolo[1,5-b]pyridazines derivatives, their preparation and thir use as cycloxygenase 2 (cox-2) inhibitors
Inventor: BESWICK PAUL
IPC: C07D487/04
Filed: 1998-09-03
Abstract: 1. Compounds of formula (I)   and pharmaceutically acceptable derivatives thereof in which: R<0> is halogen, C1-6alkyl, C1-6alkoxy, C1-6alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR<4>R<5>; R<1> and R<2> are independently selected from H, C1-6alkyl, C1-6alkyl substituted by one or more fluorine atoms, C1-6alkoxy, C1-6hydroxyalkyl, SC1-6alkyl, C(O)H, C(O) C1-6alkyl, C1-6alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2 C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)n NR<4>R<5>, (CH2)nSC1-6alkyl or C(O)N NR<4>R<5> with the proviso that when R0 is at the 4-position and is halogen, at least one of R<1> and R<2> is C1-6alkylsulphonyl, C1-6alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-6alkyl, O(CH2)nSC1-6alkyl, (CH2)n NR<4>R<5> or (CH2)nSC1-6alkyl, C(O) NR<4>R<5>; R<3> is C1-6alkyl or NH2; R<4> and R<5> are independently selected from H, or C1-6alkyl or, together with the nitrogen atom to which they are attached, form a 4 - 8 membered saturated ring; and n is 1-4. 2. Compounds as claimed in claim 1 wherein R<0> is F, C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR<4>R<5>; R<1> is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms, O(CH2)nCO2C1-4alkyl, O(CH2)nSC1-4alkyl, (CH2)nNR<4>R<5>, (CH2)nSC1-4alkyl or C(O)NR<4>R<5> or, when R<0> is C1-3alkyl, C1-3alkoxy, C1-3alkoxy substituted by one or more fluorine atoms, or O(CH2)nNR<4>R<5>, may also be H; R<2> is H; R<3> is methyl or NH2; R<4> and R<5> are independently C1-3alkyl or, together with the nitrogen atom to which they are attached, form a 5 - 6 membered saturated ring; and n is 1 - 3. 3. Compounds as claimed in claim 1 or 2 wherein R<0> is F, methyl, C1-2alkoxy, OCHF2, or O(CH2)nNR<4>R<5>; R<1> is methylsulphonyl, OCHF2, O(CH2)nCO2 C1-4alkyl, O(CH2)nSCH3, (CH2)n NR<4>R<5>, (CH2)nSCH3 or C(O)NR<4>R<5> or, when R<0> is methyl, C1-2alkoxy, OCHF2, or O(CH2)nN(CH3)2, may also be H; R<2> is H; R<3> is methyl or NH2; R<4> and R<5> are both methyl or, together with the nitrogen atom to which they are attached, form a 5 - 6 membered saturated ring; and n is 1 - 2. 4. Compounds as claimed in any one of claims 1 to 3 wherein R<0> is F, C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms; R<1> is C1-4alkylsulphonyl, C1-4alkoxy substituted by one or more fluorine atoms or, when R<0> is C1-3alkoxy or C1-3alkoxy substituted by one or more fluorine atoms, 2 3 may also be H; R<2> is H; and R<3> is methyl or NH2. 5. Compounds as claimed in any one of claims 1 to 4 wherein R<0> is at the 3- or 4-position of the phenyl ring. 6. Compounds as claimed in any one of claims 1 to 5 wherein R<1> is at the 6- position of the pyridazine ring. 7. 2-(4-Ethoxy-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine; 6-Difluoromethoxy-2-(3-fluoro-phenyl)-3-(4-methanesulfonyl-phenyl)-pyrazolo[1,5-b]pyridazine; and pharmaceutically acceptable derivatives thereof. 8. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7, which comprises reacting a compound of formula (II)   or a protected derivative thereof, with a compound of formula (III)   or a protected derivative thereof with a subsequent removal of any of the protecting group and optionally converting compounds of formula (I) prepared by the process described thereabove into pharmaceutically acceptable derivatives thereof. 9. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7, in which, if R<3> is C1-4alkyl, a compound of formula (IV)< >   or a protected derivative thereof is subjected to reacting with an oxidising agent with a subsequent removal of any of the protecting groups, and optionally converting compounds of formula (I) prepared by the process described thereabove into pharmaceutically acceptable derivatives thereof. 10. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7, in which, if R<1> is C1-4alkylsulfonyl, a compound of formula (V)   or a protected derivative thereof is subjected to reacting with an oxidising agent with a subsequent removal of any of the protecting groups, and optionally converting compounds of formula (I) prepared by the process described thereabove into pharmaceutically acceptable derivatives thereof. 11. A process for the preparation of compound of formula (I) and pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7, in which, if R<1> is a C1-4alkoxy group, substituted by one or more fluorine atoms, reacting a alcohol of formula (VI)   or a protected derivative thereof is subjected to reacting with a halofluoroalkane with a subsequent removal of any of the protecting groups, and optionally converting compounds of formula (I) prepared by the process described thereabove into pharmaceutically acceptable derivatives thereof. 12. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7 in admixture with one or more physiologically acceptable carriers or excipients. 13. A compound of formula (I) pharmaceutical composition or a pharmaceutically acceptable derivatives thereof as defined in any one of claims 1 to 7 for use in human or veterinary medicine. 14. A compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 7 for use in the treatment of a condition which is mediated by selective inhibition of COX-2. 15. A method for treating a human or an animal suffering with a disease is mediated by selective inhibition of COX-2, which comprises administering to said subject an effective amount of a compound of formula (I) or a pharmaceutically acceptable derivative as defined in any one of Claims 1 to 7. 16. The use of a compound of formula (I) or a pharmaceutically acceptable derivative thereof as defined in any one of Claims 1 to 7 for the manufacture of a therapeutic agent for the treatment of a condition which is mediated by selective inhibition of COX-2, such as an inflammatory disorder.