Patent CA-2578858-A1 (CA)
Inventor: MCCARTY CATHERINE M
IPC: A61K31/50
Filed: 1998-08-10
Abstract: Pyridazinone compounds of formula I, which are cyclooxygenase (COX) inhibitors, and in particular, are selective inhibitors of cyclooxygenase-2 (COX/2), COX-2 is the inducible isoform associated with inflammation, as opposed to the constitutive isoform, cyclooxygenase-1 (COX-1) which is an important "housekeeping"  enzyme in many tissues, including the gastrointestinal (GI) tract and the kidneys. The selectivity of these compounds for COX-2 minimizes the unwanted GI and renal side-effects seen with currently marked non-steroidal anti-inflammatory drugs (NSAIDs);      where X is selected from the group consisting of O, S, NR4, N-OR a, and N-NR b R c, wherein R4 is selected from the group consisting of alkyl, alkenyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, heterocyclic, heterocyclic alkyl, and arylalkyl; and R a, R b, and R c are independently selected from the group consisting of alkyl, cycloalkyl, cycloalkylalkyl, aryl, and arylalkyl;     R is selected from the group consisting of alkyl, alkenyl, alkynyl, alkylcarbonylalkyl, alkylsulfonylalkyl, alkylsulfonylarylalkyl, alkoxy, alkoxyalkyl, carboxy, carboxyalkyl, cyanoalkyl, haloalkyl, haloalkenyl, haloalkynyl, hydroxyalkyl, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, aryl, arylalkyl, arylalkenyl, arylalkynyl, arylalkoxy, arylhaloalkyl, arylhydroxyalkyl, aryloxy, aryloxyhydroxyalkyl, aryloxyhaloalkyl, arylcarbonylalkyl, haloalkoxyhydroxyalkyl, heterocyclic, heterocyclic alkyl, heterocyclic alkoxy, heterocyclic oxy, -C(O)R5, -(CH2)n C(O)R5, -R6-R7, -(CH2)n CH(OH)R5, -(CH2)n CH(OR d)R5, -(CH2)n C(NOR d)R5, -(CH2)n C(NR d)R5, -(CH2)n CH(NOR d)R5, -(CH2)n CH(NR d R e)R5, -(CH2)n C=C-R7, -(CH2)n[CH(CX'3)]m-(CH2)n-CX'3, -(CH2)n(C X'2)m-(CH2)n -CX'3, -(CH2)n[CH(CX'3)]m-(CH2)n -R8, -(CH2)n(C X'2)m-(CH2)n R8, -(CH2)n(CHX')m-(CH2)n - CX'3, -(CH2)n(CHX')m-(CH2)n -R8 , and -(CH2)n-R20.     wherein R5 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, aryl, arylalkyl, haloalkyl, haloalkenyl, haloalkynyl, heterocyclic, and heterocyclic alkyl;   wherein R6 is alkylene or alkenylene, or halo-substituted alkylene halo-substituted alkenylene;     R7 and R8 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;     R20 is selected from the group consisting of alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, heterocyclic, and heterocyclic alkyl;     R d and R e are independently selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkenyl, aryl, arylalkyl, heterocyclic, and heterocyclic alkyl;     X' is halogen; n is from 0 to about 10, and m is 0 to about 5;  R2 is   where X1 is selected from the group consisting of -SO2-, -SO(NR10)-, -SO-, -Se02-, PO(OR11)-, and -PO(NR12R13)-, R9 is selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, amino, -NHNH2, -N=CH(N R10R11), dialkylamino, alkoxy, thiol, alkylthiol, protecting groups, and protecting groups attached to X' by an alkylene;     X2 is selected from the group consisting of hydrogen, halogen, alkyl, alkenyl, and alkynyl;     R10, R11, R12, and R13 are independently selected from the group consisting of hydrogen, alkyl, and cycloalkyl, or R12 and R13 can be taken together, with the nitrogen to which they are attached, to form a heterocyclic ring having from 3 to 6 atoms; at least one of R1 or R3 is selected from the group consisting of:  hydroxyalkyl, hydroxyalkoxy, mercaptoalkoxy, hydroxyalkylthio, and, hydroxyalkylamino, wherein the remaining group is selected from the group consisting of hydrogen, hydroxy, hydroxyalkyl, halogen, alkyl, alkenyl, alkynyl, alkylamino, alkenyloxy, alkylthio, alkylthioalkoxy, alkoxy, alkoxyalkyl, alkoxyalkylamino, alkoxyalkoxy, amido, amidoalkyl, haloalkyl, haloalkenyloxy, haloalkoxy, cycloalkyl, cycloalkylalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkenylalkoxy, cycloalkylalkoxy, cycloalkylalkylamino, cycloalkylamino, cycloalkyloxy, cycloalkylidenealkyl, amino, aminocarbonyl, aminoalkoxy, aminocarbonylalkyl, alkylaminoaryloxy, dialkylamino, dialkylaminoaryloxy, arylamino, arylalkylamino, diarylamino, aryl, arylalkyl, arylalkylthio, arylalkenyl, arylalkynyl, arylalkoxy, aryloxy, heterocyclic, heterocyclic alkyl, heterocyclic(alkyl) amino, heterocyclic alkoxy, heterocyclic amino, heterocyclic oxy, heterocyclic thio, hydroxy, hydroxyalkyl, hydroxyalkylamino, hydroxyalkoxy,hydroxyalkylthio, mercaptoalkoxy, oxoalkoxy, cyano, nitro, and -Y-R14, wherein Y is selected from the group consisting of -O-, -S-, -C(R16) (R1 7)-, -C(O)NR21 R22-, -C(O)-, -C(O)O-, -NH-, -NC(O)-, -N=C R21 R22, N- R21 R22, a.nd -NR19- R14 is selected from the group consisting of hydrogen, halogen, alkyl, alkoxyalkyl, alkylthioalkyl, alkenyl, alkynyl, hydroxy, cycloalkyl, cycloalkylalkyl, cycloalkenylalkyl, cycloalkenyl, amino, cyano, aryl, arylalkyl, heterocyclic, and heterocyclic(alkyl), R16, R17, and R19 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano; and R21 and R22 are independently selected from the group consisting of hydrogen, alkyl, alkenyl, cycloalkyl, cycloalkenyl, alkoxy, aryl, arylalkyl, heterocyclic, heterocyclic alkyl, or cyano;   or a pharmaceutically acceptable salt, ester, or prodrug thereof.