Methods for treating osteoarthritis using dihydronapthalene or benzopyran derivatives with a further inclusion of COX-2 inhibitors

摘要

An estrogen agonist/antagonist of the compound of formula (I) wherein: A is CH2 or NR B, D and E are CH or N Y is (a) phenyl, optionally substituted with 1-3 substituents independently selected from R4, (b) napthyl, optionally substituted with 1-3 substituents independently selected from R4, (c ) C3-C8 cycloalkyl optionally substituted with 1-2 substituents independently selected from R4, (d) C3-C8 cycloalkenyl optionally substituted with 1-2 substituents independently selected from R4, (e) a five membered heterocycle with up to 2 heteroatoms selected from ûO-, -NR2 and ûS(O)n-, optionally substituted with 1-3 substituents independently selected from R4Æ, (f) a six membered heterocycle with up to 2 heteroatoms selected from ûO-, -NR2 and ûS(O)n-, optionally substituted with 1-3 substituents independently selected from R4 or (g) a bicyclic ring system consisting of five or six membered heterocycle ring fused to a phenyl ring, with the heterocycle ring containing up to 2 heteroatoms selected from ûO-, -NR2 and ûS(O)n-, optionally substituted with 1-3 substituents independently selected from R4 Z1 is û(CH2)pW(CH2)q-, -O(CH2)pCR5R6-, -O(CH2)pW(CH2)q-, -OCHR2CHR3- or ûSCHR2CHR3- G is ûNR7R8 , formula (II) wherein n is 0,1 or 2, m is 1,2 or 3 Z2 is ûNH-, -O-, -S- or ûCH2-, or a bicyclic amine containing 5 to 12 carbon atoms, either bridged or fused and optionally substituted with 1-3 substituents independently selected from R4 or Z1 and G in combination may be formula (III) W is ûCH2-, -CH=CH-, -O-, -NR2-, -S(O)n-,-C(O)-, -CR2(OH)-, -CONR2-, -NR2CO-, -C¦C- or formula (IV) R is H or C1-C6 alkyl R2 and R3 are H or C1-C4 alkyl R4 is H, halogen, alkyl, alkoxy, acyloxy, alkylthio, alkylsulfinyl, alkylsulfonyl, hydroxy alkyl, aryl alkyl, -CO2H-, -CN, -CONHOR, -SO2NHR, -NH2, alkylamino, diakylamino, -NHSO2R, -NO2, aryl or OH R5 and R6 are C1-C8 alkyl or together form a C3-C10 carbocyclic ring R7 and R8 are phenyl, carbocyclic ring saturated or unsaturated, heterocyclic ring containing up to 2 heteroatoms selected from ûO-, -N- and ûS-, H, alkyl or form a 3 to 8 membered nitrogen containing ring with R5 or R6. R7 and R8 in either linear or ring form may optionally be substituted with up to 3 substituents independently selected from alkyl, halogen, alkoxy, hydroxy and carboxy. A ring formed by R7 and R8 may be optionally fused to a phenyl ring e and n are 0, 1 or 2 m is 1,2 or 3 p and q are 0, 1, 2 or 3 is useful in the treatment of osteoarthritis.