Ortho-substituted aromatic compounds, containing three (het)aryl moieties, their preparation and their use as prostaglandin E2-(PGE2)-antagonists

摘要

The invention relates to compounds of the formula <CHEM> wherein: A is an optionally substituted ring system provided that the -Z-B-R<1> and -X-D linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms and the ring atom positioned ortho to the -X- linking group (and therefore in the 3-position relative to the -Z- linking group) is not substituted; B is an optionally substituted ring system D is optionally substituted: pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl; R<1> is positioned on ring B in a 1,3 or 1,4 relationship with the -Z- linking group in 6-membered rings and in a 1,3-relationship with the -Z- linking group in 5-membered rings and is as defined in the description; X is -OCH2-, -SCH2-, -CH2CH2-, CH2-, -O-, -S- or -N(R<4>)CH2- wherein the left hand atom is attached to A and the right hand atom is attached to D; Z is of the formula -CH(R<3>)CH(R<3>)N(R<2>)-, -N(R<2>)CH(R<3>)-, -CH(R<3>)P<1>-, -(CH(R<3>))m- or -CH(R<3>)N(R<2>)- wherein R<2> is hydrogen, C1-6alkyl (optionally substituted by hydroxy, cyano, nitro, amino, halo, C1-4alkanoyl, C1-4alkoxy or trifluoromethyl) C2-6alkenyl, C2-6alkynyl, C3-6cycloalkyl, C3-6cycloalkylC1-3alkyl, C3-6cycloalkylC2-3alkenyl, C5-6cycloalkenyl, C5-6cycloalkenylC1-3alkyl, C5-6cycloalkenylC2-3alkenyl, phenyl, phenylC1-3alkyl or 5- or 6-membered heteroarylC1-3alkyl; R<3> is hydrogen or C1-4alkyl; P<1> is oxygen or sulphur, m is 2 or 3 and R<4> is hydrogen or C1-4alkyl and wherein the left hand atom is attached to A and the right hand atom is attached to B; provided that when Z is -CH(R<3>)N(R<2>)- or -(CH(R<3>))m-, X is not -OCH2-; and N-oxides of -NR<2> where chemically possible; and S-oxides of sulphur containing rings where chemically possible; and pharmaceutically acceptable salts and in vivo hydrolysable esters and amides thereof. Processes for their preparation, intermediates in their preparation, their use as pharmaceutical agents and pharmaceutical compositions containing them. The compounds of the invention are useful in the treatment of pain such as the pain associated with joint conditions (such as rheumatoid arthritis and osteoarthritis), postoperative pain, post-partum pain, the pain associated with dental conditions (such as dental caries and gingivitis), the pain associated with burns (including sunburn), the treatment of bone disorders (such as osteoporosis, hypercalcaemia of malignancy and Paget's disease), the pain associated with sports injuries and sprains and all other painful conditions in which E-type prostaglandins wholly or in part play a pathophysiological role.