Ortho-substituted aromatic ether compounds and their use in pharmaceutical compositions for pain relief

A compound of the formula (I):

• ##STR93## wherein:
• A is an 8-, 9- or 10-membered bicyclic heteroaryl, a 5- or 6-membered heteroaryl, naphthyl or phenyl, or any of the foregoing substituted with E where E is selected from the group consisting of C.sub.1 -C.sub.6 -alkyl, mono- or di-substituted C.sub.1 --C.sub.6 -alkyl (where the substituent is independently selected from hydroxy, amino, halo, nitro, C.sub.1 -C.sub.4 -alkyl-S(O).sub.p -, C.sub.1 -C.sub.4 -alkoxy, phenyl-S(O).sub.p -, or cyano), halo, trifluoromethyl, nitro, hydroxy, amino, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 -alkylamino, cyano, C.sub.1 C.sub.6 -alkoxy, C.sub.1 -C.sub.6 -alkyl-S(O).sub.p -, phenyl-S(O).sub.p -, carbamoyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.3 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.3 -alkenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.3 -alkynyl, C.sub.1 -C4-alkoxycarbonylamino, C.sub.1 -C4-alkanoylamino, C.sub.1 -C4-alkanoyl-(N-C.sub.1 -C.sub.4 -alkyl)amino, C.sub.1 -C4-alkanesulphonamido, benzenesulphonamido, aminosulphonyl, C.sub.1 -C.sub.4 -alkylaminosulphonyl, di-C.sub.1 C.sub.4 -alkyl-aminosulphonyl, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.2 -C.sub.4 -alkanoyloxy, formyl-C.sub.1 -C.sub.4 -alkyl, trifluoro-C.sub.1 -C.sub.3 -alkylsulphonyl, hydroxyimino-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.4 -alkoxyimino-C.sub.1 -C.sub.6 -alkyl, C.sub.1 -C.sub.6 -alkylcarbamoylamino, phenyl, C.sub.1 -C.sub.4 -alkylcarbamoyl and di-C.sub.1 -C.sub.4 -alkyl-carbamoyl;
• provided that if A is a ring structure, the --OCH(R.sup.3)- and -X- linking groups are positioned in a 1,2 relationship to one another on ring carbon atoms of A, wherein p is 0, 1 or 2;
• B is phenyl or a 5- or 6-membered heteroaryl ring, or either of the foregoing substituted with G, where G is selected from the group consisting of halo, trifluoromethyl, nitro, hydroxy, C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.3 -alkyl, amino, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 -alkyl-amino, cyano, -S(O).sub.p -C.sub.1 -C.sub.6 -alkyl, carbamoyl, C.sub.1 -C.sub.4 -alkylcarbamoyl and di-C.sub.1 -C.sub.4 -alkyl-carbamoyl;
• D is pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, thienyl, furyl, pyrazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl or phenyl, or any of the foregoing mono- or di-substituted with halo, trifluoromethyl, nitro, hydroxy, amino, C.sub.1 -C.sub.4 -alkylamino, di-C.sub.1 -C.sub.4 -alkyl-amino, cyano, C.sub.1 -C.sub.6 -alkoxy, --S(O).sub.p -C.sub.1 -C.sub.4 -alkyl, --S(O).sub.p -phenyl, C .sub.1 -C.sub.4 -alkanoyl, C.sub.1 -C.sub.4 -alkyl or C.sub.1 -C.sub.4 -alkyl mono-substituted with hydroxy, halo, nitro, cyano or amino;
• R.sup.1 is carboxy, carboxy-C.sub.1 -C.sub.3 -alkyl, tetrazolyl, tetrazolyl-C.sub.1 -C.sub.3 -alkyl, tetronic acid, hydroxamic acid, sulphonic acid, or
• R.sup.1 is of the formula -CONR.sup.a R.sup.a1 :
• where R.sup.a is hydrogen or C.sub.1 -C.sub.6 -alkyl, and R.sup.a1 is J or hydrogen, where J is selected from C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, C.sub.3 -C.sub.7 -cycloalkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.1 -C.sub.6 -alkyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.6 -alkenyl, C.sub.3 -C.sub.7 -cycloalkyl-C.sub.2 -C.sub.6 -alkynyl, C.sub.5 -C.sub.7 -cycloalkenyl, C.sub.5 -C.sub.7 -cycloalkenyl-C.sub.1 -C.sub.6 -alkyl, C.sub.5 -C.sub.7 -cycloalkenyl-C.sub.2 -C.sub.6 -alkenyl, C.sub.5 -C.sub.7 -cycloalkenyl-C.sub.2 -C.sub.6 -alkynyl, or R.sup.a1 is J mono-substituted with a 5- or 6-membered saturated or partially-saturated heterocyclic ring, a 5- or 6-membered heteroaryl ring or a 5- or 6-membered heteroaryl-C.sub.1 -C.sub.3 -alkyl;
• or
• where R.sup.a and R.sup.a1 together with the nitrogen to which they are attached form a group having the formula --NH--CH(R.sup.C)--COOR.sup.D wherein R.sup.C is hydrogen, C.sub.1 -C.sub.6 -alkyl, C.sub.2 -C.sub.6 -alkenyl, C.sub.2 -C.sub.6 -alkynyl, phenyl, phenyl(C.sub.1 -C.sub.3 -alkyl), 5- or 6-membered heteroaryl or 5- or 6-membered heteroaryl(C.sub.1 -C.sub.3 -alkyl) and R.sup.D is H or C.sub.1 -C.sub.6 -alkyl, wherein any alkyl, alkenyl, alkynyl, phenyl or heteroaryl group of the foregoing is either unsubstituted or mono- substituted with E;
• R.sup.1 is of the formula --CONHSO.sub.2 J;
• X is of the formula --(CHR.sup.4).sub.n -- or --(CHR.sup.4).sub.r CR.sup.4 .dbd.CR.sup.4 (CHR.sup.4).sub.q --, where n is 1, 2 or 3;
• and r and q are either both 0, or r is 0 and q is 1, or r is 1 and q is 0;
• and
• R.sup.3 and R.sup.4 are independently selected from hydrogen or C.sub.1 -C.sub.4 -alkyl;
• wherein:
• when B is a 6-membered ring, R.sup.1 is positioned on ring B in a 1,3 or a 1,4 relationship with the --OCH(R.sup.3)-- linking group, or
• when B is a 5-membered ring, R.sup.1 is positioned in a 1,3 relationship with the --OCH(R.sup.3)-- linking group;
• or an N-oxide of any of the foregoing compounds;
• or any of the foregoing compounds having S-oxides of sulphur containing rings therein;
• or a pharmaceutically-acceptable salt or an in vivo hydrolysable ester or amide of any of the foregoing compounds;
• provided the compound of formula (I) is not 4-(2-benzyl-3-hydroxy-4-formylphenoxymethyl)-3-methoxybenzoic acid, or 4-(2-(3-phenylprop-2-en-1-yl)-3-hydroxy-4-formylphenoxymethyl)-3-methoxybe nzoic acid.