Patent ID: 6573282
Filing Date: 2003-06-03
Classification: A61K

Abstract:
A method of preventing or treating peripheral hyperalgesia, comprising administering topically to a mammal in need of such prevention or treatment an effective amount of a composition, comprising in a vehicle formulated for topical administration, one or more compounds of the following formula (I): â€ƒwherein: each of Ar1 and Ar2 are independently selected from (i) or (ii) as follows: (i) a 6- to 10-membered aryl ring system or a 5- to 10-membered heteroaryl ring system containing one or more heteroatoms, wherein the aryl and heteroaryl ring systems are each optionally substituted with one or more aryl group substituents, or (ii) optionally substituted phenyl or pyridyl groups which, together with the carbon atoms to which they are attached, form a fused ring system so that the compounds of formula (I) have the formula: A and B independently represent fused phenyl or pyridyl rings; X4 is a direct bond, â€”(CH2)nâ€”, â€”CH&boxH;CHâ€”, â€”CH&boxH;CHCH2â€”, â€”(CH2)pO(CH2)qâ€”, â€”(CH2)pS(O)r(CH2)qâ€”, â€”(CH2)pNR21(CH2)qâ€” or R21 is hydrogen or lower alkyl; m is an integer from 1 to 3; n is an integer from 0 to 3; each of p and q is 0 or 1, and the sum of p and q is no greater than 2; r is 0 to 2; R2 is a direct bond, straight or branched chain alkylene of 1 to 12 carbon atoms, which is optionally substituted with one or more hydroxy groups, or alkenylene of 2 to 6 carbon atoms and one or two double bonds; R3 is selected from Ar3, â€”Yâ€”Ar3 where Y is alkylene of 1 to 3 carbon atoms, alkenylene of 2 to 4 carbon atoms, cycloalkyl of 3 to 8 carbons, heterocycle, alkenyl, alkanoyl, alkenoyl of 3 to 10 carbons and 1 to 3 double bonds, aroyl, heteroaroyl, alkoxycarbonyl, alkenyloxycarbonyl of 3 to 10 carbons and 1 to 3 double bonds, aryloxycarbonyl, formyl (â€”CHO), cyano, aminocarbonyl (â€”CONH2), alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, or where any of the aryl groups are unsubstituted or substituted with one or more aryl substitutents, and any other groups set forth for R3 are unsubstituted or substituted with halo, hydroxy or alkoxy; and R8 is hydrogen or straight or branched chain alkyl of 1 to 6 carbon atoms, which is unsubstituted or substituted with an alkyl group substitutent; Ar3 is a 6- to 10-membered aryl ring system or a 5- to 10-membered heteroaryl ring system containing one or more heteroatoms in which the aryl and heteroaryl ring systems are each optionally substituted with one or more aryl group substituents; Ar4 is (i) heterocycle containing 1 ring or 2 or more fused rings, wherein each ring contains one or more heteroatoms and is optionally substituted with one or more aryl group substituents; (ii) a radical of the formula: where, R10, R11 and R12 are each independently selected from hydrogen, alkyl, alkyloxy, alkoxyalkyl, halo, haloalkyl, hydroxy, cyano, nitro, amino, alkylamino, di(alkyl)amino, aminocarbonyl, arylcarbonylamino, alkylcarbonylamino, alkylcarbonyl, alkylcarbonyloxy, aminosulfonyl, alkylsulfinyl, alkylsulfonyl, alkylthio, mercapto, C3-6alkenyloxy, C3-6alkynyloxy, arylalkyloxy or aryloxy, in which each group is unsubstituted or substituted with one or more substituents selected from halo, halo alkyl and alkyl, and the alkyl groups are straight or branched chains that are lower alkyl; or (iii) 1- or 2-naphthyl, dihydronaphthyl, tetrahydronaphthyl, indenyl or dihydroindenyl, each of which is optionally substituted with one or more aryl group substituents; R is hydrogen, alkyl, halo, haloalkyl, OR9 or alkenyl; R9 is hydrogen, alkyl, arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl, in which the alkyl groups are straight or branched chains of 1 to 12 carbon atoms; R4 is selected from among: (i) a 6- to 10-membered aryl ring system or a 5- to 10-membered heteroaryl ring system containing one or more heteroatoms, wherein the aryl and heteroaryl ring systems are each optionally substituted with one or more aryl group substituents; (ii) heterocyclic rings which contain one to three heteroatoms and which are unsubstituted or substituted with halo, halo lower alkyl, hydroxy, lower alkoxy or lower alkyl; (iii) alkyl of 1 to 8 carbons, which is optionally substituted with hydroxy or alkylcarbonyloxy; alkenyl of 3 to 6 carbons; cycloalkylalkyl in which the cycloalkyl contains 3 to 8 carbons and the alkyl contains 1 to 3 carbons; cycloalkenylalkyl in which the cycloalkenyl contains 3 to 8 carbons and the alkyl contains 1 to 3 carbons; X5 is O or S; R5 and R6 are independently selected from: (a) hydrogen, straight or branched chain alkyl of 1 to 12 carbon atoms, straight or branched chain alkenyl of 2 to 12 carbon atoms and one or two double bonds, a 6- to 10-membered aryl ring system, which is optionally substituted with one or more aryl group substituents, or arylalkyl; and (b) carbon chains, heteroatoms, and carbon chains containing one or more heteroatoms, so that, together with the nitrogen atom to which they are attached, form a 3- to 10-membered heterocyclic ring containing one or more heteroatoms that is unsubstituted or substituted with halo, halo lower alkyl or lower alkyl, hydroxy, lower alkoxy; (v) cyano, formyl, alkoxycarbonyl, aryloxycarbonyl, alkylcarbonyl or arylcarbonyl; (vi) â€”NR5COR5; and (vii) â€”S(O)ralkyl or â€”S(O)raryl, where r is 1 or 2; and R7 is selected from among: hydrogen; â€”OH; â€”R14OR13 in which R13 is hydrogen, lower alkyl or alkanoyl containing 2 to 5 carbon atoms, and R14 is lower alkenyl or lower alkyl; â€”CH2NR15R16 in which R15 is hydrogen, lower alkyl, lower alkanoyl, aryl or aroyl and R16 is hydrogen or lower alkyl or, together with the nitrogen atom to which they are attached, R15 and R16 form a 3 to 7-membered ring which optionally contains an additional heteroatom selected from oxygen, nitrogen or sulfur; â€”OR15; â€”C(O)H; â€”CN; â€”C(&boxH;O)â€”NR5R6; alkyl; aryl; â€”C(O)OR17 in which R17 is hydrogen, alkyl of 1 to 7 carbon atoms, alkenyl of 3 to 7 carbon atoms, an optionally substituted aryl ring system, an optionally substituted heteroaryl ring system containing one or more heteroatoms, arylalkyl, or a pharmaceutically acceptable cation; wherein the optional aryl group substituents are selected from halo, hydroxy, alkyl, cycloalkyl, cycloalkylalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, alkenyl containing 1 to 2 double bonds, alkynyl containing 1 to 2 triple bonds, haloalkyl, polyhaloalkyl, formyl, alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, arylaminocarbonyl, diarylaminocarbonyl, arylalkylaminocarbonyl, alkoxy, aryloxy, perfluoroalkoxy, alkenyloxy, alkynyloxy, arylalkoxy, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, amino, alkylamino, dialkylamino, arylamino, alkylarylamino, alkylcarbonylamino, arylcarbonylamino, azido, nitro, mercapto, alkylthio, arylthio, perfluoroalkylthio, thiocyano, isothiocyano, alkylsulfinyl, alkylsufonyl, arylsulfinyl, arylsulfonyl, aminosulfonyl, alkylaminosulfonyl, dialkylaminosulfonyl and arylaminosulfony;or a salt, hydrate or N-oxide thereof; the amount is effective to treat or prevent hyperalgesia; and wherein R3 is Ar3; â€”Yâ€”Ar3, where Y is alkylene of 1 to 3 carbon atoms; alkenylene of 2 to 4 carbon atoms; cycloalkyl of 3 to 8 carbons; heterocyclyl; alkenyl; alkanoyl that is optionally substituted with halo, hydroxy or alkoxy; alkenoyl of 3 to 10 carbons and 1 to 3 double bonds; optionally substituted aroyl; heteroaroyl; alkoxycarbonyl; alkenyloxycarbonyl of 3 to 10 carbons and 1 to 3 double bonds; aryloxycarbonyl; formyl (â€”CHO); cyano; aminocarbonyl (â€”CONH2); alkylaminocarbonyl; dialkylaminocarbonyl; arylaminocarbonyl; diarylaminocarbonyl or arylalkylaminocarbonyl.