Patent ID: 6576650
Filing Date: 2003-06-10
Classification: A61K,A61P

Abstract:
A method of treating peripheral hyperalgesia, comprising topically or locally administering to a mammal in need of such treatment an effective amount of a composition, comprising in a vehicle formulated for topical or local administration, one or more compounds of formula (I) or is an N-oxide thereof or is a pharmaceutically acceptable salt or acid thereof: where M is wherein: â€ƒis an azabicycloalkyl containing from 6 to 9 carbon atoms with at least 5 atoms in each ring and is unsubstituted or substituted with OR18 in which R18 is hydrogen or lower alkanoyl containing 2 to 7 and OR18 is at the 5 position in 5-membered rings or the 5 or 6 position in 6-membered rings and is attached in the endo or exo configuration; Ar1 and Ar2 are either (i) or (ii) as follows: (i) each is independently selected from aryl containing from 5 to 7 members in the ring and heteroaryl groups containing from 5 to 7 members in the ring with one or two heteroatoms, each is unsubstituted or substituted with one or more substituents selected from halo, haloalkyl, hydroxy, alkyl, alkyloxy, aminosulfonyl, alkylcarbonyl, nitro, haloalkyl, trifluoromethyl, amino, aminocarbonyl, phenylcarbonyl or thienyl, where the alkyl groups are straight or branched chains lower alkyl containing from 1 to 6 carbon atoms; or (ii) Ar1 and Ar2 are each independently phenyl or pyridyl groups and with the carbon to which they are commonly linked form a fused ring so that the compounds of formula (I) have the structure: where n is 0 to 3;R2 is a direct bond, straight or branched chain alkylene of 1 to 12 carbon atoms, or is alkenylene or alkynylene of 2 to 6 carbon atoms and one or two double bonds or triple bonds; R3 is Ar3, â€”Yâ€”Ar3, where Y is alkylene or alkyl having 1 to 3 carbon atoms, or is R8 is hydrogen or alkyl that is a straight or branched chain containing from 1 to 6 carbon atoms; Ar3 is aryl containing from 5 to 7 members in the ring or heteroaryl containing from 5 to 7 members in the ring with one or two heteroatoms, which is unsubstituted or substituted with one or more substituents halo lower alkyl or lower alkyl; Ar4 is either: (i) is a heterocycle containing one to three fused rings or which is unsubstituted or substituted with one or more substituents selected from halo, halo lower alkyl or lower alkyl, or (ii) Ar4 is a radical of formula: â€ƒin which 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, arlyalkyloxy, aryloxy or alkyl, in which each group is unsubstituted or substituted with one or more halo atoms, halo alkyl or alkyl, and the alkyl groups are straight or branched chains that are lower alkyl; R is hydrogen, alkyl, halo, haloalkyl or OR9; R9 is selected from alkyl, arylalkyl, alkylcarbonyl, aminoalkyl, alkylaminoalkyl or diallkylaminoalkyl, in which the alkyl groups are straight or branched chains containing 1 to 12 carbon atoms; R4 is selected from among: (i) 5- to 7-membered aryl groups, which are unsubstituted or substituted with lower alkyl, halo lower alkyl or halo, or (ii) 3 to 6 membered heterocyclic rings, containing one to three heteroatoms, that are unsubstituted or substituted with halo, halo lower alkyl or lower alkyl, or (iii) alkyl containing from 1 to 8 carbon atoms, alkenyl containing 3 to 6 carbon atoms, cycloalkyl containing from 3 to 6 carbon atoms, cycloalkyl alkyl in which the first alkyl contains 3 to 6 carbons and the second contains 1 to 3 carbons, or cycloalkenyl containing 4 to 7 carbons, or â€ƒwhere R5 and R6 are either: (i) independently selected from hydrogen, alkyl, which is a straight or branched chain containing 1 to 12 carbon atoms, alkenyl, which is straight or branched chain, containing 1 to 12, carbon atoms and one or two double bonds, or aryl, which contains 5 to 7 carbon atoms, or (ii) R5 and R6 are selected from carbon chains, heteroatoms, and carbon chains containing one or more heteroatoms, so that with the nitrogen atom to which each is attached they form a 3- to 7-membered heterocyclic ring containing one to three heteroatoms that is unsubstituted or substituted with halo, halo lower alkyl or lower alkyl; and R7 is selected from among: H; OH; â€”R14OR13 in which R13 is hydrogen or lower alkyl, alkanoyl containing 2 to 5 carbon atoms, and R14 is lower alkenyl or lower alkyl; â€”CH2NR15R16 in which R15 is hydrogen, lower alkyl or lower alkanoyl and R16 is hydrogen or lower alkyl; OR15; R22OR13, in which R22 is lower alkyl; â€”C(O)OR17 in which R17 is hydrogen, alkyl containing from 1 to 7 carbons or alkenyl having 3-7 carbon atoms, aryl or heteroaryl; or an alkali metal or alkaline earth metal salt.