Patent ID: 6245746
Filing Date: 2001-06-12
Classification: A61K,C07K,Y02A

Abstract:
A method for treating a microbial infection in an animal, comprising administering to an animal suffering from said infection an antimicrobial agent and an efflux pump inhibitor in an amount sufficient to reduce efflux pump activity,wherein said efflux pump inhibitor increases the susceptibility of said microbe to said antimicrobial agent, andwherein said efflux pump inhibitor has the chemical structure of structure 1 below: ##STR10##whereinM* is (CH.sub.2).sub.n (n=0,1, or 2)P* is CH.sub.2, carbonyl (C.dbd.O), or thiocarbonyl (C.dbd.S)S* is NH, O, or SO.sub.t (t=0,1, or 2);R is H, lower alkyl, branched alkyl, fluoroalkyl, perfluoroalkyl, carboxyalkyl, hydroxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, or 2-(3- or 4-)pyridyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH.sub.2).sub.n NR.sup.b R.sup.c, (CH.sub.2).sub.n NHC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n SC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n C.dbd.(NR.sup.a)NR.sup.b R.sup.c, or (CH.sub.2).sub.n N.dbd.CNR.sup.b R.sup.c, wherein n=1,2,3, or 4, and R.sup.a, R.sup.b, and R.sup.c are independently H, lower alkyl, phenyl, substituted phenyl, benzyl, cyano, hydroxy, or nitro, or R.sup.a +R.sup.b or R.sup.b +R.sup.c is (CH.sub.2).sub.2-3 or --CH.dbd.CH--;R.sup.1 is H, lower alkyl, branched alkyl, fluoroalkyl, perfluoroalkyl, carboxyalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, or 2-(3- or 4-)pyridyl, arylalkyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, (CH.sub.2).sub.n NR.sup.b R.sup.c, (CH.sub.2).sub.n NHC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n SC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n C.dbd.(NR.sup.a)NR.sup.b R.sup.c, or (CH.sub.2).sub.n N.dbd.CNR.sup.b R.sup.c, wherein n=1,2,3, or 4 and R.sup.a, R.sup.b, and R.sup.c are independently H, lower alkyl, phenyl, benzyl, cyano, hydroxy, or nitro, or R.sup.a +R.sup.b (or R.sup.b +R.sup.c) is (CH.sub.2).sub.2-3 or --CH.dbd.CH--;R.sup.2 is H, lower alkyl, branched alkyl, fluoroalkyl, perfluoroalkyl, aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, or 2-(3- or 4-)-pyridyl, benzofuranyl, benzothienyl, indolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, benzofuranylalkyl, benzothienylalkyl, indolylalkyl, (CH.sub.2).sub.n NR.sup.b R.sup.c, (CH.sub.2).sub.n NHC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n SC.dbd.(NR.sup.a)NR.sup.b R.sup.c, (CH.sub.2).sub.n C.dbd.(NR.sup.a)NR.sup.b R.sup.c, or (CH.sub.2).sub.n N.dbd.CNR.sup.b R.sup.c, wherein n=1,2,3, or 4 and R.sup.a, R.sup.b, and R.sup.c are independently H, lower alkyl, phenyl, benzyl, cyano, hydroxy, or nitro, or R.sup.a +R.sup.b or R.sup.b +R.sup.c is (CH.sub.2).sub.2-3 or --CH.dbd.CH--;W is (alpha-aminoacyl)amido, aminoalkyl, amino, azaheterocycles, substituted azaheterocycles, hydroxy, alkoxy, alkylthio, guanidino, amidino, or halogen; andX is aryl, 2-(or 3-)thienyl, 2-(or 3-)furyl, or 2-(3- or 4-)pyridyl, tetrahydronaphthyl, indanyl, quinolinyl, isoquinolinyl, quinoxalinyl, quinazolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, arylalkyl, thienylalkyl, furylalkyl, pyridylalkyl, quinolinylalkyl, isoquinolinylalkyl, quinoxalinylalkyl, quinazolinylalkyl, benzimidazolylalkyl, benzothiazolylalkyl, or benzoxazolylalkyl.