Leukotriene antagonist prodrugs.

摘要

A compound represented by the following structural formula (I): <CHEM> wherein (a) R1 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, alkoxy, methylthio or trifluoromethylthio, thienyl-C4 to C10 alkyl furyl-C4 to C10 alkyl,trifluoromethyl-C7 to C12 alkyl or cycloheyl-C4 to C10 alkyl; and R2 is hydrogen, bromo, chloro, methyl, trifluoromethyl, hydroxy, alkoxy or nitro; (b) or R1 is hydrogen and R2 is C8 to C13 alkyl, C7 to C12 alkoxy, C7 to C12 alkylthio, C10 to C12 1-alkynyl, 10-undecynyloxy, 11-dodecynyl, phenyl-C4 to C10 alkyl, phenyl-C3 to C9 alkoxy, phenylthio-C3 to C9 alkyl with the phenyl optionally mono substituted with bromo, chloro, trifluoromethyl, alkoxy, methylthio or trifluoromethylthio, furyl-C4 to C10 alkyl, trifluoromethyl-C7 to C12 alkyl or cyclohexyl-C4 to C10 alkyl; q is 0, 1, or 2; Y is COR3, CH(R4)(CH2)mCOR3 or CH(R4)(CH2)m-tetrazol-5-yl the tetrazol-5-yl being unsubstituted or substituted with A; <CHEM> R16 and R17 are independently hydrogen or C1-4 alkyl; j is 0 to 6; R18 is hydrogen, alkyl, COR3, SO3H, SO2NH2, COCH2OH or CHOHCH2OH; R3 is amino, (CH2)nCO2CH2CONR16R17, or OR14; R14 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, alkyl substituted amino or alkylamino, - OCH2CONR7R8, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl; R4 is hydrogen, methyl, alkoxy, fluoro or hydroxy; m is 0, or 1; R is (CH2)n @@COR6, CH(CO2H)CH2COR6, (CH2)nCO2CH2CONR16,R17, or an imidazole of the formula <CHEM> n is 0 to 6; R5 is hydrogen, amino, or NHCOCH2CH2CH(NH2)CO2H; R6 is amino, NH(CH2)nCO2H, SO3H, SO2NH2, CN, tetrazol-5-yl unsubstituted or substituted with A as defined above, or OR15; R7 is hydrogen, alkyl or alkenyl; R8 is hydrogen, alkyl, carboxyl or carboxamido, or, when R7 and R9 are hydrogen or alkyl, (CH2)mCOOR15; R9 is hydrogen, alkyl or (CH2)mCOOR15; R15 is hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, alkylarylalkyl, allayl substituted amino or alkylamino, -OCH2CONR7R8, indanyl, pivaloyloxymethyl, acetoxymethyl, propionyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl, or thienylglycyloxymethyl; provided that 1) when n is 0, R5 is hydrogen, 2) R7, R8 and R9 are not all hydrogen, 3) any of R1and R2 above are not alkylthio or phenylthioalkyl when q is 1 or 2, 4) R3 and R6 are not both hydroxy, 5) OR14 and OR15 are not simultaneously hydroxy; 6) if R4 is hydroxy and m is 0, R14 is hydrogen; or a pharmaceutically acceptable salt thereof. y