| abstract |
Compounds derived from quinoline are provided that are MIF inhibitors useful in the treatment of a variety of disorders, including the treatment of pathological conditions associated with MIF activity. This compound has the structure (1) or a stereoisomer, prodrug or pharmaceutically acceptable salt thereof, in which: X is oxygen or sulfur; Y is selected from the group consisting of -NO, -NO2, -C (= O) R5, -C (= O) OR5, -C (= O) NR5R6, -NR5C (= O) R5, -NR5SO2R5 and - S (O) mR5; Z is -CH2- or -C (= O) -; m is 0, 1 or 2; n is o, 1 or 2; with the proviso that when n is 0, Z is -C (= O) -; R1 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl, substituted heterocycloalkyl, dialkyl and R'R''N (CH2) x- where x it is 2 to 4 and where R 'and R' 'are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl or substituted heterocycloalkyl and dialkyl. R2 and R3 are independently selected from the group consisting of halogen, -R5, -OR5, -SR5 or -NR5R6; R4 is selected from the group consisting of -CH2R7, -C (= O) NR5R6, -C (= O) OR7, -C (= O) R7 and R8; R5 and R6 are independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl and substituted heterocycloalkyl; or R5 and R6 taken together with a nitrogen atom to which they are attached form a substituted heterocycle or heterocycle; R7 is selected from the group consisting of alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl and substituted heterocycloalkyl; and R8 is selected from the group consisting of hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, heterocycle, substituted heterocycle, heterocycloalkyl and substituted heterocycloalkyl; with the provisos that: R4 is not hydrogen or methyl when R1 is phenyl, R2 and R3 are both hydrogen, X is oxygen and Y is -C (= O) OCH2CH3; R4 is not methyl when R1 is methyl, R2 and R3 are both hydrogen, X is oxygen and Y is -NO2; R4 is not -CH2CH2OH when R1 is hydrogen or methyl, R2 is 7-chloro, R3 is hydrogen, X is oxygen and Y is -C (= O) OCH2CH3; and R4 is not methyl when R1 is methyl, R2 is hydrogen or 7-chloro, R3 is hydrogen, X is oxygen and Y is -C (= O) OCH2CH3. Compositions containing an MIF inhibitor are also provided in combination with a pharmaceutically acceptable carrier, as well as the use thereof in the manufacture of medicaments. The process for the preparation of said compounds and the method for detecting and selecting MIF modulating agents is also described. |