Nitroxide modified non-steroidal anti-inflammatory compounds and uses thereof in the treatment and prevention of diseases or disorders

摘要

Disclosed are nitroxide modified NSAID compounds of the formula (I) or a pharmaceutically acceptable salt or enantiomer thereof:;;in which R1, R2, R3, R4, R5, R6, R7, R8, R9, R10, R11, and n are defined herein and pharmaceutical compositions thereof. Further disclosed is a method of treating or preventing various disorders, such as inflammation, cancer, diabetes, a cardiovascular disorder, weight gain, polyps, and/or chronic pain, in a patient comprising administering an effective amount of a compound or pharmaceutically acceptable salt or enantiomer of formula (I). A method of imaging the compound or pharmaceutically acceptable salt or enantiomer of formula (I) in the body of the animal is also provided.

主权项

1. A compound of formula (I): wherein
R1 is O.;R2, R3, R4, and R5 are the same or different and are selected from the group consisting of hydrogen, C1-12 alkyl, C2-12 alkenyl, and C2-12 alkynyl;R6 and R7 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, mercapto, cyano, isothiocyanato (—NCS), C1-12 alkyl, C2-12 alkenyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-30 aryl, C1-12 alkoxy, C1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylcarbonylamino, haloalkylcarbonylamino, and an NSAID moiety having NSAID activity, wherein the NSAID moiety is optionally substituted with one or more triphenylphosphinyl C1-C12 alkyl substituents; or R6 and R7 together form ═O;R8, R9, R10, and R11 are the same or different and are selected from the group consisting of hydrogen, halogen, hydroxyl, mercapto, cyano, isothiocyanato (—NCS), C1-12 alkyl, C2-12 alkenyl, C3-8 cycloalkyl, C3-8 heterocycloalkyl, C6-30 aryl, C1-12 alkoxy, C1-12 alkylthio, amino, alkylamino, dialkylamino, arylamino, diarylamino, alkylsulfonyloxy, carboxyl, alkylcarbonyl, arylcarbonyl, hydroxyalkyl, mercaptoalkyl, carboxyalkyl, carboxyaryl, alkylcarbonylalkyl, alkylcarbonylaryl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, arylaminoalkyl, diarylaminoalkyl, alkylcarbonylamino, haloalkylcarbonylamino, and an NSAID moiety having NSAID activity, wherein the NSAID moiety is optionally substituted with one or more triphenylphosphinyl C1-C12 alkyl substituents;optionally one of R6 and R7 and one of R8 and R9 can be absent such that a double bond joins the two carbon atoms to which the remaining one of R6 and R7 and the remaining one of R8 and R9 are attached; andn is 0 or 1;with the condition that the compound of formula (I) contains at least two NSAID moieties, each optionally substituted with one or more triphenylphosphinyl C1-C12 alkyl substituents, bonded thereto;wherein the NSAID moieties are each optionally bonded through a linking group;or a pharmaceutically acceptable salt thereof or an enantiomer thereof,wherein the NSAID of the NSAID moieties is selected from the group consisting of fenoprofen, ketoprofen, oxaprozin, indomethacin, sulindac, etodolac, diclofenac, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, celecoxib, rofecoxib, valdecoxib, parecoxib, lumiracoxib, etoricoxib, nimesulide, niflumic acid, and licofenac.