Nitric oxide releasing oxindole prodrugs with analgesic and anti-inflammatory properties

摘要

Nitric oxide releasing oxindole prodrugs are described which are useful in methods of treating or preventing pain, inflammation, fever, or gastrointestinal lesions in a patient in need of such treatment, or of modifying an inflammatory disease or condition by favorably affecting the outcome thereof in said patient, wherein there is administered to said patient a therapeutically effective amount of a compound of Formula (I); and pharmaceutically acceptable salts thereof: whereinX is a covalent bond, -O-, -S-, or -N(R1)-;RA and RB are members independently selected from the group consisting essentially of H; (C1-C4)alkyl; (C3-C6)cycloalkyl; phenyl; or taken together with the carbon atom to which they are attached, form a bridging (C3-C6)cycloalkyl moiety;n is an integer selected from 1 through 6, inclusive;Y is a covalent bond -O-, -S-, or -N-;Z is -NO or -NO2;RC is a member independently selected from the group consisting essentially of H, F, Cl, Br, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, CF3, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, NO2, phenyl, (C2-C4)alkanoyl, benzoyl, thenoyl, (C2-C4)alkanamido, benzamido, and N,N-di-(C1-C3)alkylsulfamoyl;RD is a member independently selected from the group consisting essentially of H, F, Cl, Br, (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, and CF3; orRC and RD when taken together are a methylenedioxy group or an ethylenedioxy group; or form a divalent radical D, wherein D is selected from the group consisting essentially of wherein W is O or S;RE is a member independently selected from the group consisting essentially of (C1-C6)alkyl, (C3-C7)cycloalkyl, (C4-C7)cycloalkenyl, phenyl, phenyl(C1-C3)alkyl, phenoxy(C1-C3)alkyl, thiophenoxy(C1-C3)alkyl, naphtyl, bicyclo[2.2.1]heptan-2-yl, bicyclo[2.2.1]hept-5-en-2-yl, and -(CH2)m-Q-R2;R7 and R9 are independently selected from the group consisting essentially of hydrogen, (C1-C3)alkyl, -C(=O)(C1-C3)alkyl, phenyl, and -C(=O)N(R8)(R10).