Pharmaceutically active isoindoline derivatives

摘要

Isoindolin-1-one and Isoindoline-1,3-dione substituted in the 2-position with an α-(3,4-disubstituted phenyl)alkyl group and in the 4- and/or 5-position with a nitrogen-containing group are inhibitors of, and thus useful in the treatment of disease states mediated by, TNFα and phosphodiesterase. A typical embodiment is 2-[1-(3-ethoxy-4-methoxyphenyl)-2-methylsulfonylethyl]-4,5-diaminoisoindoline-1,3-dione.

主权项

1. A method of reducing elevated levels of PDE IV in a mammal, which comprises administering thereto an effective amount of a compound of formula (I): or an acid addition salt or a substantially chirally pure isomer thereof, wherein:
each of R1 and R2, independently of the other, is alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, cyano, cycloalkoxy of 3 to 18 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, or cycloalkylmethoxy in which cycloalkyl has from 3 to 18 carbon atoms;one of X and X′ is ═C═O and the other of X and X′ is ═C═O or ═CH2;R3 is —SO2—Y, —COZ, —CN, or hydroalkyl of 1 to 6 carbon atoms in which
Y is alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;Z is —NR6″R7″, alkyl of 1 to 6 carbon atoms, phenyl, or benzyl;R6″ is hydrogen, alkyl of 1 to 4 carbon atoms, cycloalkyl of 3 to 18 carbon atoms, phenyl, benzyl, or alkanoyl of 2 to 5 carbon atoms, each of which is unsubstituted or substituted with halo, amino, or alkylamino of 1 to 4 carbon atoms;R7″ is alkyl of 1 to 4 carbon atoms;n is 1, 2, or 3;one of R4 and R5 is hydrogen and the other of R4 and R5 is imidazolyl, pyrrolyl, oxadiazolyl, triazolyl, or  in which z is 0 or 1;
R6, when taken independently of R7, is selected from cycloalkanoyl whose cycloalkyl portion contains 3 to 6 carbon atoms, each of which is unsubstituted or substituted with halo, amino, monoalkylamino or dialkylamino in which each alkyl group contains 1 to 4 carbon atoms; andR7 is hydrogen, alkyl of 1 to 4 carbon atoms, methylsulfonyl, or alkoxyalkylcarbonyl of 2 to 5 carbon atoms; orR6 and R7, taken together, are alkylidene of 1 or 2 carbon atoms substituted by amino, alkylamino, or dialkylamino, in which each alkyl group has from 1 to 4 carbon atoms, or, provided z is 1, —CH═CH—CH═CH—, or —CH═CH—N═CH—; and,the carbon atom designated * constitutes a center of chirality.