Caspase inhibitors and uses thereof
AssigneeVertex Pharmaceuticals Incorporated
InventorsMichael Mortimore, Andrew Miller, John Studley, Jean-Damien Charrier
Life of this patent
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Abstract
This invention provides compounds of formula I: wherein Z is oxygen or sulfur; R1 is hydrogen, —CHN2, R, CH2OR, CH2SR, or —CH2Y; next to R3 represents a single or double bond; Y is an electronegative leaving group; R2 is CO2H, CH2CO2H, or esters, amides or isosteres thereof; R3 is a group capable of fitting into the S2 subsite of a caspase enzyme; R4 is a hydrogen or C1-6 alkyl or R3 and R4 taken together form a ring; Ring A and Ring B are each heterocyclic rings, and R and R5 are as described in the specification. The compounds are effective inhibitors of apoptosis and IL-1β secretion.
Claims8
A compound of formula Ia:
- or a pharmaceutically-acceptable salt thereof, wherein:
- next to R3 represents a single or double bond;
- Z is oxygen or sulfur;
- R1 is CH2Y;
- Y is an electronegative leaving group;
- R2 is CO2H, CH2CO2H, or esters, amides or isosteres thereof;
- R3 is hydrogen, a side chain of a natural α-amino acid, or a substituted or unsubstituted group having a molecular weight up to about 140 Daltons selected from C1-12 aliphatic, 5-14 membered aryl, (5-14 membered aryl)-(C1-12-alkyl)-, 3-9 membered heterocyclyl, or (3-9 membered heterocyclyl)-(C1-12 alkyl)-;
- wherein said R3 is optionally substituted with halogen, —R, —OR, —OH, —SH, —SR, acyloxy, phenyl (Ph), —OPh, —NO2, —CN, —NH2, —NHR, —N(R)2, —NHCOR, —NHCONHR, —NHCON(R)2, —NRCOR, —NHCO2R, —CO2R, —CO2H, —COR, —CONHR, —CON(R)2, —S(O)2R, —SONH2, —S(O)R, —SO2NHR, —NHS(O)2R, ═O, ═S, ═NNHR, ═NNR2, ═N—OR, ═NNHCOR, ═NNHCO2R, ═NNHSO2R, or ═NR;
- R is C1-6 aliphatic;
- R4 is hydrogen or a C1-6 aliphatic group that is optionally interrupted by —O—, —S—, —SO2—, —CO—, —NH—, or —N(C1-4 alkyl)-, or R3 and R4 taken together with their intervening atoms optionally form a 3-7 membered ring having 0-2 heteroatoms selected from nitrogen, oxygen or sulfur;
- Ring A is carbazole.
Dependencies are inferred from the claim text.