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US 2008/0176841 A1Published application
Epoxide inhibitors of cysteine proteases
AssigneeThe Board of Trustees of the Leland Stanford Junior University
InventorsMatthew S. Bogyo, Amir M. Sadaghiani, Steven Verhelst
Life of this patent
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Abstract
Provided herein are novel epoxide inhibitors of cysteine proteases, compositions comprising the epoxide inhibitors, and packaged pharmaceuticals. Also provided are methods of inhibiting a papain-family cysteine protease and methods of treating or preventing a disease by administering a composition containing an epoxide inhibitor of the invention. The compositions may be administered in combination with another therapeutic agent.
Claims82
A compound represented by structural formula (I):
- or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
- Y1 is O or N—R1′;
- A2 is —C(R2)(R2″)—, arylene, cycloalkylene, heteroarylene, or heterocycloalkylene, optionally substituted with 1-3 J groups;
- R2 and R2″ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, R2 and R2″ taken together with the C atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring, or R2 and R2″ taken together with the C atom to which they are attached form an alkene;
- wherein R2 and R2″ are independently optionally substituted with 1-3 J groups and wherein any alkyl carbon atom may be replaced by a heteroatom;
- R1, R1′, R2′, R3, and R3′ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom and wherein R3 and R3′ taken together with the N atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring;
- J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 μl groups;
- J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido;
- provided that when A2 is —C(R2)(R2″)—, R2 is a naturally-occurring amino acid side chain, and R2″ is H, then —Y1—R1 is not —OH, —OCH3, or —OCH2CH3;
- when A2 is —C(R2)(R2″)—, R2 is —CH2—CH(CH3)2, and R2″ is H, then R3 is not —CH2—CH2—CH2—NH—C(═NH)—NH2 or —C(H)(NH2)—CH2—CH2—CH2—NH—C(═NH)—NH2, and R3 and R3′ taken together with the N atom to which they are attached do not form a 5-membered ring substituted with carboxy;
- when A2 is —C(R2)(R2″)—, R2 is —CH2-Phenyl, and R2″ is H, then R3 and R3′ are not both —CH3;
- and
- when A2 is —C(R2)(R2″)—, R2 is —CH2—CH2—CH2—CH2—CH2—NH2, and R2″ is H, then R3 is not naphthyl.
10 more elements
A compound represented by structural formula (II):
- or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
- Y1 is O or N—H;
- A2 is —C(R2)(R2″)—, arylene, cycloalkylene, heteroarylene, or heterocycloalkylene, optionally substituted with 1-3 J groups;
- R2 and R2″ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, R2 and R2″ taken together with the C atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring, or R2 and R2″ taken together with the C atom to which they are attached form an alkene;
- wherein R2 and R2″ are independently optionally substituted with 1-3 J groups and wherein any alkyl carbon atom may be replaced by a heteroatom;
- R1 is selected from the group consisting of:
- R2′, R3, and R3′ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom;
- J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 J1 groups;
- J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido;
- provided that when Y1 is O, R1 is not
7 more elements
A compound represented by structural formula (II):
- or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
- Y1 is O or N—R1′;
- A2 is —C(R2)(R2″)—, arylene, cycloalkylene, heteroarylene, or heterocycloalkylene, optionally substituted with 1-3 J groups;
- R2″ is H;
- R2 is selected from the group consisting of:
- R1, R1′, R2′, R3, and R3′ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom and wherein R3 and R3′ taken together with the N atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring;
- J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 μl groups;
- J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido;
5 more elements
A compound represented by structural formula (II):
- or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
- Y1 is O or N—R1′;
- A2 is —C(R2)(R2″)—, arylene, cycloalkylene, heteroarylene, or heterocycloalkylene, optionally substituted with 1-3 J groups;
- R2 and R2″ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, R2 and R2″ taken together with the C atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring, or R2 and R2″ taken together with the C atom to which they are attached form an alkene;
- wherein R2 and R2″ are independently optionally substituted with 1-3 J groups and wherein any alkyl carbon atom may be replaced by a heteroatom;
- R3 is selected from the group consisting of:
- R3′ is H;
- R1, R1′, and R2′ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom;
- J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 μl groups;
- J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido;
7 more elements
A compound represented by structural formula (II):
- or a pharmaceutically acceptable derivative or prodrug thereof, wherein:
- Y1 is O or N—R1′;
- A2 is —C(R2)(R2″)—, arylene, cycloalkylene, heteroarylene, or heterocycloalkylene, optionally substituted with 1-3 J groups;
- R2 and R2″ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, R2 and R2″ taken together with the C atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring, or R2 and R2″ taken together with the C atom to which they are attached form an alkene;
- wherein R2 and R2″ are independently optionally substituted with 1-3 J groups and wherein any alkyl carbon atom may be replaced by a heteroatom;
- R1, R1′, R3, and R3′ are independently H, alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom and wherein R3 and R3′ taken together with the N atom to which they are attached complete a cyclic structure having from 4 to 8 atoms in the ring;
- R2′ is alkyl, alkenyl, alkynyl, aryl, aralkyl, aralkenyl, cycloalkyl, cycloalkenyl, heterocyclyl, heterocyclylalkyl, heterocyclylalkenyl, heteroaryl, heteroaralkyl, carboxyalkyl, or carboxamidoalkyl, and are optionally substituted with 1-3 J groups, wherein any alkyl carbon atom may be replaced by a heteroatom;
- J is alkyl, aryl, aralkyl, alkoxy, aryloxy, aralkoxy, cycloalkyl, cycloalkoxy, heterocyclyl, heterocyclyloxy, heterocyclylalkyl, heteroaryl, heteroaralkyl, keto, hydroxy, thio, amino, alkylamino, alkanoylamino, aroylamino, aralkanoylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamido and is optionally substituted with 1-3 μl groups;
- J1 is alkyl, aryl, aralkyl, alkoxy, aryloxy, heterocyclyl, heterocyclyloxy, keto, hydroxy, thio, amino, alkanoylamino, aroylamino, carboxy, carbonate, carbamate, guanidinyl, urea, halo, cyano, nitro, formyl, acyl, phosphoryl, sulfonyl, or sulfonamide.
6 more elements
Dependencies are inferred from the claim text.