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US 6,686,335 B1Granted
Hydroxamate-containing cysteine and serine protease inhibitors
AssigneeCephalon, Inc.
InventorsKurt Allen Josef, John P. Mallamo, Ron Bihovsky
Life of this patent
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Abstract
The present invention is directed to hydroxamate-containing inhibitors of cysteine and serine proteases. Methods for the use of the protease inhibitors are also described.
Claims60
A compound having the Formula I:
- or pharmaceutically acceptable salts thereof;
- wherein:
- W is A—B—D;
- A is aryl(CH2)n, heteroaryl(CH2)n, alkyl having from one to about 14 carbons, alkenyl having from two to about 14 carbons, or cycloalkyl having from 3 to about 10 carbons, said A group being optionally substituted with one or more J groups;
- B is a bond or CO, SO, SO2, OCO, NR5CO, NR5SO2, or NR5SO;
- D is a bond, an amino acid residue, or a peptide composed of 2 to about 5 amino acid residues, said amino acid residue(s) being independently defined by the formula—NH—**CH(R6)—CO—, in which ** denotes the α carbon of an α-amino acid residue possessing, when R6 is other than hydrogen, the D-configuration, the L-configuration, or a mixture of D- and L-;
- n is an integer from 0 to about 6;
- R1, R2, R3, R4, R5 and R6 are, independently, hydrogen, alkyl having from one to about 14 carbons, or cycloalkyl having from 3 to about 10 carbons, said alkyl, and cycloalkyl groups being optionally substituted with one or more J groups;
- and
- J is halogen, lower alkyl, aryl, heteroaryl, haloaryl, amino optionally substituted with one to three aryl or lower alkyl groups, guanidino, alkoxycarbonyl, amido, lower alkylamido, sulfonamido, lower alkyl sulfonamido, lower alkylsulfonyl, lower alkylsulfoxy, lower alkylthio, lower alkoxy, aryloxy, arylalkyloxy, hydroxy, carboxy, cyano, or nitro;
- and
- * denotes the α carbon of an α-amino acid residue possessing, when R2 is other than hydrogen, the D-configuration, the L-configuration, or a mixture of the D- and L-configurations.
9 more elements
A compound of the formula:
- wherein W, R1, R2, R3 and R4 are selected in accordance with the following table:
- W R1 R2 R3 R4 BnOCO Bn L-CH2CH(CH3)2 H CH3 BnOCO Bn L-CH2CH(CH3)2 H CH2CH3 BnOCO Bn L-CH2CH(CH3)2 H Bn BnOCO Bn L-CH2CH(CH3)2 H CH2C6F5 BnOCO Bn L-CH2CH(CH3)2 H tBu BnOCO Bn L-CH2CH(CH3)2 H (4-methyl- cyclohexyl) CH3SO2 CH2OCH3 D-CH2OBn H Bn CH3SO2 Bn D-CH2OBn H Bn CH3SO2 Bn D-CH2OBn H CH2CH3 BnOCO Bn L-CH(CH3)2 H Bn BnOCO (CH2)3CH3 L-CH(CH3)2 H Bn Cbz-Leu Bn L-CH2CH(CH3)2 H CH3 Cbz-Leu Bn L-CH2CH(CH3)2 H Bn PhCO (CH2)3CH3 L-Bn H CH2CH3 BnOCO Bn L-CH2CH(CH3)2 H (CH2)3CH3
- or pharmaceutically acceptable salts thereof.
A compound of formula:
- wherein * denotes the L-configuration;
- W is benzyloxycarbonyl;
- R1 is benzyl;
- R3 is H;
- R2 is —CH2CH(CH3)2 or —CH(CH3)2;
- and R4 is selected from the group consisting of —CH3, —CH2CH3, benzyl, —CH2C6F5, t-butyl, and 4-methylcyclohexyl.
3 more elements
Dependencies are inferred from the claim text.