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US 6,191,277 B1Granted
Hydroxypropylamide peptidomimetics as inhibitors of aspartyl proteases
AssigneePharmacopeia, Inc.
InventorsRoland Ellwood Dolle, III, Cullen Lee Cavallaro, Timothee Felix Herpin
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Abstract
Compounds of Formula I are disclosed as inhibitors having activity against the aspartyl proteases, plasmepsin and cathsepsin D. The compounds are useful for treatment of diseases such as malaria and Alzheimer's disease. In preferred compounds of Formula I, Y is a heterocycle, amide, sulfonamide or carbamate and Z is an acyl or a functionalized acyl. Intermediates in the solid phase synthesis of compounds of Formula I, in which compounds are attached to a solid phase support, are also disclosed.
Claims25
A compound of Formula I:
- wherein:
- R1 is selected from the group consisting of alkyl, and —(CH2)n-cycloalkyl and where n=1-3;
- R2 is H or [S]—C(O)—L—, wherein [S] is a solid support and —L— is a linker;
- Y is —OC(O)NHR3 or —NR4R5, wherein R3 is alkyl, aralkyl, aryl or aryloxyalkyl;
- R4 and R5 are independently selected from the group consisting of H, alkoxyalkyl, R3, —C(O)R3, —SO2R3,
- wherein m=0-3;
- or when R4 and R5 together with the nitrogen atom to which they attach is
- where X=NR6 or O;
- R6 is selected from the group consisting of H, R3, —C(O)R3 and —SO2R3;
- Z is selected from the group consisting of —C(O)R7, —C(O)CH(R8)OC(O)NHR3 and —C(O)CH(R8)NHC(O)R3;
- wherein
- R7 is selected from the group consisting of alkyl, aralkyl, aryl, —(CH2)m-cycloalkyl, heteroaryl,
- and
- R8 is selected from the group consisting of H, alkyl, aralkyl and —(CH2)m-cycloalkyl.
11 more elements
A compound of Formula I:
- wherein:
- R1 is selected from the group consisting of alkyl, —(CH2)n-cycloalkyl and aralkyl;
- where n=1-3;
- R2 is [S]—C(O)—L—, wherein [S] is a solid support and —L— is a linker;
- Y is —OC(O)NHR3 or —NR4R5, wherein R3 is alkyl, aralkyl, aryl or aryloxyalkyl;
- R4 and R5 are independently selected from the group consisting of H, alkoxyalkyl, R3, —C(O)R3, —SO2R3,
- wherein m=0-3;
- or when R4 and R5 together with the nitrogen atom to which they attach is
- where X=NR6 or O;
- R6 is selected from the group consisting of H, R3, —C(O)R3 and —SO3R3;
- Z is selected from the group consisting of —C(O)R7, —C(O)CH(R8)OC(O)NHR3 and —C(O)CH(R8)NHC(O)R3;
- wherein
- R7 is selected from the group consisting of alkyl, aralkyl, aryl, —(CH2)m-cyclolkyl, heteroaryl,
- and
- R8 is selected from the group consisting of H, alkyl, aralkyl and —(CH2)m-cycloalkyl.
12 more elements
A compound of Formula I:
- wherein:
- R1 is selected from the group consisting of alkyl, —(CH2)n— cycloalkyl and aralkyl;
- where n=1-3;
- R2 is H or [S]—C(O)—L—, wherein [S] is a solid support and —L— is a linker;
- Y is —OC(O)NHR3 or —NR4R5, wherein R3 is alkyl, aralkyl, aryl or aryloxyalkyl;
- R4 and R5 are independently selected from the group consisting of H, alkoxyalkyl, R3, —C(O)R3, —SO2R3,
- wherein m=0-3;
- Z is selected from the group consisting of —C(O)R7, —C(O)CH(R8)OC(O)NHR3 and —C(O)CH(R8)NHC(O)R3;
- wherein
- R7 is selected from the group consisting of alkyl, aralkyl, aryl, —(CH2)m-cycloalkyl, heteroaryl,
- and
- R8 is selected from the group consisting of H, alkyl, aralkyl and
- —(CH2)m-cycloalkyl.
10 more elements
Dependencies are inferred from the claim text.