Prodrugs and conjugates of prenylation inhibitors
AssigneePurdue Research Foundation
InventorsRichard Frederic Borch, Richard Anthony Gibbs, Michelle Martin Clark, Farid Fouad
Life of this patent
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Abstract
Described herein are neutral prodrugs of phosphorus-containing inhibitors of farnesyl transferase that include one or more phosphate fragments or analogs of phosphate fragments. Analogs of phosphate fragments include various linkers other than oxygen connecting the phosphate fragment to the remaining portion of the drug, such as but not limited to linkers forming phosphoramidates, phosphonates, difluorophosphonates, phosphordiamidates, and the like.
Claims26
A compound of the formula
- or a pharmaceutically-acceptable salt thereof,
- wherein
- R1 is —(CRAY;
- and n is an integer from 2 to about 5;
- R2 is —(CR2)mX;
- and m is an integer from 2 to about 5;
- R is in each instance independently selected from the group consisting of hydrogen, alkyl, haloalkyl and fluoro;
- or any two R are taken together with the attached carbons to form a ring;
- X is a nucleophilically labile group;
- Y is a polar group;
- Q is selected from the group consisting of O, NR4, CR9R10, CF2, and a bond;
- wherein R4 is hydrogen, alkyl, or acyl;
- R9 and R10 are independently selected from the group consisting of hydrogen, alkyl, haloalkyl, alkoxyl, and fluoro;
- or R9 and R10 along with the attached carbon form an optionally substituted ring;
- R3 is a biologically labile ester forming group;
- and
- Drug is a prenyl group.
10-15. (canceled)
The compound of claim 11 wherein R11 is a methyl group.
-19. (canceled)
The compound of claim 10 wherein the double bond between carbon atoms 2 and 3 has a trans configuration when the double bond between carbon atoms 6 and 7 has a cis configuration, and has a cis configuration when the double bond between carbon atoms 6 and 7 has a trans configuration.
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Dependencies are inferred from the claim text.