Low-calcemic oxime analogs of 1alpha,25-dihydroxy vitamin D3
AssigneesCytochroma Inc., The Johns Hopkins University
InventorsGary Posner, Mehmet Kahraman, Heung Bae Jeon, Jay A. White, Glenville Jones, Bethany Halford
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Abstract
The present invention provides novel 16-ene-C25-oxime and 16-ene-C-25-oxime ether analogs of 1α,25-dihydroxy vitamin D3, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the compound of Formula I are useful for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxy vitamin D3, for example, cell-proliferative disorders.
Claims43
A compound of Formula I, and pharmaceutically acceptable salts, hydrates, solvates, and prodrugs thereof:
- 18
- wherein
- R1 and R2 are independently selected from the group consisting of OH, OC1-6alkyl, and halo;
- R3 is C1-6alkyl;
- R4 is selected from the group consisting of H, C1-6alkyl, aryl and heteroaryl, with C1-6alkyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, halo, NH2, NHC1-4alkyl and N(C1-4alkyl)(C1-4alkyl), and with aryl and heteroaryl being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, NHC(O)C1-4alkyl, OC(O)C1-4alkyl, SOC1-4alkyl, SO2C1-4alkyl, SO2NHC1-4alkyl and SO2NH2;
- R5 is selected from the group consisting of C1-6alkyl, cyclo(C3-C6)alkyl, aryl and heteroaryl, aryl-C1-6alkyl and heteroaryl-C1-6alkyl, with C1-6alkyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, halo, NH2, NHC1-4alkyl and N(C1-4alkyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, aryl, heteroaryl, aryl-C1-6alkyl and heteroaryl-C1-6alkyl, being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, NHC(O)C1-4alkyl, OC(O)C1-4alkyl, SOC1-4alkyl, SO2C1-4alkyl, SO2NHC1-4alkyl and SO2NH2;
- and
- R6 are either both H or together form ═CH2.
A compound of Formula II and salts, hydrates and solvates thereof:
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- wherein:
- R1 and R2 are independently selected from the group consisting of OH, OC1-6alkyl,
- OPG and halo;
- PG is a protecting group;
- R3 is C1-6alkyl;
- R5 is selected from the group consisting of C1-6alkyl, cyclo(C3-C6)alkyl, aryl and heteroaryl, aryl-C1-6alkyl and heteroaryl-C1-6alkyl, with C1-6alkyl being unsubstituted or substituted with 1-4 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, halo, NH2, NHC1-4alkyl and N(C1-4alkyl)(C1-4alkyl), and with cyclo(C3-C6)alkyl, aryl, heteroaryl, aryl-C1-6alkyl and heteroaryl-C1-6alkyl, being unsubstituted or substituted with 1-5 groups independently selected from C1-4alkyl, OC1-4alkyl, OH, CF3, OCF3, halo, SH, SC1-4alkyl, NH2, NHC1-4alkyl, N(C1-4alkyl)(C1-4alkyl), CN, C(O)OH, C(O)OC1-4alkyl, C(O)NHC1-4alkyl, NHC(O)C1-4alkyl, OC(O)C1-4alkyl, SOC1-4alkyl, SO2C1-4alkyl, SO2NHC1-4alkyl and SO2NH2;
- and
- R6 are either both H or together form ═CH2.
Dependencies are inferred from the claim text.