24-sulfoximine vitamin D3 compounds
AssigneesCytochroma Inc., The Johns Hopkins University
InventorsGary Posner, Mehmet Kahraman, Uttam Saha
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Abstract
The present invention provides novel sulfoximine compounds, compositions comprising these compounds and methods of using these compounds as inhibitors of CYP24. In particular, the compounds of the invention are useful for treating diseases which benefit from a modulation of the levels of 1α,25-dihydroxy vitamin D3, for example, cell-proliferative disorders.
Claims28
A method for treating diseases which benefit from an inhibition of the catabolism of:
- 1α,25-dihydroxy vitamin D3, or analogs thereof, comprising administering to a cell or animal in need thereof, an effective amount of a compound selected from a compound of Formula I, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof:
- wherein
- R1 is selected from the group consisting of OR, OC1-4alkyl, and halo;
- R2 is selected from the group consisting of H, OH, OC1-4alkyl, and halo;
- each R3 are either both H or together form ═CH2;
- R4 is C1-4alkyl;
- represents a single or a double bond;
- each R5 can be the same or different and is selected from the group consisting of hydrogen, halo and C1-4alkyl or each R5 can be taken together to form a C3-6cycloalkyl ring;
- R6 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo;
- R7 is selected from the group consisting of H, C1-6alkyl and C(O)R8;
- and
- R8 is selected from the group consisting of C1-alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo,
- provided that when there is a double bond between C22 and C23, there is only one R5 group attached to C23 and R5 is selected from the group consisting of hydrogen, halo and C1-4alkyl, wherein the prodrug is a phenyl ester, aliphatic (C8-C24) ester, acyloxymethyl ester, carbamate or amino acid ester formed from an available hydroxy, thiol, amino or carboxy group of a compound of Formula I.
A method for increasing the efficacy of a vitamin D receptor agonist comprising co-administering, to an animal or cell in need thereof, an effective amount of a vitamin D receptor agonist and an effective amount of a compound selected from a compound of Formula I, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof:
- wherein
- R1 is selected from the group consisting of OH, OC1-4alkyl, and halo;
- R2 is selected from the group consisting of H, OH, OC1-4alkyl, and halo;
- each R3 are either both H or together form ═CH2;
- R4 is C1-4alkyl;
- represents a single or a double bond;
- each R5 can be the same or different and is selected from the group consisting of hydrogen, halo and C1-4alkyl or each R5 can be taken together to form a C3-6cycloalkyl ring;
- R6 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo;
- R7 is selected from the group consisting of H, C1-6alkyl and C(O)R8;
- and
- R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo,
- provided that when there is a double bond between C22 and C23, there is only one R5 group attached to C23 and R5 is selected from the group consisting of hydrogen, halo and C1-4alkyl, wherein the prodrug is a phenyl ester, aliphatic (C8-C24) ester, acyloxymethyl ester, carbamate or amino acid ester formed from an available hydroxy, thiol, amino or carboxy group of a compound of Formula I.
A method of treating cancer, dermatological disorders, parathyroid disorders, autoimmune disorders or bone disorders comprising administering to an animal or cell in need thereof and in combination with one or more therapies or therapeutics to treat cancer, dermatological disorders, parathyroid disorders, autoimmune disorders or bone disorders, a compound selected from a compound of Formula I, and pharmaceutically acceptable salts, hydrates, solvates and prodrugs thereof:
- wherein
- R1 is selected from the group consisting of OH, OC1-4alkyl, and halo;
- R2 is selected from the group consisting of H, OH, OC1-4alkyl, and halo;
- each R3 are either both H or together form ═CH2;
- R4 is C1-4alkyl;
- represents a single or a double bond;
- each R5 can be the same or different and is selected from the group consisting of hydrogen, halo and C1-4alkyl or each R5 can be taken together to form a C3-6cycloalkyl ring;
- R6 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo;
- R7 is selected from the group consisting of H, C1-6alkyl and C(O)R8;
- and
- R8 is selected from the group consisting of C1-6alkyl, C3-6cycloalkyl, aryl-C1-4alkyl, aryl and heteroaryl, wherein each of C1-6alkyl, C3-6cycloalkyl, aryl and heteroaryl are either unsubstituted or substituted with 1-5 substituents independently selected from the group consisting of C1-4alkyl, OC1-4alkyl, CF3, NO2 and halo,
- provided that when there is a double bond between C22 and C23, there is only one R5 group attached to C23 and R5 is selected from the group consisting of hydrogen, halo and C1-4alkyl, wherein the prodrug is a phenyl ester, aliphatic (C8-C24) ester, acyloxymethyl ester, carbamate or amino acid ester formed from an available hydroxy, thiol, amino or carboxy group of a compound of Formula I.
Dependencies are inferred from the claim text.