Method of locking 1alpha-OH of vitamin D compounds in axial orientation

A method of increasing the biological response of a 1α-hydroxylated vitamin D compound comprising

• evaluating the conformational equilibrium of the A-ring of a 1α-hydroxylated vitamin D compound to determine to what extent said 1α-hydroxyl is presented axially or equatorially;
• and
• if presented primarily equatorially, modifying the A-ring by the addition of a substituent thereto which locks said A-ring in a chair conformation that maintains the 1α-hydroxyl in said axial orientation;
• or modifying the A-ring by the addition of a substituent thereto which provides a driving force to the A-ring to adopt a chair conformation which presents the 1α-hydroxyl in said axial orientation.

A compound having the formula:

• 31
• where Y1 and Y2, which may be the same or different, are each selected from the group consisting of hydrogen and a hydroxy-protecting group;
• where Y3, Y4, Y5, Y6, Y7 and Y8, which may be the same or different, are each selected from the group consisting of hydrogen, a methyl group or substituted methyl group of the formula —CR1R2R3, an amino group or substituted amino group of the formula —NR1R2, a phosphino group or substituted phosphino group of the formula —PR1R2, an alkylsulfinyl group, an arylsulfinyl group, an alkylsulfonyl group, an arylsulfonyl group, and aryl, where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, C1-5 alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an alkyl substituted amino group, and an aryl substituted amino group, and where R1 and R2 taken together represent an oxo group or a group —(CH2)m- where m is an integer having a value of from 2 to 5;
• or Y3 and Y4 when taken together represent a methylene group;
• or Y7 and Y8 when taken together represent a methylene group;
• where Y2 and Y6, or Y2 and Y7, when taken together may represent the group —(CR1R2)n- where n is an integer having a value of from 1 to 4 and wherein any of the groups —CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom;
• where Y5 and Y8, or Y5 and Y3, or Y3 and Y8, when taken together may represent the group —(CR1R2)r- where r is an integer having a value of from 1 to 5 and wherein any of the groups —CR1R2- may be replaced by an oxygen, sulfur or nitrogen atom;
• and where Y5 and Y6 when taken together represent the group ═CR4R5 where R4 and R5, which may be the same or different, are each selected from the group consisting of hydrogen and Y3 with the proviso that R4 and R5 cannot be a hydroxyl;
• and where R4 and Y2 when taken together may represent the group —(CR1R2)s- where s is an integer having a value of from 1 to 3;
• and R is represented by the structure below 32
• where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, —OY, —CH2OY, —C≡CY and —CH═CHY, where the double bond may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —COR10 and a radical of the structure:
• 33
• where x and y, independently, represent the integers from 0 to 5, where R6 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluoro, trifluoromethyl, and C1-5-alkyl, which may be straight chain or branched and, optionally, bear a hydroxy or protected-hydroxy substituent, and where each of R7, R8, and R9, independently, is selected from deuterium, deuteroalkyl, hydrogen, fluoro, trifluoromethyl and C1-5 alkyl, which may be straight-chain or branched, and optionally, bear a hydroxy or protected-hydroxy substituent, and where R6 and R7, taken together, represent an oxo group, or an alkylidene group, ═CR7R8, or the group —(CH2)p-, where p is an integer from 2 to 5, and where R8 and R9, taken together, represent an oxo group, or the group —(CH2)q-, where q is an integer from 2 to 5, and where R10 represents hydrogen, hydroxy, protected hydroxy, or C1-5 alkyl and wherein any of the CH-groups at positions 20, 22, or 23 in the side chain may be replaced by a nitrogen atom, or where any of the groups —CH(CH3)—, —CH(R3)—, or —CH(R2)— at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.