Method of locking 1.alpha.-OH of vitamin D compounds in axial orientation
First Claim
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1. A compound having the formula:
- ##STR22## 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 --CR1 R2 R3, an amino group or substituted amino group of the formula --NR1 R2, a phosphino group or substituted phosphino group of the formula --PR1 R2, 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 --(CR1 R2)n -- where n is an integer having a value of from 1 to 4 and wherein any of the groups --CR1 R2 -- 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 --CR1 R2)r -- where r is an integer having a value of from 1 to 5 and wherein any of the groups --CR1 R2 -- may be replaced by an oxygen, sulfur or nitrogen atom; and
where Y5 and Y6 when taken together represent the group ═
CR4 R5 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 --(CR1 R2)s -- where s is an integer having a value of from 1 to 3; and
R is represented by the structure below ##STR23## where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, --OY, --CH2 OY, --C.tbd.CY and --CH.tbd.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;
##STR24## 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, .tbd.CR7 R8, 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 with the proviso that when Y3 and Y4 are both hydrogen then Y5 or Y6 cannot be alkyl, hydroxyalkyl or fluoroalkyl; and
when the compound has the formula ##STR25## where R10 is hydrogen or a hydroxyl group, then Y5 and Y6 cannot both be hydrogen;
or Y5 cannot be hydrogen and Y6 alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR1 R2, or a substituted methyl group of the formula --CR1 R2 R3 where R1, R2, or R3 is an hydroxyalkyl, aminoalkyl or alkoxyalkyl;
or Y6 cannot be hydrogen and Y5 alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR1 R2, or a substituted methyl group of the formula --CR1 R2 R3 where R1, R2 or R3 is an hydroxyalkyl, aminoalkyl or alkoxyalkyl; and
with the additional proviso that when the compound has the formula ##STR26## then Y5 and Y6 cannot both be hydrogen.
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Abstract
A method of modifying or altering the structure of a 1α-hydroxylated vitamin D compound to increase its biological activity by altering the conformational equilibrium of the A-ring to favor a chair conformation that presents the 1α-hydroxyl in the axial orientation. This is accomplished by either locking the A-ring chair conformation in a geometry having an axially orientated 1α-hydroxyl, or by the addition of one or more substituents to the A-ring which interact with other substituents in the molecule or on the A-ring to provide a driving force to the A-ring to adopt a chair conformation which presents the 1α-hydroxyl in the axial orientation.
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Citations
18 Claims
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1. A compound having the formula:
- ##STR22## 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 --CR1 R2 R3, an amino group or substituted amino group of the formula --NR1 R2, a phosphino group or substituted phosphino group of the formula --PR1 R2, 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 --(CR1 R2)n -- where n is an integer having a value of from 1 to 4 and wherein any of the groups --CR1 R2 -- 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 --CR1 R2)r -- where r is an integer having a value of from 1 to 5 and wherein any of the groups --CR1 R2 -- may be replaced by an oxygen, sulfur or nitrogen atom; and
where Y5 and Y6 when taken together represent the group ═
CR4 R5 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 --(CR1 R2)s -- where s is an integer having a value of from 1 to 3; and
R is represented by the structure below ##STR23## where the stereochemical center at carbon 20 may have the R or S configuration, and where Z is selected from Y, --OY, --CH2 OY, --C.tbd.CY and --CH.tbd.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;
##STR24## 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, .tbd.CR7 R8, 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 with the proviso that when Y3 and Y4 are both hydrogen then Y5 or Y6 cannot be alkyl, hydroxyalkyl or fluoroalkyl; and
when the compound has the formula ##STR25## where R10 is hydrogen or a hydroxyl group, then Y5 and Y6 cannot both be hydrogen;
or Y5 cannot be hydrogen and Y6 alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR1 R2, or a substituted methyl group of the formula --CR1 R2 R3 where R1, R2, or R3 is an hydroxyalkyl, aminoalkyl or alkoxyalkyl;
or Y6 cannot be hydrogen and Y5 alkyl, alkenyl, alkynyl, an amino group, a substituted amino group of the formula --NR1 R2, or a substituted methyl group of the formula --CR1 R2 R3 where R1, R2 or R3 is an hydroxyalkyl, aminoalkyl or alkoxyalkyl; and
with the additional proviso that when the compound has the formula ##STR26## then Y5 and Y6 cannot both be hydrogen. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15)
- ##STR22## 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;
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16. A method of treating renal osteodystrophy where it is desired to maintain or increase bone mass comprising administering to a patient with renal osteodystrophy an effective amount of 2α
- -methyl-19-nor-1α
,25-dihydroxyvitamin D3.
- -methyl-19-nor-1α
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17. A method of treating rickets where it is desired to maintain or increase bone mass comprising administering to a patient with rickets an effective amount of 2α
- -methyl-19-nor-1α
,25-dihydroxyvitamin D3.
- -methyl-19-nor-1α
-
18. A method of treating vitamin D resistant rickets where it is desired to maintain or increase bone mass comprising administering to a patient with vitamin D resistant rickets an effective amount of 2α
- -methyl-19-nor-1α
,25-dihydroxyvitamin D3.
- -methyl-19-nor-1α
Specification