Method of locking 1α-OH of vitamin D compounds in axial orientation
First Claim
Patent Images
1. A compound having the formula:
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where U is selected from the group consisting of a methyl, a substituted methyl group described by general formula CR1R2R3, an amino group or substituted amino group described by general formula NR1R2, a phosphino group or substituted phosphino group described by general formula PR1R2, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents 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; and
R is represented by the structure below 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;
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)—
, —
(CH2)x—
, —
(CR6R7)—
or —
(CH2)y—
, at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
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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
72 Claims
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1. A compound having the formula:
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where U is selected from the group consisting of a methyl, a substituted methyl group described by general formula CR1R2R3, an amino group or substituted amino group described by general formula NR1R2, a phosphino group or substituted phosphino group described by general formula PR1R2, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents 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; and
R is represented by the structure belowwhere 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;
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)—
, —
(CH2)x—
, —
(CR6R7)—
or —
(CH2)y—
, at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36)
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37. A compound having the formula:
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where U is selected from the group consisting of an amino group or substituted amino group described by general formula NR1R2, a phosphino group or substituted phosphino group described by general formula PR1R2, an alkyl- or arylsulfinyl group, an alkyl- or arylsulfonyl group, and aryl, and where R1, R2 and R3 are each independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aminoalkyl, halogenalkyl, alkoxyalkyl, aryloxyalkyl, aryl, halogen, hydroxyl, protected hydroxy, alkoxyl, aryloxyl, acyl, an amino group, an amino group substituted with alkyl or aryl substituents 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; and
R is represented by the structure belowwhere 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;
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)—
, —
(CH2)x—
, —
(CR6R7)—
or —
(CH2)y—
, at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72)
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Specification