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 with the proviso that U cannot be an —
OH group; 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.
1 Assignment
0 Petitions
Accused Products
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.
17 Citations
38 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 with the proviso that U cannot be an —
OH group; 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)
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7. A method of treating metabolic bone disease where it is desired to maintain or increase bone mass comprising administering to a patient with said disease an effective amount of 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 with the proviso that U cannot be an —
OH group; 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 (8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
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20. A method of treating a disease characterized by abnormal cell proliferation or cell differentiation comprising administering to a patient with said disease an effective amount of 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 with the proviso that U cannot be an —
OH group, 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 (21, 22, 23)
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24. A method of treating a disease characterized by an imbalance in the immune system comprising administering to a patient with said disease an effective amount of a compound having the formula:
-
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, alkoxy, 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 with the proviso that U cannot be an —
OH group, 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, independenly, represent the integers from 0 to 5, where R6 is selected from hydrogen, deuterium, hydroxy, protected hydroxy, fluro, trifuoromethyl, 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 (25, 26, 27)
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28. A method of treating rheumatoid arthritis comprising administering to a patient with rheumatoid arthritis an effective amount of a compound having the formula:
-
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, alkoxy, 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 with the proviso that U cannot be an —
OH group, 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 th 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 hydoxy 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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29. A method of treating asthma comprising administering to a patient with asthma an effective amount of a compound having the formula:
-
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 the value of from 2 to 5, and with the proviso that U cannot be an —
OH group, 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 —
(CH3)y—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
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30. A method of treating hypertension comprising administering to a patient with hypertension an effective amount of 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 with the proviso that U cannot be an —
OH group, 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.
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31. A method of treating hypocalcemia comprising administering to a patient hypocalcemia an effective amount of a compound having the formula:
-
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 with the proviso that U cannot be an —
OH group, 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.
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32. A method of treating hypoparathroidism comprising administering to a patient with hypoparathroidism an effective amount of a compound having the formula:
-
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 with the proviso that U cannot be an —
OH group, 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.
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33. A method of treating female infertility which comprises administering to a female mammal in need thereof an effective amount of a compound having the formula:
-
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, acyl, an amino group, an amino group substituted with alkyl or aryl substitutuents 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 with the proviso that U cannot be an —
OH group, 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 substitutuent, and where each of R7, R8, 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 th 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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34. A method of treating acne comprising administering to a patient with acne an effective amount of a compound having the formula:
-
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, alkoxy, 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 with the proviso that U cannot be an —
OH group, 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 fro 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 substituents, 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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35. A method of treating alopecia comprising administering to a patient with alopecia an effective amount of a compound having the formula:
-
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 arysulfinyl 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 with the proviso that U cannot be an —
OH group, 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 staight 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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-
36. A method of treating skin conditions selected from the group consisting of lack of skin firmness, wrinkles, lack of dermal hydration and insufficient sebum secretion which comprises administering to a patient by topical, oral or parenteral means an effective amount of a compound having the formula:
-
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 with the proviso that U cannot be an —
OH group, 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 placed 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.
-
-
37. A method of treating a disease characterized by abnormal cell proliferation or cell differentiation, said disease is psoriasis, comprising administering to a patient with said disease an effective amount of a compound having the formula:
-
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 with the proviso that U cannot be an —
OH group, 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.
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-
38. A method of treating a disease characterized by abnormal cell proliferation or cell differentiation, said disease comprising a skin disorder selected from the group consisting of dermatitis, eczema and keratosis, comprising administering to a patient with said disease an effective amount of a compound having the formula:
-
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, alkoxxAkyl, 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 with the proviso that U cannot be an —
OH group, 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, —
C0R10 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.
-
Specification