19-Nor-Vitamin D Analogs with 1,2-Dihydrofuran Ring
First Claim
Patent Images
1. A compound having the formula:
- where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula;
where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;
where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.
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Accused Products
Abstract
19-nor-vitamin D analogs having an additional dihydrofuran ring connecting the 1α-oxygen and carbon-2 of the A-ring of the analog, and pharmaceutical uses therefore, are described. These compounds exhibit selective in vitro and in vivo activities, making them therapeutic agents for the treatment or prophylaxis of autoimmune diseases, some types of cancers, secondary hyperparathyroidism, psoriasis, or other skin diseases.
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Citations
77 Claims
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1. A compound having the formula:
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where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (2, 3, 4, 5)
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6. 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D3 having the formula:
- 7. A pharmaceutical composition containing an effective amount of 1,2-dihydrofuran-25-hydroxy-19-nor-vitamin D3 together with a pharmaceutically acceptable excipient.
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10. A method of treating psoriasis comprising administering to a subject with psoriasis an effective amount of a compound having the formula:
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where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (11, 12, 13, 14, 15, 16, 17, 18, 19)
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20. A method of treating a disease selected from the group consisting of leukemia, colon cancer, breast cancer, skin cancer or prostate cancer comprising administering to a subject with said disease an effective amount of a compound having the formula:
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where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (21, 22, 23, 24, 25, 26, 27, 28)
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29. A method of treating an autoimmune disease selected from the group consisting of multiple sclerosis, lupus, diabetes mellitus, host versus graft rejection, and rejection of organ transplants, comprising administering to a subject with said disease an effective amount of a compound having the formula:
-
where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (30, 31, 32, 33, 34, 35, 36, 37)
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38. A method of treating an inflammatory disease selected from the group consisting of rheumatoid arthritis, asthma, and inflammatory bowel diseases, comprising administering to a subject with said disease an effective amount of a compound having the formula:
-
where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (39, 40, 41, 42, 43, 44, 45, 46)
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47. A method of treating a skin condition selected from the group consisting of wrinkles, lack of adequate skin firmness, lack of adequate dermal hydration and insufficient sebum secretion which comprises administering to a subject with said skin condition an effective amount of a compound having the formula:
-
where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (48, 49, 50, 51, 52, 53, 54, 55, 56)
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57. A method of treating renal osteodystrophy comprising administering to a subject with renal osteodystrophy an effective amount of a compound having the formula:
-
where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (58, 59, 60, 61, 62, 63, 64, 65)
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66. A method of treating obesity of an animal, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in an animal comprising administering to an animal in need thereof an effective amount of a compound having the formula:
-
where Y is selected from the group consisting of hydrogen and a hydroxy-protecting group, and where the group R represents an alkyl, hydrogen, hydroxyalkyl, or fluoroalkyl group, or R may represent a side chain of the formula; where Z in the above side chain structure is selected from Y, —
OY, —
CH2OY, —
C≡
CY and —
CH═
CHY, where the double bond in the side chain may have the cis or trans geometry, and where Y is selected from hydrogen, methyl, —
COR5 and a radical of the structure;where m and n, independently, represent the integers from 0 to 5, where R1 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 R2, R3, and R4, 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 R1 and R2, taken together, represent an oxo group, or an alkylidene group having a general formula CkH2k—
where k is an integer, the group ═
CR2R3, or the group —
(CH2)p—
, where p is an integer from 2 to 5, and where R3 and R4, taken together, represent an oxo group, or the group —
(CH2)q—
, where q is an integer from 2 to 5, and where R5 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)m—
, —
CR1R2—
or —
(CH2)n—
at positions 20, 22, and 23, respectively, may be replaced by an oxygen or sulfur atom.- View Dependent Claims (67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77)
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75. The method of claim 66 wherein the animal is a human.
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76. The method of claim 66 wherein the animal is a domestic animal.
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77. The method of claim 66 wherein the animal is an agricultural animal.
Specification