Cyclic ether vitamin D3 compounds, 1.alpha.(OH) 3-epi-vitamin D3 compounds and uses thereof
First Claim
Patent Images
1. An isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR8## wherein A1 is a single, a double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of a hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting of a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
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Abstract
Novel cyclic ether vitamin D3 compounds having a cyclic ether side chain are disclosed. These compounds were first identified as metabolites of 3-epi vitamin D3 produced via a tissue-specific metabolic pathway which catalyzes the formation of a cyclic ether structure. Also disclosed are 1α(OH) 3-epi vitamin D3 compounds, which are produced via the epimerization of a 3-β-hydroxyl group of 1α(OH) vitamin D3 precursor in vivo. The vitamin D3 compounds of the present invention can be used as substitutes for natural and synthetic vitamin D3 compounds.
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Citations
23 Claims
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1. An isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR8## wherein A1 is a single, a double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of a hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting of a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl. - View Dependent Claims (2, 12, 13, 14)
- -hydroxy-vitamin D3 compound having formula II as follows;
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3. A method of treating a disorder characterized by an aberrant activity of a vitamin D3 -responsive cell, comprising administering to a subject an effective amount of a vitamin D3 compound having formula II as follows:
- ##STR9## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl, such that the aberrant activity of the vitamin D3 -responsive cell is reduced. - View Dependent Claims (5, 6, 10, 11)
- ##STR9## wherein A1 is a single, double, or a triple bond;
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4. A method of treating a disorder characterized by an aberrant activity of a hyperproliferative skin cell, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR10## wherein A1 is a single, a double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of a hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroaxyalkyl, a amine or a thiol, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom;
R5 and R6 are independently selected from the group consisting of hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl, such that the aberrant activity of the hyperproliferative skin cell is reduced.
- -hydroxy-vitamin D3 compound having formula II as follows;
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7. A method of treating secondary hyperparathyroidism, comprising administering to a subject an effective amount of an isolated 3-epi of a 1α
- hydroxy-vitamin D3 compound having formula II as follows;
##STR11## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- hydroxy-vitamin D3 compound having formula II as follows;
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8. A method of treating a disorder characterized by an aberrant activity of a bone cell, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR12## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl, such that the aberrant activity of the bone cell is reduced. - View Dependent Claims (9)
- -hydroxy-vitamin D3 compound having formula II as follows;
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15. A method of treating osteoporosis, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR13## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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16. A method of treating osteodystrophy, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR14## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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17. A method of treating senile osteoporosis, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR15## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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18. A method of treating osteomalacia, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR16## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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19. A method of treating rickets, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR17## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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20. A method of treating osteis fibrosa cystica, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR18## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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21. A method of treating renal osteodystrophy, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR19## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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22. A method of treating cirrhosis, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR20## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
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23. A method of treating chronic renal disease, comprising administering to a subject an effective amount of an isolated 3-epi form of a 1α
- -hydroxy-vitamin D3 compound having formula II as follows;
##STR21## wherein A1 is a single, double, or a triple bond;
A2, A3 and A4 are each independently selected from the group consisting of a single or a double bond;
R2, R3, R4, R7, R8 and R9 are independently selected from the group consisting of hydrogen, a deuterium, a deuteroalkyl, a hydroxy, an alkyl, an alkoxide, an O-acyl, a halogen, a haloalkyl, a hydroxyalkyl, an amine or a thiol group, and wherein the pairs of R2 and R3, and R4 and R7 taken together are an oxygen atom; and
R5 and R6 are independently selected from the group consisting pf a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl.
- -hydroxy-vitamin D3 compound having formula II as follows;
Specification