Cyclic ether vitamin D3 compounds, 1.alpha.(OH) 3-epi-vitamin D3 compounds and uses thereof

• US 6,100,294 A
• Filed: 05/15/1998
• Issued: 08/08/2000
• Est. Priority Date: 05/16/1997
• Status: Expired due to Fees

• Current Assignee: Reddy G. Satyanarayana
• Original Assignee: Women & Infants Hospital of Rhode Island
• Inventors: Reddy, Satayanarayana G.
• Primary Examiner(s): Richter, Johann
• Assistant Examiner(s): Solola, Taofiq A.
• Application Number:
  US09/079,942
• Time in Patent Office: 816 Days
• Field of Search: 549/416, 514/460, 514/451, 552/653
• US Class Current: 514/451
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 19/10 for osteoporosis
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/02 Nutrients, e.g. vitamins, minerals
• CPC Class Codes: A61P 3/14 for calcium homeostasis vitamin D A61P3/02; parathyroid hormones A61P5/18; calcitonin A61P5/22; osteoporosis A61P19/10; bone metastasis A61P35/04
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/18 of the parathyroid hormones
• CPC Class Codes: C07C 401/00 Irradiation products of cholesterol or its derivatives; Vitamin D derivatives, 9,10-seco cyclopenta[a]phenanthrene or analogues obtained by chemical preparation without irradiation
• CPC Class Codes: C07D 303/14 by free hydroxyl radicals
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 309/04 with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 309/06 Radicals substituted by oxygen atoms

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.

Claims

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.

2. The compound of claim 1, which is 1α

(OH) vitamin D3, 1α

,24 dihydroxy 3-epi vitamin D₃, 1α

hydroxy 24-ethyl 3-epi vitamin D₃, 1α

hydroxy 24-methyl 3-epi vitamin D₃, or 1α

, 24-dihydroxy 24-methyl 3-epi vitamin D₃.

12. A method of ameliorating a deregulation of calcium and phosphate metabolism, comprising administering to a subject a therapeutically effective amount of a 3-epi vitamin D₃ compound of any of claims 1 or 2, so as to ameliorate the deregulation of the calcium and phosphate metabolism.

13. The method of claim 12, wherein the deregulation of the calcium and phosphate metabolism leads to osteoporosis.

14. A pharmaceutical composition comprising, a therapeutically effective amount of a vitamin D₃ compound of claim 1, and a pharmaceutically acceptable carrier.

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.

5. The method of claim 3, wherein the disorder comprises an aberrant activity of an endocrine cell.

6. The method of claim 5, wherein the endocrine cell is a parathyroid cell and the aberrant activity is processing and/or secretion of parathyroid hormone.

10. The method of claim 3, wherein the subject is a mammal.

11. The method of claim 10, wherein the mammal is a human.

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.

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.

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.

9. The method of claim 8, wherein the disorder is selected from the group consisting of osteoporosis, osteodystrophy, senile osteoporosis, osteomalacia, rickets, osteitis fibrosa cystica, renal osteodystrophy, secondary hyperparathyrodism, cirrhosis, and chronic renal disease.

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.

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.

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.

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.

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.

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.

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.

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.

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.