Cyclic ether vitamin D3 compounds, 1α(OH)3-EPI-vitamin D3 compounds and uses thereof

• US 6,479,538 B1
• Filed: 07/17/2000
• Issued: 11/12/2002
• Est. Priority Date: 05/16/1997
• Status: Expired due to Fees

• Current Assignee: Women & Infants Hospital of Rhode Island
• Original Assignee: Women & Infants Hospital of Rhode Island
• Inventors: Reddy, Satayanarayana G.
• Primary Examiner(s): SOLOLA, TAOFIQ A
• Application Number:
  US09/617,881
• Time in Patent Office: 848 Days
• Field of Search: 514/451, 514/460, 549/423, 424/562, 424/573, 424/577
• 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. A packaged compound, comprising a vitamin D3 compound having the formula I as follows:

wherein A₁, A₂ and A₃ are a single or a double bond;

X, R₁, R₂, R₃, R₄ and R₅ are selected from the group consisting of a hydrogen, a halogen, a haloalkyl, a hydroxy, a hydroxy-protecting group, an alkyl, an alkenyl, an alkynyl, an alkoxy, an aryl group and a heterocyclic group, and

packaged with instructions for use of the compound for treating a disorder characterized by an aberrant activity of a vitamin D₃-responsive cell.

4. The packaged compound of claims 1 or 2, wherein the disorder comprises an aberrant activity of a hyperproliferative skin cell.

5. The packaged compound of claims 1 or 2, wherein the disorder comprises an aberrant activity of an endocrine cell.

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

7. The packaged compound of claim 6, wherein the disorder is secondary hyperparathyroidism.

8. The packaged compound of claim 7, wherein the disorder comprises an aberrant activity of a bone cell.

9. The packaged compound 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 hyperparathyroidism, cirrhosis, and chronic renal disease.

2. A packaged compound, comprising a vitamin D3 compound having the formula II as follows:

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, and

packaged with instructions for use of the compound for treating a disorder characterized by an aberrant activity of a vitamin D₃-responsive cell.

3. The packaged compound of claim 2, wherein the vitamin D3 compound 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.