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

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.

1 . An isolated cyclic ether vitamin D3 compound having the formula (I) as follows: 
       
         
           
           
               
               
           
         
         wherein A 1 , A 2  and A 3  are a single or a double bond; X, R 1 , R 2 , R 3 , R 4  and R 5  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. 
       
     
     
         2 . An isolated 3-epi form of 1α-hydroxy-vitamin D3 compounds having the formula II as follows: 
       
         
           
           
               
               
           
         
         wherein A 1  is a single, a double, or a triple bond; A 2 , A 3  and A4 are each independently selected from the group consisting of a single or a double bond; R 2 , R 3 , R 4 , R 7 , R 8  and R 9  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 R 2  and R 3 , and R 4  and R 7  taken together are an oxygen atom; and R 5  and R 6  are independently selected from the group consisting of a hydrogen, a deuterium, a halogen, an alkyl, a hydroxyalkyl, a haloalkyl, and a deuteroalkyl. 
       
     
     
         3 . The compound of  claim 2 , which is 1α(OH) vitamin D3, 1α, 24 dihydroxy 3-epi vitamin D 3 , 1α hydroxy 24-ethyl 3-epi vitamin D 3 , 1α hydroxy 24-methyl 3-epi vitamin D 3 , or 1α, 24-dihydroxy 24-methyl 3-epi vitamin D 3 . 
     
     
         4 . A method of treating a disorder characterized by an aberrant activity of a vitamin D 3 -responsive cell, comprising administering to a subject an effective amount of a vitamin D 3  compound having the formula (I) or (II) of  claim 2 , such that the aberrant activity of the vitamin D 3 -responsive cell is reduced. 
     
     
         5 . The method of  claim 4 , wherein the disorder comprises an aberrant activity of a hyperproliferative skin cell. 
     
     
         6 . The method of  claim 4 , wherein the disorder comprises an aberrant activity of an endocrine cell. 
     
     
         7 . The method of  claim 6 , wherein the endocrine cell is a parathyroid cell and the aberrant activity is processing and/or secretion of parathyroid hormone. 
     
     
         8 . The method of  claim 7 , wherein the disorder is secondary hyperparathyroidism. 
     
     
         9 . The method of  claim 8 , wherein the disorder comprises an aberrant activity of a bone cell. 
     
     
         10 . The method of  claim 9 , 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. 
     
     
         11 . The method of  claim 4 , wherein the subject is a mammal. 
     
     
         12 . The method of  claim 11 , wherein the mammal is a human. 
     
     
         13 . 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 D 3  compound of  claim 2 , so as to ameliorate the deregulation of the calcium and phosphate metabolism. 
     
     
         14 . The method of  claim 13 , wherein the deregulation of the calcium and phosphate metabolism leads to osteoporosis. 
     
     
         15 . A pharmaceutical composition comprising, a therapeutically effective amount of a vitamin D 3  compound of  claim 2 , and a pharmaceutically acceptable carrier. 
     
     
         16 . The composition of  claim 15 , which is suitable for topical or oral administration. 
     
     
         17 . A packaged compound, comprising a vitamin D 3  compound of  claim 2 , packaged with instructions for use of the compound for treating a disorder characterized by an aberrant activity of a vitamin D 3 -responsive cell.