Synthesis and biological activity of 2-methylene analogs of calcitriol and related compounds

Abstract

Disclosed are 2-methylene analogs of vitamin D 3 and related compounds, their biological activities, and various pharmaceutical uses for these analogs. Particularly disclosed are 1α-hydroxy-2-methylene-vitamin D 3 , (20S)-1α-hydroxy-2-methylene-vitamin D 3 , and (5E)-1α,25-dihydroxy-2-methylene-vitamin D 3 , their biological activities, and various pharmaceutical uses for these compounds including methods of treating and/or preventing bone diseases and disorders.

1 . A compound having a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , and X 2 , which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group. 
       
     
     
         2 . The compound of  claim 1 , wherein X 1  and X 2  are t-butyldimethylsilyl. 
     
     
         3 . The compound of  claim 1 , wherein X 1  and X 2  are hydrogen. 
     
     
         4 . The compound of  claim 1  having a formula: 
       
         
           
           
               
               
           
         
       
       and called 1α-hydroxy-2-methylene-vitamin D 3 . 
     
     
         5 . The compound of  claim 1  having a formula: 
       
         
           
           
               
               
           
         
       
       and called (20S)-1α-hydroxy-2-methylene-vitamin D 3 . 
     
     
         6 . A pharmaceutical composition containing an effective amount of the compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         7 . A method of treating or preventing a bone disease or disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 . 
     
     
         8 . (canceled) 
     
     
         9 . A method of treating or preventing a skin disease, disorder, or condition in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 . 
     
     
         10 . A method of treating or preventing a cell proliferative disease or disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 . 
     
     
         11 . A method of treating or preventing obesity, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 . 
     
     
         12 . A method of treating secondary hyperparathyroidism of renal osteodystrophy in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 1 . 
     
     
         13 . A compound having a formula: 
       
         
           
           
               
               
           
         
         wherein: 
         X 1 , and X 2 , which may be the same or different, are each selected from hydrogen or a hydroxy-protecting group. 
       
     
     
         14 . The compound of  claim 13  having a formula: 
       
         
           
           
               
               
           
         
       
       and called (5E)-1,25-dihydroxy-2-methylene-vitamin D 3 . 
     
     
         15 . A pharmaceutical composition containing an effective amount of the compound of  claim 13  and a pharmaceutically acceptable excipient. 
     
     
         16 . A method of treating or preventing a bone disease or disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 . 
     
     
         17 . A method for increasing bone strength in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 . 
     
     
         18 . A method of treating or preventing a skin disease, disorder, or condition in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 . 
     
     
         19 . A method of treating or preventing a cell proliferative disease or disorder in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 . 
     
     
         20 . A method of treating or preventing obesity, inhibiting adipocyte differentiation, inhibiting SCD-1 gene transcription, and/or reducing body fat in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 . 
     
     
         21 . A method of treating secondary hyperparathyroidism of renal osteodystrophy in a patient in need thereof, the method comprising administering to the patient an effective amount of the compound of  claim 13 .