Stabilized thyroxine compounds

Abstract

Throxinyldimethylphosphinate was invented as a prodrug to stabilize thyroxine, a drug widely used to treat hypothyroidism and depression. The presence of the dimethylphosphinate group at the phenolic hydroxyl of thyroxine is key to preventing thyroxine from decomposing through the proposed pathway. The prodrug will be hydrolyzed in the stomach or the gut into thyroxine and the biologically inert dimethylphosphinic acid. Related products may be stabilized with the same or similar protecting groups.

1 . A composition comprising a triiodothyronine protected at a phenolic hydroxyl with a protecting group said protecting group selected from the group consisting of dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, aklylarylphosphate, acetyl, trialkylsilyl, and benzyloxy carbonyl.  
     
     
         2 . The composition  claim 1 , wherein the dialkylphosphinate is selected from a C 1  to C 18  substituted alkyl.  
     
     
         3 . The composition  claim 1 , wherein the dialkylphosphinate is selected from a C 1  to C 18  unsubstituted alkyl.  
     
     
         4 . The composition of  claim 1 , wherein the dialkylphosphinate is dimethylphosphinate  
     
     
         5 . The composition of  claim 1 , wherein the dialkylphosphinate is diethylphosphinate.  
     
     
         6 . The composition of  claim 1 , wherein the diarylphosphinate is a substituted phenyl.  
     
     
         7 . The composition of  claim 1 , wherein the diarylphosphinate is an unsubstituted phenyl.  
     
     
         8 . The composition  claim 1 , wherein the dialkylphosphate is selected from a C 1  to C 18  substituted or unsubstituted alkyl.  
     
     
         9 . The composition of  claim 1 , wherein the dialkylphosphate is dimethylphosphate  
     
     
         10 . The composition of  claim 1 , wherein the dialkylphosphate is diethylphosphate.  
     
     
         11 . The composition of  claim 1 , wherein the diarylphosphate is a substituted phenyl.  
     
     
         12 . The composition of  claim 1 , wherein the diarylphosphate is an unsubstituted phenyl.  
     
     
         13 . The composition of  claim 1 , further comprising a pharmaceutically acceptable excipient.  
     
     
         14 . A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of  claim 13 .  
     
     
         15 . The method of  claim 14  wherein said condition is hypothyroidism or depression.  
     
     
         16 . A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of  claim 1 .  
     
     
         17 . A composition comprising a reverse triiodothyronine protected at a phenolic hydroxyl with a protecting group, said protecting group selected from the group consisting of dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl.  
     
     
         18 . The composition of  claim 17 , further comprising a pharmaceutically acceptable excipient.  
     
     
         19 . A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of  claim 18 .  
     
     
         20 . The method of  claim 19  wherein said condition is hypothyroidism or depression.  
     
     
         21 . A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of  claim 17 .  
     
     
         22 . A composition comprising a 3,5 diiodothyronine protected at a phenolic hydroxyl with a protecting group, said protecting group selected from dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl  
     
     
         23 . The composition of  claim 22  wherein the 3,5 diiodothyronine is selected from 3,5 diiodothyronine, 3′,5′ diiodothyronine, and 3,3′ diiodothyronine.  
     
     
         24 . The composition of  claim 23 , further comprising a pharmaceutically acceptable excipient.  
     
     
         25 . A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of  claim 24 .  
     
     
         26 . The method of  claim 25  wherein said condition is hypothyroidism or depression.  
     
     
         27 . A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of  claim 22 .  
     
     
         28 . A composition comprising a 3-monoiodothyronine protected at a phenolic hydroxyl with a protecting group selected dialkylphosphinate, diarylphosphinate, alkylarylphosphinate, dialkylphosphate, diarylphosphate, acetyl, and benzyloxy carbonyl.  
     
     
         29 . The composition of  claim 28 , further comprising a pharmaceutically acceptable excipient.  
     
     
         30 . A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of  claim 29 .  
     
     
         31 . The method of  claim 30  wherein said condition is hypothyroidism or depression.  
     
     
         32 . A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of  claim 28 .  
     
     
         33 . A composition comprising a thyroxine protected at the phenolic hydroxyl with a protecting group selected from diarylphosphinate, alkylarylphosphinate, diarylphosphate, acetyl, and benzyloxy carbonyl.  
     
     
         34 . The composition of  claim 33 , further comprising a pharmaceutically acceptable excipient.  
     
     
         35 . A method of treating a thyroid related condition comprising treating a patient in need thereof with the composition of  claim 34 .  
     
     
         36 . The method of  claim 35  wherein said condition is hypothyroidism or depression.  
     
     
         37 . A method of stabilizing and increasing the shelf life of a thyroid hormone comprising the composition of  claim 33 .  
     
     
         38 . The pharmaceutical composition of  claim 13 ,  18 ,  24 ,  29 , or  34  wherein said composition is in the form of an ingestible tablet.  
     
     
         39 . The pharmaceutical composition of  claim 13 ,  18 ,  24 ,  29 , or  34  wherein said composition is in the form of an intravenous preparation.  
     
     
         40 . The pharmaceutical composition of  claim 13 ,  18 ,  24 ,  29 , or  34  wherein said composition is in the form of an oral dosage.