Carbidopa And L-Dopa Prodrugs And Methods Of Use

Abstract

The present disclosure relates to (a) carbidopa prodrugs, (b) pharmaceutical combinations and compositions comprising a carbidopa prodrug and/or an L-dopa prodrug, and (c) methods of treating Parkinson's disease and associated conditions comprising administering a carbidopa prodrug and an L-dopa prodrug to a subject with Parkinson's disease.

1 - 30 . (canceled) 
     
     
         31 . A crystalline polymorph of L-dopa 4′-monophosphate identified by powder X-ray diffraction wherein the crystalline polymorph is:
 crystalline L-dopa 4′-monophosphate anhydrate (i) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and 27.117±0.20; or 
 crystalline L-dopa 4′-monophosphate anhydrate (ii) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 8.468±0.20, 10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20, 24.221±0.20, 24.865±0.20, 25.647±0.20. 
 
     
     
         32 . A crystalline L-dopa 3′-monophosphate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.383±0.20. 
     
     
         33 . A crystalline L-dopa 3′4-diphosphate trihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.118±0.20, 10.342±0.20, 11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20, 24.487±0.20, and 25.11±0.20. 
     
     
         34 . A crystalline polymorph of carbidopa 4′-monophosphate identified by powder X-ray diffraction wherein the crystalline polymorph is:
 crystalline carbidopa 4′-monophosphate trihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.484±0.20, 10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20, 22.578±0.20, 22.921±0.20, and 23.822±0.20; 
 crystalline carbidopa 4′-monophosphate dihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.925±0.20, 10.28±0.20, 12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20, 22.37±0.20, and 24.167±0.20; or 
 crystalline carbidopa 4′-monophosphate dehydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 9.492±0.20, 10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.20. 
 
     
     
         35 . A crystalline polymorph of carbidopa 3′-monophosphate identified by powder X-ray diffraction wherein the crystalline polymorph is:
 crystalline carbidopa 3′-monophosphate (i) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and 22.81±0.20; or 
 crystalline carbidopa 3′-monophosphate (ii) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 4.433±0.20, 8.917±0.20, 9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20, 20.554±0.20, and 21.797±0.20. 
 
     
     
         36 . A crystalline carbidopa 3′4-diphosphate sodium salt demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 5.852±0.20, 6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20, 17.592±0.20, 18.861±0.20 and 20.305±0.20. 
     
     
         37 . A pharmaceutical composition comprising one or more of:
 crystalline L-dopa 4′-monophosphate anhydrate (i) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 10.261±0.20, 12.053±0.20, 13.759±0.20, 14.932±0.20, 16.147±0.20, 16.718±0.20, 17.34±0.20, 19.254±0.20, 20.654±0.20, 22.078±0.20, 23.599±0.20, 24.198±0.20, 25.898±0.20, 26.338±0.20, and 27.117±0.20;   crystalline L-dopa 4′-monophosphate anhydrate (ii) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 8.468±0.20, 10.234±0.20, 11.821±0.20, 13.084±0.20, 13.503±0.20, 15.48±0.20, 15.848±0.20, 16.513±0.20, 18.447±0.20, 19.346±0.20, 20.239±0.20, 21.139±0.20, 24.221±0.20, 24.865±0.20, 25.647±0.20;   crystalline L-dopa 3′-monophosphate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 8.662±0.20, 11.286±0.20, 15.079±0.20, 15.678±0.20, 16.786±0.20, 17.288±0.20, 18.438±0.20, 19.682±0.20, 20.946±0.20, 22.188±0.20, 22.671±0.20, 23.088±0.20, 24.144±0.20, 24.744±0.20, and 25.383±0.20;   crystalline L-dopa 3′4-diphosphate trihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.118±0.20, 10.342±0.20, 11.355±0.20, 12.161±0.20, 14.201±0.20, 17.36±0.20, 17.632±0.20, 19.196±0.20, 19.444±0.20, 20.83±0.20, 21.504±0.20, 22.491±0.20, 23.085±0.20, 24.487±0.20, and 25.11±0.20;   crystalline carbidopa 4′-monophosphate trihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.484±0.20, 10.05±0.20, 11.971±0.20, 13.085±0.20, 14.923±0.20, 16.095±0.20, 16.85±0.20, 17.359±0.20, 17.635±0.20, 19.269±0.20, 19.544±0.20, 21.842±0.20, 22.578±0.20, 22.921±0.20, and 23.822±0.20;   crystalline carbidopa 4′-monophosphate dihydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 7.925±0.20, 10.28±0.20, 12.344±0.20, 15.002±0.20, 15.841±0.20, 16.158±0.20, 17.565±0.20, 18.506±0.20, 19.058±0.20, 19.473±0.20, 19.702±0.20, 20.188±0.20, 20.668±0.20, 22.37±0.20, and 24.167±0.20;   crystalline carbidopa 4′-monophosphate dehydrate demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 9.492±0.20, 10.528±0.20, 15.356±0.20, 15.907±0.20, 16.165±0.20, 17.933±0.20, 18.737±0.20, 19.429±0.20, 21.176±0.20, and 22.626±0.20;   crystalline carbidopa 3′-monophosphate (i) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 9.171±0.20, 13.539±0.20, 14.23±0.20, 15.589±0.20, 15.979±0.20, 18.394±0.20, 18.832±0.20, 19.315±0.20, 22.143±0.20, and 22.81±0.20;   crystalline carbidopa 3′-monophosphate (ii) demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 4.433±0.20, 8.917±0.20, 9.654±0.20, 13.192±0.20, 15.288±0.20, 15.747±0.20, 17.886±0.20, 19.291±0.20, 20.554±0.20, and 21.797±0.20; and   crystalline carbidopa 3′4-diphosphate sodium salt demonstrating at least one characteristic peak in the powder X-ray diffraction pattern at values of two theta of 5.852±0.20, 6.861±0.20, 7.338±0.20, 11.159±0.20, 11.729±0.20, 12.953±0.20, 13.714±0.20, 14.381±0.20, 14.686±0.20, 15.479±0.20, 16.676±0.20, 17.179±0.20, 17.592±0.20, 18.861±0.20 and 20.305±0.20.   
     
     
         38 . A method of treating Parkinson's disease in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of  claim 37 . 
     
     
         39 . A pharmaceutical combination comprising a first compound corresponding in structure to Formula (I): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 1  and R 2  are each independently selected from the group consisting of hydrogen, —P(O)(OH) 2 , and —R 5 —O—P(O)(OH) 2 ; R 5  is a C 1 -C 4 -alkyl; R 6  is hydrogen or a C 1 -C 4 -alkyl; and provided that at least one of R 1  and R 2  is —P(O)(OH) 2  or —R 5 —O—P(O)(OH) 2 ; and
 a second compound corresponding in structure Formula (II): 
 
       
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein R 3  and R 4  are each independently selected from the group consisting of hydrogen, —P(O)(OH) 2 , and —R 5 —O—P(O)(OH) 2 ; R 5  is a C 1 -C 4 -alkyl; R 6  is hydrogen or a C 1 -C 4 -alkyl; and provided that at least one of R 3  and R 4  is —P(O)(OH) 2  or —R 5 —O—P(O)(OH) 2 ; and
 wherein the first compound or pharmaceutically acceptable salt thereof, and the second compound or pharmaceutically acceptable salt thereof (i) are present in separate pharmaceutical compositions or (ii) are present in a same pharmaceutical composition. 
 
       
     
     
         40 . The pharmaceutical combination of  claim 39 , wherein the first compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and the second compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         41 . The pharmaceutical combination of  claim 39 , wherein the first compound is 
       
         
           
           
               
               
           
         
       
       and the second compound is 
       
         
           
           
               
               
           
         
       
     
     
         42 . The pharmaceutical combination of  claim 39 , wherein the first compound is 
       
         
           
           
               
               
           
         
       
       and the second compound is 
       
         
           
           
               
               
           
         
       
     
     
         43 . The pharmaceutical combination of  claim 39 , wherein the first compound is 
       
         
           
           
               
               
           
         
       
       and the second compound is 
       
         
           
           
               
               
           
         
       
     
     
         44 . The pharmaceutical combination of  claim 39 , wherein the first compound is 
       
         
           
           
               
               
           
         
       
       and the second compound is 
       
         
           
           
               
               
           
         
       
     
     
         45 . The pharmaceutical combination of  claim 39 , wherein a weight ratio of the first compound or pharmaceutically acceptable salt thereof to the second compound or pharmaceutically acceptable salt thereof is from about 1:4 to about 1:10. 
     
     
         46 . The pharmaceutical combination of  claim 39 , wherein the combination is an aqueous combination suitable for intragastric, subcutaneous, intramuscular, intrajejunum, oral, intranasal or intravenous administration. 
     
     
         47 . The pharmaceutical combination of  claim 39 , wherein the combination is an aqueous combination suitable for subcutaneous administration. 
     
     
         48 . The pharmaceutical combination of  claim 39 , wherein the first compound or pharmaceutically acceptable salt thereof has a solubility of at least about 200 mg/ml in aqueous solution at about neutral pH, and the second compound or pharmaceutically acceptable salt thereof has a solubility of at least about 400 mg/ml in aqueous solution at about neutral pH. 
     
     
         49 . A method of treating Parkinson's disease comprising administering to a subject in need thereof a therapeutically effective amount of the pharmaceutical combination according to  claim 39 , wherein the first compound and the second compound (i) are administered in separate pharmaceutical compositions or (ii) are administered in a same pharmaceutical composition. 
     
     
         50 . The method of  claim 49 , wherein the first compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and the second compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         51 . The method of  claim 49 , further comprising administering another anti-Parkinson's agent to the subject. 
     
     
         52 . The method of  claim 49 , wherein the pharmaceutical combination is an aqueous combination. 
     
     
         53 . The method of  claim 52 , wherein the aqueous pharmaceutical combination is administered by intragastric, subcutaneous, intramuscular, intranasal, intrajejunum, oral or intravenous administration. 
     
     
         54 . The method of  claim 53 , wherein the aqueous pharmaceutical combination is administered by subcutaneous administration. 
     
     
         55 . The method of  claim 54 , wherein the method comprises substantially continuous administration of the pharmaceutical combination over a period of at least about 12 hours. 
     
     
         56 . A method of rescue therapy in a subject having Parkinson's disease, wherein the method comprises administering to the subject a therapeutically effective amount of the pharmaceutical combination of  claim 39 . 
     
     
         57 . A kit comprising the pharmaceutical combination of  claim 39 .