Method for the Treatment of Pompe Disease Using 1-Deoxynojirimycin Derivatives

Abstract

The present invention provides a method for increasing the activity of a mutant or wild-type α-glucosidase enzyme in vitro and in vivo by contacting the enzyme with a specific pharmacological chaperone which is a derivative of 1-deoxynojirimycin. The invention also provides a method for the treatment of Pompe disease by administration of chaperone small molecule compound which is a derivative of 1-deoxynojirimycin. The I-deoxynojirimycin derivative is substituted at the N or C1 position. Combination therapy with replacement α-glucosidase gene or enzyme is also provided.

1 - 38 . (canceled) 
     
     
         39 . A method for treating Pompe disease in an individual in need thereof, the method comprising administering to the individual:
 replacement acid α-glucosidase (Gaa); and   a 1-deoxynojirimycin derivative comprising a compound of the formula:   
       
         
           
           
               
               
           
         
       
       where R 1  is H or a straight or branched alkyl, cycloalkyl, cycloalkalkyl, alkenyl, alkoxyalkyl or aminoalkyl containing 1-12 carbon atoms, an aryl, alkylaryl, heteroaryl, or heteroaryl alkyl containing 5-12 ring atoms, where R1 is optionally substituted with one or more —OH, —OOH, —Cl, —F, —CF 3 , —OCF 3 , —O—C(═O)N-(alkyl) 2 , —BOC, -Cyano, —O-alkyl; R 2  is H; a straight or branched alkyl, cycloalkyl, alkenyl, or alkoxylalkyl, containing 1-9 carbon atoms or aryl containing 5-12 carbon atoms, wherein R 2  is optionally substituted with —OH, —COOH, —CF 3 , —OCF 3  or a heterocyclic ring; and wherein at least one of R 1  and R 2  is not H; or a pharmaceutically acceptable salt thereof,
 wherein the 1-deoxynojirimycin derivative is not 1-deoxynojirimycin or α-homonojirimycin. 
 
     
     
         40 . The method of  claim 39 , wherein R 1  is a straight or branched alkyl, cycloalkyl, or alkoxyalkyl containing 1-9 carbon atoms optionally substituted with a —OH, —COOH, CF 3 , OCF 3 , or —C(═O)N-(Me) 2 ; and R 2  is H. 
     
     
         41 . The method of  claim 39 , wherein R 1  is n-butyl, n-methyl, n-ethyl, n-cyclopropyl methyl, or n-nonyl or n-ethyl or n-butyl substituted with a —OH, —COOH, CF 3 , OCF 3 , or —C(═O)N-(Me) 2 ; or R 1  is 
       
         
           
           
               
               
           
         
       
     
     
         42 . The method of  claim 39 , wherein the DNJ derivative is selected from the group consisting of N-butyl-DNJ, N-methyl-DNJ, N-cyclopropylmethyl-DNJ, N-cyclopentylmethyl-DNJ, N-(2-(N,N-dimethylamido)ethyloxy-DNJ, N-4-t-butyloxycarbonyl-piperidnylmethyl-DNJ, N-2-R-tetrahydrofuranylmethyl-DNJ, N-2-R-tetrahydrofuranylmethyl-DNJ, N-(2-(2,2,2-trifluoroethoxy)ethyl-DNJ, N-2-methoxyethyl-DNJ, N-2-ethoxyethyl-DNJ, N-4-trifluoromethylbenzyl-DNJ, N-alpha-cyano-4-trifluoromethylbenzyl-DNJ, N-4-trifluoromethoxybenzyl-DNJ, N-4-n-pentoxybenzyl-DNJ, and N-4-n-butoxybenzyl-DNJ, or C1-nonyl DNJ. 
     
     
         43 . The method of  claim 42 , wherein R 1  is n-butyl. 
     
     
         44 . The method of  claim 39 , wherein the replacement Gaa and the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof are formulated in separate formulations. 
     
     
         45 . The method of  claim 44 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof are administered by the same route. 
     
     
         46 . The method of  claim 44 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof and the replacement Gaa are administered by different routes. 
     
     
         47 . The method of  claim 46 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof is administered by oral administration and the replacement Gaa is administered by intravenous infusion. 
     
     
         48 . The method of  claim 39 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof and the replacement Gaa are administered simultaneously. 
     
     
         49 . The method of  claim 44 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof is administered prior to or after the replacement Gaa. 
     
     
         50 . The method of  claim 39 , wherein the replacement Gaa and the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof are formulated in a single formulation. 
     
     
         51 . The method of  claim 50 , wherein the formulation is administered via intravenous infusion. 
     
     
         52 . The method of  claim 39 , wherein the 1-deoxynojirimycin derivative or pharmaceutically acceptable salt thereof is administered in an amount of from 5 mg to 75 mg per day. 
     
     
         53 . A method for treating Pompe disease in an individual in need thereof, the method comprising administering to the individual
 replacement acid α-glucosidase (Gaa); and   an amount of N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof, wherein the replacement Gaa and N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof are formulated in a single composition.   
     
     
         54 . The method of  claim 52 , wherein the replacement Gaa and N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof are administered via intravenous infusion. 
     
     
         55 . A method for treating Pompe disease in an individual in need thereof, the method comprising administering to the individual
 replacement acid α-glucosidase (Gaa); and   an amount of N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof, wherein the replacement Gaa and N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof are formulated in separate compositions.   
     
     
         56 . The method of  claim 55 , wherein the replacement Gaa and N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof are co-administered. 
     
     
         57 . The method of  claim 55 , wherein the replacement Gaa and N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof are administered by different routes. 
     
     
         58 . The method of  claim 57 , wherein the N-butyl-deoxynojirimycin or pharmaceutically acceptable salt thereof is administered in an oral dosage form.