Processes for preparing arimoclomol citrate and intermediates thereof

Abstract

The present disclosure relates to a process for preparing arimoclomol, arimoclomol citrate and key intermediates, such as ORZY-01, thereof. The disclosure further relates to a process for preparing high purity arimoclomol citrate and methods of using the same.

1 - 157 . (canceled) 
     
     
         158 . A process for preparing 
       
         
           
           
               
               
           
         
         wherein the process comprises the steps of: 
         1) mixing a compound of formula (I); 
       
       
         
           
           
               
               
           
         
         with a compound of formula (II) in a container; 
       
       
         
           
           
               
               
           
         
         in at least one first solvent at a first temperature to provide an intermediate, wherein the first solvent is selected from the group consisting of a polar protic solvent and a mixture of polar protic solvents, and the first temperature is within a range from about 70° C. to 100° C.; 
         2) wherein the intermediate formed during Step 1 is then reacted with sodium nitrite (NaNO 2 ) at a second temperature in at least one second solvent to provide 
       
       
         
           
           
               
               
           
         
         wherein the at least one second solvent is selected from the group consisting of at least one chlorinated hydrocarbon, a mixture containing at least one chlorinated hydrocarbon, or a combination thereof, and 
         wherein the second temperature is within a range from about 0° C. to 15° C. 
       
     
     
         159 . A process for preparing arimoclomol citrate, 
       
         
           
           
               
               
           
         
         comprising the steps of:
 performing the process of  claim 158  to provide, 
 
       
       
         
           
           
               
               
           
         
         
           precipitating 
         
       
       
         
           
           
               
               
           
         
       
       with dibenzoyl L-tartaric acid to provide 
       
         
           
           
               
               
           
         
         reacting 
       
       
         
           
           
               
               
           
         
       
       with at least one base to form at least one free base of 
       
         
           
           
               
               
           
         
       
       and
 d. precipitating the free base of 
 
       
         
           
           
               
               
           
         
       
       with citric acid to provide arimoclomol citrate. 
     
     
         160 . A pharmaceutical composition comprising: 
       
         
           
           
               
               
           
         
         wherein the composition is obtained by the process of  claim 159 . 
       
     
     
         161 . The pharmaceutical composition of  claim 160 , wherein the 
       
         
           
           
               
               
           
         
         (N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate) 
         comprises at least 98.0% of the pharmaceutical composition. 
       
     
     
         162 . A pharmaceutical kit comprising:
 at least one pharmaceutical composition comprising,   
       
         
           
           
               
               
           
         
         wherein the composition is obtained by the process of  claim 159 ; 
         and at least one set of instructions for use of the pharmaceutical composition in the treatment of Niemann Pick disease, type C. 
       
     
     
         163 . A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of the pharmaceutical composition of  claim 161 . 
     
     
         164 . A unit dosage form of the pharmaceutical composition of  claim 161 . 
     
     
         165 . The unit dosage form of  claim 164 , comprising N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate at a dosage from about 50 mg to about 500 mg. 
     
     
         166 . The unit dosage form of  claim 165 , wherein the unit dosage form is selected from the group consisting of about 47 mg, about 62 mg, about 93 mg, or about 124 mg. 
     
     
         167 . A kit comprising a unit dosage form according to  claim 166 , and instructions for administration. 
     
     
         168 . The kit of  claim 167 , wherein the kit further comprises prescribing information for the method of treating Niemann Pick disease, type C in a subject in need thereof. 
     
     
         169 . A composition comprising N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate having the formula: 
       
         
           
           
               
               
           
         
         wherein the composition is obtained by the process of  claim 159 . 
       
     
     
         170 . The composition of  claim 169 , wherein the 
       
         
           
           
               
               
           
         
         (N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate) 
         comprises at least 98.0% of the composition. 
       
     
     
         171 . An oral formulation comprising the composition of  claim 170  and at least one pharmaceutically acceptable excipient. 
     
     
         172 . The oral formulation of  claim 171  comprising N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate at a dosage of about 47 mg, about 62 mg, about 93 mg, or about 124 mg. 
     
     
         173 . A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a therapeutically effective amount of the oral composition of  claim 172 .