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 . A pharmaceutical composition comprising at least 94% enantiomeric excess (ee) of N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate. 
     
     
         2 . The pharmaceutical composition of  claim 1 , wherein the ee of N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate is at least 95%, at least 96%, at least 97%, or at least 98%. 
     
     
         3 . The pharmaceutical composition of  claim 1 , wherein the composition further comprises 0.1% or less methyl (Z)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidate 1-oxide, or a pharmaceutically acceptable salt thereof. 
     
     
         4 . The pharmaceutical composition of  claim 3 , wherein the composition further comprises less than 2 ppm N-nitrosopiperidine. 
     
     
         5 . The pharmaceutical composition of  claim 1 , wherein the purity of the composition is greater than or equal to 99.0% N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate as determined by HPLC. 
     
     
         6 . The pharmaceutical composition of  claim 1 , comprising particulate N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate, wherein said particles have a D10 particle size determined using Malvern Mastersizer 3000 of from about 2.0 μm to about 20.0 μm. 
     
     
         7 . The pharmaceutical composition of  claim 1 , comprising particulate N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate, wherein said particles have a D50 particle size determined using Malvern Mastersizer 3000 of from about 5.0 μm to about 60.0 μm. 
     
     
         8 . The pharmaceutical composition of  claim 1 , comprising particulate N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate, wherein said particles have a D90 particle size determined using Malvern Mastersizer 3000 of from about 30.0 μm to about 130.0 μm. 
     
     
         9 . The pharmaceutical composition of  claim 1 , wherein the composition comprises:
 a) at least 98.0% N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate;   b) 1.9% or less N-{[(2S)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide, or pharmaceutically acceptable salt thereof; and   c) 0.1% or less methyl (Z)-N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidate 1-oxide, or a pharmaceutically acceptable salt thereof.   
     
     
         10 . The pharmaceutical composition of  claim 9 , wherein the composition further comprises less than 2 ppm N-nitrosopiperidine. 
     
     
         11 . An oral formulation comprising the pharmaceutical composition of  claim 1 , and at least one pharmaceutically acceptable excipient. 
     
     
         12 . The oral formulation of  claim 11 , wherein the N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate is present at a dosage from about 50 mg to about 500 mg. 
     
     
         13 . The oral formulation of  claim 11 , wherein the oral formulation comprises from about 20% to about 60% w/w of N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate. 
     
     
         14 . The oral formulation of  claim 11 , 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. 
     
     
         15 . A unit dosage form of the pharmaceutical composition of  claim 1 , and a pharmaceutically acceptable carrier or excipient. 
     
     
         16 . The unit dosage form of  claim 15 , comprising N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide, or a pharmaceutically acceptable salt thereof at a dosage from about 50 mg to about 500 mg. 
     
     
         17 . The unit dosage form of  claim 15 , 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. 
     
     
         18 . A method of treating or preventing Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a pharmaceutical composition of  claim 1 . 
     
     
         19 . A method of treating or preventing Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered an oral formulation of  claim 11 . 
     
     
         20 . A method of treating or preventing Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a unit dosage form of  claim 15 .