Processes for preparing arimoclomol citrate and intermediates thereof
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 composition comprising:
a) at least 98.0% N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate;
b) about 1.0% to about 1.9% N-{[(2S)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide, or pharmaceutically acceptable salt thereof; and
c) about 0.05% to about 0.1% methyl (Z)—N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidate 1-oxide, or a pharmaceutically acceptable salt thereof.
2. The composition of claim 1 , wherein the composition is a pharmaceutical composition.
3. The pharmaceutical composition of claim 2 , wherein the composition further comprises less than 2 ppm N-nitrosopiperidine.
4. The pharmaceutical composition of claim 3 , wherein the composition comprises about 0.8 to about 2 ppm N-nitrosopiperidine.
5. An oral formulation comprising the composition of claim 1 and at least one pharmaceutically acceptable excipient.
6. The oral formulation of claim 5 , 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.
7. The oral formulation of claim 5 , 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.
8. The oral formulation of claim 5 , 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.
9. A unit dosage form of the composition of claim 1 and a pharmaceutically acceptable carrier or excipient.
10. The unit dosage form of claim 9 , 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.
11. The unit dosage form of claim 9 , 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.
12. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a pharmaceutical composition of claim 2 .
13. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered an oral formulation of claim 5 .
14. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a unit dosage form of claim 9 .
15. A composition comprising:
a) at least 98.0% N-{[(2R)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide citrate;
b) about 1.0% to about 1.9% N-{[(2S)-2-hydroxy-3-piperidin-1-ylpropyl]oxy}pyridine-3-carboximidoyl chloride 1-oxide, or pharmaceutically acceptable salt thereof; and
c) about 0.8 to about 2 ppm N-nitrosopiperidine, or a pharmaceutically acceptable salt thereof.
16. The composition of claim 15 , wherein the composition is a pharmaceutical composition.
17. The pharmaceutical composition of claim 16 , wherein the composition further comprises less than about 0.1% methyl (Z)—N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidate 1-oxide, or a pharmaceutically acceptable salt thereof.
18. The pharmaceutical composition of claim 17 , wherein the composition comprises about 0.05% to about 0.1% methyl (Z)—N-(2-hydroxy-3-(piperidin-1-yl)propoxy)nicotinimidate 1-oxide, or a pharmaceutically acceptable salt thereof.
19. An oral formulation comprising the composition of claim 15 , and at least one pharmaceutically acceptable excipient.
20. The oral formulation of claim 19 , 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.
21. The oral formulation of claim 19 , 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.
22. The oral formulation of claim 19 , 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.
23. A unit dosage form of the composition of claim 15 , and a pharmaceutically acceptable carrier or excipient.
24. The unit dosage form of claim 23 , 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.
25. The unit dosage form of claim 23 , 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.
26. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a pharmaceutical composition of claim 16 .
27. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered an oral formulation of claim 19 .
28. A method of treating Niemann Pick disease, type C in a subject in need thereof, wherein the subject is administered a unit dosage form of claim 23 .