Methods for the Synthesis of Pyridoxamine

• US 20100305162A1
• Filed: 08/12/2010
• Published: 12/02/2010
• Est. Priority Date: 02/09/2004
• Status: Active Grant

• Current Assignee: Nephrogenex, Inc.
• Original Assignee: Nephrogenex, Inc.
• Inventors: Degenhardt, Thorsten, Koellner, Christoph, Brand, Stephen Robert, Keilitz, Roland, Khalifah, Raja
• Granted Patent: US 8,431,712 B2
• Time in Patent Office: Days
• US Class Current: 514/335
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 9/10 for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: C07D 213/66 having in position 3 an oxygen atom and in each of the positions 4 and 5 a carbon atom bound to an oxygen, sulphur, or nitrogen atom, e.g. pyridoxal
• CPC Class Codes: C07D 213/67 2-Methyl-3-hydroxy-4,5-bis(hydroxy-methyl)pyridine, i.e. pyridoxine
• CPC Class Codes: C07D 401/06 linked by a carbon chain containing only aliphatic carbon atoms
• CPC Class Codes: C07D 401/12 linked by a chain containing hetero atoms as chain links

Abstract

The invention provides non-oxidative methods for the large scale manufacture of pyridoxamine (I) (4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine):

and salts thereof.
The invention also provides intermediate compounds for the synthesis of pyridoxamine, as well as compositions and methods for the treatment and/or prevention of conditions associated with the formation of post-Amadori advanced glycation end-products.

Claims

1. A method for preparing pyridoxamine, or salt thereof, the method comprising the steps of:

(a) protecting the hydroxyls of a compound of formula (II), or salt thereof, to form a compound of formula (III), or salt thereof;

2. A method according to claim 1 wherein step (a) comprises treating the compound of formula (II) with a hydroxyl protecting reagent.

3. A method according to claim 1 wherein step (b) comprises treating the compound of formula (III) with a cyclic imide.

4. A method according to claim 1 wherein step (c) comprises treating the compound of formula (IV) with a deprotecting agent to form the compound of formula (V).

5. A method according to claim 1 wherein step (d) comprises treating to compound of formula (V) with a deprotecting agent.

6. A method according to claim 1 wherein R is selected from the group consisting of:

alkanoyl, arylcarbonyl, lower alkoxycarbonyl;

lower alkenyloxycarbonyl;

aryl lower alkoxycarbonyl a sulfonyl derivative.

7. A method according to claim 1 wherein the cyclic imide substituent is selected from the group consisting of phthalimidyl, and succinimidyl.

8. A method according to claim 1 wherein the product of step (c) is isolated prior to carrying out step (d).

9. A method according to claim 1 wherein the product of step (c) is not isolated prior to carrying out step (d).

13. Pyridoxamine, or salt thereof, prepared according to the method of claim 1.

14. A composition comprising pyridoxamine, or salt thereof, produced by the method of claim 1, in combination with a pharmaceutically acceptable carrier.

18. A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of pyridoxamine produced by the synthetic method of claim 1, or a pharmaceutically acceptable salt thereof.

21. A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to claim 18.

10. A method for preparing pyridoxamine, the method comprising the steps of:

(a) acylating the hydroxyls of pyridoxine, to form an triester, or salt thereof, of the formula;

11. A method according to claim 11 wherein the product of step (c) is not isolated prior to carrying out step (d).

12. A method according to claim 11 wherein the product of step (c) is isolated prior to carrying out step (d).

15. A composition comprising pyridoxamine, or a pharmaceutically acceptable salt thereof, and a compound of the formula (X), or a pharmaceutically acceptable salt thereof:

16. A composition comprising pyridoxamine, or a pharmaceutically acceptable salt thereof, and a compound of the formula (XX), or a pharmaceutically acceptable salt thereof:

19. A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to claim 16.

17. A composition comprising:

pyridoxamine, or a pharmaceutically acceptable salt thereof;

a compound of the formula (X), or a pharmaceutically acceptable salt thereof;

20. A method of treating or preventing renal disease, diabetic complications in a human diabetic patient, diabetes-associated hypercholesterolemia, diabetes-associated hypertriglyceridemia, hyperlipidemia, atherosclerosis, diabetes-associated atherosclerosis, ethylene glycol-induced adverse effects, nephropathy, proteinuria, albuminuria, impaired glomerular clearance, impaired creatinine clearance, retinopathy, neuropathy, and neurodegenerative disease, the method comprising administering to a patient in need of such treatment or prevention a therapeutically effective amount of a composition according to claim 17.

22. A zwitterion of the structure:

23. A compound of formula (III), or salt thereof:

24. A compound of formula (IV), or salt thereof:

25. A compound of formula (V), or salt thereof: