Methods for the synthesis of pyridoxamine
The invention provides non-oxidative methods for the large scale manufacture of pyridoxamine (I) (4-aminomethyl-3-hydroxy-5-hydroxymethyl-2-methylpyridine): (I), 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.
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:
wherein R at each occurrence is a hydroxyl protecting group;
(b) converting the compound of formula (III), or salt thereof, to a compound of formula (IV), or salt thereof:
wherein
represents a cyclic imide substituent;
(c) converting the compound of formula (IV), or salt thereof, to a compound of formula (V)
wherein R 1 is H or is R,
wherein when R 1 is R, step (c) is followed by step (d), wherein step (d) comprises:
(d) converting the compound of formula (V), or salt thereof, to pyridoxamine (I), or a 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).
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:
(b) treating the triester formed in step (a) with phthalimide, or salt thereof, to form an phthalimido compound, or salt thereof, of the formula:
(c) treating the phthalilimido compound formed in step (b) with a primary amine to form an amide compound, or salt thereof, of the formula:
(d) treating the amide formed in step (c) with a deprotecting agent to form pyridoxamine, or salt thereof.
11 . A method according to claim 10 wherein the product of step (c) is not isolated prior to carrying out step (d).
12 . A method according to claim 10 wherein the product of step (c) is 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.
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:
17 . A composition comprising: pyridoxamine, or a pharmaceutically acceptable salt thereof; a compound of the formula (X), or a pharmaceutically acceptable salt thereof;
and a compound of the formula (XX), or a pharmaceutically acceptable salt thereof
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.
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 15 .
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 16 .
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 17 .
22 . A zwitterion of the structure:
23 . A compound of formula (III), or salt thereof:
wherein R at each occurrence is a hydroxyl protecting group.
24 . A compound of formula (IV), or salt thereof:
25 . A compound of formula (V), or salt thereof:
wherein R 1 is a hydroxyl protecting group.