US2009234011A1PendingUtilityA1
N-acetylcysteine amide (nac amide) for the treatment of diseases and conditions associated with oxidative stress
Est. expiryApr 21, 2025(expired)· nominal 20-yr term from priority
Inventors:Glenn A. Goldstein
A61P 7/06A61P 9/00A61P 9/04A61P 3/10A61P 39/06A61P 43/00A61P 7/00A61P 39/02A61P 31/18A61P 31/14A61P 31/04A61P 27/02A61P 31/20A61P 35/00A61P 33/06A61P 31/00A61P 29/00A61P 25/00A61P 21/00A61P 11/00A61P 19/08A61P 19/04A61P 11/06A61P 19/10A61P 17/02A61P 11/16C07C 233/18C07C 323/41C07C 323/60C07C 233/36A61K 31/16B82B 3/00D01D 5/00Y02A50/30
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Claims
Abstract
Methods and compositions comprising N-acetylcysteine amide (NAC amide) and derivatives thereof are used in treatments and therapies for human and non-human mammalian diseases, disorders, conditions and pathologies. Pharmaceutically or physiologically acceptable compositions of NAC amide or derivatives thereof are administered alone, or in combination with other suitable agents, to reduce, prevent, or counteract oxidative stress and free radical oxidant formation and overproduction in cells and tissues, as well as to provide a new source of glutathione.
Claims
exact text as granted — not AI-modified1 . A pharmaceutical composition for increasing glutathione levels to reduce overproduction of oxidants in cells and tissues, comprising N-acetylcysteine amide (NAC amide), or a pharmaceutically acceptable salt, ester, or derivative thereof.
2 . A method of increasing antioxidant levels in cells and tissues of an organism, comprising administering NAC amide to the organism in an amount effective to increase antioxidant levels.
3 . The method according to claim 2 , wherein said organism is a human being suffering from a condition, disease, disorder, or pathology associated with over production of oxidants.
4 . The method according to claim 3 , wherein said condition, disease, disorder, or pathology is selected from the group consisting of AIDS, diabetes, macular degeneration, congestive heart failure, cardiovascular disease, coronary artery restenosis, lung disease, inflammatory disease, asthma, RNA virus infection, DNA virus infection, sepsis, sepsis, osteoporosis, bone disease, infection by microorganisms, toxin exposure, radiation exposure, burn trauma, prion disease, neurological disease, blood disease, blood cell disease, arterial disease and muscle disease.
5 . The method according to claim 4 , wherein the condition, disease, disorder, or pathology is malaria.
6 . The method according to claim 4 , wherein the condition, disease, disorder, or pathology is tuberculosis.
7 . The method according to claim 4 , wherein the blood disease is sickle cell anemia.
8 . A method of protecting an organism from radiation-induced oxidative stress, comprising administering a radioprotective amount of NAC amide or a derivative of NAC amide to the organism.
9 . The method according to claim 8 , wherein NAC amide or derivative of NAC amide is administered orally in an amount of 500 mg/kg.
10 . A method of increasing levels of thiol antioxidants in an organism, comprising administering NAC amide or derivative of NAC amide to the organism in an amount effective to increase thiol antioxidant levels.
11 . The method according to claim 10 , wherein the thiol antioxidant is glutathione or cysteine.
12 . The method according to claim 10 , wherein the levels of thiol antioxidant increase in liver and plasma.
13 . The method according to claim 10 , wherein NAC amide or derivative of NAC amide is administered orally in an amount of 500 mg/kg.
14 . A method of killing or inhibiting the growth of bacteria in cells of an infected host, comprising:
providing NAC amide or derivative of NAC amide in an amount effective to induce the production of HIF-1 or HIF-1 α in white blood cells of the host, thereby enhancing the capacity of the white blood cells to kill or inhibit the growth of the microorganisms.
15 . A method of blocking the effects of Rac1b-induced ROS production associated with metalloproteinase activity, comprising:
administering or introducing NAC amide or derivative of NAC amide to cells, tissues, and/or a subject in need thereof, thereby targeting molecules in the pathway leading to tissue damage and degradation.
16 . A method of blocking or inhibiting the effects of MMP-3 metalloproteinase on Rac1b-induced ROS production, comprising:
administering or introducing NAC amide or derivative of NAC amide to cells, tissues, and/or a subject in need thereof, to block or inhibit the activity of MMP-3 which leads to tissue damage and degradation.
17 . A method of stimulating endogenous production of cytokines and hematopoietic factors, comprising:
administering or introducing NAC amide or derivative of NAC amide to cells, tissues, and/or a subject in need thereof for a period of time to stimulate the endogenous production to obtain a pre-determined, desired therapeutic effect.
18 . A method of detecting NAC-amide responsive changes in gene expression in a cell, tissue, and/or a subject, comprising:
administering or introducing NAC amide or derivative of NAC amide to the cell, tissue, and/or subject for a period of time to induce changes in gene expression and detecting the changes in gene expression.
19 . The method of claim 18 , wherein cell is an endothelial cell.
20 . The method of claim 18 , wherein the tissue is vascular tissue.
21 . The method of claim 18 , wherein the changes in gene expression are detected by microarray analysis, RT-PCR, Northern Blotting, immunofluorescence, immunoblotting, or enzyme-linked immunosorbent assay.
22 . The method according to claim 18 , comprising administering or providing NAC amide or derivative of NAC amide coupled to nanoparticles.
23 . A method of directed delivery of NAC amide or derivative of NAC amide to host cells expressing high levels of surface receptor for a ligand, comprising:
a) coupling NAC amide or derivative of NAC amide to the surface receptor ligand to form a NAC amide-ligand conjugate; b) adsorbing the NAC amide-ligand conjugate onto nanoparticles; and c) introducing the nanoparticles of step (b) into the host.
24 . A method of directed delivery of NAC amide or derivative of NAC amide to host cells expressing high levels of surface receptor for a ligand, comprising:
a) conjugating acetylated dendritic nanopolymers to a ligand; b) coupling the conjugated ligand of step (a) to NAC amide or derivative of NAC amide to form NAC amide-ligand nanoparticles; and c) introducing the nanoparticles of step (b) into the host.
25 . The method according to claim 23 or claim 24 , wherein the ligand is folic acid or glutathione.
26 . The method according to claim 23 or claim 24 , wherein the nanoparticles are PAMAM dendritic polymers.
27 . A compound of formula I:
wherein:
R 1 is OH, SH, or S—S-Z;
X is C or N;
Y is NH 2 , OH, CH 3 —C═O, or NH—CH 3 ;
R 2 is absent, H, or ═O
R 3 is absent or
wherein: R 4 is NH or O;
R 5 is CF 3 , NH 2 , or CH 3
and wherein: Z is
with the proviso that if R 1 is S—S-Z, X and X′ are the same, Y and Y′ are the same, R 2 and R 6 are the same, and R 3 and R 7 are the same.
28 . The compound of claim 27 , wherein R 1 is S, X is C, Y is NH 2 , R 2 is ═O, R 3 is
R 4 is O, and R 5 is CH 3 .
29 . The compound of claim 28 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
30 . The compound of claim 27 , wherein R 1 is S, X is C, Y is NH—CH 3 , R 2 is H, R 3 is
R 4 is O, and R 5 is CH 3 .
31 . The compound of claim 30 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
32 . The compound of claim 27 , wherein R 1 is S, X is N, Y is CH 3 —C═O, R 2 is H, and R 3 is absent.
33 . The compound of claim 27 , wherein R 1 is S, X is C, Y is NH 2 , R 2 is ═O, R 3 is
R 4 is O, and R 5 is CF 3 .
34 . The compound of claim 33 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
35 . The compound of claim 27 , wherein R 1 is O, X is C, Y is NH 2 , R 2 is ═O, R 3 is
R 4 is O, and R 5 is CH 3 .
36 . The compound of claim 35 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
37 . The compound of claim 27 , wherein R 1 is S, X is C, Y is OH, R 2 is absent, R 3 is
R 4 is O, and R 5 is CH 3 .
38 . The compound of claim 37 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
39 . The compound of claim 27 , wherein R 1 is S, X is C, Y is NH 2 , R 2 is ═O, R 3 is
R 4 is NH, and R 5 is NH 2 .
40 . The compound of claim 39 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
41 . The compound of claim 27 , wherein R 1 is O, X is C, Y is OH, R 2 is absent, R 3 is
R 4 is O, and R 5 is CH 3 .
42 . The compound of claim 41 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
43 . The compound of claim 27 , wherein R 1 is S—S-Z, X is C, Y is NH 2 , R 2 is ═O, R 3 is
R 4 is O and R 5 is CH 3 .
44 . The compound of claim 43 , wherein the compound is chiral and is selected from the group consisting of a D-isomer, a L-isomer, and a racemic mixture of D- and L-isomers.
45 . A process for preparing an L-isomer of the compound of claim 27 , comprising:
(a) adding a base to L-cystine diamide dihydrochloride to produce a first mixture, and subsequently heating the first mixture under vacuum; (b) adding a methanolic solution to the heated first mixture; (c) acidifying the mixture with alcoholic hydrogen chloride to obtain a first residue; (d) dissolving the first residue in a first solution comprising methanol saturated with ammonia; (e) adding a second solution to the dissolved first residue to produce a second mixture; (f) precipitating and washing the second mixture; (g) filtering and drying the second mixture to obtain a second residue; (h) mixing the second residue with liquid ammonia and an ethanolic solution of ammonium chloride to produce a third mixture; and (i) filtering and drying the third mixture, thereby preparing the L-isomer compound.
46 . The process of claim 45 , wherein the base comprises liquid ammonia or methylamine.
47 . The process of claim 45 , wherein the second solution comprises water, an acetate salt, and an anhydride.
48 . The process of claim 47 , wherein the acetate salt comprises sodium acetate or sodium trifluoroacetate.
49 . The process of claim 47 , wherein the anhydride comprises acetic anhydride or trifluoroacetic anhydride.
50 . The process of claim 45 , wherein the second solution comprises dichloromethane, triethylamine, and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea.
51 . The process of claim 45 , wherein step (h) further comprises mixing the second residue in the presence of sodium metal.
52 . The process of claim 45 , further comprising the steps of
(j) dissolving the L-isomer compound in ether; (k) adding to the dissolved L-isomer compound an ethereal solution of lithium aluminum hydride, ethyl acetate, and water to produce a fourth mixture; and (l) filtering and drying the fourth mixture, thereby preparing the L-isomer compound.
53 . A process for preparing an D-isomer of the compound of claim 27 , comprising:
(a) adding a base to D-cystine diamide dihydrochloride to produce a first mixture, and subsequently heating the first mixture under vacuum; (b) adding a methanolic solution to the heated first mixture; (c) acidifying the mixture with alcoholic hydrogen chloride to obtain a first residue; (d) dissolving the first residue in a first solution comprising methanol saturated with ammonia; (e) adding a second solution to the dissolved first residue to produce a second mixture; (f) precipitating and washing the second mixture; (g) filtering and drying the second mixture to obtain a second residue; (h) mixing the second residue with liquid ammonia, sodium metal, and an ethanolic solution of ammonium chloride to produce a third mixture; and (i) filtering and drying the third mixture, thereby preparing the L-isomer compound.
54 . The process of claim 53 , wherein the base comprises liquid ammonia or methylamine.
55 . The process of claim 53 , wherein the second solution comprises water, an acetate salt, and an anhydride.
56 . The process of claim 55 , wherein the acetate salt comprises sodium acetate or sodium trifluoroacetate.
57 . The process of claim 55 , wherein the anhydride comprises acetic anhydride or trifluoroacetic anhydride.
58 . The process of claim 53 , wherein the second solution comprises dichloromethane, triethylamine, and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea.
59 . The process of claim 53 , wherein step (h) further comprises mixing the second residue in the presence of sodium metal.
60 . The process of claim 53 , further comprising the steps of
(j) dissolving the D-isomer compound in ether; (k) adding to the dissolved D-isomer compound an ethereal solution of lithium aluminum hydride, ethyl acetate, and water to produce a fourth mixture; and (l) filtering and drying the fourth mixture, thereby preparing the D-isomer compound.
61 . A process for preparing an L-isomer of the compound of claim 27 , comprising:
(a) mixing S-benzyl-L-cysteine methyl ester hydrochloride or O-benzyl-L-serine methyl ester hydrochloride with a base to produce a first mixture; (b) adding ether to the first mixture; (c) filtering and concentrating the first mixture; (d) repeating steps (c) and (d), to obtain a first residue; (e) adding ethyl acetate and a first solution to the first residue to produce a second mixture; (f) filtering and drying the second mixture to produce a second residue; (g) mixing the second residue with liquid ammonia, sodium metal, and an ethanolic solution of ammonium chloride to produce a third mixture; and (h) filtering and drying the third mixture, thereby preparing the L-isomer compound.
62 . The process of claim 61 , wherein the base comprises a methanolic solution of ammonia or methylamine.
63 . The process of claim 61 , wherein the second solution comprises water, an acetate salt, and an anhydride.
64 . The process of claim 63 , wherein the acetate salt comprises sodium acetate or sodium trifluoroacetate.
65 . The process of claim 63 , wherein the anhydride comprises acetic anhydride or trifluoroacetic anhydride.
66 . The process of claim 61 , wherein the second solution comprises dichloromethane, triethylamine, and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea.
67 . The process of claim 61 , further comprising the steps of
(j) dissolving the L-isomer compound in ether; (k) adding to the dissolved L-isomer compound an ethereal solution of lithium aluminum hydride, ethyl acetate, and water to produce a fourth mixture; and (l) filtering and drying the fourth mixture, thereby preparing the L-isomer compound.
68 . A process for preparing an D-isomer of the compound of claim 27 , comprising:
(a) mixing S-benzyl-D-cysteine methyl ester hydrochloride or O-benzyl-D-serine methyl ester hydrochloride with a base to produce a first mixture; (b) adding ether to the first mixture; (c) filtering and concentrating the first mixture; (d) repeating steps (c) and (d), to obtain a first residue; (e) adding ethyl acetate and a first solution to the first residue to produce a second mixture; (f) filtering and drying the second mixture to produce a second residue; (g) mixing the second residue with liquid ammonia, sodium metal, and an ethanolic solution of ammonium chloride to produce a third mixture; and (h) filtering and drying the third mixture, thereby preparing the D-isomer compound.
69 . The process of claim 68 , wherein the base comprises a methanolic solution of ammonia or methylamine.
70 . The process of claim 68 , wherein the second solution comprises water, an acetate salt, and an anhydride.
71 . The process of claim 70 , wherein the acetate salt comprises sodium acetate or sodium trifluoroacetate.
72 . The process of claim 70 , wherein the anhydride comprises acetic anhydride or trifluoroacetic anhydride.
73 . The process of claim 68 , wherein the second solution comprises dichloromethane, triethylamine, and 1,3-bis(benzyloxycarbonyl)-2-methyl-2-thiopseudourea.
74 . The process of claim 68 , further comprising the steps of
(j) dissolving the D-isomer compound in ether; (k) adding to the dissolved D-isomer compound an ethereal solution of lithium aluminum hydride, ethyl acetate, and water to produce a fourth mixture; and (l) filtering and drying the fourth mixture, thereby preparing the D-isomer compound.
75 . A process for preparing a compound of claim 27 , comprising:
(a) mixing cystamine dihydrochloride with ammonia, water, sodium acetate, and acetic anhydride to produce a first mixture; (b) allowing the first mixture to precipitate; (c) filtering and drying the first mixture to produce a first residue; (d) mixing the second residue with liquid ammonia, sodium metal, and an ethanolic solution of ammonium chloride to produce a second mixture; (e) filtering and drying the second mixture, thereby preparing the compound.
76 . A NAC amide compound or derivative selected from the group consisting of:
77 . A food additive comprising NAC amide or a NAC amide derivative of claim 76 .Cited by (0)
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