Compositions and methods for the treatment of zellweger spectrum disorder
OwnerJoseph Hacia, Nancy E. Braverman +2inventors
InventorsJoseph Hacia, Nancy E. Braverman, Patricia Dranchak, James Inglese
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Abstract
Provided herein are methods of treating Zellweger spectrum disorder (ZSD) in a subject in need thereof or improving peroxisome assembly in a cell in need thereof comprising administering to the subject a therapeutically effective amount of Compounds of Formula I or II.
Claims21
A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I:
- or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
- wherein:
- is a single or a double bond;
- X is NR2 or CR5R5 when is a single bond or X is N or CR5 when is a double bond;
- X5 is N or CR5, provided that at least one of X and X5 is N or NR2;
- each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
- each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30;
- each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- or an optionally substituted —NR20R30;
- each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl;
- an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
- each R6 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or hydroxy;
- and
- m is 0, 1, or 2.
A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula II:
- or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
- wherein:
- X1 is O, S, or NR2;
- X2 is N or CR5;
- each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- or an optionally substituted —NR20NR30;
- each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
- each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30;
- each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
- each R3 and R4 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- an optionally substituted C2-C8 alkenyl, or a hydroxy;
- Y and Z independently is O, S, or NR2;
- n is 0, 1, 2, or 3;
- m is 0, 1, or 2;
- and
- p is 0, 1, 2, or 3.
A method of treating Zellweger spectrum disorder in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound selected from the group consisting of naltriben methanesulfonate hydrate, actinonin, CGP 57380, indirubin-3′-oxime, naltrindole hydrochloride, H-8 dihydrochloride, apigenin, 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine dihydrochloride, nifedipine, Bay 11-7085, BAY 61-3606 hydrochloride hydrate, pentamidine isethionate salt, Bay 11-7082, 6-methylaminopurine 9-ribofuranoside, leflunomide, 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride, IRAK-1/4 Inhibitor I, P1,P4-di(adenosine-5′) tetraphosphate ammonium salt, 6-bromoinirubin-3′-oxime, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride, roscovitine, SP600125, HA-100, TBBz, ribavirin, piribedil maleate salt, LY-294,002 hydrochloride, tetracaine hydrochloride, LFM-A13, N-acetyltryptamine, and tyrphostin AG 1478, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing.
A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula I:
- or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
- wherein:
- is a single or a double bond;
- X is NR2 or CR5R5 when is a single bond or X is N or CR5 when is a double bond;
- X5 is N or CR5, provided that at least one of X and X5 is N or NR2;
- each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
- each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20NR30;
- each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- or an optionally substituted —NR20NR30;
- each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl;
- an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
- each R6 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or hydroxy;
- and
- m is 0, 1, or 2.
A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound of Formula II:
- or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing,
- wherein:
- X1 is O, S, or NR2;
- X2 is N or CR5;
- each R1 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- or an optionally substituted —NR20NR30;
- each R2 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, or an optionally substituted C2-C8 alkenyl;
- each R5 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted C2-C8 alkenyl, an optionally substituted ═NR6, or an optionally substituted —NR20R30,
- each R20 and R30 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy, an optionally substituted 5-10 membered aryl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 3-10 membered cycloalkyl, or an optionally substituted 5-10 membered heterocyclyl;
- each R3 and R4 independently is H, an optionally substituted C1-C8 alkyl, an optionally substituted C1-C8 alkoxy;
- an optionally substituted C2-C8 alkenyl, or a hydroxy;
- Y and Z independently is O, S, or NR2;
- n is 0, 1, 2, or 3;
- m is 0, 1, or 2;
- and
- p is 0, 1, 2, or 3.
A method of improving peroxisome assembly in a cell in need thereof comprising administering to the cell a therapeutically effective amount of a compound selected from the group consisting of naltriben methanesulfonate hydrate, actinonin, CGP 57380, indirubin-3′-oxime, naltrindole hydrochloride, H-8 dihydrochloride, apigenin, 1-(5-isoquinolinylsulfonyl)-3-methylpiperazine dihydrochloride, nifedipine, Bay 11-7085, BAY 61-3606 hydrochloride hydrate, pentamidine isethionate salt, Bay 11-7082, 6-methylaminopurine 9-ribofuranoside, leflunomide, 8-(diethylamino)octyl-3,4,5-trimethoxybenzoate hydrochloride, IRAK-1/4 Inhibitor I, P1,P4-di(adenosine-5′) tetraphosphate ammonium salt, 6-bromoinirubin-3′-oxime, 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine dihydrochloride, roscovitine, SP600125, HA-100, TBBz, ribavirin, piribedil maleate salt, LY-294,002 hydrochloride, tetracaine hydrochloride, LFM-A13, N-acetyltryptamine, and tyrphostin AG 1478, or a tautomer thereof, or a pharmaceutically acceptable salt of each of the foregoing, or an N-oxide of each of the foregoing, or a pharmaceutically acceptable solvate of each of the foregoing.
Dependencies are inferred from the claim text.