Methods of treating lysosomal storage disorders using arimoclomol and miglustat prodrugs

Abstract

The present technology relates to methods of treating neurodegenerative diseases and disorder, such as lysosomal storage disorders, by administering a combination prodrugs of arimoclomol and prodrugs of miglustat. The present technology further provides methods of synthesizing said prodrugs and compositions comprising said prodrugs.

Description

Attorney Docket No. 68547WO01METHODS OF TREATING LYSOSOMAL STORAGE DISORDERS USING ARIMOCLOMOL AND MIGLUSTAT PRODRUGSSTATEMENT OF RELATED APPLICATIONS

[0001] This application claims priority to U. S. Application No. 63 / 737,975, filed on December 23, 2024, the entire contents of which are incorporated herein by reference.STATEMENT OF FEDERAL FUNDING

[0002] No U. S. Federal Funding was used to develop the instant technology.BACKGROUND OF THE TECHNOLOGY

[0003] The lysosomal storage diseases are a rare group of diseases, characterized by the accumulation of substances in the lysosomal compartment and resulting destabilization hereof, with a resulting devastating effect for affected individuals. Substances accumulate in the lysosomal compartment due to deficiencies in the enzymes involved in their catabolism. Among these lysosomal storage disorders are Niemann-Pick type C (NPC) disease and Gaucher disease (GD), both of which are caused by a build-up of fatty substances.

[0004] Arimoclomol citrate is approved in the United States for treating NPC and miglustat is approved in the United States for treatment of type I GD. Both arimoclomol and miglustat need to be administered multiple times a day in order to maintain therapeutically effective plasma levels.

[0005] It is believed in the art that brain absorption of miglustat is low, likely around 20%, which results in requiring a higher dosage to achieve therapeutic effect before the drug is cleared by the kidneys. These higher dosage requirements result in gastrointestinal effects believed to be caused by inhibition of intestinal disaccharidases which leads to, for example, carbohydrate malabsorption, diarrhea, abdominal pain, flatulence, bloating, vomiting, nausea, anorexia, dyspepsia, nutrient deficiency, weight loss, and stunted growth.

[0006] There exists a need in the art for forms of miglustat with increased bioavailability and more consistent plasma levels.

[0007] There exists a further need in the art for forms of miglustat that can more efficiently cross the blood-brain barrier and result in higher brain absorption and reduced side effects. There exists a further need in the art for forms of miglustat that do not or minimally interact with disaccharidesAttorney Docket No. 68547WO01to reduce gastrointestinal side effects. There exists a still further need in the art for forms of miglustat that reduce the number of daily unit doses administered from 3 down to 1 or 2.

[0008] There exists a need in the art for methods of treating lysosomal storage disorders using prodrugs of arimoclomol and miglustat that provide improved bioavailability and / or more consistent plasma levels of the active components over longer periods of time.

[0009] Currently, oral treatments for lysosomal storage disorders are accomplished by multiple doses of drugs such as arimoclomol and / or salts thereof.

[0010] Currently, there exists a need in the art for forma of arimoclomol with slower absorption and / or longer half-life that result in longer release profiles that provide more consistent plasma levels of the drugs. There exists a still further need in the art for forms of arimoclomol that reduce the number of daily unit doses administered to a patient in need thereof.SUMMARY OF THE DISCLOSURE

[0011] The present technology relates to methods of treating neurodegenerative diseases and disorders, such as lysosomal storage disorders, with a combination of an arimoclomol (N-[(2R)-2-hydroxy-3-piperidin-l-ylpropoxy]-l-oxidopyridin-l-ium-3-carboximidoyl chloride) prodrug and a miglustat (butylimino)- 1,5-dideoxy-D-glucitol, / V-butyl-deoxynojirimycin) prodrug.

[0012] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof.

[0013] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate,Attorney Docket No. 68547WO01phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0014] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0015] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, the method comprising, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0016] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the groupAttorney Docket No. 68547WO01consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C. Tay-Sachs disease, Sandhoff disease. GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0017] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II. Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0018] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0019] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0020] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0021] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0022] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0023] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3. adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0024] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0025] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0026] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0027] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0028] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.Attorney Docket No. 68547WO01

[0029] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation.

[0030] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

[0031] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oral formulation is a solid oral dosage formulation.

[0032] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip.

[0033] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the oral formulation is a liquid oral dosage formulation.

[0034] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0035] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, arimoclomol, eliglustat, N-acetyl-L-leucine and 2-hydroxypropyl-|3-cyclodextrin, and combinations thereof; or pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine. 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

[0036] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method comprises administering to the patient in need thereof a composition comprising the therapeutically effective amount of a prodrug of arimoclomol and the therapeutically effective amount of the prodrug of miglustat.

[0037] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I:Attorney Docket No. 68547WO01Cl O owherein X is selected from the group consisting of R, [O-R], [NR’R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkyl sulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.

[0038] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound having a structure of Formula IA:FkNAttorney Docket No. 68547WO01wherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol; or a pharmaceutically acceptable salt thereof.

[0039] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound having a structure of Formula IB:wherein R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkyl sulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy,Attorney Docket No. 68547WO01cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0040] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound of Formula IC:wherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo. arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0041] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound of Formula ID:Rwherein R is selected from the group consisting of alkenyl, alkenyl, aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroaryl thio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0042] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the compound of Formula I is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate,Attorney Docket No. 68547WO01saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0043] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0044] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders (OLSDs).

[0045] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease. Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease typeAttorney Docket No. 68547WO01C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0046] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0047] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0048] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis. beta-mannosidosis. and fucosidosis.

[0049] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the groupAttorney Docket No. 68547WO01consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis TV.

[0050] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0051] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0052] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0053] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0054] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0055] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0056] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the compound of Formula I is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0057] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.Attorney Docket No. 68547WO01

[0058] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of the compound of Formula I is administered in an oral formulation.

[0059] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation. In a still further aspect, wherein the oral formulation is a solid oral dosage formulation selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip,. I a further aspect, the oral formulation is a liquid oral dosage formulation selected from the group consisting of syrups, emulsions, solutions, slurry, and suspensions.

[0060] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat. eliglustat, N-acetyl-L-leucine. arimoclomol and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol and combinations thereof.

[0061] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:Attorney Docket No. 68547WO01administering to the patient in need thereof a therapeutically effective amount of a compounds having a structure of Formula II:X (II)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.

[0062] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the compound of Formula II is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate,Attorney Docket No. 68547WO01pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0063] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0064] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0065] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease typeAttorney Docket No. 68547WO01C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0066] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0067] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0068] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis. beta-mannosidosis. and fucosidosis.

[0069] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the groupAttorney Docket No. 68547WO01consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis TV.

[0070] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0071] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0072] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0073] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0074] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0075] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0076] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the compound of Formula II is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0077] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.Attorney Docket No. 68547WO01

[0078] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of a compound of Formula II is administered in an oral formulation. In a further aspect, the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation. In certain aspects, the oral formulation is a solid oral dosage formulation. In a still further aspect, the solid oral dosage formulation is selected from a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0079] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oral formulation is a liquid oral dosage formulation. In a further aspect, the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0080] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to a patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, eliglustat, N-acetyl-L-Leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-Leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.Attorney Docket No. 68547WO01

[0081] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula III:(III)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH],Owherein each Y is independently H orX,wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; andcomposition comprising a therapeutically effective amount of a prodrug of arimoclomol, or a pharmaceutically acceptable salt thereof.

[0082] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIIA:where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0083] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIIB:Attorney Docket No. 68547WO01OH(IIIB)where R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0084] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIIC:OHN(IIIC)where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl,Attorney Docket No. 68547WO01alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkyl sulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo. arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0085] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIID:OH O NHwhere R is selected from the group consisting alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cyclohetero alkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy,Attorney Docket No. 68547WO01heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0086] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the pharmaceutically acceptable salt of the compound of Formula III is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0087] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0088] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neurodegenerative or metabolic diseaseAttorney Docket No. 68547WO01or disorder is a lysosomal storage disorder. In certain aspects, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0089] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0090] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0091] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.Attorney Docket No. 68547WO01

[0092] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I. Sialidosis type II. aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0093] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0094] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0095] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0096] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neuronal ceroid lipofuscinosis isAttorney Docket No. 68547WO01selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0097] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0098] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0099] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0100] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the compound of Formula III is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg,Attorney Docket No. 68547WO01alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0101] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0102] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the compound of Formula III is administered in an oral formulation.

[0103] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation, In a still further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the oral formulation is a solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip. In a still further aspect, the oral formulation is a liquid oral dosage formulation.Attorney Docket No. 68547WO01

[0104] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0105] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.

[0106] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula IV:OH OH(IV)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl,Attorney Docket No. 68547WO01alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkyl sulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a prodrug of arimoclomol or a pharmaceutically acceptable salt thereof,

[0107] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the pharmaceutically acceptable salt of the compound of Formula IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0108] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the pharmaceutically acceptable salt of theAttorney Docket No. 68547WO01prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0109] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder In certain aspects, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0110] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0111] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPSAttorney Docket No. 68547WO01IT, Hunter syndrome), MPS TIT, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS TV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0112] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0113] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0114] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0115] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.Attorney Docket No. 68547WO01

[0116] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis. beta-mannosidosis. fucosidosis, aspartylglucosaminuria.

[0117] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0118] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof the composition comprising the therapeutically effective amount of the compound of Formula IV and the composition comprising a therapeutically effective amount of the prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0119] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0120] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0121] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the compound of Formula IV is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0122] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0123] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of a compound of Formula IV is administered in an oral formulation.

[0124] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

[0125] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oral formulation is a solid oral dosage formulation. In certain aspects, the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0126] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oral formulation is a liquid oral dosage formulation. In certain aspects, the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0127] In a further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.Attorney Docket No. 68547WO01

[0128] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol selected from Formula I and Formula II,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat selected from Formula III and Formula IV,or a pharmaceutically acceptable salt thereof.

[0129] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the prodrug of arimoclomol, is a compound of Formula I or Formula II.

[0130] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the prodrug of miglustat is a compound of Formula III or Formula IV.

[0131] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the compound of Formula I-IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-Attorney Docket No. 68547WO01toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0132] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0133] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease. Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0134] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.Attorney Docket No. 68547WO01

[0135] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0136] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0137] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0138] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0139] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0140] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0141] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof the composition comprising the therapeutically effective amount of the prodrug of arimoclomol and the composition comprising the therapeutically effective amount of the prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0142] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0143] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.Attorney Docket No. 68547WO01

[0144] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0145] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0146] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation,

[0147] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.Attorney Docket No. 68547WO01

[0148] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oral formulation is a solid oral dosage formulation. In a still further aspect, the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0149] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the oral formulation is a liquid oral dosage formulation. In a still further aspect the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0150] In a further aspect, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional active pharmaceutical ingredient selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof or a pharmaceutically acceptable salts thereof. In a still further aspect, the at least one additional active pharmaceutical ingredient is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

[0151] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of a prodrug of arimoclomol;or a pharmaceutically acceptable salt thereof.

[0152] In certain aspects, the present technology relates to a composition comprising:Attorney Docket No. 68547WO01a therapeutically effective amount of a prodrug of miglustat;or a pharmaceutically acceptable salt thereof.

[0153] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of a compound of Formula I;or a pharmaceutically acceptable salt thereof.

[0154] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of a compound of Formula II;or a pharmaceutically acceptable salt thereof.

[0155] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of a compound of Formula III;or a pharmaceutically acceptable salt thereof.

[0156] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of a compound of Formula IV;or a pharmaceutically acceptable salt thereof.

[0157] In certain aspects, the present technology relates to a composition comprising:a therapeutically effective amount of at least one compound selected from the group consisting of Formula I and Formula II,or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of at least one compound selected from the group consisting of Formula III and Formula IV,or a pharmaceutically acceptable salt thereof.

[0158] In certain aspects, the present technology relates to a kit comprising:at least one of the previously described compositions; andinstructions for use.BRIEF SUMMARY OF THE DRAWINGS

[0159] FIG 1 shows the plasma concentration of arimoclomol following administration of ethyl-O-CO-ARIM compared to administration of arimoclomol for 6 hours.

[0160] FIG 2 shows the plasma concentration of arimoclomol following administration of hexyl -O-CO-ARIM compared to administration of arimoclomol for 6 hours.

[0161] FIG. 3 shows the plasma concentration of arimoclomol following administration of benzoyl- ARIM and cinnamoyl- ARIM compared to administration of arimoclomol for 6 hours.Attorney Docket No. 68547WO01

[0162] FIG. 4 shows the plasma concentration of arimoclomol following administration of ethyl-O-CO-ARIM compared to administration of arimoclomol for 6 hours.

[0163] FIG. 5 shows the plasma concentration of arimoclomol following administration of butyryl-ARIM and Val-ARIM compared to administration of arimoclomol for 6 hours.

[0164] FIG. 6 shows the plasma concentration of arimoclomol following administration of ethylsuccinyl-ARIM compared to administration of arimoclomol for 6 hours.

[0165] FIG. 7 shows the plasma concentration of arimoclomol following administration of glutaryl-ARIM and ethyloxyglutaryl-ARIM compared to administration of arimoclomol for 6 hours.

[0166] FIG. 8 shows the plasma concentration of arimoclomol following administration of octanoyl-ARIM and hexanoyl-ARIM compared to administration of arimoclomol for 6 hours.

[0167] FIG. 9 shows the plasma concentration of arimoclomol following administration of decanoyl-ARIM and dodecanoyl-ARIM compared to administration of arimoclomol for 6 hours.

[0168] FIG. 10 shows the plasma concentration of arimoclomol following administration of amino-PEG2-acetyl-ARIM and sorboyl-ARIM compared to administration of arimoclomol for 6 hours.

[0169] FIG. 11 shows the plasma concentration of arimoclomol following administration of anisoyl-ARIM compared to administration of arimoclomol for 6 hours.

[0170] FIG. 12 shows the plasma concentration of arimoclomol following administration of amino-PEG4-propanoyl-ARIM compared to administration of arimoclomol for 6 hours.

[0171] FIG. 13 shows the plasma concentration of arimoclomol following administration of Phe-ARIM and Tyr-ARIM compared to administration of arimoclomol for 6 hours.

[0172] FIG. 14 shows the plasma concentration of arimoclomol following administration of succinyl- ARIM compared to administration of arimoclomol for 6 hours.

[0173] FIG. 15 shows the plasma concentration of arimoclomol following administration of adipoyl- ARIM compared to administration of arimoclomol for 6 hours.

[0174] FIG. 16 shows the plasma concentration of arimoclomol following administration of maleoyl- ARIM compared to administration of arimoclomol for 6 hours.

[0175] FIG. 17 shows the plasma concentration of arimoclomol following administration of benzoyl-NH-CO-ARIM compared to administration of arimoclomol for 6 hours.Attorney Docket No. 68547WO01

[0176] FIG. 18 shows the plasma concentration of arimoclomol following administration of N-methoxy-N(Me)CO-OCH2-ARIM compared to administration of arimoclomol for 6 hours.

[0177] FIG. 19 shows the plasma concentration of arimoclomol following administration of ARIM- succinyl- ARIM compared to administration of arimoclomol for 6 hours.

[0178] FIG. 20 shows the plasma concentration of arimoclomol following administration of ARIM- glutaryl- ARIM compared to administration of arimoclomol for 6 hours.

[0179] FIG.21 shows the plasma concentration of arimoclomol following administration ARIM-adipoyl-ARIM compared to administration of arimoclomol for 6 hours.

[0180] FIG. 22 shows the plasma concentration of arimoclomol following administration of ARIM-terephthaloyl-ARIM compared to administration of arimoclomol for 6 hours.

[0181] FIG. 23 shows the plasma concentration of arimoclomol following administration of ARIM-(cyclohexane-l,3-dicarbonyl)-ARIM compared to administration of arimoclomol for 6 hours.

[0182] FIG 24. shows the plasma concentration of miglustat following administration of ethyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0183] FIG. 25 shows the plasma concentration of miglustat following administration of octyl-O-CO-MIG and isopropyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0184] FIG. 26 shows the plasma concentration of miglustat following administration of butyl-O-CO-MIG and octyanoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0185] FIG. 27 shows the plasma concentration of miglustat following administration of hexyl-O-CO-MIG and p-anisyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0186] FIG. 28 shows the plasma concentration of miglustat following administration of decanoyl-OCH2O-CO-MIG and decyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0187] FIG. 29 shows the plasma concentration of miglustat following administration of p-tolyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0188] FIG. 30 shows the plasma concentration of miglustat following administration of 2-chlorophenyl-O-CO-MIG and 4-chlorophenyl-O-CO-MIG compared to administration of miglustat for 6 hours.

[0189] FIG. 31 shows the plasma concentration of miglustat following administration of hypogalloyl-OCH₂O-CO-MIG, p-resorcyloyl-OCH₂O-CO-MIG, and hexanoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.Attorney Docket No. 68547WO01

[0190] FIG. 32 shows the plasma concentration of miglustat following administration of benzoyl-OCH2O-CO-MIG and p-salicyloyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0191] FIG. 33 shows the plasma concentration of miglustat following administration of m-toluoyl-OCH₂O-CO-MIG and S-phenoxybenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0192] FIG. 34 shows the plasma concentration of miglustat following administration of p-anisoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0193] FIG. 35 shows the plasma concentration of miglustat following administration of m-anisoyl-OCH₂O-CO-MIG and terephthaloyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0194] FIG. 36 shows the plasma concentration of miglustat following administration of 3-trifluoromethoxybenzoyl-OCH₂O-CO-MIG and 3,5-dimethoxybenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0195] FIG. 37 shows the plasma concentration of miglustat following administration of 3-ethoxybenzoyl-OCH₂O-CO-MIG and 2-fluorobenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0196] FIG. 38 shows the plasma concentration of miglustat following administration of m-salicyloyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0197] FIG. 39 shows the plasma concentration of miglustat following administration of 3-fluorobenzoyl-OCH₂O-CO-MIG and o-salicyloyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0198] FIG. 40 shows the plasma concentration of miglustat following administration of 4-fluorobenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0199] FIG. 41 shows the plasma concentration of miglustat following administration of 2,6-difluorobenzoyl-OCH₂O-CO-MIG and 3-fluoro-4-methoxybenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0200] FIG. 42 shows the plasma concentration of miglustat following administration of 2,4-difluorobenzoyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0201] FIG. 43 shows the plasma concentration of miglustat following administration of piperonyloyl-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.Attorney Docket No. 68547WO01

[0202] FIG. 44 shows the plasma concentration of miglustat following administration of Val-OCH₂O-CO-MIG and Leu-OCH₂O-CO-MIG compared to administration of miglustat for 6 hours.

[0203] FIG. 45 shows the plasma concentration of miglustat following administration of amino-PEG4-propanoyl-MIG compared to administration of miglustat for 6 hours.

[0204] FIG. 46 shows the plasma concentration of miglustat following administration of ethoxycarbonyl-NH-CO-MIG compared to administration of miglustat for 6 hours.

[0205] FIG. 47 shows the plasma concentration of miglustat following administration of phenyl-N(Me)-CO-MIG and N-piperidinyl-CO-MIG compared to administration of miglustat for 6 hours.DETAILED DESCRIPTION

[0206] This disclosure provides methods for treating neurodegenerative or metabolic disorders by administering, alone or in combination, prodrugs of arimoclomol and miglustat. This disclosure further provides pharmaceutical compositions comprising the same.

[0207] Currently neurodegenerative or metabolic disorders such as Niemann-Pick disease type C and Gaucher Disease are treated by administering, alone or in combination, arimoclomol and miglustat. The standard dosing regimen comprises administering up to 3 unit doses per day in order to maintain effective plasma levels of the drugs.

[0208] Furthermore, brain absorption of miglustat is low, likely around 20%, which results in requiring a higher dosage to achieve therapeutic effect; and that the higher dosage requirement of miglustat results in gastrointestinal effects believed to be caused by inhibition of intestinal disaccharidases, which causes for example, carbohydrate malabsorption, diarrhea, abdominal pain, flatulence, bloating, vomiting, nausea, anorexia, dyspepsia, nutrient deficiency, weight loss, and stunted growth.

[0209] The inventors discovered that arimoclomol can be modified at either the 2-hydroxy or N-piperidine position with substituent groups that are cleaved by enzymes which release unconjugated arimoclomol.

[0210] The presently described compounds unexpectedly display much better pharmacokinetics characterized by either lower maximum plasma concentrations (Cmax) or Cmax values comparable to unmodified arimoclomol and / or miglustat, longer times to maximum plasma concentration (Tmax), and longer half-life (t½). This results in a longer elimination phase with higher plasma concentrations over a longer period of time as measured by Area Under the Curve (AUC). These improved pharmacokinetics allow for dosages that result in therapeutically effective plasma levelsAttorney Docket No. 68547WO01for longer periods of time per dose, meaning patients need fewer doses per day, even only a single dose per day.

[0211] Reference will now be made in detail to exemplary embodiments of the claimed invention. While the claimed invention will be described in conjunction with the exemplary embodiments, it will be understood that it is not intended to limit the claimed invention to those embodiments. To the contrary, it is intended to cover alternatives, modifications, and equivalents, as may be included within the spirit and scope of the claimed invention, as defined by the appended claims.

[0212] Those of ordinary skill in the art may make modifications and variations to the embodiments described herein without departing from the spirit or scope of the claimed invention. In addition, although certain methods and materials are described herein, other methods and materials that are similar or equivalent to those described herein can also be used to practice the claimed invention.

[0213] In addition, any of the compositions or methods provided, disclosed, or described herein can be combined with one or more of any of the other compositions and methods provided, disclosed, or described herein.I. Definitions

[0214] “A” and “an” as it relates to the present technology, means the singular form, but includes the plural form unless clear from the context.

[0215] “About” as it related to the present technology means, as it applied to measured quantities, + / - 10% of the stated measured value; for example “about 100 mg” means 100 mg + / - 10%, i.e.90-110 mg. Unless specifically stated or obvious from context, as used herein, the term “about” is understood as within a range of normal tolerance in the art, for example, within two standard deviations of the mean. About can be understood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, 0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear from context, all numerical values provided herein can be modified by the term about.

[0216] As used herein, the term “or” means, and is used interchangeably with, the term “and / or,” unless context clearly indicates otherwise.

[0217] As used herein, the term “such as” means, and is used interchangeably with, the phrase “such as, for example” or “such as but not limited.”

[0218] As used herein, the term “subject” means a human or animal, including but not limited to a human or animal patient.Attorney Docket No. 68547WO01

[0219] Ranges provided herein are understood to be shorthand for all of the values within the range. For example, a range of 1 to 50 is understood to include any number, combination of numbers, or sub-range from the group consisting 1, 2, 3, 4, 5, 6, 7, 8, 9, 10. 11. 12. 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50.

[0220] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the methods described herein belong. Any reference to standard methods (e.g.. ASTM, TAPPI, AATCC, etc.) refers to the most recent available version of the method at the time of filing of this disclosure unless otherwise indicated.

[0221] “Arimoclomol” as it related to the present technology means N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-l-oxide-3-carboximidoyl chloride, its stereoisomers and the acid addition salts thereof. Stereoisomers of arimoclomol include, but are not limited to (+)-(R)-N-[2-hydroxy-3-(l-piperidinyl)-propoxy] -pyridine- l-oxide-3-carboximidoyl chloride. (-)-(S)-N-[2-hydroxy-3-(l-piperidinyl)-propoxy] -pyridine- l-oxide-3-carboximidoyl chloride, (Z)-(R)-N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-l-oxide-3-carboximidoyl chloride, (E)-(R)-N42-hydroxy-3-(l-piperidinyl)-propoxy] -pyridine- l-oxide-3 carboximidoyl chloride, (Z)-(S)-N-[2-hydroxy-3-(l-piperidinyl)-propoxy] -pyridine- l-oxide-3-carboximidoyl chloride; and (E)-(S)-N-[2-hydroxy-3-(l-piperidinyl)-propoxy]-pyridine-l-oxide-3-carboximidoyl chloride.

[0222] “ARIM” as it relates to the present technology refers to an arimoclomol moiety that is part of a larger molecular structure.

[0223] “ELIG” as it relates to the present technology refers to an eliglustat moiety that is part of a larger molecular structure.

[0224] “MIG” as it relates to the present technology refers to an miglustat moiety that is part of a larger molecular structure.

[0225] “Cholesterol,” as it relates to the present technology means free cholesterol or cholest-5-en-3[3-ol. “Cholesterol” as it relates to the present technology includes, and may be used interchangeably with “unesterified cholesterol” as defined below.

[0226] “Coordinated Lysosomal Expression and Regulation” and / or “CLEAR” as it relates to the present technology means a transcriptional network directed primarily by certain transcription factors including, for example, TFEB and MiT / TFE factors (TFE3, MITF, TFEC) that bind toAttorney Docket No. 68547WO01promoter sequences enriched in genes related to lysosomal and autophagic functions to coordinate processes that include but are not limited to lysosomal biogenesis, autophagy, autophagosomelysosome fusion, lipid catabolism, and cellular stress-adaptation pathways.

[0227] “Drug” or “medicament” as it related to the present technology includes biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body.

[0228] “Esterified cholesterol” as it relates to the present technology means a form of cholesterol where the hydroxyl group of the cholesterol molecule has been conjugated with a fatty acid to form an ester-bond that links the cholesterol molecule and the fatty acid. In most animal tissues, an enzyme acyl-CoA:cholesterol acyltransferase (ACAT) or sterol O-acyl-transferase (SCAT) synthesizes cholesterol esters from CoA esters of fatty acids and cholesterol. ACAT exists in two forms, both of which are intracellular enzymes found in the endoplasmic reticulum and are characterized by multiple transmembrane domains and a catalytic histidine residue in a hydrophobic domain.

[0229] “Niemann-Pick disease type C Clinical Severity Scale” and / or “NPCCSS” as it relates to the present technology means a composite clinical severity scale (hereafter “NPCCSS”; see Yanjanin et al.). A full “17-domain NPCCSS score” incorporates clinical signs and symptoms in nine major (ambulation, cognition, eye movement, fine motor, hearing, memory, seizures, speech, swallowing) and eight minor (auditory brainstem response, behavior, gelastic cataplexy, hyperreflexia, incontinence, narcolepsy, psychiatric, respiratory problems) domains to determine a score which describes the severity of the subject's NPC progression (a higher score, the more progressed / severe the disease is). An abridged “5-domain NPCCSS score” is successfully used by clinicians and incorporates clinical signs and symptoms from the major domains of ambulation, cognition, fine motor, speech and swallowing (see Cortina-Borja). An “4-domain NPCCSS score” is used based on Ambulation, Fine Motor Skills, Speech, and Swallow domains.

[0230] “Impaired cholesterol trafficking” as it relates to the present technology means a reduced ability to remove cholesterol from the cell through the normal lysosomal pathway.

[0231] “Including,” as it relates to the present technology means, and is used interchangeably with, the phrase “including but not limited to.”

[0232] “Isoform 1” as it relates to the present technology means a mature form of NPC1 protein.Attorney Docket No. 68547WO01

[0233] “Lipid storage disorders” or “lipidoses” are a subgroup of the lysosomal storage disorders in which harmful amounts of lipids accumulate in the intracellular space due to reduced expression or function of the enzymes needed to metabolize lipids. Over time, this excessive storage of lipids can cause permanent cellular and tissue damage, particularly in the brain, peripheral nervous system, liver, spleen and bone marrow.

[0234] Lipids are a broad group of naturally-occurring molecules which include fats, waxes, sterols, fat-soluble vitamins (such as vitamins A, D, E and K), monoglycerides, diglycerides, phospholipids, and others. The main biological functions of lipids include energy storage, as structural components of cell membranes, and as important signaling molecules.

[0235] Lipids may be broadly defined as hydrophobic or amphiphilic small molecules; the amphiphilic nature of some lipids allows them to form structures such as vesicles, liposomes, or membranes in an aqueous environment. Biological lipids originate entirely or in part from two distinct types of biochemical subunits: ketoacyl and isoprene groups. Using this approach, lipids may be divided into eight categories: fatty acyls, glycerolipids. glycerophospholipids, sphingolipids, saccharolipids and polyketides (derived from condensation of ketoacyl subunits); and sterol lipids and prenol lipids (derived from condensation of isoprene subunits). Although the term lipid is sometimes used as a synonym for fats, fats are a subgroup of lipids called triglycerides. Lipids also encompass molecules such as fatty acids and their derivatives (including tri-, di-, and monoglycerides and phospholipids), as well as other sterol-containing metabolites such as cholesterol.

[0236] “Lysosomal Sphingolipid Hydrolysis” as it relates to the present technology means a multitude of enzymes are involved in the lysosomal catabolism of sphingolipids (or glycophingolipids). These enzymes, or more specifically hydrolases, are each responsible for the degradation of a specific sphingolipid. The lysosomal sphingolipid hydrolases interact with sphingolipid activator proteins (SAP or saposins) to stimulate the activity of said hydrolases. SAPs are considered to facilitate the enzyme / sub state interaction between water-soluble enzymes and membrane-bound substrates. Further, the lipid composition of late endosomal and lysosomal compartments is characterized by the presence of negatively charged phospholipids such as BMP and PI (phosphatidylinositol), which also stimulates the activity of some hydrolases. The BMP-dependent lysosomal hydrolases include sialidase, a-galactosidase A, glucosylceramidase, [3-galactosylceramidase, arylsulfatase A, acid ceramidase and Sphingomyelinase.Attorney Docket No. 68547WO01

[0237] “Maturation,” “maturing,” or “mature” as it relates to the present technology means the process and / or characteristic of a protein reaching its folded state.

[0238] “Mechanism of Action of Arimoclomol” or “Arimoclomol MOA” as it related to the present technology means the biological pathway by which arimoclomol treats the NPC Disease State. Arimoclomol targets NPC etiology by both NPC 1 -independent and NPC 1 -dependent pathways: (1) via the NPC 1 -independent pathway, arimoclomol upregulates expression of certain CLEAR genes other than NPC1, thereby improving overall cell health by, for example, increasing lysosomal biogenesis and / or autophagy flux; (2) via the NPC 1 -dependent pathway, CLEAR gene upregulation increases production of the NPC1 protein. Though still mutated, overproducing the reduced function protein improves lysosomal function and cholesterol elimination.

[0239] “Myelin Basic Protein” and / or “MBP” as it relates to the present technology means a protein believed to be important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. MBP maintains the correct structure of myelin, interacting with the lipids in the myelin membrane.

[0240] “Patient” as it relates to the present technology means a human or animal subject in need of treatment.

[0241] “Rearing” as it relates to the present technology means a functional behavior in rodents that plays an important role in exploring and interacting with the environment. As such, rearing is a complex behavior that involves aspects such as locomotion, balance, exploratory drive, spatial awareness, cognitive mapping, sequence learning, and decision making. Therefore, the ability to rear is not simply an indicator of muscle function but a broader marker of brain health in rodents. The same brain regions (particularly the cerebellum, hippocampus, and midbrain) that are responsible for controlling rearing behavior in rodents are involved in recruiting muscles during movements related to fine motor function and swallow in humans. Rearing activity in NPC mice is therefore an appropriate indicator of neuronal health in brain regions relevant to functional endpoints like the Fine Motor Skills and Swallow domains of the NPCCSS in human NPC patients

[0242] “Saposin Deficiency” as it relates to the present technology means a disease (in both humans and mice) caused by prosaposin / saposin deficiencies which leads to severe neurological deficits. Human patients with point mutations in the saposin A, B and C show phenotypes of Krabbe disease, metachromatic leukodystrophy and Gaucher disease, indicating that their primaryAttorney Docket No. 68547WO01in vivo substrates are galactosylceramide, sulfatide and glucosylceramide, respectively. Krabbe disease, atypical, due to saposin A deficiency: An inherited biochemical disorder which results in neurological regression within a few months of birth. Death usually occurs during the first few years of life. The disorder is similar to Krabbe disease but is differentiated by the genetic origin of the biochemical defect. Krabbe disease involves a defect in the galactocerebrosidase gene whereas atypical Krabbe disease involves a defect in the prosaposin gene which causes a deficiency of saposin A. Saposin B, previously known as SAP-1 and sulfatide activator, stimulates the hydrolysis of a wide variety of substrates including cerebroside sulfate, GM1 ganglioside, and globotriaosylceramide by arylsulfatase A, acid beta-galactosidase, and alpha-galactosidase, respectively. Human saposin B deficiency, transmitted as an autosomal recessive trait, results in tissue accumulation of cerebroside sulfate and a clinical picture resembling metachromatic leukodystrophy (activator-deficient metachromatic leukodystrophy) although with normal arylsulfatase activity. Saposin B deficiency is a heterogeneous disease with a spectrum similar to that in metachromatic leukodystrophy. Saposin (SAP-) C is required for glucosylceramide degradation, and its deficiency results in a variant form of Gaucher disease; non-neuronopathic Gaucher disease due to SAP-C deficiency. Very high levels of chitotriosidase activity, chemokine CCL18, and increased concentration of glucosylceramide in plasma and normal -glucosidase activity in skin fibroblasts are observed in the patients. A missense mutation, p. L349P, located in the SAP-C domain and another mutation, p. MIL, located in the initiation codon of the prosaposin precursor protein has been identified. In a few non-neuronopathic Gaucher patients, a mutation in both Saposin C and saposin D has been identified. Combined saposin C and D deficiencies in mice lead to a neuronopathic phenotype with glucosylceramide and alpha-hydroxy ceramide accumulation. In mice, saposin D deficiency is associated with ceramide accumulation, partial loss of Purkinje cells and impaired urinary system function. This phenotype does not mimic the embryonic lethality exhibited by mice with complete deficiency of acid ceramidase, saposin D's cognate enzyme Two mutations are known in humans that result in complete inactivation of all four saposins and prosaposin. Total saposin deficiency is a devastating disease with involvement of multiple organs and multiple sphingolipids. Combined saposin deficiency (or prosaposin deficiency) has been reported in a case presenting with a severe neurovisceral dystrophy which caused death as a neonate. Multiple sphingolipids were elevated in the urine, with globotriaosylceramide showing the greatest increase. A novel mutation in the PSAP gene wasAttorney Docket No. 68547WO01identified, being homozygous for a splice-acceptor site mutation two bases upstream of exon 10. This mutation led to a premature stop codon and yielded low levels of transcript.

[0243] “Transcription Factor EB” as it relates to the present technology means protein that in humans is encoded by the TFEB gene. TFEB is a master gene for lysosomal biogenesis. It encodes a transcription factor that coordinates expression of lysosomal hydrolases, membrane proteins and genes involved in autophagy. Upon nutrient depletion and under aberrant lysosomal storage conditions such as in lysosomal storage diseases, TFEB translocate from the cytoplasm to the nucleus, resulting in the activation of its target genes.

[0244] “Transcription Factor E3” as it relates to the present technology means a protein that in humans is encoded by the TFE3 gene. TFE3, like TFEB, binds to CLEAR (Coordinated Lysosomal Expression and Regulation) motifs in the promoter regions of lysosomal and autophagy-related genes, thereby activating genes involved in lysosomal biogenesis and autophagy.

[0245] “Treating” as it related to the present technology means any of the following: (1) delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0246] “Unesterified cholesterol” as it relates to the present technology means “free cholesterol,” or cholest-5-en-3P-ol.

[0247] “Upregulate,” “upregulation,” or “upregulates” as it relates to the present technology means a process by which gene expression increases. Upregulation can be determined by measuring an increase in the presence of nucleotide strands such as DNA and / or RNA or an increase of the quantity of protein encoded by the gene which is expressed by the cell.I. Methods of Treating Neurodegenerative or Metabolic Diseases or Disorders Using Prodrugs of Arimoclomol and Miglustat

[0248] In an embodiment, this disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:Attorney Docket No. 68547WO01administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof.

[0249] It will be appreciated by a person skilled in the art that in the embodiments described herein, the order in which the prodrug of arimoclomol and the prodrug of miglustat are administered in needs not follow the order of recitation. In certain embodiments, the prodrug of arimoclomol and the prodrug of miglustat are administered at the same time. In other embodiments, the prodrug of miglustat may be administered first. In other embodiments, the prodrug of arimoclomol may be administered first.

[0250] “Pharmaceutically acceptable salt” as it relates to the present technology means a salt which is not harmful to the subjects. Such salts include pharmaceutically acceptable basic or acid addition salts as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.

[0251] Acid addition salts include, but are not limited to, salts of inorganic acids as well as organic acids. Representative examples of suitable inorganic acids include hydrochloric, hydrobromic, hydroiodic, phosphoric, sulfuric, nitric acids and the like. Representative examples of suitable organic acids include formic, acetic, trichloroacetic, trifluoroacetic, propionic, benzoic, cinnamic, citric, fumaric, glycolic, lactic, maleic, malic, malonic, mandelic, oxalic, picric, pyruvic, salicylic, succinic, methanesulfonic, ethanesulfonic, tartaric, ascorbic, pamoic, bismethylene salicylic, ethanedisulfonic, gluconic, citraconic, aspartic, stearic, palmitic, EDTA, glycolic, p-aminobenzoic, glutamic, benzenesulfonic, p-toluenesulfonic acids and the like. Further examples of pharmaceutically acceptable inorganic or organic acid addition salts include the pharmaceutically acceptable salts listed in J. Pharm. Sci. 66, 2, (1977) which is incorporated herein by reference.

[0252] Other pharmaceutically acceptable salts include, but are not limited to, acetate, / -aspartate, besylate, bicarbonate, carbonate, d-camsylate, Z-camsylate, citrate, edisylate, formate, fumarate, gluconate, hydrobromide / bromide, hydrochloride / chloride, d-lactate, / -lactate, d, / -lactate, d,l-malate, / -malate, mesylate, pamoate, phosphate, succinate, sulfate, bisulfate, d-tartrate, / -tartrate, d, / -tartrate, meso-tartrate, benzoate, gluceptate, d-g neuron ate, hibenzate, isethionate, malonate,Attorney Docket No. 68547WO01methyl sulfate, 2-napsylate, nicotinate, nitrate, orotate, stearate, tosylate, thiocyanate, acefyllinate, aceturate, aminosalicylate, ascorbate, borate, butyrate, camphorate, camphocarbonate, decanoate, hexanoate, cholate, cypionate, dichloroacetate, edentate, ethyl sulfate, furate, fusidate, galactarate, galacturonate, gallate, gentisate, glutamate, glutarate, glycerophosphate, heptanoate, hydroxybenzoate, hippurate, phenylpropionate, iodide, xinafoate. lactobionate, laurate, maleate, mandelate, methanesulfonate, myristate, napadisilate, oleate, oxalate, palmitate, picrate, pivalate, propionate, pyrophosphate, salicylate, salicylsulfate, sulfosalicylate, tannate, terephthalate, thiosalicylate, tribrophenate. valerate, valproate, adipate, 4-acetamidobenzoate, camsylate, octanoate, estolate, esylate, glycolate, thiocyanate, or undecylenate. In the preferred embodiments, the anionic salt form is selected from the group consisting of chloride, hydrogen carbonate (bicarbonate), iodide, bromide, citrate, acetate, formate, salicylate, hydrogen sulfate (bisulfate), hydroxide, nitrate, hydrogen sulfite (bisulfite), propionate, benzene sulfonate, hypophosphite, phosphate, bromate, iodate, chlorate, fluoride, nitrite.

[0253] “Neurodegenerative and or metabolic diseases or disorder” as it related to the present disclosure means a disease or disorder wherein damage to tissue occurs due to a build up of a substance is tissue. In such diseases or disorders, build up of a substance in, for example, the neuron and or brain cells results in the progressive deterioration and death of nerve cells (neurons) in the brain and nervous system, leading to a decline in function over time. By way of another example, build up of a different substance in tissue such as the liver results in progressive deterioration and death of liver tissue, leading to a decline is function over time. Many of the neurodegenerative and or metabolic diseases or disorders contemplated are lysosomal storage disorders.

[0254] “Lysosomal storage disorder” or “Lysosomal Storage Disorders” as it related to the present technology means a disease or disorder associated with reduced lysosomal function. Lysosomal storage diseases (LSDs) are a group of approximately 40 rare inherited metabolic disorders that result from defects in lysosomal function. LSDs are caused by lysosomal dysfunction usually as a consequence of deficiency of a single enzyme required for the metabolism of lipids, glycoproteins or mucopolysaccharides. Although each disorder results from different gene mutations that translate into a deficiency in enzyme activity, they all share a common biochemical characteristic — all lysosomal disorders originate from an abnormal accumulation of substances inside the lysosome.Attorney Docket No. 68547WO01

[0255] Individually LSDs occur with incidences of less than 1:100.000, however, as a group the incidence is about 1:5000-1:10.000. Most of these disorders are autosomal recessively inherited, however a few are X-linked recessively inherited, such as Fabry disease.

[0256] The lysosomal storage diseases are generally classified by the nature of the primary stored material involved, and can be broadly broken into the following: lipid storage disorders (or lipidoses), mainly sphingolipidoses (including Gaucher's and Niemann-Pick diseases); gangliosidosis (including Tay-Sachs disease); leukodystrophies; mucopolysaccharidoses (including Hunter syndrome and Hurler disease); glycoprotein storage disorders (glycoproteinosis); and nucolipidoses.

[0257] Depending on the severity of the disease patients either die at a young and unpredictable age. many within a few months or years of birth, whereas others survive into early adulthood finally succumbing to the various pathologies of their particular disorder. The symptoms of LSD vary, depending on the particular disorder and can be mild to severe. They can include developmental delay, movement disorders, seizures, dementia, deafness and / or blindness. Some people with LSD have enlarged livers (hepatomegaly) and enlarged spleens (splenomegaly), pulmonary and cardiac problems, and abnormal bone growth.

[0258] The majority of patients are initially screened by an enzyme assay, which is the most efficient method to arrive at a definitive diagnosis. In some families where the disease-causing mutation(s) is known and in certain genetic isolates, mutation analysis may be performed. As there may be numerous different mutations, sequencing of the gene encoding the particular affected enzyme is sometimes necessary to confirm the diagnosis. Prenatal diagnosis may be useful when there is a known genetic risk factor.

[0259] TFEB and TFE3 activate expression of genes responsible for lysosomal protein synthesis. Lysosomes are organelles responsible for removing waste from the cell. Genes activated by TFEB and TFE3 are collectively known as the CLEAR network of genes. In cells unaffected by NPC, normally assembled and maturated proteins migrate to the lysosomal membrane where they play a critical role in transporting cholesterol and other lipids out of the lysosome. In healthy cells, this process supports elimination of waste (autophagy) and healthy neuronal function.

[0260] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0261] In a still further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0262] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, the method comprising, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.Attorney Docket No. 68547WO01

[0263] “Other Lysosomal Storage Disorders” or “OLSD) as it related to the present disclosure are Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS DC), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0264] “A prodrug of arimoclomol” as it relates to the present disclosure, means a modified form of arimoclomol. Arimoclomol is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients 2 years of age and older.

[0265] The recommended oral dosage of arimoclomol, in combination with miglustat, for patients with an actual body weight of: >8 kg to 15 kg, is 47 mg of arimoclomol free-base three times a day, > 15 kg to 30 kg, is 62 mg of arimoclomol free-base three times a day, > 30 kg to 55 kg, is 93 mg of arimoclomol free-base three times a day, > 55 kg, is 124 mg of arimoclomol free-base three times a day. Alternatively, the oral dosage is: 8-15 kg, 31 mg of arimoclomol free-base three times a day, >15-22 kg, 47 mg or arimoclomol free-base three times a day, >22-38 kg, 62 mg of arimoclomol free-base three times a day, >38-55 kg, 93 mg of arimoclomol free-base three times a day, and >55kg, 124 mg of arimoclomol free-base three times a day.

[0266] For patients with an eGFR > 15 to < 50 mL / minute, the recommended oral dosage of arimoclomol, in combination with miglustat, for patients with an actual body weight of [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]: 8 kg to 15 kg, is 47 mg two times a day, > 15 kg to 30 kg, is 62 mg two times a day, > 30 kg to 55 kg, is 93 mg two times a day, > 55 kg, is 124 mg two times a day

[0267] However, for patients who have difficulty swallowing capsules, administer arimoclomol in one of two ways: Oral Administration: Carefully open the capsule and sprinkle the entire contents into 15 mL of water or apple juice or 15 mL of soft food (e.g„ applesauce, pudding, or yogurt). Stir the mixture for 15 seconds. Consume the entire mixture immediately. Feeding Tube Administration (nasogastric or gastric tube): Carefully open the capsule and sprinkle the entire contents into 20 mL of water. Do not add the capsule contents to other liquids besides water. Stir the mixture for 15 seconds. Administer the entire mixture immediately via feeding tube. Flush the feeding tube with 5 mL of water after administration.Attorney Docket No. 68547WO01

[0268] “A prodrug of miglustat” as it relates to the present disclosure means a modified form of miglustat. Miglustat is indicated for the treatment of certain lysosomal storage disorders in adult patients for whom enzyme replacement therapy is not a therapeutic option, by administering a 200 mg unit dosage three times a day. [Zavesca Label]

[0269] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease. Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0270] “Gaucher Disease” as it relates to the present technology means a disease caused by a defect in the glucosylceramidase enzyme (also known as glucocerebrosidase and acid β-glucosidase); a 55.6 KD, 497 amino acids long protein. Glucosylceramidase is responsible for the conversion of glycosylceramide (or glucocerebroside) to ceramide; the defect thus leads to an accumulation of glycosylceramide. Its activity is stimulated by BMP and is dependent on saposins. Gaucher's disease is the most common of the lysosomal storage diseases. Fatty material can collect in the spleen, liver, kidneys, lungs, brain and bone marrow. Symptoms may include enlarged spleen and liver, liver malfunction, skeletal disorders and bone lesions that may be painful, severe neurologic complications, swelling of lymph nodes and (occasionally) adjacent joints, distended abdomen, a brownish tint to the skin, anemia, low blood platelets and yellow fatty deposits on the sclera. Persons affected most seriously may also be more susceptible to infection. The disease shows autosomal recessive inheritance and therefore affects both males and females. Different mutations of glucosylceramidase determine the remaining activity of the enzyme, and, to a large extent, the phenotype. Research suggests that heterozygotes for particular glucosylceramidase mutations are at an increased risk of Parkinson's disease and particular malignancies (non-Hodgkin lymphoma, melanoma and pancreatic cancer). Glycosylceramide is a cell membrane constituent of red and white blood cells. The macrophages that clear these cells are unable to eliminate theAttorney Docket No. 68547WO01waste product, which accumulates in fibrils, and turn into Gaucher cells, which appear on light microscopy to resemble crumpled-up paper.

[0271] Gaucher's disease has three common clinical subtypes. Each type has been linked to particular mutations. In all, there are about 80 known mutations. Type I (or nonneuropathic type) Gaucher Disease is the most common form of the disease occurring in approximately 1 in 50,000 live births. It occurs most often among persons of Ashkenazi Jewish heritage. 100 times the occurrence in the general populace. Symptoms may begin early in life or in adulthood and include enlarged liver and grossly enlarged spleen (together hepatosplenomegaly); the spleen can rupture and cause additional complications. Skeletal weakness and bone disease may be extensive. Spleen enlargement and bone marrow replacement cause anemia, thrombocytopenia and leukopenia. The brain is not affected, but there may be lung and, rarely, kidney impairment. Patients in this group usually bruise easily (due to low levels of platelets) and experience fatigue due to low numbers of red blood cells. Depending on disease onset and severity, type 1 patients may live well into adulthood. Many patients have a mild form of the disease or may not show any symptoms. Type II (or acute infantile neuropathic Gaucher's disease) typically begins within 6 months of birth and has an incidence rate of approximately 1 in 100,000 live births. Symptoms include an enlarged liver and spleen, extensive and progressive brain damage, eye movement disorders, spasticity, seizures, limb rigidity, and a poor ability to suck and swallow. Affected children usually die by age 2. Type III (the chronic neuropathic Gaucher Disease) can begin at any time in childhood or even in adulthood and occurs in approximately 1 in 100,000 live births. It is characterized by slowly progressive but milder neurologic symptoms compared to the acute or type 2 version. Major symptoms include an enlarged spleen and / or liver, seizures, poor coordination, skeletal irregularities, eye movement disorders, blood disorders including anemia and respiratory problems. Patients often live into their early teen years and adulthood.

[0272] The National Gaucher Foundation states that around 1 in 100 people in the general U. S. population is a carrier for type 1 Gaucher's disease, giving a prevalence of 1 in 40,000; among Ashkenazi Jews the rate of carriers is considerably higher, at roughly 1 in 15. Type 2 Gaucher's disease shows no particular preference for any ethnic group. Type 3 Gaucher's disease is especially common in the population of the Northern Swedish region of Norrbotten where the incidence of the disease is 1 in 50,000. For type 1 and most type 3 patients, enzyme replacement treatment with intravenous recombinant glucosylceramidase can decrease liver and spleen size, reduce skeletalAttorney Docket No. 68547WO01abnormalities, and reverse other manifestations. The rarity of the disease means that dose-finding studies have been difficult to conduct, so there remains controversy over the optimal dose and dosing frequency. Due to the low incidence, this has become an orphan drug in many countries. Successful bone marrow transplantation cures the non-neurological manifestations of the disease, because it introduces a monocyte population with active glucosylceramidase. However, this procedure carries significant risk and is rarely performed in Gaucher patients. Surgery to remove the spleen (splenectomy) may be required on rare occasions if the patient is anemic or when the enlarged organ affects the patient's comfort. Blood transfusion may benefit some anemic patients. Other patients may require joint replacement surgery to improve mobility and quality of life. Other treatment options include antibiotics for infections, antiepileptics for seizures, bisphosphonates for bone lesions, and liver transplants. Substrate reduction therapy may prove to be effective in stopping Type 2, as it can cross through the blood barrier into the brain. There is currently no effective treatment for the severe brain damage that may occur in patients with types 2 and 3 Gaucher disease.

[0273] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0274] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.Attorney Docket No. 68547WO01

[0275] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I. Sialidosis type II. aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.“Sialidosis” or “Mucolipidosis type 1” as it relates to the present technology means a caused by a defect in the sialidase enzyme (or alpha-neuraminidase). Sialidase is responsible for the conversion of GM3 to lactosylceramide; the defect thus leads to an accumulation of GM3. Its activity is stimulated by BMP and is dependent on saposins. Sialidosis is inherited in an autosomal recessive manner. Symptoms are either present at birth or develop within the first year of life. In many affected infants, excessive swelling throughout the body is noted at birth. These infants are often born with coarse facial features, such as a flat nasal bridge, puffy eyelids, enlargement of the gums, and excessive tongue size (macroglossia). Many infants with are also born with skeletal malformations such as hip dislocation. Infants often develop sudden involuntary muscle contractions (called myoclonus) and have red spots in their eyes (cherry red macules). They are often unable to coordinate voluntary movement (called ataxia). Tremors, impaired vision, and seizures also occur. Tests reveal abnormal enlargement of the liver (hepatomegaly) and spleen (splenomegaly) and extreme abdominal swelling. Infants generally lack muscle tone (hypotonia) and have mental retardation that is either initially or progressively severe. Many patients suffer from failure to thrive and from recurrent respiratory infections. Most infants with ML I die before the age of 1 year. Sialidosis may be sub-categorized according to the age at which symptoms begin and the types of symptoms present. The effects of the disease may range from mild to severe.

[0276] Sialidosis is a rare disorder that has no racial predilection. Very little population data are available, but a study from the Netherlands reported a frequency of approximately 1 case in 2,175,000 live births. However, this rate may not apply to all populations, some of which could have a higher incidence; moreover, missed clinical recognition is an important factor when newborn screening is not an option.

[0277] “Metachromatic Leukodystrophy (MLD)” or “Arylsulfatase A deficiency” as it relates to the present technology means a disease caused by a defect in the arylsulfatase A enzyme (orAttorney Docket No. 68547WO01cerebroside-sulfatase). Arylsulfatase A is responsible for the conversion of sulfatide (or cerebroside 3-sulfate) to galactosylceramide; the defect thus leads to an accumulation of sulfatide. Its activity is stimulated by BMP and is dependent on saposins. It is a lysosomal storage disease which is commonly listed in the family of leukodystrophies. Leukodystrophies affect the growth and / or development of myelin, the fatty covering which acts as an insulator around nerve fibers throughout the central and peripheral nervous systems. Like many other genetic disorders that affect lipid metabolism, there are several forms of MLD, which are late infantile, juvenile, and adult: In the late infantile form, which is the most common form MLD, affected children begin having difficulty walking after the first year of life. Symptoms include muscle wasting and weakness, muscle rigidity, developmental delays, progressive loss of vision leading to blindness, convulsions, impaired swallowing, paralysis, and dementia. Children may become comatose. Untreated, most children with this form of MLD die by age 5, often much sooner. Children with the juvenile form of MLD (onset between 3-10 years of age) usually begin with impaired school performance, mental deterioration, and dementia and then develop symptoms similar to the late infantile form but with slower progression. Age of death is variable, but normally within 10 to 15 years of symptom onset. The adult form commonly begins after age 16 as a psychiatric disorder or progressive dementia. Adult-onset MLD progresses more slowly than the late infantile and juvenile forms, with a protracted course of a decade or more. In rare cases the body can compensate for the deficiency and the person will exhibit no symptoms.

[0278] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0279] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0280] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0281] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5. late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0282] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0283] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).Attorney Docket No. 68547WO01

[0284] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0285] “Nieman-Pick Disease” or “NP” as it relates to the present technology means a group of rare genetic diseases of varying severity. These are inherited metabolic disorders in which sphingomyelin accumulates in lysosomes in cells of many organs. NP types A, A / B, and B are caused by mutations in the SMPD1 gene, which causes a deficiency of an acid sphingomyelinase (ASM). NP type C (NPC) is now considered a separate disease, as SMPD1 is not involved, and there is no deficiency in ASM. State. Arimoclomol targets NPC etiology by both NPC1-independent and NPC 1 -dependent pathways: (1) via the NPC 1 -independent pathway, arimoclomol upregulates expression of all CLEAR genes, thereby mitigating the deleterious effects of impaired cholesterol trafficking and improving overall cell health; (2) via the NPC 1 -dependent pathway, CLEAR gene upregulation increases production of the NPC1 protein. Though still mutated, overproducing the reduced function protein improves lysosomal function and cholesterol elimination.

[0286] “Myelin Basic Protein” and / or “MBP” as it relates to the present technology means a protein believed to be important in the process of myelination of nerves in the nervous system. The myelin sheath is a multi-layered membrane, unique to the nervous system, that functions as an insulator to greatly increase the velocity of axonal impulse conduction. MBP maintains the correct structure of myelin, interacting with the lipids in the myelin membrane.

[0287] “Nieman-Pick Disease Type C” or “NPC” as it relates to the present technology means a rare progressive genetic disorder characterized by an inability of the body to transport cholesterol and other fatty substances (lipids) inside of cells. This leads to the abnormal accumulation of these substances within various tissues of the body, including brain tissue. Without wishing to be bound by theory, NPC is believed to be caused by one or mutations in the NPC1 and or NPC2 gene

[0288] “Nieman-Pick Type C Protein 1” or “NPC1” as it relates to the present technology means the gene encoding the Niemann-Pick type C protein 1, also referred to in the art as the NPC intracellular cholesterol transporter 1. The term “NPC1” refers to the protein product of the NPC1Attorney Docket No. 68547WO01gene. In patients with NPC, the NPC1 protein has substantially diminished quantity and functionality because mutations in NPC genes prevent most NPC1 protein from completing assembly and maturation in the endoplasmic reticulum and Golgi apparatus. Furthermore, the small amount of NPC1 protein that does localize in the lysosome is thought to be less effective, leading to cholesterol accumulation and neuronal death.

[0289] “NPCl'^ it relates to the present technology means a mouse model that possesses two null allele mutations in the NPC1 gene which results in expression of a non-functional mutant NPC1 protein.

[0290] as it relates to the present technology means a mouse model that possesses a point mutation in the NPC1 genes which results in expression of a mutant NPC1 protein with reduced function compared to wild-type NPC1 protein.

[0291] “NPC 1 -dependent” as it relates to the present technology means a biological pathway that involves the NPC1 gene and / or the NPC1 protein.

[0292] “NPC 1 -independent” as it relates to the present technology means a biological pathway that does not involve the NPC1 gene or NPC 1 protein.

[0293] In certain patients with NPC, the NPC1 protein has substantially diminished quantity and functionality because mutations in NPC genes prevent most NPC1 protein from completing assembly and maturation in the endoplasmic reticulum and Golgi apparatus (Figure 12, Panel B). Furthermore, the small amount of NPC1 protein that does localize in the lysosome is thought to be less effective, leading to cholesterol accumulation and neuronal death.

[0294] “Fabry Disease” as it relates to the present technology means a disease is caused by a defect in the a-galactosidase A enzyme, a-galactosidase A is responsible for the conversion of globotriaosylceramide to lactosylceramide; the defect thus leads to an accumulation of globotriaosylceramide (also abbreviated as Gb3, GL-3, or ceramide trihexoside). Its activity is stimulated by BMP and is dependent on saposins. Fabry disease is also known as Anderson-Fabry disease, Angiokeratoma corporis diffusum, Ruiter-Pompen-Wyers syndrome, Ceramide trihexosidosis, and Sweeley-Klionsky disease. It is an X-linked recessive (inherited) disease that affects hemizygous males, as well as both heterozygous and homozygous females; males tend to experience the most severe clinical symptoms, while females vary from virtually no symptoms to those as serious as males. This variability is thought to be due to X-inactivation patterns during embryonic development of the female. Symptoms include anhidrosis (lack of sweating), fatigue,Attorney Docket No. 68547WO01angiokeratomas (benign cutaneous injury of capillaries), burning extremity pain and ocular involvement. Angiokeratomas are tiny, painless papules that appear at any region of the body, but are predominant on the thighs, buttocks, lower abdomen, and groin. Cosmetic ocular involvement may be present showing cornea verticillata (also known as vortex keratopathy). Keratopathy may be the presenting feature in asymptomatic carriers and must be differentiated from other causes of vortex keratopathy (e.g. drug deposition in the cornea). Other ocular findings that can be seen include conjunctival aneurysms, posterior spoke-like cataracts, papilloedema, macular edema, optic atrophy and retinal vascular dilation. Kidney complications are a common and serious effect of the disease; renal insufficiency and renal failure may worsen throughout life. Proteinuria is often the first sign of kidney involvement. Cardiac complications may also occur; heart related effects worsen with age and may lead to increased risk of heart disease. Cerebrovascular effects lead to an increased risk of stroke. Other symptoms include tinnitus, vertigo, nausea, and diarrhea. Symptoms are typically first experienced in early childhood and can be very difficult to understand; the rarity of Fabry disease to many clinicians sometimes leads to misdiagnoses or ignorance. Manifestations of the disease usually increase in number and severity as an individual age.

[0295] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0296] “Pharmaceutically effective amount” as it relates to the present technology means an amount that has a pharmacological effect. “Pharmaceu tic ally effective amount” may be used interchangeably with “therapeutically effective amount,” which as used herein, means an amount effective for treating a disease or condition. A “therapeutically acceptable salt” as used herein is a pharmaceutically acceptable salt of arimoclomol in the composition of the present technology,Attorney Docket No. 68547WO01which, when used in a therapeutically effective amount, is effective for treating a disease, condition, or syndrome.

[0297] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0298] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation. In a further embodiment, the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation. In certain embodiments, the oral formulation is a solid oral dosage formulation selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip,. Alternatively, the oral formulation is a liquid oral dosage formulation selected from the group consisting of syrups, emulsions, solutions, slurry, and suspensions.

[0299] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the method comprises administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting ofAttorney Docket No. 68547WO01bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or pharmaceutically acceptable salts thereof. Alternatively, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

[0300] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I:wherein X is selected from the group consisting of R, [O-R], [NR'R2]. and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of, alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; andcomposition comprising a therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.Attorney Docket No. 68547WO01

[0301] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of the compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound having a structure of Formula IA:Cl cr Qwherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0302] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula IA is a compound having a structure selected from:Attorney Docket No. 68547WO01wherein n is 1-50;or a pharmaceutically acceptable salt thereof.

[0303] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IA and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein n is alternatively 1-10, alternatively 11-20, alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15,Attorney Docket No. 68547WO01alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33-49, alternatively 44-50.

[0304] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of the compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound having a structure of Formula IB:RL / RN2wherein R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkyl sulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryl oxy, heteroarylsulfinyl, heteroaryl sulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0305] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IB and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the compound of Formula IB is a compound having a structure selected from:or a pharmaceutically acceptable salt thereof.

[0306] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound of Formula IC:(IC)wherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy,Attorney Docket No. 68547WO01heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0307] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IC and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula IC is a compound having a structure selected from:Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01wherein n is 1-50;or a pharmaceutically acceptable salt thereof.

[0309] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IC and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein n is alternatively 1-10, alternatively 11-20, alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15, alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33-49, alternatively 44-50.

[0310] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IC and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula IC is a compound having a structure selected from the group consisting of:Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01wherein n is 1-50;or a pharmaceutically acceptable salt thereof.

[0311] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula I is a compound of Formula ID:Attorney Docket No. 68547WO01wherein R is selected from the group consisting of alkenyl, alkenyl, aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0312] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of the compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula ID is a compound having a structure selected from the group consisting of:

[0313] O, O'Attorney Docket No. 68547WO01wherein n is 1-50;or a pharmaceutically acceptable salt thereof.

[0314] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula ID and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein n is alternatively 1-10, alternatively 11-20, alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15, alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33- 49, alternatively 44-50.

[0315] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the compound of Formula I is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0316] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0317] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders (OLSDs).

[0318] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C. Tay-Sachs disease, Sandhoff disease. GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0319] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II. Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0320] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0321] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis. beta-mannosidosis, and fucosidosis.Attorney Docket No. 68547WO01

[0322] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0323] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0324] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0325] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5. late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0326] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selectedAttorney Docket No. 68547WO01from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0327] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0328] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0329] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the therapeutically effective amount of the compound of Formula I is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0330] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of theAttorney Docket No. 68547WO01prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0331] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of the compound of Formula I is administered in an oral formulation.

[0332] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation. In a still further aspect, wherein the oral formulation is a solid oral dosage formulation selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip,. I a further aspect, the oral formulation is a liquid oral dosage formulation selected from the group consisting of syrups, emulsions, solutions, slurry, and suspensions.

[0333] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula I and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof; or pharmaceutically acceptable salts thereof. In a still further embodiment, the at least one additional compound is selected from theAttorney Docket No. 68547WO01group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.

[0334] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a therapeutically effective amount of a compounds having a structure of Formula II:x(II)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.

[0335] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the compound of Formula II is selected from the group consisting of:wherein n is 1-50;or a pharmaceutically acceptable salt thereof.

[0337] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein n is alternatively 1-10, alternatively 11-20,Attorney Docket No. 68547WO01alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15, alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33-49, alternatively 44-50.

[0338] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the compound of Formula II is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0339] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0340] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder isAttorney Docket No. 68547WO01selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders

[0341] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease. Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0342] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B). MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0343] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0344] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0345] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0346] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0347] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis. aspartylglucosaminuria.

[0348] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5. late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.Attorney Docket No. 68547WO01

[0349] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0350] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0351] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0352] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the therapeutically effective amount of the compound of Formula II is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.Attorney Docket No. 68547WO01

[0353] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0354] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising a therapeutically effective amount of a compound of Formula II is administered in an oral formulation. In a further embodiment, the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation. In a still further embodiment, the oral formulation is a solid oral dosage formulation. In a still further embodiment, the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0355] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oral formulation is a liquid oral dosage formulation. In a further embodiment, the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0356] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula II and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-β-cyclodextrin, arimoclomol and combinations thereof; or pharmaceutically acceptable salts thereof. In a still further embodiment, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.

[0357] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:

[0358] administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound having a structure selected from:Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof.

[0360] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound having a structure selected from:Attorney Docket No. 68547WO01, and wherein n is 1-50;or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof.

[0361] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I having the following structure:or a pharmaceutically acceptable salt thereof; andadministering to the patient in need a composition comprising a therapeutically effective amount of a prodrug of miglustat.Attorney Docket No. 68547WO01

[0362] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I having the following structure:or a pharmaceutically acceptable salt thereof; andadministering to the patient in need a composition comprising a therapeutically effective amount of a prodrug of miglustat.

[0363] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I having the following structure:Attorney Docket No. 68547WO01or a pharmaceutically acceptable salt thereof; andadministering to the patient in need a composition comprising a therapeutically effective amount of a prodrug of miglustat.

[0364] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I having the following structure:or a pharmaceutically acceptable salt thereof; andadministering to the patient in need a composition comprising a therapeutically effective amount of a prodrug of miglustat.

[0365] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:Attorney Docket No. 68547WO01administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula I having the following structure:or a pharmaceutically acceptable salt thereof; andadministering to the patient in need a composition comprising a therapeutically effective amount of a prodrug of miglustat.

[0366] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula III:.0x0'' 'R (ill)wherein X is selected from the group consisting of R, [0-R], [NRXR2], and [NRH],Owherein each Y is independently H orX,wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl,Attorney Docket No. 68547WO01alkyl sulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; andcomposition comprising a therapeutically effective amount of a prodrug of arimoclomol or a pharmaceutically acceptable salt thereof.

[0367] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of the compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, the method comprising administering to the patient in need thereof a therapeutically effective amount of a compound of Formula III, wherein the compound of Formula III is a compound of Formula IIIA:where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy. arylcycloalkyl, aryloxy. aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl,Attorney Docket No. 68547WO01cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0368] In a further embodiment, the present disclosure describes a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of the compound of Formula IIIA and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula IIIA has a structure selected from the group consisting of:Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01Attorney Docket No. 68547WO01wherein n is 1-50;or a pharmaceutically acceptable salt thereof.Attorney Docket No. 68547WO01

[0369] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IIIA and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. the method comprising administering to the patient in need thereof a therapeutically effective amount the compound of Formula IIIA, wherein n is alternatively 1-10, alternatively 11-20, alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15, alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33-49, alternatively 44-50.

[0370] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIIB:O N N R‘where R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl,Attorney Docket No. 68547WO01heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0371] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IIIB and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula IIIB has a structure selected from the group consisting of:or a pharmaceutically acceptable salt.

[0372] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula III is a compound of Formula IIIC:where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl,Attorney Docket No. 68547WO01arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl. cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyL haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0373] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IIIC and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula IIIC is a compound having a structure selected from the group consisting of:OHAttorney Docket No. 68547WO01OHor a pharmaceutically acceptable salt thereof.

[0374] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula IIIC has a structure selected from the group consisting of:Attorney Docket No. 68547WO01OH MO.1 AM Aor a pharmaceutically acceptable salt thereof.

[0375] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. the compound of Formula III is a compound of Formula IIID:Attorney Docket No. 68547WO01where R is selected from the group consisting alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

[0376] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IIID and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the compound of Formula IIID has a structure selected from the group consisting of:Attorney Docket No. 68547WO01or a pharmaceutically acceptable salt thereof.

[0377] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IIID and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein n is alternatively 1-10, alternatively 11- 20, alternatively 21-30, alternatively 31-40, alternatively 41-50, alternatively 1-12, alternatively 5-15, alternatively 8-17, alternatively 13-22, alternatively 19-27, alternatively 25-38, alternatively 33-49, alternatively 44-50.

[0378] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III, wherein the compound of Formula III has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0379] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula III, wherein the compound of Formula III has a structure selected from:or a pharmaceutically acceptable salt thereof.

[0380] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the pharmaceutically acceptable salt of the compound of Formula III is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0381] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate,Attorney Docket No. 68547WO01pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0382] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0383] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0384] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A,Attorney Docket No. 68547WO01Morquio syndrome type B), MPS VT, Maroteaux-Lamy syndrome, MPS VTI, Sly syndrome, MPS IX, and Natowicz syndrome.

[0385] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0386] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I. Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0387] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0388] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0389] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis. beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0390] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0391] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0392] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0393] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of arimoclomol, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0394] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the compound of Formula III is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0395] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0396] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the compound of Formula III is administered in an oral formulation.

[0397] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation, In a still further aspect, the present technology related to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, wherein the oral formulation is a solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip. In a still further aspect, the oral formulation is a liquid oral dosage formulation.

[0398] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0399] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula III and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof. In a further embodiment, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.

[0400] In an embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula IV:Attorney Docket No. 68547WO01wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a prodrug of arimoclomol or a pharmaceutically acceptable salt thereof.

[0401] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the compound of Formula IV has a structure selected from the group consisting of:Attorney Docket No. 68547WO01OH\, HO and HO or a pharmaceutically acceptable salt thereof.

[0402] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the pharmaceutically acceptable salt of the compound of Formula IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0403] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the pharmaceutically acceptable salt of theAttorney Docket No. 68547WO01prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0404] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder In certain aspects, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0405] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0406] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPSAttorney Docket No. 68547WO01IT, Hunter syndrome), MPS TIT, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS TV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

[0407] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0408] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0409] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0410] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.Attorney Docket No. 68547WO01

[0411] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis. beta-mannosidosis. fucosidosis, aspartylglucosaminuria.

[0412] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0413] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0414] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0415] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

[0416] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the compound of Formula IV is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0417] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0418] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of a compound of Formula IV is administered in an oral formulation.

[0419] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the methodAttorney Docket No. 68547WO01comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

[0420] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oral formulation is a solid oral dosage formulation. In certain aspects, the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0421] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol, wherein the oral formulation is a liquid oral dosage formulation. In certain aspects, the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

[0422] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative and or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound of Formula IV and a composition comprising a therapeutically effective amount of a prodrug of arimoclomol. wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine, arimoclomol, and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof. In a further aspect, the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-β-cyclodextrin, arimoclomol, and combinations thereof.Attorney Docket No. 68547WO01

[0423] In certain aspects, the present technology relates to a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of miglustat having the following structure:OHor a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of arimoclomol, or a pharmaceutically acceptable salt thereof

[0424]

[0425] In certain aspects, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof

[0426] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the prodrug of arimoclomol, is a compound of Formula I or Formula II.

[0427] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the prodrug of miglustat is a compound of Formula III or Formula IV.

[0428] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the prodrug of arimoclomol is a compound of Formula I or Formula II and the prodrug of miglustat is a compound of Formula III or Formula IV.

[0429] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the pharmaceutically acceptable salt of the compound of Formula IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

[0430] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate,Attorney Docket No. 68547WO01saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

[0431] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder. In a still further aspect, the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

[0432] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease. Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

[0433] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.Attorney Docket No. 68547WO01

[0434] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

[0435] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

[0436] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

[0437] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

[0438] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeuticallyAttorney Docket No. 68547WO01effective amount of a prodrug of miglustat, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

[0439] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

[0440] In a further aspect, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

[0441] In a further aspect, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis. galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

[0442] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.Attorney Docket No. 68547WO01

[0443] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day,

[0444] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat. wherein the therapeutically effective amount of the prodrug of miglustat is between about 1 mg and about 5000 mg per day. In a still further aspect, the therapeutically effective amount ranges from about 50 mg to about 2500 mg, alternatively about 100 mg to about 2000 mg, alternatively about 200 mg to about 1500 mg, alternatively about 500 mg to about 1000 mg per day.

[0445] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation,

[0446] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.Attorney Docket No. 68547WO01

[0447] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition comprising a therapeutically effective amount of a prodrug of miglustat, wherein the oral formulation is a solid oral dosage formulation. In a still further aspect, the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

[0448] In a further embodiment, the present disclosure provides a method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol and a composition ...

Claims

Attorney Docket No. 68547WO01CLAIMSWhat is claimed:

1. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate. saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

3. The method of claim 1, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate. saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

4. The method of claim 1-3, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder.

5. The method of claim 4, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storageAttorney Docket No. 68547WO01disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

6. The method of claim 5, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3. Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

7. The method of claim 5, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

8. The method of claim 5, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

9. The method of claim 5, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease. Sialidosis Type I. Sialidosis type II. aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

10. The method of claim 5, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

11. The method of claim 5, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.Attorney Docket No. 68547WO0112. The method of claim 5, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

13. The method of claim 5, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

14. The method of claim 5, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

15. The method of claim 5, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

16. The method of claim 6, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

17. The method of any one of claim 1-16, wherein the therapeutically effective amount of a prodrug of arimoclomol is between about 1 mg and about 5000 mg per day.

18. The method of any one of claims 1-17, wherein the therapeutically effective amount of a prodrug of miglustat is between about 1 mg and about 5000 mg per day.

19. The method of any one of claims 1-18, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation.Attorney Docket No. 68547WO0120. The method of any one of claims 1-19, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

21. The method of claims 1- 20, wherein the oral formulation is a solid oral dosage formulation.

22. The method of claim 21, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip.

23. The method of claima 1- 20, wherein the oral formulation is a liquid oral dosage formulation.

24. The method of claim 23, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

25. The method of claims 1-24, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, arimoclomol, eliglustat. N-acetyl-L-leucine and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof;or pharmaceutically acceptable salts thereof.

26. The method of claim 25, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.Attorney Docket No. 68547WO0127. The method of claims 1 -26, wherein the method comprises administering to the patient in need thereof a composition comprising the therapeutically effective amount of a prodrug of arimoclomol and the therapeutically effective amount of the prodrug of miglustat.

28. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compound having a structure of Formula I:wherein X is selected from the group consisting of R, [O-R], [NRXR2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof; andcomposition comprising a therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.Attorney Docket No. 68547WO0129. The method of claim 29, wherein the compound of Formula l is a compound having a structure of Formula IA:Nwherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

30. The method of claim 29, wherein the compound of Formula I is a compound having a structure of Formula IB:R1x / RN2Nwherein R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo,Attorney Docket No. 68547WO01arylcarbonyl, arylcarbonylamino, arylcarbonyl oxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

31. The method of claim 29, wherein the compound of Formula I is a compound of Formula IC:wherein R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo. arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.Attorney Docket No. 68547WO0132. The method of claim 29, wherein the compound of Formula T is a compound of Formula ID:R NHwherein R is selected from the group consisting of alkenyl, alkenyl, aminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

33. The method of claims 29-33, wherein the pharmaceutically acceptable salt of the compound of Formula I is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

34. The method of claims 29-34, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acidAttorney Docket No. 68547WO01phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

35. The method of claims 30-35, wherein the neurode generative or metabolic disease or disorder is a lysosomal storage disorder.

36. The method of claim 36, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders (OLSDs).

37. The method of claim 36, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1. Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

38. The method of claim 36, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I. Hurler syndrome. Hurler-Scheie syndrome. Scheie syndrome, MPS II. Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

39. The method of claim 36, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.Attorney Docket No. 68547WO0140. The method of claim 36, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis. beta-mannosidosis, and fucosidosis.

41. The method of claim 36, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

42. The method of claim 36, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

43. The method of claim 36, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

44. The method of claim 36, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

45. The method of claim 36, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

46. The method of claim 36, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

47. The method of claim 37, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.Attorney Docket No. 68547WO0148. The method of any one of claim 29-48, wherein the therapeutically effective amount of a compound of Formula I is between about 1 mg and about 5000 mg per day.

49. The method of any one of claims 29-49, wherein the therapeutically effective amount of a prodrug of miglustat is between about 1 mg and about 5000 mg per day.

50. The method of any one of claims 30-52, wherein the composition comprising a therapeutically effective amount of the compound of Formula I is administered in an oral formulation.

51. The method of any one of claims 30-51, wherein the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

52. The method of claim 49 or 50, wherein the oral formulation is a solid oral dosage formulation.

53. The method of claim 53, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a thin strip, an oral thin film (OTF), and an oral strip,.

54. The method of claim 51 or claim 52, wherein the oral formulation is a liquid oral dosage formulation.

55. The method of claim 55, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, slurry, and suspensions.

56. The method of any one of claims 29-56,wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least oneAttorney Docket No. 68547WO01additional compound is selected from the group consisting of bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof;or pharmaceutically acceptable salts thereof.

57. The method of claim 57, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

58. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a therapeutically effective amount of a compounds having a structure of Formula II:X (II)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; andAttorney Docket No. 68547WO01a therapeutically effective amount of a prodrug of miglustat or a pharmaceutically acceptable salt thereof.

59. The method of claims 59, wherein the pharmaceutically acceptable salt of the compound of Formula II is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

60. The method of claims 59-61, wherein the pharmaceutically acceptable salt of the prodrug of miglustat is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

61. The method of claims 59-62, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder.

62. The method of claim 63, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

63. The method of claim 63, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1. Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease typeAttorney Docket No. 68547WO01C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

64. The method of claim 63, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome). MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome,65. The method of claim 63, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

66. The method of claim 63, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

67. The method of claim 63, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

68. The method of claim 63, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

69. The method of claim 63, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

70. The method of claim 63, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.Attorney Docket No. 68547WO0171. The method of claim 63, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

72. The method of claim 63, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease. Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

73. The method of claim 64, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

74. The method of any one of claim 59-75, wherein the therapeutically effective amount of a compound of Formula II is between about 1 mg and about 5000 mg per day.

75. The method of any one of claims 61-79, wherein the therapeutically effective amount of a prodrug of miglustat is between about 1 mg and about 5000 mg per day.

76. The method of any one of claims 59-78, wherein the composition comprising a therapeutically effective amount of a compound of Formula II is administered in an oral formulation.

77. The method of any one of claims 59-78, wherein the composition comprising a therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

78. The method of claim 76 or claim 77, wherein the oral formulation is a solid oral dosage formulation.Attorney Docket No. 68547WO0179. The method of claim 80, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

80. The method of claim 76 or claim 77. wherein the oral formulation is a liquid oral dosage formulation.

81. The method of claim 82, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

82. The method of any one of claims 59-83,wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound, wherein the at least one additional compound is selected from the group consisting of bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine and 2-hydroxypropyl-0-cyclodextrin, and combinations thereof;or pharmaceutically acceptable salts thereof.

83. The method of claim 84, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-0-cyclodextrin, and combinations thereof.

84. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula III:Y O XN.wherein X is selected from the group consisting of R, [O-R], [NRXR2], and [NRH],Attorney Docket No. 68547WO01owherein each Y is independently H or ‘ X,wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; andcomposition comprising a therapeutically effective amount of a prodrug of arimoclomol or a pharmaceutically acceptable salt thereof.

85. The method of claim 86, wherein the compound of Formula III is a compound of Formula IIIA:(IIIA)where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl,Attorney Docket No. 68547WO01arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

86. The method of claim 86, wherein the compound of Formula III is a compound of Formula IIIB:OH O N'N R2where R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.Attorney Docket No. 68547WO0187. The method of claim 86, wherein the compound of Formula III is a compound of Formula IIIC:where R is selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, aryl thioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

88. The method of claim 89, wherein the compound of Formula III is a compound of Formula IIID:(IIID)where R is selected from the group consisting alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl,Attorney Docket No. 68547WO01arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycol;or a pharmaceutically acceptable salt thereof.

89. The method of claims 86-90, wherein the pharmaceutically acceptable salt of the compound of Formula III is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

90. The method of claims 89-95, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

91. The method of claims 89-97, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder.Attorney Docket No. 68547WO0192. The method of claim 93, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

93. The method of claim 93, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

94. The method of claim 93, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome), MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

95. The method of claim 93, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

96. The method of claim 93, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis. beta-mannosidosis. and fucosidosis.

97. The method of claim 93, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.Attorney Docket No. 68547WO0198. The method of claim 93, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

99. The method of claim 93, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

100. The method of claim 93, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

101. The method of claim 93, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

102. The method of claim 93, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elastic um (PXE).

103. The method of claim 94, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

104. The method of any one of claim 86-105, wherein the therapeutically effective amount of the compound of Formula III is between about 1 mg and about 5000 mg per day.

105. The method of any one of claims 86-106, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day.Attorney Docket No. 68547WO01106. The method of any one of claims 86-107, wherein the composition comprising the therapeutically effective amount of the compound of Formula III is administered in an oral formulation.

107. The method of any one of claims 86-108, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation.

108. The method of claim 106 or 107, wherein the oral formulation is a solid oral dosage formulation.

109. The method of claim 110, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

110. The method of claim 106or 107, wherein the oral formulation is a liquid oral dosage formulation.

111. The method of claim 112, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

112. The method of any one of claims 86-113, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L- leucine and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof;or a pharmaceutically acceptable salts thereof.

113. The method of claim 119, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-p-cyclodextrin, and combinations thereof.Attorney Docket No. 68547WO01114. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a compounds having a structure of Formula IV:OH(IV)wherein X is selected from the group consisting of R, [O-R], [NR1R2], and [NRH] wherein O is oxygen, N is nitrogen, H is hydrogen, andR, R1and R2are independently selected from the group consisting of alkenyl, alkenylaminocarbonyl, alkoxy, alkoxycarbonyl, alkyl, alkylamino, alkylaminocarbonyl, alkylammonium, alkylcarbonyl, alkylcarbonylamino, alkylcarbonyloxy, alkylsulfinyl, alkylsulfonyl, alkylthio, alkynyl, alkynylaminocarbonyl, aryl, substituted aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkynyl, arylamino, arylaminocarbonyl, arylammonium, arylazo, arylcarbonyl, arylcarbonylamino, arylcarbonyloxy, arylcycloalkyl, aryloxy, aryloxyalkyl, arylsulfinyl, arylsulfinylalkyl, arylsulfonyl, arylsulfonylamino, arylthio, arylthioalkyl, cycloalkenyl, cycloalkenylalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylamino, cycloalkyloxy, cycloalkynyl, cycloheteroalkyl, cycloheteroalkylalkyl, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkenyl, heteroarylalkyl, heteroarylamino, heteroarylcarbonyl, heteroarylcarbonylamino, heteroaryloxo, heteroaryloxy, heteroarylsulfinyl, heteroarylsulfonyl, heteroarylthio, polycycloalkenyl, polycycloalkenylalkyl, polycycloalkyl, polycycloalkylalkyl, and polyethylene glycolor a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a prodrug of arimoclomol or a pharmaceutically acceptable salt thereof.

115. The method of claims 116, wherein the pharmaceutically acceptable salt of the compound of Formula IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride,Attorney Docket No. 68547WO01hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate. In a still further aspect the pharmaceutically acceptable salt is citrate.

116. The method of claims 116 or 117, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

117. The method of claims 116-118, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder.

118. The method of claim 119, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

119. The method of claim 120, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1. Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease type C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.Attorney Docket No. 68547WO01120. The method of claim 120, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome). MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

121. The method of claim 120, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

122. The method of claim 120, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

123. The method of claim 120, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

124. The method of claim 120, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

125. The method of claim 120, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

126. The method of claim 120, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.

127. The method of claim 120, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.Attorney Docket No. 68547WO01128. The method of claim 120, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis, sialic acid storage disease, Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

129. The method of claim 121, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

130. The method of any one of claim 116-131, wherein the therapeutically effective amount of the compound of Formula IV is between about 1 mg and about 5000 mg per day.

131. The method of any one of claims 116-132, wherein the therapeutically effective amount of the prodrug of arimoclomol is between about 1 mg and about 5000 mg per day.

132. The method of any one of claims 116-133, wherein the composition comprising the therapeutically effective amount of a compound of Formula IV is administered in an oral formulation.

133. The method of any one of claims 121-141, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

134. The method of claim 133 or 134, wherein the oral formulation is a solid oral dosage formulation.

135. The method of claim 136, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet, a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.Attorney Docket No. 68547WO01136. The method of claim 134 or 135, wherein the oral formulation is a liquid oral dosage formulation.

137. The method of claim 138, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

138. The method of any one of claims 116-140, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof.

139. The method of claim 147, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

140. A method of treating a neurodegenerative or metabolic disease or disorder in a patient in need thereof, the method comprising:administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,or a pharmaceutically acceptable salt thereof; anda composition comprising a therapeutically effective amount of a prodrug of miglustat, or a pharmaceutically acceptable salt thereof141. The method of claim 142, wherein the prodrug of arimoclomol, is a compound of Formula I or Formula II.

142. The method the claim 143, wherein the prodrug of miglustat is a compound of Formula III or Formula IV.Attorney Docket No. 68547WO01143. The method of claim 144, wherein the prodrug of arimoclomol is a compound of Formula I or Formula II and the prodrug of miglustat is a compound of Formula III or Formula IV.

144. The method of claims 142-145, wherein the pharmaceutically acceptable salt of the compound of Formula IV is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

145. The method of claims 142-146, wherein the pharmaceutically acceptable salt of the prodrug of arimoclomol is selected from the group consisting of sulfate, citrate, acetate, oxalate, chloride, hydrochloride, bromide, hydrobromide, iodide, hydroiodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate.

146. The method of claims 142-147, wherein the neurodegenerative or metabolic disease or disorder is a lysosomal storage disorder.

147. The method of claim 148, wherein the lysosomal storage disorder is selected from the group consisting of sphingolipidoses, mucopolysaccharidoses (MPS), lysosomal glycogen storage disorders, oligosaccharidoses, mucolipidoses, lipid storage disorders, glycoproteinoses, neuronal ceroid lipofuscinoses (NCL), peroxisomal biogenesis disorders (Zellweger spectrum disorders), and other lysosomal storage disorders.

148. The method of claim 149, wherein the sphingolipidosis is selected from the group consisting of Gaucher disease type 1, Gaucher disease type 2, Gaucher disease type 3, Fabry disease, Niemann-pick disease type A, Niemann-pick disease type B, Niemann-pick disease typeAttorney Docket No. 68547WO01C, Tay-Sachs disease, Sandhoff disease, GM1 gangliosidosis, metachromatic leukodystrophy (MLD), Krabbe disease, and Farber lipogranulomatosis.

149. The method of claim 149, wherein the mucopolysaccharidosis is selected from the group consisting of MPS I, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, MPS II, Hunter syndrome). MPS III, Sanfilippo syndrome type A, Sanfilippo syndrome type B, Sanfilippo syndrome type C, Sanfilippo syndrome type D, MPS IV, Morquio syndrome type A, Morquio syndrome type B), MPS VI, Maroteaux-Lamy syndrome, MPS VII, Sly syndrome, MPS IX, and Natowicz syndrome.

150. The method of claim 149, wherein the lysosomal glycogen storage disorder is selected from the group consisting of Pompe disease and glycogen storage disease type II.

151. The method of claim 149, wherein the oligosaccharidosis is selected from the group consisting of Schindler disease, Sialidosis Type I, Sialidosis type II, aspartylglucosaminuria, alpha-mannosidosis, beta-mannosidosis, and fucosidosis.

152. The method of claim 149, wherein the mucolipidosis is selected from the group consisting of mucolipidosis II, I-cell disease, mucolipidosis III, pseudo-Hurler polydystrophy, and mucolipidosis IV.

153. The method of claim 149, wherein the lipid storage disorder is selected from the group consisting of Wolman disease, cholesteryl ester storage disease, and Farber disease.

154. The method of claim 149, wherein the glycoproteinosis is selected from the group consisting of alpha-mannosidosis, beta-mannosidosis, fucosidosis, aspartylglucosaminuria.

155. The method of claim 149, wherein the neuronal ceroid lipofuscinosis is selected from the group consisting of infantile NCL, CLN1, CLN5, late infantile NCL, CLN2, juvenile NCL, CLN3, adult NCL, Kufs disease, CLN4, congenital NCL, and CLN10.Attorney Docket No. 68547WO01156. The method of claim 149, wherein the peroxisomal biogenesis disorder is selected from the group consisting of Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease.

157. The method of claim 149, wherein the other lysosomal storage disorder is selected from the group consisting of Danon disease, cystinosis. sialic acid storage disease. Salla disease, lysosomal acid lipase deficiency (LAL-D), multiple sulfatase deficiency, pycnodysostosis, galactosialidosis, hyaluronidase deficiency (MPS IX), Hermansky-Pudlak syndrome, and pseudoxanthoma elasticum (PXE).

158. The method of claim 150, wherein the Niemann Pick disease Type C is Niemann Pick disease Type C 1 or Niemann Pick disease Type C 2.

159. The method of any one of claim 142-160, wherein the therapeutically effective amount of a prodrug of arimoclomol is between about 1 mg and about 5000 mg per day.

160. The method of any one of claims 142-161, wherein the therapeutically effective amount of a prodrug of miglustat is between about 1 mg and about 5000 mg per day.

161. The method of any one of claims 142-162, wherein the composition comprising the therapeutically effective amount of the prodrug of arimoclomol is administered in an oral formulation.

162. The method of any one of claims 142-163, wherein the composition comprising the therapeutically effective amount of the prodrug of miglustat is administered in an oral formulation.

163. The method of claim 163 or 164, wherein the oral formulation is a solid oral dosage formulation.

164. The method of claim 165, wherein the solid oral dosage formulation is selected from the group consisting of a sublingual, a gummy, a chewable tablet, a rapidly dissolving tablet, a tablet,Attorney Docket No. 68547WO01a capsule, a caplet, a troche, a lozenge, an oral powder, a solution, a thin strip, an oral thin film (OTF), and an oral strip.

165. The method of claim 163 or 164, wherein the oral formulation is a liquid oral dosage formulation.

166. The method of claim 167, wherein the liquid oral dosage formulation is selected from the group consisting of syrups, emulsions, solutions, and suspensions.

167. The method of any one of claims 142-168, wherein the method further comprises administering to the patient in need thereof a therapeutically effective amount of at least one additional compound selected from bimoclomol, miglustat, eliglustat, N-acetyl-L-leucine and 2-hydroxypropyl-P-cyclodextrin, and combinations thereof; or a pharmaceutically acceptable salts thereof.

168. The method of claim 167, wherein the at least one additional compound is selected from the group consisting of N-acetyl-L-leucine, 2-hydroxypropyl-P-cyclodextrin, and combinations thereof.

169. A method of treating Niemann-Pick Disease, type C, in a patient in need thereof, the method comprising:Administering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of arimoclomol,Or a pharmaceutically acceptable salt thereof; andAdministering to the patient in need thereof a composition comprising a therapeutically effective amount of a prodrug of miglustat.

170. The method of claim 169, wherein the patient in need thereof is 2 years of age or less.

171. A composition comprising:a therapeutically effective amount of a prodrug of arimoclomol;Attorney Docket No. 68547WO01or a pharmaceutically acceptable salt thereof.

172. A composition comprising:a therapeutically effective amount of a prodrug of miglustat;or a pharmaceutically acceptable salt thereof.

173. A composition comprising:a therapeutically effective amount of a compound of Formula I;or a pharmaceutically acceptable salt thereof.

174. A composition comprising:a therapeutically effective amount of a compound of Formula II;or a pharmaceutically acceptable salt thereof.

175. A composition comprising:a therapeutically effective amount of a compound of Formula III;or a pharmaceutically acceptable salt thereof.

176. A composition comprising:a therapeutically effective amount of a compound of Formula IV;or a pharmaceutically acceptable salt thereof.

177. A composition comprising:a therapeutically effective amount of a compound selected from the group consisting of Formula I and Formula II,or a pharmaceutically acceptable salt thereof; anda therapeutically effective amount of a compound selected from the group consisting of Formula III and Formula IV,or a pharmaceutically acceptable salt thereof.

178. A kit comprising:Attorney Docket No. 68547WO01the composition of any one of claims 170-175; andinstructions for use.

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