WO2015153971A1

WO2015153971A1 - Methods of treating sleep disorders associated with neurodegenerative diseases

Info

Publication number: WO2015153971A1
Application number: PCT/US2015/024246
Authority: WO
Inventors: Matthew During
Original assignee: Ovid Therapeutics Inc.
Priority date: 2014-04-03
Filing date: 2015-04-03
Publication date: 2015-10-08

Abstract

Methods of treating a subject with a neurodegenerative disease or central nervous system disorder; methods of reducing, delaying, or preventing one or more symptoms of a neurodegenerative disease or central nervous system disorder in a subject; and methods for increasing neuroprotection in a subject are disclosed. The methods typically include administering the subject an effective amount of a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine, or a pharmaceutically acceptable salt thereof, to reduce, delay, or prevent one or more symptoms of a neurodegenerative disease or central nervous system disorder. Typically, the compound is administered in a pharmaceutical composition including a pharmaceutically acceptable carrier or excipient. In some embodiments, the subject has not been clinically diagnosed with neurodegenerative disease or central nervous system disorder based on physical symptoms.

Description

METHODS OF TREATING SLEEP DISORDERS ASSOCIATED WITH NEURODEGENERATIVE DISEASES

This application claims priority to U.S. Provisional Application No. 61/974,904 entitled "Methods of Treating Neurodegenerative Diseases and Increasing Neuroprotection" filed April 3, 2014, U.S. Provisional

Application No. 61/974,913 entitled "Methods of Treating Huntington's Disease" filed April 3, 2014, and U.S. Provisional Application No.

61/974,922 entitled "Methods of Treating Amyotrophic Lateral Sclerosis" filed April 3, 2014, and where permissible each of which is incorporated by reference in its entirety. .

FIELD OF THE INVENTION

The field of the invention generally relates to methods of treating neurodegenerative diseases and increasing neuroprotection with a

composition including an N-[2-(7-methoxy- 1 -naphthyl)ethyl]acetamide.

BACKGROUND OF THE INVENTION

The term neurodegenerative disease is an umbrella term for a range of conditions which primarily affect the neurons in the human brain. Despite differences in the initial insult causing the injury, many other central nervous system disorders including stroke, traumatic brain injury, and spinal cord injury can also be linked to neurodegenerative diseases through common underlying mechanisms of nerve cell damage and destruction. Although different neurodegenerative diseases are characterized by a broad range of symptoms, as research progresses, many similarities appear that relate these diseases at the molecular level. The diseases are often linked by one or more underlying pathophysiologies such as protein misfolding and accumulation, membrane damage, mitochondrial dysfunction, and dysfunctional

programmed cell death pathways. Many of the diseases and disorders are also linked by one or more sleep-related disorders, such as insomnia, sleep- disordered breathing, hypersomnia, a circadian rhythm disorder, parasomia, REM sleep behavior disorder, and sleep-related movement disorders

(Jennum, et al., "CHAPTER 39: Sleep disorders in neurodegenerative disorders and stroke", European Handbook of Neurological Management, Volume 1, 2nd Edition (Ed. Gilhus, et al.) Blackwell Publishing Ltd. 2011). Furthermore, approaches to treating both neurodegenerative diseases and other central nervous system disorders include neuroprotective agents such as glutamate antagonists and antioxidants, which target excitotoxicity and oxidative stress, respectively.

Although many advances have been made, the treatments for neurodegenerative diseases remain largely inadequate. For example, subjects with Parkinson's disease (PD) are often treated with drugs that increase the brain's supply of dopamine. However, over time the benefits of drugs frequently diminish or become less consistent.

Likewise, the treatments for other central nervous system disorders are also insufficient. For example, initial treatment traumatic brain injury (TBI), which occurs when an external force traumatically injures the brain, typically includes measures to insure or restore proper oxygen supply to the brain and the rest of the body, maintain adequate blood flow, manage blood pressure, and increase neuroprotection. Nonetheless, many individuals have chronic or permanent symptoms associated with the trauma. For example, some individuals develop a condition referred to as chronic traumatic brain injury (CTBI), which causes cognitive, behavioral, and physical

impairments. A severe form of CTBI, referred to as dementia pugilistica can include dementia, memory problems, and parkinsonism (tremors and lack of coordination).

Therefore, there is a need for additional therapeutic options for treating neurodegenerative diseases and other central nervous system disorder.

Accordingly, it is an object of the invention to provide methods for treating and preventing the clinical symptoms of neurodegenerative diseases and other central nervous system disorder.

SUMMARY OF THE INVENTION

Methods of treating a subject with a neurodegenerative disease or central nervous system disorder, and methods of reducing, delaying, or preventing one or more symptoms of a neurodegenerative disease or central nervous system disorder in a subject are disclosed. The methods typically include administering to the subject an effective amount of a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in the subject. In some embodiments, the methods are effective to reduce, delay, or prevent one or more other clinical symptoms of a

neurodegenerative disease or central nervous system disorder. In particular embodiments, the methods are effective to reduce, delay, or prevent one or more other clinical symptoms of Huntington's disease or amyotrophic lateral sclerosis.

A preferred l-alkoxy-(2-acylaminoethyl)naphthalene derivative is agomelatine or a pharmaceutically acceptable salt thereof. The agomelatine can be in a crystalline form, or an amorphous or non-crystalline form.

Typically, the compound is administered in a pharmaceutical composition including a pharmaceutically acceptable carrier or excipient. The 1-alkoxy- (2-acylaminoethyl)naphthalene or a derivative thereof can be the singular active agent in the pharmaceutical composition.

In some embodiments, the pharmaceutical composition is formulated for extended release. In a preferred embodiment, the composition is only administered to the subject once every 24 to 48 hours, for example, in the evening before the subject falls asleep. In some embodiments the composition is administered to the subject by a transdermal route. In a particular embodiment, the composition is administered to the subject by contacting a transdermal patch or gel with the skin of the subject.

In some embodiments, the subject has at least 36, preferably at least 40, trinucleotide repeats of CAG in one or both copies of the subject's Huntingtin (HTT) gene.

DETAILED DESCRIPTION OF THE INVENTION

I. Definitions

As used herein, the term "carrier" or "excipient" refers to an organic or inorganic ingredient, natural or synthetic inactive ingredient in a formulation, with which one or more active ingredients are combined.

As used herein, the term "pharmaceutically acceptable" means a nontoxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.

As used herein, the terms "effective amount" or "therapeutically effective amount" means a dosage sufficient to alleviate one or more symptoms of a disorder, disease, or condition being treated, or to otherwise provide a desired pharmacologic and/or physiologic effect. The precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, etc.), the disease or disorder being treated, as well as the route of administration and the pharmacokinetics of the agent being administered.

As used herein, the term "prevention" or "preventing" means to administer a composition to a subject or a system at risk for or having a predisposition for one or more symptom caused by a disease or disorder to cause cessation of a particular symptom of the disease or disorder, a reduction or prevention of one or more symptoms of the disease or disorder, a reduction in the severity of the disease or disorder, the complete ablation of the disease or disorder, stabilization or delay of the development or progression of the disease or disorder.

II. Compositions

Methods for treating neurodegenerative diseases and central nervous system disorders, and increasing neuroprotection are provided. As discussed in more detail below, the methods typically include administering a subject in need thereof an effective amount of a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine.

As discussed in more detail below, the methods typically include administering a subject in need thereof an effective amount of a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine.

A. l-aIkoxy-(2-acylaminoethyl)naphthalenes

The compositions include a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, such as those disclosed in U.S. Patent No. 5,194,614, which is specifically incorporated by reference herein in its entirety.

The compound can be of the general formula (I):

in which

A represents a

-(CH₂)2-N~C-R2

Rl O

group,

R represents a linear or branched lower alkyl group,

Ri represents a hydrogen atom or a linear or branched lower alkyl group, and

R₂ represents

a hydrogen atom,

a linear or branched lower alkyl group or a cycloalkyl group optionally substituted by a halogen atom,

an aryl or heteroaryl or lower arylalkyl or substituted aryl or substituted heteroaryl or substituted arylalkyl group, it being understood that by heteroaryl group is understood an unsaturated mono- or bicyclic group including 1 to 3 heteroatoms chosen from among nitrogen, oxygen or sulfur, with each ring comprising 4 or 5 apexes, and that by aryl group is understood phenyl or naphthyl,

an imidazolyl group optionally reduced and/or substituted by an oxo group,

a group of formula:

where G represents a linear or branched lower alkyl group, and R₃ and t, identical or different, both represent a lower alkyl group or a hydrogen atom or a phenyl or lower phenylalkyl group, or R₃ and R* form, with the nitrogen atom to which they are attached, a mono- or bicyclic heterocyclic system which may or may not be aromatic, with each ring having five or six apexes optionally including another heteroatom and being optionally substituted by one or more lower alkyl, or oxo, aryl or lower arylalkyl, or substituted aryl or substituted lower arylalkyl groups, it being understood that the term substituted qualifying the aryl and arylalkyl, and heteroaryl, groups in the definition of R₂, R₃ and R₄ means that these groups are substituted by one or more radicals chosen from among lower alkyl, lower alkoxy, trifluoromethyl or a halogen atom, or Ri forms with R₂ and the N-CO group a heterocyclic system of formula:

with A being a linear or branched alkyl radial comprising 2 to 8 carbon atoms, their isomers, epimers and diastereoisomers as well as, if the case arises, their addition salts with a pharmaceutically acceptable acid, it being understood that lower alkyl and lower alkoxy mean groups comprising 1 to 6 carbon atoms and that cycloalkyl means groups comprising 3 to 8 carbon atoms.

Among the pharmaceutically acceptable acids which can, if the case arises, be added to compounds of formula (I) to obtain a salt there may be mentioned, without implied limitation, hydrochloric, sulfuric, tartaric, maleic, fumaric, oxalic, methanesulfonic and camphoric acids, etc.

The subject of the present invention is also a process for preparing compounds of formula (I), which includes using as starting material a compound of formula (II):

(Π) in which R and Ri have the same meaning as in formula (I), which is treated either with a compound of formula (III):

EOC— G—N

\

m

(III)

in which E means a starting group chosen from among hydroxyl, lower alkoxy or a halogen, and G, R₃ and R have the same meaning as in formula (I), optionally in the presence of an alkaline agent, to lead to a compound of formula (I/A), a particular case of compounds of formula (I):

R₂ here meaning a group

group,

which can be purified, if so desired, by conventional techniques such as chromatography and crystallization, and which can be converted into a salt, if so desired, by a pharmaceutically acceptable acid,

or with an acyl chloride of formula (IV):

CI— CO— R'2

(IV)

or with the corresponding acid anhydride,

R'₂ here meaning

an aryl or heteroaryl or lower arylalkyl group, optionally substituted by one or more halogen atoms or groups chosen from among lower alkyl, lower alkoxy or trifluoromethyl, an imidazolyl group optionally reduced and/or substituted by an oxo group,

to lead to a compound of formula (I/B):

a particular case of compounds of formula (I) in which R, and R'₂ have the same definition as above, which can be purified, if necessary, by conventional techniques such as chromatography and/or crystallization, when R'₂ represents a linear or branched lower alkyl group substituted by a halogen atom, a compounds of formula (I/B) which, can be subjected, if so desired, to the action of an amine of formula (V):

HN

\

4 (V)

in which R₃ and R₄ have the same definition as above, in excess or in the presence of a tertiary amine or of a salt of an alkali metal, to lead to a compound of formula (I/A) as defined above, which, if so desired, is purified by a conventional technique such as chromatography and/or crystallization, and/or converted into a salt by a pharmaceutically acceptable acid,

a compound of formula (I/B) which, when R'₂ represents a linear or branched alkyl substituent comprising at least two carbon atoms and substituted by a halogen atom, and when simultaneously Ri represents a hydrogen atom, can be subjected, if so desired, to the action of a strong base, and preferably an alcoholate of an alkali metal, to lead to a compound of

formula (I/C):

(I/C)

in which R has the same meaning as above and A represents a linear or branched alkyl group comprising 2 to 8 carbon atoms, a particular case of compounds of formula (I) for which Ri and R₂ form with NCO a monocyclic system substituted by an oxo group, and optionally substituted by one or more lower alkyl groups, which is purified, if so desired, by a technique chosen from among crystallization and chromatography.

In the most preferred embodiments, the compound is N-[2-(7- methoxy-l-naphthyl)ethyl]acetamide having the structure:

which is also referred to as agomelatine, or an isomer, epimer, or

diastereoisomer thereof.

Agomelatine is a melatonin receptor agonist (MT1 (Ki=0. InM) and

MT2 (Ki=0.12nM)) and a 5-HT2C (Ki=631nM) receptor antagonist sold under the trade names VALDOXAN®, THYMANAX®, and MELITOR®. Binding studies indicate that it has no effect on monoamine uptake and no affinity for adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors, or other serotonergic receptors.

Methods of making agomelatine and other l-alkoxy-(2- acylaminoethyl)naphthalenes are described in U.S. Patent No. 5,194,614, 7,250,531, and 7,498,466. The compounds can be prepared as hydrates or as addition salts with a pharmaceutically acceptable acid or base. The compounds can be in crystalline form, or in non-crystalline form.

In a particular preferred embodiment, the compound is the crystalline II form of agomelatine disclosed in U.S. Patent No. 7,250,531. The crystalline II form of agomelatine, is characterized by the following parameters obtained from the powder diagram obtained using a Bruker AXS D8 high-resolution diffractometer having a 20 angular range of 3°-90°, a step of 0.01° and 30 s per step: monoclinic crystal lattice lattice parameters: a=20.0903 A, b=9.3194 A, c=15.4796 A, β=108.667° space group: P2_x/n number of molecules in the unit cell: 8 unit cell volume: V_unit cell=2746.742 A³ density: d=1.13 g/cm³.

Advantages of this crystalline form include that it allows for especially rapid and efficient filtration as well as the preparation of pharmaceutical formulations having a consistent and reproducible composition, which is especially advantageous when the formulations are to be used for oral administration. The form is also sufficiently stable to enable prolonged storage without special conditions in respect of temperature, light humidity, or oxygen levels.

B. Formulations

Pharmaceutical compositions can be for administration by parenteral (intramuscular, intraperitoneal, intravenous (IV) or subcutaneous injection), enteral, transdermal (either passively or using iontophoresis or

electroporation), or transmucosal (nasal, pulmonary, vaginal, rectal, or sublingual) routes of administration or using bioerodible inserts and can be formulated in dosage forms appropriate for each route of administration.

The compositions are most typically administered systemically. Drugs can be formulated for immediate release, extended release, or modified release. A delayed release dosage form is one that releases a drug (or drugs) at a time other than promptly after administration. An extended release dosage form is one that allows at least a twofold reduction in dosing frequency as compared to that drug presented as a conventional dosage form (e.g. as a solution or prompt drug-releasing, conventional solid dosage form). A modified release dosage form is one for which the drug release

characteristics of time course and/or location are chosen to accomplish therapeutic or convenience objectives not offered by conventional dosage forms such as solutions, ointments, or promptly dissolving dosage forms. Delayed release and extended release dosage forms and their combinations are types of modified release dosage forms.

Formulations are prepared using a pharmaceutically acceptable

"carrier" composed of materials that are considered safe and effective and may be administered to an individual without causing undesirable biological side effects or unwanted interactions. The "carrier" is all components present in the pharmaceutical formulation other than the active ingredient or ingredients. The term "carrier" includes but is not limited to diluents, binders, lubricants^ desintegrators, fillers, and coating compositions.

"Carrier" also includes all components of the coating composition which may include plasticizers, pigments, colorants, stabilizing agents, and glidants. The delayed release dosage formulations may be prepared as described in references such as "Pharmaceutical dosage form tablets", eds. Liberman et. al. (New York, Marcel Dekker, Inc., 1989), "Remington - The science and practice of pharmacy", 20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000, and "Pharmaceutical dosage forms and drug delivery systems", 6^th Edition, Ansel et.al., (Media, PA: Williams and Wilkins, 1995) which provides information on carriers, materials, equipment and process for preparing tablets and capsules and delayed release dosage forms of tablets, capsules, and granules.

The compound can be administered to a subject with or without the aid of a delivery vehicle. Appropriate delivery vehicles for the compounds are known in the art and can be selected to suit the particular active agent. For example, in some embodiments, the active agent(s) is incorporated into or encapsulated by a nanoparticle, microparticle, micelle, synthetic lipoprotein particle, or carbon nanotube. For example, the compositions can be incorporated into a vehicle such as polymeric microparticles which provide controlled release of the active agent(s). In some embodiments, release of the drug(s) is controlled by diffusion of the active agent(s) out of the microparticles and/or degradation of the polymeric particles by hydrolysis and/or enzymatic degradation.

Suitable polymers include ethylcellulose and other natural or synthetic cellulose derivatives. Polymers which are slowly soluble and form a gel in an aqueous environment, such as hydroxypropyl methylcellulose or polyethylene oxide, may also be suitable as materials for drug containing microparticles or particles. Other polymers include, but are not limited to, polyanhydrides, poly (ester anhydrides), polyhydroxy acids, such as polylactide (PLA), polyglycolide (PGA), poly(lactide-co-glycolide) (PLGA), poly-3-hydroxybut rate (PHB) and copolymers thereof, poly-4- hydroxybutyrate (P4HB) and copolymers thereof, polycaprolactone and copolymers thereof, and combinations thereof. In some embodiments, both agents are incorporated into the same particles and are formulated for release at different times and/or over different time periods. For example, in some embodiments, one of the agents is released entirely from the particles before release of the second agent begins. In other embodiments, release of the first agent begins followed by release of the second agent before the all of the first agent is released. In still other embodiments, both agents are released at the same time over the same period of time or over different periods of time,

a. Formulations for Parenteral Administration

Compounds and pharmaceutical compositions thereof can be administered in an aqueous solution, by parenteral injection. The formulation may also be in the form of a suspension or emulsion. In general, pharmaceutical compositions are provided including effective amounts of the active agent(s) and optionally include pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants and/or carriers. Such compositions include diluents sterile water, buffered saline of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength; and optionally, additives such as detergents and solubilizing agents (e.g., TWEEN® 20, TWEEN® 80 also referred to as polysorbate 20 or 80), antioxidants (e.g., ascorbic acid, sodium metabisulfite), and preservatives (e.g., Thimersol, benzyl alcohol) and bulking substances (e.g., lactose, mannitol). Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. The formulations may be lyophilized and redissolved/resuspended immediately before use. The formulation may be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. b. Oral Immediate Release Formulations

Suitable oral dosage forms include tablets, capsules, solutions, suspensions, syrups, and lozenges. Tablets can be made using compression or molding techniques well known in the art. Gelatin or non-gelatin capsules can prepared as hard or soft capsule shells, which can encapsulate liquid, solid, and semi-solid fill materials, using techniques well known in the art.

Examples of suitable coating materials include, but are not limited to, cellulose polymers such as cellulose acetate phthalate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate; polyvinyl acetate phthalate, acrylic acid polymers and copolymers, and methacrylic resins that are commercially available under the trade name Eudragit^® (Roth Pharma, Westerstadt, Germany), Zein, shellac, and polysaccharides.

Additionally, the coating material may contain conventional carriers such as plasticizers, pigments, colorants, glidants, stabilization agents, pore formers and surfactants.

Optional pharmaceutically acceptable excipients present in the drug- containing tablets, beads, granules or particles include, but are not limited to, diluents, binders, lubricants, disintegrants, colorants, stabilizers, and surfactants. Diluents, also termed "fillers," are typically necessary to increase the bulk of a solid dosage form so that a practical size is provided for compression of tablets or formation of beads and granules. Suitable diluents include, but are not limited to, , dicalcium phosphate dihydrate, calcium sulfate, lactose, sucrose, mannitol, sorbitol, cellulose,

microcrystalline cellulose, kaolin, sodium chloride, dry starch, hydrolyzed starches, pregelatinized starch, silicone dioxide, titanium oxide, magnesium aluminum silicate and powder sugar.

Binders are used to impart cohesive qualities to a solid dosage formulation, and thus ensure that a tablet or bead or granule remains intact after the formation of the dosage forms. Suitable binder materials include, but are not limited to, starch, pregelatinized starch, gelatin, sugars (including sucrose, glucose, dextrose, lactose and sorbitol), polyethylene glycol, waxes, natural and synthetic gums such as acacia, tragacanth, sodium alginate, cellulose,including hydorxypropylmethylcellulose, hydroxypropylcellulose, ethylcellulose, and veegum, and synthetic polymers such as acrylic acid and methacrylic acid copolymers, methacrylic acid copolymers, methyl methacrylate copolymers, aminoalkyl methacrylate copolymers, polyacrylic acid/polymethacrylic acid and polyvinylpyrrolidone.

Lubricants are used to facilitate tablet manufacture. Examples of suitable lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, glycerol behenate, polyethylene glycol, talc, and mineral oil.

Disintegrants are used to facilitate dosage form disintegration or "breakup" after administration, and generally include, but are not limited to, starch, sodium starch glycolate, sodium carboxymethyl starch, sodium carboxymethylcellulose, hydroxypropyl cellulose, pregelatinized starch, clays, cellulose, alginine, gums or cross linked polymers, such as cross- linked PVP (Polyplasdone XL from GAF Chemical Corp).

Stabilizers are used to inhibit or retard drug decomposition reactions which include, by way of example, oxidative reactions.

Surfactants may be anionic, cationic, amphoteric or nonionic surface active agents. Suitable anionic surfactants include, but are not limited to, those containing carboxylate, sulfonate and sulfate ions. Examples of anionic surfactants include sodium, potassium, ammonium of long chain alkyl sulfonates and alkyl aryl sulfonates such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium dodecylbenzene sulfonate; dialkyl sodium sulfosuccinates, such as sodium bis-(2- ethylthioxyl)-sulfosuccinate; and alkyl sulfates such as sodium lauryl sulfate. Cationic surfactants include, but are not limited to, quaternary ammonium compounds such as benzalkonium chloride, benzethonium chloride, cetrimonium bromide, stearyl dimethylbenzyl ammonium chloride, polyoxyethylene and coconut amine. Examples of nonionic surfactants include ethylene glycol monostearate, propylene glycol myristate, glyceryl monostearate, glyceryl stearate, polyglyceryl-4-oleate, sorbitan acylate, sucrose acylate, PEG-150 laurate, PEG-400 monolaurate, polyoxyethylene monolaurate, polysorbates, polyoxyethylene octylphenylether, PEG- 1000 cetyl ether, polyoxyethylene tridecyl ether, polypropylene glycol butyl ether, Poloxamer^® 401, stearoyl monoisopropanolamide, and polyoxyethylene hydrogenated tallow amide. Examples of amphoteric surfactants include sodium N-dodecyl-. beta. -alanine, sodium N-lauryl-.beta.-iminodipropionate, myristoamphoacetate, lauryl betaine and lauryl sulfobetaine.

If desired, the tablets, beads granules or particles may also contain minor amount of nontoxic auxiliary substances such as wetting or emulsifying agents, dyes, pH buffering agents, and preservatives.

c. Extended release dosage forms

The extended release formulations are generally prepared as diffusion or osmotic systems, for example, as described in "Remington - The science and practice of pharmacy" (20th ed., Lippincott Williams & Wilkins, Baltimore, MD, 2000). A diffusion system typically consists of two types of devices, reservoir and matrix, and is well known and described in the art. The matrix devices are generally prepared by compressing the drug with a slowly dissolving polymer carrier into a tablet form. The three major types of materials used in the preparation of matrix devices are insoluble plastics, hydrophilic polymers, and fatty compounds. Plastic matrices include, but not limited to, methyl acrylate-methyl methacrylate, polyvinyl chloride, and polyethylene. Hydrophilic polymers include, but are not limited to, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and carbopol 934, polyethylene oxides. Fatty compounds include, but are not limited to, various waxes such as carnauba wax and glyceryl tristearate.

Alternatively, extended release formulations can be prepared using osmotic systems or by applying a semi-permeable coating to the dosage form. In the latter case, the desired drug release profile can be achieved by combining low permeable and high permeable coating materials in suitable proportion. The devices with different drug release mechanisms described above could be combined in a final dosage form comprising single or multiple units. Examples of multiple units include multilayer tablets, capsules containing tablets, beads, granules, etc.

An immediate release portion can be added to the extended release system by means of either applying an immediate release layer on top of the extended release core using coating or compression process or in a multiple unit system such as a capsule containing extended and immediate release beads.

Extended release tablets containing hydrophilic polymers are prepared by techniques commonly known in the art such as direct compression, wet granulation, or dry granulation processes. Their formulations usually incorporate polymers, diluents, binders, and lubricants as well as the active pharmaceutical ingredient. The usual diluents include inert powdered substances such as any of many different kinds of starch, powdered cellulose, especially crystalline and microcrystalline cellulose, sugars such as fructose, mannitol and sucrose, grain flours and similar edible powders. Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such as sodium chloride and powdered sugar. Powdered cellulose derivatives are also useful. Typical tablet binders include substances such as starch, gelatin and sugars such as lactose, fructose, and glucose. Natural and synthetic gums, including acacia, alginates, methylcellulose, and polyvinylpyrrolidine can also be used. Polyethylene glycol, hydrophilic polymers, ethylcellulose and waxes can also serve as binders. A lubricant is necessary in a tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant is chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid and hydrogenated vegetable oils.

Extended release tablets containing wax materials are generally prepared using methods known in the art such as a direct blend method, a congealing method, and an aqueous dispersion method. In a congealing method, the drug is mixed with a wax material and either spray- congealed or congealed and screened and processed.

d. Delayed release dosage forms

Delayed release formulations are created by coating a solid dosage form with a film of a polymer which is insoluble in the acid environment of the stomach, and soluble in the neutral environment of small intestines.

The delayed release dosage units can be prepared, for example, by coating a drug or a drug-containing composition with a selected coating material. The drug-containing composition may be, e.g., a tablet for incorporation into a capsule, a tablet for use as an inner core in a "coated core" dosage form, or a plurality of drug-containing beads, particles or granules, for incorporation into either a tablet or capsule. Preferred coating materials include bioerodible, gradually hydrolyzable, gradually water- soluble, and/or enzymatically degradable polymers, and may be conventional "enteric" polymers. Enteric polymers, as will be appreciated by those skilled in the art, become soluble in the higher pH environment of the lower gastrointestinal tract or slowly erode as the dosage form passes through the gastrointestinal tract, while enzymatically degradable polymers are degraded by bacterial enzymes present in the lower gastrointestinal tract, particularly in the colon. Suitable coating materials for effecting delayed release include, but are not limited to, cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose acetate succinate,

hydroxypropylmethyl cellulose phthalate, methylcellulose, ethyl cellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and/or ethyl methacrylate, and other methacrylic resins that are commercially available under the tradename Eudragit^®. (Rohm Pharma; Westerstadt, Germany), including Eudragit^®. L30D-55 and L100-55 (soluble at pH 5.5 and above), Eudragit^®. L-100 (soluble at pH 6.0 and above), Eudragit^®. S (soluble at pH 7.0 and above, as a result of a higher degree of esterification), and Eudragits . NE, RL and RS (water-insoluble polymers having different degrees of permeability and expandability); vinyl polymers and copolymers such as polyvinyl pyrrolidone, vinyl acetate, vinylacetate phthalate, vinylacetate crotonic acid copolymer, and ethylene- vinyl acetate copolymer; enzymatically degradable polymers such as azo polymers, pectin, chitosan, amylose and guar gum; zein and shellac. Combinations of different coating materials may also be used. Multi-layer coatings using different polymers may also be applied.

The preferred coating weights for particular coating materials may be readily determined by those skilled in the art by evaluating individual release profiles for tablets, beads and granules prepared with different quantities of various coating materials. It is the combination of materials, method and form of application that produce the desired release characteristics, which one can determine only from the clinical studies.

The coating composition may include conventional additives, such as plasticizers, pigments, colorants, stabilizing agents, glidants, etc. A plasticizer is normally present to reduce the fragility of the coating, and will generally represent about 10 wt. % to 50 wt. % relative to the dry weight of the polymer. Examples of typical plasticizers include polyethylene glycol, propylene glycol, triacetin, dimethyl phthalate, diethyl phthalate, dibutyl phthalate, dibutyl sebacate, triethyl citrate, tributyl citrate, triethyl acetyl citrate, castor oil and acetylated monoglycerides. A stabilizing agent is preferably used to stabilize particles in the dispersion. Typical stabilizing agents are nonionic emulsifiers such as sorbitan esters, polysorbates and polyvinylpyrrolidone. Glidants are recommended to reduce sticking effects during film formation and drying, and will generally represent approximately 25 wt. % to 100 wt. % of the polymer weight in the coating solution. One effective glidant is talc. Other glidants such as magnesium stearate and glycerol monostearates may also be used. Pigments such as titanium dioxide may also be used. Small quantities of an anti-foaming agent, such as a silicone (e.g., simethicone), may also be added to the coating composition. Methods of manufacturing

As will be appreciated by those skilled in the art and as described in the pertinent texts and literature, a number of methods are available for preparing drug-containing tablets, beads, granules or particles that provide a variety of drug release profiles. Such methods include, but are not limited to, the following: coating a drug or drug-containing composition with an appropriate coating material, typically although not necessarily incorporating a polymeric material, increasing drug particle size, placing the drug within a matrix, and forming complexes of the drug with a suitable complexing agent.

The delayed release dosage units may be coated with the delayed release polymer coating using conventional techniques, e.g., using a conventional coating pan, an airless spray technique, fluidized bed coating equipment (with or without a Wurster insert). For detailed information concerning materials, equipment and processes for preparing tablets and delayed release dosage forms, see Pharmaceutical Dosage Forms: Tablets, eds. Lieberman et al. (New York: Marcel Dekker, Inc., 1989), and Ansel et al., Pharmaceutical Dosage Forms and Drug Delivery Systems, 6.sup.th Ed. (Media, PA: Williams & Wilkins, 1995).

A preferred method for preparing extended release tablets is by compressing a drug-containing blend, e.g., blend of granules, prepared using a direct blend, wet-granulation, or dry-granulation process. Extended release tablets may also be molded rather than compressed, starting with a moist material containing a suitable water-soluble lubricant. However, tablets are preferably manufactured using compression rather than molding. A preferred method for forming extended release drug-containing blend is to mix drug particles directly with one or more excipients such as diluents (or fillers), binders, disintegrants, lubricants, glidants, and colorants. As an alternative to direct blending, a drug-containing blend may be prepared by using wet-granulation or dry-granulation processes. Beads containing the active agent may also be prepared by any one of a number of conventional techniques, typically starting from a fluid dispersion. For example, a typical method for preparing drug-containing beads involves dispersing or dissolving the active agent in a coating suspension or solution containing pharmaceutical excipients such as polyvinylpyrrolidone, methylcellulose, talc, metallic stearates, silicone dioxide, plasticizers or the like. The admixture is used to coat a bead core such as a sugar sphere (or so-called "non-pareil") having a size of approximately 60 to 20 mesh.

An alternative procedure for preparing drug beads is by blending drug with one or more pharmaceutically acceptable excipients, such as microcrystalline cellulose, lactose, cellulose, polyvinyl pyrrolidone, talc, magnesium stearate, a disintegrant, etc., extruding the blend, spheronizing the extrudate, drying and optionally coating to form the immediate release beads.

e. Formulations for Mucosal and Pulmonary

Administration

Active agent(s) and compositions thereof can be formulated for pulmonary or mucosal administration. The administration can include delivery of the composition to the lungs, nasal, oral (sublingual, buccal), vaginal, or rectal mucosa. In a particular embodiment, the composition is formulated for and delivered to the subject sublingually.

In one embodiment, the compounds are formulated for pulmonary delivery, such as intranasal administration or oral inhalation. The respiratory tract is the structure involved in the exchange of gases between the atmosphere and the blood stream. The lungs are branching structures ultimately ending with the alveoli where the exchange of gases occurs. The alveolar surface area is the largest in the respiratory system and is where drug absorption occurs. The alveoli are covered by a thin epithelium without cilia or a mucus blanket and secrete surfactant phospholipids. The respiratory tract encompasses the upper airways, including the oropharynx and larynx, followed by the lower airways, which include the trachea followed by bifurcations into the bronchi and bronchioli. The upper and lower airways are called the conducting airways. The terminal bronchioli then divide into respiratory bronchiole, which then lead to the ultimate respiratory zone, the alveoli, or deep lung. The deep lung, or alveoli, is the primary target of inhaled therapeutic aerosols for systemic drug delivery.

Pulmonary administration of therapeutic compositions comprised of low molecular weight drugs has been observed, for example, beta- androgenic antagonists to treat asthma. Other therapeutic agents that are active in the lungs have been administered systemically and targeted via pulmonary absorption. Nasal delivery is considered to be a promising technique for administration of therapeutics for the following reasons: the nose has a large surface area available for drug absorption due to the coverage of the epithelial surface by numerous microvilli, the subepithelial layer is highly vascularized, the venous blood from the nose passes directly into the systemic circulation and therefore avoids the loss of drug by first- pass metabolism in the liver, it offers lower doses, more rapid attainment of therapeutic blood levels, quicker onset of pharmacological activity, fewer side effects, high total blood flow per cm , porous endothelial basement membrane, and it is easily accessible.

The term aerosol as used herein refers to any preparation of a fine mist of particles, which can be in solution or a suspension, whether or not it is produced using a propellant. Aerosols can be produced using standard techniques, such as ultrasonication or high-pressure treatment.

Carriers for pulmonary formulations can be divided into those for dry powder formulations and for administration as solutions. Aerosols for the delivery of therapeutic agents to the respiratory tract are known in the art. For administration via the upper respiratory tract, the formulation can be formulated into a solution, e.g., water or isotonic saline, buffered or unbuffered, or as a suspension, for intranasal administration as drops or as a spray. Preferably, such solutions or suspensions are isotonic relative to nasal secretions and of about the same pH, ranging e.g., from about pH 4.0 to about pH 7.4 or, from pH 6.0 to pH 7.0. Buffers should be physiologically compatible and include, simply by way of example, phosphate buffers. For example, a representative nasal decongestant is described as being buffered to a pH of about 6.2. One skilled in the art can readily determine a suitable saline content and pH for an innocuous aqueous solution for nasal and/or upper respiratory administration.

Preferably, the aqueous solution is water, physiologically acceptable aqueous solutions containing salts and or buffers, such as phosphate buffered saline (PBS), or any other aqueous solution acceptable for administration to an animal or human. Such solutions are well known to a person skilled in the art and include, but are not limited to, distilled water, de-ionized water, pure or ultrapure water, saline, phosphate-buffered saline (PBS). Other suitable aqueous vehicles include, but are not limited to, Ringer's solution and isotonic sodium chloride. Aqueous suspensions may include suspending agents such as cellulose derivatives, sodium alginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agent such as lecithin. Suitable preservatives for aqueous suspensions include ethyl and n-propyl p- hydroxybenzoate.

In another embodiment, solvents that are low toxicity organic (i.e. nonaqueous) class 3 residual solvents, such as ethanol, acetone, ethyl acetate, tetrahydrofuran, ethyl ether, and propanol may be used for the formulations. The solvent is selected based on its ability to readily aerosolize the formulation. The solvent should not detrimentally react with the compounds. An appropriate solvent should be used that dissolves the compounds or forms a suspension of the compounds. The solvent should be sufficiently volatile to enable formation of an aerosol of the solution or suspension.

Additional solvents or aerosolizing agents, such as freons, can be added as desired to increase the volatility of the solution or suspension.

In one embodiment, compositions may contain minor amounts of polymers, surfactants, or other excipients well known to those of the art. In this context, "minor amounts" means no excipients are present that might affect or mediate uptake of the compounds in the lungs and that the excipients that are present are present in amount that do not adversely affect uptake of compounds in the lungs.

Dry lipid powders can be directly dispersed in ethanol because of their hydrophobic character. For lipids stored in organic solvents such as chloroform, the desired quantity of solution is placed in a vial, and the chloroform is evaporated under a stream of nitrogen to form a dry thin film on the surface of a glass vial. The film swells easily when reconstituted with ethanol. To fully disperse the lipid molecules in the organic solvent, the suspension is sonicated. Nonaqueous suspensions of lipids can also be prepared in absolute ethanol using a reusable PARI LC Jet+ nebulizer (PARI Respiratory Equipment, Monterey, CA).

Dry powder formulations ("DPFs") with large particle size have improved flowability characteristics, such as less aggregation, easier aerosolization, and potentially less phagocytosis. Dry powder aerosols for inhalation therapy are generally produced with mean diameters primarily in the range of less than 5 microns, although a preferred range is between one and ten microns in aerodynamic diameter. Large "carrier" particles

(containing no drug) have been co-delivered with therapeutic aerosols to aid in achieving efficient aerosolization among other possible benefits.

Polymeric particles may be prepared using single and double emulsion solvent evaporation, spray drying, solvent extraction, solvent evaporation, phase separation, simple and complex coacervation, interfacial polymerization, and other methods well known to those of ordinary skill in the art. Particles may be made using methods for making microspheres or microcapsules known in the art. The preferred methods of manufacture are by spray drying and freeze drying, which entails using a solution containing the surfactant, spraying to form droplets of the desired size, and removing the solvent.

The particles may be fabricated with the appropriate material, surface roughness, diameter and tap density for localized delivery to selected regions of the respiratory tract such as the deep lung or upper airways. For example, higher density or larger particles may be used for upper airway delivery. Similarly, a mixture of different sized particles, provided with the same or different active agents may be administered to target different regions of the lung in one administration. f. Topical and Transdermal Formulations

Transdermal formulations may also be prepared. These will typically be gels, ointments, lotions, sprays, or patches, all of which can be prepared using standard technology. Transdermal formulations can include penetration enhancers.

A "gel" is a colloid in which the dispersed phase has combined with the continuous phase to produce a semisolid material, such as jelly.

An "oil" is a composition containing at least 95% wt of a lipophilic substance. Examples of lipophilic substances include but are not limited to naturally occurring and synthetic oils, fats, fatty acids, lecithins, triglycerides and combinations thereof.

A "continuous phase" refers to the liquid in which solids are suspended or droplets of another liquid are dispersed, and is sometimes called the external phase. This also refers to the fluid phase of a colloid within which solid or fluid particles are distributed. If the continuous phase is water (or another hydrophilic solvent), water-soluble or hydrophilic drugs will dissolve in the continuous phase (as opposed to being dispersed). In a multiphase formulation (e.g., an emulsion), the discreet phase is suspended or dispersed in the continuous phase.

An "emulsion" is a composition containing a mixture of non-miscible components homogenously blended together. In particular embodiments, the non-miscible components include a lipophilic component and an aqueous component. An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in- water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non- volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.

"Emollients" are an externally applied agent that softens or soothes skin and are generally known in the art and listed in compendia; such as the "Handbook of Pharmaceutical Excipients", 4 Ed., Pharmaceutical Press, 2003. These include, without limitation, almond oil, castor oil, ceratonia extract, cetostearoyl alcohol, cetyl alcohol, cetyl esters wax, cholesterol, cottonseed oil, cyclomethicone, ethylene glycol palmitostearate, glycerin, glycerin monostearate, glyceryl monooleate, isopropyl myristate, isopropyl palmitate, lanolin, lecithin, light mineral oil, medium-chain triglycerides, mineral oil and lanolin alcohols, petrolatum, petrolatum and lanolin alcohols, soybean oil, starch, stearyl alcohol, sunflower oil, xylitol and combinations thereof. In one embodiment, the emollients are ethylhexylstearate and ethylhexyl palmitate.

"Surfactants" are surface-active agents that lower surface tension and thereby increase the emulsifying, foaming, dispersing, spreading and wetting properties of a product. Suitable non-ionic surfactants include emulsifying wax, glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polysorbate, sorbitan esters, benzyl alcohol, benzyl benzoate, cyclodextrins, glycerin monostearate, poloxamer, povidone and combinations thereof. In one embodiment, the non-ionic surfactant is stearyl alcohol.

"Emulsifiers" are surface active substances which promote the suspension of one liquid in another and promote the formation of a stable mixture, or emulsion, of oil and water. Common emulsifiers are: metallic soaps, certain animal and vegetable oils, and various polar compounds.

Suitable emulsifiers include acacia, anionic emulsifying wax, calcium stearate, carbomers, cetostearyl alcohol, cetyl alcohol, cholesterol, diethanolamine, ethylene glycol palmitostearate, glycerin monostearate, glyceryl monooleate, hydroxpropyl cellulose, hypromellose, lanolin, hydrous, lanolin alcohols, lecithin, medium-chain triglycerides,

methylcellulose, mineral oil and lanolin alcohols, monobasic sodium phosphate, monoethanolamine, nonionic emulsifying wax, oleic acid, poloxamer, poloxamers, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters,

polyoxyethylene stearates, propylene glycol alginate, self-emulsifying glyceryl monostearate, sodium citrate dehydrate, sodium lauryl sulfate, sorbitan esters, stearic acid, sunflower oil, tragacanth, triethanolamine, xanthan gum and combinations thereof. In one embodiment, the emulsifier is glycerol stearate.

A "lotion" is a low- to medium- viscosity liquid formulation. A lotion can contain finely powdered substances that are in soluble in the dispersion medium through the use of suspending agents and dispersing agents.

Alternatively, lotions can have as the dispersed phase liquid substances that are immiscible with the vehicle and are usually dispersed by means of emulsifying agents or other suitable stabilizers. In one embodiment, the lotion is in the form of an emulsion having a viscosity of between 100 and 1000 centistokes. The fluidity of lotions permits rapid and uniform application over a wide surface area. Lotions are typically intended to dry on the skin leaving a thin coat of their medicinal components on the skin's surface.

A "cream" is a viscous liquid or semi-solid emulsion of either the "oil-in-water" or "water-in-oil type". Creams may contain emulsifying agents and/or other stabilizing agents. In one embodiment, the formulation is in the form of a cream having a viscosity of greater than 1000 centistokes, typically in the range of 20,000-50,000 centistokes. Creams are often time preferred over ointments as they are generally easier to spread and easier to remove.

An emulsion is a preparation of one liquid distributed in small globules throughout the body of a second liquid. The dispersed liquid is the discontinuous phase, and the dispersion medium is the continuous phase. When oil is the dispersed liquid and an aqueous solution is the continuous phase, it is known as an oil-in- water emulsion, whereas when water or aqueous solution is the dispersed phase and oil or oleaginous substance is the continuous phase, it is known as a water-in-oil emulsion. The oil phase may consist at least in part of a propellant, such as an HFA propellant. Either or both of the oil phase and the aqueous phase may contain one or more surfactants, emulsifiers, emulsion stabilizers, buffers, and other excipients. Preferred excipients include surfactants, especially non-ionic surfactants; emulsifying agents, especially emulsifying waxes; and liquid non- volatile non-aqueous materials, particularly glycols such as propylene glycol. The oil phase may contain other oily pharmaceutically approved excipients. For example, materials such as hydroxylated castor oil or sesame oil may be used in the oil phase as surfactants or emulsifiers.

A sub-set of emulsions are the self-emulsifying systems. These drug delivery systems are typically capsules (hard shell or soft shell) comprised of the drug dispersed or dissolved in a mixture of surfactant(s) and lipophillic liquids such as oils or other water immiscible liquids. When the capsule is exposed to an aqueous environment and the outer gelatin shell dissolves, contact between the aqueous medium and the capsule contents instantly generates very small emulsion droplets. These typically are in the size range of micelles or nanoparticles. No mixing force is required to generate the emulsion as is typically the case in emulsion formulation processes.

The basic difference between a cream and a lotion is the viscosity, which is dependent on the amount/use of various oils and the percentage of water used to prepare the formulations. Creams are typically thicker than lotions, may have various uses and often one uses more varied oils/butters, depending upon the desired effect upon the skin. In a cream formulation, the water-base percentage is about 60-75 % and the oil-base is about 20-30 % of the total, with the other percentages being the emulsifier agent, preservatives and additives for a total of 100 %.

An "ointment" is a semisolid preparation containing an ointment base and optionally one or more active agents. Examples of suitable ointment bases include hydrocarbon bases (e.g., petrolatum, white petrolatum, yellow ointment, and mineral oil); absorption bases (hydrophilic petrolatum, anhydrous lanolin, lanolin, and cold cream); water-removable bases (e.g., hydrophilic ointment), and water-soluble bases (e.g., polyethylene glycol ointments). Pastes typically differ from ointments in that they contain a larger percentage of solids. Pastes are typically more absorptive and less greasy that ointments prepared with the same components.

A "gel" is a semisolid system containing dispersions of small or large molecules in a liquid vehicle that is rendered semisolid by the action of a thickening agent or polymeric material dissolved or suspended in the liquid vehicle. The liquid may include a lipophilic component, an aqueous component or both. Some emulsions may be gels or otherwise include a gel component. Some gels, however, are not emulsions because they do not contain a homogenized blend of immiscible components.

Suitable gelling agents include, but are not limited to, modified celluloses, such as hydroxypropyl cellulose and hydroxyethyl cellulose; Carbopol homopolymers and copolymers; and combinations thereof.

Suitable solvents in the liquid vehicle include, but are not limited to, diglycol monoethyl ether; alklene glycols, such as propylene glycol; dimethyl isosorbide; alcohols, such as isopropyl alcohol and ethanol. The solvents are typically selected for their ability to dissolve the drug. Other additives, which improve the skin feel and/or emolliency of the formulation, may also be incorporated. Examples of such additives include, but are not limited, isopropyl myristate, ethyl acetate, C12-C15 alkyl benzoates, mineral oil, squalane, cyclomethicone, capric/caprylic triglycerides, and combinations thereof.

Foams consist of an emulsion in combination with a gaseous propellant. The gaseous propellant consists primarily of hydrofluoroalkanes (HFAs). Suitable propellants include HFAs such as 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoropropane (HFA 227), but mixtures and admixtures of these and other HFAs that are currently approved or may become approved for medical use are suitable. The propellants preferably are not hydrocarbon propellant gases which can produce flammable or explosive vapors during spraying. Furthermore, the compositions preferably contain no volatile alcohols, which can produce flammable or explosive vapors during use.

Buffers are used to control pH of a composition. Preferably, the buffers buffer the composition from a pH of about 4 to a pH of about 7.5, more preferably from a pH of about 4 to a pH of about 7, and most preferably from a pH of about 5 to a pH of about 7. In a preferred embodiment, the buffer is triethanolamine.

Preservatives can be used to prevent the growth of fungi and microorganisms. Suitable antifungal and antimicrobial agents include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetylpyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, and thimerosal.

Additional agents that can be added to the formulation include penetration enhancers. In some embodiments, the penetration enhancer increases the solubility of the drug, improves transdermal delivery of the drug across the skin, in particular across the stratum corneum, or a combination thereof. Some penetration enhancers cause dermal irritation, dermal toxicity and dermal allergies. However, the more commonly used ones include urea, (carbonyldiamide), imidurea, N, N-diethylformamide, N- methyl-2-pyrrolidone, l-dodecal-azacyclopheptane-2-one, calcium thioglycate, 2-pyrrolidone, N,N-diethyl-m-toluamide, oleic acid and its ester derivatives, such as methyl, ethyl, propyl, isopropyl, butyl, vinyl and glycerylmonooleate, sorbitan esters, such as sorbitan monolaurate and sorbitan monooleate, other fatty acid esters such as isopropyl laurate, isopropyl myristate, isopropyl palmitate, diisopropyl adipate, propylene glycol monolaurate, propylene glycol monooleatea and non-ionic detergents such as BRIJ^® 76 (stearyl poly(10 oxyethylene ether), BRIJ^® 78 (stearyl poly(20)oxyethylene ether), BRIJ^® 96 (oleyl poly(10)oxyethylene ether), and BRIJ^® 721 (stearyl poly (21) oxyethylene ether) (ICI Americas Inc. Corp.). Chemical penetrations and methods of increasing transdermal drug delivery are described in Inayat, et al., Tropical Journal of Pharmaceutical Research, 8(2):173-179 (2009) and Fox, et al., Molecules, 16:10507-10540 (2011). In some embodiments, the penetration enhancer is, or includes, an alcohol such ethanol, or others disclosed herein or known in the art.

Delivery of drugs by the transdermal route has been known for many years. Advantages of a transdermal drug delivery compared to other types of medication delivery such as oral, intravenous, intramuscular, etc., include avoidance of hepatic first pass metabolism, ability to discontinue

administration by removal of the system, the ability to control drug delivery for a longer time than the usual gastrointestinal transit of oral dosage form, and the ability to modify the properties of the biological barrier to absorption.

Controlled release transdermal devices rely for their effect on delivery of a known flux of drug to the skin for a prolonged period of time, generally a day, several days, or a week. Two mechanisms are used to regulate the drug flux: either the drug is contained within a drug reservoir, which is separated from the skin of the wearer by a synthetic membrane, through which the drug diffuses; or the drug is held dissolved or suspended in a polymer matrix, through which the drug diffuses to the skin. Devices incorporating a reservoir will deliver a steady drug flux across the membrane as long as excess undissolved drug remains in the reservoir; matrix or monolithic devices are typically characterized by a falling drug flux with time, as the matrix layers closer to the skin are depleted of drug. Usually, reservoir patches include a porous membrane covering the reservoir of medication which can control release, while heat melting thin layers of medication embedded in the polymer matrix (e.g., the adhesive layer), can control release of drug from matrix or monolithic devices. Accordingly, the active agent can be released from a patch in a controlled fashion without necessarily being in a controlled release formulation.

Patches can include a liner which protects the patch during storage and is removed prior to use; drug or drug solution in direct contact with release liner; adhesive which serves to adhere the components of the patch together along with adhering the patch to the skin; one or more membranes, which can separate other layers, control the release of the drug from the reservoir and multi-layer patches, etc., and backing which protects the patch from the outer environment.

Common types of transdermal patches include, but are not limited to, single-layer drug-in-adhesive patches, wherein the adhesive layer contains the drug and serves to adhere the various layers of the patch together, along with the entire system to the skin, but is also responsible for the releasing of the drug; multi-layer drug-in-adhesive, wherein which is similar to a single- layer drug-in-adhesive patch, but contains multiple layers, for example, a layer for immediate release of the drug and another layer for control release of drug from the reservoir; reservoir patches wherein the drug layer is a liquid compartment containing a drug solution or suspension separated by the adhesive layer; matrix patches, wherein a drug layer of a semisolid matrix containing a drug solution or suspension which is surrounded and partially overlaid by the adhesive layer; and vapor patches, wherein an adhesive layer not only serves to adhere the various layers together but also to release vapor. Methods for making transdermal patches are described in U.S. Patent Nos. 6,461,644, 6,676,961, 5,985,311, and 5,948,433.

In a particularly preferred embodiment, the l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof, is formulated for transdermal delivery and administered using a transdermal patch. In some embodiments, the formulation, the patch, or both are designed for extended release of the 1- alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof,

g. Exemplary Formulation

In a particular embodiment, a formula for the preparation of 1000 tablets each containing 25 mg of active ingredient includes:

N-[2-(7-methoxy-l-naphthyl)ethyl]acetamide - 25 g

Lactose monohydrate - 62 g Magnesium stearate - 1.3 g

Povidone - 9 g

Anhydrous colloidal silica - 0.3 g

Cellulose sodium glycolate - 30 g

Stearic acid - 2.6 g

III. Methods of Treatment

A. Treatment Protocol

The methods typically include administering a subject in need thereof an effective amount of a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof. For example, in some embodiments, the method includes administering a subject in need thereof a pharmaceutical composition including an effective amount of one or more active agents wherein at least one of the active agents is a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof. Suitable formulations and routes of administration are discussed above. In a particular embodiment the agomelatine is a crystalline agomelatine.

The effective amount or therapeutically effective amount can be a dosage sufficient to treat, inhibit, or alleviate one or more symptoms of a neurodegenerative disease or central nervous system disorder, or to otherwise provide a desired pharmacologic and/or physiologic effect, for example, reducing, inhibiting, or reversing one or more of the underlying pathophysiological mechanisms underlying neurodegeneration. The precise dosage will vary according to a variety of factors such as subject-dependent variables (e.g., age, immune system health, clinical symptoms etc.).

Exemplary symptoms, pharmacologic, and physiologic effects are discussed in more detail below.

The methods can include administering to the subject an effective amount of a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in the subject.

In a preferred embodiment, the l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof, is administered to the subject in an effective amount to decrease sleep disruption. In another preferred embodiment, the l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof, is administered to the subject in an effective amount to increase slow- wave sleep in the subject as discussed in more detail below.

In some embodiments, the methods are effective to reduce, delay, or prevent one or more other clinical symptoms of a neurodegenerative disease or central nervous system disease or disorder.

Particularly preferred embodiments include formulations for extended release. For example, the formulation can suitable for

administration once daily or less. In some embodiments, the composition is only administered to the subject once every 24-48 hours, preferably at night before sleep.

A preferred route of administration is transdermal, for example, a transdermal patch or gel that is contacted with the skin of the subject. In a particular embodiment, the transdermal formulation is administered to a subject at night, prior to the subject going to sleep. As discussed in more detail below, in some methods a subject in need thereof is transdermally administered an amount of a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof effective to decrease sleep disruption or increase slow wave sleep in the subject. In a particular embodiment, the transdermal formulation is administered to a subject at night, prior to the subject going to sleep using a transdermal patch.

In general, by way of example only, dosage forms useful in the disclosed methods can include doses in the range of 0.1 to 1,000 mg, 1 to 200 mg, 5 to 175 mg, 7.5 to 150 mg, or 10 to 125 mg, or 12.5 to 150 mg, or 15 to 125 mg, or 17.5 to 100 mg, or 20 to 75 mg, or 22.5 to 60 mg, or 25 to 50 mg, with doses of 10 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 75 mg, and 100 mg being specific examples of preferred doses. Typically, such dosages are administered once daily to a human. In some embodiments, the dosage is 1-100 mg/day, or 25-50 mg/day, for example 25 mg/day or 50 mg/day or 100 mg/day. In some embodiments, the subject is started a low dose and the dosage is escalated in the drug is well tolerated in the subject. For example, in a particular embodiments, a subject is administered a starting dose of 25 mg per day. The dose can be escalated to 50 mg, or greater per day after one week if well tolerated.

In some embodiments, the effect of the composition on a subject is compared to a control. For example, the effect of the composition on a particular symptom, pharmacologic, or physiologic indicator can be compared to an untreated subject, or the condition of the subject prior to treatment. In some embodiments, the symptom, pharmacologic, or physiologic indicator is measured in a subject prior to treatment, and again one or more times after treatment is initiated. In some embodiments, the control is a reference level, or average determined based on measuring the symptom, pharmacologic, or physiologic indicator in one or more subjects that do not have the disease or condition to be treated (e.g., healthy subjects). In some embodiments, the effect of the treatment is compared to a conventional treatment that is known the art, such as one of those discussed herein.

In some embodiments, a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered in combination with one or more additional active agents. The combination therapies can include administration of the active agents together in the same admixture, or in separate admixtures. Therefore, in some embodiments, the pharmaceutical composition includes two, three, or more active agents. Such formulations typically include an effective amount of a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof. The different active agents can have the same, or different mechanisms of action. In some embodiments, the combination results in an additive effect on the treatment of the disease or disorder. In some embodiments, the combinations results in a more than additive effect on the treatment of the disease or disorder.

The pharmaceutical compositions can be formulated as a

pharmaceutical dosage unit, also referred to as a unit dosage form.

B. Combination Therapies

A l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof can be the singular active agent administered to treat a subject in need thereof; or the l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof can be administered in combination with another agent to treat the subject.

In some embodiments, the active agent(s) is administered in combination with a co-therapy such as dietary changes with or without dietary supplements, exercise, psychological and/or psychosocial counseling, physical therapy, occupational therapy, and speech therapy.

In particular embodiments, a combination therapy includes a 1- alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof and one or more conventional treatments for neurodegeneration, or for increasing or enhancing neuroprotection, such as those discussed herein. Exemplary neuroprotective agents are known in the art in include, for example, glutamate antagonists, antioxidants, and NMDA receptor stimulants. Other neuroprotective agents and treatments include caspase inhibitors, trophic factors, anti-protein aggregation agents, therapeutic hypothermia, and erythropoietin. In some embodiments, a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered to a subject in combination with a treatment that increase nerve regeneration. In a particular embodiment, a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered to a subject in combination with a conventional treatment for Parkinson's disease, such as levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), a dopamine agonist, or an MAO-B inhibitor. Other common agents that can be used in combination the disclosed combinations include amantadine and anticholinergics for treating motor symptoms, clozapine for treating psychosis, cholinesterase inhibitors for treating dementia, and modafinil for treating daytime sleepiness.

1. Preferred Combination Therapies for Treating Huntington's Disease

In particular embodiments, a combination therapy includes a 1- alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof and one or more conventional treatments for HD, such as those discussed herein. For example, in some embodiments, the combination therapy includes a dopamine blocker to help reduce abnormal behaviors and movements, or a drug such as amantadine and tetrabenazine to control movement, etc. Other drugs that help to reduce chorea include neuroleptics and benzodiazepines. Compounds such as amantadine or remacemide have shown preliminary positive results. Hypokinesia and rigidity, especially in juvenile cases, can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with valproic acid. Psychiatric symptoms can be treated with medications similar to those used in the general population. Selective serotonin reuptake inhibitors and mirtazapine have been recommended for depression, while atypical antipsychotic drugs are recommended for psychosis and behavioral problems.

2. Preferred Combination Therapies for Amyotrophic Lateral Sclerosis

In particular embodiments, a combination therapy includes a 1- alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof and one or more conventional treatments for ALS, such as those discussed herein.

For example, the only compound yielding borderline significance with respect to survival time is riluzole (RILUTEK®) (2-amino-6- (trifluoromethoxy) benzothiazole), an antiexcitotoxin. Therefore, in some embodiments, the l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered to a subject in combination with riluzole.

Other medications, most used off-label, and interventions can reduce symptoms due to ALS. Some treatments improve quality of life and a few appear to extend life. Common ALS-related therapies are reviewed in Gordon, Aging and Disease, 4(5):295-310 (2013), which is specifically incorporated by reference herein in its entirety. Exemplary ALS treatments and interventions are provided in Table 1, below, which is adapted from Gordon, Aging and Disease, 4(5):295-310 (2013).

Table 1: Treatments for ALS

(Gordon, Aging and Disease, 4(5):295-310 (2013)

*shi0w¾ to urcc a enefica effect a L Therefore, in some embodiments, a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof, is administered to a subject in combination with one or more of the agents or treatments provided in Table 1.

A number of other agents have been tested in one or more clinical trials with efficacies ranging from non-efficacious to promising. Exemplary agents are reviewed in Carlesi, et al., Archives Italiennes de Biologie, 149:151-167 (2011), which is specifically incorporated by reference herein in its entirety. For example, in some embodiments, a l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine is administered to a subject in combination with an agent that reduces excitotoxicity such as talampanel (8-methyl-7H-l,3- dioxolo(2,3)benzodiazepine), a cephalosporin such as ceftriaxone, or memantine; an agent that reduces oxidative stress such as coenzyme Q10, manganoporphyrins, KNS-760704 [(6R)-4,5,6,7-tetrahydro-N6-propyl-2,6- benzothiazole-diamine dihydrochloride, RPPX], or edaravone (3 -methyl- 1- phenyl-2-pyrazolin-5-one, MCI-186); an agent that reduces apoptosis such as histone deacetylase (HDAC) inhibitors including valproic acid, TCH346 (Dibenzo(b,f)oxepin- 10-ylmethyl-methylprop-2-ynylamine), minocycline, or tauroursodeoxycholic Acid (TUDCA); an agent that reduces

neuroinflammation such as thalidomide and celastol; a neurotropic agent such as insulin-like growth factor 1 (IGF-1) or vascular endothelial growth factor (VEGF); a heat shock protein inducer such as arimoclomol; or an autophagy inducer such as rapamycin or lithium.

C. Conditions, Symptoms, and Subjects to be Treated

1. Conditions to be Treated

The disclosed compositions are typically administered to subjects with a neurodegenerative disorder, in need of neuroprotection, or a combination thereof. Neurodegeneration refers to the progressive loss of structure or function of neurons, including death of neurons.

Neurodegeneration can be caused by a genetic mutation or mutations; protein misfolding; intracellular mechanisms such as dysregulated protein degradation pathways, membrane damage, mitochondrial dysfunction, or defects in axonal transport; defects in programmed cell death mechanisms including apoptosis, autophagy, cytoplasmic cell death; and combinations thereof. More specific mechanisms common to neurodegenerative disorders include, for example, oxidative stress, mitochondrial dysfunction, excitotoxicity, inflammatory changes, iron accumulation, and/or protein aggregation. Therefore, in some embodiments, the disclosed compositions are administered to a subject in need thereof in an effective amount to reduce or prevent one or more mechanisms that cause neurodegeneration.

In some embodiments, the disclosed compositions are administered in an effective amount to increase neuroprotection, neurorecovery, neurorescue or neuroregeneration in a subject in need thereof. Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing neurodegenerative insult the relative preservation of neuronal integrity can be measured as a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation (Casson, et al., Clin. Experiment. Ophthalmol, 40 (4): 350-7 (2012)).

Neuroprotective approaches can be used to treat many central nervous system (CNS) disorders including neurodegenerative diseases, stroke, traumatic brain injury, and spinal cord injury. Neuroprotection aims to prevent or slow disease progression and secondary injuries by halting or at least slowing the loss of neurons. Despite differences in symptoms or injuries associated with CNS disorders, many of the mechanisms behind neurodegeneration (discussed above) are the same.

2. Subjects

The methods disclosed herein can be used to treat subjects with a neurological or neurodegenerative disease or disorder, a subject in need to neuroprotection, for a combination thereof. Exemplary neurodegenerative diseases include, but are not limited to, Huntington's Disease (HD),

Amyotrophic Lateral Sclerosis (ALS), Parkinson's Disease (PD) and PD- related disorders, Alzheimer's Disease (AD) and other dementias, Prion Diseases such as Creutzfeldt- Jakob Disease, Corticobasal Degeneration, Frontotemporal Dementia, HIV-Related Cognitive Impairment, Mild Cognitive Impairment, Motor Neuron Diseases (MND), Spinocerebellar Ataxia (SCA), Spinal Muscular Atrophy (SMA), Friedreich's Ataxia, Lewy Body Disease, Alpers' Disease, Batten Disease, Cerebro-Oculo-Facio- Skeletal Syndrome, Corticobasal Degeneration, Gerstmann-Straussler- Scheinker Disease, Kuru, Leigh's Disease, Monomelic Amyotrophy, Multiple System Atrophy, Multiple System Atrophy With Orthostatic Hypotension (Shy-Drager Syndrome), Multiple Sclerosis (MS),

Neurodegeneration with Brain Iron Accumulation, Opsoclonus Myoclonus, Posterior Cortical Atrophy, Primary Progressive Aphasia, Progressive Supranuclear Palsy, Vascular Dementia, Progressive Multifocal

Leukoencephalopathy, Dementia with Lewy Bodies, Lacunar syndromes, Hydrocephalus, Wernicke-Korsakoff s syndrome, post-encephalitic dementia, cancer and chemotherapy-associated cognitive impairment and dementia, and depression-induced dementia and pseudodementia.

Exemplary conditions or subjects that may benefit from or be in need of neuroprotection include, but are not limited to, subjects having had, subjects with, or subjects likely to develop or suffer from a

neurodegenerative disease, a stroke, a traumatic brain injury, a spinal cord injury, Post-Traumatic Stress syndrome, or a combination thereof.

a. Huntington's Disease

Huntington's disease (HD) is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and psychiatric problems. The chronic pathology in HD leads to numerous associated troubles including cognitive dysfunctions, more specifically dysfunction in thought and mental representations, changes in reasoning, in judgment.

HD is caused by an autosomal dominant mutation in either of an individual's two copies of the Huntingtin (HTT) gene. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully penetrant. Mutation of either of a person's HTT genes can cause the disease. Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age (Walker, et al, Lancet, 369(9557):218-28 (2007)).

Epidemiological studies show an HD prevalence of 0.5-10 per

100,000 persons. The disease is believed to affect nearly 30,000 individuals in the United States. HD is considered an orphan disease by both U.S. and European regulatory bodies (FDA and EMA respectively).

Currently, there is no approved, fully satisfactory, recognized treatment for HD. In particular, despite a dire need for such therapies, there is no current disease modifying treatment for HD. Significant ongoing research efforts include strategies to knockdown the mutant htt allele, but none have translated to human use.

The only FDA approved drug for this indication is tetrabenazine. Tetrabenazine improves chorea by approximately 25%, and as such provides considerable symptomatic improvement. However, tetrabenazine has significant side effects, including the ability to worsen depression and to make movement more difficult. Depression and suicidal ideation are absolute contraindications for tetrabenazine. Considering depression occurs in -30% of the HD population, this is a considerable subset (Slaughter, et al., CNSSpectr., 6(4):306-26 (2001)). Moreover, tetrabenazine does not alleviate other symptoms of Huntington's disease, and it does not slow the progression of the disease or stop the underlying disease process.

Nonetheless, most neurologists feel that the overall benefits of the drug outweigh the side effects, especially considering that there is no other approved therapy for HD. More recently, drugs such as venlafaxine, paroxetine and

escitalopram have been recommended. However, numerous side effects have been listed for these treatments, the most frequently reported ones being sedation, pharmaco-dependency, alcohol interaction, and a non-negligible impact on cardiovascular and/or sexual function. In most cases, stopping of the treatments leads to a discontinuation syndrome, which can be

problematic for patients.

In some embodiments, the methods disclosed herein are used to treat a subject with Huntington's disease. In some embodiments, the subject exhibits one or more of the HD clinical symptoms, one or more HD molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. In some embodiments, the subject exhibits one or more symptoms discussed herein, but does not exhibit all of the symptoms. Therefore, in some embodiments, the subject does not have one or more of the symptoms disclosed herein or elsewhere. For example, in some embodiments, the subject does not exhibit one or any combination of the following symptoms: stress, sleep disorders, anxiety, seasonal depression, insomnia and tiredness due to "jet lag," schizophrenia, panic attacks, melancholy, the regulation of appetite, insomnia, psychotic problems, epilepsy, Parkinson's disease, senile dementia, the various disorders resulting from normal or pathological ageing, migraine, memory loss, Alzheimer's disease, disorders of cerebral circulation, cardiovascular pathologies, pathologies of the digestive system, fatigue due to appetite disorders, obesity, pain, psychotic disorders, diabetes, senile dementia, sexual dysfunction, or cancer.

In some embodiments, the subject has been medically diagnosed as having HD by exhibiting clinical (e.g., physical) symptoms of the disease. Excessive unintentional movements of any part of the body are often the first clinical symptoms. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first diagnosed and are most typically only recognized in hindsight or when they develop further. Disease progression can be measured using the unified Huntington's disease rating scale which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments (Huntington Study Group, Movement Disorders, 11(2):136-142 (1996)).

Medical imaging, such as computerized tomography (CT) and magnetic resonance imaging (MRI), and functional neuroimaging techniques, such as fMRI and PET, can supplement analysis of physical symptoms but are typically not diagnostic alone.

Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or embryo carries an expanded copy of the trinucleotide repeat in the HTT gene that causes the disease. The U.S.

government sponsored genetic disease compendium, the Online Mendelian Inheritance in Man (OMIM) database, gives HD a phenotype number #143100. The gene/locus is huntingtin (HTT), and is located on Chromosome 4pl6.3 with the Gene/Locus MIM number of 613004. Assignment of the 143100 number to the OMIM entry is because -Huntington disease (HD) is a monogenetic disorder caused by an expanded trinucleotide repeat (CAG)n, encoding glutamine, in the gene encoding huntingtin (HTT; 613004) on chromosome 4pl6.3. The genetic test for HD consists of a blood test which counts the numbers of CAG repeats in each of the HTT alleles.

Cutoffs for genetic testing are given as follows according to De Die- Smulders, et al., Human Reproduction Update, 19(3):304— 315 (2013).

40 or more CAG repeats: full penetrance allele (FPA). A "positive test" or "positive result" generally refers to this case. A person who tests positive for the disease will develop HD sometime within their lifetime, provided he or she lives long enough for the disease to appear.

36 to 39 repeats: incomplete or reduced penetrance allele (RPA). It may cause symptoms, usually later in the adult life. There is a maximum risk of 60% that a person with an RPA will be symptomatic at the age of 65 years, and a 70% risk of being symptomatic at the age of 75 years. 27 to 35 repeats: intermediate allele (IA), or large normal allele. It is not associated with symptomatic disease in the tested individual, but may expand upon further inheritance to give symptoms in offspring.

26 or less repeats: Not associated with HD.

A positive result is considered different than a clinical diagnosis, since it may be obtained decades before the symptoms begin. The test can tell a person who originally had a 50 percent chance of inheriting the disease if their risk goes up to 100 percent or is eliminated.

Elsewhere, the range of repeat numbers for normal individual is 9 to 36, and 37 or greater in HD individuals (Duyao et al., Nat Genet. , 4(4):387- 92 (1993)).

Therefore, in some embodiments, the subject has a "positive result", or is determined to have incomplete or reduced penetrance allele (RPA), or is determined to have intermediate allele (IA), or large normal allele by genetic testing, but does not exhibit any of the clinical symptoms, or the clinical symptoms are too mild for an affirmative medical diagnosis. In a particular embodiment, the subject has a "positive result" but does not exhibit any of the clinical symptoms, or the clinical symptoms are too mild for an affirmative medical diagnosis. Accordingly, in some embodiments, the compounds or compositions disclosed herein are administered prior to a clinical diagnosis of HD.

b. Amyotrophic Lateral Sclerosis

Amyotrophic lateral sclerosis (ALS) is a fatal motor neuron disease, affecting both the first and second order motor neurons. The progression of ALS is characterized by a degeneration of motor neurons associated with a demyelination in the anterior horn of the spinal cord. The etiology is only partially understood. Of the 5-10% familial cases, 20% carry a mutation of the superoxide dismutase 1 (SODl) gene. Such a mutation is also present in 5% of the sporadic cases (Rowland, et al, New Engl J Med, 44:1688-1700 (2001)). Three to four percent 3%-4% of familial cases are due to pathogenic variants in either the TDP-43 or FUS gene (Mackenzie, et al., Lancet Neurol, 9:995-1007 (2010)). Several potential mechanisms of motor neuron degeneration in ALS have been proposed. These include the involvement of environmental factors, genetic factors, autoimmune phenomena, increased oxidative stress, glutamate toxicity, viral infections, protein aggregation, mitochondrial dysfunction, cytoskeletal abnormalities, impairment of axonal transport and pro-apoptotic alterations (Carlesi, et al., Archives Italiennes de Biologie, 149(l):151-67 (2011)). It has also been proposed that ALS affects glial cells surrounding motor neurons, altered interactions between these cell types, has emerged as an additional mechanism in the disease pathogenesis. However, the cause of ALS is still unclear.

The only compound yielding borderline significance with respect to survival time is riluzole (RILUTEK®) (2-amino-6-(trifluoromethoxy) benzothiazole), an antiexcitotoxin.

In some embodiments, the methods disclosed herein are used to treat a subject with amyotrophic lateral sclerosis. In some embodiments, the subject exhibits one or more of the ALS clinical symptoms, one or more ALS molecular symptoms, or a combination thereof, such as those discussed herein and elsewhere. In some embodiments, the subject exhibits one or more symptoms discussed herein, but does not exhibit all of the symptoms. Therefore, in some embodiments, the subject does not have one or more of the symptoms disclosed herein or elsewhere. For example, in some embodiments, the subject does not exhibit one or any combination of the following symptoms: stress, sleep disorders, anxiety, seasonal depression, insomnia and tiredness due to "jet lag," schizophrenia, panic attacks, melancholy, the regulation of appetite, insomnia, psychotic problems, epilepsy, Parkinson's disease, senile dementia, the various disorders resulting from normal or pathological ageing, migraine, memory loss, Alzheimer's disease, disorders of cerebral circulation, cardiovascular pathologies, pathologies of the digestive system, fatigue due to appetite disorders, obesity, pain, psychotic disorders, diabetes, senile dementia, sexual dysfunction, or cancer. In some embodiments, the subject has been medically diagnosed as having ALS by exhibiting clinical (e.g., physical) symptoms of the disease. As discussed above, in some patients the appearance of sleep-related disorder precede a clinical diagnosis of ALS. Therefore, in some embodiments, the compounds or compositions disclosed herein are administered prior to a clinical diagnosis of ALS. In some embodiments, a genetic test indicates that the subject has one or more genetic mutations associated with ALS.

3. Symptoms

In some embodiments, the disclosed compositions are administered in an effective amount to reduce or prevent one or more molecular or clinical symptoms of a neurodegenerative disease, to increase or enhance neuroprotection, or a combination thereof. Molecular pathologies that underlie or are typical of many neurodegenerative diseases are discussed above. Clinical symptoms are discussed in more detail below.

a. Sleep-related Symptoms

In some embodiments, the compositions are administered in an effective amount to reduce, alleviated, or prevent one or more sleep related symptoms. Sleep is an active process generated and modulated by a complex set of neural systems located mainly in the hypothalamus, brainstem, and thalamus. Sleep is altered in many neurological diseases due to mechanisms including lesions of the brain areas that control sleep and wakefulness, lesions or diseases that produce pain, reduced mobility, and treatments. Excessive daytime sleepiness (EDS), sleep fragmentation, insomnia, sleep-disordered breathing (SDB), nocturnal behavioral phenomena such as rapid eye movement (REM) sleep behavior disorder or nocturnal seizures, restless legs syndrome, and periodic leg movement syndrome (PLMS) are common symptoms and findings in neurological disorders (Jennum, et al., "CHAPTER 39: Sleep disorders in

neurodegenerative disorders and stroke", European Handbook of

Neurological Management, Volume 1, 2nd Edition (Ed. Gilhus, et al.) Blackwell Publishing Ltd. 2011), which is specifically incorporated by reference herein in its entirety. In some cases, sleep disorders precede and influence the disease course in neurological diseases, particularly those involving daytime functioning, quality of life, morbidity, and mortality.

Therefore, in some embodiments, the compositions disclosed herein are administered to a subject in an effective amount to reduce or prevent one or more of sleep-related symptoms selected from the group consisting of excessive daytime sleepiness (EDS), sleep fragmentation, insomnia, sleep- disordered breathing (SDB), nocturnal behavioral phenomena such as rapid eye movement (REM) sleep behavior disorder or nocturnal seizures, restless legs syndrome, periodic leg movement syndrome (PLMS), or any

combination thereof. In some preferred embodiments, the composition is administered in an effective amount to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep

architecture, increase REM sleep, or a combination thereof in a subject in need thereof.

Sleep and circadian dysfunction may be caused by other symptoms of a neurodegenerative disease or condition, or may be caused by factors that are independent of the disease. Sleep and circadian dysfunction can be caused by personal habits, lifestyle or environment, for example, staying up too late, getting up too early, taking drugs that interfere with sleep, and/or over-stimulation due to late-night activities such as work, television, etc. Sleep disorders may precede and influence the disease course in neurological diseases, involving daytime functioning, quality of life, morbidity, and mortality. For example, sleep disturbances have been reported to gradually worsen with disease progression in some neurodegenerative diseases, indicating a relationship between the severity of disease and the

neurodegenerative process. However, poor sleep can also be a consequence of several disturbances such as anxiety, depression, pain, choking, sialorrhea, fasciculations, cramps, nocturia and the inability to get comfortable and move freely in bed, etc. Sleep disorders may also have many reflections on patients with neurodegenerative diseases, including excessive daytime somnolence, fatigue, impaired cognition, reduced quality of life and survival (Lo Coco, et al., Neurodegenerative Disease Management, 2(3):315-324 (2012)).

Circadian rhythms and sleep are two different processes, although the terms are often used interchangeably. Circadian rhythms are biological processes that change roughly every 24 hours. They are orchestrated by a small part of the brain known as the suprachiasmatic nucleus or SCN, which regulates the body's activities including when to get up and when to go to bed. Sleep is a circadian behavior, but is just one of many circadian behaviors that are influenced by the SCN. Others include heart rate, hormone secretion, blood pressure and body temperature.

During the night, sleep follows a predictable pattern, moving back and forth between deep restorative sleep (deep sleep) and more alert stages (collective referred to as Non-REM or NREM) and dreaming (REM sleep). Specifically, the sleep cycle includes stages W (wakefulness), Nl (NREM 1), N2 (NREM 2), N3 (NREM3), and R (REM). Sleep stages can be identified by monitoring a subject's brain electrical activity (e.g., brain waves). The criteria for each stage, and methods for determining the stage of a sleeping subject, and profiling a subject's sleep architecture are described in Iber, et al., "The AASM Manual for the Scoring of Sleep and Associated Events, American Academy of Sleep Medicine", pg. 1-57 (2007), which is specifically incorporated by reference herein in its entirety.

Together, the stages of REM and non-REM sleep form a complete sleep cycle. Each cycle typically lasts about 90 minutes and repeats four to six times over the course of a typical night's sleep. A normal adult spends approximately 50% of total sleep time in Stage 2 sleep, 20% in REM sleep, and 30% in the remaining stages, including deep sleep. For example, a typical first sleep cycle, Nl, is characterized by a low- voltage, mixed- frequency pattern, and may last for about 1 to about 10 minutes. The second stage, N2, comes next is characterized by sleep spindles and/or K complexes in the EEG recording. N2 generally lasts about 10 to about 25 minutes. As N2 sleep progresses, there is a gradual appearance of the high- voltage, slow- wave activity characteristic of N3, the third stage of NREM sleep. This stage, which generally lasts about 20 to about 40 minutes, is referred to as "slow-wave," "delta," or "deep" sleep. Following the N3 stage of sleep, a series of body movements usually signals an "ascent" to lighter NREM sleep stages. Typically, a 5 to 10 minute period of N2 precedes the initial REM sleep episode. REM sleep episodes, the first of which may last only one to five minutes, generally become longer through the night. During a typical night, N3 sleep occupies less time in the second cycle than the first and may disappear altogether from later cycles. The average length of the first NREM-REM sleep cycle is between 70 and 100 minutes; the average length of the second and later cycles is about 90 to 120 minutes. REM sleep makes up about 20 to 25 percent of total sleep in typical healthy adults ("Natural Patterns of Sleep" healthysleep.med.harvard.edu/healthy/science/what/sleep- patterns-rem-nrem, A resource from the Division of Sleep Medicine at Harvard Medical School (2007)).

The duration of the stages of the sleep cycle alone, or in combination with the cycling of the stages can be referred to as a subject's sleep architecture. In some embodiments, neurodegenerative disease subjects have disrupted sleep architecture, for example, an alteration in the duration of one or more sleep cycles, an alternation in the duration or number of sleep cycles, or any combination thereof compared to a control or reference value. A control or reference value in this case can be, for example, an average, normal duration for the stage, or average normal duration or number of cycles in subject or subjects that do not suffer from disrupted or disturbed sleep architecture (e.g., a healthy subject). Therefore, in some embodiments, a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered to a subject in an effective amount to normalize a subject's sleep architecture, for example, by bring one or more aspects of the subject's sleep architecture into closer alignment with that of a normal subject.

Slow- wave sleep (SWS), often referred to as deep sleep, consists of

N3, non-rapid eye movement sleep. The 1968 categorization of the combined Sleep Stages 3 - 4 was reclassified in 2007 as Stage N3. An epoch (30 seconds of sleep) which consists of 20% or more of slow wave (delta) sleep, is now considered to be stage 3 (Gazzaniga, Just the Facts 101, e-Study Guide for: Psychological Science, Content Technologies Inc., 2014). Slow-wave sleep is believed to be important to consolidate new memories, and sleep deprivation studies with humans indicate that among other things, an important function of slow- wave sleep may be to allow the brain to recover from its daily activities. Therefore, in some embodiments a 1- alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered to a subject in an effective amount in increase the length of one or more N3 stages during a subject's sleep, increase the number of N3 stages during a subject's sleep, or a combination thereof.

Rapid eye movement (REM) sleep is a stage of sleep characterized by the rapid and random movement of the eyes and can be classified into two categories: tonic and phasic. Criteria for REM sleep includes rapid eye movement, low muscle tone and a rapid, low- voltage EEG - features which can be identified by polysomnogram. REM sleep typically occupies 20-25% of total sleep, about 90-120 minutes of a night's sleep.

In some embodiments, the a l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof is administered in an effective amount to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in the subject in an amount effective to reduce or prevent one or more other clinical symptoms of a neurodegenerative or neurological disease or disorder.

i. Huntington's Disease

In some embodiments, the composition is administered in an effective amount to decrease sleep disruption, decrease circadian

dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in a subject with, or at risk of developing, Huntington's Disease. Evidence is emerging that subjects with HD can suffer from abnormalities in both sleep and in the control of daily or 'circadian' rhythms (Morton, "HDBuzz Special Feature: Huntington's disease and sleep" HDbuzz.net/115, (ed., Wild), February 06, 2013).

Therefore, sleep and circadian dysfunction are symptoms of HD. Other sleep-related symptoms in patients with Huntington's disease in the diminishment of involuntary movements tend to diminish during sleep, sleep disturbances, including disturbed sleep pattern with an increased sleep onset latency, reduced sleep efficiency, frequent nocturnal awakenings, and more time spent awake with less slow wave sleep (Jennum, et al, "CHAPTER 39: Sleep disorders in neurodegenerative disorders and stroke", European

Handbook of Neurological Management, Volume 1, 2nd Edition (Ed. Gilhus, et al.) Blackwell Publishing Ltd. 2011 , and references cited therein). These abnormalities can correlate in part with the duration of illness, severity of clinical symptoms, and degree of atrophy of the caudate nucleus. The sleep phenotype of Huntington's disease may also include insomnia, advanced sleep phase, periodic leg movements, sleep behaviour disorder (RBD), and reduced REM sleep. Reduced REM sleep may precede chorea, and mutant huntingtin may exert an effect on REM sleep and motor control during sleep.

Sleep and circadian dysfunction may be caused by other symptoms of HD, or may be caused by factors that are independent of the disease. Sleep and circadian dysfunction can be caused by personal habits, lifestyle or environment, for example, staying up too late, getting up too early, taking drugs that interfere with sleep, and/or over-stimulation due to late-night activities such as work, television, etc. Sleep and circadian disturbance in HD patients are likely to contribute to HD symptoms that are worsened by sleep deprivation, such as irritability and anxiety. Furthermore, HD subjects may not have the same neurological reserves to handle sleep deprivation that healthy subjects rely upon.

ii. Amyotrophic Lateral Sclerosis

In some embodiments, the composition is administered in an effective amount to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in a subject with, or at risk of developing, amyotrophic lateral sclerosis (ALS). Sleep-wake problems are frequent, although often unrecognized, complications of ALS. Sleep disorders such as insomnia, sleep-disordered breathing and restless legs syndrome have all been reported in patients with ALS, despite the limited number of studies and the small populations investigated so far (Lo Coco, et al., Neurodegenerative Disease Management, 2(3):315-324 (2012)). The prognosis in ALS is closely related to respiratory muscle strength, and sudden nocturnal death often occurs during sleep. Respiratory indices such as low nocturnal oxygen saturation are associated with a poorer prognosis. Patients with

diaphragmatic involvement may have significantly reduced REM sleep. Furthermore, patients with dementias often present circadian disturbances which have been treated with melatonin and light therapy. (Jennum, et al., "CHAPTER 39: Sleep disorders in neurodegenerative disorders and stroke", European Handbook of Neurological Management, Volume 1, 2nd Edition (Ed. Gilhus, et al.) Blackwell Publishing Ltd. 2011).

Therefore, sleep and/or circadian dysfunction can be symptoms of ALS. Sleep and circadian dysfunction may be caused by other symptoms of ALS, or may be caused by factors that are independent of the disease. Sleep and circadian dysfunction can be caused by personal habits, lifestyle or environment, for example, staying up too late, getting up too early, taking drugs that interfere with sleep, and/or over-stimulation due to late-night activities such as work, television, etc. Sleep disorders may precede and influence the disease course in neurological diseases, involving daytime functioning, quality of life, morbidity, and mortality. For example, sleep disturbances have been reported to gradually worsen with disease progression in ALS, indicating a relationship between the severity of disease and the neurodegenerative process. However, poor sleep can also be a consequence of several disturbances such as anxiety, depression, pain, choking, sialorrhea, fasciculations, cramps, nocturia and the inability to get comfortable and move freely in bed. Sleep disorders may have many reflections on patients with ALS, including excessive daytime somnolence, fatigue, impaired cognition, reduced quality of life and survival (Lo Coco, et al., Neurodegenerative Disease Management, 2(3):315-324 (2012)).

b. Other Symptoms

In some embodiments, the compositions are administered in an effective amount to reduce, alleviate, or prevent one or more other clinical symptoms associated with a neurodegenerative disease or central nervous system disorder. Symptoms of neurodegenerative diseases are known in the art and vary from disease to disease. In some embodiments, the exhibits one or any combination of the following symptoms or diseases: stress, sleep disorders, anxiety, seasonal depression, insomnia and tiredness due to "jet lag," schizophrenia, panic attacks, melancholy, the regulation of appetite, insomnia, psychotic problems, epilepsy, Parkinson's disease, senile dementia, various disorders resulting from normal or pathological aging, migraine, memory loss, Alzheimer's disease, disorders of cerebral circulation, cardiovascular pathologies, pathologies of the digestive system, fatigue due to appetite disorders, obesity, pain, psychotic disorders, diabetes, senile dementia, sexual dysfunction, or cancer. In some embodiments, the subject does not exhibit one or more of the preceding symptoms.

In some embodiments, the subject has been medically diagnosed as having a neurodegenerative disease or a condition in need of neuroprotection by exhibiting clinical (e.g., physical) symptoms of the disease. As discussed above, in some patients the appearance of sleep-related disorder precedes a clinical diagnosis of a disease. Therefore, in some embodiments, the compounds or compositions disclosed herein are administered prior to a clinical diagnosis of a disease or condition. In some embodiments, a genetic test indicates that the subject has one or more genetic mutations associated with a neurodegenerative disease or central nervous system disorder.

Neurodegenerative diseases are typically more common in aged individuals. Therefore in some embodiments, the subject is greater the 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100 years in age. i. Huntington's Disease

Clinical symptoms of HD are known in the art and include behavioral disturbances including, but not limited to, hallucinations, irritability, moodiness, restlessness, fidgeting, paranoia, psychosis, suicidal thoughts, and suicide attempts; abnormal and/or unusual movements including, but not limited to, chorea, facial movements such as grimaces, head turning to shift eye position, quick, sudden, sometimes wild jerking movements of the arms, legs, face, and other body parts, slow, uncontrolled movements, unsteady gait, small unintentionally initiated or uncompleted motions, and lack of coordination; cognitive impairment and/or dementia-related symptoms including, but not limited to, disorientation and/or confusion, loss of judgment, loss of memory, personality changes, and speech changes; and other symptoms including anxiety, stress, tension, difficulty swallowing, speech impairment, rigidity, slow movements, tremor, malnutrition, and weight loss. Neuropsychiatric features are a core component of the disease.

Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include muscle atrophy, cardiac failure, impaired glucose tolerance, weight loss, osteoporosis and testicular atrophy.

A number of studies have examined the prevalence of the myriad of symptoms in subjects with Huntington's disease. Shiwach, Acta Psychiatr Scand, 90(4) :241-6 (1994) reports the results of a retrospective study of 110 patients with Huntington disease in 30 families. The study found the minimal lifetime prevalence of depression to be 39%. The frequency of symptomatic schizophrenia was 9%, and significant personality change was found in 72% of the sample. The age at onset was highly variable. Some showed signs in the first decade and some not until over 60 years of age.

Rosenberg, et al., J Med Genet., 32(8):600-4 (1995) describes a double-blind study on 33 persons at risk for HD who had applied for genetic testing. Significantly inferior cognitive functioning was disclosed in gene carriers by a battery of neuropsychologic tests covering attentional, visuospatial, learning, memory, and planning functions. Primarily, attentional, learning, and planning functions were affected.

Bamford, et al., Neurology, 45(10):1867-73 (1995) reports a prospective analysis of neuropsychologic performance and CT scans of 60 individuals with Huntington disease. The study found that psychomotor skills showed the most significant consistent decline among cognitive functions assessed.

Marshall, et al., Arch Neurol, 64(1):116-21 (2007) reports a study comparing psychiatric manifestations among 29 HD mutation carriers with no clinical symptoms, 20 HD mutation carriers with mild motor symptoms, 34 manifesting HD patients, and 171 nonmutation controls. The mild motor symptoms group and the manifesting HD group showed significantly higher scores for obsessive-compulsive behavior, interpersonal sensitivity, anxiety, paranoia, and psychoticism compared to the nonmutation control group. The mutation carriers without symptoms had higher scores for anxiety, paranoid ideation, and psychoticism compared to the nonmutation control group. The results indicated that individuals in the preclinical stage of HD exhibit specific psychiatric symptoms, and that additional symptoms may manifest later in the disease course. Suicidal ideation is a frequent finding in

Huntington disease and physicians should be aware of increased suicide risk both in asymptomatic at-risk patients and symptomatic patients (Walker, et al., Lancet, 369(9557):218-28 (2007)).

The mechanisms underlying HD are explored in Wang, et al., Journal ofNeuroscience, 31(41):14496-14507 (2011), which is discussed in more detail below. The study shows that mutant huntingtin (htt)-mediated toxicity in cells, mice, and humansis associated with loss of the type 1 melatonin receptor (MT1). High levels of MT1 receptor were found in mitochondria from the brains of wild-type mice but much less in brains from HD mice, melatonin inhibited mutant htt- induced caspase activation and preserved

MT1 receptor expression. Therefore, in some embodiments, the compounds and compositions disclosed herein are administered to a subject with HD in an effective amount to treat one or more molecular symptoms of HD, for example, to reduce, delay or inhibit mutant to-induced caspase activation; to reduce or prevent loss of MT1 receptor expression, particularly in the mitochondria of cell of the subject; or a combination thereof.

ii. Amyotrophic Lateral Sclerosis

Clinical symptoms of ALS are known in the art. For example, the earliest symptoms of ALS are typically weakness and/or muscle atrophy. Other early symptoms include trouble swallowing, cramping, or stiffness of affected muscles; muscle weakness affecting an arm or a leg; and/or slurred and nasal speech, and in some cases dementia.

To be diagnosed with ALS, a patient must have signs and symptoms of both upper and lower motor neuron damage that cannot be attributed to other causes. The diagnosis depends on progressive degeneration of upper (UMN) and lower (LMN) motor neurons findings by history and

examination and is accurate 95% of the time when made by an experienced clinician (Gordon, Aging and Disease, 4(5):295-310 (2013)).

Electromyography can be used to confirm widespread lower motor neuron disease and exclude other diseases such as multifocal motor neuropathy with conduction block. Brain and spinal MRI rule out conditions that affect the UMN, including cervical spondylosis. Occasionally the brain MRI shows bilateral signal changes within the corticospinal tracts, a finding that is pathognomonic of ALS. The El Escorial criteria help standardize diagnosis for clinical research studies (Brooks, et al., Amyotroph Lateral Scler Other Motor Neuron Disord, 1 :293-299 (2000)).

Over time, patients experience increasing difficulty moving, swallowing (dysphagia), and speaking or forming words (dysarthria).

Symptoms of upper motor neuron involvement include tight and stiff muscles (spasticity) and exaggerated reflexes (hyperreflexia) including an overactive gag reflex. An abnormal reflex commonly called Babinski's sign also indicates upper motor neuron damage. Symptoms of lower motor neuron degeneration include muscle weakness and atrophy, muscle cramps, and fleeting twitches of muscles that can be seen under the skin (fasciculations). Degeneration of bulbar upper motor neurons can cause exaggeration of motor expressions of emotion.

Progression is subject-specific, however, eventually most patients are not able to walk or use their hands and arms. They also lose the ability to speak and swallow their food, and most end on a portable ventilator. The rate of progression can be measured using an outcome measure called the "ALS Functional Rating Scale Revised (ALSFRS-R)", a 12-item instrument administered as a clinical interview or patient-reported questionnaire that produces a score between 48 (normal function) and 0 (severe disability).

A survey-based study amongst clinicians showed that they rated a

20% change in the slope of the ALSFRS-R would be clinically meaningful (Castrillo-Viguera, et al, Amyotroph Lateral Scler, 11(1-2): 178-80 (2010)). Therefore, in some embodiments, l-alkoxy-(2-acylaminoethyl)naphthalene or a derivative thereof, preferably agomelatine or a pharmaceutically acceptable salt thereof, is administered to a subject an amount effective to change in the slope of the ALSFRS-R of a subject 1%, 5%, 10%, 15%, 20%, or more. In some embodiments, the ALSFRS-R score of the subject is taken prior to, and one or more after initiation of treatment. In some embodiments, the ALSFRS-R score takes day, weeks, months, or more to improve.

iii. Parkinson's Disease

In a particular embodiment, the disclosed compositions are used to treat a subject with Parkinson's disease or suffering from parkinsonism or Parkinson's syndrome. PD is a degenerative disorder of the central nervous system. Symptoms of PD are well known in the art and reviewed in

Jankovic, et al, J. Neurol. Neurosurg. Psychiatr., 79(4): 368-76 (2007). The motor symptoms of Parkinson's disease result from the death of dopamine- generating cells in the substantia nigra, a region of the midbrain. The cause of the cell death remains unknown. Early in the course of the disease, the most obvious symptoms are movement-related and include, but are not limited to, shaking, rigidity, slowness of movement and difficulty with walking and gait. In particular, four motor symptoms considered hallmarks of PD are tremor, rigidity, slowness of movement, and postural instability. The main motor symptoms are collectively called parkinsonism, or a "parkinsonian syndrome".

Later, thinking and behavioral problems may arise and can range from mild to severe, with dementia commonly occurring in the advanced stages of the disease, whereas depression is the most common psychiatric symptom. Other common neuropsychiatric disturbances includes disorders of speech, cognition, mood, behavior, and thought. Cognitive disturbances, which can occur in the initial stages of the disease and sometimes prior to diagnosis, include executive dysfunction, which can include problems with planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions, and selecting relevant sensory information; fluctuations in attention and slowed cognitive speed; and memory loss.

Other symptoms include sensory, sleep and emotional problems. In fact, disturbances of sleep and wake are among the most common and disabling non-motor manifestations of PD, affecting as many as 90% of patients (Videnovic, et al., JAMA Neurol.

doi:10.1001/jamaneurol.2013.6239, published online February 24, (2014)).

A physician's diagnosis of PD typically comes from a combination of medical history and neurological examination. Brain scans of people with PD typically look normal, but can be used to rule out disorders that could give rise to similar symptoms. Although no lab test exists for PD, medical organizations have created diagnostic criteria to facilitate and standardize the diagnostic process. See, for example, the UK Parkinson's Disease Society Brain Bank, the U.S. National Institute of Neurological Disorders and Stroke, and the PD Society Brain Bank which all provide criteria for diagnosing PD.

Parkinson's disease is more common in older people, with most cases occurring after the age of 50. There is no cure for PD, and the disease is most typically managed using one or a combination of levodopa (usually combined with a dopa decarboxylase inhibitor or COMT inhibitor), dopamine agonists and MAO-B inhibitors. Other common agents include amantadine and anticholinergics for treating motor symptoms, clozapine for treating psychosis, cholinesterase inhibitors for treating dementia, and modafinil for treating daytime sleepiness. Surgery and deep brain stimulation can be used, most typically when drugs are no longer effective. Gene therapies, stem cell transplants, neuroprotective agents, are also being developed as treatment options for PD.

iv. Traumatic Brain Injury

In another particular embodiment, the disclosed compositions are used to treat a subject suffering from traumatic brain injury (TBI).

Traumatic brain injury occurs when an external mechanical force, typically head trauma, causes brain dysfunction.

Traumatic brain injury can have wide-ranging physical and psychological effects. Some signs or symptoms may appear immediately after the traumatic event, while others may not appear until days or weeks later. Symptoms of TBI include, but are not limited to, loss of

consciousness; a state of being dazed, confused or disoriented; memory or concentration problems; headache, dizziness or loss of balance; nausea or vomiting; sensory problems such as blurred vision, ringing in the ears or a bad taste in the mouth; sensitivity to light or sound; mood changes or mood swings; feeling depressed or anxious; fatigue or drowsiness; difficulty sleeping; sleeping more than usual, agitation, combativeness or other unusual behavior; slurred speech; inability to awaken from sleep; weakness or numbness in fingers and toes; loss of coordination; convulsions or seizures, dilation of one or both pupils of the eyes; and/or clear fluids draining from the nose or ears. In children, additional symptoms include change in eating or nursing habits; persistent crying and inability to be consoled; unusual or easy irritability; change in ability to pay attention; change in sleep habits; sad or depressed mood; and/or loss of interest in favorite toys or activities.

TBI can be diagnosed using the Glasgow Coma Scale, a 15-point test that helps a doctor or other emergency medical personnel assess the initial severity of a brain injury by checking a person's ability to follow directions and move their eyes and limbs. The coherence of speech also provides important clues. Abilities are scored numerically with higher scores indicating more mild injury. Imaging such as computerized tomography (CT) and magnetic resonance imaging (MRI), as well as intracranial pressure monitoring can also be used to assist in the diagnoses by helping to identify the local(s) and extent of the trauma.

Conventional treatments for TBI include administration of agents such as diuretics, anti-seizer drugs, and coma-inducing drugs; surgery to remove clotted blood, repair skull fractures, and/or relieve pressure inside the skull.

D. Treatment Rationale

Certain l-alkoxy-(2-acylaminoethyl)naphthalenes and derivatives thereof such as agomelatine have properties which indicate that they can alleviate one or more of symptoms of a neurodegenerative disorder and/or reduce or prevent the progression of the disease, and/or increase

neuroprotection in a subj ect in need thereof.

Studies indicate that the MTl receptor axis, or signaling through the MTl receptor has significant influence on cell viability in preclinical cellular (in vitro) and in vivo animal models of HD. Specifically, Wang, et al., Journal of Neuroscience, 31(41):14496-14507 (2011), reports that melatonin delays disease onset and mortality in a transgenic mouse model of HD. The study shows that mutant huntingtin (htt)-mediated toxicity in cells, mice, and humans is associated with loss of the type 1 melatonin receptor (MTl). High levels of MTl receptor were found in mitochondria from the brains of wild- type mice but much less in brains from HD mice, melatonin inhibited mutant htt-induced caspase activation and preserved MTl receptor expression. The effects of melatonin were blocked with the MTl antagonist luzindole.

Moreover, administration of melatonin increased the life span of HD mice by 21%. Of 32 pharmacological interventions in this model, only 5 have shown similar >20% extension in life span.

Other studies related to the neuroprotective role of melatonin, and method of use thereof are discussed in Reiter, et al., Ann N Y Acad Sci. , 890:471-85 (1999), Venkatramanujam, et al., TherAdv Neurol Disord, 4(5) 297-317 (2011), Pandi-Perumal, et al., Progress in Neurobiology, 85:335- 353 (2008), Weishaupt, et al., J Pineal Res., 41:313-323 (2006), WO 2007114948, and U.S. Patent Nos. 6,353,015 and 7,361,681 which describes use of melatonin to treat ALS, and Videnovic, et al., JAMA Neurol, doi:10.1001/jamaneurol.2013.6239, published online February 24, (2014), which describes circadian melatonin rhythm and excessive daytime sleepiness in Parkinson's disease.

Agomelatine exhibits a dual mechanism of action wherein it is an agonist of receptors of the melatoninergic system, and also an antagonist of the 5 -HT 2C receptor. This is evident in physiological effects observed when directly compared against the MT1/2 agonists, ramelteon and tasimelteon. Binding studies indicate that agomelatine has no effect on monoamine uptake and no affinity for α, β adrenergic, histaminergic, cholinergic, dopaminergic and benzodiazepine receptors. Agomelatine has been shown to increase noradrenaline and dopamine release specifically in the frontal cortex and has no influence on the extracellular levels of serotonin, and resynchronise circadian rhythms in animal models of circadian rhythm disruption. 5-HT receptor modulators are described in U.S. Published Application Nos. 2008/0280886, 2008/0214559, and

2005/0203130.

The dual action of agomelatine is important in the context of cell proliferation and survival in the brain. For example, Soumier et al.,

Neuropsychopharmacology, 34(ll):2390-403 (2009), showed that agomelatine induced cell proliferation and survival in the ventral

hippocampus, and this property required both the serotoninergic antagonist and melatoninergic agonist activity of the drug. Furthermore, agomelatine induced the expression of the potent cell survival factor, BDNF (Soumier et al., Neuropsychopharmacology, 34(11):2390-403 (2009)), an effect which is also observed with ritanserin, a drug with similar 5HT 2C antagonist potency, but without melatoninergic activity.

Agomelatine also increases slow wave sleep in human subjects and normalizes the sleep architecture in depressed subjects (Quera Salva et al., Int J Neuropsychopharmacol., 10(5):691-6 (2007), Quera Salva et al, Hum Psychopharmacol, 25(3):222-9 (2010)), and this effect appears related to its 5HT 2C antagonist properties (Descamps et al., Psychopharmacology (Berl), 205(1):93-106 (2009)).

In a particularly preferred embodiment, the methods are employed to treat HD. Certain l-alkoxy-(2-acylaminoethyl)naphthalenes such as agomelatine have properties which indicate that they can alleviate one or more of the non-motor symptoms of HD, and/or reduce or prevent the progression of the disease.

HD is an autosomal dominant progressive neurodegenerative disorder with a distinct phenotype characterized by chorea, dystonia, incoordination, cognitive decline, and behavioral difficulties. There is progressive, selective neural cell loss and atrophy in the caudate and putamen. HD, including clinical features, population genetics, molecular biology, and animal models were well known in the art. See, for example, Walker, et al., Lancet,

369(9557):218-28 (2007), which is specifically incorporated by reference herein in its entirety.

HD is associated with a suicide rate approximately eight times that of the normal population, with suicidal ideation and attempted suicide found in up to 20% of the HD population (Hubers, et al., J Affect Disord. , 136(3):550- 7 (2012).; Wetzel, et al., Psychiatry Res., 188(3):372-6 (2011)), with depressed mood found in greater than 40% (Hubers, et al., J Affect

Z¾sorc/.,151(l):248-58 (2013)). Moreover, anxiety is found in -35%, irritability in -40%, and apathy in -50%.

Additionally, HD is associated with a major sleep disturbance.

Accurate EMG recordings and polysomnography are difficult because of the chorea, but sleep studies indicate that there is a reduction in slow wave sleep, and disruption of normal sleep architecture.

This constellation of symptoms provides a challenge for most psychotropic medications. For example, antidepressants of the SSRI class may induce apathy, and are minimally effective at combating anhedonia. In contrast, agomelatine in depressed subjects has been shown to reverse the apathy associated with the antidepressant, escitalopram (De Berardis et al., Psychiatry Clin Neuroscl, 67(3):190-1 (2013)), and in a head-to-head comparison was much more effective that the SNRI, venlafaxine on anhedonia. Moroever, anti-depressants of the SSRI class can be associated with a short term increase in suicidal ideation, sufficient to warrant a warning when prescribed in the U.S. In contrast, agomelatine has not been reported to be associated with suicidal ideation.

Accordingly, it is believed that by virtue of its dual mechanism of action, agomelatine can singularly and simultaneously treat two separate underlying pathophysiological causes of HD.

E. Efficacy and Safety of Agomelatine

1. Efficacy

Studies show that agomelatine acts on the central nervous system and can be used for the treatment of major depression, generalized anxiety disorder, seasonal affective disorder, sleep disorders, cardiovascular pathologies, pathologies of the digestive system, insomnia and fatigue due to jet-lag, appetite disorders and obesity. Agomelatine has shown an antidepressant-like effect in animal models of depression (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm desynchronisation and in models related to stress and anxiety. In humans, agomelatine has positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset.

The efficacy and safety of agomelatine in major depressive episodes was studied in a clinical program including 7,900 patients treated with agomelatine. Ten placebo controlled trials have been performed to investigate the short term efficacy of agomelatine in major depressive disorder in adults, with fixed dose and/or dose up-titration. At the end of treatment (over 6 or 8 weeks), significant efficacy of 25-50 mg of agomelatine was demonstrated in 6 out of the ten short-term double-blind placebo-controlled trials. Primary endpoint was change in Hamilton Rating Scale for Depression (HRSD-17) score from baseline. Agomelatine failed to differentiate from placebo in two trials where the active control, paroxetine or fluoxetine showed assay sensitivity.

Agomelatine was not compared directly with paroxetine and fluoxetine as these comparators where added in order to ensure assay sensitivity of the trials. In two other trials it was not possible to draw any conclusions because the active controls, paroxetine or fluoxetine, failed to differentiate from placebo. However, these studies did not allow for an increase in the start dose of agomelatine, paroxetine or fluoxetine even if the response was not adequate.

Efficacy was also observed in more severely depressed patients

(baseline Hamilton Depression Rating Scale (HAM-D) > 25) in all positive placebo-controlled trials. The response rates were statistically significantly higher with agomelatine compared with placebo.

Superiority (2 trials) or non-inferiority (4 trials) has been shown in six out of seven efficacy trials in heterogeneous populations of depressed adult patients versus SSRI/SNRI (sertraline, escitalopram, fluoxetine, venlafaxine or duloxetine). The anti-depressive effect was assessed with the HAMD-17 score either as primary or secondary endpoint.

The maintenance of antidepressant efficacy was demonstrated in a relapse prevention trial. Patients responding to 8/10-weeks of acute treatment with open-label 25-50 mg of VALDOXAN® once daily were randomized to either 25-50 mg of VALDOXAN® once daily or placebo for further 6 months. VALDOXAN® at a dosage of 25-50 mg once daily demonstrated a statistically significant superiority compared to placebo (p=0.0001) on the primary outcome measure, the prevention of depressive relapse, as measured by time to relapse. The incidence of relapse during the 6 months double-blind follow up period was 22% and 47% for

VALDOXAN® and placebo, respectively.

Agomelatine is also discussed in Stein, J Clin. Psychiatry, 2014 Feb 18. [Epub ahead of print], pages 1-11 and supplementary data pages 1-15; and Sanchez-Barcelo, et al., Recent Patents on Endocrine, Metabolic, and Immune Drug Discovery, 1(2):142-151 (2007). 2. Safety

Agomelatine also has a good acceptability profile for patients.

Agomelatine is devoid of the usually side effects associated with

psychotropic drugs. Furthermore, the discontinuation syndrome observed when the treatment is stopped with classical psychotropic drugs, is not observed with agomelatine.

Agomelatine does not alter daytime vigilance and memory in healthy volunteers. In depressed patients, treatment with 25 mg of VALDOXAN® increased slow wave sleep without modification of REM (Rapid Eye Movement) sleep amount or REM latency. VALDOXAN® at a dosage of 25 mg also induced an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients.

In a specific sexual dysfunction comparative trial with remitted depressed patients there was a numerical trend (not statistically significant) towards less sexual emergent dysfunction than venlafaxine for Sex Effects Scale (SEXFX) drive arousal or orgasm scores on agomelatine. The pooled analysis of trials using the Arizona Sexual Experience Scale (ASEX) showed that agomelatine was not associated with sexual dysfunction. In healthy volunteers agomelatine preserved sexual function in comparison with paroxetine. Agomelatine had neutral effect on heart rate and blood pressure in clinical trials.

In a trial designed to assess discontinuation symptoms by the Discontinuation Emergent Signs and Symptoms (DESS) check- list in patients with remitted depression, agomelatine did not induce

discontinuation syndrome after abrupt treatment cessation.

Agomelatine has no abuse potential as measured in healthy volunteer studies on a specific visual analogue scale or the Addiction Research Center Inventory (ARCI) 49 check-list.

A placebo-controlled 8-week trial of 25-50 mg/day of agomelatine in elderly depressed patients (> 65 years, N=222, of which 151 were on agomelatine) demonstrated a statistically significant difference of 2.67 points on HAM-D total score, the primary outcome. Responder rate analysis favored agomelatine. No improvement was observed in very elderly patients (>75 years, N= 69, of which 48 were on agomelatine). Tolerability of agomelatine in elderly patients was comparable to that seen in the younger adults.

Claims

I claim:

1. A method of treating a subject with a neurodegenerative disease or a central nervous system disorder comprising administering to a subject with a neurodegenerative disease or a central nervous system disorder a

pharmaceutical composition comprising an effective amount of a 1-alkoxy- (2-acylaminoethyl)naphthalene or a derivative thereof and a

pharmaceutically acceptable carrier or excipient to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in the subject.

2. A method of reducing, delaying, or preventing one or more symptoms of a neurodegenerative disease or a central nervous system disorder in a subject comprising administering to the subject a

pharmaceutically acceptable carrier or excipient to decrease sleep disruption, decrease circadian dysfunction, increase slow wave sleep, normalize sleep architecture, increase REM sleep, or a combination thereof in the subject in an amount effective to reduce, delay, or prevent the appearance of one or more symptoms of the neurodegenerative disease or the central nervous system disorder in the subject.

3. The method of claim 2, wherein the subject has not been clinically diagnosed with the neurodegenerative disease or the central nervous system disorder based on physical symptoms.

4. The method of any of claims 2-3 , wherein the subj ect has no physical symptoms of the neurodegenerative disease or the central nervous system disorder or the clinical symptoms are too mild for an affirmative diagnosis of the neurodegenerative disease or the central nervous system disorder.

5. The method of any one of claims 1-4, wherein the l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof is agomelatine or a pharmaceutically acceptable salt thereof.

6. The method of claim 5, wherein agomelatine is in a crystalline form.

7. The method of claim 5, wherein agomelatine is an amorphous or noncrystalline form.

8. The method of any one of claims 1-7, wherein the l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof is the singular active agent.

9. The method of any one of claims 1 -8, wherein pharmaceutical composition consists of an effective amount of the l-alkoxy-(2- acylaminoethyl)naphthalene or a derivative thereof and one or more pharmaceutically acceptable carriers or excipients.

10. The method of any one of claims 1-9, wherein the pharmaceutical composition is formulated for extended release.

11. The method of any one of claims 1-10, wherein the pharmaceutical composition is administered once every 24-48 hours.

12. The method of any one of claims 1-11, wherein the pharmaceutical composition is administered transdermally.

13. The method of claim 12, wherein the pharmaceutical composition is administered by contacting a transdermal patch comprising the

pharmaceutical composition with the skin of the subject.

14. The method of any one of claims 1-13, wherein the pharmaceutical composition is administered to the subject in the evening prior to sleep.

15. The method of any one of claims 1-14, wherein the

neurodegenerative disease is selected from the group consisting of

Amyotrophic Lateral Sclerosis (ALS), Huntington's Disease (HD),

Parkinson's Disease (PD) and PD-related disorders, Alzheimer's Disease (AD) and other dementias, Prion Diseases such as Creutzfeldt- Jakob Disease, Corticobasal Degeneration, Frontotemporal Dementia, HIV-Related Cognitive Impairment, Mild Cognitive Impairment, Motor Neuron Diseases (MND), Spinocerebellar Ataxia (SCA), Spinal Muscular Atrophy (SMA), Friedreich's Ataxia, Lewy Body Disease, Alpers' Disease, Batten Disease, Cerebro-Oculo-Facio-Skeletal Syndrome, Corticobasal Degeneration, Gerstmann-Straussler-Scheinker Disease, Kuru, Leigh's Disease, Monomelic Amyotrophy, Multiple System Atrophy, Multiple System Atrophy With Orthostatic Hypotension (Shy-Drager Syndrome), Multiple Sclerosis (MS), Neurodegeneration with Brain Iron Accumulation, Opsoclonus Myoclonus, Posterior Cortical Atrophy, Primary Progressive Aphasia, Progressive Supranuclear Palsy, Vascular Dementia, Progressive Multifocal

16. The method of claim 15, wherein the neurodegenerative disease is Parkinson's disease.

17. The method of any one of claims 1-14, wherein the subject has suffered from a stroke, a traumatic brain injury, a spinal cord injury, or post traumatic stress syndrome.

18. The method of claim 17, wherein the subject has suffered from a traumatic brain injury.

19. The method of claim 15, wherein the neurodegenerative disease is Huntington's disease.

20. The method of claim 19, wherein the subject has at least 36 trinucleotide repeats of CAG in one or both copies of the subject's

Huntingtin (HTT) gene.

21. The method of claim 20, wherein the subject has at least 40 trinucleotide repeats of CAG in one or both copies of the subject's

Huntingtin (HTT) gene.

22. The method of any one of claims 19-21 , wherein the subject has not been clinically diagnosed with HD based on physical symptoms.

23. The method of any one of claims 19-22, wherein the subject has no physical symptoms of HD or the clinical symptoms are too mild for an affirmative diagnosis of HD.

24. The method of claim 15, wherein the neurodegenerative disease is ALS.

25. The method of claim 15, wherein the subject has not been clinically diagnosed with ALS based on physical symptoms.

26. The method of any one of claims 24-25, wherein the subject has no physical symptoms of ALS or the clinical symptoms are too mild for an affirmative diagnosis of ALS.