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1. WO2019109150 - PROCÉDÉS DE TRAITEMENT DE L'AGITATION

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METHODS OF TREATING AGITATION

Field

The present disclosure relates generally to the treatment of agitation and in particular agitation associated with neurodegenerative disorders such as dementia. The patent disclosure enables the manufacture of medicaments as well as compositions containing same for use in methods of therapy for treating agitation associated with neurodegenerative disorders such as dementia.

Background

For many years physicians have attempted to improve the care and quality of life of patients with neurodegenerative disorders such as dementia, multiple sclerosis, and so on, who exhibit agitation, much of which has not been successful. While neurodegenerative disorders like dementia are characterised by cognitive defects such as disorientation, memory loss and diminished intellectual functioning, these are often not the symptoms that cause the most distress to patient and caregivers alike.

In the middle and later stages of the illness, as many as 50% of patients with dementia will exhibit agitation. Of the approximately 4 million people in the United States who suffer from dementia, 70% will become psychotic within the first six or seven years of the illness. The term agitation refers to a range of behavioural disturbances including aggression, combativeness, shouting, hyperactivity and disinhibition. It is the symptoms of agitation such as uncooperativeness with necessary care, motoric hyperactivity, verbal abuse and disinhibition that are the most stressful aspect of caring for a person with a

neurodegenerative disorder.

The nonspecific neuropsychiatric symptoms of agitation can generate feelings of frustration, fear and helplessness in both the patients and their caregivers. Coping mechanisms may fail and give way to intolerance as family members try to deal with these problems day after day. Caring and concern can quickly turn to annoyance, outright anger and even patient abuse. The lack of understanding, patience and unrealistic expectations from some caregivers can also compound the problem. For instance, elderly people with dementia, having lost their mental powers, may not be able to communicate the exact problem. Some caregivers may see the affected elderly people as manipulative rather than as victims of unavoidable changes. Physicians also working with patients experiencing the effects of agitation are also not immune to these problems.

The first line of defence in addressing agitation associated with neurodegenerative disorders is a careful diagnostic evaluation for other medical conditions, psychiatric problems or social/environmental disturbances that can underlie behavioural disturbances. The medical model, making use of a thorough history, with physical examination and laboratory tests, may offer clues to reverse underlying physical disorders, such as infections, medication side effects, neurological diseases, metabolic disorders or pain.

Global agitation and aggression can be hard to manage safely without pharmacotherapy -but what to administer is also a problem in both young and elderly persons diagnosed with neurodegenerative disorders. There are many factors which may explain the cause of agitation but ultimately the person has a mood and behavioural disturbance and is biologically experiencing a profound loss of their ability to negotiate new information and stimulus. It is a direct result of their disease - the progressive deterioration of brain cells.

Situations which may also lead to or provoke agitation in dementia include: behavioral and environmental management is the initial therapeutic approach, for instance, moving to a new residence or nursing home, changes in environment, such as travel, hospitalization or the presence of houseguests, changes in caregiver arrangements, misperceived threats, or fear and fatigue resulting from trying to make sense out of a seemingly confusing world.

There are problems with the treatment of agitation associated with neurodegenerative disorders, for example the source must be identified.

Some patients, for instance, elderly dementia patients experiencing agitation, are susceptible to drug abuse or withdrawal due to changed tolerability and not being aware of their medication regimes - e.g., withdrawal from drugs such as antipsychotics, anticholinergic drugs, long acting benzodiazepines, barbiturates may cause agitation and other symptoms.

Some possible treatment options which have been reported to offer some assistance but quite often present further problems include:

Antipsychotics - Frequent non-responders, Adverse effects: pseudo parkinsonism, sedation, Increased risk of stroke and death - FDA have issued“Black Box Warning”, dizziness, sedation, weight gain, constipation, movement disorders, black box warnings for use in elderly (stroke);

Benzodiazepines (BZDs) are the most commonly prescribed medications for anxiety and insomnia, not recommended for long-term treatment for chronic conditions with associated psychiatric comorbidity, pharmacodynamics and pharmacokinetics for BZDs change in elderly, therapeutic window is often reduced, BZDs are associated with sedation, addiction and tolerance and cognitive disturbances may cause falls in the elderly and they are also highly addictive;

SSRIs and SNRIs antidepressants and atypical antipsychotics are also often used to treat agitation and anxiety, antidepressants have modest efficacy, late onset of action, discontinuation syndrome, and associated with restlessness, often lead to more agitation, sleep disturbances, GI effects; and some exacerbated psychotic symptoms;

Cholinesterase inhibitors have also been shown to reduce delusions, suspicion, hallucinations and agitation in clinical trials - this reflects the interrelationship between cognitive difficulties and disruptive behavior;

Accordingly, there is a very real, unmet need to produce medicaments to effectively treat agitation associated with neurodegenerative disorders which provides long term advantages while at the same time avoids some or all of the adverse side effects discussed above .

Summary

The instant disclosure teaches that the compound of formula (I) may be effective in treating agitation associated with neurodegenerative disorders, for instance, agitation in elderly and non-elderly patients suffering from dementia (such as Lewy Body Dementia), agitation in patients suffering from multiple sclerosis, agitation in patients suffering from Alzheimer’s disease, agitation in patients suffering from Huntington’s disease, and so on.

Accordingly, provided herein is a method of treating agitation associated with neurodegenerative disorders in a patient in need thereof, the method including the step of administering an effective amount of a compound of formula (I) or pharmaceutically acceptable salt thereof:


The compound of formula (I) or a pharmaceutically acceptable salt thereof is generally given for a time and under conditions sufficient to treat agitation associated with neurodegenerative disorders in a patient in need thereof.

The present disclosure further enables the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating agitation associated with neurodegenerative disorders in a patient in need thereof.

Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, for treating agitation associated with neurodegenerative disorders in a patient in need thereof.

Also provided herein is the use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating agitation associated with neurodegenerative disorders in a patient in need thereof, the method including the step of administering to said patient a compound of formula (I), or a pharmaceutically acceptable salt thereof, in the absence of adjunct antidepressant therapy.

Brief Description of the Figures

Figure 1 - In humans, Example 1 significantly reduced the number and intensity of panic symptoms experienced during a CCK-4 induced panic attack. The 18-item Panic Symptoms Scale (PSS) was used to evaluate the effect of Example 1 (2000 mg) versus placebo treatment. Data shown was measured at 10 minutes post CCK-4 injection (Mean ± SEM; n=l5 healthy volunteers who panicked).

Figure 2 - In humans Example 1 significantly reduced the intensity of Defensive Behavior in the Joystick Operated Runway Task (JORT). During fMRI, patients“played a game” to evaluate drug effects on the intensity of avoidance behavior to a threat stimulus (mild electric shock). Patients used a joystick to prevent the green dot being caught by the red dot. In half of the trials, a lightning symbol appeared on the screen to indicate that a mild shock would be delivered if the dots made contact. Compared to placebo treated patients, Example 1 (300 and 2000 mg; p.o.) significantly decreased the intensity of threat avoidance behavior (Mean ± SEM; n = 21).

Figure 3 - The Peak Saccadic Velocity parameter has been validated as the most sensitive measure of the sedative effects of BZDs. In this study, Lorazepam was sedating as indicated by the effects on peak saccadic velocity which was reduced at 6h, 9h and l2h. Both dose levels of Example 1 did not affect peak saccadic velocity, indicating lack of sedative side effects.

Figure 4 - In humans doses of Example 1 did not induce sleepiness on the Karolinska Sleepiness Scale whereas Lorazepam significantly induced subjective sleepiness at 6h and 9h.

Figure 5 - Quantitative EEG profiling showed an increase in the delta band from 6h to l2h post-dosing with Lorazepam in both the resting and vigilance controlled settings. The 300 and 2000 mg doses of Example 1 produced some increase in delta in the resting condition only. Lack of increase during vigilance controlled sessions indicated a low likelihood of sedation for Example 1.

Detailed Description of the Invention

The present disclosure contemplates the treatment of agitation associated with patients suffering from neurodegenerative disorders. The term ‘neurodegenerative disorders’ encompasses a condition leading to the progressive loss of structure or function of neurons, including death of neurons. Examples of neurodegenerative diseases contemplated herein include AIDS dementia complex, adrenoleukodystrophy, alexander disease, Alpers' disease, amyotrophic lateral sclerosis, ataxia telangiectasia, Batten disease, bovine spongiform encephalopathy, Canavan disease, corticobasal degeneration, Creutzfeldt-Jakob disease, dementia with Lewy bodies, fatal familial insomnia, frontotemporal lobar degeneration, Huntington's disease, infantile Refsum disease, Kennedy's disease, Krabbe disease, Lyme disease, Machado-Joseph disease, multiple sclerosis, multiple system atrophy, neuroacanthocytosis, Niemann-Pick disease, Parkinson's disease, Pick's disease, primary lateral sclerosis, multiple sclerosis, progranulin, progressive supranuclear palsy, protein aggregation, Refsum disease, Sandhoff disease, diffuse myelinoclastic sclerosis, Shy-Drager syndrome, spinocerebellar ataxia, subacute combined degeneration of spinal cord, Tabes dorsalis, Tay-Sachs disease, toxic encephalopathy, transmissible spongiform encephalopathy, and Wobbly hedgehog syndrome.

The present disclosure also contemplates the treatment of agitation in an elderly patient suffering from dementia. The term“dementia” as used herein refers to a broad category of brain diseases that cause a long term and also gradual decrease in the ability to think and recall that is severe enough to adversely affect a person’s daily functioning. Common symptoms include emotional problems, problems with language and demotivation.

It is proposed herein that the compound of formula (I) may treat agitation associated with patients suffering from neurodegenerative disorders.

Persons of skill in the art would be familiar with the lag period of traditional antidepressant medications, and with the heightened anxiety produced by the newer generation antidepressants, including S SRI’s, SNRI’s and NRI’s in the early stages of treatment before the antidepressant effects are seen (within 2-4 weeks). Thus, in certain embodiments, the compounds described herein, which have acute anti-panic activity in humans, can be administered to a patient in need thereof as a substitute or replacement for traditional antidepressant medication which may not be effective in reducing agitation.

Replacing traditional antidepressant medication with the present compounds can be advantageous, particularly where the traditional medication is associated with one or more adverse effects ( e.g ., anxiety, nausea, headaches, erectile dysfunction, early-onset suicidal tendencies, etc.). Examples of traditional antidepressant medication would be known to those skilled in the art and include, but are not limited to, selective serotonin re-uptake inhibitors (SSRI), serotonin/noradrenalin re-uptake inhibitors, selective noradrenalin re uptake inhibitors, monoamine oxidase inhibitors, tricyclic antidepressants, lithium and other mood stabilisers, atypical antidepressants, and hormones such as estrogen or progestogen.

In other embodiments, the present compound is administered to a patient in need thereof, together with traditional antidepressants for a period of about 2-4 weeks, to address the symptoms of depression and agitation. In other embodiments, the patient is treated with both the present compounds and one or more traditional antidepressant medication (administered sequentially or in combination) for the duration of the treatment period. Such combination therapy may be particularly useful, for example, where the combination

of the present compounds and the one or more traditional antidepressant medication provide relief from depression in the acute lag phase of the treatment period and/or where an additive or synergistic antidepressant therapeutic effect is required to treat the agitation.

In some embodiments, a patient according to the methods of the present invention does not suffer from an anxiety disorder. In certain embodiments, a patient does not suffer from a phobia. In certain embodiments, a patient does not suffer from one or more of agoraphobia, agoraphobia without history of panic disorder, animal phobia, and social phobia. In certain embodiments, a patient does not suffer from one or more of obsessive-compulsive disorder, stress disorders including post-traumatic and acute stress disorder, and substance-induced anxiety disorder. In certain embodiments, a patient does not suffer from generalized anxiety disorder. In certain embodiments, a patient does not suffer from social anxiety disorder. Yet in all of the above the patient is experiencing agitation associated with a neurodegenerative disorder.

In some embodiments, a patient according to the methods of the present invention does not suffer from one or more of neuroses, convulsions, migraine, depressive disorder, bipolar disorder, psychotic disorder, neurodegeneration arising from cerebral ischemia, attention deficit hyperactivity disorder, Tourette's syndrome, speech disorder, and disorders of circadian rhythm. In certain embodiments, a patient does not suffer from one or more of single-episode or recurrent major depressive disorder, dysthymic disorder, bipolar I or bipolar II manic disorder, and cyclothymic disorder. In certain embodiments, a patient does not suffer from schizophrenia. In certain embodiments, a patient does not suffer from stuttering. Yet in all of the above the patient is experiencing agitation associated with a neurodegenerative disorder.

In some embodiments, a patient according to the methods of the present invention does not suffer from one or more of pain or nociception, emesis, eating disorder, premenstrual syndrome, muscle spasm or spasticity, hearing disorder, urinary incontinence, and the effects of substance abuse or dependency. In certain embodiments, a patient does not suffer from one or more of acute emesis, delayed emesis, anticipatory emesis, emesis induced by

chemotherapy or radiation, motion sickness, and post-operative nausea and vomiting. In certain embodiments, a patient does not suffer from anorexia nervosa or bulimia nervosa. In certain embodiments, a patient does not suffer from tinnitus or age-related hearing impairment. In certain embodiments, a patient does not suffer from alcohol withdrawal.

Yet in all of the above the patient is experiencing agitation associated with a neurodegenerative disorder.

“Treat”,“treating” or“treatment” with regard to a disorder or disease refers to alleviating the effects of the disorder or disease. As used herein, the terms“treat”,“treatment” and “treating” refer to the reduction or amelioration of the progression, severity and/or duration of condition, or the amelioration of one or more symptoms (e.g., one or more discernible symptoms) of said condition (i.e.,“managing” without“curing” the condition), resulting from the administration of one or more therapies (e.g., one or more therapeutic agents such as a compound or composition of the invention). In other embodiments the terms“treat”, “treatment” and “treating” refer to the inhibition of the progression of a condition described herein, either physically by, e.g., stabilization of a discernible symptom or physiologically by, e.g., stabilization of a physical parameter, or both.

In certain embodiments, the present compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, are administered to said patient sequentially (i.e., before or after) or in combination with an antidepressant compound (i.e., with existing antidepressant therapy).

In addition, the present compound may have the further added advantage in that it is free of sedative side effects which may adversely affect a patient's quality of life.

Sudden discontinuation of antidepressant medication may produce withdrawal effects caused by physical dependence on the drug. Compounds can be evaluated for physical dependence in a simple animal model where, following a period of chronic dosing (e.g., for 14-20 days), the study drug is stopped and measurements of food intake, body weight

and body temperature are taken over the next 5 days. The symptoms of abrupt discontinuation of the drug are manifest as significantly reduced appetite, weight loss and drop in body temperature. This model is suitable for detecting the effects across a broad range of drug classes including opiates, antidepressants and benzodiazepines. Abrupt withdrawal of the present compounds tested did not produce any changes in these parameters indicating that the compounds do not produce physical dependence and supporting their suitability for chronic use to treat mood disorders such as depression. The present compound may also be used as a combination therapy due to their lack of side effects of CYP liabilities (but may also replace), e.g. combining the treatment with other antidepressants such as benzodiazepines (e.g., alprazolam, diazepam, lorazepam, clonezepam), selective serotonin re-uptake inhibitors (SSRI) (e.g. citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, indalpine, paroxetine, sertraline, zimelidine, vilaxodone), serotonin norepinephrine reuptake inhibitors (SNRI) (e.g. venlafaxine, duloxetine, desvenlafaxine, milnacipran), monoamine oxidase inhibitors (e.g. phenelzine, moclobemide), tricyclic antidepressants (e.g. trimipramine, imipramine), tetracyclic antidepressants (e.g. mertazepine, maprotiline), mood stabilisers (e.g. lithium, sodium valproate, valproic acid), atypical antidepressants (e.g. bupropion), acetylcholinesterase inhibitors (e.g. donepezil, galantamine, rivastigmine), atypical antipsychotics (e.g. risperidone, aripiprizole, quetiapine, olanzapine), and hormones such as estrogen and progestogen

The compound encompassed herein may also be used as therapy, e.g. combining the treatment with other neurodegenerative treatments, such as acetylcholineesterase inhibitors (e.g. Aricept, Exelon), and treatments for multiple sclerosis (e.g. Avonex, Betaseron, Copaxone, Tysabri, Gilenya).

The compound disclosed herein may be administered to the patient in a treatment effective amount. In some embodiments, a treatment effective amount is a therapeutically effective amount or a prophylactically effective amount. The term “therapeutically effective amount” as used herein means that amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal or human that is being sought by a researcher, medical doctor or other clinician. The therapeutically effective amount of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to ameliorate, cure or treat the disease or disorder or one or more of its symptoms.

As used herein, the term "effective amount" relates to an amount of compound which, when administered according to a desired dosing regimen, provides the desired therapeutic activity. Dosing may occur at intervals of minutes, hours, days, weeks, months or years or continuously over any one of these periods. Suitable dosages lie within the range of about 0.1 ng per kg of body weight to 1 g per kg of body weight per dosage. The dosage may be in the range of 1 mg to 1 g per kg of body weight per dosage, such as is in the range of 1 mg to 1 g per kg of body weight per dosage. In one embodiment, the dosage may be in the range of 1 mg to 500 mg per kg of body weight per dosage. In another embodiment, the dosage may be in the range of 1 mg to 250 mg per kg of body weight per dosage. In yet another embodiment, the dosage may be in the range of 1 mg to 100 mg per kg of body weight per dosage, such as up to 50 mg per body weight per dosage.

In an embodiment, the method comprises administering to a patient in need thereof the present compound in a dosage to provide an effective amount in vivo that will reduce the signs of agitation, including, but not limited to the general agitation. In an embodiment, an effective amount in vivo has an in vitro equivalent concentration that is sufficient to decrease agitation by at least 20%, or at least 50%.

Thereafter, treatment with the present compounds may be continued throughout the treatment period or it may be ceased or replaced with traditional therapeutic compounds. Methods of determining the effective amount of the present compound that is required for reduced signs of agitation in vivo would be familiar to those skilled in the art. For example, reduction of signs of agitation can be determined by monitoring the degree and occurrence of one or more of the following

The terms“administer”,“administering” or“administration” in reference to a compound, composition or formulation of the invention means introducing the compound into the system of the animal in need of treatment. When the compound of the invention is provided in combination with one or more other active agents,“administration” and its variants are each understood to include concurrent and/or sequential introduction of the compound and the other active agents.

In certain embodiments, an effective amount of a compound for administration one or more times a day to a 70 kg adult human may comprise about 0.0001 mg to about 3000 mg, about 0.0001 mg to about 2000 mg, about 0.0001 mg to about 1000 mg, about 0.001 mg to about 1000 mg, about 0.01 mg to about 1000 mg, about 0.1 mg to about 1000 mg, about 1 mg to about 1000 mg, about 1 mg to about 100 mg, about 10 mg to about 1000 mg, or about 100 mg to about 1000 mg, of a compound per unit dosage form.

In certain embodiments, the compound of the invention may be at dosage levels sufficient to deliver from about 0.001 mg/kg to about 100 mg/kg, from about 0.01 mg/kg to about 50 mg/kg, from about 0.1 mg/kg to about 40 mg/kg, from about 0.5 mg/kg to about 30 mg/kg, from about 0.01 mg/kg to about 10 mg/kg, from about 0.1 mg/kg to about 10 mg/kg, and from about 1 mg/kg to about 25 mg/kg, of patient body weight per day, one or more times a day, to obtain the desired therapeutic effect.

Suitable dosage amounts and dosing regimens can be determined by the attending physician and may depend on the particular condition being treated, the severity of the condition as well as the general age, health and weight of the patient. It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

The active ingredient may be administered in a single dose or a series of doses. While it is possible for the active ingredient to be administered alone, it is preferable to present it as a composition, preferably as a pharmaceutical composition. The formulation of such compositions is well known to those skilled in the art. The composition may contain any suitable carriers, diluents or excipients. These include all conventional solvents, dispersion media, fillers, solid carriers, coatings, antifungal and antibacterial agents, dermal penetration agents, surfactants, isotonic and absorption agents and the like. It will be understood that the compositions of the invention may also include other supplementary physiologically active agents.

The compound and pharmaceutical compositions described herein can be used in combination therapy with one or more additional therapeutic agents. For combination treatment with more than one active agent, where the active agents are in separate dosage formulations, the active agents may be administered separately or in conjunction. In addition, the administration of one element may be prior to, concurrent to, or subsequent to the administration of the other agent.

When co-administered with other agents, e.g., when co-administered with another anti anxiety or anti-depressant medication, an“effective amount” of the second agent will depend on the type of drug used. Suitable dosages are known for approved agents and can be adjusted by the skilled artisan according to the condition of the patient, the type of condition(s) being treated and the amount of a compound described herein being used. In cases where no amount is expressly noted, an effective amount should be assumed. For example, compounds described herein can be administered to a patient in a dosage range from between about 0.01 to about 10,000 mg/kg body weight/day, about 0.01 to about 5000 mg/kg body weight/day, about 0.01 to about 3000 mg/kg body weight/day, about 0.01 to about 1000 mg/kg body weight/day, about 0.01 to about 500 mg/kg body weight/day, about 0.01 to about 300 mg/kg body weight/day, about 0.01 to about 100 mg/kg body weight/day.

When“combination therapy” is employed, an effective amount can be achieved using a first amount of the compound of Formula I or a pharmaceutically acceptable salt thereof, and a second amount of an additional suitable therapeutic agent.

In certain embodiments, the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an effective amount (i.e., each in an amount which would be therapeutically effective if administered alone). In other embodiments, the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and the additional therapeutic agent are each administered in an amount which alone does not provide a therapeutic effect (a sub-therapeutic dose). In yet other embodiments, the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof can be administered in an effective amount, while the additional therapeutic agent is administered in a sub-therapeutic dose. In still other embodiments, the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, can be administered in a sub-therapeutic dose, while the additional therapeutic agent is administered in an effective amount.

As used herein, the terms “in combination” or “co-administration” can be used interchangeably to refer to the use of more than one therapy (e.g., one or more prophylactic and/or therapeutic agents). The use of the terms does not restrict the order in which therapies (e.g., prophylactic and/or therapeutic agents) are administered to a patient.

Co-administration encompasses administration of the first and second amounts of the compounds in an essentially simultaneous manner, such as in a single pharmaceutical composition, for example, capsule or tablet having a fixed ratio of first and second amounts, or in multiple, separate capsules or tablets for each. In addition, such co administration also encompasses use of each compound in a sequential manner in either order. When co-administration involves the separate administration of the first amount of the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a second amount of an additional therapeutic agent, the compounds are administered sufficiently close in time to have the desired therapeutic effect. For example, the period of time between each administration which can result in the desired therapeutic effect, can range from minutes to hours and can be determined taking into account the

properties of each compound such as potency, solubility, bioavailability, plasma half-life and kinetic profile. For example, the compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and the second therapeutic agent can be administered in any order within about 24 hours of each other, within about 16 hours of each other, within about 8 hours of each other, within about 4 hours of each other, within about 1 hour of each other or within about 30 minutes of each other.

More, specifically, a first therapy ( e.g ., a therapeutic agent such as the compound described herein) can be administered prior to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks before), concomitantly with, or subsequent to (e.g., 5 minutes, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 24 hours, 48 hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, or 12 weeks after) the administration of a second therapy to a patient.

Examples of therapeutic agents that may be combined with the compound of this disclosure, either administered separately or in the same pharmaceutical composition, include, but are not limited to muscle relaxants, anticonvulants, hypnotics, anaesthetics, analgesics, cholinergics, antidepressants, mood stabilisers, anxiolytics, etc.

In an embodiment, the second therapeutic agent is a SSRI selected from the following: citalopram (Celexa, Cipramil, Cipram, Dalsan, Recital, Emocal, Sepram, Seropram, Citox, Cital)

dapoxetine (Priligy)

escitalopram (Lexapro, Cipralex, Seroplex, Esertia)

fluoxetine (Prozac, Fontex, Seromex, Seronil, Sarafem, Ladose, Motivest, Flutop, Fluctin (EUR), Fluox (NZ), Depress (UZB), Lovan (AUS), Prodep (HMD)) fluvoxamine (Luvox, Fevarin, Faverin, Dumyrox, Favoxil, Movox)

paroxetine (Paxil, Seroxat, Sereupin, Aropax, Deroxat, Divarius, Rexetin, Xetanor, Paroxat, Loxamine, Deparoc)

sertraline (Zoloft, Lustral, Serlain, Asentra)

vilazodone (Viibryd)

In another embodiment the second therapeutic agent is a tetracyclic antidepressant (TeCA) selected from the group consisting of:

Amoxapine (Amokisan, Asendin, Asendis, Defanyl, Demolox, Moxadil)

Maprotiline (Deprilept, Ludiomil, Psymion)

Mazindol (Mazanor, Sanorex)

Mianserin (Bolvidon, Depnon, Norval, Tolvon)

Mirtazapine (Remeron, Avanza, Zispin, Miro)

Setiptiline (Tecipul)

In another embodiment the second therapeutic agent is a serotonin-noradrenaline reuptake inhibitor (SNRI) selected from the group consisting of:

Desvenlafaxine (Pristiq)

Duloxetine (Cymbalta, Ariclaim, Xeristar, Yentreve, Duzela)

Milnacipran (Ixel, Savella, Dalcipran, Toledomin)

Venlafaxine (Effexor, Efexor)

In another embodiment the second therapeutic agent is a Noradrenaline reuptake inhibitor (NRI) selected from the group consisting of:

Atomoxetine (Tomoxetine, Strattera, Attentin)

Mazindol (Mazanor, Sanorex)

Reboxetine (Edronax, Norebox, Prolift, Solvex, Davedax, Vestra)

Viloxazine (Vivalan, Emovit, Vivarint, Vicilan)

In another embodiment the second therapeutic agent is a monoamine oxidase inhibitor (MAOI) selected from the group consisting of:

Benmoxin (Nerusil, Neuralex)

Hydralazine (Apresoline)

Iproclozide (Sursum)

Iproniazid (Marsilid, Iprozid, Ipronid, Rivivol, Propilniazida)

Isocarboxazid (Marplan)

Isoniazid (Laniazid, Nydrazid)

Mebanazine (Actomol)

Nialamide (Niamid)

Octamoxin (Ximaol, Nimaol)

Phenelzine (Nardil, Nardelzine)

Pheniprazine (Catron)

Phenoxypropazine (Drazine)

Pivalylbenzhydrazine (Tersavid)

Procarbazine (Matulane, Natulan, Indicarb)

Caroxazone (Surodil, Timostenil)

Echinopsidine (Adepren)

Furazolidone (Furoxone, Dependal-M)

Finezolid (Zyvox, Zyvoxam, Zyvoxid)

Tranylcypromine (Parnate, Jatrosom)

Brofaromine (Consonar)

Metralindole (Inkazan)

Minaprine (Cantor)

Moclobemide (Aurorix, Manerix)

Pirlindole (Pirazidol)

Toloxatone (Humoryl)

Fazabemide (Pakio, Tempium)

Pargyline (Eutonyl)

Rasagiline (Azilect)

Selegiline (Deprenyl, Eldepryl, Emsam)

In another embodiment the second therapeutic agent is a tricyclic antidepressant (TCA) selected from the group consisting of:

Amitriptyline (Tryptomer, Elavil, Tryptizol, Laroxyl, Sarotex, Lentizol)

Butriptyline (Evadene, Evadyne, Evasidol, Centrolese)

Clomipramine (Anafranil)

Desipramine (Norpramin, Pertofrane)

Dosulepin (Prothiaden, Dothep, Thaden and Dopress)

Doxepin (Aponal, Adapine, Doxal, Deptran, Sinquan, Sinequan, Zonalon, Xepin, Silenor)

Imipramine (Antideprin, Deprimin, Deprinol, Depsol, Depsonil, Dynaprin, Eupramin, Imipramil, Irmin, Janimine, Melipramin, Surplix, Tofranil)

Lofepramine (Gamanil, Tymelyt, Lomont)

Nortriptyline (Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren, Nortrilen) Protriptyline (Vivactil)

Trimipramine (Surmontil, Rhotrimine, Stangyl)

The compound and compositions provided herein can be administered by any route, including enteral ( e.g ., oral), parenteral, intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, transdermal, interdermal, rectal, intravaginal, intraperitoneal, topical (as by powders, ointments, creams, and/or drops), mucosal, nasal, bucal, sublingual; by intratracheal instillation, bronchial instillation, and/or inhalation; and/or as an oral spray, nasal spray, and/or aerosol. Specifically contemplated routes are oral administration, intravenous administration (e.g., systemic intravenous injection), regional administration via blood and/or lymph supply, and/or direct administration to an affected site. In general, the most appropriate route of administration will depend upon a variety of factors including the nature of the agent (e.g., its stability in the environment of the gastrointestinal tract), and/or the condition of the patient (e.g., whether the patient is able to tolerate oral administration).

The exact amount of a compound required to achieve an effective amount will vary from patient to patient, depending, for example, on species, age, and general condition of a patient, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two

weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations ( e.g two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations).

The carrier must be pharmaceutically "acceptable" in the sense of being compatible with the other ingredients of the composition and not injurious to the patient. Compositions include those suitable for oral, rectal, nasal, topical (including buccal and sublingual), vaginal or parental (including subcutaneous, intramuscular, intravenous, and intradermal) administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy. Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then if necessary shaping the product.

Pharmaceutically acceptable excipients include any and all solvents, diluents, or other liquid vehicles, dispersions, suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as suited to the particular dosage form desired. General considerations in formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington’s Pharmaceutical Sciences , Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 2lst Edition (Lippincott Williams & Wilkins, 2005).

Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the compound of the present invention (the“active ingredient”) into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a“unit dose” is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a patient and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

Relative amounts of the active ingredient, the pharmaceutically acceptable excipient, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the patient treated and further depending upon the route by which the composition is to be administered. By way of example, the composition may comprise between 0.1% and 100% (w/w) active ingredient.

Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavouring, and perfuming agents may also be present in the composition.

Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, and mixtures thereof.

Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch

(starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, and mixtures thereof.

Exemplary surface active agents and/or emulsifiers include natural emulsifiers (e.g., acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g., bentonite (aluminum silicate) and Veegum (magnesium aluminum silicate)), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g., carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate (Tween 20), polyoxyethylene sorbitan (Tween 60), polyoxyethylene sorbitan monooleate (Tween 80), sorbitan monopalmitate (Span 40), sorbitan monostearate (Span 60], sorbitan tristearate (Span 65), glyceryl monooleate, sorbitan monooleate (Span 80)), polyoxyethylene esters (e.g., polyoxyethylene monostearate (Myrj 45), polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor™), polyoxyethylene ethers, (e.g., polyoxyethylene lauryl ether (Brij 30)), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and/or mixtures thereof.

Exemplary binding agents include starch (e.g., cornstarch and starch paste), gelatin, sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g., acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose,

hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, and/or mixtures thereof.

Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer’s solution, ethyl alcohol, and mixtures thereof.

Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and mixtures thereof.

Exemplary natural oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary synthetic oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and mixtures thereof.

Compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, sachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be presented as a bolus, electuary or paste.

A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder ( e.g inert diluent, preservative disintegrant (e.g., sodium starch glycolate, cross-linked polyvinyl pyrrolidone, cross-linked sodium carboxymethyl cellulose) surface-active or dispersing agent. Moulded tablets may be made by moulding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent. The tablets may optionally be coated or scored and may be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile. Tablets may

optionally be provided with an enteric coating, to provide release in parts of the gut other than the stomach.

The active ingredient can be in micro-encapsulated form with one or more excipients. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose, or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredients, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavouring, and perfuming agents. In certain embodiments for parenteral administration, the conjugates of the invention are mixed with solubilizing agents such as Cremophor™, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and mixtures thereof.

Compositions suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavoured base, usually sucrose and acacia or tragacanth gum; pastilles comprising the active ingredient in an inert basis such as gelatine and glycerin, or sucrose and acacia gum; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Compositions suitable for topical administration to the skin may comprise the compounds dissolved or suspended in any suitable carrier or base and may be in the form of lotions, gel, creams, pastes, ointments and the like. Suitable carriers include mineral oil, propylene glycol, polyoxyethylene, polyoxypropylene, emulsifying wax, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water. Transdermal patches may also be used to administer the compounds of the invention.

Compositions for rectal administration may be presented as a suppository with a suitable base comprising, for example, cocoa butter, glycerin, gelatine or polyethylene glycol.

Compositions suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Compositions suitable for parenteral administration include aqueous and non-aqueous isotonic sterile injection solutions which may contain anti-oxidants, buffers, bactericides and solutes which render the composition isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The compositions may be presented in unit-dose or multi-dose sealed containers, for example, ampoules and vials, and may be stored in a freeze-dried (lyophilised) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets of the kind previously described. An injectable preparation can be a sterile injectable solution,

suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in l,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer’s solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables. The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In certain embodiments, unit dosage compositions are those containing a daily dose or unit, daily sub-dose, as herein above described, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the active ingredients particularly mentioned above, the compositions of this invention may include other agents conventional in the art having regard to the type of composition in question, for example, those suitable for oral administration may include such further agents as binders, sweeteners, thickeners, flavouring agents disintegrating agents, coating agents, preservatives, lubricants and/or time delay agents. Suitable sweeteners include sucrose, lactose, glucose, aspartame or saccharine. Suitable disintegrating agents include cornstarch, methylcellulose, polyvinylpyrrolidone, xanthan gum, bentonite, alginic acid or agar. Suitable flavouring agents include peppermint oil, oil of wintergreen, cherry, orange or raspberry flavouring. Suitable coating agents include polymers or copolymers of acrylic acid and/or methacrylic acid and/or their esters, waxes, fatty alcohols, zein, shellac or gluten. Suitable preservatives include sodium benzoate, vitamin E, alpha-tocopherol, ascorbic acid, methyl paraben, propyl paraben or sodium bisulphite. Suitable lubricants include magnesium stearate, stearic acid, sodium oleate, sodium chloride or talc. Suitable time delay agents include glyceryl monostearate or glyceryl distearate.

The phrase "pharmaceutically acceptable salt," as used herein, refers to pharmaceutically acceptable organic or inorganic salts of a provided compound. For use in medicine, the salts of the provided compounds will be pharmaceutically acceptable salts. Other salts may, however, be useful in the preparation of provided compounds or of their pharmaceutically acceptable salts. Pharmaceutically acceptable salts are well known in the art. For example, Berge et ah, describe pharmaceutically acceptable salts in detail in J. Pharm. Sci. (1977) 66:1-19, incorporated herein by reference in its entirety. A pharmaceutically acceptable salt involves the inclusion of another molecule such as an acetate ion, a succinate ion or other counter ion. The counter ion may be any organic or inorganic moiety that stabilizes the charge on the parent compound. Furthermore, a pharmaceutically acceptable salt may have more than one charged atom in its structure. When multiple charged atoms are present in the parent drug, its pharmaceutically acceptable salts will have multiple counter ions and these can be several instances of the same counter ion or different counter ions. Hence, a pharmaceutically acceptable salt can have one or more charged atoms in the parent compound and/or one or more counter ions.

Pharmaceutically acceptable salts of the compounds described herein include those derived from suitable inorganic and organic acids and bases. In some embodiments, the salts can be prepared in situ during the final isolation and purification of the compounds. In other embodiments the salts can be prepared from the free form of the compound in a separate synthetic step.

When a provided compound is acidic or contains a sufficiently acidic bioisostere, suitable "pharmaceutically acceptable salts" refers to salts prepared form pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particular embodiments include ammonium, calcium, magnesium, potassium and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,N -dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine tripropylamine, tromethamine and the like. Quartemary ammonium salts such as N+(CI-4 alkyl)4 are also included.

When a provided compound is basic or contains a sufficiently basic bioisostere, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include, but are not limited to, acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, carbonic, boric, sulfamic, propionic, butyric, hydroxymaleic, mucic, phenylacetic, sulfanilic, aspartic, edetic, stearic, palmitic, oleic, lauric, ascorbic, valeric, perchloric, malonic, p-toluenesulfonic acid and the like. Particular embodiments include citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric and tartaric acids. Other exemplary salts include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, palmoate (i.e., l,l'-methylene-bis-(2-hydroxy-3-naphthoate)), adipate, alginate, ascorbate, aspartate, cyclopentanepropionate, borate, butyrate, camphorate, digluconate, dodecylsulfate, ethanesulfonate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, 2-hydroxyethanesulfonate, lactobionate, laurate, lauryl sulphate, malonate, 2-naphthalenesulfonate, nicotinate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, stearate, thiocyanate, undecanoate, and valerate salts.

The preparation of the pharmaceutically acceptable salts described above and other typical pharmaceutically acceptable salts is more fully described by Berge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977:66: 1-19.

Basic nitrogen-containing groups may be quartemised with such agents as lower alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others.

The compounds and pharmaceutical formulations described herein may be contained in a kit. The kit may include single or multiple doses of two or more agents, each packaged or formulated individually, or single or multiple doses of two or more agents packaged or formulated in combination. Thus, one or more agents can be present in first container, and the kit can optionally include one or more agents in a second container. The container or containers are placed within a package, and the package can optionally include administration or dosage instructions. A kit can include additional components such as syringes or other means for administering the agents as well as diluents or other means for formulation. Thus, the kits can comprise: a) a pharmaceutical composition comprising a compound described herein and a pharmaceutically acceptable carrier, vehicle or diluent; and b) a container or packaging. The kits may optionally comprise instructions describing a method of using the pharmaceutical compositions in one or more of the methods described herein ( e.g . preventing or treating one or more of the diseases and disorders described herein). The kit may optionally comprise a second pharmaceutical composition comprising one or more additional agents described herein for co therapy use, a pharmaceutically acceptable carrier, vehicle or diluent. The pharmaceutical composition comprising the compound described herein and the second pharmaceutical composition contained in the kit may be optionally combined in the same pharmaceutical composition.

A kit includes a container or packaging for containing the pharmaceutical compositions and may also include divided containers such as a divided bottle or a divided foil packet. The container can be, for example a paper or cardboard box, a glass or plastic bottle or jar, a re-sealable bag (for example, to hold a "refill" of tablets for placement into a different container), or a blister pack with individual doses for pressing out of the pack according to a therapeutic schedule. It is feasible that more than one container can be used together in a single package to market a single dosage form. For example, tablets may be contained in a bottle which is in turn contained within a box.

An example of a kit is a so-called blister pack. Blister packs are well known in the packaging industry and are being widely used for the packaging of pharmaceutical unit dosage forms (tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff material covered with a foil of a preferably transparent plastic material. During the packaging process, recesses are formed in the plastic foil. The recesses have the size and shape of individual tablets or capsules to be packed or may have the size and shape to accommodate multiple tablets and/or capsules to be packed. Next, the tablets or capsules are placed in the recesses accordingly and the sheet of relatively stiff material is sealed against the plastic foil at the face of the foil which is opposite from the direction in which the recesses were formed. As a result, the tablets or capsules are individually sealed or collectively sealed, as desired, in the recesses between the plastic foil and the sheet. Preferably the strength of the sheet is such that the tablets or capsules can be removed from the blister pack by manually applying pressure on the recesses whereby an opening is formed in the sheet at the place of the recess. The tablet or capsule can then be removed via said opening.

It may be desirable to provide written memory aid containing information and/or instructions for the physician, pharmacist or patient regarding when the medication is to be taken. A "daily dose" can be a single tablet or capsule or several tablets or capsules to be taken on a given day. When the kit contains separate compositions, a daily dose of one or more compositions of the kit can consist of one tablet or capsule while a daily dose of another or more compositions of the kit can consist of several tablets or capsules. A kit can take the form of a dispenser designed to dispense the daily doses one at a time in the order of their intended use. The dispenser can be equipped with a memory-aid, so as to further facilitate compliance with the regimen. An example of such a memory-aid is a mechanical counter which indicates the number of daily doses that have been dispensed.

Another example of such a memory-aid is a battery-powered micro-chip memory coupled with a liquid crystal readout, or audible reminder signal which, for example, reads out the date that the last daily dose has been taken and/or reminds one when the next dose is to be taken.

It will be appreciated that any compound that is a prodrug of the compound of formula (I) described herein, is also within the scope and spirit of the invention. The term "pro-drug" is used in its broadest sense and encompasses those derivatives that are converted in vivo to the compounds of the invention. Such derivatives would readily occur to those skilled in the art, and include, for example, compounds where a free hydroxy group is converted into an ester, such as an acetate or phosphate ester. Procedures for esterifying, e.g., acylating, the compounds of the invention are well known in the art and may include treatment of the compound with an appropriate carboxylic acid, anhydride or chloride in the presence of a suitable catalyst or base.

The compound of the invention may be in crystalline form either as the free compounds or as solvates (e.g., hydrates) and it is intended that both forms are within the scope of the present invention. Methods of solvation are generally known within the art.

Furthermore, depending on the substitution pattern the compounds of the present invention may be capable of undergoing tautomerism. Accordingly, all possible tautomers of the compound of the present invention fall within the scope and spirit of the invention.

Those skilled in the art will appreciate that the invention described herein in susceptible to variations and modifications other than those specifically described. It is to be understood that the invention includes all such variations and modifications which fall within the spirit and scope. The invention also includes all of the steps, features, compositions and compounds referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.

Throughout this specification and the claims which follow, unless the context requires

otherwise, the word "comprise", and variations such as "comprises" and "comprising", will be understood to imply the inclusion of a stated integer or step or group of integers or steps but not the exclusion of any other integer or step or group of integers or steps.

The reference in this specification to any prior publication (or information derived from it), or to any matter which is known, is not, and should not be taken as an acknowledgment or admission or any form of suggestion that that prior publication (or information derived from it) or known matter forms part of the common general knowledge in the field of endeavour to which this specification relates.

Certain embodiments of the invention will now be described with reference to the following examples which are intended for the purpose of illustration only and are not intended to limit the scope of the generality hereinbefore described.

Examples

Synthetic Protocols

Example 1

Preparation of Morpholino 6-(2,3-dihydro-lH-inden-2-yl)amino-l-ethyl-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxamide (Example 1)


Example la) 2-Hydroxy-5-nitronicotinic acid


To 2-hydroxynicotinic acid (3.6 mmol) in sulfuric acid (30% free S03, 2 ml) was added sodium nitrate (7.2 mmol) portionwise over 20 min. The solution was allowed to stir for 20 h at room temperature. The solution was then poured onto ice-water and the precipitate that formed was filtered off, washed with water and dried in a vacuum oven to afford a pale yellow solid (45%).

ESIMS: M-l: 183

1H NMR (300 MHz, DMSO) d 8.94 (1H, d, H-4), 8.67 (1H, d, H-6).

Example lb) 2-Chloro-5-nitronicotinic acid


2-Hydroxy-5-nitronicotinic acid (2.7 mmol) in a mixture of /V,/V-di methyl formamidc (2.7 mmol) and thionyl chloride (5 ml) was heated at 80°C for 1 h. The mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added ice- water (20 ml) and with vigorous stirring a precipitate formed. The precipitate was filtered off and dried in a vacuum oven to give a white solid (68%).

ESIMS: M-l: 201.


9.30 (1H, d, H-4), 8.83 (1H, d, H-6).

Example lc) 2-Methoxy-5-nitro-nicotinic acid


To 2-chloro-5-nitronicotinic acid (1.0 mmol) in methanol was added a solution of sodium methoxide in methanol (2.4 mmol, freshly prepared from sodium metal in methanol). The solution was refluxed for 2 h and the mixture was allowed to cool and concentrated in vacuo. To the resulting residue was added 10% citric acid solution (20 ml) and the solution extracted with ethyl acetate (20 ml). The organic layer was dried (MgS04) and concentrated in vacuo. The residue was crystallised from water to give a yellow-white solid (73%).

ESIMS: M-l 197.

1H NMR (300 MHz, DMSO) d 9.30 (1H, d, H-4), 8.83 (1H, d, H-6), 4.05 (3H, s, OCH3).

Example Id) Ethyl 3-oxo-3-(5-nitro-2-methoxypyridin-3-yl)propionate

o o OH O

2-Methoxy-5-nitronicotinic acid (36 mmol) and phosphorous pentachloride (72 mmol) were heated at l00°C for 2h. The excess reagent was removed in vacuo to give an oily residue.

To a solution of ethyl potassium malonate (75.6 mmol) and triethylamine (72 mmol) in acetonitrile (110 ml) was added magnesium chloride (90 mmol) portionwise over 10 min. This solution was allowed to stir for 8 h at 35°C. To this solution was added dropwise a solution of the pyridyl chloride (from above) in acetonitrile (15 ml) at 0°C over 20 min. The solution was allowed to warm to room temperature and stirred for 20 h. To this solution was added diethyl ether (100 ml) and 1N hydrochloric acid solution until the pH 5-6 was reached. The two layers were separated and the organic layer was washed with water (100 ml). The organic layer was then dried (MgS04) and concentrated in vacuo. The resulting residue was then patiented to column chromatography eluting with dichloromethane to afford a clear oily liquid (78%). The NMR spectrum of this compound showed evidence of ketone-enol tautomerism.

ESIMS: M-l: 267.

1H NMR (300 MHz, DMSO) d 9.17 (d, 0.6H), 9.05 (d, 0.4H), 8.96 (d, 0.4H), 8.94 (d, 0.6H), 6.20 (s, 0.4H), 4.31-4.13 (m, 5H, OMe+OCH2), 3.99 (s, 1.2H), 1.33 (t, 3x0.4H),

1.22 (t, 3x0.6H).

Example le) Ethyl l-ethyl-l,4-dihydro-6-nitro-4-oxo-l,8-naphthyridine-3-carboxylate


The pyridyl malonate (18 mmol) and triethylorthoformate (23.4 mmol) in acetic anhydride (8 ml) were refluxed for 1 h. The solution was allowed to cool and the excess acetic anhydride was distilled off in vacuo. To the resulting residue in acetonitrile (40 ml) was added dropwise ethylamine (36 mmol) in diethyl ether (20 ml) and the solution was allowed to stir for 5 h at room temperature. The solution was then allowed to cool and was concentrated in vacuo. The residue was dissolved in dichloromethane (60 ml) and washed with water (2 x 60 ml). The organic layer was then dried (MgS04) and concentrated in vacuo. The resulting residue was patiented to column chromatography eluting with 100% dichloromethane, and then 2% methanol/dichloromethane to give a white solid (78%).

ESIMS: M+l: 292.

1H NMR (300 MHz, CDC13) d 9.50 (1H, d, H-5), 9.44 (1H, d, H-7), 8.66 (1H, s, H-2), 4.53 (2H, q, OCH2), 4.39 (2H, q, NCH2), 1.51 (3H, t, OCH2CH3), 1.40 (3H, t, NCH9CTR)· Example If) Ethyl 1 -ethyl-1, 4-dihydro-6-amino-4-oxo-l,8-naphthyridine-3-carboxylate


The naphthyridine (1.7 mmol) in /V,/V-dimethyl formamide (10 ml) was hydrogenated over Raney nickel (0.17 mmol) for 4h at rt. The mixture was filtered through Celite and washed with tetrahydrofuran. The filtrate was evaporated to dryness. Crystallisation from ethanol obtained the residue as a pale yellow solid (67%).

ESIMS: M+l: 262.

1H NMR (300 MHz, DMSO) d 8.65 (1H, s, ArH), 8.22 (1H, d, / = 2.9 Hz, ArH), 7.62 (1H, d, / = 2.9 Hz, ArH), 5.76 (2H, s, NH2), 4.39 (2H, q, / = 6.9 Hz, OCH2), 4.17 (2H, q,

J = 12 Hz, NCH2), 1.24 (3H, t, J = 6.9 Hz, OCH2CH3), 1.23 (3H, t, J = 7.0 Hz,

NCH2CH3).

Example lg) Ethyl 6-(2,3-dihydro-lH-inden-2-ylamino)-l-ethyl-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate


A stirred solution of the 6-aminonaphthyridinone above (0.1 mmol), sodium sulfate (1.0 mmol), 2-indanone (0.15 mmol) and AcOH (7.5 ml) in dichloroethane (30 ml) under a nitrogen atmosphere was allowed to mature for 15 mins at room temperature. Sodium triacetoxyborohydride (0.15 mmol) was then added in one portion and the solution was allowed to stir for 4 h at rt (the reaction was monitored by TLC). A second addition of sodium sulfate (1.0 mmol), 2-indanone (0.15 mmol) and sodium triacetoxyborohydride

(0.15 mmol) and stirring overnight was required to drive the reaction to completion. The reaction mixture was quenched with 10% sodium hydrogen carbonate solution and dichloromethane added to dilute the solution. The organic layer was separated from the aqueous layer and the organic layer dried (MgS04). The organic layer was concentrated in vacuo and the resulting residue patiented to silica column chromatography, gradient eluting with 100 % dichloromethane and then 1 % MeOH/dichloromethane to give an oily residue. The residue was triturated using diethyl ether and the solid was filtered off at the pump to afford a pale yellow solid (78 %).

ESIMS: M+l: 378.

1H NMR (300 MHz, CDCI3) 5 8.64 (1H, s, H-2), 8.30 (1H, d,H-5), 7.55 (1H, d, H-7), 7.23-7.10 (4H, m, 4xArH), 6.69 (1H, d, NH), 4.41 (2H, q,OCH2), 4.38-4.23 (1H, m, NCH), 4.17 (2H, q, NCH2), 3.32 (2H, dd, CHCHri. 2.81 (2H, dd, CHCH2), 1.32 (3H, t, QCH9CH3)· 1.25 (3H, t, NCH2CH3).

Example lh) Morpholino 6-(2,3-dihydro-lH-inden-2ylamino)-l-ethyl-l,4-dihydro-4-oxo-1, 8-naphthyridine-3-carboxamide


Example 1

Trimethylaluminium (0.8 mmol, 2M in toluene) was added dropwise to a stirred solution of morpholine (0.8 mmol) in dichloromethane (5 ml). The mixture was stirred for 15 mins and then the naphthyridine (0.4 mmol) in dichloromethane (5 ml) was added. The mixture was then stirred for 20 h at 35°C. The mixture was cooled and then quenched by adding 2 N hydrochloric acid (10 ml) dropwise. The organic layer was then separated, dried (MgS04) and concentrated in vacuo. The resulting residue was triturated with diethyl ether to give a white solid (78%).

ESIMS: M+l: 419.

1H NMR (300 MHz, CDCI3) d 8.16(1H, d, ArH), 8.04 (1H, s, ArH), 7.76 (d, 1H, ArH), 7.24 - 7.12 (m, 4H, ArH), 4.47 - 4.33 (4H, m-complex, NH-CH + CTECHA. 3.75 (s, 6H, morpholino), 3.42 - 3.35 (m-complex, 4H, morpholino + CHCHA, 2.87 (dd, 2H, CHCHA, 1.43 (t, 3H, CH3).

Biological data

A) Example 1 reduces painc symptoms in humans

In humans, Example 1 significantly reduced the number and intensity of panic symptoms experienced during a CCK-4 induced panic attack. The 18-item Panic Symptoms Scale (PSS) was used to evaluate the effect of Example 1 (2000 mg) versus placebo treatment. Data shown was measured at 10 minutes post CCK-4 injection (Mean ± SEM; n=l5 healthy volunteers who panicked). This is shown in Figure 1.

B) Example 1 reduces threat avoidance behaiviour in humans

In humans, Example 1 significantly reduced the intensity of Defensive Behavior in the Joystick Operated Runway Task (JORT). During fMRI, patients“played a game” to evaluate drug effects on the intensity of avoidance behavior to a threat stimulus (mild electric shock). Patients used a joystick to prevent the green dot being caught by the red dot. In half of the trials, a lightning symbol appeared on the screen to indicate that a mild shock would be delivered if the dots made contact. Compared to placebo treated patients, Example 1 (300 and 2000 mg; p.o.) significantly decreased the intensity of threat avoidance behavior (Mean ± SEM; n = 21). This is shown in Figure 2.

C) In humans. Example 1 does not produce feelings associated with drugs of abuse

The Addiction Research Centre Inventory (ARCI49) is a 49-item standardized questionnaire for assessing the subjective effects of psychoactive drugs to indicate their potential for abuse liability.

Single doses of Example 1 (300 and 2000 mg) and Lorazepam (2 mg) were evaluated with

placebo in a 4-way crossover study in humans. Example 1 did not affect any of the ARCI subgroups, indicating that it did not have abuse potential, whereas subjects treated with Lorazepam reported significant feelings associated with the Benzedrine, LSD and Pentobarbital/ Chlorpromazine/Alcohol groups (sedation, dysphoria and psychotomimetic changes) as expected. (n=59 subjects, ns=not significant).

Subsequently, in a repeat dosing study with Example 1, no effects were seen on any of the ARCI subgroups, indicating that Example 1 did not have abuse potential following repeat dosing.

D) Example 1 is not sedating in humans.

This has been evaluated on several parameters (saccadic eye movement, quantitative EEG, the Karolinska Sleepiness Scale) in a 4-way crossover study in human subjects with Example 1 at 300 mg, Example 1 at 2000 mg, Lorazepam at 2 mg and placebo control. Evaluations were performed at 3.5h, 6h, 9h and l2h post dosing (n=24).