WO2009079763A1

WO2009079763A1 - Fluorinated aryl amide compounds

Info

Publication number: WO2009079763A1
Application number: PCT/CA2008/002215
Authority: WO
Inventors: Abdelmalik Slassi; Methvin Isaac; Tao Xin; Guy Higgins
Original assignee: Cascade Therapeutics Inc.
Priority date: 2007-12-21
Filing date: 2008-12-17
Publication date: 2009-07-02

Abstract

A compound of Formula I : The compound can be used in the treatment of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia and other related CNS disorders.

Description

Fluorinated Aryl Amide Compounds

Field of the Invention

The present invention relates to fluorinated aryl amide derivatives, to processes for making the same, to a pharmaceutical composition containing the derivative, and use thereof in the treatment of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia anxiety and other related CNS disorders.

Background of the Invention

Epilepsy, a common neurological disorder characterized by recurrent spontaneous seizures, is considered to be a major health problem that affects approximately one to two percent of the population worldwide (Brown et. al. N.. Engl. J. Med., 2001, 344:1145-1151 ). Epilepsy also poses a considerable economic burden on society. The direct costs of epilepsy vary significantly depending on the severity of the disease and the response to treatment. Despite the considerable progress in our understanding of the pathophysiology and pharmacotherapy of seizures and epilepsy (McNamara Nature, 1999, 399:A15-A22), the cellular basis of human epilepsy remains an enigma. In the absence of etiological understanding, approaches to pharmacotherapy must be directed to the control of symptoms, that is the suppression of seizures. More concerning is that current antiepileptic drugs do not halt the underlying natural progression of the disorder.

Over the years, there has been considerable success in the development of novel antiepileptic drugs (AED) along with new improved formulations. These include older 'first generation' drugs such as carbamazepine, phenobarbital, valproic acid and newer, 'second generation' drugs such as lamotrigine, vigabatrin, tiagabine, topiramate, gabapentin and levetiracetam (Brazil and Pedly, Ann. Rev. Med., 1998, 49:135-162; McCabe, Expert Opinion. Pharmacother, 2000, 1 :633-674). The selection of an antiepileptic drug for treatment is predicated on its efficacy for the specific type of seizures, tolerability and safety (Regesta and Tanganelli, Epilepsy Res., 1999, 34:109- 122; Kwan and Brodie, N. Engl. J. Med., 2000, 342:314-319).

Epileptic seizures can be either generalized (generalized epileptic seizure), originating in both hemispheres of the brain simultaneously, or partial (focal seizures) originating in one or more parts of one or both hemispheres, most commonly the temporal lobe. With generalized seizures, consciousness is always impaired or lost. Consciousness may be maintained in partial seizures but partial seizures may become generalized seizures in a process referred to as secondary generalization, at which point consciousness is lost. In patients the type of epilepsy or epileptic syndrome are further classified according to features such as the type of seizure, etiology, age of onset and electroencephalogram. Epilepsy or epileptic syndromes can be either idiopathic (etiology or cause is unknown) with a presumed genetic basis or symptomatic (acquired). The known potential causes of epilepsy include brain tumors, infections, traumatic head injuries, perinatal insults, developmental malformations, cerebrovascular diseases, febrile seizures and status epilepticus (Loscher, Trends Pharmacol. ScI, 2002, 23:113-118).

Traditionally, pharmacological strategies for treatment of epilepsy are aimed at suppressing either the initiation or the propagation of seizures rather than the underlying processes that lead to epilepsy. Some epileptic patients are unresponsive to current antiepileptic drug treatment and for this reason the major goal in epilepsy research has been to develop drugs with greater anticonvulsant efficacy and less toxicity than existing drugs (Bauer and Reuber, Expert Opinion. Emerging Drugs, 2003, 8:457-467).

The compounds of this invention were strategically designed with the objective of identifying a broad spectrum antiepileptic drug (AED) with a favorable safety and tolerability profile. A broad spectrum profile could distinguish these compounds not only from other first-generation AED such as phenytoin (PHT) and carbamazepine (CBZ) but also from many of the second-generation compounds such as pregabalin and levetiracetam. In preclinical studies, compounds that demonstrate broad anticonvulsant activity in acute rodent seizure models of electroshock and chemical origin (e.g. MES and PTZ) may show efficacy in suppressing spike and wave discharges in the GAERS (Genetic Absence Epilepsy Rat from Strasbourg) model of generalized absence epilepsy.

A number of clinical anticonvulsants including phenytoin, carbamazepine, lamotrigine, gabapentin and pregabalin are widely utilized in the management of neuropathic pain (Collins et al. Expert Opinion Emerging Drugs, 2005, 10:95-108). Neuropathic pain results from a cascade of neurobiological events, which tend to induce electrical hyperexcitability within somatosensory conduction pathway. Since electrical hyperexcitability is also the hallmark of epileptic seizure activity, it is not surprising that anticonvulsants are among the first agents adopted in the treatment of neuropathic pain and remain the first option in clinical use.

In recent years pain management has become an area of increasing focus in the medical profession, partly due to the growing elderly population, issues surrounding quality of life and the growing numbers of patients reportedly suffering from pain. Pain is both a sensory and emotional experience, and is generally associated with tissue damage or inflammation. Typically, pain is divided into two general categories - acute pain and chronic pain. Both differ in their etiology, pathophysiology, diagnosis, and most importantly treatment.

Acute pain is short term, and is typically of readily identifiable cause. Patients suffering from acute pain typically respond well to medications. In contrast, chronic pain - medically defined as pain that lasts for 3-6 months or longer, is often not associated with an obvious injury; indeed, patients can suffer from protracted pain that persists for months or years after the initial insult. Whilst acute pain is generally favorably treated with medications, chronic pain is often much more difficult to treat, generally requiring expert care. According to the American Chronic Pain Association, over 86 million Americans suffer from chronic pain, and the management of chronic pain has long been recognized as an unmet clinical need. Most chronic pain is neuropathic in nature (also referred to as neuralgia). Neuropathic pain can, for instance, manifest itself as burning, stabbing, and shock-like sensations.

Unfortunately, neuropathic pain management is at best inconsistent, and often ineffective. This is in part due to the subjective nature of the pain, but also due to poor diagnosis, especially when the chronic pain is not clearly associated with a nerve injury or other insult. Moreover, few, if any, ethical drugs have been prospectively developed for the treatment of chronic pain. Instead, the current medications used to treat chronic pain are "borrowed" from other diseases, most commonly antiepileptic drugs and antidepressants.

Current first-line treatments for chronic pain include opioids, analgesics such as gabapentin, and tricyclic antidepressants. When opioids are administered over prolonged periods, undesirable side effects such as drug tolerance, chemical dependency and even physiological addiction can occur. Of treatment remedies currently available for chronic pain, at best approximately 30% are effective in significantly diminishing the pain, and even these may lose their efficiency over time. Although numerous pharmacological agents are available for the treatment of neuropathic pain, a definitive therapy has remained elusive.

In instances in which treatment with a single agent proves to be unsuccessful, combination therapy is often then explored as a second line treatment. For example, such combination therapy may employ administration of an opioid agent with an adjuvant analgesic, although the relative doses of each are often subject to prolonged trial and error periods. Often, triple drug therapy is necessary. Such therapy generally involves a combination of tricyclic antidepressants, anticonvulsants and a systemic local anesthetic. Patient compliance drops significantly, however, when treatment requires the administration of multiple pharmacologic agents. Recently, researchers reported the use of a combination of morphine and gabapentin in a randomized study for controlling nerve pain (Gilron, et al., N. Eng. J. Med., 2005, 352:1281-82).

It is not only important to consider overall pain relief, but also the type of pain relief. For example, chronic pain is typically viewed as allodynia or hyperalgesia. Allodynia is pain sensation from a stimulus which is not normally painful. This allodynia is typically caused by a physical stimulus and is thus referred to as tactile or mechanical allodynia. Hyperalgesia is an exaggerated sensation form a stimulus which is normally painful. The hyperalgesia can occur from a variety of stimuli but, commonly, a patient's reaction to hot or cold stimuli is reported. Importantly, physicians often report that the current drugs are most effective at relieving hyperalgesia, although most patients present allodynia, particularly mechanical allodynia.

In addition to poor and/or inconsistent efficacy, these medications have several other undesirable properties such as adverse events, duration of action, and complicated dosing and titration regimens.

The most common side-effect of the non-opiate drugs is sedation or somnolence. Based upon data from the package inserts for these drugs, as many as 20-30% of patients experience sedation. As mentioned above, the population greatest at risk for chronic pain is the elderly. For the elderly, experiencing significant and persistent sedation poses other risks, mainly locomotor function impairment. Such impairment in motor function can lead to falls and the inability to perform many daily functions such as driving.

The duration of action is also a limitation for the most of the leading therapies. This is particularly important as pain, and especially nighttime pain, can lead to depression, insomnia and other factors which impact the patients' overall quality of life. A recent study suggests that patients with chronic pain and concurrent major depression and insomnia report the highest levels of pain- related impairment. This study also found that insomnia in the absence of major depression is also associated with increased pain and distress. (Wilson et al., Clin. J. Pain 2002, 18:77-83) Therefore, achieving pain relief with sufficient duration to achieve relief through the night is an important factor for neuropathic pain drugs. Pain-relief drugs such as gabapentin are taken once or more during the night to achieve pain relief, thus disturbing sleep and exacerbating the patient's overall quality of life.

Neuropathic pain (NP) is generally thought of a maladaptive chronic condition in which pain originates from damaged nerves, often yielding pain that is out of proportion to the extent of any injury. Damage can occur from a physical injury such as trauma or from chemical injury such as chemotherapeutics (e.g. paclitaxel). Neuropathic pain of this type is an important component of a number of syndromes of varying etiologies whose common characteristic is the development of a prolonged and profound pain state. Among these conditions are spinal cord injury, post-herpetic neuralgia, diabetic neuropathy, phantom limb pain, stump/neuroma pain, post-ischemic pain (stroke), fibromyalgia, complex regional pain syndrome (CRPS), chemotherapy- induced neuropathic pain, vertebral disk rapture, trigeminal neuralgia and others.

Recently, however, it has been recognized that neuropathic pain can also manifest itself in the absence of an identifiable nerve injury. These indications include AIDS and mirror image pain. The lack of any nerve injury but unmistakable chronic pain has led to increased interest in the role of glial cells in the maintenance of the neuropathic pain state (Watkins and Maier, Drug

Disc. Today: Ther. Strategies 2004, 1 :83-88; Watkins and Maier, Nat. Rev. Drug Discovery 2003, 2:973-985). More specifically, recent research has demonstrated that glial cells enhance the release of neurotransmitters which relay pain information to the spinal cord and, even more strikingly, release substances which increase the excitability of pain-responsive neurons in the spinal cord. These substances, called pro-inflammatory cytokines, create and maintain exaggerated or pathological pain responses (Wieseler-Frank et al., Neurosignals 2005, 14:166-174). Blocking the activation of glial cells reduces pro-inflammatory cytokines and reverses pathological pain. To date, no therapeutics have been approved which have a putative glial cell-attenuation mechanism for the treatment of neuropathic pain. Molecules which are glial cell-attenuators may play an important role in the treatment of neuropathic pain.

In light of the above shortcomings in current approaches for treating chronic pain there exists a need for improved compositions and methods for treating pain, particularly neuropathic pain and its associated symptoms and, more specifically, neuropathic pain associated with certain conditions such as fibromyalgia, among others. Such approaches should ideally overcome one or more of the problems associated with existing methods for treating chronic pain. The present invention meets these needs.

At present no analgesic exists which is highly potent in various pain syndromes. Different mechanisms leading to inflammatory or neuropathic pain make it difficult to identify compounds which have general analgesic activity. We are only at the beginning of understanding the mechanisms behind different pain syndromes like cancer pain (e.g. tumor-induced bone cancer pain), chemotherapy-induced pain or nucleoside-induced pain, all of which seem to have various molecular origins. Antidepressants, anticonvulsants or opioids, which describe groups of compounds used in pain treatment, do not have a common pattern regarding their efficacy in treatment of pain syndromes. This makes it difficult to predict the activity of new compounds in the various pain syndromes and demands a detailed characterization in multiple models of pain in animals.

Neuropathic pain after injury or dysfunction to the peripheral or central nervous system remains a difficult clinical problem for which effective treatments are lacking (Bennett, Ann. Neurol. 1994, 35:S38-S41 ). Anticonvulsants are used for the management of some forms or neuropathic pain (Sindrup and Jenssen, Pain 1999, 389-400; Jensen, Eur. J. Pain 2002, 6: 61-68).

Migraine is a disease condition characterized by episodes of head pain that is often throbbing and frequently unilateral, and can be severe. In migraine without aura, attacks are usually associated with nausea, vomiting or sensitivity to light, sound or movement. In some patients, migraine attacks are usually preceded or accompanied by transient focal neurological symptoms, which are usually visual; such patients are described as having migraine with aura.

Both migraine and epilepsy are usually included in the spectrum of neurological chronic disorders with episodic manifestations that are known to be characterized by recurrent attacks of nervous system dysfunction with a return to baseline between attacks.

The hypothesis of a possible clinical continuum between migraine and epileptic syndromes as entities resulting from altered neuronal excitability with a similar genetic basis has been postulated (Haut et al. Lancet Neurol 2006, 5:148-157). Epilepsy is a comorbid condition of migraine; it occurs more commonly in patients with migraine than in the general population, and the prevalence of migraine in epileptic patients is higher than in controls.

Some antiepileptic drugs (AEDs) are effective in the prevention of migraine (Rogawski et al Nat. Med. 2004, 10:685-692; Silbestein, S. D., Trends Pharmacol. Sci. 2006, 27:410-415). A rationale for this use is the hypothesis that migraine and epilepsy share several pathogenetic mechanisms. Studies, showing the efficacy of some AEDs in migraine prophylaxis, have been recently described (Calabresi et al. Trends Pharmacol. Sci. 2007, 28:188- 195). Moreover, kindling, a pathological plastic change lowering the threshold for subsequent attacks, which occurs in experimental epilepsy, has some similarities with the process of sensitization postulated in pain, in addition to migraine (Post et al., Epilepsy Res. 2002, 50: 203-219; Calabresi et al. Trends Pharmacol. Sci. 2005, 26:62-68). These plastic changes require the long-term modulation of gene expression both in epilepsy and in migraine. Cortical spreading depression (CSD), a spreading neurological depolarization wave, is thought to be implicated in the neurological symptoms in migraine with aura, in addition to the pathophysiology of epilepsy (James et al. Trends Neuroscience. 2001 , 24:62-68; Somjen, Physiol. Rev. 2001 , 81 : 1065-1096)

Interestingly, there is also strong evidence that CSD serves as an initiating event for migraine visual aura and pain (Moskowitz et al. Nat. Med. 2002, 8:136-142). CSD is a transient suppression of cortical activity, which starts locally and spreads throughout the tissue. CSD usually leads to trigeminal activation and, putatively, to the release of CGRP. AEDs have been shown to suppress CSD and to reduce CSD-induced release of CGRP and is therefore of potential importance in the clinical treatment of acute migraine, the prophylactic treatment of migraine and for the treatment of other forms of chronic headache and/or CSD-associated disorder (Ayata et al. Ann. Neurol. 2006, 59:652-661 ; Akerman et al. Neuroreport 2005, 16:1383-1387).

Anxiety is broadly defined as a state of unwarranted or inappropriate worry often accompanied by restlessness, tension, distraction, irritability and sleep disturbances. This disproportionate response to environmental stimuli can hyperactivate the hypothalamic-pituitary-adrenal axis and the autonomic nervous system, resulting in somatic manifestation of anxiety, including shortness of breath, sweating, nausea, rapid heartbeat and elevated blood pressure (Sanford et al. Pharmacol. Ther. 2000, 88:197-212). Anxiety disorders represent a range of conditions and as a result have been classified into multiple distinct conditions, including generalized anxiety disorder (GAD), panic attack, post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and social phobias (Sanford et al. Acta. Psychiatr. Scand. Suppl. 1998, 393:74-80).

Generalized anxiety disorder (GAD) is the most common of the anxiety disorders that is characterized by excessive and persistent worries. In the general population the lifetime prevalence rate of GAD range from 4.1 to 6.6 % with somewhat higher rates in woman than in man. The individual with GAD worries about life events such as marital relationship, job performance, health, money and social status. Individuals with GAD startle easily and may suffer from depression. Some of the specific symptoms of GAD include restlessness, motor tension, difficulty concentrating, irritability, and sleep disturbances and the severity of the symptoms over time and may be linked to the changing nature of the environmental stressor. With age, GAD symptoms become less severe.

Panic Disorder is a well-studied psychiatric condition that consists of multiple disabling panic attacks characterized by and intense autonomic arousal. In addition, heightened fear and anxiety states occur both during and between panic attacks. Approximately 3% of woman and 1.5% of men have panic attacks. During a panic attack, the individual experiences multiple symptoms including light-headedness, a pounding heart and difficulty in breathing. Panic disorder may be caused by an oversensitive brain system regulating autonomic functions. Potential brain regions involved in panic attack are the locus ceruleus, hippocampus and amygdala. Pathophysiology in the brain GABA-benzodiazepine receptor system may also contribute to the production of panic attack.

Post traumatic stress disorder (PTSD) is another example of a disorder associated with intense fear and anxiety states that require psychiatric treatment. PTSD results from exposure to a life threatening or traumatic event. Individuals with PTSD have recurring thoughts of the terrifying event. Reenactment of the event varies in duration from a few seconds or hours to several days. Individuals with major depression, with panic disorders or lacking strong social supports are vulnerable to develop PTSD

Anxiety disorders, which occur in 10% to 30% of the population, represent not only a significant public health issue but place a substantial economic burden on society. A number of drugs have either been developed or are being developed for treating the different subclasses of anxiety. Some of these agents such as tricyclic antidepressants and β-adrenoreceptor antagonists found either limited use in treating specific disorders such as performance anxiety (e.g. β-adrenoreceptor antagonists suppression of the sympathetic manifestations of anxiety) or have fallen out of favor for reasons of efficacy and/or safety. Currently, direct and indirect serotonin receptor agonists (e.g. selective serotonin reuptake inhibitors (SSRI) and buspirone) and benzodiazepines are most often prescribed for treating anxiety disorders with benzodiazepine receptor agonist being a preferred therapeutic modality (Atack et al. Curr. Drug Targets CNS Neurol. Disord. 2003, 2:213-232; Stahl et al. J. CHn. Psychiatry 2002, 63:756-757 ; Uhlenhuth et al. J. CHn. Psychopharmacol. 1999, 19:23S-24S; Varia et al. Int. CHn. Psychopharmacol. 2002, 17:103-107; Vaswani et al. Prog. Neuropsychopharmacol. Biol. Psychiatry 2003, 27:85-102). The ability of benzodiazepines to enhance g- aminobutyric acid (GABA) neurotransmission safely and rapidly is central to their effectiveness in treating anxiety disorder especially GAD and panic disorders (Stahl et al. J. CHn. Psychiatry 2002, 63: 756-757). Benzodiazepines act by positively modulating the inhibitory neurotransmitter GABA through an allosteric site on the GABA A receptor complex, a ligand-gated chloride ion channel. Nonetheless, the use of benzodiazepines is limited by side effects associated with enhanced GABAnergic neurotransmission, manifesting as sedation, muscle relaxation, amnesia and ataxia. Moreover, the potential for abuse and physical dependence is associated with the long-term use of benzodiazepines. Furthermore, some forms of anxiety such as OCD are relatively resistant to benzodiazepine treatment. These therapeutic limitations and the societal burdens of anxiety provide the impetus for the development of novel anxiolytics or anxioselective agents.

The concept of anxioselectivity is used to describe anxiolysis in the absence of side effects typically associated with benzodiazepines. This search for alternative strategies to treat anxiety disorders have led to the growing use of

SSRIs, in addition to a number of other molecular targets including metabotropic glutamate receptors (mGluRs) that are currently under evaluation (Schoepp et al., Nat. Rev. Drug Dis. 2005, 4(2):131-144). However, none of the alternative targets has been shown to match either the efficacy or rapid onset of benzodiazepine.

Summary of the Invention

The present invention relates to fluorinated aryl amides and there use in the treatment of epilepsy, neuropathic and inflammatory pain and anxiety disorders (e.g. generalized anxiety disorder (GAD), panic attack, post traumatic stress disorder (PTSD), obsessive compulsive disorder (OCD) and social phobias).

In one aspect, there is provided a compound of Formula I:

Formula I

wherein:

Ri and R₂ are each independently selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteoaryl;

R₃ and R₄ are each independently selected from the group consisting of H, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteoaryl;

or R₃ and R₄ connect to form a three to seven-membered ring; and

R₅ and R₆ are each independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteoaryl or R₅ and R₆ connect to form a three to seven- membered ring; and/or

A pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.

In another aspect, the alkyl group is CrC₆. In a further aspect, Ri and R₂ are optionally substituted with one or more independently-selected groups R₈. Rs is selected from the group consisting of OH, CN, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl C(O)R₉, C(O)OR₉, SO₂R₉ and C(O)NR₉Rio; Rg and R₁₀ are independently selected from the group consisting of H, alkyl and cycloalkyl. In yet a further aspect, R₃ and R₄ are independently selected from the group consisting of H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

In a specific aspect, R₁ is alkyl; R₂ is a substituted aryl; R₃ to R₆ are H. In a more specific aspect, R₂ is substituted with one or more independently- selected groups Rs, wherein R₈ is selected from halo and haloalkyl.

In another aspect, there is provided use of the compound of Formula I in the treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders.

In another aspect, there is provided a pharmaceutical composition comprising a compound of Formula I and at least one pharmaceutically acceptable carrier and/or excipient. In a further aspect, the carrier is a pharmaceutically- acceptable carrier.

In another aspect, there is provided a pharmaceutical composition comprising therapeutically effective amount of a compound of Formula I to treat medical conditions such as epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders; such compositions can comprise a compound of Formula I in association with one or more pharmaceutically acceptable diluents, excipients and/or inert carriers.

In another aspect, there is provided a method for treating at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound or composition noted above. In a further aspect, the mammal is a human. In still a further aspect, the compound or composition is administered orally and/or parenterally. In yet another aspect, the compound or composition is administered intravenously and/or intraperitoneal^.

In yet a further aspect, there is provided the use of the compound or composition noted above for manufacture of a medicament for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders. In yet a further aspect, there is provided the use of the compound or composition noted above for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal. In a further aspect, the mammal is a human. In still a further aspect, the compound or composition is administrable orally and/or parenterally. In yet another aspect, the compound or composition is administrable intravenously and/or intraperitoneal^.

The novel features of the present invention will become apparent to those of skill in the art upon examination of the following detailed description of the invention. It should be understood, however, that the detailed description of the invention and the specific examples presented, while indicating certain embodiments of the present invention, are provided for illustration purposes only because various changes and modifications within the spirit and scope of the invention will become apparent to those of skill in the art from the detailed description of the invention and claims that follow.

Definitions

Unless specified otherwise within this specification, the nomenclature used in this specification generally follows the examples and rules stated in

Nomenclature of Organic Chemistry, Sections A, B, C, D, E, F, and H,

Pergamon Press, Oxford, 1979, which is incorporated by references herein for its exemplary chemical structure names and rules on naming chemical structures. Optionally, a name of a compound may be generated using a chemical naming program: ACD/ChemSketch, Version 5.09/September 2001 ,

Advanced Chemistry Development, Inc., Toronto, Canada.

The compounds of the present invention may have asymmetric centers, chiral axes, and chiral planes (e.g., as described in: E. L. Eliel and S. H. Wilen, Stereo-chemistry of Carbon Compounds, John Wiley & Sons, New York, 1994, pages 1119-1190), and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers and mixtures thereof, including optical isomers, being included in the present invention.

Generally, reference to a certain element such as hydrogen or H is meant to, if appropriate, include all isotopes of that element. The following terms are meant to encompass unsubstituted and/or substituted.

The term "alkyl" as used herein means a straight- or branched-chain hydrocarbon radical; in one aspect, having from one to eight carbon atoms, and includes, for example, and without being limited thereto, methyl, ethyl, propyl, isopropyl, t-butyl and the like. As noted above, "alkyl" encompasses substituted alkyl. Substituted alkyl includes, for example, and without being limited thereto, haloalkyl, hydroxyalkyl, cyanoalkyl, and the like. This is applied to any of the groups mentioned herein. Groups such as "alkenyl", "alkynyl", "aryl", etc. encompass substituted "alkenyl", "alkynyl", "aryl", etc.

The term "alkenyl" as used herein means a straight- or branched-chain alkenyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, ethenyl, 1-propenyl, 1-butenyl and the like. The term "alkenyl" encompass radicals having "cis" and "trans" orientations, or alternatively,"E" and "Z" orientations.

The term "alkynyl" as used herein means a straight- or branched-chain alkynyl radical; in one aspect, having from two to eight carbon atoms, and includes, for example, and without being limited thereto, 1-propynyl (propargyl), 1- butynyl and the like.

The term "cycloalkyl" as used herein means a carbocyclic system (which may be unsaturated) containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have from three to seven carbon atoms, and includes, for example, and without being limited thereto, cyclopropyl, cyclohexyl, cyclohexenyl and the like.

The term "heterocycloalkyl" as used herein means a heterocyclic system (which may be unsaturated) having at least one heteroatom selected from N, S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In one aspect, the ring(s) may have a three- to seven-membered cyclic group and includes, for example, and without being limited thereto, piperidinyl, piperazinyl, pyrrolidinyl, tetrahydrofuranyl and the like.

The term "alkoxy" as used herein means a straight- or branched-chain alkoxy radical; in one aspect, having from one to eight carbon atoms and includes, for example, and without being limited thereto, methoxy, ethoxy, propyloxy, isopropyloxy, f-butoxy and the like.

The term "halo" as used herein means halogen and includes, for example, and without being limited thereto, fluoro, chloro, bromo, iodo and the like, in both radioactive and non-radioactive forms.

The term "alkylene" as used herein means a difunctional branched or unbranched saturated hydrocarbon radical; in one aspect, having one to eight carbon atoms, and includes, for example, and without being limited thereto, methylene, ethylene, n-propylene, n-butylene and the like.

The term "alkenylene" as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one double bond, and includes, for example, and without being limited thereto, ethenylene, n-propenylene, n-butenylene and the like.

The term "alkynylene" as used herein means a difunctional branched or unbranched hydrocarbon radical; in one aspect, having two to eight carbon atoms, and having at least one triple bond, and includes, for example, and without being limited thereto, ethynylene, n-propynylene, n-butynylene and the like. The term "aryl" , alone or in combination, as used herein means a carbocyclic aromatic system containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In particular embodiments, aryl is one, two or three rings. In one aspect, the aryl has five to twelve ring atoms. The term "aryl" encompasses aromatic radicals such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. The "aryl" group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

The term "heteroaryl", alone or in combination, as used herein means an aromatic system having at least one heteroatom selected from N, S and/or O and containing one or more rings wherein such rings may be attached together in a pendent manner or may be fused. In particular embodiments, heteroaryl is one, two or three rings. In one aspect, the heteroaryl has five to twelve ring atoms. The term "heteroaryl" encompasses heteroaromatic radicals such as pyridyl, indolyl, furyl, benzofuryl, thienyl, benzothienyl, quinolyl, oxazolyl and the like. The "heteroaryl" group may have 1 to 4 substituents such as lower alkyl, hydroxyl, halo, haloalkyl, nitro, cyano, alkoxy, lower alkylamino and the like.

The term "three to seven-membered ring" encompasses saturated and unsaturated rings including, but not limited to, substituted or unsubstituted cycloalkyl, substituted or unsubstituted hetercycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteroaryl.

It is understood that substituents and substitution patterns on the compounds of the invention may be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art, as well as those methods set forth below. If a substituent is itself substituted with more than one group, it is understood that these multiple groups may be on the same carbon or on different carbons, as long as a stable structure results.

The term "pharmaceutically acceptable salt" means either an acid addition salt or a basic addition salt which is compatible with the treatment of patients.

A "pharmaceutically acceptable acid addition salt" is any non-toxic organic or inorganic acid addition salt of the base compounds represented by Formula I or any of its intermediates. Illustrative inorganic acids which form suitable salts include hydrochloric, hydrobromic, sulfuric and phosphoric acid and acid metal salts such as sodium monohydrogen orthophosphate and potassium hydrogen sulfate. Illustrative organic acids which form suitable salts include the mono-, di- and tricarboxylic acids. Illustrative of such acids are, for example, acetic, glycolic, lactic, pyruvic, malonic, succinic, glutaric, fumaric, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic, benzoic, hydroxybenzoic, phenylacetic, cinnamic, salicylic, 2-phenoxybenzoic, p- toluenesulfonic acid and other sulfonic acids such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Either the mono- or di-acid salts can be formed, and such salts can exist in either a hydrated, solvated or substantially anhydrous form. In general, the acid addition salts of these compounds are more soluble in water and various hydrophilic organic solvents, and generally demonstrate higher melting points in comparison to their free base forms. The selection criteria for the appropriate salt will be known to one skilled in the art. Other non-pharmaceutically acceptable salts e.g. oxalates may be used for example in the isolation of compounds of Formula I for laboratory use, or for subsequent conversion to a pharmaceutically acceptable acid addition salt.

A "pharmaceutically acceptable basic addition salt" is any non-toxic organic or inorganic base addition salt of the acid compounds represented by Formula I or any of its intermediates. Illustrative inorganic bases which form suitable salts include lithium, sodium, potassium, calcium, magnesium or barium hydroxides. Illustrative organic bases which form suitable salts include aliphatic, alicyclic or aromatic organic amines such as methylamine, trimethyl amine and picoline or ammonia. The selection of the appropriate salt may be important so that an ester functionality, if any, elsewhere in the molecule is not hydrolyzed. The selection criteria for the appropriate salt will be known to one skilled in the art.

"Solvate" means a compound of Formula I or the pharmaceutically acceptable salt of a compound of Formula I wherein molecules of a suitable solvent are incorporated in a crystal lattice. A suitable solvent is physiologically tolerable at the dosage administered as the solvate. Examples of suitable solvents are ethanol, water and the like. When water is the solvent, the molecule is referred to as a hydrate.

The term "stereoisomers" is a general term for all isomers of the individual molecules that differ only in the orientation of their atoms in space. It includes mirror image isomers (enantiomers), geometric (cis/trans) isomers and isomers of compounds with more than one chiral centre that are not mirror images of one another (diastereomers).

The term "treat" or "treating" means to alleviate symptoms, eliminate the causation of the symptoms either on a temporary or permanent basis, or to prevent or slow the appearance of symptoms of the named disorder or condition.

The term "therapeutically effective amount" means an amount of the compound of Formula I which is effective in treating the named disorder or condition.

The term "pharmaceutically acceptable carrier" means a non-toxic solvent, dispersant, excipient, adjuvant or other material which is mixed with the active ingredient in order to permit the formation of a pharmaceutical composition, i.e., a dosage form capable of administration to the patient. One example of such a carrier is a pharmaceutically acceptable oil typically used for parenteral administration. Detailed Description

One embodiment of the invention provides a compound of Formula I:

Formula I

wherein:

or R₃ and R₄ connect to form a three to seven-membered ring; and

R₅ and R₆ are each independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted haloalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, and substituted or unsubstituted heteoaryl or R₅ and Re connect to form a three to seven- membered ring; and/or

It will be understood by those of skill in the art that when compounds of the present invention contain one or more chiral centers, the compounds of the invention may exist in, and be isolated as, enantiomeric or diastereomeric forms, or as a racemic mixture. The present invention includes any possible enantiomers, diastereomers, racemates or mixtures thereof, of a compound of Formula I. The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate or chemical or enzymatic resolution methodology, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described thereafter.

It will also be understood by those of skill in the art that certain compounds of the present invention may exist in solvated, for example hydrated, as well as unsolvated forms. It will further be understood that the present invention encompasses all such solvated forms of the compounds of Formula I.

Within the scope of the invention are also salts of the compounds of Formula I. Generally, pharmaceutically acceptable salts of compounds of the present invention are obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, for example an alkyl amine with a suitable acid, for example, HCI or acetic acid, to afford a salt with a physiologically acceptable anion. It is also possible to make a corresponding alkali metal (such as sodium, potassium, or lithium) or an alkaline earth metal (such as a calcium) salt by treating a compound of the present invention having a suitably acidic proton, such as a carboxylic acid or a phenol, with one equivalent of an alkali metal or alkaline earth metal hydroxide or alkoxide (such as the ethoxide or methoxide), or a suitably basic organic amine (such as choline or meglumine) in an aqueous medium, followed by conventional purification techniques. Additionally, quaternary ammonium salts can be prepared by the addition of alkylating agents, for example, to neutral amines.

In one embodiment of the present invention, the compound of Formula I may be converted to a pharmaceutically acceptable salt or solvate thereof, particularly, an acid addition salt such as a hydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate, tartrate, citrate, methanesulphonate or p-toluenesulphonate.

In another embodiment of the compound of Formula I, the alkyl group is d- C₆. In a further embodiment, Ri and R₂ are optionally substituted with one or more independently-selected groups R₈. Re is selected from the group consisting of OH, CN, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl C(O)R₉, C(O)OR₉, SO₂Rg and C(O)NR₉R₁₀; R₉ and Ri₀ are independently selected from the group consisting of H, alkyl and cycloalkyl. In yet a further embodiment, R₃ and R₄ are independently selected from the group consisting of H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

In a specific embodiment of the compound of Formula I, Ri is alkyl; R₂ is a substituted aryl; R₃ to R₆ are H. In a more specific embodiment, R₂ is substituted with one or more independently-selected groups Rs, wherein Rs is selected from halo and haloalkyl.

Specific examples of the present invention include the following compounds, their pharmaceutically acceptable salts, hydrates, solvates, optical isomers, or combinations thereof:

3-[3,5-bis(trifluoromethyl) phenyl]-3-fluorobutanamide; 3-[3,5-bis(trifluoromethyl)phenyl]-3-fluoropentanamide; 3-(3'-chlorophenyl)-3-fluoropentanamide; 3-[3'-trifluoromethylphenyl]-3-fluorobutanamide; 3-[3'-fluoro,5'-(trifluoromethyl) phenyl]-3-fluorobutanamide; 3-[3'fluoro,5'-(trifluoromethyl)phenyl]-3-fluoropentanamide; 3-(3'-trifluoromethyl)phenyl-3-fluoropentanamide;

3-(3'chloro,5'-(trifluoromethyl)phenyl-3-fluorobutanamide; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.

For pharmaceutical use, the compounds of the invention are, for instance, administered orally, sublingually, rectally, nasally, vaginally, topically (including the use of a patch or other transdermal delivery device), by pulmonary route by use of an aerosol, or parenterally, including, for example, intramuscularly, subcutaneously, intraperitoneal^, intra-artehally, intravenously or intrathecally. Administration can be by means of a pump for periodic or continuous delivery. The compounds of the invention are administered alone, or are combined with a pharmaceutically-acceptable carrier or excipient according to standard pharmaceutical practice. For the oral mode of administration, the compounds of the invention are used in the form of tablets, capsules, lozenges, chewing gum, troches, powders, syrups, elixirs, aqueous solutions and suspensions, and the like. In the case of tablets, carriers that are used include lactose, sodium citrate and salts of phosphoric acid. Various disintegrants such as starch, and lubricating agents such as magnesium stearate and talc, are commonly used in tablets. For oral administration in capsule form, useful diluents are lactose and high molecular weight polyethylene glycols. If desired, certain sweetening and/or flavoring agents are added. For parenteral administration, sterile solutions of the compounds of the invention are usually prepared, and the pHs of the solutions are suitably adjusted and buffered. For intravenous use, the total concentration of solutes should be controlled to render the preparation isotonic. For ocular administration, ointments or droppable liquids may be delivered by ocular delivery systems known to the art such as applicators or eye droppers. Such compositions can include mucomimetics such as hyaluronic acid, chondroitin sulfate, hydroxypropyl methylcellulose or polyvinyl alcohol, preservatives such as sorbic acid, EDTA or benzylchromium chloride, and the usual quantities of diluents and/or carriers. For pulmonary administration, diluents and/or carriers will be selected to be appropriate to allow the formation of an aerosol.

Suppository forms of the compounds of the invention are useful for vaginal, urethral and rectal administrations. Such suppositories will generally be constructed of a mixture of substances that is solid at room temperature but melts at body temperature. The substances commonly used to create such vehicles include theobroma oil, glycerinated gelatin, hydrogenated vegetable oils, mixtures of polyethylene glycols of various molecular weight and fatty acid esters of polyethylene glycol. For example, see Remington's Pharmaceutical Sciences, 16th Ed. (Mack Publishing, Easton, PA, 1980, pp. 1530-1533) for further discussion of suppository dosage forms. Analogous gels or creams can be used for vaginal, urethral and rectal administrations.

Numerous administration vehicles will be apparent to those of ordinary skill in the art, including without limitation slow release formulations, liposomal formulations and polymeric matrices.

Examples of pharmaceutically acceptable acid addition salts for use in the present invention include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and arylsulphonic acids, for example. Examples of pharmaceutically acceptable base addition salts for use in the present invention include those derived from non-toxic metals such as sodium or potassium, ammonium salts and organoamino salts such as triethylamine salts. Numerous appropriate such salts will be known to those of ordinary skill. The physician or other health care professional can select the appropriate dose and treatment regimen based on the subject's weight, age, and physical condition. Dosages will generally be selected to maintain a serum level of compounds of the invention between about 0.01 μg/cc and about 1000 μg/cc, preferably between about 0.1 μg/cc and about 100 μg/cc. For parenteral administration, an alternative measure of preferred amount is from about 0.001 mg/kg to about 10 mg/kg (alternatively, from about 0.01 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg), will be administered. For oral administrations, an alternative measure of preferred administration amount is from about 0.001 mg/kg to about 10 mg/kg (from about 0.1 mg/kg to about 10 mg/kg), more preferably from about 0.01 mg/kg to about 1 mg/kg (from about 0.1 mg/kg to about 1 mg/kg). For administrations in suppository form, an alternative measure of preferred administration amount is from about 0.1 mg/kg to about 10 mg/kg, more preferably from about 0.1 mg/kg to about 1 mg/kg.

When introducing elements disclosed herein, the articles "a", "an", "the", and "said" are intended to mean that there are one or more of the elements. The terms "comprising", "having", "including" are intended to be open-ended and mean that there may be additional elements other than the listed elements.

The above disclosure generally describes the present invention. A more complete understanding can be obtained by reference to the following specific Examples. These Examples are described solely for purposes of illustration and are not intended to limit the scope of the invention. Changes in form and substitution of equivalents are contemplated as circumstances may suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation. Examples:

Specific examples of the present invention include Compounds 1 to 8 as illustrated in the following table, their pharmaceutically acceptable salts, hydrates, solvates, optical isomers, and combinations thereof:

Compound Structure Name

3-[3,5-bis(trifluoromethyl) phenyl]- 3-fluorobutanamide

3-[3,5-bis(thfluoromethyl) phenyl]- 3-fϊuoropentanamide

3-(3'-chlorophenyl)-3- fluoropentanamide

3-(3'-trifluoromethyl phenyl)-3- fluorobutanamide

3-[3'-fluoro,5'-(trifluoromethyl) phenyl]-3-fluorobutanamide

The introduction of the fluorine atom into these compounds brings about dramatic changes in the physical and chemical properties of the parent molecules, and sometimes results in the enhancement of pharmacokinetic properties and biological activities. The unique properties of the fluorine atom include its small size, low polarizability, high electronegativity and its ability to form strong bonds with carbon. Replacement of hydrogen atoms can sometimes result in improved thermal and metabolic stability. Improved metabolic stability is usually a desirable feature since the possibility exists that in vivo decomposition may produce toxic effects.

Methods of Preparation

Another aspect of the present invention provides processes for preparing compounds of formula I, or salts or hydrates thereof. Examples of processes for the preparation of the compounds in the present invention are described herein.

Throughout the following description of such processes it is to be understood that, where appropriate, suitable protecting groups will be added to, and subsequently removed from, the various reactants and intermediates in a manner that will be readily understood by one skilled in the art of organic synthesis. Conventional procedures for using such protecting groups as well as examples of suitable protecting groups are described, for example, in "Protective Groups in Organic Synthesis", T.W. Green, P. G. M. Wuts, Wiley- Interscience, New York, 1999. It is also to be understood that a transformation of a group or substituent into another group or substituent by chemical manipulation can be conducted on any intermediate or final product on the synthetic path toward the final products, in which the possible type of transformation is limited only by inherent incompatibility of other functionalities carried by the molecule at that stage to the conditions or reagents employed in the transformation. Such inherent incompatibilities, and ways to circumvent them by carrying out appropriate transformations and synthetic steps in a suitable order, will be readily understood to the one skilled in the art of organic synthesis. Examples of transformations are given below, and it is to be understood that the described transformations are not limited only to the generic groups or substituents for which the transformations are exemplified. References and descriptions on other suitable transformations are given in "Comprehensive Organic Transformations - A Guide to Functional Group Preparations" R. C. Larock, VHC Publishers, Inc. 1989. References and descriptions of other suitable reactions are described in textbooks of organic chemistry, for example, "Advanced Organic Chemistry", March, 4th ed. McGraw Hill, 1992 or, "Organic Synthesis", Smith, McGraw Hill, 1994. Techniques for purification of intermediates and final products include for example, straight and reversed phase chromatography on column or rotating plate, recrystallisation, distillation and liquid-liquid or solid-liquid extraction, which will be readily understood by the one skilled in the art. The definitions of substituents and groups are as in formula I except where defined differently. The term "room temperature" and "ambient temperature" shall mean, unless otherwise specified, a temperature between 16 and 25 ⁰C.

Abbreviations

atm Atmosphere aq. Aqueous

BINAP 2,2'-bis(diphenylphosphino)-1 ,1 '-binaphthyl

Boc terf-butoxycarbonyl

CDI N,N'-Carbonyldiimidazole

DCC N.N-Dicyclohexylcarbodiimide

DCM Dichloromethane

DBU Diaza(1 ,3)bicyclo[5.4.0]undecane

DEA N,N-Diisopropyl ethylamine

DIBAL-H Diisobutylaluminium hydride

DIC N.N'-Diisopropylcarbodiimide

DMAP N,N-Dimethyl-4-aminopyhdine

DMF Dimethylformamide

DMSO Dimethylsulfoxide

DPPF Diphenylphosphinoferrocene

EA Ethyl acetate

EDCI N-[3-(dimethylamino)propyl]-N'-ethylcarbodiimide hydrochloride

EDC 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide

Et₂O Diethyl ether

EtOAc Ethyl acetate

EtOH Ethanol

EtI lodoethane

Et Ethyl

Fmoc 9-fluorenylmethyloxycarbonyl h hour(s)

HetAr Heteroaryl HOBt N-Hydroxybenzotriazole

HBTU O-(Benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate

HPLC High performance liquid chromatography

LAH Lithium aluminium hydride

LCMS HPLC mass spec

MCPBA m-Chloroperbenzoic acid

MeCN Acetonitrile

MeOH Methanol min Minutes

MeI lodomethane

MeMgCI Methyl magnesium chloride

Me Methyl n-BuLi 1 -Butyllithium

NaOAc Sodium acetate

NMR Nuclear magnetic resonance

NMP N-Methyl pyrrolidinone nBuLi 1 -Butyl lithium o.n. Over night

RT Room temperature

TEA Triethylamine

THF Tetrahydrofuran nBu normal Butyl

OMs Mesylate or methane sulfonate ester

OTs Tosylate, toluene sulfonate or 4-methylbenzene sulfonate ester

PCC Pyridinium chlorochromate

PPTS Pyridinium p-toluenesulfonate

TBAF Tetrabutylammonium fluoride pTsOH p-Toluenesulfonic acid

SPE Solid phase extraction (usually containing silica gel for mini chromatography) sat. Saturated Preparation of Compounds

B Formula I Scheme 1

Compounds of Formula I may be prepared according Schemel described above (See Morwick, T., Tetrahedron Letters, 1980, Vol. 21 , p. 3227-3230) by the reaction of the appropriately substituted ketones with the corresponding organometallic such as the lithio anion of mask acetamide reagent N₁O- bis(trimethylsilyl)acetamide A. The resulting alcohol intermediate B is subjected to fluorination conditions (e.g. DAST fluoride to provide the compounds of Formula I. In the event that the eliminated by-products E and F are obtained in addition to the desired product D from the hydroxy-amide as represented by structure C as shown in Scheme 2 (R2 in this case is CH2-A where A can be any alkyl, haloalkyl, alkyloxy containing group etc.), the double-bond or alkene by product can be further transformed into the desired compound by an anti-Markovnikov type addition of HF (eg include addition of F and Br via HF and NBS followed by reduction, see Wagner et al, J. Am. Chem. Soc 108 (34), p. 7739-7744, 1986) .

Scheme 2 Alternatively, compounds of Formula 1 wherein R3 and R4 are hydrogen (K) may be prepared from terminal alkenes H (alkenes are either commercial or readily available from the ketone G) by well established procedures. The terminal alkene can be reacted with N-bromosuccinimide as a source of electrophilic bromide and thethylamine tris(hydrofluoride) or trimethylamine bis (hydrofluohde) as very mild nucleophilic fluorinating agents to give the bromo fluoro adduct I (J. Prak. Chem. 342, p. 52-57, 2000; Org. Syn. Coll. VoU 0 p. 128, 2004; Org. Syn. Coll. Vol.76), p. 159, 1999; Liebigs. Ann. p. 1289-1294, 1996. Nucleophilic displacement of the bromide with cyano nucleophiles (such as KCN of NaCN) provides the nitrile J. Subsequent hydrolysis of the nitrile under basic or acidic reaction conditions affords the desired amides of formula K (Scheme 3).

Reagents and Conditions: (a) i. MeMgBr, Ether, O⁰C; ii. KHSO₄, 14O⁰C or p-TsOH; (b) Et₃N-3HF, NBS, CH₂CI₂, 12 h r.t.; (c) NaCN or KCN, DMF; (d) NaOH or H₂SO₄

Scheme 3

I

M ^N

R = H or Alkyl

Reagents and Conditions: (a) i. R'₃SiCI, LiHMDS, THF, O⁰C; ii. SelectFluor, AcCN (b) LiAIH₄ or BH₃ in THF; (c) PBr₃ or NBS in CH₂CI₂ Scheme 4 Compounds of formula 1 may also be prepared from readily accessible α- Fluoro-substituted carboxylic acids or derivatives (e.g. esters) as in Scheme 4, (HeIv. Chim. Acta. 72, p. 1248-1252, 1989; Tetrahedron Lett. 47 (23), p. 7641-7644, 2006) or α-Fluoro-substituted carboxaldehydes (see J. Am. Chem. Soc. 126 p.5585, 2004, Angew. Chem. Int. Ed. 44 (24), 3706-3710, 2005) as in Scheme 5. The α-Fluoro-substituted adducts M and Q can be reduced to the fluoro alcohol N. The alcohol can then be transformed into the corresponding leaving group such as a halide, mesylate, triflate or tosylate and the subsequently converted to the nitrile precursor followed by hydrolysis to the amides of formula 1 as above. The precursors Q can be obtained from the terminal alkenes H by epoxidation followed by the metal catalysed Meerwein Rearrangement of the epoxide to the desired carboxaldehydes P. The α-Fluoro-substituted carboxylic acids M were generated from electrophilic fluorination of the of the a ketene acetal intermediate the was prepared in situ by the alkyl chlorosilane and lithium hexamethyldisilazane (LiHMDS), where as the corresponding α-Fluoro-substituted aldehydes were prepared under organocatalytic conditions with proline R as catalyst and NFSI as the electrophilic source of fluorine.

H O P Q Reagents and Conditions : (a) mCPBA, CH₂CI₂ (b) Pd(OAc)₂, P(t-Bu)₃, CH₂CI₂, 12 h r.t.; (c) i. NFSI, 20 mol% R, THF, , 25⁰C; d) NaBH₄

Scheme 5

N-RuorobenzenesdfoniiTicle (NFSI)

The optically active forms of the compound of the invention may be prepared, for example, by chiral chromatographic separation of a racemate or chemical or enzymatic resolution methodology, by synthesis from optically active starting materials or by asymmetric synthesis based on the procedures described there after. Some of the approaches to prepare chiral compounds of the invention wherein Ri is aryl or substituted aryl, R₂ is alkyl (e.g. Methyl) and R₃ and R₄ are both hydrogens are outlined in Scheme 6, Scheme 7, Scheme 8 and Scheme 9.

Method 1 : Use of Imidazolidinones as the Asymmetric Organocatalyst in Chiral Fluorination of Aldehydes

0 s = Ph

-N

H

Reagents and Conditions : (a) i. NFSI, 20 mol% S, THF, iPrOH, -1O⁰C; ii. NaBH₄; (b) NBS, CH₂CI₂, 12 h r.t; (c) NaCN or KCN, DMF; (d) NaOH or H₂SO4

Scheme 6

Chiral α-Fluorination of aldehyde 1 is the key transformation to be performed under asymmetric organocatalytic conditions with Imidazolidinone A as a dichloroacetic acid salt as catalyst and N-fluorobenzenesulfonimide (NFSI) as the electrophilic source of fluorine (see J. Am. Chem. Soc. 2005, 127 :8826- 8826; Chem. Eur. J. 2006, 12, 6039). An alternative source of electrophilic fluorine to evaluate would be Selectfluor.

The aldehydes 1 can be easily obtained from the terminal alkenes by epoxidation followed by the metal catalysed Meinwald Rearrangement of the epoxide to the desired carboxaldehydes (J. Org. Chem. 1997, 62, 6547; Tet. Lett. 2003, 44:7687). The chiral alcohol 2 can be converted to the corresponding halide (eg with PBr3 in ether; NBS or CBr4) or to the corresponding Tosylate or Mesylate followed by cyanation to afford the chiral intermediate 3. Hydrolysis of the nitrile 3 should give the desired chiral amides in high enantiomeric excesses (ee).

Method 2: Use of Evans Chiral Oxazolidinones Derivatives in Chiral Fluorination

3. LiHMDS or NaHMDS; 4. NFSI or Selectfluor 5

Scheme 7

The readily accessible racemic α-Methyl-α-arylpropionic acid 5 (see

Tetrahedron Letters 2006, 47(23): 7641-7644) can be converted to the various chiral oxazilidinones. A Fluorination of these Evans intermediate (Tetrahedron Asymmetry 2002, 13: 1645-1649) with electrophilic fluorinating agents (such as NSFI and Selectfluor) should provide intermediate 6 which on reduction with agents such as LiBH4 (see J. Org. Chem. 1997, 62, 7546- 7547) affords the chiral alcohol 2. The key alcohol intermediate 2 can then be easily transformed into the desired amides as in Scheme 6

Method 3: Use of Evans Chiral Oxazolidinones Derivatives in Chiral Methylation of the Fluorinated Derivatives

TTUHCF

³- LiHMDS Or NaHMDSj R²X

Scheme 8

The readily accessible racemic α-fluoro-α-arylpropionic acids 7 (Tetrahedron Letters 2006, 47 (23): 7641-7644) can be converted to the various chiral oxazilidinone. Methylation of the Evans intermediate (Tetrahedron Asymmetry 2002, 13: 1645-1649) should provide intermediate 6 which on reduction with agents such as LiBH4 (J. Org. Chem. 1997, 62, 7546-7547) affords the chiral alcohol 2 as above. The key alcohol intermediate 2 can then be easily transformed into the desired amides as in Scheme 6.

Method 4: Ezymatic and Crystallization Methods to chirally pure Compounds OH

.C

Scheme 9

Another useful approach, although a less preferred strategy based on overall yields of chiral material obtained, involves resolution of racemic mixture. This approach is still a viable alternative to obtain a single entantiomer in high enantiomeric purity. The racemic α-fluoro-α-arylpropanol 6 (Liebigs Ann. 1996, 1289; J. Prakt. Chem. 2000, 342: 52-57) can be enzymatically resolved through Lipase-catalysed esterification to afford 4 (see Tetrahedron Asymmetry 1997, 8: 399-408). The racemic alcohol 6 can be easily obtained from the racemic α-fluoro-α-arylpropionic acid 7 (see Tetrahedron Letters 2006, 47 (23): 7641-7644) by reduction with agents such as BH3 in THF. Alternatively, the racemic acid 7 can potentially be subjected chiral amine salt screening to give through kinetic crystallization the enantio-enriched salt which then affords the single enantiomer 8. Subsequent reduction of 8 gives the chiral alcohol 4. The key intermediate form can then be easily transformed into the desired amides as in Scheme 6.

All starting materials are commercially available or earlier described in the literature. The ¹ H and ¹³C NMR spectra were recorded either on Bruker 300, Bruker DPX400 or Varian +400 spectrometers operating at 300, 400 and 400 MHz for

¹ H NMR respectively, using TMS or the residual solvent signal as reference, in deuterated chloroform as solvent unless otherwise indicated. All reported chemical shifts are in ppm on the delta-scale, and the fine splitting of the signals as appearing in the recordings (s: singlet, br s: broad singlet, d: doublet, t: triplet, q: quartet, m: multiplet). Unless otherwise indicated, in the tables below ¹H NMR data was obtained at 300 MHz, using CDCI₃ as the solvent.

Purification of products were also done using Chem Elut Extraction Columns (Varian, cat #1219-8002), Mega BE-SI (Bond Elut Silica) SPE Columns (Varian, cat # 12256018; 12256026; 12256034), or by flash chromatography in silica-filled glass columns.

Example 1. General procedure for the preparation of DL- hydroxybenzenamides

Under Nitrogen gas, N,O-bis(trimethylsilyl)acetamide (10 mmol) was dissolved in 25 ml. of THF and cooled to -78°C. A solution of 2.5 N n-BuLi in hexanes (4.4 ml_, 11 mmol) was then added dropwise to the mixture, keeping the temperature below -70⁰C. The reaction was stirred under N₂ for 15 minutes. A solution of the benzylketone (10 mmol) was dissolved in 25 ml_ of THF, which was added dropwise to the reaction mixture keeping the temperature below -70⁰C. The reaction was stirred at -78°C for 90 minutes. The reaction mixture was allowed to warm to room temperature. Water (5OmL) was added to the reaction, followed by 1 N HCI (12.5mL) and the aqueous phase was extracted with ethyl acetate. The organic phase was dried, concentrated and purified by column chromatography (40% ethyl acetate in hexanes). Triturating with hexanes gave the title compounds as white solids. Using the above procedure, the following compounds were synthesized:

Example 2. General procedure for fluorination of DL-hydroxy- benzenamides

DL-hydroxybenzenamide (1.58 mol) was dissolved in 50 mL of dichloromethane and cooled to -78 ⁰C. Three equivalents of DAST (diethylaminosulfate trifluoride) were added and the reaction was stirred for 3 hours at -78°C. The reaction was quenched with brine and extracted with ethyl acetate. The organic layer was dried and purified by column chromatography (50% ethyl acetate in hexanes). The resulting products were triturated with hexanes to give white solids.

Using the above procedure, the following compounds were synthesized:

Chiral HPLC Separation of Fluorobenzenamide compounds

Example 3. Chiral HPLC of 3-[3,5-bis(trifluoromethyl) phenyl]-3- fluorobutanamide

As described in Scheme 10, the racemic mixture of the example 2.1 was separated to the pure enantiomers labeled as enantiomer 1 (Example 3.1 ) and enantiomer 2 (Example 3.2).

Example 2.1

Enantiomer 1 Enantiomer 2

[Example 3.1] [Example 3.2]

Scheme 10

Analytical column:

Chiral separation was carried out to resolve the two enantiomers using a Chiralcel OJ column. 10% EtOH/hexanes was used for chiral separation, with a flow rate of 12 mL/min. The first peak (Example 3.1 ) was eluted at 5.65 minutes and the second peak (Example 3.2) was eluted at 9 minutes.

Preparatory Chiral HPLC column:

Chiralpak AS-H column: Dimensions: 20 x 250 mm, was used to separate two enantiomers. The solvent system, 100% EtOH, was used at a flow rate of 6 mL/min to achieve baseline resolution. Roughly 0.2 mL of a 190 mg/mL solution in EtOH was injected. The first peak (Example 3.1 , 1.28 g) eluted at 10-11.5 mins and the second peak (Example 3.2, 1.19 g) eluted at 11.5-13 mins.

Example 4: Chiral HPLC of 3-[3'-chloro-5'-(trifluoromethyl)phenyl]-3- fluorobutanamide In a similar manner to Example 2.1 , the racemic 3-[3'-chloro-5' (tήfluoromethyl)phenyl]-3-fluorobutanamide Example 2.8 was resolved into its enantiomer 1 (Example 4.1) and enantiomer 2 (Example 4.2) (Scheme 11 )

Example 2.8

enantiomer 1 enantiomer 2 [Example 4.1] [Example 4.2]

Scheme 11

Preparatory Chiral HPLC Column:

Chiralpak AS-H column: Dimensions: 20 x 250 mm, was used to separate two enantiomers. The solvent system, 100% EtOH, was used at a flow rate of 6 ml_/min to achieve baseline resolution. Roughly 0.4 ml_ of a 170 mg/mL solution in EtOH was injected. The first peak (Example 4.1 , 1.31 g) eluded at 11.5-13 mins and the second peak (Example 4.2, 1.37 g) eluded at 13.5-15 mins.

Determine the absolute stereochemistry of Fluoro-benzenamide compounds

To prove the absolute stereochemistry, one of the enantiomers, Example 3.2, was derivatized. The goal was to obtain a crystalline material to determine the absolute stereochemistry using X-ray crystallography. Among the methods of creating derivatives, the most promising approaches are to either sulfonylate (using Tosyl chloride) or acylate (using p-bromobenzoyl chloride) the amide moiety of Example 3.2 (Tetrahedron Asymmetry 2001 , 12, 1589-1593). Both of these derivatives would contain a heavy atom which is crucial for determination of absolute stereochemistry via X-ray crystallography. Deprotonation of the amide was carried out using LiHMDS followed by reaction with Tosyl chloride or p-bromobenzoyl chloride. Both reactions yielded crystalline products after purification. It was found that the enantiomerically pure p-bromobenzoyl derivative was successfully synthesized from Example 3.2 (Scheme 12), and the X-ray quality crystals were obtained via slow evaporation of isopropyl alcohol. X-ray crystallography of the N-[3-(3,5-Bis-trifluoromethyl-phenyl)-3-fluoro-butyryl]-4-bromo- benzamide (Example 5.1 ) determined the absolute stereochemistry of Example 3.2 to be (S). Hence the absolute configuration of the other enantiomer Example 3.1 is (R).

Example 3.2 Example 5.1

(i) LiHMDS, p-bromobenzoyl chloride, THF, O⁰C;

Scheme 12

Example 5.1 : N-[3-(3,5-Bis-trifluoromethyl-phenyl)-3-fluoro-butyryl]-4- bromo-benzamide

To a flame dried 10 ml RBF under argon was added Example 3.2 (32 mg, 0.1 mmol) and 2 ml anhydrous THF. The solution was cooled to -78⁰C and LiHMDS (1.0 M in THF, 150 μl, 0.15 mmol) was added dropwise. The resulting solution was warmed to -4O⁰C and allowed to stir for 30 min at which point it was cooled back to -78⁰C and p-bromobenzoyl chloride (44 mg. 0.2 mmol) was added. The solution was warmed to RT over 1 h and stirred for an additional hour. The reaction was quenched with 1 ml sat NH₄CI and extracted with CH₂CI₂, the organic phases were combined and dried over sodium sulphate and concentrated under reduced pressure. Purified by Prep TLC, 50% EtOAc in hexane to give the expected compound Example 5.1 (21 mg, 42%) as a crystalline solid (R_f= 0.5 25% EtOAc in hexane) 1 H-NMR (CDCI₃, 300 MHz) 8.47(br s, 1 H), 7.90 ( s, 1 H),7.82 (s, 1 H), 7.65 (br s, 4H),3.75 (m, 2H),1.91 (d, 3H, J=22.8Hz) HRMS El: C₁₉H₁₃NO₂ ⁷⁹BrF₇ CaIc 499.0018 found 499.0006 19F NMR (CDCI₃, 300 MHz) -63(s), -144(m).

In-vivo Pharmacological Testing

Animals and housing

Male, Sprague-Dawley rats and CD-1 mice were used for all studies. All animals were allowed ad-lib access to food and water except during experiment. Animals were housed within an animal vivarium maintained under a 12 h light:dark cycle (lights on: 07:00 h), and all experiments were conducted in the animals light phase. For all experiments, animals were habituated to the vivarium for a minimum of 72 h before experimentation. The experimental procedures used in the present investigation were conducted under the Association for Assessment and Accreditation of Laboratory Animal Care (AAALAC) and the Canadian Council on Animal Care (CCAC) guidelines.

All compounds were sonicated in 5% Tween 80® in saline and injected in a dose volume of 5 ml/kg or 10 ml/kg (rat), and 10 ml/kg (mouse). Drugs were administered by either the oral or intraperitoneal route.

Mouse maximal electroshock (MES) assay (epilepsy indication)

Following a defined pretreatment period, mice received a maximal electroshock (45 mA, 0.2 s duration, 60 Hz) via corneal electrodes moistened with saline. Preliminary experiments established that this stimulus intensity elicited a full tonic seizure in >95% of control animals. Protection was defined as absence of a full tonic seizure within 10 s of stimulus delivery. To establish drug potency, test drug or vehicle was administered 1 h prior to MES test. The effective dose of compound necessary to protect against tonic seizures to 50% of controls (i.e. ED₅₀) was determined by curve fitting program (Prism v.4.02).

Twenty minutes before the MES procedure, the animals were tested on a fixed speed rotorod (best score from 3 trials at 16 r.p.m, trial duration = 60 s) to give an early assessment of drug effect on gross motor function. The ED₅₀ dose to disrupt rotorod performance was expressed as a ratio of the MES ED₅₀ to define a Protective index (Pl).

Several examples were active in this assay, with ED₅₀ values of below 100mg/kg. Some stereoselectivity was evident between examples 4.1 and 4.2, with 4.1 being the slightly more potent enantiomer.

Mouse subcutaneous pentylenetetrazol (s.c PTZ) assay (epilepsy indication) Sixty minutes following drug or vehicle pretreatment, all mice received a single subcutaneous injection of pentylenetetrazol (PTZ; 85 mg/kg). The animals were then transferred to single observation cages (dimension: 1 1 .5" x 7.5" x 5") and observed continuously for 30 min. Preliminary experiments established that at the 85 mg/kg s.c dose of PTZ, at least one single episode of clonic seizure was elicited in >95% of control animals. Protection was defined as complete absence of a clonic seizure over the 30 min observation period. In the event of a seizure, the onset latency from PTZ injection was recorded.

Examples 2.1 and 2.2 demonstrated anticonvulsant activity in this assay with protection against s.c PTZ seizures in 6/1 1 (55%) and 3/6 (50%) animals respectively at an oral dose of 100mg/kg. Stereoselectivity was evident between examples 4.1 and 4.2, with 4.1 being the more potent enantiomer.

Mouse 6Hz assay (epilepsy indication):

Sixty minutes following drug or vehicle pretreatment, all mice received an electrical stimulus (6 Hz, 0.2 ms pulse width, 3 s duration, 32 mA) via corneal electrodes moistened with saline (ECT unit 57800; Ugo Basile). Preliminary experiments established that these stimulus parameters elicited a psychomotor seizure, defined as the expression of at least one of the following behaviors: stun/immobility, forelimb clonus, straub tail, vibrissae tremor, lateral head movement in >95% of control animals. Protection was defined as complete absence of all the above behaviors within 20s of stimulus delivery. The effective dose of compound necessary to protect against psychomotor seizures to 50% of controls (i.e. ED₅₀) was determined by curve fitting program (Prism v.4.02). Rat maximal electroshock (MES) assay (epilepsy indication)

Male Sprague-Dawley rats of body weight 80-100 g were used for these studies. Each experiment was conducted over 3 consecutive days. On day 1 and 2, each rat received a single electrical stimulus (150 mA, 0.2 s duration, 60 Hz) via corneal electrodes moistened with saline (Shock stimulator type

221 : Harvard apparatus). Only rats that displayed a full tonic extensor on day

1 and 2 were entered into the drug study conducted on day 3. Typically this reflected approximately 70-90% of the initial group. In this way, rats which did not produce a reliable tonic extensor to the MES stimulus were excluded from the experiment.

On the test day following a defined drug pretreatment period, rats received a maximal electroshock (150 mA, 0.2 s duration, 60 Hz) via corneal electrodes. Protection was defined as absence of a full tonic seizure within 10 s of stimulus delivery. Twenty minutes before the MES procedure, the animals were tested on a fixed speed rotorod (best score from 3 trials at 8 r.p.m, trial duration = 60 s) to give an early assessment of drug effect on gross motor function.

To establish drug potency, test drug or vehicle was administered 1 h prior to MES test, to separate experimental groups. The effective dose of compound necessary to protect against tonic seizures to 50% of controls (i.e. ED₅₀) was determined by curve fitting program (Prism v.4.02). Examples 2.1 and 2.2 both protected against tonic seizures in 6/6 (100%) and 5/5 (100%) animals respectively at an oral dose of 30 mg/kg.

Rat subcutaneous pentylenetetrazol (s.c PTZ) assay (epilepsy indication)

Male Sprague-Dawley rats of body weight 95-115 g were used for these studies. Thirty minutes following drug or vehicle pretreatment (i.p. route), all rats received a single subcutaneous injection of penylenetetrazol (75 mg/kg). The animals were then transferred to single observation cages (dimension: 19" x 10" x 8") and observed continuously for 30 min. Preliminary experiments established that at the 75 mg/kg s.c dose of PTZ, at least one single episode of clonic seizure was elicited in approximately 95% of control animals. Protection was defined as complete absence of a clonic seizure over the 30min observation period. In the event of a seizure, the onset latency from PTZ injection was recorded.

Example 2.1 demonstrated anticonvulsant activity in this assay with protection against s.c PTZ seizures in 5/8 (62%) animals at an i.p. dose of 30 mg/kg.

Genetic Absence Epilepsy Rats from Strasbourg (GAERS) model of absence-type seizures (epilepsy indication):

Male GAERS rats (Wistar derived) were anaesthetized with ketamine (100 mg/kg i.p.)/diazepam (0.2 ml i.p.) and each implanted with 5 monopolar stainless steel electrodes positioned over the frontal and parietal cortices. The electrodes were embedded in acrylic resin and fixed to the skull with anchoring screws. For recording, the animals were placed in an observation chamber, and connected via flexible wires to the electroencephalograph, for free movement during EEG recording.

Each drug was examined in a group of 8 rats. After a brief adaptation to the test chamber, a reference EEG was recorded for 20 min. The drug or its vehicle was then administered and the EEG recorded for up to 80 min.^' During the recording period the rats were continuously monitored and prevented from falling asleep by gentle sensory stimulation. For each treatment, the mean cumulative duration of absence EEG (duration of 6-8 Hz spike-wave activity) was recorded over 20 min time bin. Test drugs were evaluated in a single experiment at a single dose using a cross-over design to control for any potential order effects of treatment. A one week interval separated each treatment. Treatment effects were compared to vehicle. The data for Example 3.1 are summarized in the following two Tables A and B

Table A: Effect of Example 3.1 (60mg/kg i.p.) against the duration of slow wave discharge (SWD) EEG

*p<0.05 vs. vehicle control at equivalent timepoint.

Rat amygdala kindling model (epilepsy indication):

The amygdala kindling model is a model of complex partial seizures with secondary generalization (Albright and Burnham, Epilepsia, 1980, 21 : 681 - 689; Fisher, Brain Res. Rev. 1989, 14: 245-278). Complex partial epilepsy is the most common type of epilepsy in adults and is often drug resistant

(Blume, New York: Kluwer Academic/Plenum Publishers. 2002 p.9-18). It is the focal amygdaloid EEG afterdischarge that models complex partial seizures. The generalized seizures model tonic-clonic seizures (Albright and Burnham, Epilepsia, 1980, 21 : 681-689). The inhibition of EEG afterdischarge suggests that drug has efficacy for the treatment of complex partial seizures.

All drugs were administered by the intraperitoneal route in a final dose volume of 5 ml/kg body weight. Drug pretreatment times were 60 min. All drugs were freshly prepared on the day of experiment. One week after arrival at the vivarium, subjects were anaesthetized with isoflurane and implanted with a bipolar electrode (MS303/1 ; Plastics One; Roanoke, VA, USA) aimed at the right basolateral amygdala. The following co-ordinates were used: anterior-posterior: -2.6mm; lateral: +4.8mm; ventral: - 9.0mm. Anterior-posterior and lateral measurements were from bregma, the ventral measurement was from the skull surface. The incisor bar was set at +5.0mm. Subjects weighed 210-26Og at the time of surgery.

Two weeks after surgery, kindling was begun. The kindling stimulus, administered once daily, was a 1 s train of 60Hz biphasic square-wave pulses at an intensity of 40OuA (peak-to-peak). The stimulation was produced by a Grass model S-88 stimulator in series with two PSIU 6 stimulus isolation units (Grass Instruments, Quincy, MA, USA). Electrographic activity (EEG) was recorded on a model 6 electroencephalogram (Grass Instruments). Frequencies <5Hz or >60Hz were filtered out. Subjects were kindled to a criterion of 30 stage 5 (Racine, 1972) seizures. (Racine scale: 0 = no visible response; 1 = facial automatism [licking, chewing]; 2 = head nodding; 3 = head nodding plus forelimb clonus; 4 = head nodding, forelimb clonus, rearing; 5 = head nodding, forelimb clonus, rearing, falling over).

After the 30^th stage 5 seizure, the afterdischarge threshold for each subject was determined by using the ascending series technique (Pinel et al, 1976). This technique involves a step-wise increase in stimulation until an EEG afterdischarge is seen and a behavioural seizure occurs. The current that first produced an afterdischarge with a generalized seizure was considered the afterdischarge threshold. Subjects were then tested for stability at an intensity of 120% of their afterdischarge threshold. Stability testing involved triggering a seizure at 120% of threshold every second day for a period of 10 days. Only subjects that had five consecutive stage 5 seizures at 140% of their threshold were used in subsequent drug tests. Of the 20 rats that entered the study, 13 demonstrated appropriate stability of response to the kindling stimulus. The remaining rats were rejected based on unstable baseline or surgical complications.

The 13 rats were randomly allocated into 2 groups of n=7 and n=6, and used in Experiments 1 and 2 respectively. In each study, a repeated measures, design was used, with each animal receiving each treatment in a counterbalanced design. A minimum of 5 days elapsed between each treatment cycle.

Following a further washout period of 7 days, a subgroup of 7 rats from experiments 1 and 2 were entered into a new experiment.

Effect of Example 4.1 on kindled seizures in the rat:

Acute drug (Example 4.1 ) pretreatment was tested in drug naϊve rats (n=6) fully kindled to stage 5 seizures. Thus, in vehicle pretreated rats, delivery of a 1 s train of 60Hz biphasic square wave pulse at 40OuA intensity resulted in Stage 5 seizures (medan = 5) and mean EEG afterdischarge duration of 127+9 s. Example 4.1 (10-30mg/kg IP) produced a dose related attenuation of generalized convulsions elicited by amygdala kindling. At the 30mg/kg dose, Example 4.1 significantly suppressed the ADD induced by stimulus, and the animals had a median seizure score of 2. The data references are summarized in the Table C.

Table C:

ADD: Repeated measures ANOVA: F(2,10) = 17.3, p<0.001 Pairwise Multiple Comparison Procedures (Tukey Test):

Comparison D iff of Means q P

Vehicle vs. Example 4.1 30mg/kg 86.1 8.184 O.001

Vehicle vs. Example 4.1 10mg/kg 56.8 5.398 0.009

Example 4.1 10mg/kg vs. 30mg/kg 29.3 2.786 0.170

Example 4.1 (10-30 mg/kg IP) produced a dose related suppression of kindled seizures. At the 10-30 mg/kg doses, both drugs suppressed the EEG after discharge duration elicited by the stimulus. In these animals, the seizure rating was also reduced. Following a washout period, the effect of the drug was investigated in seven rats previously used to test the effect of Example 4.1. Baseline EEG after discharge duration, and behavioural scores were similar across experiments, suggesting stability of the kindled state in these animals. At the dose range of 10-30 mg/kg, Example 4.1 produced a non-significant attenuation of amygdala kindled seizures.

Rat conditioned emotional responding assay procedure (anxiety):

Male, Sprague-Dawley rats of approximate body weight 350-450 g were placed on a restricted food diet (45 min free access per day) and trained over a 1-2 week period to press a lever for food reward (45 mg food pellet, Bioserv, USA) on a variable reinforcement schedule (Operant boxes: Med Associates, USA; Kestrel Control System: Conclusive Marketing, UK). Operant schedule requirements were gradually increased from a variable interval 5 s schedule (VI5) to a final variable interval 40 s schedule (VI40). Daily session (5 days/week) were lasting for a 40 min period. Once stable baseline responding had been attained, two periods of a 2 min conditioning stimulus (CS) was introduced into the session. Each CS consisted of a 2.9-kHz tone and illumination of a cue light positioned above the lever. The 2 min CS was terminated by a 0.5 s unavoidable footshock of 0.3-0.8 mA intensity (individual titration). The first CS was presented at approximately 10 min (range 5-15 min) and the second CS pairing at approximately 30 min (range 25-35 min) into the test session. On drug test days, and occasional training days, footshock was not delivered. The number of lever presses recorded during the two 2 min CS periods (A), and the number of lever presses recorded in the 2 min periods immediately prior to the two CS periods (B) were measured and a suppression ratio (SR) was calculated using the following formula: SR = (A) / (A₊B).

A SR of 0 reflects no responding during the CS periods, i.e. a complete suppression of lever pressing for food by the CS, and a SR of 0.5 reflects equivalent responding during both the CS and 2min period prior to CS, i.e. no suppression of lever pressing for food by the CS. Animals were trained daily until their SR was lower than 0.1. Thus in drug untreated animals, the SR value was typically 0-0.1 , whereas established anti-anxiety agents such as diazepam increased this value to 0.4-0.5 (e.g. Stanhope and Dourish, Psychopharmacol. 1996, 128: 293-303; Martin et al. Pharmacol. Biochem. Behav., 2002, 71 , 615-625). In addition to SR, the total number of lever presses emitted by the animals over the 40min test session was measured.

Drug testing was conducted according to a repeated measures design, with each animal receiving each dose of drug treatment or vehicle control in a balanced fashion. In each experiment, a standard dose of diazepam (2mg/kg i.p.) was included as a positive control. This optimized dose was based on a previous study evaluating multiple doses of diazepam.

Examples 4.1 and 4.2 were both active in the CER assay, with efficacy similar to diazepam.

Rat Formalin Test (pain)

Male Sprague-Dawley rats were pretreated with the vehicle (0.9% saline or 5% Tween 80® in saline) or the test compound (10 ml/kg i.p.) and placed in the test chamber. The test chamber is made of Plexiglas (30 cm x 30 cm x 30 cm) placed over another similar chamber. The bottom chamber consisted of a mirror angled at 45° to provide an unobstructed view of the rat's paws. After a pretreatment time of 30 min (which is also the period of acclimatization of the rat to the test chamber), formalin (2.5%, 50 μl) was given subcutaneously into the plantar surface of one hind paw. Each rat was returned to the test chamber immediately following formalin injection. The number of paw licks and flinches were scored for each 5 min block for the next 60 min.

Compounds of the invention were effective in significantly reducing the nociceptive responses, particularly during the second phase of formalin test. For example, both examples 3.1 and 3.2 (60 mg/kg i.p.) produced a significant decrease in the number of paw licks. This effect was most pronounced in the second (late) phase as defined by the % inhibition compared to vehicle controls.

Freund's Complete Adjuvant (FCA) Model (Inflammatory Pain)

Male Sprague-Dawley rats were injected with 100 μl of FCA (Sigma) into the dorsum of one of the hind paws after initially testing them in paw pressure (Randall-Selitto Method) and paw volume (plethysmometry) tests. Two days post FCA injection the effect of the test compound/vehicle was tested in these rats. Basal readings were taken in the two tests before any drug or vehicle administration. Readings were again taken 30, 60 and 180 min following administration of the compound/vehicle. Both the control (uninjected) paw and the FCA-injected paw were tested.

The sensitivity of rats to mechanical pressure applied to the paw was measured using the Randall-Selitto apparatus (Analgesy-meter, Ugo Basile,

Italy). The rat's paw was placed on a small plinth under a cone-shaped pusher. Increasing force was applied to the paw by depressing a pedal switch until vocalization or paw withdrawal. The minimum force (measured in g) required to elicit this vocalization/withdrawal is the paw pressure threshold. The cut-off was set at 15Og. The paw volume was measured by using a plethysmometer (Ugo Basile, Italy). The paw was immersed into water in a Perspex cell and the volume displacement sensed by a transducer and displayed.

Examples 3.1 and 3.2 (60 mg/kg i.p.) increased the withdrawal threshold of the FCA treated paw at 60 min post dosing compared to pre-treatment baseline, which is suggestive of an analgesic effect in this test. There was no effect of drug on withdrawal threshold of the untreated paw, nor was there any effect of either drug on paw volume.

Spinal Nerve Injury (SNI) Model (Neuropathic Pain)

The SNI model of neuropathic pain was developed in rats using the procedure described by Decostered and Woolf, Pain 2000, 87: 149-158. Under isoflurane anesthesia, the skin on the lateral surface of the thigh was incised and a section was made directly through the biceps femoris muscle exposing the sciatic nerve and its three terminal branches: the sural, common peroneal and tibial nerves. The common peroneal and the tibial nerves were tight- ligated with 6-0 suture and sectioned distal to the ligation, removing 2-4 mm of the distal nerve stump. Extreme care was taken to avoid any contact with or stretching of the intact sural nerve. Following surgery, hemostasis was confirmed and the muscles were sutured in layers using 4-0 suture and the skin was closed with 4-0 suture and metal clips.

Male, Sprague-Dawley rats were used. Testing of compounds was done 21 days post-operatively. After initial basal readings were taken, the test compound or vehicle was administered. The readings were taken again 30, 60 and 180 min after the compound/vehicle administration. Both the control (uninjured) and the SNI paw were tested. The presence of mechanical allodynia was assessed using the Dynamic Plantar Aesthesiometer (Ugo Basile, Italy) which is a modified version of the Von Frey Hair test. In this, a test filament is positioned below the animal's hind paw and the unit is activated which causes the filament to move up and touch the plantar surface of the hind paw. Increasing force is applied to the paw via the filament. When the animal withdraws its paw, the unit is inactivated automatically and the threshold force required to elicit the paw withdrawal is displayed. A single reading was taken per timepoint. The cut-off force was set at 50 g. The tests were done on both the non-injured (control) and the injured (SNI) paw. Pilot studies showed the presence of mechanical allodynia 7 days after the surgery and lasted up to 4 weeks (end of the test period).

Cold allodynia was assessed by using the acetone test. In this test, 25 μl of acetone is sprayed on to the plantar surface of the hind paw. Evaporation of acetone causes cooling of the skin. The cold stimulus sets up nociceptive responses from the injured paw as evidenced by paw lifting, paw licking and grooming. The duration of the nociceptive responses is noted. Similar stimulus to the uninjured (control) paw usually does not elicit nociceptive responses.

In the case of the SNI model (Von Frey Hair test), the maximum reversal possible was computed as Percent Maximum Possible Effect (MPE) (e.g. Stohr et al, Eur. J. Pharmacol. 2006, 10: 241 -249):

In the SNI model of neuropathic pain, example 2.1 at a dose of 30 mg/kg i.p. was effective at reducing the mechanical allodynia evident in the denervated paw as measured using the Von Frey test. Cold allodynia in the neuropathic rats was also significantly reduced by this compound.

* p<0.05 vs. SNI paw vehicle pretreated group at 30min.

Claims

We claim:

1. A compound of Formula I:

Formula I

wherein:

or R₃ and R₄ connect to form a three to seven-membered ring; and

2. The compound according to Claim 1 , wherein the alkyl is a C-i-Cβ alkyl.

3. The compound according to Claim 1 or 2, wherein Ri and R₂ are optionally substituted with one or more independently-selected groups Rs, wherein R₈ is selected from the group consisting of OH, CN, halo, alkyl, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, heterocycloalkyl C(O)R₉, C(O)ORg, SO₂Rg and C(O)NR₉Ri₀; R₉ and R-io are independently selected from the group consisting of H, alkyl and cycloalkyl.

4. The compound according to any one of Claims 1 to 3, wherein R₃ and R₄ are independently selected from the group consisting of H, halo, substituted or unsubstituted haloalkyl, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, and substituted or unsubstituted heterocycloalkyl.

5. The compound according to any one of Claim 1 , wherein Ri is alkyl; R₂ is a substituted aryl; and R₃ to R₆ are H.

6. The compound according to Claim 5, wherein R₂ is substituted with one or more independently-selected groups R₈, wherein R₈ is selected from halo and haloalkyl.

7. A compound selected from:

3-[3,5-bis(trifluoromethyl) phenyl]-3-fluorobutanamide; 3-[3,5-bis(trifluoromethyl)phenyl]-3-fluoropentanamide; 3-(3'-chlorophenyl)-3-fluoropentanamide; 3-[3'-trifluoromethylphenyl]-3-fluorobutanamide; 3-[3'-fluoro,5'-(trifluoromethyl) phenyl]-3-fluorobutanamide; 3-[3'fluoro,5'-(trifluoromethyl)phenyl]-3-fluoropentanamide; 3-(3'-trifluoromethyl)phenyl-3-fluoropentanamide; and 3-(3'chloro,5'-(trifluoromethyl)phenyl-3-fluorobutanamide; and/or a pharmaceutically-acceptable salt, hydrate, solvate, isoform, tautomer, optical isomer, or combination thereof.

8. A pharmaceutical composition comprising a compound according to any one of Claims 1 to 7 and at least one pharmaceutically acceptable carrier and/or excipient.

9. A method for treating at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of Claims 1 to 7.

10. A method for treating at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal, comprising administering to the mammal a therapeutically effective amount of a composition according to Claim 8.

11. The method according to Claim 9 or 10, wherein the mammal is a human.

12. The method according to Claim 9, wherein the compound is administered orally and/or parenterally.

13. The method according to Claim 10, wherein the composition is administered orally and/or parenterally.

14. The method according to Claim 9, wherein the compound is administered intravenously and/or intraperitoneal^.

15. The method according to Claim 10, wherein the compound is administered intravenously and/or intraperitoneal^.

16. Use of a compound according to any one of Claims 1 to 7 for manufacture of a medicament for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal.

17. Use of a composition according to Claim 8 for manufacture of a medicament for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal.

18. Use of a compound according to any one of Claims 1 to 7 for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal.

19. Use of a composition according to Claim 8 for treatment of at least one of epilepsy, neuropathic pain, acute and chronic inflammatory pain, migraine, tardive dyskinesia, anxiety and other related CNS disorders in a mammal.

20. The use according to any one of Claims 16 to 19, wherein the mammal is a human.

21. The use according to Claim 16 or 18, wherein the compound is administrable orally and/or parenterally.

22. The use according to Claim 17 or 19, wherein the composition is administrable orally and/or parenterally.

23. The use according to Claim 16 or 18, wherein the compound is administrable intravenously and/or intraperitoneal^.

24. The use according to Claim 17 or 19, wherein the compound is administrable intravenously and/or intraperitoneal^.