EP2285818A2 - Béloxépine, ses énantiomères et certains de leurs analogues convenant au traitement de la douleur - Google Patents

Béloxépine, ses énantiomères et certains de leurs analogues convenant au traitement de la douleur

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Publication number
EP2285818A2
EP2285818A2 EP09712730A EP09712730A EP2285818A2 EP 2285818 A2 EP2285818 A2 EP 2285818A2 EP 09712730 A EP09712730 A EP 09712730A EP 09712730 A EP09712730 A EP 09712730A EP 2285818 A2 EP2285818 A2 EP 2285818A2
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Prior art keywords
beloxepin
pain
composition
enantiomerically pure
mammal
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EP09712730A
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German (de)
English (en)
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EP2285818A4 (fr
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Bertrand Le Bourdonnec
Roland Dolle
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Adolor Corp
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Adolor Corp
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Publication of EP2285818A4 publication Critical patent/EP2285818A4/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A—HUMAN NECESSITIES
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    • A61P11/00—Drugs for disorders of the respiratory system
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/10—Drugs for genital or sexual disorders; Contraceptives for impotence
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • A61P17/04—Antipruritics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/06—Antimigraine agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • Acute and chronic pain of both nociceptive and non-nociceptive origin are disabling conditions that affect significant numbers of individuals. Pain is frequently characterized by increased sensitivity to normally non-noxious stimuli (allodynia) and/or painful stimuli (hyperalgesia).
  • antidepressants such as norepinephrine and serotonin (5HT) reuptake inhibitors have been used as a first- line therapy for treating certain types of pain, for example, pain associated with diabetic neuropathy, postherpetic neuralgia, fibromyalgia, irritable bowel syndrome and interstitial cystitis, none of these therapies has proven to be universally effective.
  • Racemic ( ⁇ )-beloxepin also known as “Org-4428” and "c ⁇ - 1,2,3, 4,4a, 13b- hexahydro-2,10-dimethyldiben-[2,3:6,7]oxepino [4,5c]pyridine-4a-ol]
  • ⁇ -beloxepin also known as "Org-4428” and "c ⁇ - 1,2,3, 4,4a, 13b- hexahydro-2,10-dimethyldiben-[2,3:6,7]oxepino [4,5c]pyridine-4a-ol]
  • beloxepin is a highly specific inhibitor of noradrenaline reuptake in synaptosomes from rat and primate brain in in vitro assays, having greater than 100-fold less affinity for other monoamine carriers ⁇ i.e., serotonin and dopamine transporters), and no or very weak affinity for noradrenergic, histaminergic and cholinergic receptors (Sperling & Demling, 1997, Drugs of Today 33(2):95-102). It is also reported to have modest affinity for the 5HT 2 c receptor (Claghorn & Lesem, 1996, Progress Drug Res 46:243-262).
  • beloxepin was noted to exhibit antidepressant properties by offsetting acquired immobility behavior, reserpine- induced hypothermia, and conditioned avoidance behavior. In these tests, beloxepin did not cause sedation, motor impairment or other untoward side effects. Its profile on EEG-defined sleep/wake behavior is compatible with that of a nonsedative antidepressant with sleep- improving properties (Sperling & Demling, 1997, supra).
  • beloxepin displayed linear kinetics over a broad range, with a dose-independent t max of one to four hours and tm of 11 to 15 hr following doses of 10 to 500 mg.
  • beloxepin is not a selective inhibitor of the norepinephrine transporter ("NET"), as reported in the literature.
  • antidepressants including those that inhibit reuptake of NE (NRIs) and/or 5HT (SRIs) have been used as a first-line therapy for treating both acute and chronic pain that is either nociceptive or non-nociceptive in origin, for example, neuropathy, post-herpetic neuralgia (PHN), pain associated with fibromyalgia, pain associated with irritable bowel syndrome and interstitial cystitis (Sindrup and Jensen, 1999, Pain 83(3):389-400; Collins et al, 2000, J. Pain & Symptom Management 20(6):449-458; Crowell et al, 2004, Current Opin. Invest. Drugs 5 (7): 736-742).
  • NRI compounds e.g., reboxetine
  • dual NRI/SRI compounds e.g., duloxetine
  • tricyclic antidepressants e.g., amitriptyline
  • beloxepin produced an observed mean threshold of approximately 15 g - nearly 5 times greater - under the same experimental conditions than reboxetine.
  • beloxepin produced a tactile antiallodynic effect that was 852% greater than that observed with vehicle-treated controls, and nearly 100% of that observed with sham-operated animals.
  • Beloxepin also exhibited extremely robust activity in rodent models of acute nociceptive pain (FIGs. 6A and 6B), inflammatory pain (FIG. 7 and FIG. 9), neuropathic pain (FIG. 10 and Example 12), post-operative incisional pain (FIG. 12, FIG. 13, FIG. 14, and Example 13), and visceral pain (FIG. 8).
  • FIGS. 6A and 6B beloxepin exhibited anti-nociceptive activity almost equivalent to that of 3 mg/kg morphine.
  • beloxepin exhibited nearly complete reversal of hyperalgesia in rats treated with Freund's Complete Adjuvant (FCA), and with reference to FIG. 8, beloxepin inhibited acetic acid-induced writhing in mice a dose-dependent fashion.
  • beloxepin i.e. ( ⁇ )-beloxepin
  • ( ⁇ )-beloxepin is a racemic mixture of two enantiomers.
  • the chemical structure of beloxepin is illustrated below:
  • the (-) enantiomer binds with approximately 8-fold higher affinity at the NET than the (+) enantiomer, while being devoid of any significant affinity at the 5HT 2A , 5HT 2B and 5HT 2c receptors.
  • the (+) enantiomer which binds the NET with only weak affinity, displayed high affinity and antagonist activity at the 5HT 2 A, 5HT 2 B and 5HT 2c receptors.
  • beloxepin rather than being a single compound with a single activity, is really three different compounds with three distinct biological activities: (i) racemic ( ⁇ )-beloxepin, a dual NRI/5HT 2A , 2B , 2C antagonist; (ii) (+)-beloxepin, a 5HT 2A , 2B , 2C antagonist; and (iii) (-)-beloxepin, an NRI. All of these biological activities are known to correlate with therapeutic uses.
  • compositions comprising (-)-beloxepin and optionally one or more acceptable carriers, excipients or diluents.
  • the (-)-beloxepin may be present in the composition as a non-racemic mixture enriched in the (-) enantiomer.
  • the (-)-beloxepin is substantially enantiomerically pure (-)-beloxepin.
  • the (-)-beloxepin is enantiomerically pure.
  • the (-)-beloxepin can be present in the composition in the form of the free base, or in the form of a salt. In some embodiments, the (-)-beloxepin is present in the form of a pharmaceutically acceptable acid addition salt.
  • the (-)-beloxepin composition can be used in vitro or in vivo, as will be described in more detail below.
  • the composition can be formulated for administration to animals in veterinary contexts, or for administration to humans via virtually any route or mode of administration, including but not limited to, oral, topical, ocular, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, inhalation or insufflation.
  • the composition is formulated for oral administration, for example, to humans.
  • the present disclosure provides methods of treating diseases and disorders responsive to treatment with NRI compounds.
  • the methods generally comprise administering to a mammal, including a human, suffering from a disease or indication responsive to treatment with an NRI compound an amount of a (-)-beloxepin composition described herein effective to treat the disease or disorder.
  • the (-)-beloxepin composition comprises beloxepin that is enriched in the (-) enantiomer.
  • the beloxepin composition comprises substantially enantiomerically pure (-)-beloxepin.
  • the beloxepin composition comprises enantiomerically pure (-)-beloxepin.
  • DSM-IV Diagnostic and Statistic Manual of Mental Disorders IV
  • mood disorders such as, for example, depression
  • anxiety disorders such as, for example OCD
  • eating disorders such as, for example, anorexia nervosa and bulimia nervosa
  • impulse disorders such as, for example, trichotillomania
  • sleep disorders such as, for example, insomnia related to opioid withdrawal
  • personality disorders such as, for example, ADHD
  • somatoform disorders such as certain types of pain
  • NRI compounds Another important class of diseases or indications known to be responsive to treatment with selective NRI compounds is pain, including both acute and chronic pain, whether nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin (discussed further below). All of these diseases or disorders are expected to respond to treatment with various embodiments of the (-)-beloxepin compositions described herein.
  • the (-)-beloxepin composition can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating indications responsive to NRI therapy and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the (-)-beloxepin compositions described herein in a regimen to treat diseases and/or disorders responsive to NRI therapy are provided in a later section.
  • the present disclosure provides methods of inhibiting the NE transporter. Inhibiting this transporter generally results in inhibition of reuptake of NE.
  • the methods generally comprise contacting a NE transporter with an amount of (-)-beloxepin effective to inhibit the NET. In some embodiments, the method is carried out in the absence of (+)-beloxepin.
  • the NE transporter is contacted with a (-)-beloxepin composition as described herein.
  • the (-)-beloxepin composition comprises beloxepin that is enriched in the (-) enantiomer.
  • the (-)-beloxepin composition comprises substantially enantiomerically pure (-)-beloxepin. In some embodiments, the (-)-beloxepin composition comprises enantiomerically pure (-)-beloxepin.
  • the methods can be practiced in vitro with isolated transporters or cells that express the NE transporter, or in vivo as a therapeutic approach towards the treatment of diseases or disorders that are, at least in part, mediated by dysregulated reuptake of NE.
  • diseases or disorders that are, at least in part, mediated by reuptake of NE include, but are not limited to, those listed above.
  • the present disclosure provides methods of treating pain in mammals, including humans.
  • the methods generally comprise administering to a mammal suffering from pain, including a human, an amount of a (-)-beloxepin composition described herein effective to treat the pain.
  • the (-)-beloxepin composition comprises beloxepin that is enriched in (-) enantiomer.
  • the (-)-beloxepin composition comprises substantially enantiomerically pure (-)-beloxepin.
  • the (-)-beloxepin composition comprises enantiomerically pure (-)-beloxepin.
  • the methods can be used to treat numerous different types of pain syndromes, including acute or chronic pain that is either nociceptive in origin (for example somatic or visceral) or non-nociceptive in origin (for example neuropathic or sympathetic).
  • the pain is nociceptive pain including, but not limited to, inflammatory pain such as that associated with inflammatory bowel syndrome ("IBS") or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis.
  • IBS inflammatory bowel syndrome
  • the pain is non-nociceptive pain including, but not limited to, neuropathic pain such as postherpetic neuralgia (PHN), trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • neuropathic pain such as postherpetic neuralgia (PHN), trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • PPN postherpetic neuralgia
  • trigeminal neuralgia focal peripheral nerve injury
  • anesthesia dolorosa anesthesia dolorosa
  • central pain for example, post-stroke pain
  • the (-)-beloxepin composition can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating pain and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the (-)-beloxepin compositions described herein in a pain treatment or pain management regimen are provided in a later section.
  • the present disclosure provides compositions comprising (+)-beloxepin and optionally one or more acceptable carriers, excipients or diluents.
  • the (+)-beloxepin may be present in the composition as a non-racemic mixture enriched in the (+) enantiomer.
  • the (+)-beloxepin is substantially enantiomerically pure (+)-beloxepin.
  • the (+)-beloxepin is enantiomerically pure.
  • the (+)-beloxepin can be present in the composition in the form of the free base, or in the form of a salt.
  • the (+)-beloxepin is present in the form of a pharmaceutically acceptable acid addition salt.
  • the (+)-beloxepin composition can be used in vitro or in vivo, as will be described in more detail below.
  • the composition can be formulated for administration to animals in veterinary contexts, or for administration to humans via virtually any route or mode of administration, including but not limited to, oral, topical, ocular, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, inhalation or insufflation.
  • the composition is formulated for oral administration, for example, to humans.
  • the 5HT 2 A receptor is known to mediate, at least in part, several CNS functions ⁇ e.g., neuronal excitation, behavior, learning, anxiety), smooth muscle contraction (including vasoconstriction and vasodilation) and platelet aggregation.
  • CNS functions e.g., neuronal excitation, behavior, learning, anxiety
  • smooth muscle contraction including vasoconstriction and vasodilation
  • platelet aggregation e.g., platelet aggregation.
  • Antagonists of the 5HT 2 A receptor having established therapeutic utilities include, but are not limited to nefazodone (used to treat depression); trazodone (used to treat depression with or without anxiety, chronic insomnia, fibromyalgia, control of nightmares or disturbed sleep and, off-label, panic disorder, diabetic neuropathy, bulimia nervosa, obsessive compulsive disorder, alcohol withdrawal and schizophrenia); mirtazipine (used to treat moderate to severe depression and, off-label, panic disorder, anxiety disorder, obsessive compulsive disorder, post traumatic stress disorder, sleep apnea, and pruritis); ketanserin (classified by the World Health Organization and the NIH as an antihypertensive); cyproheptadine (used to treat hay fever and other allergies, stimulate appetite in underweight individuals, combat SSRI-induced sexual dysfunction, to treat Cushing's syndrome and as a prophylactive for migraines); pizotifen (
  • volinanserin currently evaluated in Phase III clinical trials for the treatment of sleep maintenance insomnia
  • eplivanserin currently evaluated in Phase III clinical trials for the treatment of sleep maintenance insomnia
  • atypical antipsychotics including clozapine, risperidone, olanzapine, quetiepine, ziprasidone, aripiprazole, paliperidone, asenapine, iloperidone, all of which are approved for use in the US, and sertindole, zotepine, amisulpride, bifeprunox and meperone, which are approved for use in countries other than the US (used to treat a variety of mood and sleep disorders, and in some cases, psychotic disorders such as schizophrenia, acute mania, bipolar mania, bipolar maintenance and psychotic agitation).
  • 5HT 2 A antagonists have been noted in WO 2006/100519, where it was stated that such compounds would be effective in the treatment of neurological conditions, including sleep disorders such as insomnia, psychotic disorders such as schizophrenia, and also depression, anxiety, panic disorder, obsessive-compulsive disorder, pain, eating disorders such as anorexia nervosa, and dependency or acute toxicity associated with narcotic agents such as LSD or MDMA.
  • sleep disorders such as insomnia
  • psychotic disorders such as schizophrenia
  • depression depression
  • anxiety, panic disorder obsessive-compulsive disorder
  • pain eating disorders
  • eating disorders such as anorexia nervosa
  • dependency or acute toxicity associated with narcotic agents such as LSD or MDMA.
  • Such compounds were further alleged to be beneficial in controlling the extrapyramidal symptoms associated with the administration of neuroleptic agents. They were also alleged to be effective in lowering of intraocular pressure and hence in treating glaucoma, and as effective in treating menopausal symptoms, in particular
  • the 5HT 2A receptor is also associated with the contraction of vascular smooth muscle, platelet aggregation, thrombus formation and coronary artery spasms. Accordingly, selective 5HT 2 A antagonists may have potential in the treatment of cardiovascular diseases. For example, sarpogrelate, a selective 5HT 2 A antagonist, has been introduced clinically as a therapeutic agent for the treatment of ischemic diseases associated with thrombosis (Nagatomo, et al, 2004, Pharmacology & Therapeutics 104(l):59-81).
  • the 5HT 2 B receptor is known to mediate, at least in part, gastric contractions.
  • Yohimbine a 5HT 2 A and/or 5HT 2 B antagonist has been shown in clinical studies to be useful in treating male impotence, and has been prescribed for treatment of erectile dysfunction, S SRI -induced sexual dysfunction, female hypersexual disorder, post traumatic stress disorder (PTSD), and to facilitate recall of traumatic memories in patients with PTSD.
  • PTSD post traumatic stress disorder
  • Antagonists of the 5HT 2 B receptor have also been asserted as useful for the treatment of disorders of the GI tract, especially disorders involving altered mobility, including irritable bowel syndrome (WO 01/08668), disorders of gastric motility, dyspepsia, GERD, tachygastria, migraine/neurogenic pain (WO 97/44326); pain (U.S. Patent No. 5,958,934); anxiety and depression (WO 97/44326); benign prostatic hyperplasia (U.S. Patent No.
  • the 5HT 2C receptor is known to mediate, at least in part, several CNS functions (anxiety, choroid plexus), and cerebrospinal fluid (CSF) secretion.
  • Antagonists of the 5HT 2 c receptor having established therapeutic utilities include, but are not limited to, mesulergine (possibly useful for treating Parkinson's disease); agomelatine (currently in development for treatment of depression by Novartis); and methysergide (useful for treating and prophylaxis of migraine headaches). It is expected that all of these diseases and disorders will likewise respond to treatment with (+)-beloxepin.
  • Antagonists of the 5HT 2 c receptor have also been asserted as useful for the treatment of CNS disorders such as anxiety, depression (both bipolar and unipolar), single or recurrent major depressive episodes, with or without psychotic features, catatonic features, melancholic features, atypical features or postpartum onset, dysthymic disorders with early or late onset and with or without atypical features, neurotic depression, post traumatic stress disorder, social phobia, vascular dementia with depressed mood, mood disorders induced by alcohol, amphetamines, cocaine, hallucinogens, inhalants, opioids, phencyclidine, sedatives, hypnotics, anxiolytics and the like; schizoaffective disorder of the depressed type, adjustment disorder with depressed mood, epilepsy, obsessive compulsive disorders, migraine, Alzheimer's disease, with early or late onset and/or with depressed mood; cognitive disorders including dementia, amnestic disorders and cognitive disorders not otherwise specified, sleep disorders (including
  • the present disclosure provides methods of treating diseases and disorders responsive to treatment with 5HT 2 antagonist compounds.
  • the methods generally comprise administering to a mammal, including a human, suffering from a disease or indication responsive to treatment with a 5HT 2 antagonist compound an amount of a (+)-beloxepin composition described herein effective to treat the disease or disorder.
  • the disease or disorder is responsive to treatment with a compound that antagonizes one of the 5HT 2 A, 5HT 2 B or 5HT 2 c receptors.
  • Non-limiting examples of diseases and disorders that respond to treatment with 5HT 2 A, 5HT 2 B, 5HT 2 c selective and nonselective antagonists are provided above ⁇ also see Leysen, 2004, Current Drug Targets: CNS & Neurological Disorders 3(1): 11-26).
  • the disease or disorder is responsive to treatment with a dual antagonist that antagonizes 5HT 2 A, 2 B, 5HT 2 A, 2C , or 5HT 2 B, 2 c-
  • the disease or disorder is responsive to treatment with a triple 5HT 2A , 2B , 2 c antagonist.
  • the (+)-beloxepin composition comprises beloxepin that is enriched in the (+) enantiomer. In some embodiments, the beloxepin composition comprises substantially enantiomerically pure (+)-beloxepin. In some embodiments the beloxepin composition comprises enantiomerically pure (+)-beloxepin.
  • the (+)-beloxepin composition can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating indications responsive to 5HT antagonist compounds and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the (+)-beloxepin compositions described herein in a regimen to treat diseases and/or disorders responsive to 5HT2 antagonist therapy are provided in a later section.
  • the present disclosure provides methods of antagonizing 5HT2 receptors, including the 5HT 2 A, 5HT 2B and/or 5HT 2 c receptor subtypes.
  • the methods generally comprise contacting a 5HT2 receptor with an amount of (+)-beloxepin effective to antagonize the receptor (as measured in a conventional cellular assay). In some embodiments, the method is carried out in the absence of (-)-beloxepin.
  • the 5HT2 receptor is contacted with a (+)-beloxepin composition as described herein.
  • the (+)-beloxepin composition comprises beloxepin that is enriched in the (+) enantiomer.
  • the (+)-beloxepin composition comprises substantially enantiomerically pure (+)-beloxepin. In some embodiments, the (+)-beloxepin composition comprises enantiomerically pure (+)-beloxepin.
  • the methods can be practiced in vitro with isolated receptors or cells that express one or more of the 5HT2 receptor subtypes 2A, 2B or 2C, or in vivo as a therapeutic approach towards the treatment of diseases or disorders that are, at least in part, mediated by antagonisms of the 5HT2 receptor, including one or more of the 5HT 2 A, 5HT 2 B and 5HT 2 c receptor subtypes. Specific examples of diseases or disorders that are, at least in part, mediated by such receptor antagonism include, but are not limited to, those listed above.
  • (+) enantiomer of beloxepin is also useful for treating pain. Indeed, in experiments carried out by the applicants and reported herein, (+)-beloxepin exhibited therapeutic efficacy in a rodent model of pain.
  • the present disclosure provides methods of treating pain in mammals, including humans.
  • the methods generally comprise administering to a mammal suffering from pain, including a human, an amount of a (+)-beloxepin composition described herein effective to treat the pain.
  • the (+)-beloxepin composition comprises beloxepin that is enriched in (+) enantiomer.
  • the (+)-beloxepin composition comprises substantially enantiomerically pure (+)-beloxepin.
  • the (+)-beloxepin composition comprises enantiomerically pure (+)-beloxepin.
  • the methods can be used to treat numerous different types of pain syndromes, including acute or chronic pain that is either nociceptive in origin (for example somatic or visceral) or non-nociceptive in origin (for example neuropathic or sympathetic).
  • the pain is nociceptive pain including, but not limited to, inflammatory pain such as that associated with IBS or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis.
  • the pain is non-nociceptive pain including, but not limited to, neuropathic pain (such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa), central pain (for example, post- stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa
  • central pain for example, post- stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis
  • peripheral neuropathy for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies.
  • the (+)-beloxepin composition can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating pain and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the (+)-beloxepin compositions described herein in a pain treatment or management regimen are provided in a later section.
  • Analogs of beloxepin are known in the art. For example, analogs of beloxepin are described in US Patent No. 4,977,158, the disclosure of which is incorporated herein by reference. These analogs are expected to exhibit anti-pain activities similar to beloxepin.
  • the present disclosure provide a method of treating pain in a mammal comprising administering to a mammal suffering from pain, including a human, an amount of beloxepin and/or a beloxepin analog effective to treat the pain.
  • the beloxepin or beloxepin analog can be administered as the compound per se, or in the form of a composition.
  • the beloxepin or beloxepin analog can be included in the composition as the free base, or in the form of a salt.
  • the beloxepin and/or beloxepin analog is included in the composition in the form of a pharmaceutically acceptable salt.
  • composition can be formulated for administration to animals in veterinary contexts, or for administration to humans, via virtually any route or mode of administration, including, but not limited to, oral, topical, ocular, buccal, systemic, nasal, injection, transdermal, rectal, vaginal, inhalation or insufflation.
  • the composition is formulated for oral administration, for example, to humans.
  • the methods can be used to treat numerous different types of pain syndromes, including acute or chronic pain that is either nociceptive (for example somatic or visceral) or non-nociceptive (for example neuropathic or sympathetic) in origin.
  • the pain is nociceptive pain including, but not limited to, surgical pain, inflammatory pain such as that associated with inflammatory bowel syndrome ("IBS") or rheumatoid arthritis, pain associated with cancer, and pain associated with osteoarthritis.
  • IBS inflammatory bowel syndrome
  • osteoarthritis pain associated with osteoarthritis.
  • the pain is non-nociceptive pain including, but not limited to, neuropathic pain such as postherpetic neuralgia (“PHN”), trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • PPN postherpetic neuralgia
  • trigeminal neuralgia focal peripheral nerve injury
  • anesthesia dolorosa central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • central pain for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis
  • peripheral neuropathy for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies
  • the beloxepin and/or beloxepin analog can be administered alone, or it can be administered in combination with, or adjunctively to, one or more other drugs useful for treating pain and/or other indications.
  • drugs that can be used in combination with, or adjunctively to, the beloxepin and/or beloxepin analogs in a pain treatment or management regimen are provided in a later section.
  • beloxepin is administered in combination with, or adjunctively to, one or more beloxepin analogs.
  • n is 0 or 1 ;
  • X is O or S
  • R 1 represents one or two identical or different substituents selected from H, OH, halogen, C1-C4 alkyl and Ci-C 4 alkoxy;
  • R 2 represents one or two identical or different substituents selected from H, OH, halogen, Ci-C 4 alkyl and Ci-C 4 alkoxy;
  • R and R are two substituents which are in the cis configuration and R is OH and R > 4 is H;
  • R 5 is H or Ci-C 4 alkyl.
  • beloxepin analogs comprise racemates and (+)-cis and (-)-cis enantiomers having distinct biological activities that correlate with the activities of the corresponding ( ⁇ )-, (+)- and (-)-beloxepin isomers. Accordingly, the various enantiomers of the beloxepin analogs of structural formula (I) that correspond to the (-) enantiomer of beloxepin can be used in the compositions and methods described herein.
  • FIG. 1 provides a graph demonstrating the antiallodynic effect of beloxepin (30 mg/kg IP) in L5 SNL rats 14 days post surgery;
  • FIG. 2 provides a graph demonstrating the antiallodynic effect of beloxepin (3, 10 and 30 mg/kg IP) in L5 SNL rats 16 days post surgery;
  • FIG. 3 provides a graph illustrating the superior antiallodynic effect of beloxepin (30 mg/kg IP) as compared to reboxetine, a selective norepinephrine reuptake inhibitor (30 mg/kg IP), in L5 SNL rats;
  • FIG. 4 provides a graph demonstrating the antiallodynic effect of orally administered beloxepin (60 mg/kg PO) in L5 SNL rats 8 days post surgery;
  • FIG. 5 provides a graph comparing the antiallodynic effects produced by beloxepin, duloxetine, amitriptyline, and reboxetine (each at a concentration of 30 mg/kg IP) in L5 SNL rats;
  • FIGS. 6 A and 6B provide graphs demonstrating the robust anti-nociceptive activity of beloxepin in a rodent model of acute nociception
  • FIG. 7 provides a graph illustrating the robust antihyperalgesia activity of beloxepin in an animal model of inflammatory pain (rats treated with Freund's Complete Adjuvent);
  • FIG. 8 provides a graph illustrating the robust activity of beloxepin in a rodent model of visceral pain (mice treated with acetic acid);
  • FIG. 9 provides a graph comparing the mechanical antihyperalgesic effects of
  • FIG. 10 provides a graph demonstrating the antiallodynic effect of orally administered beloxepin (60 mg/kg PO) in L5 SNL rats 7 days post surgery;
  • FIG. 11 provides a graph comparing the antiallodynic effects of beloxepin, duloxetine, and esreboxetine (each compound dosed at 30 mg/kg IP) in L5 SNL rats;
  • FIG. 12 provides a graph demonstrating the antiallodynic effect of beloxepin (30 mg/kg IP) in the rat hindpaw incisional model 24 hours post surgery;
  • FIG. 13 provides a graph demonstrating the antiallodynic effect of orally-administered beloxepin (60 mg/kg IP) in the rat hindpaw incisional model 24 hours post surgery;
  • FIG. 14 provides a graph demonstrating the antiallodynic effect of intravenously-administered beloxepin (3 mg/kg IV) in the rat hindpaw incisional model 24 hours post surgery.
  • FIG. 15 provides a graph illustrating the inhibition of CYP2D6 (dextromethorphan O-demethylation) by beloxepin and quinidine.
  • FIG. 16 provides a graph demonstrating the antiallodynic effect of (+)- and (-)-beloxepin (30 mg/kg IP) in L5 SNL rats 8 days post surgery;
  • FIG. 17 provides a graph demonstrating the antiallodynic effect of (-)-beloxepin (30 mg/kg IP) in L5 SNL rats 14 days post surgery;
  • FIG. 18 provides a graph demonstrating the antiallodynic effect of orally administered (-)-beloxepin (60 mg/kg PO) in L5 SNL rats 7 days post surgery;
  • FIG. 19 provides a graph demonstrating the antiallodynic effect of orally administered (+)-beloxepin (60 mg/kg PO) in L5 SNL rats 14 days post surgery;
  • FIG. 20 provides a graph demonstrating the antiallodynic effect of (-)-beloxepin (30 mg/kg IP) in the rat hindpaw incisional model 24 hours post surgery;
  • FIG. 21 provides a graph demonstrating the antiallodynic effect of (+)-beloxepin (30 mg/kg IP) in the rat hindpaw incisional model 24 hours post surgery;
  • FIG. 22 provides a graph depicting the antinociceptive effects of (-)-beloxepin (30 mg/Kg) in the rat 50 0 C hot plate model.
  • FIG. 23 provides a graph depicting the antinociceptive effects of (+)-beloxepin (30 mg/Kg) in the rat 50 0 C hot plate model.
  • the present disclosure concerns the use of beloxepin and/or its analogs to treat pain.
  • the disclosure is based, in part, on the surprising discovery that beloxepin, which is a weak selective inhibitor of NE reuptake, nonetheless produces significant and robust activity across a broad spectrum of rodent models of various types of pain syndromes, including rodent models of acute nociceptive pain, inflammatory pain, visceral pain and neuropathic pain.
  • inhibition of NE reuptake correlates with efficacy in the treatment of pain (see, Max et al., 1992, supra; Collins et al., 2000, supra; Atkinson et al, 1999, supra; Levental et al, 2007, supra).
  • beloxepin Based on its weak activity at the NET, beloxepin would not be expected to be useful in treating pain. Yet, it produces robust activity in numerous animal models of pain, and in the case of tactile anitallodynia, activity of magnitude greater than that observed with numerous compounds known to be effective in treating pain.
  • compositions comprising the (-) enantiomer of racemic ( ⁇ )-beloxepin, and methods of use of the (-)-enantiomer of racemic ( ⁇ )-beloxepin and compositions comprising the (-)-enantiomer of racemic ( ⁇ )-beloxepin
  • compositions comprising the (+) enantiomer of racemic ( ⁇ )-beloxepin, and methods of use of the (+)-enantiomer of racemic ( ⁇ )-beloxepin and compositions comprising the (+)-enantiomer of racemic ( ⁇ )-beloxepin.
  • Racemic beloxepin (( ⁇ )-beloxepin), i.e., "beloxepin,” also known as “Org-4428” and "c ⁇ -l,2,3,4,4a,13b-hexahydro-2,10-dimethyldiben-[2,3:6,7]oxepino [4,5c]pyridine-4a-ol]," is illustrated below:
  • n 0 or 1 ;
  • X is O or S;
  • R 1 represents one or two identical or different substituents selected from H, OH, halogen, C1-C4 alkyl and Ci-C 4 alkoxy
  • R 2 represents one or two identical or different substituents selected from H, OH, halogen, Ci -C 4 alkyl and Ci-C 4 alkoxy
  • R 3 and R 4 are two substituents which are in the cis configuration, where R 3 is OH and R 4 is H;
  • R 5 is H or Ci-C 4 alkyl.
  • Beloxepin analogs according to structural formula (I) are referred to herein as "beloxepin analogs," or other grammatical equivalents.
  • beloxepin analogs can be used in the various compositions and methods described herein and the various illustrative embodiments described for beloxepin apply also to the beloxepin analogs as if such embodiments were specifically described.
  • Beloxepin, its (+)- and (-)-enantiomers, and/or the analogs thereof ⁇ i.e. analogs of beloxepin, (+)- beloxepin, and (-)-beloxepin), can be used in the various methods described herein as the compound per se, or can be included in a composition formulated for, among other things, a specific mode of administration.
  • the beloxepin or beloxepin analog can be present in the composition as the free base, or in the form of a salt, for example, an acid additional salt. In some embodiments, such salts are pharmaceutically acceptable salts.
  • a racemic composition is "enriched" in a particular enantiomer when that enantiomer is present in excess over the other enantiomer, i.e., when that enantiomer comprises more than 50% of the total beloxepin in the composition.
  • a composition that is enriched in a particular enantiomer will typically comprise at least about 60%, 70%, 80%, 90%, or even more, of the specified enantiomer.
  • the amount of enrichment of a particular enantiomer can be confirmed using conventional analytical methods routinely used by those skilled in the art, including NMR spectroscopy in the presence of chiral shift reagents, gas chromatographic analysis using chiral columns, and high pressure liquid chromatographic analysis using chiral columns.
  • a single enantiomer will be substantially free of the other enantiomer.
  • substantially free of is meant that the composition comprises less than about 10% of the specified undesired enantiomer, as established using conventional analytical methods routinely used by those of skill in the art, such as the methods mentioned above.
  • the amount of undesired enantiomer comprising the compound composition may be less than 10%, for example, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1% or even less.
  • Enantiomerically enriched compound compositions that contain at least about 90% of a specified enantiomer are referred to herein as "substantially enantiomerically pure.”
  • substantially enantiomerically pure compositions of chirally active compounds can contain in the range of at least about 90%, 91%, 92%, 93%, 94%, 95%, 96% or 97%, or even more (including any amount falling with the range of about 90-100%) of a specified enantiomer.
  • compositions of chirally active compounds that contain at least about 98% of a specified enantiomer are referred to herein as "enantiomerically pure.”
  • enantiomerically pure compositions of chirally active compounds can contain in the range of at least about 98%, 99%, or even more (including any amount falling with the range of about 98-100%) of a specified enantiomer.
  • Structural formula (I) is beloxepin when X is O, n is 1, R 1 and R 4 are each H, R 2 is 2-methyl, R 3 is OH and R 5 is methyl.
  • the corresponding (-)-beloxepin analogs can also be used in the various compositions and methods described herein, and the various illustrative embodiments described for (-)-beloxepin apply also to the corresponding (-)-beloxepin analogs as if such embodiments were specifically described.
  • the beloxepin can be present as a non-racemic mixture enriched in the (-) enantiomer, as the substantially enantiomerically pure (-) enantiomer or as the enantiomerically pure (-) enantiomer.
  • the compositions comprise substantially enantiomerically pure (-)-beloxepin or enantiomerically pure (-)-beloxepin.
  • the (-)-beloxepin can be present in the composition as the free base, or in the form of a salt, for example, an acid additional salt.
  • the (-)-beloxepin is present in the composition in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, etc.), ary
  • the (-)-beloxepin is present in the composition as the free base. In some embodiments, the (-)-beloxepin is present in the composition as an organic acid addition salt.
  • Structural formula (I) is beloxepin when X is O, n is 1, R 1 and R 4 are each H, R 2 is 2-methyl, R 3 is OH and R 5 is methyl.
  • the corresponding (+)-beloxepin analogs can also be used in the various compositions and methods described herein and the various illustrative embodiments described for the (+)-beloxepin apply also to the corresponding (+)-beloxepin analogs as if such embodiments were specifically described.
  • the beloxepin can be present as a non-racemic mixture enriched in the (+) enantiomer, as the substantially enantiomerically pure (+) enantiomer or as the enantiomerically pure (+) enantiomer.
  • compositions comprise substantially enantiomerically pure (+)-beloxepin or enantiomerically pure (+)-beloxepin.
  • Methods for synthesizing racemic beloxepin and isolating the (+) enantiomer via chiral separation are described in a later section.
  • the (+)-beloxepin can be present in the composition as the free base, or in the form of a salt, for example, an acid additional salt.
  • the (+)-beloxepin is present in the composition in the form of a pharmaceutically acceptable salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids or organic acids.
  • Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, etc.), ary
  • the (+)-beloxepin is present in the composition as the free base. In some embodiments, the (+)-beloxepin is present in the composition as an organic acid addition salt.
  • pharmaceutically acceptable salts are those salts that retain substantially one or more of the desired pharmacological activities of the parent compound and which are suitable for administration to humans.
  • Pharmaceutically acceptable salts include, but are not limited to, acid addition salts formed with inorganic or organic acids. Inorganic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, hydrohalide acids (e.g.
  • Organic acids suitable for forming pharmaceutically acceptable acid addition salts include, by way of example and not limitation, acetic acid, trifluoroacetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, palmitic acid, benzoic acid, 3-(4-hydroxybenzoyl) benzic acid, cinnamic acid, mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid, ethanesulfonic acid, 1 ,2-ethane-disulfonic acid, 2- hydroxyethanesulfonic acid, etc.), ary
  • Beloxepin can be synthesized or prepared using methods described in the literature, for example, beloxepin can be synthesized as described in US Patent No. 4,977,158, the disclosure of which is incorporated herein by reference, and the (+) and (-) enantiomers isolated by conventional chiral chromatography (see, e.g., Chiral Separation Techniques: A Practical Approach, 2nd ed., Wiley- VCH, Weinheim, 2001). Beloxepin analogs can also be synthesized using the methods described in US Patent No. 4,977,158 and the corresponding (+) and (-) enantiomers isolated by conventional chiral chromatography.
  • Pain is generally understood to refer to the perception or condition of unpleasant sensory or emotional experience, which may or may not be associated with actual damage to tissues. It is generally understood to include two broad categories: acute and chronic (see, e.g., Analgesics, Buschmann et ah, Wiley- VCH, Verlag GMbH & Co. KgaA, Weinheim, 2002; Jain, 2000, Emerging Drugs 5(2):241-257) that is either of nociceptive origin (for example somatic or visceral) or non-no ciceptive origin (for example neuropathic or sympathetic).
  • nociceptive origin for example somatic or visceral
  • non-no ciceptive origin for example neuropathic or sympathetic
  • Acute pain generally includes nociceptive pain arising from strains/sprains, burns, myocardial infarction, acute pancreatitis, surgery, trauma and cancer.
  • Chronic pain generally includes nociceptive pain, including, but not limited to, inflammatory pain such as that associated with IBS or rheumatoid arthritis, pain associated with cancer and pain associated with osteoarthritis; and non-nociceptive pain, including, but not limited to, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • beloxepin is surprisingly effective at treating pain in rodent models of neuropathic, acute nociceptive, inflammatory and visceral pain. Based upon this animal data, it is expected that beloxepin and beloxepin analogs will be useful in treating various different pain syndromes including, but not limited to, acute pain of nociceptive origin, such as, for example, surgical pain, chronic pain of nociceptive origin, such as, for example, inflammatory pain or cancer pain, and chronic pain of non-nociceptive origin, such as, for example, neuropathic pain.
  • acute pain of nociceptive origin such as, for example, surgical pain
  • chronic pain of nociceptive origin such as, for example, inflammatory pain or cancer pain
  • chronic pain of non-nociceptive origin such as, for example, neuropathic pain.
  • a "therapeutically effective" amount of a compound or composition is an amount that eradicates or ameliorates the underlying disease or indication being treated and/or that eradicates or ameliorates one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, not withstanding that the patient may still be afflicted with the underlying disease or indication.
  • Therapeutic benefits also includes halting or slowing the progression of the disease or indication, regardless of whether improvement is realized.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the depression or the symptoms thereof, including, but not limited to, changes in mood, feeling of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, self-deprecation, insomnia, anorexia, weight loss, decreased energy and libido, and hormonal circadian rhythms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the anxiety disorder or one of the symptoms thereof including, but are not limited to, a fear of losing control of one's own actions, a sense of terror arising from no apparent reason, a dread of catastrophe, uneasiness, nervousness, nagging uncertainty about future events, headaches, fatigue, and sub-acute autonomic symptoms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the pain or the symptoms thereof, including, but not limited to, shooting sensations, burning sensations, electrical sensations, aching, discomfort, soreness, tightness, stiffness, sleeplessness, numbness, and weakness.
  • An effective amount may also be an amount of a composition that blocks the onset of pain or the symptoms thereof.
  • the composition may be administered therapeutically after the onset of sensation of pain or one or more of its symptoms, and/or prophylactically prior to the onset of sensation of pain or one or more of its symptoms.
  • the composition may be administered in response to the sensation of pain or one or more of its symptoms and prophylactically thereafter to avoid its recurrence.
  • (-)-beloxepin binds the norepinephrine ("NE") transporter, and inhibits NE reuptake.
  • NE norepinephrine
  • the use of NRI compounds to treat a variety of diseases and disorders mediated, at least in part, by dysregulated NE reuptake is well documented.
  • the NRI atomoxetine (sold under the tradename STATTERA by Eli Lilly & Co.) is approved in the US for the treatment of attention deficit disorder (ADD) and attention deficit hyperactivity disorder (ADHD);
  • the NRI reboxetine (sold under the tradename EDRONAX by Pharmacia-Upjohn) is approved in the UK and Ireland for the treatment of depressive illness;
  • the NRI viloxazine (sold under the tradename VIVALAN by AstraZeneca) is approved in the US for the treatment of depression;
  • the NRI maprotiline (sold under the tradename LUDIOMIL by Ciba-Geigy Corporation) is approved in the US for the treatment of depressive illness in patients with depressive neurosis (dysthymic disorder), manic-depressive illness, major depressive disorder and the relief of anxiety associated with depression;
  • the NRI nortriptyline (sold under the tradename Aventyl ® by Eli Lilly) is approved in the US for the treatment
  • racemic ( ⁇ )-beloxepin has been established in the literature (beloxepin has a reported logBB of 0.82; Kelder et ah, 1999, Pharm. Res. 16:1514). Accordingly, the (-)-beloxepin compositions described herein are expected to be useful to treat any disease and/or disorder mediated, at least in part, by dysregulated NE reuptake.
  • the (-)-beloxepin compositions described herein will be useful to treat all of the various diseases that respond to treatment with other NRI agents, including, by way of example and not limitation, atomoxetine, reboxetine, maprotiline, and nortriptyline.
  • Diseases and disorders known to be mediated, at least in part, by dysregulated NE reuptake, and that are known to respond to treatment with NRI compounds, and that are expected to be treatable with the (-)-beloxepin compositions described herein include, but are not limited to, urinary disorders, including urinary incontinence; mood disorders such as depression and seasonal affective disorder (SAD); cognitive disorders such as dementia; psychotic disorders such as schizophrenia and mania; anxiety disorders; personality disorders such as ADHD; eating disorders such as anorexia nervosa and bulimia nervosa; chemical dependencies resulting from addictions to drugs or substances of abuse such as addictions to nicotine, alcohol, cocaine, heroin, phenobarbital and benzodiazepines; withdrawal syndromes; endocrine disorders such as hyperprolactinaemia; impulse disorders such as trichotillomania and kleptomania; tic disorders such as Tourette's syndrome; gastrointestinal tract disorders such as irritable bowel syndrome (IBS), ileus, gastropar
  • DSM-IV Diagnostic and Statistic Manual of Mental Disorders IV
  • mood disorders such as, for example, depression
  • anxiety disorders such as, for example OCD
  • eating disorders such as, for example, anorexia nervosa and bulimia nervosa
  • impulse disorders such as, for example, trichotillomania
  • sleep disorders such as, for example, insomnia related to opioid withdrawal
  • personality disorders such as, for example, ADHD
  • somatoform disorders such as certain types of pain.
  • the (-)-compositions described herein are used to treat such mood disorders.
  • Pain is also thought to be mediated at least in part by NE reuptake. Pain is generally understood to refer to the perception or condition of unpleasant sensory or emotional experience, which may or may not be associated with actual damage to tissues. It is generally understood to include two broad categories, acute and chronic (see, e.g., Buschmann et al., (2002) “Analgesics,” Wiley VCH, Verlag GMbH & Co. KgaA, Weinheim; Jain, 2000, “Emerging Drugs” 5(2):241 257), and can be of either nociceptive origin (for example somatic or visceral) or non-nociceptive origin (for example neuropathic or sympathetic).
  • nociceptive origin for example somatic or visceral
  • non-nociceptive origin for example neuropathic or sympathetic
  • Acute pain generally includes nociceptive pain arising from strains/sprains, burns, myocardial infarction, acute pancreatitis, surgery, trauma and cancer.
  • Chronic pain generally includes nociceptive pain, including, but not limited to, inflammatory pain such as that associated with IBS or rheumatoid arthritis, pain associated with cancer and pain associated with osteoarthritis; and non-nociceptive pain, including, but not limited to, neuropathic pain (for example post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa), central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • neuropathic pain for example post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa
  • central pain for example, post-stroke
  • (-)-beloxepin is effective at treating pain in a rodent model of neuropathic pain.
  • the (-)-beloxepin compositions described herein will be useful in treating various different pain syndromes, including chronic pain of nociceptive origin, such as, for example, inflammatory pain, and chronic pain of non-nociceptive origin, such as, for example, neuropathic pain.
  • the (-)-beloxepin compositions described herein are used to treat pain, including the various types pain discussed above. It is also expected that the (-)-beloxepin compositions described herein will also be useful for blocking the onset of pain.
  • compositions comprise beloxepin that is enriched in the (-) enantiomer. In some embodiments, such compositions comprise substantially enantiomerically pure (-)-beloxepin. In some embodiments, such compositions comprise enantiomerically pure (-)-beloxepin.
  • the therapy can be applied following the onset of pain and/or one or more of its symptoms, or prophylactically to avoid or delay its onset.
  • the (-)-beloxepin composition When used to treat various diseases or disorders discussed herein, the (-)-beloxepin composition will generally be administered in amounts effective to treat the particular disease or disorder. As will be recognized by skilled artisans, what is understood to be “therapeutically effective” and providing therapeutic benefit oftentimes depends upon the specific disease or disorder being treating. Skilled artisans will be able to ascertain a therapeutically effective amount based upon long established criteria for the particular indication.
  • a "therapeutically effective" amount of a composition is an amount that eradicates or ameliorates the underlying disease or indication being treated and/or that eradicates or ameliorates one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, not withstanding that the patient may still be afflicted with the underlying disease or indication.
  • Therapeutic benefits also includes halting or slowing the progression of the disease or indication, regardless of whether improvement is realized.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the depression or the symptoms thereof, including, but not limited to, changes in mood, feeling of intense sadness, despair, mental slowing, loss of concentration, pessimistic worry, agitation, self-deprecation, insomnia, anorexia, weight loss, decreased energy and libido, and hormonal circadian rhythms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the anxiety disorder or one of the symptoms thereof including, but are not limited to, a fear of losing control of one's own actions, a sense of terror arising from no apparent reason, a dread of catastrophe, uneasiness, nervousness, nagging uncertainty about future events, headaches, fatigue, and sub-acute autonomic symptoms.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the pain or the symptoms thereof, including, but not limited to, shooting sensations, burning sensations, electrical sensations, aching, discomfort, soreness, tightness, stiffness, sleeplessness, numbness, and weakness.
  • An effective amount may also be an amount of a composition that blocks the onset of pain or the symptoms thereof.
  • the composition may be administered therapeutically after the onset of sensation of pain or one or more of its symptoms, and/or prophylactically prior to the onset of sensation of pain or one or more of its symptoms. Is some embodiments, the composition may be administered in response to the sensation of pain or one or more of its symptoms and prophylactically thereafter to avoid its recurrence
  • (+)-beloxepin binds to and antagonizes the 5HT 2 A, 5HT 2 B and 5HT 2 c receptor subtypes.
  • Antagonists of the 5HT 2 receptors are useful for treating a variety of different diseases and disorders, mediated at least in party by dysfunction of 5-HT uptake, including but not limited to the following: neurological conditions, including sleep disorders (including disturbances of Circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy); psychotic disorders such as schizophrenia, depression, anxiety, panic disorder, obsessive compulsive disorder, pain; eating disorders (anorexia, anorexia nervosa and anorexia bulimia), mood disorders (including social phobia, vascular dementia with depressed mood), extrapyramidal symptoms associated with the administration of neuroleptic agents; lowering of intraocular pressure and hence in treating glaucoma, treatment of menopausal symptoms, in particular, hot flushes; cardiovascular diseases
  • migraine/neurogenic pain migraine/neurogenic pain
  • benign prostatic hyperplasia hypertension, priapism, asthma, obstructive airway disease, incontinence, bladder dysfunction, disorders of the uterus (dysmenorrhea, pre term labor, post partum remodeling, endometriosis, and fibrosis); pulmonary hypertension; epilepsy, Alzheimer's disease, cognitive disorders including dementia, amnestic and cognitive disorders; disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • the compositions and methods disclosed herein are also useful as memory and/or cognition enhancers in healthy humans.
  • (+)-beloxepin compositions described herein are expected to be useful to treat any disease and/or disorder mediated, at least in part, by dysregulation of the 5HT 2 receptor, e.g., 5HT 2 receptor antagonism generally, and 5HT 2 A, 5HT 2 B and/or 5HT 2 c receptor antagonism specifically.
  • (+)-beloxepin compositions described herein will be useful to treat many different diseases that respond to treatment with other 5HT 2 antagonists, including, by way of example and not limitation, neurological conditions, including sleep disorders (including disturbances of Circadian rhythm, dyssomnia, insomnia, sleep apnea and narcolepsy); psychotic disorders such as schizophrenia, depression, anxiety, panic disorder, obsessive compulsive disorder, pain; eating disorders (anorexia, anorexia nervosa and anorexia bulimia), mood disorders (including social phobia, vascular dementia with depressed mood), extrapyramidal symptoms associated with the administration of neuroleptic agents; lowering of intraocular pressure and hence in treating glaucoma, treatment of menopausal symptoms, in particular, hot flushes; cardiovascular diseases; disorders of the GI tract, especially disorders involving altered mobility, including irritable bowel syndrome; disorders of gastric motility, dyspepsia, GERD,
  • migraine/neurogenic pain migraine/neurogenic pain
  • benign prostatic hyperplasia hypertension, priapism, asthma, obstructive airway disease, incontinence, bladder dysfunction, disorders of the uterus (dysmenorrhea, pre-term labor, post partum remodelling, endometriosis, and fibrosis); pulmonary hypertension; epilepsy, Alzheimer's disease, cognitive disorders including dementia, amnestic and cognitive disorders; disorders associated with spinal trauma and/or head injury such as hydrocephalus.
  • the compositions and methods disclosed herein are also useful as memory and/or cognition enhancers in healthy humans.
  • Pain is generally understood to refer to the perception or condition of unpleasant sensory or emotional experience, which may or may not be associated with actual damage to tissues. It is generally understood to include two broad categories; acute and chronic (see, e.g., Buschmann et ah, 2002, "Analgesics,” Wiley VCH, Verlag GMbH & Co. KgaA, Weinheim; Jain, 2000, Expert Opinion on Emerging Drugs 5(2):241-257), and can be of nociceptive origin (for example somatic or visceral) or non-nociceptive origin (for example neuropathic or sympathetic).
  • nociceptive origin for example somatic or visceral
  • non-nociceptive origin for example neuropathic or sympathetic
  • Acute pain generally includes nociceptive pain arising from strains/sprains, burns, myocardial infarction, acute pancreatitis, surgery, trauma and cancer.
  • Chronic pain generally includes nociceptive pain, including, but not limited to, inflammatory pain such as that associated with IBS or rheumatoid arthritis, pain associated with cancer and pain associated with osteoarthritis; and non-nociceptive pain, including, but not limited to, neuropathic pain such as post-herpetic neuralgia, trigeminal neuralgia, focal peripheral nerve injury, anesthesia dolorosa, central pain (for example, post-stroke pain, pain due to spinal cord injury or pain associated with multiple sclerosis), and peripheral neuropathy (for example, diabetic neuropathy, inherited neuropathy or other acquired neuropathies).
  • (+)-beloxepin is effective at treating pain in a rodent model of pain. Based upon this animal data, it is expected that the (+)-beloxepin compositions described herein will be useful in treating various different pain syndromes, including chronic pain of nociceptive origin, such as, for example, inflammatory pain, and chronic pain of non-nociceptive origin, such as, for example, neuropathic pain. Accordingly, in some embodiments, the (+)-beloxepin compositions described herein are used to treat pain, including the various types pain discussed above. It is also expected that the (+)-beloxepin compositions disclosed herein will be useful for blocking the onset of pain.
  • the (+)-beloxepin composition comprises beloxepin that is enriched in the (+) enantiomer. In some embodiments, such compositions comprise substantially enantiomerically pure (+)-beloxepin. In some embodiments, such compositions comprise enantiomerically pure (+)-beloxepin.
  • the (+)-beloxepin composition When used to treat various diseases or disorders discussed herein, the (+)-beloxepin composition will generally be administered in amounts effective to treat the particular disease or disorder. As will be recognized by skilled artisans, what is understood to be “therapeutically effective” and providing therapeutic benefit oftentimes depends upon the specific disease or disorder being treating. Skilled artisans will be able to ascertain a therapeutically effective amount based upon long established criteria for the particular indication.
  • a "therapeutically effective" amount of a composition is an amount that eradicates or ameliorates the underlying disease or indication being treated and/or that eradicates or ameliorates one or more of the symptoms associated with the underlying disorder such that the patient reports an improvement in feeling or condition, not withstanding that the patient may still be afflicted with the underlying disease or indication.
  • Therapeutic benefits also includes halting or slowing the progression of the disease or indication, regardless of whether improvement is realized, including those diseases, conditions, and indications disclosed above.
  • a therapeutically effective amount is an amount of composition that eradicates or ameliorates the pain or the symptoms thereof, including, but not limited to, shooting sensations, burning sensations, electrical sensations, aching, discomfort, soreness, tightness, stiffness, sleeplessness, numbness, and weakness.
  • An effective amount may also be an amount of a composition that blocks the onset of pain or the symptoms thereof.
  • An effective amount may also be an amount of a composition comprising (+)-beloxepin that blocks the onset of pain or the symptoms thereof.
  • the therapy can be applied following the onset of pain and/or one more of its symptoms, or prophylactically to avoid or delay its onset.
  • Beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs can be used alone, or in combination with, or adjunctively to, other therapeutic agents to treat pain.
  • beloxepin and/or its analogs can be combined with other analgesics, including but not limited to, cannabinoids and opioids.
  • cannabinoids include cannabinoids and opioids.
  • cannabinoids are available that may be suitable for use in combination therapy, including, but not limited to, a cannabinoid that is selected from a ⁇ 9 -tetrahydrocannabinol and cannabidiol, and mixtures thereof.
  • the (-)-beloxepin compositions described herein will be useful in combination therapy for the treatment of pain. Accordingly, the (-)-beloxepin compositions described herein can be combined with other analgesics, including but not limited to, cannabinoids and opioids.
  • cannabinoids are available that may be suitable for use in combination therapy, including, but not limited to, a cannabinoid that is selected from a ⁇ 9 -tetrahydrocannabinol and cannabidiol, and mixtures thereof.
  • (+)-beloxepin compositions described herein will be useful in combination therapy for the treatment of pain. Accordingly, the (+)-beloxepin compositions can be combined with other analgesics, including but not limited to, cannabinoids and opioids.
  • cannabinoids are available that may be suitable for use in combination therapy, including, but not limited to, a cannabinoid that is selected from a ⁇ 9 -tetrahydrocannabinol and cannabidiol, and mixtures thereof.
  • beloxepin (-)-beloxepin, (+)-beloxepin, and/or their analogs may be used in combination with at least one opioid.
  • opioids are available that may be suitable for use in combination therapy to treat pain.
  • the combination therapy may involve an opioid that is selected from, but not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol,
  • the opioid component of the combination therapy may further include one or more other active ingredients that may be conventionally employed in analgesic and/or cough-cold-antitussive combination products.
  • active ingredients include, for example, aspirin, acetaminophen, phenylpropanolamine, phenylephrine, chlorpheniramine, caffeine, and/or guaifenesin.
  • Typical or conventional ingredients that may be included in the opioid component are described, for example, in the Physicians ' Desk Reference, 1999, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the opioid component may further include one or more compounds that may be designed to enhance the analgesic potency of the opioid and/or to reduce analgesic tolerance development.
  • Such compounds include, for example, dextromethorphan or other NMDA antagonists (Mao et al, 1996, Pain 67:361), L-364,718 and other CCK antagonists (Dourish et al, 1988, Eur. J. Pharmacol 147:469), NOS inhibitors (Bhargava et al, 1996, Neuropeptides 30:2), PKC inhibitors (Bilsky et al, 1996, J. Pharmacol. Exp. Ther.
  • beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs may be used with at least one non opioid analgesic, such as for example, diclofenac, a COX2 inhibitor, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • non opioid analgesic such as for example, diclofenac, a COX2 inhibitor, aspirin, acetaminophen, ibuprophen, naproxen, and the like, and mixtures thereof.
  • antiinflammatories include, but are not limited to, corticosteroids, aminoarylcarboxylic acid derivatives such as, but not limited to, etofenamate, meclofenamic acid, mefanamic acid, niflumic acid; arylacetic acid derivatives such as, but not limited to, acemetacin, amfenac cinmetacin, clopirac, diclofenac, fenclofenac, fenclorac, fenclozic acid, fentiazac, glucametacin, isozepac, lonazolac, metiazinic acid, oxametacine, proglumetacin, sulindac, tiaramide and tolmetin; aryl
  • beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs can also be used in combination with each other.
  • the combination therapy involves administration of two or more beloxepin analogs, or beloxepin and one or more beloxepin analogs.
  • Compounds that inhibit NE reuptake have been used in combination with other therapies to treat various indications.
  • amitryptiline has been used in combination with chlordiazepoxide to treat anxiety disorder and major depressive disorder, and has been used in combination with perphenazine to treat anxiety disorder, schizophrenia and major depressive disorder.
  • Nortryptiline has been used in combination with budenoside to treat asthma. It is expected that the (-)-beloxepin compositions described herein will also be useful in combination therapies.
  • the (-)-beloxepin compositions described herein may be used in combination with, or as an adjunct to, other agents.
  • the two agents may be administered in a single pharmaceutical compositor or they may be administered in separate pharmaceutical compositions.
  • the two components may be administered by the same route of administration or by a different route of administration.
  • the two components also may be administered simultaneously with each other or sequentially.
  • each component of the combination therapy may be administered separately but sufficiently closely in time to the administration of the other component as to provide the desired effect.
  • combination therapy involving the (-)-beloxepin compositions described herein is useful in many contexts, the other agent used with the (-)-beloxepin composition will depend on the specific disease or indication being treated. The skilled artisan will be able to ascertain what other agent to use in combination with the (-)-beloxepin compositions based upon long established criteria for the particular indication.
  • the combination therapy may include the administration of the (-)-beloxepin compositions described herein with other agents known to inhibit reuptake of NE.
  • the combination therapy may include the administration of the (-)-beloxepin compositions with agents which do not inhibit the reuptake of NE.
  • the (-)-beloxepin compositions are administered in combination with compounds that inhibit other monoamine transporters, such as the 5HT transporter.
  • the (-)-beloxepin compositions are administered in combination with a selective serotonin reuptake inhibitor (SSRI), such as, but not limited to, fluoxetine, paroxetine, fluvoxamine, citaprolam, or sertraline, to treat depression.
  • SSRI selective serotonin reuptake inhibitor
  • MAOIs monoamine oxidase inhibitor
  • the (+)-beloxepin compositions may be used in combination with, or as an adjunct to, other agents.
  • the two agents may be administered in a single pharmaceutical compositor or they may be administered in separate pharmaceutical compositions.
  • the two components may be administered by the same route of administration or by a different route of administration.
  • the two components also may be administered simultaneously with each other or sequentially.
  • each component of the combination therapy may be administered separately but sufficiently closely in time to the administration of the other component as to provide the desired effect.
  • the combination therapy may include the administration of the (+)-beloxepin compositions described herein with other agents known to antagonize 5HT2 receptors generally, and 5HT 2 A, 5HT 2 B and/or 5HT 2 c receptors specifically.
  • the combination therapy may include the administration of the (+)-beloxepin compositions described herein with agents which do not antagonize 5HT2 receptors.
  • CYP2D6 cytoplasmic antidepressants used off-label to treat pain
  • many tricyclic antidepressants used off-label to treat pain are metabolized by CYP2D6.
  • Use of inhibitors of this enzyme in combination therapy regimens can therefore dramatically increase their levels.
  • Co-administration of CYP2D6 inhibitors with substrates of CYP2D6 can also prolong the QT interval, leading to arrythmias.
  • CYP2D6 inhibitors would likely reduce the efficacy of such CYP2D6-activated drugs.
  • clinical evidence suggest that CYP2D6-activated prodrugs such as codeine and tramadol are less effective in patients who are genetically deficient in CYP2D6 or in patients receiving potent CYP2D6 inhibitors.
  • Cytochrome P4502D6 (CYP2D6) is a polymorphic member of the P450 superfamily, which is absent in 5-9% of the Caucasian population, resulting in a deficiency in drug oxidation known as debrisoquine/sparteine polymorphism. Metabolism by polymorphic isoenzymes such as CYP2D6 can be problematic in drug development because of the wide variation in the pharmacokinetics of the patient population. CYP2D6 metabolises many currently used drugs, which include ⁇ -blockers, antidepressants, and neuroleptics (Bertz and Granneman, 1997, Clin. Pharmokinet. 32(3):210-58).
  • NSAIDs nonsteroidal anti-inflammatory drugs
  • SSRIs selective serotonin reuptake inhibitors
  • dosages may need to be adjusted when beloxepin and/or its analogs are administered in combination with, or adjunctively to, drugs that are either metabolized by or activated by, CYP2D6.
  • Many drugs that would be useful in compositions described herein are metabolized or activated by CYP2D6. Since (-)-beloxepin does not appreciably inhibit this P450 isoenzyme, combination therapy with (-)-beloxepin can be applied without having to alter dosages of drugs metabolized by or activated by CPY2D6.
  • dosages may need to be adjusted when the (+)-beloxepin compositions are administered in combination with, or adjunctively to, drugs that are either metabolized by or activated by, CYP2D6.
  • Beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs (or salts thereof) may be combined with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice as described, for example, in Remington 's Pharmaceutical Sciences, 2005, the disclosure of which is hereby incorporated herein by reference, in its entirety.
  • the relative proportions of active ingredient and carrier may be determined, for example, by the solubility and chemical nature of the compounds, chosen route of administration and standard pharmaceutical practice.
  • the beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs (or salts thereof) compositions described herein may be administered to a mammalian subject in a variety of forms adapted to the chosen route of administration, e.g. , orally or parenterally .
  • Parenteral administration in this respect includes administration by the following routes: intravenous, intramuscular, subcutaneous, intraocular, intrasynovial, transepithelial including transdermal, ophthalmic, sublingual and buccal; topically including ophthalmic, dermal, ocular, rectal and nasal inhalation via insufflation, aerosol and rectal systemic.
  • compositions comprising beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs, (and salts thereof) may be formulated for oral administration, for example, with an inert diluent or with an assimilable edible carrier, or it may be enclosed in hard or soft shell gelatin capsules, or it may be compressed into tablets, or it may be incorporated directly with the food of the diet.
  • the active compound may be incorporated with excipient and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions or preparations may be prepared so that an oral dosage unit form contains from about 0.1 to about 1000 mg of each beloxepin enantiomer (and all combinations and subcombinations of ranges and specific concentrations therein).
  • the tablets, troches, pills, capsules and the like may also contain one or more of the following: a binder such as gum tragacanth, acacia, corn starch or gelatin; an excipient, such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; a sweetening agent such as sucrose, lactose or saccharin; or a flavoring agent such as peppermint, oil of wintergreen or cherry flavoring.
  • a binder such as gum tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrating agent such as corn starch, potato starch, alginic acid and the like
  • a lubricant such as magnesium stearate
  • a sweetening agent such as sucrose, lactose or saccharin
  • a flavoring agent such as peppermint
  • any material used in preparing any dosage unit form is preferably pharmaceutically pure and substantially non toxic in the amounts employed.
  • compositions may also be formulated for parental or intraperitoneal administration.
  • Solutions of the beloxepin enantiomers as free bases or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose.
  • a dispersion can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations may contain a preservative to prevent the growth of microorganisms.
  • compositions suitable for administration by injection typically include, for example, sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form is preferably sterile and fluid to provide easy syringability. It is preferably stable under the conditions of manufacture and storage and is preferably preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • the carrier may be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, liquid polyethylene glycol and the like), suitable mixtures thereof, and vegetable oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of a dispersion, and by the use of surfactants.
  • a coating such as lecithin
  • surfactants for example, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium sulfate, sodium stearate, sodium stearate, and gelatin.
  • Sterile injectable solutions may be prepared by incorporating the active compounds in the required amounts, in the appropriate solvent, with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions may be prepared by incorporating the sterilized active ingredient into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation may include vacuum drying and the freeze drying technique that yields a powder of the active ingredient, plus any additional desired ingredient from the previously sterile filtered solution thereof.
  • Beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs (or salts thereof), will generally be administered in a therapeutically effective amount, as described herein.
  • the quantity of beloxepin and/or beloxepin analog compounds will depend upon a variety of factors, including, for example, the particular pain indication or syndrome being treated, the mode of administration, whether the desired benefit is prophylactic or therapeutic, the severity of the pain indication or syndrome being treated, the age and weight of the patient, and the bioavailability of the beloxepin, (-)-beloxepin, (+)-beloxepin, and/or their analogs (or salts thereof) administered. Determination of an effective dosage is well within the capabilities of those skilled in the art.
  • Dosage amounts will typically be in the range of from about 0.0001 or 0.001 or 0.01 mg/kg/day total active compound(s) to about 0.1 or 1.0 or 2.0 or 2.5 or 5.0 or 10.0 or 20.0 or 25.0 or 50.0 or 75.0 or 100 mg/kg/day total active compound(s), with an expected dose of about 5 mg/kg/day to about 1500 mg/kg/day total active compound(s), but may be higher or lower, depending upon, among other factors, the factors mentioned above.
  • Dosage amount and interval may be adjusted individually to provide plasma levels of active compound(s), which are sufficient to maintain therapeutic or prophylactic effect.
  • the compositions may be administered once per day or multiple times per day, depending upon, among other things, the mode of administration, the specific indication being treated and the judgment of the prescribing physician.
  • the effective local concentration of active compounds and/or compositions may not be related to plasma concentration. Skilled artisans will be able to optimize effective local dosages without undue experimentation.
  • Initial dosages of the (-)-beloxepin compound and/or compositions useful for the treatment of pain can be estimated from in vivo data, such as the animal data described in the Examples section.
  • an effective dosage of beloxepin for the treatment of pain in humans may be obtained by administering a dose of beloxepin sufficient to achieve a plasma concentration similar to that achieved following the administration of 30 mg/kg, i.p. to rats, or 60 mg/kg PO to rats.
  • the effective dose of beloxepin for the treatment of pain is the dosage required to achieve the plasma concentration achieved when 30 mg/kg beloxepin is administered i.p. to rats, or when 60 mg/kg beloxepin is administered orally to rats.
  • an effective dosage of (-)-beloxepin for the treatment of pain in humans may be obtained by administering a dose of (-)-beloxepin sufficient to achieve a plasma concentration similar to that achieved following the administration of 30 mg/kg, i.p. to rats.
  • the effective dose of (-)-beloxepin for the treatment of pain is the dosage required to achieve the plasma concentration achieved when 30 mg/kg (-)-beloxepin is administered i.p. to rats.
  • oral doses of beloxepin, (-)-beloxepin, and (+)-beloxepin of between about 10 mg/day to about 20 or 25 or 30 or 35 or 40 or 45 or 50 or 60 or 70 or 80 or 90 or 95 or 100 or 200 or 500 or 750 or 1000 or 1500 mg/day will be effective in treating pain.
  • some embodiments involve the administration of an oral dosage of beloxepin that ranges from about 10 mg/day to about 500 mg per dose, one or more times per day. It is expected that similar dosage ranges of beloxepin analogs will be effective.
  • the proper dosage of the combined agents will be readily ascertainable by a skilled artisan based on long established criteria.
  • a cannabinoid, opioid and/or other agent is used in combination with beloxepin, (-)-beloxepin, and (+)-beloxepin
  • the dosage will typically range from about 0.01 to about 100 mg/kg/day of the cannabinoid, opioid and/or other active compound and about 0.001 to about 100 mg/kg/day of beloxepin, (-)-beloxepin, or (+)-beloxepin,.
  • the dosage may be about 0.1 to about 10 mg/kg/day of the cannabinoid, opioid and/or other active compound and about 0.01 to about 10 mg/kg/day of beloxepin, and in other embodiments, the daily dosage may be about 1.0 mg of the cannabinoid, opioid and/or other active compound and about 0.1 mg of beloxepin.
  • a cannabinoid compound e.g., ⁇ 9 -tetrahydrocannabinol or cannabidiol
  • an opioid compound e.g.
  • the dosage may generally range from about 15 to about 200 mg of the cannabinoid, opioid and/or other agent, and about 0.1 to about 4 mg of beloxepin, (-)-beloxepin, or (+)-beloxepin. It is expected that similar dosage ranges will be effective for combination therapies with analogs of beloxepin, (-)-beloxepin, and/or (+)-beloxepin.
  • kits may be assembled in the form of kits.
  • the kit provides the compounds(s) and reagents to prepare a composition for administration.
  • the composition may be in a dry or lyophilized from, or in a solution, particularly a sterile solution.
  • the reagent may comprise a pharmaceutically acceptable diluent for preparing a liquid formulation.
  • the kit may contain a device for administration or for dispensing the compositions, including, but not limited to, syringe, pipette, transdermal patch or inhalant.
  • kits may include other therapeutic agents for use in conjunction with the compositions described herein.
  • the therapeutic agents may be provided in a separate form, or mixed with the compositions described herein.
  • Kits can include appropriate instructions for preparation and administration of the composition, side effects of the compositions, and any other relevant information.
  • the instructions may be in any suitable format; including, but not limited to, printed matter, videotape, computer readable disk, or optical disk.
  • the reaction was degassed by bubbling nitrogen through the stirring mixture for 10 minutes. The mixture was then heated at 80 0 C for 2 days under nitrogen. The reaction was cooled to room temperature and diluted with 1 : 1 diethyl ether/hexanes. While stirring, the mixture was carefully acidified with 6M HCl, then diluted with water and the layers were separated. The aqueous layer was washed with 1 : 1 diethyl ether/hexanes and all organics were combined and washed with 0.5M sodium carbonate. The basic aqueous layers were combined, acidified with 6M HCl and the product was extracted with diethyl ether.
  • the reaction mixture was diluted with 0.5 M HCl and the layers were separated. The organics were concentrated and dried to give 28 g of a crude light yellow oil.
  • the mesylate was dissolved in toluene (200 niL) and l,8-diazabicyclo[5.4.0]undec-7-ene (42.6 mL, 285 mmol, 5.0 eq) was added. The mixture was heated at 115°C for 1 hour and diluted with water. The layers were separated and the organics were concentrated and purified by a silica gel plug eluting with 5-15% ethyl acetate/hexanes to give 14.76 g of a light yellow oil.
  • Example 2 Beloxepin Is an Inhibitor of NE Reuptake
  • [ 3 H]nisoxetine (1.0 nM) was incubated with various concentrations of beloxepin for 2 hours at 4 0 C with membranes prepared from Chinese hamster ovary cells (CHO) cells heterologously expressing the cloned human NE transporter (hNET). Bound radioactivity was determined by scintillation spectroscopy. Non-specific binding was defined as the amount of binding that occurred in the presence of 1.0 ⁇ M desipramine. The K was determined using standard methods.
  • the IC50 of NE reuptake inhibition was determined by measuring the degree to which various concentrations of beloxepin inhibited incorporation of [ 3 H]norepinephrine into rat hypothalamus synaptosomes (measurements carried out for 20 minutes at 37 0 C).
  • the IC 50 of 5HT reuptake inhibition was determined by measuring the degree to which various concentrations of beloxepin inhibitied incorporation of [ 3 H] -5 HT into rat brain synaptosomes (measurements carried out for 15 min at 37 0 C.
  • the IC50 of DA reuptake inhibition was determined by measuring the degree to which various concentration of beloxepin inhibited incorporation of [ 3 H]-DA into rat striatum synaptosomes (measurements carried out for 15 min at 37 0 C).
  • K ⁇ DAT 16% inhibition of binding at 10 ⁇ M in a competition assay
  • Agonist effects at the 5HT 2 A receptor were assessed by incubation at 22 0 C of a series of concentrations of test compound with intact HEK-293 cells heterologously expressing the cloned human 5HT2A receptor and measuring intracellular [Ca 2+ ] by fluorimetry according to the method of Jerman et al., 2001, Eur. J. Pharmacol. 414:23-30).
  • Antagonist effects were assessed by the ability of a series of concentrations of test compound to block the increase in intracellular [Ca 2+ ] that occurred in the presence of 3.0 nM serotonin under the same conditions.
  • EC50 and IC50 values were determined using standard methods.
  • Agonist effects at the 5HT 2 B receptor were assessed by incubation at 22 0 C of a series of concentrations of test compound with intact CHO cells heterologously expressing the cloned human 5HT 2B receptor and measuring intracellular [Ca 2+ ] by fluorimetry according to the method of Porter et al., 1991, Brit. J. Pharmacol. 128:13-20.
  • Antagonist effects were assessed by the ability of a series of concentrations of test compound to block the increase in intracellular [Ca 2+ ] that occurred in the presence of 0.3 nM serotonin under the same conditions.
  • EC50 and IC50 values were determined using standard methods.
  • Agonist effects at the 5HT 2 c receptor were assessed by incubation at 22 0 C of a series of concentrations of test compound with intact CHO cells heterologously expressing the cloned human 5HT 2 c receptor and measuring intracellular [Ca 2+ ] by fluorimetry according to the method of Jerman et al., 2001, Eur. J. Pharmacol. 414:23-30.
  • Antagonist effects were assessed by the ability of a series of concentrations of test compound to block the increase in intracellular [Ca 2+ ] that occurred in the presence of 3.0 nM serotonin under the same conditions.
  • EC50 and IC50 values were determined using standard methods.
  • racemic ( ⁇ ) beloxepin is a dual NRI/5HT 2 A, 2 B, 2C antagonist and that, quite surprisingly, the NRI activity is contributed virtually exclusively by the (-) enantiomer and the 5HT 2A , 2B , 2C antagonist activity virtually exclusively by the (+) enantiomer.
  • Example 3 Inhibition of Cytochrome P450 Isoenzyme CYP2D6 by Beloxepin, (-)-Beloxepin, and (+)-Beloxepin
  • Protocol The ability of Beloxepin to inhibit dextromethorphan O-demethylation (CYP2D6) was investigated using pooled male human hepatic microsomes. Beloxepin was incubated with human liver microsomes at concentrations of 0, 0.1, 0.3, 1, 3, 10, 30 and 100 ⁇ M Beloxepin. The 200 ⁇ L incubations were conducted in duplicate in 0.1 M potassium phosphate buffer (pH 7.4) with 0.02 mg of microsomal protein, 3 mM MgCl 2 , 1 mM EDTA and 7.5 ⁇ M of the probe substrate dextromethorphan in a 96-well polypropylene plate maintained at 37 0 C.
  • CYP2D6 dextromethorphan O-demethylation
  • Dextrorphan and the internal standard were eluted with 10 mM ammonium formate with 0.1% formic acid: 0.1% formic acid in acetonitrile (80:20, v/v) run under gradient conditions at 1.0 mL/min.
  • a MDS Sciex API4000 (Applied Biosystems, Foster City, CA) triple quadrupole mass spectrometer equipped with a Turbo Ionspray ionization source was used as the detector.
  • the instrument was operated in positive ion mode using multiple reaction monitoring (MRM) with specific precursor-product ion pairs for dextrorphan and the internal standard.
  • MRM multiple reaction monitoring
  • the mass transitions were m/z 280.2>262.2 for the internal standard and m/z 258.2>157.0 for dextrorphan.
  • Dextrorphan and the internal standard had retention times of approximately 1.54 and 2.00 minutes, respectively.
  • beloxepin formulations for injection were prepared using acidified sterile water for injection (SWIJ) as a diluent. To start, a few drops (never more than 400 ⁇ l for a final volume of approximately 14 ml) of 1 M HCl was added to neat beloxepin. Glass beads were added and the solution vortexed vigorously for 2-3 minutes, followed by sonication in a water bath for 3-5 minutes to break up larger particles. The SWIJ was then added to QS to final total volume, the formulation vortexed for 2-3 minutes and then sonicated in warm water for approximately 30-60 minutes. Beloxepin was formulated as a 10 mg/ml solution.
  • control vehicle was prepared using the same volumes of 1 M HCl and SWIJ diluent as the test beloxepin formulation.
  • Example 5 Beloxepin Exerts Its Antiallodynic Effect in a Dose- Dependent Fashion
  • Protocol A dose response experiment was performed in L5 SNL rats at 16 days post surgery (3, 10 and 30 mg/kg IP beloxepin). In the experiment, animals were tested for tactile allodynia at 30 min post treatment.
  • the sham-operated control group which were operated on but not subject to nerve ligation, contained 4 animals.
  • the treatment group contained at least six animals.
  • Example 6 Beloxepin is Superior to NE Reuptake Inhibitors, Mixed Serotonin/NE Reuptake Inhibitors and Tricyclic Antidepressants in Treatment of Neuropathic Pain
  • FIG. 3 The results of a direct comparison of beloxepin with reboxetine, are illustrated in FIG. 3, and demonstrate that beloxepin is approximately 4-fold more effective.
  • FIG. 5 depicts the results of a direct comparison of the antiallodynic effects produced by beloxepin, duloxetine, amitriptyline, and reboxetine in the rat L5 Spinal Nerve Ligation Model (30 mg/kg IP; * p ⁇ 0.05 compared to vehicle -treated L5 SNL rats; rats were tested at 30 minutes or, for amitriptyline, 60 minutes post-drug administration). The data indicate that beloxepin was the most effective of the compounds tested.
  • Example 7 Beloxepin and (-)-Beloxepin Therapy Is Effective In An Animal Model of Neuropathic Pain When Administered Orally
  • Protocol A time course experiment was performed with beloxepin (60 mg/kg PO) in L5 SNL rats at 8-days post surgery. Rats were tested at 30, 60, 120 and 240 min post beloxepin. All test groups contained at least six animals.
  • Protocol A time course experiment was performed with (-)-beloxepin (60 mg/kg PO) in L5 SNL rats at 7 days post-surgery. Rats were tested at 30, 60, 120, and 240 minutes post- drug.
  • FIGS. 6A and 6B show the results of the experiment in which beloxepin was administered.
  • FIG. 6A shows the latency (in seconds) between placement on the hot plate and paw lick response.
  • IP beloxepin
  • FIG. 6B shows the percentage of maximal effect achieved (% MPE) in the same experiment.
  • FCA Freund's Complete Adjuvant
  • paw pressure thresholds were determined before and at specified times after drug treatment. All test groups contained at least six animals.
  • Protocol The ability of beloxepin to treat visceral pain was demonstrated in a rodent model of acetic acid-induced writhing
  • male ICR mice (20 - 25 g) were treated with vehicle or test compound orally 25 min prior to the intraperitoneal administration of 0.6% of acetic acid.
  • Five minutes after treatment with acetic acid the number of writhes was counted for 10 min.
  • a writhe is defined as the extension of both front and hind limbs with a concave stretch of the abdomen.
  • the mean number of writhes was determined for each treatment group and the percent inhibition of the vehicle response was calculated using the following formula:
  • mice Number of writhes in vehicle treated mice
  • Example 11 A Mixture of (+)-Beloxepin And (-)-Beloxepin Is Effective In An Animal Model Of Inflammatory Pain (FCA-Induced Mechanical Hyperalgesia)
  • Protocol A time course experiment was performed with beloxepin (60 mg/kg PO in L5 SNL rats at 7 days post-surgery. Rats were tested at 30, 60, 120, and 240 minutes post- drug.
  • Protocol In a further experiment with this animal model of pain, a comparison of the time courses for mechanical antiallodynia in the rat L5 SNL model for beloxepin, duloxetine (a drug approved for the treatment of diabetic neuropathy), and esreboxetine (a compound in Phase III clinical trials for the treatment of fibromyalgia and diabetic neuropathy). The data obtained are depicted in FIG. 11.
  • racemic beloxepin (30 mg/kg IP) was comparable in efficacy to duloxetine (30 mg/kg IP), and the peak antiallodynic effect of racemic beloxepin was greater than that measured in rats treated with esreboxetine (30 mg/kg IP).
  • Example 13 Beloxepin, (-)-Beloxepin, and (+)-Beloxepin Are Effective In An Animal Model Of Post-Operative Pain (Rat Hindpaw Incisional Pain Model)
  • racemic beloxepin produced a significant antiallodynic effect at all four time points (maximum hindpaw withdrawal threshold ⁇ 29 grams or 544% of the threshold value for vehicle treated rats at the 30 minute time point).
  • the antiallodynic effect produced by racemic beloxepin in this assay is considered very robust.
  • Protocol A second time course experiment was performed with racemic beloxepin in the hindpaw incision model after oral (PO) administration. At 24 hours post-surgery, rats received vehicle or racemic beloxepin (60 mg/kg PO). Rats were tested for tactile allodynia at 30, 60, 120 and 240 minutes after administration of beloxepin.
  • racemic beloxepin produced a significant antiallodynic effect at all four time points (maximum hindpaw withdrawal threshold ⁇ 24 grams at the 30 and 60 minute time points).
  • the antiallodynic effect produced by beloxepin in this assay is considered very robust and is comparable to the effect that was observed after IP administration.
  • Protocol A third time course experiment was performed with racemic beloxepin in the hindpaw incision model after intravenous (IV) administration. At 24 hours post-surgery, rats received vehicle or beloxepin (3 mg/kg IV). The 3 mg/kg IV dose is a dose that is 10- fold lower than a dose that produced a significant respiratory or cardiovascular side effect. Rats were tested for tactile allodynia at 30, 60, 120 and 240 minutes after administration of beloxepin.
  • racemic beloxepin produced a significant antiallodynic effect at the 30 and 120 minute time points (maximum hindpaw withdrawal threshold ⁇ 21 grams at the 30 minute time point).
  • the antiallodynic effect produced by beloxepin in this assay at the 30 minute time point is considered very robust and comparable to the antiallodynic effect observed with a dose of 60 mg/kg PO of racemic beloxepin at the 30 minute time point.
  • (-)-beloxepin produced a significant antiallodynic effect at the 30 and 120 minute time point (maximum hindpaw withdrawal threshold ⁇ 19 grams or 426% of the threshold value for vehicle treated rats at the 30 minute time point).
  • the antiallodynic effect produced by (-)-beloxepin at the 30 minute, but not 120 minute, time point is considered robust.
  • (+)-beloxepin produced a significant antiallodynic effect at the 30 and 60 minute time points (maximum hindpaw withdrawal threshold ⁇ 28 grams at the 30 minute time point).
  • the antiallodynic effect produced by (+)-beloxepin in this assay is considered very robust and comparable to the effect observed with racemic beloxepin at the 30 minute time point.

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Abstract

La présente invention concerne des procédés destinés au traitement de la douleur au moyen de béloxépine, d'énantiomères de béloxépine, et de certains de leurs analogues.
EP09712730A 2008-02-19 2009-02-19 Béloxépine, ses énantiomères et certains de leurs analogues convenant au traitement de la douleur Withdrawn EP2285818A4 (fr)

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