Deuterated analogs of entevoxin and methods of administration without

Abstract

The present invention relates to deuterated artevorin compositions and methods for administration in the treatment of a variety of diseases, disorders or conditions without autoinduction of metabolism.

Description

Technical Field

[0001] The present disclosure relates to deuterated etifoxine compositions and methods of administering deuterated etifoxine without metabolic auto - induction. The compositions and methods disclosed herein are useful for treating a variety of conditions such as treating anxiety and result in a reduced dose of deuterated etifoxine and an improved dosing frequency. Background Art

[0002] The absorption, distribution, metabolism, and excretion (ADME) properties of a drug are key characteristics of any drug and can mean the difference between a safe and effective drug on the one hand and clinical and commercial failure on the other. While recent advances in pharmaceutical formulation technologies (as well as drug conjugates or prodrugs) have provided some ability to improve ADME in limited situations, potential ADME problems remain a major cause of drug failure in clinical trials. A common ADME problem for currently approved drugs and drug candidates is rapid metabolism. In in vitro and pre - clinical testing, otherwise highly potent drug candidates may be metabolized too quickly and cleared from the body, resulting in minimal to no pharmacological effect. "Quick - fix" efforts to overcome rapid metabolism include administering the drug at very high levels or very frequently. Both of these solutions to rapid metabolism have problems, including: increased side effects of the drug to maintain therapeutic drug levels, increased exposure to metabolites that may be toxic or induce increased metabolism of concomitant drugs or their own metabolism, and reduced patient compliance due to frequent dosing during the day.

[0003] In limited situations, metabolic inhibitors have been used to improve the characteristics of specific drugs (see Kempf, D. et al. Antimicrobial Agents and Chemotherapy, 41(3), p. 654 (1997); Wang, L. et al. Clinical Pharmacology and Therapeutics, 56(6 Pt.1), p. 659 (1994). However, this strategy has not been widely adopted and can lead to serious unwanted side effects and undesirable drug - drug interactions.

[0004] The optimization of drug structures by chemists typically involves an iterative process of structural modification to improve bioactivity and / or metabolic properties. However, a better metabolic profile is often achieved at the expense of biological potency and efficacy, as significant structural modifications to the desired pharmacophore structure are required to halt or slow the biodegradation process. A potential strategy to improve the metabolic profile of a drug without significantly altering its biological potency and efficacy is to replace (substitute) one or more hydrogen atoms with deuterium, thereby slowing cytochrome P450-mediated metabolism. Deuterium is an isotope of hydrogen that contains an extra neutron in its nucleus and is safe, stable, and non-radioactive. Due to the increased mass of deuterium compared to hydrogen, the bond between carbon and deuterium has higher energy (is stronger) compared to the bond between hydrogen and carbon, and can reduce the metabolic reaction rate. The reduced metabolic reaction rate can have a favorable impact on the ADME properties of the molecule, giving improved potency, efficacy, safety, and tolerability. The other physical characteristics of deuterium are essentially the same as those of hydrogen, and no biological effects are expected for molecules with deuterium substitution.

[0005] In the last four decades, only a few drugs that incorporate deuterium substitution to improve metabolism have been approved (see Blake, M. et al. J. Pharm. Sci., 64, p. 367 (1975); Foster, A. Adv. Drug Res., 14, p. 1 (1985); Kushner, D. et al. Can. J. Physiol. Pharmacol., p. 79 (1999); Fisher M. et al. Curr. Opin. Drug Discov. Devel., 9, p. 101 (2006)). However, the outcome of deuterium replacement of hydrogen on the metabolic rate has been unpredictable and has led to variable results. In some cases, the metabolic clearance of the deuterated compound in vivo is reduced, while in other cases, the clearance is unchanged, and in yet other cases, an unexpected increase in metabolic clearance is shown. This variability has led ADME experts to question or reject deuterium substitution as a strategic drug design modification to reduce the metabolic rate (see Foster and Fisher).

[0006] Even when the sites and positions of known metabolism are known, deuterium replacement does not have a predictable effect on the metabolic rate. Only by preparing specific deuterium-substituted drugs (candidates) and testing them can the extent of the change in the metabolic rate be determined. See Fukuto, J. et al. J. Med. Chem., 34(9), p. 2871 (1991). Many (if not most) drug candidates have multiple sites where metabolism is possible; however, this is unique for each drug molecule, thus making deuterium replacement a different study of its effect on each candidate. See Harbeson, L. and Tung, R. Medchem News, 2, p. 8 (2014) and the references therein. There are several examples of drug candidates where deuterium substitution of hydrogen has led to an increase in the metabolic rate and / or a metabolic switch, or no in vivo change in the molecular profile even after a decrease in metabolism. Harbeson et al. revealed that selective deuteration of paroxetine at predicted metabolically labile positions actually produced analogs with increased metabolism confirmed in vivo (Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery and Development, 46 annual report in medicinal chemistry, 403-417 (2011)). In addition, Miwa reported that deuteration of metabolically labile sites may lead to an enhancement (or switch) of alternative metabolic pathways, with then uncertain consequences (Miwa, G., Lu, A., Kinetic Isotope Effects and 'Metabolic Switching' in Cytochrome P450-Catalyzed Reactions, 7 Bioessays, 215-19 (1987)). Phentermine has been deuterated to reduce its metabolic rate; however, replacement of the hydrogens of N,N-dimethyl with deuterium did not result in an observed change (Allan B. Foster, "Deuterium Isotope Effects in the Metabolism of Drugs and Xenobiotics: Implications for Drug Design", Advances in Drug Research, (14), 1-40 (1985)).Similarly, deuteration of the metabolically active site of tramadol did not result in an increased duration of effect (Shao et.al., "Derivatives of Tramadol for Increased Duration of Effect", Bioorganic and Medicinal Chemistry Letters, (16), 691-94 (2006)).

[0007] Etifoxine [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] was initially disclosed in U.S. Patent 3,725,404 to Hoffmann, I et al. Etifoxine has been shown to be an effective, rapidly acting human anxiolytic with minimal sedative and ataxic side effects.Stein, D., Adv. Ther. 32(1), p. 57 (2015); Nguyen, N. et al., Hum. Psychopharm. 21, p. 139 (2006); Micallef, J., Fundam. Clin. Pharmacol., 15(3), p. 209 (2001).

[0008] The hydrochloride salt of etifoxine [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] is known as Stresam TM , and is sold primarily in France and a limited number of other global markets for the treatment of anxiety (specifically, anxiety with somatic manifestations). The short half-life of etifoxine in humans (4-6 hours) significantly limits its use. The recommended dosing regimen for etifoxine is three times daily (or higher doses, twice daily). This regimen can be quite inconvenient for patients and can lead to non-adherence to dosing and reduced efficacy.See Santana, L. et al, Patient Preference and Adherence, 5, p. 427 (2011). Studies have also shown significant inter-individual variability in pharmacokinetic parameters, especially at dose C 最At a macro level (see etifoxine package insert information, Lundbeck Argentina SA). Variability between patients and within patients is largely based on differences in drug metabolism capacity. Reducing variability between patients and within patients is desirable because it impedes optimal treatment. Poor metabolizers may be at higher risk of off-target side effects due to higher drug concentrations. Ultra-rapid metabolizers may not achieve sufficient efficacy due to excessive reduction of drug concentration. (See Wilkinson, G. The New England Journal of Medicine (352), 2211-21 (2005). Enhancing the metabolic stability of etifoxine will reduce variability between patients and within patients because metabolic capacity becomes less of a determining factor in drug ADME.

[0009] Deuterated etifoxine for the treatment of anxiety was previously disclosed in U.S. Patent Nos. 10,080,755 and 10,736,901, both to Olivier Dasse and entitled “Deuterated Analogs of Etifoxine, Their Derivatives and Uses Thereof.” The patent discloses administering deuterated etifoxine hydrochloride to rats at 50 mg / kg, which achieved significantly higher AUC and C 最大 . The AUC 0-12 and C 最 of the hydrochloride salt of the compound described in Example 1 were 2.5 times and 1.7 times greater than those of etifoxine hydrochloride. These results suggest that reduced pre-systemic metabolism leads to higher bioavailability of the unchanged drug. Reducing pre-systemic metabolism can result in less variability between and within doses. Increased drug exposure can lead to a reduced dosing frequency because the minimum drug therapeutic level can be achieved over a longer time period. Increased drug exposure also allows for dose reduction, resulting in fewer potential adverse events because similar drug plasma levels can be achieved with lower doses.

[0010] Etifoxine exhibits autoinduction, whereby continuous administration over time leads to the induction of one or more CYP enzymes responsible for the metabolism of these agents. The phenomenon of autoinduction cannot be observed from single-dose studies and requires careful monitoring of the administration effect of the drug over a multi-day period. In the case of autoinduction occurring, it may be necessary to increase the drug dose over time to counteract the effect of increased metabolism. This becomes increasingly important in the development of drug products for the treatment of chronic conditions, where multi-day dosing and long-term continuous treatment are required. Thus, despite the promising and beneficial effects of etifoxine, there is still a need for continued development of treatment regimens that improve the drug bioavailability over time for chronic conditions. SUMMARY OF THE INVENTION

[0011] Briefly, the present invention generally relates to methods for treating anxiety and other disorders in a subject in need thereof, wherein the compound is a compound of formula (I):

[0012]

[0013] including its pharmaceutically acceptable salts, solvates and prodrugs, wherein each X 1 、X 2 、X 3 is independently selected from hydrogen or deuterium, wherein the compound is administered at a dose and frequency effective to treat a disease, disorder or condition without autoinductive metabolism of the compound. Autoinductive metabolism can be quantified by an ARC 最大 and ARAUC 0-12 less than 1.0 over a 7-day period. Thus, the present invention includes administering the drug at a dose and frequency such that the ARC 最大 and ARAUC 0-12 over a 7-day period is less than 1.0. An ARC 最大 and ARAUC 0-12 level greater than or equal to 1.0 over a 7-day period indicates a lack of autoinduction.

[0014] According to a particular embodiment, the dosing frequency may vary according to the dose and may include QID (four times a day), TID (three times a day), BID (two times a day) or QD (once a day). In one aspect, the dose may include 100 mg or less. The dose range may further be from 25 to 100 mg, including any value therebetween. In certain instances, the dose range may be from 50 mg to 100 mg. In one embodiment of the present invention, the dose is 60 mg administered QD (once a day).

[0015] Methods for treating anxiety can include one or more specific types of anxiety, including but not limited to one or more of the following: panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, social anxiety disorder, anxiety disorder due to a medical condition, substance-induced anxiety disorder, and / or anxiety with somatic manifestations, anxiety with comorbid depression, adjustment disorder with anxiety, separation anxiety, acute anxiety, selective mutism, medication-induced anxiety disorder.

[0016] The compound can be one or more selected from the compounds of formula (I) above, particularly including 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine, or a pharmaceutically acceptable salt thereof. It should be understood that the level of deuterium isotope exceeds the natural abundance of deuterium. For example, the compound can include deuterium with an abundance of at least 3340 times the natural abundance of deuterium. In certain embodiments, the composition is a racemate. Other forms of the compound of formula (I) can be used, including the R-enantiomer or S-enantiomer, and mixtures of these enantiomers in different ratios (such as 3:1 or 4:1, etc.). BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 A graph showing the mean ± SD plasma concentration-time curves in rats after 50 mg / kg GRX-917 and etifoxine.

[0018] Figure 2A Arithmetic mean plasma concentration of deuterated etifoxine in healthy human volunteers on day 1 after a single oral dose (linear scale).

[0019] Figure 2B Arithmetic mean plasma concentration of deuterated etifoxine in healthy human volunteers on day 1 after a single oral dose (semi-logarithmic scale).

[0020] Figure 3A Arithmetic mean plasma concentration of deuterated etifoxine in healthy human volunteers after a single oral dose of deuterated etifoxine q12 h (bid) for 7 days (linear scale).

[0021] Figure 3B Arithmetic mean plasma concentration of deuterated etifoxine in healthy human volunteers after a single oral dose of deuterated etifoxine q12 h (bid) for 7 days (semi-logarithmic scale). DETAILED DESCRIPTION

[0022] The present invention relates to the therapeutic use of deuterated analogues of etifoxine in dosage regimens suitable for multi-day administration, such as in the treatment of chronic conditions such as chronic anxiety.

[0023] Etifoxine has been extensively studied preclinically and has demonstrated efficacy in animal models of many CNS and psychiatric disorders, such as anxiety, pain, inflammation, neurodegeneration, inflammatory pain, nerve injury, multiple sclerosis, alcohol withdrawal, epilepsy and light-induced retinopathy. Verleye, M. et al., Pharmacol. Biochem. Behav., 82(4), p.712(2005); Ugale, R. et al., Brain Res., 12, p.193(2007); Verleye, M. et al., Alcohol, 43(3), p.197(2009); Aouad, M. et al., Pain, 147(1-3), p.54(2009); Girard, C. et al., J. Neuroendocrinol., 24(1), p.71(2012); Zhou, X. et al., Mol. Med. Rep., 8(1), p.75(2013); Aouad. M. et al., Eur. J. Pain. 18(2), p.258(2014); Aouad. M. et al., Pain, 155(2), p.408(2014); Zhou, X. et al., Muscle Nerve, 50(2), p.235(2014): Dai, T. et al., J. Reconstr. Microsurg., 30(6), p.381(2014); Juif, P. et al., Neuropharmacology, 91, p.117(2015), Verleye, M et al. WO 2015113991.

[0024] It has been described in the scientific literature that etifoxine acts by allosterically modulating the GABA.sub.A ion channel complex and increasing the levels of endogenous and neuroactive steroids. Verleye, M. et al., Neuroreport., 10(15), p. 3207 (1999): Verleye, M. et al., Neurosci. Lett., 301(3), p. 191 (2001), Hamon, A. et al., Neuropharmacology, 45(3), p. 293 (2003); Ugale, R. et al., Brain Res., 12, p. 193 (2007); Verleye, M. et al., Pharmacol. Biochem. Behav., 82(4), p. 712 (2005).

[0025] Neuroactive and neuroactive steroids have been shown to have anti-inflammatory activity. For example, progesterone and allopregnanolone reduce both cytokines IL-1β and TNF-α in a TBI model (see He, J. et al. Experimental Neurology, 189, p. 404 (2004)). In addition, dehydroepiandrosterone (DHEA), which is mainly synthesized in the adrenal gland, inhibits the synthesis of cytokines IL-6 and TNF (see Straub, R. Rheumatology, 39, p. 624 (1999). By increasing the levels of neuroactive and / or neuroactive steroids, etifoxine is thought to be effective in treating neuroinflammation, peripheral inflammation, and various inflammatory conditions.

[0026] Neuroactive and neuroactive steroids have been shown to be neuroregenerative and neuroprotective in preclinical models, see Brinton, R. Nature Reviews Endocrinology 9, 241-250 (2013) and Borowicz, K., et.al. Frontiers in Endocrinology 2(50), P. 1 (2011). Similarly, etifoxine has also been shown to have preclinical neuroregenerative and neuroprotective effects (Girard et.al. Journal of Neuroendocrinology 24, 71-81 (2011), Girard et.al. Clinical and Experimental Pharmacology and Physiology 36, 655-661 (2009), Zhou et.al. Muscle Nerve. 50(2): 235-43 (2014)).

[0027] Definition

[0028] Unless otherwise expressly indicated herein, the definitions of the terms used are the standard definitions used in the fields of organic synthesis and pharmaceutical science.

[0029] The articles “a” and “an” are used herein to refer to one or more than one (i.e., at least one) grammatical object of the article. For example, “element” means one element or more than one element.

[0030] As used herein, the term “or” is generally used in the sense of including “and / or” unless the context in which it is used clearly indicates otherwise.

[0031] When compounds, salts, etc. are used in the plural form, they are also considered to mean a single compound, salt, etc.

[0032] As used herein, “solvate” refers to a stoichiometrically variable complex formed by a solute (such as a compound of formula (I) or its salt, ester or prodrug) and a solvent. For the purposes of the present invention, such a solvent may not interfere with the biological activity of the solute. Examples of suitable solvents include water, methanol, ethanol and acetic acid. Generally, the solvent used is a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. Generally, the solvent used is water.

[0033] “Isomer” means any compound having the same molecular formula but differing in the nature or order of bonding or the arrangement of atoms in space. Examples of such isomers include, for example, the E-isomer and Z-isomer of a double bond, enantiomers and diastereomers. Unless otherwise expressly indicated, the compounds of the present invention depicted with straight lines are intended to cover single isomers and / or both isomers, and mean any compound having the same molecular formula but differing in the nature or order of bonding or the arrangement of atoms in space.

[0034] The term “GABA A receptor” refers to a protein complex that detectably binds GABA and mediates a dose-dependent change in chloride ion conductance and membrane polarization. Receptors that generally preferably include naturally occurring mammalian (especially human or rat) GABA A receptor subunits, although the subunits can be modified provided that any modification does not significantly inhibit the ability of the receptor to bind GABA (i.e., retains at least 50% of the binding affinity of the receptor for GABA). Standard ligand binding assays known in the art can be used to evaluate the binding affinity of a candidate GABA A receptor for GABA. There are multiple GABA AReceptor subtypes that fall within the term "GABA A receptor". These subtypes include, but are not limited to, the α.sub.1-6, β.sub.1-3, γ.sub.1-3, π, θ, ε, δ, and σ.sub.1-3 receptor subtypes. GABA A receptors can be obtained from a variety of sources, such as from rat cortical preparations or from cells expressing cloned human GABA A receptors. Specific subtypes can be readily prepared using standard techniques (e.g., by introducing mRNA encoding the desired subunit into a host cell).

[0035] As used herein, "CNS disorder" is a disease or disorder of the central nervous system that can be treated, prevented, managed, or improved with the compounds or compositions provided herein. Certain CNS disorders are associated with alterations in the GABA AReceptor modulation is responsive, and some CNS disorders are responsive to increased endogenous neurosteroids and neuroactive steroids. Some CNS disorders include components in which the peripheral nervous system (“PNS”) is also impaired. Exemplary CNS disorders include multiple sclerosis, spinal muscular atrophy (believed to be due to loss of neuronal cell function in the anterior horn of the spinal cord), muscle relaxation in spinal spasticity, cerebral palsy, trigeminal neuralgia, migraine, Alzheimer's disease, Huntington's disease, Parkinson's disease, Creutzfeldt-Jakob's disease, Friedreich disease, retinal degeneration and light-induced retinal damage (including photoretinitis, retinitis pigmentosa, age-related macular degeneration (AMD) and macular degeneration, delirium, dementia and amnesia, and other cognitive disorders (delirium; dementia, such as Alzheimer type dementia, vascular dementia, dementia due to HIV disease, dementia due to head trauma, dementia due to Parkinson's disease, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob's disease, dementia due to general medical conditions, substance-induced dementia, dementia due to multiple etiologies, NOS (abbreviated as NOS “not otherwise specified” hereinafter) dementia; amnestic disorders (such as amnestic disorders due to general medical conditions, substance-induced amnestic disorders, NOS amnestic disorders: NOS cognitive disorders); ischemic or hemorrhagic cerebrovascular events, including stroke and traumatic brain injury (TBI), phakomatoses (especially neurofibromatosis), amyotrophic lateral sclerosis, schizophrenia, mood disorders (such as depressive disorders, including major depressive disorder - single episode or recurrent, dysthymic disorder, NOS depressive disorder; bipolar disorder, including bipolar type I disorder, bipolar type II disorder, cyclothymic disorder, NOS bipolar disorder, mood disorder due to general medical conditions, substance-induced mood disorder, NOS mood disorder), drug withdrawal symptoms, stuttering, autism, autism spectrum disorder, and convulsive disorders such as epilepsy.CNS disorders also include mental disorders described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), and include anxiety disorders (panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, posttraumatic stress disorder, acute stress disorder, generalized anxiety disorder, social anxiety disorder, anxiety disorder due to a medical condition, substance-induced anxiety disorder, anxiety disorder not otherwise specified (NOS)), mood disorders, sleep disorders (primary sleep disorders such as primary insomnia, primary hypersomnia, narcolepsy, breathing-related sleep disorder, circadian rhythm sleep disorder, NOS sleep disorder: parasomnias, including nightmare disorder, sleep terror disorder, sleepwalking disorder, NOS parasomnias; sleep disorders secondary to another mental disorder such as sleep disorders secondary to anxiety, mood disorder and / or other mental disorders; sleep disorders due to a general medical condition and substance-induced sleep disorder), attention deficit, attention deficit hyperactivity and disruptive behavior disorders (attention deficit / hyperactivity disorder - combined type, predominantly inattentive type and predominantly hyperactive-impulsive type: NOS attention deficit / hyperactivity disorder; conduct disorder, oppositional defiant disorder and NOS disruptive behavior disorder) and substance-related disorders. Mental disorders also include eating disorders such as anorexia and bulimia. The American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V) describes additional mental disorders and the criteria for these disorders, the contents of which are hereby incorporated by reference in their entirety. Also included are rare diseases and other neurosteroid deficiency disorders in pediatric epilepsy, including Rett Syndrome, Angelman Syndrome, infantile spasms, CDKL5 epilepsy, postpartum depression, tremors, fragile X syndrome, Dravet’s syndrome, Prader Willi, 15q11-q13 duplication deletion syndrome, autoimmune epileptic encephalopathy, Lennox Gastaut Syndrome, childhood absence epilepsy, menstrual epilepsy, status epilepticus, suicidal ideation, other genetic epilepsy syndromes, seizures, traumatic brain injury, ischemic stroke, spinal cord injury, premenstrual dysphoric disorder, chronic pain and / or migraine.

[0036] As used herein, "PNS disorder" is a disease or condition of the peripheral nervous system that can be treated, prevented, managed or improved with the compounds or compositions provided herein. Certain PNS disorders respond to increased endogenous neuroactive steroids. Some PNS disorders involve motor and / or sensory nerve dysfunction and may include components in which the spinal cord and / or brain are also impaired. Exemplary PNS disorders include neuropathic disorders (neuropathic disorders include neuropathies associated with metabolic disorders such as diabetic neuropathy, drug-induced neuropathies such as alcohol-induced neuropathy and vincristine-induced neuropathy, neuropathies associated with inflammatory processes such as in Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, neuropathies associated with enzyme deficiencies such as in Fabry's disease and Krabbe's disease, peripheral neuropathy, infectious neuropathic conditions such as post-herpetic and HIV-induced neuralgia, hereditary motor and sensory neuropathies such as Charcot-Marie-Tooth disease) and radiculoneuropathic diseases.

[0037] As used herein, "neural degenerative processes" are characterized by the dysfunction and death of neurons, leading to loss of nerve function mediated by the brain (CNS), spinal cord and PNS. Among other things, they can be caused by pathological conditions collectively referred to as neurodegenerative diseases or emotional, traumatic or exposure to toxins.

[0038] As used herein, "neuroprotective property" is the ability of the compounds of the invention to treat neural degenerative processes.

[0039] As used herein and unless otherwise specified, the terms "neurosteroid" and "neuroactive steroid" refer to steroids that are naturally produced in a subject and that alter neuronal excitability by interacting with ligand-gated ion channels and other cell surface receptors. Neurosteroids are produced in the brain. Neuroactive steroids are produced by the conversion of adrenal steroids or gonadal steroids of peripheral origin. Examples of neurosteroids and neuroactive steroids are: pregnenolone, pregnanolone, allopregnanolone, tetrahydrodeoxycorticosterone, dehydroepiandrosterone and progesterone. Neuroactive steroids can have effects in the CNS and peripherally.

[0040] As used herein, the term "treat" means to reduce, reverse, inhibit, attenuate, decrease, prevent or stabilize the development or progression of a disease (including the diseases or disorders described herein), reduce the severity of the disease or improve the symptoms associated with the disease. In one aspect, treatment does not include prevention.

[0041] "Disease" means any condition or disorder that impairs or interferes with the normal function of cells, tissues or organs.

[0042] As used herein, "subject" is an animal, typically a mammal, including a human, such as a patient.

[0043] As used herein and unless otherwise specified, the terms "therapeutically effective amount" and "effective amount" of a compound refer to an amount sufficient to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease, to delay or minimize one or more symptoms associated with the disease or disorder to be treated. The terms "therapeutically effective amount" and "effective amount" can encompass an amount that improves overall treatment, reduces or avoids symptoms, or the cause of the disease or disorder, or enhances the therapeutic efficacy of another therapeutic agent.

[0044] The terms "co-administer" and "in combination with" include the administration of two therapeutic agents (e.g., a compound of the invention and lorazepam) simultaneously, concurrently, or sequentially without a specific time limit. In one embodiment, the two agents are present in the subject at the same time or exert their biological or therapeutic effects simultaneously. In one embodiment, the two therapeutic agents are in the same composition or unit dosage form. In another embodiment, the two therapeutic agents are in separate compositions or unit dosage forms.

[0045] It will be appreciated that there are some variations in the natural isotope abundances in synthetic compounds, depending on the source of the chemical materials used in the synthesis. Thus, etifoxine preparations will inherently contain small amounts of deuterated isotopologues. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotope substitution in the compounds of the invention. See, e.g., Wada, E et al., Seikagaku, 1994, 66:15; Gannes, L Z et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0046] In the compounds of the invention, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", that position is understood to have hydrogen in its natural abundance isotopic composition. Further, unless otherwise specified, when a position is specifically designated as "D" or "deuterium", that position is to be understood as having a deuterium abundance of at least 3340 times the natural abundance of deuterium (which is 0.015%), i.e., at least 50.1% deuterium incorporation.

[0047] As used herein, the term "isotope enrichment factor" means the ratio between the isotopic abundance of a specified isotope and its natural abundance. In some embodiments, the compounds of the invention have an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation, at each specified deuterium atom), at least 4000 (60% deuterium incorporation), at least 4500 (67.5% deuterium incorporation), at least 5000 (75% deuterium), at least 5500 (82.5% deuterium incorporation), at least 6000 (90% deuterium incorporation), at least 6333.3 (95% deuterium incorporation), at least 6466.7 (97% deuterium incorporation), at least 6533 (98% deuterium incorporation), at least 6600 (99% deuterium incorporation) or at least 6633.3 (99.5% deuterium incorporation) for each specified deuterium atom.

[0048] The term "isotopologue" refers to a substance that differs from a particular compound of the invention only in its isotopic composition.

[0049] When referring to the compounds of the invention, the term "compound" refers to a collection of molecules having the same chemical structure, except that isotopic variations may exist among the constituent atoms of the molecules. Thus, it should be clear to those skilled in the art that a compound represented by a specific chemical structure containing the indicated deuterium atoms will also contain a lesser amount of isotopologues having hydrogen atoms at one or more of the specified deuterium positions in that structure. The relative amount of such isotopologues in the compounds of the invention will depend on a variety of factors, including the isotopic purity of the deuterated reagents used to make the compounds and the efficiency of deuterium incorporation in the individual synthetic steps used to prepare the compounds. However, as set forth above, the relative amount of such isotopologues will total less than 49.9% of the compound. In other embodiments, the relative amount of such isotopologues will total less than 47.5%, less than 40%, less than 32.5%, less than 25%, less than 17.5%, less than 10%, less than 5%, less than 3%, less than 1% or less than 0.5% of the compound.

[0050] As used herein, the term "pharmaceutically acceptable" refers to a component that is suitable for use in contact with the tissues of humans and other mammals within the scope of reasonable medical judgment, without excessive toxicity, irritation, allergic response, etc., and having a reasonable benefit / risk ratio commensurately. "Pharmaceutically acceptable salts" means any non-toxic salts that, upon administration to a recipient, are capable of directly or indirectly providing the compounds of the present invention. "Pharmaceutically acceptable counterions" are the ionic portions of salts that are non-toxic when released from the salts upon administration to a recipient. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, and organic acids such as p-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, p-bromobenzenesulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, and related inorganic and organic acids. Accordingly, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, caprates, octanoates, acrylates, formates, isobutyrates, caprates, heptanoates, propiolates, oxalates, malonates, succinates, suberates, sebacates, fumarates, maleates, butyne-1,4-dioates, hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfonates, xylenesulfonates, phenylacetates, phenylpropionates, phenylbutyrates, citrates, lactates, β-hydroxybutyrates, glycolates, maleates, tartrates, methanesulfonates, propanesulfonates, naphthalene-1-sulfonates, naphthalene-2-sulfonates, mandelates, and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid. Standard methods for preparing pharmaceutically acceptable salts and their formulations are well known in the art and are disclosed in various references, including, for example, "Remington: The Science and Practice of Pharmacy". A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0051] The compounds of the present invention, including the compounds of formula I, may contain asymmetric carbon atoms, for example, as a result of deuterium substitution or otherwise. Accordingly, the compounds of the present invention may exist as a single enantiomer or as a mixture of two enantiomers. Thus, the compounds of the present invention may exist as a racemic mixture or a scalemic mixture, or as individual respective stereoisomers that are substantially free of the other possible stereoisomers. As used herein, the term "substantially free of other stereoisomers" means that there are less than 25% of the other stereoisomers, preferably less than 10% of the other stereoisomers, more preferably less than 5% of the other stereoisomers, and most preferably less than 2% of the other stereoisomers, or there are less than "X" % of the other stereoisomers (where X is a number from 0 to 100 (inclusive)). Methods for obtaining or synthesizing a single enantiomer of a given compound are known in the art and can be applied, where feasible, to the final compound or starting materials or intermediates.

[0052] Unless otherwise indicated, when the disclosed compounds are named or depicted in structural form without specifying stereochemistry and having one or more chiral centers, it is to be understood that all possible stereoisomers of the compound are represented.

[0053] As used herein, the term "stable compound" refers to a compound (including, formulated as a therapeutic product, an intermediate for the production of a therapeutic compound, an isolable or storable intermediate compound, a therapeutic for treating a disease or disorder responsive to a therapeutic agent) having sufficient stability to permit its manufacture and to maintain the integrity of the compound for a sufficient period of time for the purposes detailed herein.

[0054] Both "D" and "d" refer to deuterium. Unless otherwise indicated, "stereoisomer" refers to both enantiomers and diastereomers.

[0055] The term "optionally deuterium-substituted" means that one or more hydrogen atoms in the indicated moiety may be replaced by the corresponding number of deuterium atoms.

[0056] The present invention includes prodrugs of the compounds of formula I above. Generally, such prodrugs will be functional derivatives of the compounds of formula I which are readily convertible in vivo to the desired compounds of formula I. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Design of Prodrugs, ed. H. Bundgaard, Elsevier, 1985. Such prodrugs include, but are not limited to, ester prodrugs of alcohols and acids and phosphate prodrugs of alcohols. Prodrugs can be formulated to achieve the purposes of improved chemical stability, improved patient acceptance and compliance, improved bioavailability, prolonged duration of action, improved organ selectivity, improved formulation (including, increased hydrosolubility) and / or reduced side effects (including toxicity).

[0057] When the compounds of the present invention have at least one asymmetric center, they can exist as enantiomers accordingly. When the compounds have two or more asymmetric centers, they can additionally exist as diastereoisomers. In particular, etifoxine exists as a racemic mixture, and R-etifoxine and S-etifoxine have been prepared. U.S. Patent No. 8,110,569. The present invention includes deuterated analogs of R-etifoxine and deuterated analogs of S-etifoxine. It should be understood that all such stereoisomers and mixtures thereof in any proportions are encompassed within the scope of the present invention. When the compounds have geometric isomers, all such isomers and mixtures thereof in any proportions are encompassed within the scope of the present invention. Tautomers of the compounds of the present invention are encompassed in the present application. Thus, for example, a carbonyl group includes its enol tautomer.

[0058] As used herein, "pure S-etifoxine" is a deuterated analog substantially free of deuterated R-etifoxine analogs (i.e., enantiomeric excess). In other words, the "S" form of deuterated etifoxine is substantially free of the "R" form of the compound and is thus in enantiomeric excess over the "R" form.

[0059] The term "enantiomerically pure" or "pure enantiomer" indicates that a compound comprises greater than 75% by weight, greater than 80% by weight, greater than 85% by weight, greater than 90% by weight, greater than 91% by weight, greater than 92% by weight, greater than 93% by weight, greater than 94% by weight, greater than 95% by weight, greater than 96% by weight, greater than 97% by weight, greater than 98% by weight, greater than 98.5% by weight, greater than 99% by weight, greater than 99.2% by weight, greater than 99.5% by weight, greater than 99.6% by weight, greater than 99.7% by weight, greater than 99.8% by weight or greater than 99.9% by weight of an enantiomer. In certain embodiments, the weight is based on the total weight of the deuterated altivudine analogue.

[0060] As used herein and unless otherwise indicated, the term "enantiomerically pure R-altivudine" refers to a deuterated analogue that is at least about 80% by weight deuterated R-altivudine and at most about 20% by weight deuterated S-altivudine, at least about 90% by weight deuterated R-altivudine and at most about 10% by weight deuterated S-altivudine, at least about 95% by weight deuterated R-altivudine and at most about 5% by weight deuterated S-altivudine, at least about 99% by weight deuterated R-altivudine and at most about 1% by weight deuterated S-altivudine, at least about 99.9% by weight deuterated R-altivudine or at most about 0.1% by weight deuterated S-altivudine. In certain embodiments, the weight is based on the total weight of the deuterated altivudine analogue.

[0061] As used herein and unless otherwise indicated, the term "enantiomerically pure S-altivudine" refers to a deuterated analogue that is at least about 80% by weight deuterated S-altivudine and at most about 20% by weight deuterated R-altivudine, at least about 90% by weight deuterated S-altivudine and at most about 10% by weight deuterated R-altivudine, at least about 95% by weight deuterated S-altivudine and at most about 5% by weight deuterated R-altivudine, at least about 99% by weight deuterated S-altivudine and at most about 1% by weight deuterated R-altivudine or at least about 99.9% by weight deuterated S-altivudine and at most about 0.1% by weight deuterated R-altivudine. In certain embodiments, the weight is based on the total weight of the deuterated altivudine analogue.

[0062] As used herein, the term "AUC" 0-12 means the area under the concentration-time curve from time 0 to time 12 hours.

[0063] As used herein, the term "AUC" 0-24” means the area under the concentration-time curve from time 0 to 24 hours.

[0064] As used herein, the term “AUC 最后 ” means the area under the concentration-time curve from time 0 to the time of the last quantifiable concentration (t 最 after), calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for decreasing concentrations.

[0065] As used herein, the term “AUC inf ” means the area under the concentration-time curve extrapolated from time 0 to infinity.

[0066] As used herein, the term “C 最大 ” means the maximum observed plasma concentration.

[0067] As used herein, the term “C 最小 ” means the minimum observed mean of the plasma concentrations observed before dosing (within the initial dosing interval (day 7)).

[0068] As used herein, the term “ARC 最大 ” means the C 最大 accumulation ratio: C 最大 (day 7) divided by C 最大 (day 1).

[0069] As used herein, the term “ARAUC 0-12 ” means the AUC 0-12 accumulation ratio: AUC 0-12 (day 7) divided by AUC 0-12 (day 1).

[0070] As used herein, the term “PK” means pharmacokinetics.

[0071] As used herein, the term “q12h” means every 12 hours.

[0072] As used herein, the term “T 最大 ” means the time of the maximum observed plasma concentration.

[0073] As used herein, the term “t 1 / 2 ” means the apparent plasma terminal elimination half-life.

[0074] Multiday therapeutic use of etifoxine

[0075] The hydrochloride salt of etifoxine [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] (referred to as Stresam TM)It is known to exhibit metabolic induction, whereby administration over time results in the induction of metabolism in humans. Deuterated etifoxine for the treatment of anxiety was previously disclosed in U.S. Patent No. 10,736,901, entitled “Deuterated Analogs of Etifoxine, Their Derivatives and Uses Thereof” by Olivier Dasse. The ‘901 patent discloses various deuterated analogs of etifoxine and methods for their manufacture, and its teachings regarding deuterated analogs of etifoxine and methods for their manufacture are incorporated herein by reference. The inventors fully expect that deuterated etifoxine exhibits a metabolic induction similar to that of etifoxine.

[0076] During multi-day human clinical trials involving deuterated etifoxine, the inventors confirmed that deuterated etifoxine exhibits a similar metabolic auto-induction to etifoxine at doses greater than 100 mg bid. However, the inventors unexpectedly found that the metabolic induction of deuterated etifoxine is different from the known metabolic induction of etifoxine (non-deuterated). That is, when administered within the therapeutic dosing range (100 mg bid), deuterated etifoxine does not exhibit metabolic induction. Based on this unexpected finding, the inventors have developed a novel dosing regimen for deuterated etifoxine for the treatment of chronic conditions such as chronic anxiety.

[0077] The inventors have found that administering deuterated etifoxine at a dose of 150 mg bid (twice daily) induces metabolism. The following examples show that administering deuterated etifoxine at a dose of 100 mg bid does not induce metabolism. Consider administering deuterated etifoxine at a dose that does not induce metabolism. Such a dose may include any dose less than 150 mg bid, and preferably includes any dose that can be administered, such as 145 mg bid, 140 mg bid, 135 mg bid, 130 mg bid, 125 mg bid, 120 mg bid, 115 mg bid, 110 mg bid, 105 mg bid, 100 mg bid, 95 mg bid, 90 mg bid, 85 mg bid, 80 mg bid, 75 mg bid, 70 mg bid, 65 mg bid, 60 mg bid, 55 mg bid, 50 mg bid, 45 mg bid, 40 mg bid, 35 mg bid, 30 mg bid, 25 mg bid, 20 mg bid, 15 mg bid, 10 mg bid or less.

[0078] The present inventors anticipate that the same total daily amount of 300 qd of deuterated etifoxine will be equivalent to 150 mg bid for induction of metabolism. Accordingly, a qd regimen equivalent to 200 qd has been shown to avoid induction of metabolism. The inventors contemplate that 200 mg qd, 190 mg qd, 180 mg qd, 170 mg qd 160 mg qd, 150 mg qd, 140 mg qd, 130 mg qd, 120 mg qd, 110 mg qd, 100 mg qd, 90 mg qd, 80 mg qd, 70 mg qd, 60 mg qd, 60 mg qd, 50 mg qd, 40 mg qd, 30 mg qd 20 mg q d can be administered in a manner that avoids induction of metabolism.

[0079] The ability to administer deuterated etifoxine in a manner that avoids autoinduction of metabolism can advantageously provide a dosing regimen lower than would otherwise be required. The present inventors contemplate a dosing regimen for the treatment of chronic underlying anxiety that comprises administering deuterated etifoxine at 100 mg qd and preferably lower. For example, a dosing regimen for the treatment of chronic anxiety can comprise 100 mg qd, 90 mg qd, 80 mg qd, 70 mg qd, 60 mg qd or lower.

[0080] Other indications can be treated with deuterated etifoxine at different doses and dosing frequencies in a manner that avoids autoinduction.

[0081] In addition to racemic deuterated etifoxine, the present inventors also contemplate the use of deuterated S-etifoxine, deuterated R-etifoxine by any of the above methods.

[0082] Metabolic differences between deuterated etifoxine and etifoxine

[0083] The present inventors studied the comparative stability of deuterated etifoxine and etifoxine in human, rat and mouse liver microsomes:

[0084]

[0085] In human, rat and mouse liver microsomes, deuterated etifoxine is metabolically more stable than etifoxine (lower intrinsic clearance (Clint) and longer half-life) (Table 1). Due to this greater metabolic stability, GRX-917 is expected to have better oral bioavailability than etifoxine. In addition, after administration of GRX-917, the ratio of GRX-917 to M4 is expected to be higher than the ratio of etifoxine to M4 after an equivalent dose of etifoxine. The major metabolite (M4) is an enzyme inducer and contributes to autoinduction in vivo. In rats, this improved metabolic stability translates to an approximately 3-fold higher AUC for GRX-917 compared to etifoxine, as Figure 1 shown in.

[0086] Multiple Ascending Dose Study of Deuterated Etiracetam in Healthy Subjects

[0087] This was a Phase 1, single-center, prospective, randomized, double-blind, placebo-controlled study of multiple ascending doses (MAD) of the racemic form of deuterated etiracetam administered orally to healthy adult male and female subjects.

[0088] The first dose of the study drug was administered on Day 1. From Day 1 to Day 6, subjects then received oral doses of the study drug twice daily (q12h). The last single dose of the study drug was administered on Day 7. Each dose of the study drug was administered with a glass of 240 mL of water at the end of a standard meal. Meals were provided 30 minutes before dosing and completed within 30 minutes or less. On Day 1 and Day 7, subjects were required to fast for 8 hours before breakfast dosing and for 2 hours after dosing (during which time water was freely available).

[0089] Fifty-eight (58) subjects joined the MAD part of the study (43 subjects on deuterated etiracetam and 15 subjects on placebo). All available data for the 43 subjects treated with deuterated etiracetam were included in the PK population.

[0090] Deuterated Etiracetam - Multiple Oral Doses on Day 7 Pharmacokinetics

[0091] Table 2 presents the geometric mean (CV%) trough concentrations (12 hours after the last dose) of deuterated etiracetam on Days 2, 4, 5, 6, and 7 after dosing q12h (bid).

[0092]

[0093]

[0094] At each dose level, the geometric mean trough deuterated etiracetam concentration increased up to Day 4 at 100 and 150 mg q12h and up to Day 2 at 200 and 300 mg q12h. Subsequently, the trough concentration decreased until 12 hours after the last dose on Day 7, indicating possible autoinduction.

[0095] Table 3 presents the geometric mean (CV%) PK parameters of deuterated etiracetam on Day 7 after 7 days of dosing q12h (bid).

[0096]

[0097] Since the standard for reporting half-life values requires that the terminal phase span at least 2 half-lives (i.e., span > 2), only 1 / 9, 3 / 8, 3 / 13, and 0 / 9 of the subjects had a half-life that could be accurately determined under the 100, 150, 200, and 300 mg q12h dosing regimens. At 100 mg q12h, the two geometric mean accumulation ratios (ARCmax and AUC0-12) of deuterated etifoxine were 1.04 and 1.31, respectively, indicating minimal accumulation and no autoinduction after multiple dosing for 7 days. However, at doses greater than 100 mg q12h, the geometric mean ARCmax and ARAUC0-12 decreased to less than one and generally decreased as the dose increased, reaching 0.551 and 0.737, respectively, at 300 mg q12h, which indicates an autoinductive effect.

[0098] Within the dose range on Day 7, AUC0-12 and Cmax increased in a dose-proportional manner. Statistical analysis of dose proportionality confirmed dose proportionality, with slope estimates (90% CI) for Cmax and AUC0-12 of 0.86 (0.66, 1.07) and 0.91 (0.67, 1.14), respectively. Statistical analysis indicated that Tmax on Day 7 was not dose-dependent.

[0099] Time-dependent kinetics

[0100] When deuterated etifoxine was administered at 100 mg BID for 7 days, there was no demonstrated decrease in exposure. However, at doses greater than 100 mg BID, ARCmax and ARAUC0-12 decreased below 1, indicating an autoinductive effect.

[0101] Renal elimination

[0102] Deuterated etifoxine demonstrated low renal clearance. The dose fraction excreted as deuterated etifoxine was < 0.004%.

[0103] Conclusions

[0104] After single and multiple oral administrations of 100 - 300 mg q12h, deuterated etifoxine was rapidly absorbed, with a median Tmax ranging from 2.00 to 3.52 h post-dose.

[0105] Plasma deuterated etifoxine concentrations on Day 7 declined exponentially in an apparent overall biphasic manner, with geometric mean t1 / 2 ranging from 38.8 to 82.1 h.

[0106] Deuterated etifoxine Cmax and AUC0-12 increased in a dose-proportional manner on Day 7.

[0107] The cumulative deuterated etifoxine after 7 days of multiple dosing was minimal at 100 mg q12h, where the maximum ARC and ARAUC0-12 values were 1.04 and 1.31, respectively; however, at doses greater than 100 mg BID, these values decreased to between 0.551 and 0.863, indicating autoinduction.

[0108] Example 1

[0109] Deuterated etifoxine was administered to human patients at a dose of 100 mg BID (twice daily) for the treatment of anxiety over a period of at least 7 days. The maximum AUC and ARAUC equal to or greater than one for a period of at least 7 days 0-12 demonstrated the lack of autoinduction of deuterated etifoxine metabolism.

[0110] Example 2

[0111] Deuterated etifoxine was administered to human patients at a dose of 100 mg QD (once daily) for the treatment of anxiety over a period of at least 7 days. The maximum AUC and ARAUC equal to or greater than one for a period of at least 7 days 0-12 demonstrated the lack of autoinduction of deuterated etifoxine metabolism.

[0112] Example 3

[0113] Deuterated etifoxine was administered to human patients at a dose of 60 mg QD (once daily) for the treatment of anxiety over a period of at least 7 days. The maximum AUC and ARAUC equal to or greater than one for a period of at least 7 days 0-12 demonstrated the lack of autoinduction of deuterated etifoxine metabolism.

[0114] Example 4

[0115] Deuterated etifoxine was administered to human patients at a dose of 50 mg QD (once daily) for the treatment of anxiety over a period of at least 7 days. The maximum AUC and ARAUC equal to or greater than one for a period of at least 7 days 0-12 demonstrated the lack of autoinduction of deuterated etifoxine metabolism.

[0116] Other embodiments and uses of the present invention will be apparent to those skilled in the art by considering the specification and practice of the invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are hereby specifically and fully incorporated by reference. The specification and examples are to be considered as merely exemplary, where the true scope and spirit of the invention are indicated by the following claims.

Claims

1. A method for treating a disease or disorder in a subject in need thereof, comprising orally administering a compound to the subject, wherein the compound is a compound of formula (I): including its pharmaceutically acceptable salts, solvates and prodrugs, wherein each X 1 , X 2 , X 3 is independently selected from hydrogen or deuterium, wherein said compound is administered at a dose and frequency equal to or greater than 1.0 to effectively treat anxiety and exhibit an ARC 最大 and ARAUC 0-12 over a 7-day period.

2. The method according to claim 1, wherein, ARC within a 7-day period 最大 is C on the 7th day 最大 divided by C on the 1st day 最大 The ratio of.

3. The method according to any one of the preceding claims, wherein, Administration is BID or QD.

4. The method according to any one of the preceding claims, wherein, The dose is 100 mg or less.

5. The method according to any one of the preceding claims, wherein, The dose range is 20 mg to 100 mg.

6. The method according to any one of the preceding claims, wherein, The dose is 60 mg administered QD.

7. The method according to any one of the preceding claims, wherein, The disease or disorder is selected from panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a medical condition, substance-induced anxiety disorder, or anxiety with somatic manifestations.

8. The method according to any one of the preceding claims, wherein, The compound is 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine or a pharmaceutically acceptable salt thereof.

9. The method according to any one of the preceding claims, wherein, The compound comprises deuterium at an abundance of at least 3340 times the natural abundance of deuterium.

10. The method according to any one of the preceding claims, wherein, The compound is a racemate.

11. A method for treating a disease or disorder in a subject in need thereof, comprising orally administering to the subject 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine, wherein the compound is administered at a dose and frequency effective to treat anxiety and exhibit an ARC 最大 and ARAUC 0-12 equal to or greater than 1.

0.

12. The method according to claim 11, wherein, Administration is BID or QD.

13. The method according to any one of claims 11-12, wherein Administration is QD.

14. The method according to any one of claims 11 - 13, wherein, The dose is 100 mg or less.

15. The method according to any one of claims 11-14, wherein, The dose range is 50 mg to 100 mg.

16. The method according to any one of claims 11-15, wherein The dose is 60 mg administered QD.

17. The method according to any one of claims 11-16, wherein, The disease or disorder is selected from panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, anxiety disorder due to a medical condition, substance-induced anxiety disorder, or anxiety with somatic manifestations.

18. The method according to any one of claims 11-17, wherein The compound is 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine or a pharmaceutically acceptable salt thereof.

19. The method according to any one of claims 11-18, wherein, The compound comprises deuterium at an abundance of at least 3340 times the natural abundance of deuterium.

20. The method according to any one of claims 11-19, wherein The compound is a racemate.

21. A pharmaceutical composition comprising a compound of formula (I): including its pharmaceutically acceptable salts, solvates and prodrugs, wherein each X 1 , X 2 , X 3 is independently selected from hydrogen or deuterium, and a pharmaceutically acceptable excipient, wherein the compound is present in an amount such that when administered once daily, it exhibits an ARC 最大 and ARAUC 0-12 equal to or greater than 1.0 over a 7-day period.

22. The pharmaceutical composition according to claim 21, wherein, The compound is 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,1-benzoxazin-2-amine or a pharmaceutically acceptable salt thereof.

23. The pharmaceutical composition according to any one of claims 21 or 22, wherein The amount range is 20 mg to 100 mg.

24. The pharmaceutical composition according to any one of claims 21 to 23, wherein, The amount is 60 mg administered QD.

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