A deuterated analogue of ethifoxine and a method of administration that does not induce metabolic autoinduction.

Abstract

The present invention relates to a deuterated ethifoxine composition and a method of administration that does not involve metabolic autoinduction in the treatment of various diseases, disorders, or symptoms.

Description

[Technical Field]

[0001] This disclosure relates to deuterated ethifoxine compositions and methods for administering deuterated ethifoxine without metabolic autoinduction. The compositions and methods disclosed herein are useful for treating a wide variety of conditions, such as anxiety disorders, and result in lower doses and improved administration frequencies of deuterated ethifoxine. [Background technology]

[0002] The absorption, distribution, metabolism, and elimination (ADME) properties of a drug are crucial characteristics of any drug and can be the difference between a safe and effective drug and one that fails clinically and commercially. While recent advances in drug formulation technology (and drug conjugates or prodrugs) have offered some ability to improve ADME in limited cases, underlying ADME problems remain a major cause of drug failure in clinical trials. A common ADME challenge for currently approved drugs and drug candidates is rapid metabolism. Drug candidates that are otherwise highly effective in vitro and preclinical trials may be metabolized too quickly, eliminated from the body, and exert little or no pharmacological effect. "Band-Aid" attempts to overcome rapid metabolism include administering at very high levels or very frequent doses. Both of these solutions to rapid metabolism come with problems including increased drug side effects to maintain therapeutic drug levels, increased exposure to metabolites that may be toxic or induce increased metabolism of concomitant drugs or themselves, and decreased patient compliance due to frequent daytime administration.

[0003] In limited cases, 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(6Pt.l), p.659 (1994)). However, this strategy is not widely used and can result in serious unwanted side effects and undesirable drug-drug interactions.

[0004] Optimizing drug structures by chemists typically involves iterative structural modification processes to improve biological activity and / or metabolic properties. However, a better metabolic profile is often achieved at the expense of biological potency and efficacy due to significant structural modifications of the desired pharmacophore structure required to halt or slow down the biological degradation process. A potential strategy for improving the metabolic profile of a drug without substantially 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 additional 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 (stronger) compared to the bond between hydrogen and carbon, and can slow down metabolic reaction rates. A slower metabolic reaction rate can favorably affect the ADME properties of the molecule, potentially giving it improved potency, efficacy, safety, and tolerability. Other physical properties of deuterium are essentially identical to those of hydrogen, and deuterium substitution is not expected to have any biological effects on molecules.

[0005] Over nearly 40 years, only a few drugs using 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 effects of deuterium substitution of hydrogen on metabolic rate have been unpredictable and have yielded a variety of results. In some cases, deuterated compounds showed decreased metabolic clearance in vivo, in others there was no change in clearance rate, and in yet another case, unexpectedly, an increase in metabolic clearance rate. This variation has led ADME experts to question or reject deuterium substitution as a strategic modification of drug design to slow metabolic rates (see Foster and Fisher).

[0006] Even when the site and location of metabolism are known, deuterium substitution does not have a predictable effect on metabolic rate. The degree of change in metabolic rate can only be determined by the preparation and testing of drugs (candidates) with specific deuterium substitutions. See Fukuto, J. et al. J. Med. Chem., 34(9), p.2871 (1991). Many, if not most, drug candidates have multiple sites on which they can be metabolized, but these are unique to each drug molecule, so deuterium substitution is a different study for its effect on each candidate. See Harbeson, L. and Tung, R. Medchem News, 2, p.8 (2014) and its references. There are some examples of drug candidates where deuterium substitution of hydrogen resulted in an increase in metabolic rate and / or metabolic switching, or did not result in any change in the molecular profile in vivo, even after metabolic deceleration. Harbeson et al. demonstrated that selective deuteration of paroxetine at a predicted metabolically unstable site actually generated an analog that showed increased metabolism in vivo (Scott L. Harbeson and Roger D. Tung, Deuterium in Drug Discovery and Development, 46 annual report in medicinal chemistry, 403-417 (2011)). Furthermore, Miwa reported that deuteration at a metabolically unstable site can lead to enhancement (or switching) of alternative metabolic pathways, which in turn can lead to previously unknown consequences (Miwa, G., Lu, A., Kinetic Isotope Effects and 'Metabolic Switching' in Cytochrome P450-Catalyzed Reactions, 7 Bioessays, 215-19 (1987)).Deuterated phentermine slowed its metabolic rate, but replacing N,N-dimethyl hydrogen with deuterium did not produce any 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, deuterated the metabolically active site of tramadol did not result in an extension of the duration of its effect (Shao et. al., “Derivatives of Tramadol for Increased Duration of Effect”, Bioorganic and Medicinal Chemistry Letters, (16), 691-94 (2006)).

[0007] Ethiphoxine [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,1-benzoxazine] was first disclosed in U.S. Patent No. 3,725,404 by Hoffmann, I et al. Ethiphoxine has been shown to be an effective acute-acting anxiolytic in humans 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] Ethiphoxine hydrochloride [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,l-benzoxazine], known as Stresam®, is marketed primarily in France and a limited number of other markets worldwide for the treatment of anxiety disorders (specifically, anxiety disorders with physical symptoms). The short half-life of etiphoxine in humans (4-6 hours) is a significant limitation in its use. The recommended dosing schedule for etiphoxine is three times daily (or twice daily for higher doses). This schedule can be very inconvenient for patients and may contribute to non-compliance and reduced efficacy. See Santana, L. et al, Patient Preference and Adherence, 5, p.427 (2011). Studies have also been conducted, particularly at dose C max Significant individual variability in pharmacokinetic parameters is observed in the relationship (see ethihoxine package insert information, Lundbeck Argentina SA). Inter-patient and intra-patient variability is primarily based on differences in drug metabolic capacity. Reducing inter-patient and intra-patient variability is desirable as it interferes with optimal treatment. Individuals with poor metabolism may be at higher risk of off-target side effects due to higher drug levels. Individuals with excessive metabolism may not achieve relief due to insufficient efficacy because drug levels are excessively low. (See Wilkinson, G. The New England Journal of Medicine (352), 2211-21 (2005). Enhancing the metabolic stability of ethihoxine would reduce inter-patient and intra-patient variability because metabolic capacity would be less of a determinant in drug ADME.)

[0009] Deuterated ethifoxine for the treatment of anxiety disorders was previously disclosed in U.S. Patents 10,080,755 and 10,736,901, both by Olivier Dasse, entitled "Deuterated Analogs of Etifoxine, Their Derivatives and Uses Thereof." These patents showed that deuterated ethifoxine hydrochloride administered to rats at a dose of 50 mg / kg exhibited significantly higher AUC and C25 levels compared to undeuterated ethifoxine hydrochloride. max It was disclosed that this was achieved. AUC of the hydrochloride salt of the compound described in Example 1 0-12 and C max These values ​​are 2.5 times and 1.7 times greater than those of etiphoxine hydrochloride. These results indicate a decrease in systemic pre-circulating metabolism, which results in higher bioavailability of the unchanged drug. A decrease in systemic pre-circulating metabolism can result in smaller variability between and within doses. Increased drug exposure may lead to a decrease in administration frequency, as minimal drug therapeutic levels can be achieved over longer periods. Increased drug exposure also allows for dose reductions, as similar drug plasma levels can be achieved at lower doses, thus reducing potential adverse events.

[0010] Ethiphoxine exhibits an autoinduction effect, meaning that continuous administration leads to the induction of CYP enzymes, which are responsible for the metabolism of these drugs. This autoinduction phenomenon cannot be observed in single-dose studies, and careful monitoring of the effects of drug administration over several days is necessary. If autoinduction occurs, increasing the drug dose over time may be necessary to counteract the effects of increased metabolism. This is becoming increasingly important in the development of drugs for treating chronic conditions that require administration over several days and prolonged continuous treatment. Consequently, despite the desirable and beneficial effects of etiphoxine, there is a continuing need to develop treatment regimens that improve drug bioavailability over time for chronic conditions. [Overview of the project]

[0011] Briefly, the present invention generally relates to a method for treating anxiety and other disorders in a subject that requires treatment of anxiety and other disorders, the compound being of formula (I): [Chemical formula] a compound of (including its pharmaceutically acceptable salts, solvates and prodrugs), wherein each X 1 , X 2 , X 3 is independently selected from hydrogen or deuterium, and the compound is administered at a dose and frequency effective for the treatment of a disease, disorder or symptom without self-inducing the metabolism of the compound. Self-induction of metabolism is less than 1.0 over 7 days, ARC max and ARAUC 0-12 can be quantified by. Accordingly, the present invention includes administering a drug at a dose and frequency that results in an ARC max and ARAUC 0-12 less than 1.0 over 7 days. Levels of ARC max and ARAUC 0-12 greater than or equal to 1.0 over 7 days indicate a lack of self-induction.

[0012] According to certain embodiments, the dosing frequency can be varied to include QID (4 times a day), TID (3 times a day), BID (2 times a day) or QD (1 time a day) depending on the dose. In one aspect, the dose can include 100 mg or less. The dose can further be in the range of 25 - 100 mg (including any value therebetween). In certain cases, the dose can be in the range of 50 mg - 100 mg. In one embodiment of the present invention, the dose is 60 mg administered QD (once a day).

[0013] The treatment methods for anxiety disorders may include one or more of, but are not limited to, 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 medical condition, substance-induced anxiety disorder, and / or anxiety disorder with somatic symptoms, anxiety disorder with co-existing depression, adjustment disorder with anxiety, separation anxiety disorder, acute anxiety, selective mutism, drug-induced anxiety disorder, and one or more specific types of anxiety disorders may be included.

[0014] The compound can be one or more of the compounds selected from the above formula (I), specifically 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 contain deuterium at an abundance at least 3340 times higher than the natural abundance of deuterium. In certain embodiments, the composition is a racemate. Other forms of the compound of formula (I) may be used, including the R-enantiomer or S-enantiomer, and mixtures of these enantiomers in various ratios such as 3:1 or 4:1.

Brief Description of the Drawings

[0015] [Figure 1] A chart showing the mean ± SD plasma concentration-time profile after administration of 50 mg / kg of GRX-917 and etifoxine in rats.

[0016] [Figure 2A] Arithmetic mean plasma concentration (linear scale) of deuterated etifoxine after single oral administration (day 1) in healthy human volunteers.

[0017] [Figure 2B]This is the arithmetic mean plasma concentration (semi-logarithmic scale) of deuterated ethifoxine after a single oral administration (day 1) in healthy human volunteers.

[0018] [Figure 3A] This is the arithmetic mean plasma concentration (linear scale) of deuterated ethifoxine after a single oral administration of deuterated ethifoxine over 7 days with a q12h (bid) in healthy human volunteers.

[0019] [Figure 3B] This is the arithmetic mean plasma concentration (semi-logarithmic scale) of deuterated ethifoxine after a single oral administration of deuterated ethifoxine over 7 days with a q12h (bid) in healthy human volunteers. [Modes for carrying out the invention]

[0020] The present invention relates to the therapeutic use of a deuterated analog of ethifoxine in a dosage regimen suitable for administration over several days, such as for the treatment of chronic symptoms like chronic anxiety disorder.

[0021] Ethiphoxine has been extensively studied preclinically and has shown efficacy in many animal models of CNS and psychiatric disorders, including anxiety, pain, inflammation, neurodegeneration, inflammatory pain, nerve injury, multiple sclerosis, alcohol withdrawal, epilepsy, and photo-induced lesions of the retina. 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. WO2015113991.

[0022] Ethifoxine is described in scientific literature as acting through allosteric regulation of the GABA sub-A ion channel complex and by increasing the levels of endogenous neurosteroids 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).

[0023] Neurosteroids and neuroactive steroids exhibit anti-inflammatory activity; for example, progesterone and allopregnanolone reduce both the cytokines IL-1β and TNF-α in a model of TBI (see He, J. et al. Experimental Neurology, 189, p. 404 (2004)). Furthermore, dehydroepiandrosterone (DHEA), which is mainly synthesized in the adrenal glands, inhibits the synthesis of the cytokines IL-6 and TNF (see Straub, R. Rheumatology, 39, p. 624 (1999)). By increasing the levels of neurosteroids and / or neuroactive steroids, ethihoxine is thought to be effective in treating neuroinflammation, peripheral inflammation, and various inflammatory symptoms.

[0024] Neurosteroids and neuroactive steroids have been shown to be regenerative 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, ethifoxine has also shown preclinically regenerative 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)).

[0025] definition Unless otherwise specified herein, the definitions of terms used are standard definitions used in the fields of organic synthesis and pharmaceuticals.

[0026] The articles "a" and "an" are used herein to refer to one or more (i.e., at least one) grammatical objects of the article. For example, "an element" means one or more elements.

[0027] As used herein, the term “or” is generally used to include “and / or” unless the context of use clearly indicates otherwise.

[0028] When the plural form is used for compounds, salts, etc., it is interpreted to also refer to a single compound, salt, etc.

[0029] As used herein, “solvate” refers to a variable stoichiometric complex formed by a solute (e.g., a compound of formula (I) or its salt, ester, or prodrug) and a solvent. Such solvents for the purposes of the present invention may not impede 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.

[0030] "Isomer" means any compound having the same molecular formula but differing in the nature or order of the bonding or arrangement of atoms in space. Examples of such isomers include, for example, E- and Z-isomers of double bonds, enantiomers, and diastereomers. Unless otherwise specified, the compounds of the present invention, in which bonding is shown using a linear relationship, are intended to encompass a single isomer and / or both isomers and mean any compound having the same molecular formula but differing in the nature or order of the bonding or arrangement of atoms in space.

[0031] "GABA A The term "receptor" refers to a protein complex that detectably binds to GABA and mediates dose-dependent changes in chloride conductance and membrane polarization. Naturally occurring mammalian (particularly human or rat) GABA A Receptors containing receptor subunits are generally preferred, but any modification may involve subunit modification as long as it does not substantially inhibit the receptor's GABA-binding ability (i.e., at least 50% of the receptor's binding affinity to GABA is retained). Candidate GABA for GABA A The receptor binding affinity can be evaluated using standard ligand binding assays known in the art. A Various GABAs that fall within the scope of the term "receptor" AReceptor subtypes exist. These subtypes include, but are not limited to, α-sub1-6, β-sub1-3, γ-sub1-3, π, θ, ε, δ, and σ-sub1-3 receptor subtypes. GABA A The receptor can be obtained from various sources, for example, from rat cortical preparations or cloned human GABA. A It can be obtained from cells expressing the receptor. Specific subtypes can be readily prepared using standard techniques (for example, by introducing mRNA encoding the desired subunit into host cells).

[0032] As used herein, “CNS disorder” is a disorder or condition of the central nervous system that can be treated, prevented, managed or mitigated using the compounds or compositions provided herein. Certain CNS disorders are those in which GABA is present in the subject. AResponsive to receptor modulation, some CNS disorders are responsive to increases in endogenous neurosteroids and neuroactive steroids. Some CNS disorders include components that also impair the peripheral nervous system ("PNS"). Exemplary CNS disorders include multiple sclerosis, spinal muscular atrophy (thought to be caused by loss of neuronal 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 disease, Friedreich's disease, retinal degeneration and photo-induced damage to the retina (including photoretinitis, retinitis pigmentosa, age-related macular degeneration (AMD), and macular degeneration), delirium, dementia, and amnesia and other cognitive impairments (delirium; dementia, e.g., Alzheimer's disease, vascular dementia, dementia due to HIV disease, dementia due to head injury, dementia due to Parkinson's disease, dementia due to Huntington's disease, dementia due to Pick's disease, dementia due to Creutzfeldt-Jakob disease, dementia due to systemic disease, substance-induced cognition). Examples of conditions that may be classified as depressive disorders include dementia, dementia NOS (hereinafter, "not otherwise specified" will be abbreviated as NOS); amnesia (e.g., amnesia due to systemic conditions, substance-induced amnesia, amnesia NOS: cognitive impairment NOS); ischemic or hemorrhagic cerebrovascular events including stroke and traumatic brain injury (TBI); facomatosis (especially neurofibromatosis); amyotrophic lateral sclerosis; schizophrenia; mood disorders (e.g., major depressive disorder - single episode or recurrent; dysthymic disorder; depressive disorders including depressive disorder NOS; bipolar disorder, e.g., bipolar I disorder, bipolar II disorder, cyclothymic disorder, bipolar disorder NOS; mood disorders due to systemic conditions, substance-induced mood disorders, mood disorders NOS); drug withdrawal symptoms; stuttering; autism; autism spectrum disorder; and convulsive disorders such as epilepsy.Furthermore, CNS disorders also include mental disorders listed in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-V), including anxiety disorders (panic disorder without agoraphobia, panic disorder with agoraphobia, agoraphobia without a history of panic disorder, specific phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, social anxiety disorder, conditional anxiety disorder, substance-induced anxiety disorder, and unspecified (NOS) anxiety disorder), mood disorders, and sleep disorders (primary sleep disorders, e.g., primary insomnia, primary hypersomnia, narcolepsy, respiratory-related sleep disorders, etc.). Circadian rhythm sleep disorders, insomnia NOS; parasomnias NOS including nightmare disorders, night terrors, and sleepwalking; sleep disorders secondary to other mental disorders, such as anxiety, mood disorders, and / or other mental disorders (sleep disorders due to general medical conditions and substance-induced sleep disorders); attention deficit, attention deficit hyperactivity, and disruptive behavior disorders (attention deficit / hyperactivity disorder - combined, inattentive, and hyperactive-impulsive types: attention deficit / hyperactivity disorder NOS; behavior disorders, oppositional defiant disorder, and disruptive behavior disorders NOS); and substance-related disorders. Mental disorders also include eating disorders such as anorexia and bulimia. Further mental disorders and their criteria are described in the American Psychiatric Association's Diagnostic and Statistical Manual of Mental Disorders, 5th sup.th edition (DSM-V), the contents of which are incorporated herein by reference in their entirety.Rare diseases and childhood epilepsies include Rett syndrome, Angelman syndrome, infantile spasms, CDKL5 epilepsy, postpartum depression, tremor, fragile X syndrome, Dravet syndrome, Prader-Willi syndrome, 15q11-q13 duplication deletion syndrome, autoimmune epileptic encephalopathy, Lennox-Gastaut syndrome, childhood absence epilepsy, menstrual epilepsy, status epilepticus, suicidal ideation, other hereditary epilepsy syndromes, seizures, traumatic brain injury, ischemic stroke, spinal cord injury, premenstrual dysphoric disorder, and other neurosteroid deficiency disorders including chronic pain and / or migraines.

[0033] As used herein, “PNS disorder” is a disorder or condition of the peripheral nervous system that can be treated, prevented, managed or mitigated using the compounds or compositions provided herein. Certain PNS disorders are responsive to an increase in endogenous neuroactive steroids. Some PNS disorders may include components that are impaired with motor and / or sensory nerve dysfunction, and the spinal cord and / or brain. Exemplary PNS disorders include neuropathic disorders (which include neuropathies associated with metabolic disorders such as diabetic neuropathy, drug-induced neuropathy such as alcohol-induced and vincristine-induced neuropathy, neuropathy associated with inflammatory processes such as Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, enzyme-deficiency-related neuropathy such as Fabry disease and Krabbe disease, peripheral neuropathy, infectious neuropathic symptoms such as postherpetic neuralgia and HIV-induced neuralgia, and hereditary motor and sensory neuropathy such as Charcot-Marie-Tooth disease) and radicular neuropathy.

[0034] As used herein, “neurodegenerative processes” are characterized by the dysfunction and death of neurons that result in loss of neuronal function mediated by the brain (CNS), spinal cord, and PNS. They may arise from collectively known pathological conditions, among other things, under the terms neurodegenerative disease or morbidity, trauma, or exposure to toxins.

[0035] As used herein, “neuroprotective properties” refer to the ability of the compounds of the present invention to treat neurodegenerative processes.

[0036] As used herein, unless otherwise specified, the terms “neurosteroid” and “neuroactive steroid” refer to steroids that are naturally produced in the subject and alter neuronal excitability through interactions with ligand-gated ion channels and other cell surface receptors. Neurosteroids are produced in the brain. Neuroactive steroids are produced by the conversion of peripherally derived adrenal steroids or gonadal steroids. Examples of neurosteroids and neuroactive steroids include pregnenolone, pregnanolonone, allopregnanolone, tetrahydrodeoxycorticosterone, dehydroepiandrosterone, and progesterone. Neuroactive steroids can affect the CNS and periphery.

[0037] As used herein, the term “to treat” means to reduce, reverse, inhibit, weaken, alleviate, halt, or stabilize the onset or progression of a disease (including any disease or disorder described herein), reduce the severity of the disease, or improve symptoms associated with the disease. In one embodiment, treatment does not include prevention.

[0038] "Disease" means any condition or disorder that impairs or interferes with the normal functioning of a cell, tissue, or organ.

[0039] As used herein, “subject” refers to an animal, typically a mammal including humans such as patients.

[0040] As used herein, unless otherwise specified, the terms “therapeutic effective dose” and “effective dose” of a compound mean an amount sufficient to provide a therapeutic benefit in the treatment, prevention, and / or management of a disease or disorder in order to delay or minimize one or more symptoms associated with the disease or disorder being treated. The terms “therapeutic effective dose” and “effective dose” may include an amount that improves the overall treatment, reduces or avoids the symptoms or causes of a disease or disorder, or enhances the therapeutic effect of another therapeutic agent.

[0041] The terms “simultaneous administration” and “in combination” include administering two therapeutic agents (e.g., the compound of the present invention and lorazepam) simultaneously, concurrently, or sequentially without any specific time constraints. In one embodiment, both agents are present in the subject simultaneously 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.

[0042] It is recognized that some variation in the natural isotopic abundance occurs in the synthesized compound depending on the origin of the chemicals used in the synthesis. Therefore, preparations of ethifoxine essentially contain small amounts of deuterated isotopologs. Despite this variation, the concentrations of naturally abundant stable hydrogen and carbon isotopes are small and insignificant compared to the degree of stable isotopic substitution of the compounds of the present invention. See, for example, Wada, E et al., Seikagaku, 1994, 66:15 and Gannes, LZ et al., Comp Biochem Physiol Mol Integr Physiol, 1998, 119:725.

[0043] In the compounds of the present invention, any atom not specifically designated as a particular isotope represents 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 naturally occurring isotopic composition. Also, unless otherwise specified, when a position is specifically designated as "D" or "deuterium," that position is understood to have deuterium at an abundance at least 3340 times greater than the naturally occurring abundance of deuterium, which is 0.015% (i.e., at least 50.1% of deuterium incorporated).

[0044] As used herein, the term “isotope enrichment factor” means the ratio between the isotopic abundance and the natural abundance of a particular isotope. In some embodiments, the compounds of the present invention have an isotopic enrichment factor of at least 3500 (52.5% deuterium incorporation in each designated 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 designated deuterium atom.

[0045] The term "isotopolog" refers to a species of the specific compound of the present invention that differs only in its isotopic composition.

[0046] When referring to the compounds of the present invention, the term “compound” refers to a set of molecules having the same chemical structure, except that they may have isotopic variations between the constituent atoms of the molecule. Therefore, it will be apparent to those skilled in the art that a compound represented by a particular chemical structure containing a deuterium atom also includes a smaller amount of isotopologs having a hydrogen atom at one or more of the designated deuterium positions in its structure. The relative amount of such isotopologs in the compounds of the present invention depends on several factors, including the isotopic purity of the deuterated reagent used to prepare the compound and the efficiency of deuterium incorporation in the various synthetic steps used to prepare the compound. However, as stated above, the total relative amount of such isotopologs is less than 49.9% of the compound. In other embodiments, the total relative amount of such isotopologs is 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.

[0047] Where used herein, the term "pharmaceutically acceptable" refers to a component that, within the bounds of reasonable medical judgment, is suitable for use in contact with human and other mammalian tissues without excessive toxicity, irritation, allergic response, etc., and that is commensurate with a reasonable benefit-risk ratio. "pharmaceutically acceptable salt" means any non-toxic salt that, when administered to a recipient, can deliver the compound of the present invention, either directly or indirectly. "pharmaceutically acceptable counterion" is the ionic portion of a salt that is non-toxic when released from the salt upon administration to a recipient. Acids commonly used to form pharmaceutically acceptable salts include inorganic acids, such as hydrogen sulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, and phosphoric acid, as well as organic acids, such as para-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, para-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, and acetic acid, as well as related inorganic and organic acids. Therefore, such pharmaceutically acceptable salts include sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, hydrogen phosphates, dihydrogen phosphates, metaphosphates, pyrophosphates, chlorides, bromides, iodides, acetates, propionates, decanoates, caprylates, acrylates, formates, isobutyrates, caprinates, heptanoates, propioates, oxalates, malons, succinates, suberates, sebacinates, fumarates, maleates, butin-1,4-dioate, hexin-1,6-dioxide. Examples include oate, benzoates, chlorobenzoates, methylbenzoates, dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates, terephthalates, sulfons, xylene sulfons, phenyl acetate, phenylpropionate, phenyl butyrate, citrate, lactate, beta-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelic acid, 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 in particular 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, for example, "Remington: The Science and Practice of Pharmacy," A. Gennaro, ed., 20th edition, Lippincott, Williams & Wilkins, Philadelphia, Pa.

[0048] The compounds of the present invention (including the compounds of formula I) may contain an asymmetric carbon atom, for example, as a result of deuterium substitution or otherwise. Therefore, the compounds of the present invention may exist as individual enantiomers or mixtures of two enantiomers. Thus, the compounds of the present invention may exist as either racemic or scaremic mixtures, or as individual stereoisomers substantially free of other possible stereoisomers. As used herein, the term “substantially free of other stereoisomers” means that there are less than 25% other stereoisomers, preferably less than 10% other stereoisomers, more preferably less than 5% other stereoisomers, most preferably less than 2% other stereoisomers, or less than “X”% other stereoisomers (where X is a number between 0 and 100, including both ends). Methods for obtaining or synthesizing individual enantiomers of a given compound are known in the art and can be applied practically to the final compound or to starting materials or intermediates.

[0049] Unless otherwise specified, if a disclosed compound is named or described structurally without specifying its stereochemistry and has one or more chiral centers, it is understood to represent all possible stereoisomers of the compound.

[0050] When used herein, the term “stable compound” means a compound that is stable enough to enable its manufacture and maintains its integrity for a period of time sufficient to be useful for any of the purposes detailed herein, including formulation into therapeutic products, intermediates for use in the production of therapeutic compounds, isolateable or storable intermediate compounds, and treatment of therapeutically responsive diseases or conditions.

[0051] Both "D" and "d" refer to deuterium. Unless otherwise specified, "stereoisomer" refers to both enantiomers and diastereomers.

[0052] The phrase "may be substituted with deuterium" means that one or more hydrogen atoms in the referenced part may be replaced by a corresponding number of deuterium atoms.

[0053] The present invention includes prodrugs of the compounds of Formula I described above. Generally, such prodrugs are functional derivatives of the compounds of Formula I that can be readily converted in vivo to the desired compound 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 from alcohols and acids, and phosphate prodrugs of alcohols. Prodrugs may be formulations that achieve the goals of improved chemical stability, improved patient tolerability and compliance, improved bioavailability, longer duration of action, improved organ selectivity, improved formulation (including increased water solubility), and / or reduced side effects (including toxicity).

[0054] If a compound of the present invention has at least one chiral center, it may exist as an enantiomer accordingly. If a compound has two or more chiral centers, they may further exist as diastereoisomers. Specifically, ethiphoxine exists as a racemic mixture, and R-ethiphoxine and S-ethiphoxine have been prepared. U.S. Patent No. 8,110,569. The present invention includes deuterated analogs of R-ethiphoxine and deuterated analogs of S-ethiphoxine. It should be understood that all such stereoisomers and mixtures thereof in any proportion are included within the scope of the present invention. If a compound has geometric isomers, all such isomers and mixtures thereof in any proportion are included within the scope of the present invention. Tautomers of the compounds of the present invention are included in this application. For example, carbonyl includes its enol tautomer.

[0055] As used herein, “pure S-ethyphoxine” is a deuterated analog that is substantially free of the deuterated R-ethyphoxine analog (i.e., enantiomeric excess). In other words, the “S” form of deuterated ethyphoxine is substantially free of the “R” form of the compound and is therefore enantiomeric excess of the “R” form.

[0056] The terms “enantiomerically pure” or “pure enantiomer” mean that the compound contains enantiomers in amounts 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. In certain embodiments, weight is based on the total weight of the deuterated ethyphoxine analog.

[0057] As used herein, unless otherwise specified, the term “enantiomerically pure R-ethiphoxine” refers to a deuterated analog of at least about 80 wt% deuterated R-ethiphoxine and at most about 20 wt% deuterated S-ethiphoxine, at least about 90 wt% deuterated R-ethiphoxine and at most about 10 wt% deuterated S-ethiphoxine, at least about 95 wt% deuterated R-ethiphoxine and at most about 5 wt% deuterated S-ethiphoxine, at least about 99 wt% deuterated R-ethiphoxine and at most about 1 wt% deuterated S-ethiphoxine, at least about 99.9 wt% deuterated R-ethiphoxine, or at most about 0.1 wt% deuterated S-ethiphoxine. In certain embodiments, weight is based on the total weight of the deuterated ethiphoxine analogs.

[0058] As used herein, unless otherwise specified, the term “enantiomerically pure S-ethiphoxine” means at least about 80 wt% deuterated S-ethiphoxine and at most about 20 wt% deuterated R-ethiphoxine, at least about 90 wt% deuterated S-ethiphoxine and at most about 10 wt% deuterated R-ethiphoxine, at least about 95 wt% deuterated S-ethiphoxine and at most about 5 wt% deuterated R-ethiphoxine, at least about 99 wt% deuterated S-ethiphoxine and at most about 1 wt% deuterated R-ethiphoxine, or at least about 99.9 wt% deuterated S-ethiphoxine and at most about 0.1 wt% deuterated R-ethiphoxine. In certain embodiments, weight is based on the total weight of the deuterated ethiphoxine analogs.

[0059] The term "AUC" used in this specification 0-12 The term "area under the concentration-time curve" refers to the area under the concentration-time curve from time 0 to time 12 hours.

[0060] The term "AUC" used in this specification 0-24The term "area under the concentration-time curve" refers to the area under the concentration-time curve from time 0 to time 24 hours.

[0061] The term "AUC" used in this specification last The term "time 0" refers to the quantifiable concentration (t) calculated using the linear trapezoidal law for increasing concentration and the logarithmic law for decreasing concentration, from time 0 to the last quantifiable concentration. last This refers to the area under the concentration-time curve up to the time )

[0062] The term "AUC" used in this specification inf The term "area under the concentration-time curve" refers to the area under the concentration-time curve extrapolated from time 0 to infinity.

[0063] The term "C" used herein max The term "maximum observed plasma concentration" refers to the highest observed plasma concentration.

[0064] The term "C" used herein min The term "minimum plasma concentration" refers to the minimum plasma concentration observed before administration (over the initial dosing interval (day 7)).

[0065] The term "ARC" as used herein max The term "C" is max Cumulative ratio:C max (Day 7) C max This means the result of dividing by (Day 1).

[0066] The term "ARAUC" used in this specification 0-12 The term "AUC" is used. 0-12 Cumulative ratio: AUC 0-12 (Day 7) AUC 0-12 This means the result of dividing by (Day 1).

[0067] As used herein, the term "PK" means pharmacokinetics.

[0068] As used herein, the term "q12h" means every 12 hours.

[0069] The term "T" used in this specificationmax The term "peak plasma concentration" refers to the time at which the maximum observed plasma concentration is reached.

[0070] The term "t" used in this specification 1 / 2 The term "apparent plasma terminal elimination half-life" refers to the apparent plasma terminal elimination half-life.

[0071] Therapeutic use of etiphoxine for several days Ethifoxine hydrochloride [6-chloro-2-(ethylamino)-4-methyl-4-phenyl-4H-3,l-benzoxazine], known as Stresam™, is known to induce metabolism, and continuous administration leads to metabolic induction in humans. Deuterated ethifoxine for the treatment of anxiety disorders was previously disclosed in U.S. Patent No. 10,736,901 by Olivier Dasse, entitled “Deuterated Analogs of Etifoxine, Their Derivatives and Uses Thereof”. The '901 patent discloses various deuterated analogs of ethifoxine and methods for their preparation, and its teachings regarding deuterated analogs of ethifoxine and methods for their preparation are incorporated herein by reference. The inventors fully anticipated that deuterated ethifoxine would exhibit a metabolic induction effect similar to that of ethifoxine.

[0072] During a multi-day human clinical trial using deuterated ethifoxine, the inventors confirmed that deuterated ethifoxine exhibited a similar metabolic autoinduction effect to ethifoxine at doses exceeding 100 mg bid. However, the inventors surprisingly discovered that the metabolic induction of deuterated ethifoxine differed from that known for ethifoxine (non-deuterated). Specifically, deuterated ethifoxine did not exhibit metabolic induction when administered within the therapeutic dose range (100 mg bid). Based on this surprising discovery, the inventors developed a novel dosage regimen of deuterated ethifoxine useful for treating chronic symptoms such as chronic anxiety disorder.

[0073] The inventors have found that deuterated ethifoxine administered at a dose of 150 mg bid (twice daily) induces metabolism. The following example shows that metabolism was not induced when deuterated ethifoxine was administered at a dose of 100 mg bid. The aim is to administer deuterated ethifoxine at a dose that does not induce metabolism. Such doses may include any dose less than 150 mg bid, preferably including 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 any dose less than that.

[0074] The inventors anticipate that the same total daily dose of 300 mg qd of deuterated ethifoxine corresponds to a 150 mg bid to induce metabolism. Therefore, qd regimens corresponding to 200 mg qd have been shown to avoid metabolic induction. The inventors intend that doses of 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, and 20 mg qd can be administered in a manner that avoids metabolic induction.

[0075] The ability to administer deuterated ethifoxine in a manner that avoids metabolic autoinduction may advantageously provide lower dose regimens than those that would otherwise be required. The inventors envision a dose regimen for treating anxiety disorders on a long-term basis, comprising administering deuterated ethifoxine in doses of 100 mg qd, preferably lower. For example, possible dose regimens for treating chronic anxiety disorders may include 100 mg qd, 90 mg qd, 80 mg qd, 70 mg qd, 60 mg qd, or less.

[0076] Other indications may be treated with deuterated ethifoxine in a manner that avoids self-induction at different doses and administration frequencies.

[0077] In addition to racemic deuterated ethiphoxine, the inventors intend to use deuterated S-ethiphoxine and deuterated R-ethiphoxine using any of the above methods.

[0078] Metabolic differences between deuterated ethyphoxine and ethyphoxine The inventors studied the comparative stability of deuterated ethifoxine and ethifoxine in human, rat, and mouse liver microsomes. [Table 1]

[0079] Deuterated ethifoxine is metabolically more stable than ethifoxine in human, rat, and mouse liver microsomes (lower intrinsic clearance (Clint) and longer half-life) (Table 1). As a result of this greater metabolic stability, GRX-917 is expected to have better oral bioavailability than ethifoxine. Furthermore, the ratio of GRX-917 to M4 after administration of GRX-917 is expected to be higher than the ratio of ethifoxine to M4 after equivalent administration of ethifoxine. The major metabolite (M4) is an enzyme inducer and contributes to in vivo autoinduction. In rats, this improved metabolic stability results in an AUC approximately three times larger for GRX-917 compared to ethifoxine, as shown in Figure 1.

[0080] Repeated dose escalation study using deuterated ethifoxine in healthy subjects This was a phase 1, single-center, prospective, randomized, double-blind, placebo-controlled trial of repeated dose escalation (MAD) of orally administered racemic deuterated ethifoxine in healthy adult males and females.

[0081] The first dose of the study drug was administered on day 1. From days 1 to 6, subjects received oral administration of the study drug twice daily (q12h). The final monotherapy dose of the study drug was administered on day 7. Each dose of the study drug was given with a 240 mL glass of water at the end of a standard meal. The meal was provided 30 minutes before administration and completed within 30 minutes. On days 1 and 7, subjects were required to fast for 8 hours before administration at breakfast and 2 hours after administration (water was freely available during this time).

[0082] Fifty-eight subjects were enrolled in the MAD portion of the study (43 subjects receiving deuterated ethyhoxine and 15 subjects receiving placebo). All available data from the 43 subjects treated with deuterated ethyhoxine were included in the PK population.

[0083] Deuterated ethifoxine - Pharmacokinetics of repeated oral administration on day 7 Table 2 shows the geometric mean (CV%) trough concentrations (12 hours after the final dose) of deuterated ethifoxine on days 2, 4, 5, 6, and 7 after q12h(bid) administration. [Table 2]

[0084] At each dose level, the geometric mean trough of deuterated ethifoxine concentration increased up to day 4 for 100 and 150 mg q12h, and up to day 2 for 200 and 300 mg q12h. Subsequently, trough concentrations decreased up to 12 hours post-final dose on day 7, indicating a possible autoinduction effect.

[0085] Table 3 shows the geometric mean (CV%) PK parameters of deuterated ethifoxine on day 7 after 7 days of q12h(bid) administration. [Table 3]

[0086] The criterion for reporting half-life values ​​required that the terminal stage spanned at least two half-lives (i.e., span > 2). Therefore, only subjects at 1 / 9, 3 / 8, 3 / 13, and 0 / 9 in the 100, 150, 200, and 300 mg q12h dosing regimens had half-lives that could be accurately determined. At 100 mg q12h, the geometric mean cumulative ratios (ARCmax and AUC0-12) of both deuterated ethifoxine were 1.04 and 1.31, respectively, indicating minimal accumulation during 7-day repeated dosing and suggesting no autoinduction. However, the geometric mean ARCmax and AUC0-12 decreased to less than 1 at doses above 100 mg q12h and generally decreased as the dose increased to 0.551 and 0.737, respectively, at 300 mg q12h, suggesting an autoinduction effect.

[0087] Over the dose range up to 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) of 0.86 (0.66, 1.07) and 0.91 (0.67, 1.14), respectively, for Cmax and AUC0-12. Statistical analysis showed that Tmax was independent of the dose on day 7.

[0088] time-dependent dynamics Deuterated ethifoxine did not reduce exposure when administered at a 100 mg BID for 7 days, but ARCmax and ARAUC0-12 decreased to less than 1 at doses above 100 mg BID, demonstrating a self-inducing effect.

[0089] renal excretion Deuterated ethifoxine showed low renal clearance. The percentage of the dose excreted as deuterated ethifoxine was <0.004%.

[0090] conclusion After single and repeated oral administration of 100–300 mg over 12 hours, deuterated ethifoxine was rapidly absorbed with a median Tmax ranging from 2.00 to 3.52 hours post-administration.

[0091] Plasma deuterated ethifoxine concentrations decreased exponentially on day 7 in an apparent overall biphasic pattern, with a geometric mean t1 / 2 ranging from 38.8 to 82.1 hours.

[0092] The Cmax and AUC0-12 of deuterated ethifoxine increased proportionally with the dose on day 7.

[0093] The cumulative deuterated ethihoxine during repeated administration over 7 days was lowest at 100 mg q12h, with ARCmax and ARAUC0-12 values ​​of 1.04 and 1.31, respectively; however, these values ​​decreased between 0.551 and 0.863 at doses above 100 mg BID, indicating a self-inducing effect.

[0094] Example 1 Deuterated ethifoxine is administered to human patients at a dose of 100 mg BID (twice daily) for the treatment of anxiety for at least 7 days. The lack of autoinduction of deuterated ethifoxine metabolism is observed for at least 7 days, with AUCmax and ARAUC of 1 or higher. 0-12 This is demonstrated by [the following].

[0095] Example 2 Deuterated ethifoxine is administered to human patients at a dose of 100 mg QD (once daily) for the treatment of anxiety for at least 7 days. The lack of autoinduction of deuterated ethifoxine metabolism is observed for at least 7 days, with AUCmax and ARAUC being greater than 1. 0-12 This is demonstrated by [the following].

[0096] Example 3 Deuterated ethifoxine is administered to human patients at a dose of 60 mg QD (once daily) for the treatment of anxiety for at least 7 days. The lack of autoinduction of deuterated ethifoxine metabolism is observed for at least 7 days, with AUCmax and ARAUC of 1 or higher. 0-12 This is demonstrated by [the following].

[0097] Example 4 Deuterated ethifoxine is administered to human patients at a dose of 50 mg QD (once daily) for the treatment of anxiety for at least 7 days. The lack of autoinduction of deuterated ethifoxine metabolism is observed for at least 7 days, with AUCmax and ARAUC being greater than 1. 0-12 This is demonstrated by [the following].

[0098] Other embodiments and uses of the present invention will be apparent to those skilled in the art from the discussion herein and the practice of the present invention disclosed herein. All references cited herein, including all U.S. and foreign patents and patent applications, are incorporated herein by reference specifically and completely. This specification and examples are intended to be considered illustrative only, together with the true scope and spirit of the invention as set forth by the appended claims.

Claims

1. A method for treating a disease or disorder in a subject requiring treatment of a disease or disorder, comprising the step of orally administering a compound to the subject, wherein the compound is of formula (I): 【Chemistry 1】 (In the formula, each １ , X ２ , X ３ (This is independently selected from hydrogen or deuterium.) Compounds of (including their pharmaceutically acceptable salts, solvates, and prodrugs), The compound is effective in treating anxiety disorders, and the ARC is 1.0 or higher over a 7-day period. ｍａｘ and ARAUC ０－１２ A method of administration in a dose and frequency that produces the desired effect.

2. 7-day ARC ｍａｘ The method according to claim 1, wherein the ratio is the ratio obtained by dividing the Cmax on day 7 by the Cmax on day 1.

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

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

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

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

7. The method according to any 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 phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, conditional anxiety disorder, substance-induced anxiety disorder, or anxiety disorder with physical symptoms.

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

9. The method according to any of the preceding claims, wherein the compound contains deuterium in an abundance at least 3340 times greater than the natural abundance of deuterium.

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

11. A method for treating a disease or disorder in a subject requiring treatment of a disease or disorder, comprising the step of orally administering 6-chloro-N-(ethyl-d5)-4-methyl-4-phenyl-4H-3,l-benzoxazine-2-amine to the subject, wherein the compound is effective in treating anxiety disorders and has an ARC of 1.0 or higher over 7 days. ｍａｘ and ARAUC ０－１２ A method of administration in a dose and frequency that produces the desired effect.

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

13. The method according to claim 11 or 12, wherein the administration is QD.

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

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

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

17. The method according to any one of claims 11 to 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 phobias, social phobias, obsessive-compulsive disorder, post-traumatic stress disorder, acute stress disorder, generalized anxiety disorder, conditional anxiety disorder, substance-induced anxiety disorder, or anxiety disorder with physical symptoms.

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

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

20. The method according to any one of claims 11 to 19, wherein the compound is a racemic mixture.

21. Equation (I): 【Chemistry 2】 (wherein each X １ , X ２ , X ３ is independently selected from hydrogen or deuterium) A pharmaceutical composition comprising a compound (including its pharmaceutically acceptable salts, solvates, and prodrugs) and a pharmaceutically acceptable excipient, wherein the compound, when administered once daily, has an ARC of 1.0 or higher over seven days. ｍａｘ and ARAUC ０－１２ A pharmaceutical composition present in an amount exhibiting [a certain characteristic].

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

23. The pharmaceutical composition according to claim 21 or 22, wherein the amount is in the range of 20 mg to 100 mg.

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

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