GABAA receptor modulators and uses thereof

Abstract

Use of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a salt thereof is described herein. Also described herein are compositions, such as dosage forms, of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a salt thereof and uses thereof.

Description

[Technical Field]

[0001] Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 413,065, filed October 4, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Gamma-aminobutyric acid (GABA) receptors respond to the neurotransmitter GABA, the major inhibitory compound in the vertebrate central nervous system. A Receptors appear in all organisms with a nervous system. A Modulation of the GABA receptor may be useful in therapeutically addressing diseases or disorders of the central nervous system. A This may be a side effect of therapeutic intervention of the GABA receptor. Furthermore, a phase II study using a non-benzodiazepine anxiolytic (i.e., 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine) was discontinued due to toxicity in long-term administration studies. Therefore, the potential for GABAergic treatment to reduce the negative side effects of therapeutic interventions, including concurrent sedation and toxicity, is unclear. A The development of receptor therapeutics is needed. Summary of the Invention [Means for solving the problem]

[0003]

[0003] Described herein are uses of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a salt thereof. Also described herein are compositions, such as dosage forms of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile (Compound 1) or a pharmaceutically acceptable salt thereof, and uses thereof.

[0004]

[0004] Compound 1 or a salt thereof may also be referred to herein as the active compound or active ingredient. Compound 1 is shown below as the free base.

[0005] [ka] [Brief explanation of the drawings]

[0006] [Figure 1] FIG. 1 shows the onset of REM, NREM, and REM latency from Example 1. [Figure 2] FIG. 2 shows the change in the delta spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 3]

[0007] FIG. 3 shows changes in the theta spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 4]

[0008] FIG. 4 shows the changes in the alpha spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 5]

[0009] FIG. 5 shows changes in the beta spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 6]

[0010] FIG. 6 shows the changes in the low gamma spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 7]

[0011] FIG. 7 shows the changes in the high gamma spectral band over time (0-12 hours post-administration) during NREM in the frontal cortex from Example 1 (Compound 1 and lorazepam). [Figure 8]

[0012] FIG. 8 shows changes in the delta spectral band over time (0-12 hours post-dose) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 9]

[0013] FIG. 9 shows changes in the beta spectral band over time (0-12 hours post-administration) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 10]

[0014] FIG. 10 shows changes in the theta spectral band over time (0-12 hours post-administration) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 11]

[0015] FIG. 11 shows changes in the low gamma spectral band over time (0-12 hours post-administration) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 12]

[0016] FIG. 12 shows changes in the alpha spectral band over time (0-12 hours post-administration) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 13]

[0017] FIG. 13 shows the changes in the high gamma spectral band over time (0-12 hours post-administration) during NREM in the parietal cortex from Example 1 (Compound 1 and lorazepam). [Figure 14]

[0018] FIG. 14 shows the percent change of spectral bands during NREM from Example 1. [Figure 15] FIG. 15 shows the PK profile of Compound 1. [Figure 16] Figure 16 shows the mean plasma concentrations. [Figure 17]

[0019] Figure 17 shows the change from baseline (CFB) in EEG alpha power ((uV)2) at Fz-Cz eyes open. [Figure 18]

[0020] Figure 18 shows the change from baseline in EEG beta power ((uV)2) during Fz-Cz eye closure. [Figure 19]

[0021] Figure 19 shows the change from baseline in EEG theta power ((uV)2) during Fz-Cz eye closure. [Figure 20]

[0022] Figure 20 shows the change from baseline in EEG theta power ((uV)2) during Fz-Cz eyes-open. [Figure 21]

[0023] Figure 21 shows that Compound 1 significantly reduced SPV (p=<0.05*) consistent with an anxiolytic-like profile. *p value refers to the entire 12-day dosing period. DETAILED DESCRIPTION OF THE INVENTION

[0007] definition

[0024] Certain terms, whether used alone or as part of a phrase or another term, are defined below.

[0008]

[0025] The articles "a" and "an" refer to one or to more than one of the grammatical object of the article.

[0026] Numerical values ​​relating to measurements are subject to measurement error, which places limitations on the precision of the numerical values. For this reason, the term "about" adjusts all numerical values ​​set forth herein unless otherwise indicated. The term "about" typically indicates that a numerical value may vary by no more than 10%, no more than 5%, or no more than 1%. In some embodiments, the last decimal place of a numerical value set forth herein indicates its degree of precision. In some embodiments, unless another tolerance is indicated, the maximum tolerance is ascertained by rounding to the last decimal place, or to the last significant digit if a given numerical value does not contain a decimal.

[0009]

[0027] The term "amelioration" refers to a reduction in the severity of at least one indicator of a condition or disease, such as a delay or slowing of the progression of one or more indicators of the condition or disease. The severity of the indicator may be determined by subjective or objective criteria known to those skilled in the art.

[0010]

[0028] The term " composition " and " pharmaceutical composition " refer to the mixture of at least one compound described herein and carrier or pharmaceutically acceptable carrier, respectively. Pharmaceutical composition facilitates the administration of compound to patient or subject. There are many techniques for administering composition, including but not limited to intravenous administration, oral administration, intranasal administration, rectal administration, intravaginal administration, aerosol, parenteral administration, buccal administration, sublingual administration, ocular administration, intrapulmonary administration, transdermal administration and topical administration.

[0011]

[0029] The terms "effective amount" and "therapeutically effective amount" refer to an amount of a therapeutic compound, such as a compound described herein, administered to a subject, either in a single dose or as part of a series, effective to produce the desired therapeutic effect.

[0012]

[0030] The term "pharmaceutically acceptable carrier" refers to a pharmaceutically acceptable material, composition, or carrier, such as a liquid filler, solid filler, stabilizer, dispersant, suspending agent, diluent, excipient, thickener, solvent, or encapsulating material, that is involved in carrying or transporting at least one compound described herein in or to a patient so that the compound can perform its intended function. The carrier to be administered must be "acceptable" in the sense of being compatible with the other ingredients of a particular formulation containing the compound described herein and not harmful to the patient. Other ingredients that may be included in the pharmaceutical compositions or dosage forms described herein are known in the art and are described, for example, in "Remington's Pharmaceutical Sciences" (Genaro (ed.), Mack Publishing Co., 1985), the entire contents of which are incorporated herein by reference.

[0013]

[0031] The term "pharmaceutically acceptable salt" refers to a derivative of a compound of the present disclosure where the parent compound is modified by converting an existing acid or base moiety into its salt form. A list of salts can be found in "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (P. Henrich Stahl & Camille G. Wermuth (eds.), VHCA & Wiley-VCH, 2002), the entire contents of which are incorporated herein by reference.

[0014]

[0032] The term "solid form" includes, but is not limited to, polymorphs, crystalline forms, amorphous forms, solvates, and hydrates of a compound.

[0033] The term "treatment" or "treating" refers to the application of one or more specific procedures used to ameliorate a disease. "Prophylactic" treatment refers to reducing the rate of progression of the disease or condition being treated, delaying the onset of the disease or condition, or reducing the severity of its onset.

[0015]

[0034] The recitation of ranges of values ​​herein is merely intended to serve as a shorthand method of individually referring to each separate value falling within the range. Unless otherwise indicated herein, each separate value is incorporated herein as if it were individually set forth herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples or exemplary phrases (such as "for example," "etc.", etc.) provided herein is intended merely to facilitate understanding of the described subject matter and does not otherwise pose a limitation on the scope of the claimed subject matter. No phrase herein should be construed as indicating any non-claimed element essential to practicing the described subject matter.

[0016]

[0035] Each group member of a group formed from alternative elements or embodiments of the present disclosure may be referred to and claimed individually or in any combination with other members of the group or other elements found herein. Furthermore, a described group member may be included in or excluded from another described group for reasons of convenience or patentability.

[0017]

[0036] Throughout this specification, reference to a patent or publication document is incorporated herein by reference in its entirety.

[0037] The embodiments of the present disclosure are presented by way of example only and are therefore not limited to that precisely as shown and described.

[0018] Dosage form

[0038] 2',6-Difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile (Compound 1) or a pharmaceutically acceptable salt thereof has been shown to be a selective allosteric modulator of GABA receptors at the α2, α3, and α5 subtypes. A GABA, which can act at the benzodiazepine site of the receptorA It is a receptor modulator. Compound 1 or a salt thereof described herein can be synthesized using any suitable method starting from a compound available from a commercial source, or can be prepared using the method described in U.S. Patent No. 6,936,608 or 6,617,326 or U.S. Patent Application Publication No. 2021 / 0040103. The general method for preparing the compounds described herein can be modified by using appropriate reagents and conditions for the introduction of various moieties found in the formulas shown herein.

[0019]

[0039] The present invention provides compositions, such as pharmaceutical compositions, including dosage forms of Compound 1 or a pharmaceutically acceptable salt thereof, and uses thereof. In some embodiments, Compound 1 is provided as the phosphate salt of Compound 1. The dosage (mg / kg) used in rat studies can be extrapolated to a human equivalent dosage by multiplying the rat dosage by a factor of 0.162 (J Basic Clin Pharm. March 2016-May 2016;7(2):27-31). Thus, in some embodiments, dosage forms provided herein contain about 1.5 to about 100 μg / mL of Compound 1 or a salt thereof. In some embodiments, dosage forms provided herein contain about 15 to about 20 μg / mL of Compound 1 or a salt thereof. In some embodiments, dosage forms provided herein contain 3 μg / mL of Compound 1 or a salt thereof. In some embodiments, dosage forms provided herein contain about 10 to about 100 μg / mL of Compound 1 or a salt thereof. In some embodiments, dosage forms provided herein contain about 20 μg / mL of Compound 1 or a salt thereof.

[0020]

[0040] In some embodiments, the dosage forms provided herein may include a first pharmaceutically acceptable carrier. In some embodiments, the first pharmaceutically acceptable carrier includes methyl 2-hydroxyethylcellulose. In some embodiments, the dosage form includes about 0.1 to about 3% w / w methyl 2-hydroxyethylcellulose. In some embodiments, the dosage form includes about 0.5% or about 2% w / w methyl 2-hydroxyethylcellulose. In some embodiments, the dosage forms provided herein independently further include a second, third, or more pharmaceutically acceptable carriers. Advantageously, a pharmaceutically acceptable carrier, such as methyl 2-hydroxyethylcellulose, may enable Compound 1 or a salt thereof to remain suspended in the dosage form for longer than a composition that does not include methyl 2-hydroxyethylcellulose. In other words, the inclusion of methyl 2-hydroxyethylcellulose in the dosage form may delay sedimentation of suspended Compound 1 or a salt thereof. Thus, the dosage forms provided herein may be stable against sedimentation for up to 6 or 8 days when stored at room temperature (about 20 to about 25°C). Undesired settling of the active ingredient poses several problems, including the risk of reducing the amount of active ingredient drawn or dispensed into the container when the dosage form is a liquid dosage form.

[0021]

[0041] In some embodiments, the dosage forms provided herein contain Compound 1 or a salt thereof at a dose of about 0.002 to about 1 mg / kg. In some embodiments, the dosage forms provided herein contain Compound 1 or a salt thereof at a dose of about 0.002 to about 0.2 mg / kg. In some embodiments, the dosage forms provided herein contain Compound 1 or a salt thereof at a dose of about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.016 mg / kg, about 0.05 mg / kg, about 0.15 mg / kg, or about 0.16 mg / kg, or any range therebetween. In some embodiments, the dosage forms provided herein contain Compound 1 or a salt thereof at a dose of about 0.01 to about 1 mg / kg. In some embodiments, the dosage forms provided herein contain Compound 1 or a salt thereof at a dose of about 0.03 mg / kg, about 0.1 mg / kg, about 0.3 mg / kg, or about 1 mg / kg, or any range therebetween.

[0022]

[0042] In some embodiments, the dosage form comprises about 0.5, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, or 5.0 mg of the free base equivalent of Compound 1 or a phosphate salt of Compound 1. In some embodiments, the dosage form of the present invention comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, 25, or 30 μmol of Compound 1 or a salt thereof, such as a phosphate salt thereof.

[0023]

[0043] In some embodiments, the dosage form is a liquid or solid dosage form. In some embodiments, the dosage form is an oral dosage form. method

[0044] Thus, in some embodiments, the present invention provides a method comprising administering a dosage form provided herein to a subject. In some embodiments, the subject is suffering from a disease or condition for which Compound 1 or a salt thereof is useful for treating.

[0024]

[0045] Dosage forms described herein comprising Compound 1 and pharmaceutically acceptable salts thereof (e.g., phosphate salts of Compound 1) can be used as described in U.S. Pat. Nos. 6,936,608 or 6,617,326 or U.S. Patent Application Publication No. 2021 / 0040103. Thus, in some embodiments, the dosage forms provided herein are useful in treating certain disorders, including disorders of the central nervous system, in subjects in need thereof. In some embodiments, the dosage forms provided herein are useful in treating certain disorders, including disorders of the central nervous system, in subjects in need thereof. AIn some embodiments, the dosage forms provided herein are useful for treating receptor-related diseases or diseases or disorders of the central nervous system in subjects in need of such treatment. In some embodiments, the dosage forms provided herein are useful for treating anxiety, cognitive impairment, or convulsions in subjects in need of such treatment. In some embodiments, the dosage forms provided herein are useful for treating adverse neurological conditions in subjects in need of such treatment. In some embodiments, the dosage forms provided herein are used to treat a variety of conditions, including alcoholism, anxiety, autism (e.g., autism resulting from SCN2a mutations, fragile X syndrome, or autism associated with ion channel dysfunction), cognitive impairment, depression, drug addiction, epilepsy (e.g., focal epilepsy, generalized epilepsy, Dravet syndrome, childhood absence epilepsy (CEA), juvenile absence epilepsy, juvenile myoclonic epilepsy (JME), West syndrome, Lennox-Gastaut syndrome (LGS), sunflower syndrome, status epilepticus, nerve agent-induced seizures, alcohol withdrawal tremor, traumatic brain injury, tuberous sclerosis complex, Doze syndrome, Rasmussen syndrome, early myoclonic encephalopathy, malignant focal migrating partial seizures of infancy, epilepsy with sustained spike-and-wave during slow-wave sleep, Landau-Klöffner syndrome, benign epilepsy with centrotemporal spikes, , benign familial neonatal infantile convulsions, cortical dysplastic focal epilepsy syndrome, generalized epilepsy with febrile seizures plus (GEFS+), myoclonic atonic epilepsy, malignant focal migrating partial seizures of infancy, Ohtahara syndrome (also known as early infantile epileptic encephalopathy), or partial epilepsy with febrile seizures plus), generalized anxiety disorder, pruritus (e.g., chronic pruritus, neurogenic pruritus, uremic pruritus, neurodermatitis, back paresthesia, atopic dermatitis, The compounds are useful in treating prurigo nodularis, psoriasis, psychogenic pruritus or aquatic pruritus), muscle spasms, pain (e.g., fibromyalgia, inflammatory pain, neuropathic pain, diabetic peripheral neuropathy, chemotherapy-induced pain, HIV-associated neuropathy, posterior herpetic neuralgia, musculoskeletal pain, rheumatoid arthritis, osteoarthritis, postoperative pain, burn pain, sunburn pain or phantom limb pain), panic disorder, itch, or schizophrenia in a subject in need thereof.

[0025]

[0046] Additional disorders that the dosage form described herein is useful for treating include anxiety disorders such as panic disorder with or without agoraphobia, agoraphobia without a history of panic disorder, other phobias including animal phobia and social phobia, social anxiety disorder, obsessive-compulsive disorder, stress disorder including post-traumatic and acute stress disorder, and generalized or substance-induced anxiety disorder, neurosis, convulsion, migraine, depressive disorder or bipolar disorder, for example, single episode or recurrent major depressive disorder, dysthymic disorder, bipolar I and bipolar II manic disorder, and circadian disorder, including schizophrenia, neurodegeneration resulting from cerebral ischemia, attention deficit hyperactivity disorder, speech disorder including stuttering, and circadian rhythm disorder, for example, in subjects suffering from jet lag or shift work effects.In some embodiments, the anxiety disorder is post-traumatic stress disorder (PTSD).

[0026]

[0047] Other disorders for which the dosage forms provided herein may be effective include pain and nociception, acute, delayed, and anticipatory emesis, particularly vomiting including chemotherapy- and radiation-induced emesis as well as motion sickness, and postoperative nausea and vomiting, eating disorders including anorexia nervosa and bulimia nervosa, premenstrual syndrome, muscle spasms or spasticity, for example in paraplegic patients, hearing impairment, including tinnitus and age-related hearing loss, urinary incontinence, and the effects of drug abuse and dependence, including alcohol withdrawal. The dosage forms provided herein may also be effective as premedications before anesthesia or minor surgeries such as endoscopy, including gastroscopy.

[0027]

[0048] In some embodiments, provided herein are methods comprising administering a therapeutically effective amount of a dosage form herein comprising a phosphate salt of Compound 1 to a subject in need thereof.

[0049] In some embodiments, provided herein are methods in which the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered a comparable (e.g., equimolar) dose of lorazepam.

[0028]

[0050] In some embodiments, provided herein are methods comprising administering a therapeutically effective amount of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof to a subject in need thereof, wherein the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered an equivalent dose of lorazepam.

[0029]

[0051] In some embodiments of the methods of the present invention, delta, theta, or delta and theta electroencephalogram (EEG) oscillatory power from a subject is reduced by about 20% or more during non-REM sleep compared to a subject administered an equivalent dose of lorazepam.

[0030]

[0052] In some embodiments of the methods of the present invention, delta, theta, or delta and theta EEG oscillatory power is measured in the frontal cortex, parietal cortex, or frontal and parietal cortex of the subject's brain.

[0031]

[0053] In some embodiments of the methods of the present invention, the subject receives GABA A In some embodiments, the patient suffers from a receptor-related disease or a disease or disorder of the central nervous system. In some embodiments, the disease comprises anxiety. In some embodiments, the disease comprises generalized anxiety disorder. In some embodiments, the disease is a CNS disorder. In some embodiments, the disease comprises epilepsy.

[0032]

[0054] In some embodiments, GABA A Provided herein are methods for treating a receptor-related disease or a disease or disorder of the central nervous system in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a dosage form of the invention, wherein optionally the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered a comparable dose of lorazepam.

[0033]

[0055] In some embodiments, GABAA Provided herein is a method for treating a receptor-related disease or a disease or disorder of the central nervous system in a subject in need thereof, comprising administering a therapeutically effective amount of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate to the subject, wherein the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered an equivalent dose of lorazepam.

[0034]

[0056] In some embodiments, a method includes administering a dosage form of the invention to a subject, further comprising generating pharmacokinetic parameters for the compound in the subject, wherein the dosage form is administered once daily, and the dosage form comprises about 0.5, 1.0, 1.5, or 2.0 mg of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate, and the pharmacokinetic parameters have a T of about 3 hours. max Or about 60-70 hours T 1 / 2 Or both.

[0035]

[0057] In some embodiments, a method includes administering a dosage form of the invention to a subject, further comprising generating pharmacokinetic parameters for the compound in the subject, wherein the dosage form is administered once daily and the dosage form comprises about 1, 2, 3, 4, or 5 μmol of 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile phosphate, and the pharmacokinetic parameters have a T of about 3 hours. max Or about 60-70 hours T 1 / 2 Or both.

[0036]

[0058] In some embodiments, provided herein are methods of treating an anxiety disorder in a subject in need thereof comprising administering to the subject a dosage form herein.

[0037]

[0059] In some embodiments of these methods, the administration is oral once daily.

[0060] In some embodiments of these methods, the dosage form comprises 1, 2, or 3 tablets or capsules containing the compound.

[0038]

[0061] In some embodiments of these methods, the dosage form comprises about 1.0, 1.3, 2.0, 2.6, 3.0, 3.1, 3.8, 4.0, 4.1, 5.0, or 5.1 μmol of 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile or 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile monophosphate.

[0039]

[0062] In some embodiments of these methods, the dosage form comprises about 2 mg of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile monophosphate.

[0040]

[0063] In some embodiments of these methods, 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof is present at steady state in the plasma of the subject when a once-daily dose of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate is administered, wherein the once-daily dose comprises at least six consecutive days of administration.

[0041]

[0064] In some embodiments of these methods, the steady state C of the compound in the subject's plasma is about 10-50 ng / mL. max Includes:

[0065] In some embodiments, a method of treating anxiety (e.g., generalized anxiety disorder) in a subject in need thereof includes administering to the subject a dosage form of the invention (e.g., comprising about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 μmol of Compound 1 or a phosphate salt of Compound 1, or a milligram equivalent), wherein the dosage form is administered once daily, and the dosage form is administered in a single dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 μmol. Provided herein are methods comprising administering a dosage form containing 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate salt of ol, wherein the once-daily administration comprises administration of the dosage form for at least 12 consecutive days, and wherein the subject experiences reduced mydriasis upon administration of the dosage form compared to administration of the dosage form once-daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days.

[0042]

[0066] The actual dosage level of Compound 1 or a salt thereof, i.e., the active compound, in the dosage forms described herein may be varied to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration without toxicity to the patient.

[0043]

[0067] In particular, the selected dosage level will depend on a variety of factors, including the activity of the particular active ingredient used, the time of administration, the rate of excretion of the active ingredient, the duration of treatment, other drugs, compounds, or materials used in combination with the active ingredient, and the age, sex, weight, condition, general health, and medical history of the patient being treated.

[0044]

[0068] Administration routes include but are not limited to oral administration, intranasal administration, rectal administration, intravaginal administration, aerosol, parenteral administration, buccal administration, sublingual administration, ocular administration, pulmonary administration and topical administration.In some embodiments, oral or intranasal administration route is oral inhalation or intranasal inhalation administration route.The dosage form for use described herein can be formulated to be suitable for administration by any suitable route to achieve the specific method applied.

[0045]

[0069] Thus, administration of the dosage forms described herein includes various enteral or parenteral techniques selected from, but not limited to, any acceptable form of oral administration, e.g., tablets, liquids (e.g., suspensions of particles), capsules, powders, etc., any acceptable form of topical or transdermal administration, including, e.g., drops, sprays, creams, gels, ointments, or patches, any acceptable form of oral, intranasal, sublingual, ocular, intrapulmonary, and / or inhalation administration, any acceptable form of rectal administration, any acceptable form of vaginal administration, any acceptable form of peristissue and intrastitial administration, including, e.g., intraperitoneal, intramuscular, subcutaneous, intravenous, or intraarticular injection, any acceptable form of intravesical administration, including, e.g., catheter instillation, and by placement devices, including, e.g., implants, stents, patches, pellets, catheters, osmotic pumps, suppositories, bioerodible delivery systems, non-bioerodible delivery systems, or another sustained-release or sustained-release implant system.

[0046]

[0070] Local administration significantly increases the delivery of the active ingredient to a specific location compared to the entire mammalian body, while systemic administration essentially results in the delivery of the active ingredient to the entire body of the individual. Suitable administration routes for treating the central nervous system-related diseases or disorders disclosed herein also include both central and peripheral administration. Central administration essentially results in the delivery of the active ingredient to the central nervous system of the individual, and includes, for example, intranasal administration, intrathecal administration, epidural administration, and cranial injection or cranial implant. In some embodiments, central administration is used to administer the dosage forms described herein.

[0047]

[0071] Central administration via the intranasal route, which targets drug absorption through the vascular network of the nasal cavity, is distinct from administration via nasal inhalation, which delivers drugs via the pulmonary system. The latter typically uses liquid or dry powder aerosols with an average particle size of less than about 10 microns, while central administration can be achieved using average particle sizes of about 10 microns or greater. Mists and aerosols can be generated using nebulizers, dry powder inhalers, pressurized aerosols, and atomizing pumps. It is also feasible to use nasal drops (e.g., liquid particle suspensions) for central administration via the intranasal route.

[0048]

[0072] Peripheral administration essentially results in delivery of the active ingredient to any area outside the central nervous system of an individual, and includes any route of administration other than direct administration to the spinal column or brain. kit

[0073] In some embodiments, provided herein is a packaged dosage form comprising a container containing a therapeutically effective amount of Compound 1 or a salt thereof and instructions for using the dosage form according to one or more of the methods provided herein.

[0049]

[0074] The dosage forms and related materials of the present invention can be commercialized using conventional processes in the art, including appropriate sterilization and packaging. For example, the materials can be treated with UV / visible radiation (200-500 nm), for example, using photoinitiators with different absorption wavelengths (e.g., Irgacure 184, 2959), preferably water-soluble initiators (e.g., Irgacure 2959). Such irradiation typically occurs for a period of 1-60 minutes, although longer irradiation times may be applied depending on the particular method. Finally, materials according to the present disclosure can be sterile packaged and packaged in an appropriate container (e.g., box) (e.g., accompanied by a specific product information leaflet) to maintain sterility until use.

[0050]

[0075] According to further embodiments, the described dosage forms can also be provided in kit form, combined with other components necessary to administer the materials to a patient. For example, the disclosed kits for use in the treatments described herein can further include, for example, administration materials.

[0051]

[0076] Kits may be designed in a variety of forms based on the particular deficiency they are designed to treat.

[0077] The dosage forms provided herein may be prepared and packaged for storage at ambient or elevated temperatures. For example, solutions of Compound 1 or a salt thereof at about 20 μg / mL in water or about 0.12 to about 7.2 mg / mL in about 0.5% methyl 2-hydroxyethylcellulose in water have been found to be stable (i.e., exhibit no appreciable deterioration) for up to about 6 to about 8 days when stored at room temperature (about 20 to about 25° C.). This is advantageous because commercially viable dosage forms can benefit from stability at temperatures higher than those requiring refrigeration or sub-zero temperatures during transportation and storage at the point of use.

[0052]

[0078] When the dosage forms provided herein are stored in polyolefin plastic containers, discoloration of the dosage forms may be reduced compared to, for example, polyvinyl chloride plastic containers. Without being bound by theory, the containers may reduce exposure of the contents of the container to electromagnetic radiation, whether it be visible light (e.g., having a wavelength of about 380-780 nm) or ultraviolet (UV) light (e.g., having a wavelength of about 190-320 nm (UVB light) or about 320-380 nm (UVA light)). Some containers also include the ability to reduce adhesion or adsorption of active ingredients to the container surface, thereby effectively lowering the concentration of the active ingredient in the solution. Some containers also include the ability to reduce exposure of the contents of the container to infrared light, or a second component with such ability. Some containers further include the ability to reduce exposure of the contents of the container to heat or moisture. Containers that can be used include those made from polyolefins such as polyethylene, polypropylene, polyethylene terephthalate, polycarbonate, polymethylpentene, polybutene, or combinations thereof, particularly polyethylene, polypropylene, or combinations thereof. In some embodiments, the container is a glass container.The container can be further placed inside a second container, such as a paper container, a cardboard container, a paperboard container, a metal film container, or a foil container, or a combination thereof, to further reduce the exposure of the contents of the container to UV light, visible light, or infrared light.The manufactured article that is beneficial to reduce discoloration, decomposition, or both during storage includes a dosage form comprising Compound 1 or a salt thereof.The dosage form provided in the present invention may require storage for up to 3 months or longer, and in some cases up to 1 year or longer.The container can be any form suitable for containing contents, such as a bag, a bottle, or a box.

[0053]

[0079] The following examples further illustrate embodiments of the present disclosure, but do not in any way limit the teachings or disclosure set forth herein. [Example]

[0054] Example 1: Evaluation of Sleep Stage-Specific Pharmaco-EEG (Electroencephalography) Signatures of Compound 1 in Wirelessly Implanted Rats

[0080] Young adult male Sprague-Dawley (SD) rats (approximately 275-325 grams upon arrival) were used for the study. Implanted animals were used for Study 1 and Study 2. Rats were housed three per cage upon arrival. A 12-hour / 12-hour light / dark cycle was maintained throughout the course of the study. Room temperature was maintained between 20°C and 23°C, and relative humidity was maintained at approximately 50%. Food and water were available ad libitum throughout the study period. After surgery, rats were housed individually. After a recovery period (7-10 days), animals were transported to an electroencephalogram (EEG) recording room and placed on a dry sensor interface (DSI) receiver for recording.

[0055] Test 1

[0081] Compound 1 was administered orally (per os (PO)) at 0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, or 1 mg / kg in 0.5% TYLOSE MH300® solution (supplied as 2% methyl 2-hydroxyethylcellulose in water, viscosity 150-450 mPa*s (centipoise, cP)). Formulations were prepared daily by weighing the test items, grinding them to a fine powder using a mortar and pestle, adding a few drops of vehicle, mixing with the test items to obtain a homogenous mixture, gradually adding the vehicle, transferring the mixture to a graduated flask, rinsing the mortar and pestle, adding the rinse solution to the graduated flask, homogenizing the suspension by manual stirring, and then bringing to the final volume with vehicle. Before any sampling, the formulations were agitated by magnetic stirring at room temperature. A 20 μg / mL standard solution was found to be stable for 6 days when stored at room temperature. Analytical samples diluted from the dosage formulation at concentrations ranging from 0.12 to 7.2 mg / mL in 0.5% TYLOSE MH300® solution were found to be stable for 8 days when stored at room temperature. Compounds were protected from light (e.g., in opaque bottles such as plastic or glass) when not in use.

[0056]

[0082] Vehicle and four doses of Compound 1 were evaluated in a crossover design ensuring n=12 rats per group. After a 4-day washout, recordings were performed on a Monday and Friday dosing / recording schedule. EEG recordings began at approximately 6 PM (lights off). Dosing occurred at approximately 10 PM (4 hours after lights off). EEG recordings were continuous for 48 hours.

[0057]

[0083] Animals were implanted with a DSI telemetry device (F50-EET) configured with a three-channel (lead pair) configuration. Each EEG channel on the DSI transmitter serves as a differential input measuring the difference between the positive and negative leads: Frontal / Parietal (Right): (+) 2 mm anterior, 2 mm lateral, (-) 4 mm posterior, 2 mm lateral; Frontal / Frontal (Bihemispheric): (+) 2 mm anterior, 2 mm lateral (Right); (-) 2 mm anterior, 2 mm lateral (Left); and Neck EMG.

[0058]

[0084] EEG was recorded wirelessly from rats in their cages using a DSI DataQuest ART. A 12-hour light and 12-hour dark light cycle was maintained for the duration of the experiment. Animals were acclimated to dosing (vehicle administration) for two days before any data collection took place. Recording began two hours before compound administration and continued continuously for 48 hours after dosing.

[0059]

[0085] Raw EEG recordings were manually scored using Neuroscore software (Data Sciences International) to identify the following sleep stages: Active Wake, Quiet Wake, NREM, and REM.

[0060]

[0086] Artifacts were removed from the data offline using NeuroScore (DSI). Sleep stages were manually assigned to each 10-s epoch using EEG, EMG, and LMA according to a previously described conventional method (Ivarsson et al., 2005; Parmentier-Batteur et al., 2012; Leiser et al., 2014, 2015) using frontal-parietal EEG, motor activity (LMA), and EMG: active wakefulness (low-amplitude EEG with less regularity and high EMG and LMA activity); quiet wakefulness (low-amplitude EEG with less regularity and no EMG and LMA activity); NREM (consisting of high-amplitude irregular waves dominated by delta (1–4 Hz), low EMG, and no LMA); and REM sleep (stable low-amplitude waves dominated by theta (4–8 Hz), near-absent EMG, and no LMA).

[0061]

[0087] Sleep stage data were exported from the Neuroscore report template for 15-minute sleep state times (from 2 hours before dosing to 4 hours after dosing). The first sleep and first REM onsets were also reported directly from the Neuroscore report template. Latency was calculated as the time interval from the onset of the first REM stage after the onset of NREM (i.e., TREM-TNREM = REM latency). Hypnograms were generated using the percentage time spent in each sleep stage per hourly time bin. Time in each sleep state was calculated as a percentage of total time in each sleep state (mean ± standard error of the mean, SEM). Data for individual animals were organized by treatment group, sleep state, and bin and exported to GraphPad PRISM for statistics and graphical illustration.

[0062]

[0088] Spectral analysis was performed using Matlab. Briefly, time-domain signals collected for multiple channels were compiled in DSI / Neuroscore, and then the EDF files were imported into Matlab. Excel files with specific timestamps for baseline and post-administration were also imported into Matlab for time-locking. In Matlab, power spectral density (PSD) was calculated using Welch's method. Next, both raw and relative spectral power were calculated for each of six frequency bands (delta, theta, alpha, beta, low gamma, and high gamma) and each 1 Hz subband. The 2-hour data recorded before compound administration was pooled and defined as "baseline." Percent changes from baseline were calculated for each channel, subject, dose level, spectral band, and time segment. Mean raw, relative, and percent changes for each frequency band were calculated for each group. Spectral analysis included quantifying raw, relative, and percent change spectral power for the traditionally defined EEG bands (delta (0.5-3.9 Hz), theta (4-7.9 Hz), alpha (8-11.9 Hz), beta (12-29.9 Hz), low gamma (30-50 Hz), and high gamma (51-100 Hz)) per rat per recording. Additionally, the 1-100 Hz EEG spectrum was represented as a line plot.

[0063] Test 2

[0089] Intraperitoneal (IP) lorazepam 1 mg / kg was dissolved in saline. Following Study 1, all rats (n=12) received a single dose of lorazepam. These data were combined into Study 1 and analyzed similarly.

[0064] Sleep results (see Figure 1)

[0090] Compound 1 at 1 mg / kg delayed the onset of REM and increased REM latency. Compound 1 and lorazepam decreased active wakefulness, but only Compound 1 also decreased quiet wakefulness. Compound 1 and lorazepam increased NREM.

[0065]

[0091] Figure 1 shows REM, NREM onset, and REM latency. Onset is the time (minutes) at which the first period of REM begins. Latency is defined as the time from the onset of NREM to the onset of the first REM period (i.e., TREM-TNREM=REM latency). *p<0.05, ANOVA with Dunnett's multiple comparison test.

[0066] Spectral results (see Figures 2-14)

[0092] Prefrontal cortex: Compound 1 and lorazepam increased beta, low, and high gamma during active and quiet wakefulness. Both Compound 1 and lorazepam increased beta during REM. Both Compound 1 and lorazepam decreased theta and alpha during NREM. Compound 1 also decreased delta and increased low and high gamma during NREM, effects lasting up to 48 hours at high doses, while lorazepam decreased theta, alpha, and beta but increased low gamma, effects lasting up to 9 hours after administration.

[0067]

[0093] Fronto-parietal cortex: Compound 1 decreased alpha during active wakefulness but increased beta, low-, and high-gamma. Compound 1 decreased delta during quiet wakefulness but increased beta, low-, and high-gamma, effects that persisted for up to 48 hours. Lorazepam decreased theta and increased beta and low- and high-gamma, but the effects did not persist beyond 4 hours post-administration. During REM, Compound 1 decreased theta and alpha but increased beta and low-gamma, while lorazepam increased theta, alpha, beta, and low-gamma, but these effects did not persist very long. Compound 1 decreased delta, theta, and alpha during NREM, with the effects on delta and theta persisting for up to 48 hours post-administration. Increases in low- and high-gamma persisted for up to 48 hours with Compound 1, but only for up to 2 hours with lorazepam.

[0068]

[0094] Figures 2-7 show the change in spectral bands over time during NREM (0-12 hours post-dose, frontal cortex, Compound 1, and lorazepam), Figures 8-13 show the change in spectral bands over time during NREM (0-12 hours post-dose, parietal cortex, Compound 1, and lorazepam), and Figure 4 shows the percent change in spectral bands during NREM. Figures 2-7 and 8-13 identify the percent change from baseline EEG power bands over time for each frequency in each sleep state in the parietal cortex after treatment with Compound 1 or lorazepam. Pre-dose values ​​were averaged from 2 hours of baseline recording, and post-dose values ​​were calculated in 60-minute bins for up to 24 hours. Figures show the percent change from baseline for each of the indicated frequency bands over the 24-hour post-dose period. Statistics: *p<0.05 vs. vehicle, ANOVA and Dunnett's multiple comparison test.

[0069] overview

[0095] Compound 1 (1 mg / kg) did not alter NREM onset but decreased the latency to REM onset. Lorazepam also decreased the latency to NREM onset.

[0070]

[0096] During quiet wakefulness, Compound 1 increased beta and low gamma. Lorazepam increased low and high gamma and decreased delta. During active wakefulness, Compound 1 increased low gamma and decreased alpha (parietal cortex). During non-REM, Compound 1 suppressed power in low frequencies (delta, theta, and alpha) and increased higher frequencies (gamma). During REM, Compound 1 increased beta.

[0071]

[0097] Lorazepam induces a faster time to non-REM sleep than Compound 1 (Figure 1). Compound 1 does not decrease the time to non-REM sleep (Figure 1). This is important because non-REM is the first stage of sleep (light sleep).

[0072]

[0098] During non-REM sleep, Compound 1 induces significant decreases in delta and theta power across all doses (ANOVA with Dunnett's multiple comparison test). This is seen in the plots in Figure 4, which report a 40% decrease in delta / theta during non-REM sleep. Figures 2-7 (frontal cortex) and Figures 8-13 (parietal cortex) also show the dose-dependent and lorazepam-related decreases in delta and theta power induced by Compound 1.

[0073] Example 2: Compound 1, α1-blocking GABA in the elevated plus maze and pharmacological EEG A Preclinical evaluation of α2,3,5PAM.

[0099] Background: Nonselective gamma-aminobutyric acid type A (GABA) analogs, such as benzodiazepines, A Positive allosteric modulators (PAMs) have been shown to be anxiolytic agents, but the clinical use of PAMs has been limited to α1-subunit-containing GABA receptor antagonists. A Subtype-selective (α2, α3, or α5 subunit) GABA receptors drive the beneficial effects of GABA modulation without the undesirable effects resulting from activation of α1 subunit-containing receptors, which are limited by significant side effects primarily mediated by receptor activation. A Several attempts have been made to generate modulators.

[0074]

[0100] Compound 1 is a GABA receptor containing α2, α3, and α5 subunits. A GABA activates neurotransmission through receptors but blocks α1 A The anxiolytic potential of Compound 1 was evaluated after acute and chronic administration in rodent anxiety models such as the elevated plus maze (EPM), and sleep-wake electroencephalography (EEG) profiles were characterized in rats induced by increasing doses of Compound 1.

[0075]

[0101] Methods: The in vitro pharmacology of compound 1 was investigated using human GABA receptor agonists. AThe receptors α1 / β3 / γ2, α2 / β2 / γ2, α2 / β3 / γ2, α3 / β3 / γ2, and α5 / β3 / γ2 were evaluated using the SyncroPatch platform in PAM mode. Adult male SD rats (N = 130, N = 10 per condition) were used for in vivo pharmacology studies. Compound 1 was evaluated using the EPM test to assess anxiety. The following metrics were automatically recorded: distance traveled, time spent in each arm, and number of entries into each arm. Compound 1 was administered orally at 0.1, 0.3, and 1 mg / kg to target approximately 30%, 50%, and 80% receptor occupancy, respectively, 1 hour after administration. Acutely administered rats were also tested 24 hours after administration. Another cohort was administered chronically once daily for 14 days and tested 1 hour after the final administration to evaluate the anxiolytic properties of Compound 1 after continuous target engagement. Chlordiazepoxide was used as a positive control. Data were analyzed by ANOVA, followed by post-hoc analysis where appropriate.

[0076]

[0102] Adult male SD rats (N = 12 in a crossover design) were used for pharmacological EEG testing. Sleep-stage-specific pharmacological EEG signatures of compound 1 were assessed after oral administration of compound 1 (0.03 mg / kg, 0.1 mg / kg, 0.3 mg / kg, and 1 mg / kg) to target a wide range of receptor occupancies. Lorazepam (1 mg / kg) was used as a positive control. Rats were implanted with telemetry devices. Recording began 2 hours before compound administration and continued for 48 hours after administration. Spectral analysis involved quantifying changes in spectral power across conventional EEG bands (delta 0.5-3.9 Hz, theta 4-7.9 Hz, alpha 8-11.9 Hz, beta 12-29.9 Hz, low gamma 30-49.9 Hz, and high gamma 50-100 Hz).

[0077]

[0103] Sleep analysis was also performed 2 hours before and 12 hours after administration of Compound 1, as well as 23-25 ​​and 46-48 hours after administration of Compound 1. Several variables were analyzed: sleep structure as percent time in active wakefulness, quiet wakefulness, NREM, REM, and latency to sleep. To assess drug effects on the power of different EEG spectral bands and across each sleep stage, ANOVA with Dunnett's multiple comparisons was applied to each 15-minute bin independently.

[0078]

[0104] All experimental protocols for animal studies were approved by the Institutional Animal Care and Use Committee and were conducted in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.

[0079]

[0105] Result: GABA A The functional in vitro activity of Compound 1 against GABA receptors demonstrated that Compound 1 inhibits GABA subtype-specific A Compound 1 was shown to be a PAM. A Compound 1 did not drive Cl- flux in the α1 / β3 / γ2 subtypes. A The EC50 values ​​for the α2 / β2 / γ2, α2 / β3 / γ2, α3 / β3 / γ2, and α5 / β3 / γ2 subtypes were 0.80 nM, 0.82 nM, 2.47 nM, and 0.20 nM, respectively, and the GABA A E of 50%, 89%, 113%, and 96% for subtypes α2 / β2 / γ2, α2 / β3 / γ2, α3 / β3 / γ2, and α5 / β3 / γ2, respectively. max showed.

[0080]

[0106] In vivo characterization of Compound 1 in the EPM assay showed that Compound 1 demonstrated an anxiolytic-like profile by increasing the distance traveled in the open arms. The effect was comparable to that demonstrated by the reference anxiolytic compound, chlordiazepoxide. Chronic administration of Compound 1 produced anxiolytic effects of similar magnitude. These data demonstrate potent anxiolytic activity in chronically administered rodents.

[0081]

[0107] The EEG profile induced in rats by administering Compound 1 was also examined. Compound 1 induced EEG changes that exhibited an anxiolytic profile and mimicked the spectral EEG signatures that have been associated with other subtype-selective GABA modulators. This spectral EEG signature can be used as an indicator of central pathway involvement in rodents and as a translational bridge to clinical research.

[0082]

[0108] Conclusions: Compound 1 is anxiolytic-like in rodents after acute and subchronic (14-day) administration, without any loss of action despite target engagement throughout the study period. Sleep-wake pattern and EEG profile analysis indicate a non-sedative anxiolytic profile of Compound 1. These data support clinical investigation of Compound 1 in anxiety-related indications.

[0083] Example 3: A multiple ascending dose study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 at plasma steady state in healthy volunteers

[0084] [Table 1]

[0085] [Table 2]

[0086]

[0109] GABA plays many of its roles AGABA is the major fast inhibitory neurotransmitter in humans, acting through receptor activation. A The GABA receptor is a ligand-gated chloride channel composed of five protein subunits (a mixture of α1-6, β1-3, γ1-3, δ, ε, θ, and π). GABA receptors contain α1, α2, α3, or α5 subunits in combination with βx and γ2 subunits in a 2:2:1 (α:β:γ) ratio. A The receptor forms an allosteric binding site separate from the site where GABA binds. This site, called the benzodiazepine binding site, allows for positive allosteric modulation of the ion channel. GABA in the CNS A Approximately 90% of receptors contain benzodiazepine binding sites, and those that do are classified into subtypes according to their α-subunit. Expression patterns of α-subtypes vary throughout the CNS, resulting in differences in their pharmacology.

[0087]

[0110] Without being bound by theory, gamma-aminobutyric acid (GABA A ) modulation is one pharmacological approach for the treatment of epilepsy, anxiety, and other central nervous system (CNS) disorders. However, long-term therapeutic benefit from nonselective pharmacological agents is limited due to a rapid loss of efficacy and significant side effects, including sedation, dizziness, and ataxia. Nonselective GABA A The side effects of agonists are mainly due to GABA A This may be due to α1-subtype activity. Compound 1 inhibits α1GABA A It is an α2 / α3 / α5-subtype selective positive allosteric modulator that does not potentiate the effects of receptor subtypes and therefore may be effective, well tolerated, and useful long-term for the treatment of epilepsy, anxiety, or other CNS disorders.

[0088]

[0111] A clinical study was developed to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of Compound 1 at plasma steady state in 40 healthy human volunteers. Compound 1 (provided as the phosphate salt of Compound 1) was administered to participants once daily (QD) for 12 days as multiple ascending doses of 0.5 mg (N=6), 1.0 mg (N=6), 1.5 mg (N=6), 2.0 mg (N=6), or 5.0 mg (N=6).

[0089] safety results

[0112] Safety and tolerability of Compound 1 were assessed by listing and summarizing Compound 1 dose versus placebo (observed values ​​and change from baseline, where applicable) on the following scales: treatment-emergent adverse events (TEAEs), clinical laboratory assessments, vital signs, electrocardiogram, physical examination, pregnancy test, C-SSRS, and MOAA / S (Modified Observer Assessment of Alertness / Sedation). Continuous safety data were summarized by dose level with descriptive statistics (n, arithmetic mean, standard deviation (SD), median, minimum, and maximum). Categorical safety data were summarized by dose level with incidence counts and percentages (%).

[0090]

[0113] All TEAEs were transient in nature and did not require treatment or intervention.

[0114] No severe TEAEs or serious adverse events (SAEs) occurred. The majority of participants (34 / 40, 85.0%) experienced TEAEs of mild severity, while 5 / 40 participants (12.5%) experienced six TEAEs of moderate severity.

[0091]

[0115] The most commonly reported TEAEs were somnolence and fatigue. The occurrence of somnolence in the Compound 1 cohort was nearly twice as common as in placebo-treated participants pooled across all cohorts.

[0092]

[0116] There was no apparent overall association between increasing dose and the frequency and / or type of TEAEs.

[0117] Mean changes in clinical laboratory values ​​and vital signs were similar across all treatment cohorts, including placebo.

[0093]

[0118] No clinically relevant increases in heart rate-corrected mean QT (QTcF) according to Fridericia's cube root formula were observed.

[0119] No consistent differences between treatments or physical examination findings were observed for concomitant medication use.

[0094]

[0120] No participants had a positive response to questions about suicidal ideation or behavior on the C-SSRS after any treatment.

[0121] Objective MOAA / S (Modified Observer Assessment of Awareness / Sedation) scoring showed no clear difference in sedation from placebo across the titration cohorts. A decrease in MOAA / S score for alertness / sedation indicates a participant's impaired alertness and increased sedation as determined objectively by a clinician. Treatment with Compound 1 resulted in little to no impairment in alertness and no significant sedation. For the 5.0 mg Compound 1, one participant was rated with an MOAA / S score of 2 ("responds only to mild stimulation or shaking"). For other participants in the 5.0 mg Compound 1 cohort and all other cohorts, MOAA / S scores were greater than 3, indicating no difference in sedation from placebo across the titration cohorts.

[0095] Pharmacokinetic results

[0122] Blood samples were collected and plasma concentrations were measured using a validated high performance liquid chromatography / liquid chromatography-mass spectrometry / mass spectrometry method. PK parameters evaluated were C max , T max , AUC from administration to the end of administration (AUC 0~t ), AUC 0~24 , AUC 0~inf , t 1 / 2, the terminal rate constant (λz), the apparent total clearance of drug from plasma (CL / F), and the apparent volume of distribution during the terminal phase after non-intravenous administration (Vz / F).

[0096]

[0123] Plasma concentration data for Compound 1 were summarized by dose level and planned sampling time point using descriptive statistics (n, SD, median, minimum, maximum, geometric mean, and coefficient of variation (CV%) for the geometric mean) for the PK analysis set. Area under the concentration curve from time 0 to infinity (AUC) from Cohorts 1, 2, 3, 4, and 5 was also calculated. 0~inf ) (Day 1), area under the concentration curve from 0 to 24 hours (AUC 0~24 ) (day 12), and the highest concentration (C max Dose proportionality on the log scale for Compound 1 based on (Day 1 and Day 12) values ​​was examined using a model with fixed effects for log dose and time point (Day 1 or Day 12) and log dose × day interaction, and a random effect for participant.

[0097]

[0124] Compound 1 was rapidly absorbed, with a median time to maximum concentration (T max ) varied from 3 hours at a maximum of 2.0 mg on day 1 to 4.5 hours at 5.0 mg.

[0125] average C max and AUC 0~24 increased generally in a dose- and concentration-proportional manner.

[0098]

[0126] Steady state was achieved by repeated dosing for 6 to 12 days.

[0127] Compound 1 follows a biexponential decay with an apparent terminal half-life (t 1 / 2 ) ±SD ranged between 39 ± 9 hours for 5.0 mg and 66 ± 24 hours for 0.5 g.

[0099]

[0128] Variability in primary PK parameters was tolerable up to 5.0 mg repeated dosing over 12 days.

[0129] Specifically, samples for PK analysis were obtained pre-dose and 0.5, 1, 1.5, 3, 6, 8, 10, and 12 hours post-dose on Days 1 and 12, with additional samples obtained on each dosing day (24 hours after the previous day's dose) and 24, 72, 168, and 336 hours after the last dose on Day 12. Compound 1 concentrations for all individuals exceeded the LLOQ of 0.0500 ng / mL at 0.5 hours post-dose except for participant, whose concentration exceeded the LLOQ at 1 hour post-dose.

[0100]

[0130] The PK profile of Compound 1 followed a bi-exponential decay as seen by the distinct difference between the two distinct slopes in the decay portion of the PK profile on a log-linear scale (Figure 15). The absorption and distribution phases were T max The mean plasma concentrations ranged from 0.01 to 0.12 hours (median 3 hours) to approximately 12 hours, after which the elimination phase began. A summary of the PK parameters for Compound 1 at all dose levels is shown in Table 3, and a visualization of the mean plasma concentrations is shown in Figure 16.

[0101]

[0131] In summary, Median T max On both Days 1 and 12, peak concentrations were observed at 3 hours for all doses except for 5.0 mg Compound 1, where peak concentrations on Day 1 occurred at a median of 4.50 hours. max did not change appreciably with increasing doses (Table 3).

[0102] average C max ±SD increased dose-proportionally over the dose range studied, Average C on the first day max ±SD were 4.6 ± 2 ng / mL, 8.5 ± 3 ng / mL, 18.8 ± 7 ng / mL, 19.6 ± 4 ng / mL, and 49.7 ± 13 ng / mL for 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg of Compound 1, respectively (Table 3). On day 12, the average C max±SD were 11.7 ± 4 ng / mL, 23.3 ± 5 ng / mL, 41.7 ± 5 ng / mL, 49.8 ± 17 ng / mL, and 99.1 ± 14 ng / mL for 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg, respectively (Table 3).

[0103] The AUC increased dose-proportionally over the dose range studied, Mean ± SD AUC 0~24 were 53±7 ng*h / mL, 118±27 ng*h / mL, 217±48 ng*h / mL, 244±48 ng*h / mL, and 642±125 ng*h / mL for 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg doses, respectively, on day 1 (Table 3). Mean ± SD AUC tau were 198±51 ng*h / mL, 410±115 ng*h / mL, 706±84 ng*h / mL, 873±331 ng*h / mL, and 1804±242 ng*h / mL for 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg doses, respectively, on day 12 (Table 3).

[0104] Highest individual AUC achieved 0~24 and AUC tau were 853.4 ng*h / mL and 2171.8 ng*h / mL at 5.0 mg, respectively (Table 3). Dose-proportional PK was observed across the dose range investigated. max and AUC tau Both parameters were confirmed.

[0105] Steady-state accumulation of Compound 1 was observed, with mean accumulation ratios ±SD ranging from 3 ± 0.3 to 4 ± 0.7. With increasing doses 1 / 2 Or there is no tendency for λz to change, Average (±SD)t 1 / 2 were 66±24 hours, 61±29 hours, 51±18 hours, 61±26 hours, and 39±9 hours for 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg of Compound 1, respectively; In the 5.0 mg Compound 1 cohort, the 72-hour post-dose PK sampling time point was eliminated to reduce participant burden. 1 / 2 may have been affected by it.

[0106] Based on the mean concentrations at the end of the dosing interval, steady-state plasma concentrations were reached after 6 to 12 days of Compound 1 administration. PK variability was measured by C max , AUC tau , and t 1 / 2 In the cases of , coefficients of variation ranging between 12% and 36%, between 12% and 38%, and between 23% and 48%, respectively, were acceptable.

[0107] The last quantifiable concentration, determined directly from individual concentration-time data, is in the range between 0.1 ng / mL and 9.5 ng / mL. The median time to last quantifiable concentration was approximately 24 hours on day 1 and ranged from 73 to 384 hours on day 12 in all cohorts, respectively.

[0108] AUC on day 1 0~inf , CL / F, Vz / F, and dose-normalized AUC 0~inf The elimination phase is not fully captured before the next dose, resulting in a t 1 / 2 Since it cannot be derived, it cannot be calculated, and Dose standardization C max and AUC 0~24 was consistent with linear kinetics, with the controversial exception of median dose-normalized C max was higher on days 1 and 12 and the median dose-standardized AUC 0~24 However, on day 1, the dose of Compound 1 was higher at 1.5 mg.

[0109] [Table 3-1]

[0110] [Table 3-2]

[0111] Summary of pharmacokinetic findings

[0132] Compound 1 is rapidly absorbed, with a median T max on day 1 varied from 3 hours at a maximum of 2.0 mg to 4.5 hours at 5.0 mg.

[0112]

[0133] average C max and AUC 0~24 increased generally in a dose- and concentration-proportional manner.

[0134] Steady state was achieved by repeated dosing for 6 to 12 days.

[0113]

[0135] Compound 1 follows a biexponential decay with an apparent terminal phase t 1 / 2 ±SD ranged between 39 ± 9 hours for 5.0 mg and 66 ± 24 hours for 0.5 g.

[0136] Variability in primary PK parameters was tolerable up to 5.0 mg repeated dosing over 12 days.

[0114] Pharmacodynamic results

[0137] Pharmacodynamic analyses included NEUROCART® assessment, cognitive assessment, the Visual Verbal Learning Task (VVLT), and quantitative electroencephalography (qEEG). All PD analyses were based on the PD analysis set. For all PD endpoints, baseline was calculated as the mean of measurements on day -1.

[0115]

[0138] NEUROCART®, VVLT, and qEEG assessments were listed and summarized at baseline and each post-baseline time point using descriptive statistics (absolute values ​​and change from baseline). To establish whether significant treatment effects could be detected for repeatedly measured NEUROCART® parameters, each parameter was analyzed with a mixed-model analysis of covariance (ANCOVA) with treatment, time, and treatment x time as fixed factors, participant as random factor, and (mean) baseline measure as covariate.

[0116]

[0139] Unexpectedly, Compound 1 significantly reduced saccade peak velocity (SPV) at 1.0 mg, 2.0 mg, and 5.0 mg on day 1, an effect that persisted up to day 12, supporting a sustained effect on wakefulness during repeated dosing.

[0117]

[0140] Compound 1 reduced adaptive pursuit at doses ≥ 1.0 mg and significantly increased body sway at 5.0 mg on day 1, but this was not the case on day 12, suggesting acute effects on sustained attention that converge over time during repeated dosing and a lack of effects on global psychomotor function and postural balance at doses < 5.0 mg.

[0118]

[0141] Compound 1 had no consistent effect on visual analog scale (VAS) vigilance. Compound 1 significantly reduced VAS vigilance at 2.0 mg on day 1 but not on day 12, whereas VAS vigilance at 5.0 mg remained unaffected on day 1 but significantly reduced on day 12.

[0119]

[0142] Compound 1 had no consistent psychotomimetic or autonomic effects.

[0143] Compound 1 adversely affected memory encoding, retrieval, and consolidation at 5.0 mg on day 1, but had no consistent effect on the VVLT. This effect disappeared by day 12.

[0120]

[0144] Compound 1 demonstrated the most consistent effects on qEEG at doses above 1.5 mg, where the alpha and theta power decreases on day 12 showed dose or concentration dependence and target engagement, whereas the beta power increase on day 12 did not show dose or concentration dependence.

[0121]

[0145] NEUROCART® Evaluation Summary. Compound 1 administered orally for up to 12 days: Saccade peak velocity (SPV) was significantly reduced at 1.0 mg, 2.0 mg, and 5.0 mg doses on both days 1 and 12. Overall, no clear dose-dependent effect on SPV was observed. The reductions on day 1 did not return to baseline either 24 hours after dosing or on day 12, indicating a sustained effect on wakefulness during repeated dosing up to day 12.

[0122] Only the highest dose level of 5.0 mg significantly increased saccade reaction time on day 1, but not on day 12. Smooth pursuit eye movements were significantly reduced at 0.5 mg, 1.5 mg, and 5.0 mg on day 1, but not on day 12.

[0123] Doses of 1.0 mg and above significantly reduced adaptive pursuit on day 1, but not on day 12, indicating an acute effect on sustained attention that converges over time during repeated dosing up to day 12.

[0124] The highest dose level of 5.0 mg significantly increased body sway on day 1, but not on day 12, indicating acute effects on psychomotor function and postural balance that converge over time during repeated dosing up to day 12. The lack of significant effects at dose levels below 5.0 mg indicates a lack of effect on overall psychomotor function and postural balance.

[0125] VAS alertness was significantly reduced at 2.0 mg on day 1 but not on day 12, whereas VAS alertness at 5.0 mg remained unaffected on day 1 but significantly reduced on day 12, with no significant reductions observed at other dose levels.

[0126] There was no effect on VAS mood or VAS calmness at any dose on either day 1 or day 12. Effects on the Bowdle VAS were demonstrated to be inconsistent: VAS external perception and VAS internal perception remained unaffected at 1.0 mg, 2.0 mg, and 5.0 mg on days 1 and 12 but increased significantly at 1.5 mg, while VAS euphoria increased significantly at 0.5 mg on days 1 and 12 and at 1.5 mg on day 12, with no apparent dose-related effect.

[0127] The left pupil / iris ratio was significantly reduced at 1.0 mg, 1.5 mg, and 5.0 mg on day 1, but not on day 12, indicating mydriasis that appears after the first dose that converges over time during repeated dosing up to day 12. The effects on SPV, body sway, VAS internal perception, VAS external perception, and VAS euphoria were less consistent in the 1.5 mg cohort compared with other dose levels.

[0128]

[0146] Overview of the visual language learning task. Compound 1 administered orally for 12 days: On day 12, but not day 1, 1.0 mg significantly increased reaction times for delayed word recognition. On day 1, 1.5 mg significantly increased reaction times for delayed word recognition, but not on day 12.

[0129] On day 12, 2.0 mg significantly reduced delayed word recognition, but not immediate or delayed recall, and not on day 1. On day 1, 5.0 mg significantly reduced immediate recall and delayed recall / recognition, but not on day 12.

[0130]

[0147] Compound 1 demonstrated inconsistent effects on reaction time for delayed word recognition up to 1.5 mg. Compound 1 at 2.0 mg on day 12 adversely affected memory encoding but not memory consolidation or retrieval, whereas Compound 1 at 5.0 mg on day 1 adversely affected memory encoding, retrieval, and consolidation. The latter disappeared by day 12, supporting tolerance to such effects after repeated dosing. Overall, Compound 1 had no consistent effects on VVLT parameters.

[0131]

[0148] Summary of quantitative electroencephalography. Compound 1 administered orally for 12 days demonstrated the following effects on qEEG: Alpha-Power is On day 12, there was a significant decrease in Fz-Cz (eyes closed) at 1.5 mg, 2.0 mg, and 5.0 mg.

[0132] There is a significant decrease in Fz-Cz (eyes open) at 1.5 mg on day 1 and at 1.5 mg, 2.0 mg, and 5.0 mg on day 12. There is a significant decrease in Pz-O1 (eyes closed) at 1.5 mg on day 1 and at 1.5 mg, 2.0 mg, and 5.0 mg on day 12.

[0133] On day 12, there was a significant decrease in Pz-O1 (eyes open) at 1.5 mg, 2.0 mg, and 5.0 mg. On day 12, there was a significant decrease in Pz-O2 (eyes closed) at 1.5 mg, 2.0 mg, and 5.0 mg.

[0134] On day 12, there was a significant decrease in Pz-O2 (eyes open) at 1.5 mg, 2.0 mg, and 5.0 mg. Beta-power is There is a significant increase in Fz-Cz (eyes closed) at 2.0 mg and 5.0 mg on day 1, but none of these doses do so on day 12.

[0135] There was a significant increase in Fz-Cz (eyes open) at 2.0 mg and 5.0 mg on day 1, and at 0.5 mg, 2.0 mg, and 5.0 mg on day 12. There is no treatment effect on Pz-O1 or Pz-O2 (eye open and eye closed) at any dose on days 1 or 12.

[0136] Delta Power is On day 12, there was a significant decrease in Fz-Cz (eyes closed) at all dose levels. On day 12, only 1.0 mg showed a significant decrease in Fz-Cz (eyes open).

[0137] On day 12, there was a significant decrease in Pz-O1 (eyes closed) at 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg. On day 12, there was a significant decrease in Pz-O2 (eyes closed) at all dose levels. On day 12, there was a significant decrease in Pz-O1 and Pz-O2 (eyes open) at 1.5 mg, 2.0 mg, and 5.0 mg.

[0138] Gamma-power is There is a significant increase in Fz-Cz (eyes closed and eyes open) at 2.0 mg on day 1 and at 2.0 mg and 5.0 mg on day 12.

[0139] On day 1, there was a significant decrease in Pz-O1 (eyes closed and eyes open) at 1.5 mg, 2.0 mg, and 5.0 mg. On Day 12, there was no treatment effect on Pz-O2 (eyes closed) at any dose level except 5.0 mg. There was no therapeutic effect on Pz-O2 (open eye) at any dose level. Theta power is On day 12, there was a significant decrease in Fz-Cz (eyes closed and eyes open) at 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg. On day 12, there was a significant decrease in Pz-O1 and Pz-O2 (eyes closed and eyes open) at 1.5 mg, 2.0 mg, and 5.0 mg.

[0140]

[0149] In summary, the most consistent effects on qEEG were decreased alpha and theta power and increased beta power at Compound 1 above 1.5 mg on day 12. However, while the effects on alpha (Figure 17) and theta power (Figures 18 and 19) on day 12 suggest a dose or concentration dependency, this did not appear to be the case for beta power on day 12 (Figure 20).

[0141] Summary of Pharmacodynamic Findings

[0150] Compound 1 significantly reduced SPV at 1.0 mg, 2.0 mg, and 5.0 mg on day 1, an effect that persisted up to day 12, supporting a sustained effect on wakefulness during repeated dosing.

[0142]

[0151] Compound 1 significantly decreased adaptive pursuit at doses of 1.0 mg and above and significantly increased body sway at 5.0 mg on day 1, but this was not the case on day 12, suggesting acute effects on sustained attention that converge over time during repeated dosing and a lack of effects on global psychomotor function and postural balance at doses below 5.0 mg.

[0143]

[0152] Compound 1 significantly reduced VAS vigilance at 2.0 mg on day 1 but not on day 12, whereas VAS vigilance at 5.0 mg remained unaffected on day 1 but was significantly reduced on day 12, indicating inconsistent effects on subjective sedation that can be considered in line with the adaptive tracking and body sway findings.

[0144]

[0153] Compound 1 demonstrated no consistent psychotomimetic (VAS Bowdle) or autonomic nervous system (pupil size) effects.

[0154] The effects of Compound 1 on the VVLT were rather inconsistent: 5.0 mg of Compound 1 adversely affected memory encoding, retrieval, and consolidation on day 1 but not on day 12, supporting tolerance to such effects after repeated dosing.

[0145]

[0155] Compound 1 demonstrated the most consistent effects on qEEG at doses above 1.5 mg, where the alpha and theta power decreases on day 12 showed dose or concentration dependence and target engagement, whereas the beta power increase on day 12 did not show dose or concentration dependence.

[0146] Discussion and Overall Conclusions

[0156] Compound 1 represents a new therapeutic modality for the potential treatment of epilepsy, anxiety, spasticity, or other CNS disorders. This study was conducted in healthy male and female participants to evaluate the safety, tolerability, PK, and PD of Compound 1.

[0147]

[0157] Twelve consecutive days of administration of 0.5 mg, 1.0 mg, 1.5 mg, 2.0 mg, and 5.0 mg of Compound 1 were generally safe and well tolerated in healthy volunteers. No deaths, SAEs, or TEAEs leading to discontinuation were reported.

[0148]

[0158] The majority of TEAEs were mild in severity. Two moderate TEAEs of drowsiness were reported with the 2.0 mg and 5.0 mg doses of Compound 1, and one moderate TEAE of balance disturbance was reported with the 5.0 mg dose. All TEAEs were transient and did not require treatment or intervention. Drowsiness and fatigue were the most frequently reported TEAEs, but they also occurred in approximately 50% of placebo-treated participants. There was no clear relationship between increasing dose and the occurrence of drowsiness and fatigue. 20.0% of participants receiving Compound 1 experienced dizziness, but this was not the case for any participants receiving placebo; 30.0% and 10.0% of participants receiving Compound 1 and placebo, respectively, reported orthostatic dizziness.

[0149]

[0159] Compound 1 up to 5.0 mg demonstrated no difference from placebo in sedation as measured using the MOAA / S.

[0160] Compound 1 is rapidly absorbed, with a median T maxOn day 1, the dose ranged from 3 hours at a maximum of 2.0 mg to 4.5 hours at 5.0 mg.

[0150]

[0161] Average peak concentration (C max ) and the mean 0-24 hour area under the concentration curve (AUC 0~24 ) generally increased in a dose- and concentration-proportional manner.

[0162] Compound 1 concentration follows a biexponential decrease with an apparent terminal phase t 1 / 2 ±SD ranged between 39 ± 9 hours for 5.0 mg and 66 ± 24 hours for 0.5 g.

[0151]

[0163] Steady state was achieved by repeated dosing for 6 to 12 days, and PK variability was acceptable.

[0164] Unexpectedly, Compound 1 significantly reduced SPV at doses of 1.0 mg, 2.0 mg, and 5.0 mg, and such reduction was sustained for up to 12 days.

[0152]

[0165] Compound 1 acutely significantly decreased adaptive tracking at doses of 1.0 mg and above and significantly increased body sway at 5.0 mg, but this was not true after repeated dosing up to 12 days.

[0153]

[0166] There were no consistent effects on VAS vigilance and no signs of psychotomimetic or autonomic effects either acutely or after repeated dosing for up to 12 days.

[0167] Compound 1 demonstrated inconsistent effects on the VVLT at doses up to 2.0 mg, while at 5.0 mg it acutely adversely affected memory encoding, retrieval, and consolidation for up to 12 days.

[0154]

[0168] Compound 1 demonstrated sustained reduction in wakefulness, but this was not associated with effects on sustained attention or postural stability, subjective sedation, or memory impairment after repeated administration for up to 12 days within a dose range between 1.0 mg and 5.0 mg.

[0155]

[0169] Compound 1 demonstrated the most consistent effects on qEEG at doses above 1.5 mg, where the alpha and theta power decreases on day 12 were dose- or concentration-dependent, but the beta power increase on day 12 was not dose- or concentration-dependent.

[0156]

[0170] A 12-day, randomized, double-blind, placebo-controlled, multiple ascending dose study was conducted in healthy volunteers. Repeated dosing of Compound 1 up to 5.0 mg for 12 days was safe and well tolerated. Furthermore, Compound 1 demonstrated a PD profile showing a lack of adverse sedative, psychomotor, or memory effects between 1.0 mg and 5.0 mg after repeated dosing for up to 12 days, and sustained reduction in wakefulness supported by qEEG findings confirming sustained central target engagement. The observed PK parameters of Compound 1 support QD dosing.

Claims

1. 1. A method comprising administering to a subject a dosage form of a compound which is 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof; the dosage form comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 μmol of the compound; and the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered a corresponding equimolar dose of lorazepam; or delta, theta, or delta and theta electroencephalogram (EEG) oscillatory power from the subject is reduced by about 20% or more during non-REM sleep compared to a subject administered a corresponding equimolar dose of lorazepam; or the method further comprising generating pharmacokinetic parameters for the compound in the subject, the pharmacokinetic parameters having a T ｍａｘ Or about 60 to 70 hours T １／２ or both, or the subject has a steady state of the compound in the subject's plasma, the steady state having a C of the compound of about 10 to 50 ng / mL ｍａｘ contains, or wherein the administration is once daily including at least 12 consecutive days of administration of the dosage form; or wherein the administration is once daily administration comprising administration of the dosage form for at least 12 consecutive days, and wherein the subject experiences reduced mydriasis with administration of the dosage form compared to administration of the dosage form once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days. method.

2. 1) about 1.5 to about 100 μg of compound per mL of dosage form; or 2) a dosage of about 0.002 to about 1 mg of compound per kg of subject; or 3) about 0.5, 0.63, 1.0, 1.3, 1.5, 1.9, 2.0, 2.5, 5.0, or 6.25 mg of the compound; or 4) about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 μmol of the compound Including, the compound is 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile free base or 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate; Dosage form.

3. 3. The dosage form of claim 2, comprising about 20 μg / mL of the compound.

4. 3. The dosage form of claim 2, further comprising a pharmaceutically acceptable carrier.

5. 3. The dosage form of claim 2, comprising methyl 2-hydroxyethyl cellulose.

6. 3. The dosage form of claim 2, comprising about 0.1 to about 3% w / w methyl 2-hydroxyethylcellulose.

7. 3. The dosage form of claim 2, comprising about 0.5 to about 2% w / w methyl 2-hydroxyethylcellulose.

8. 3. The dosage form of claim 2, wherein the dosage comprises about 0.005 mg / kg, about 0.01 mg / kg, about 0.015 mg / kg, about 0.016 mg / kg, about 0.03 mg / kg, about 0.05 mg / kg, about 0.1 mg / kg, about 0.15 mg / kg, about 0.16 mg / kg, about 0.3 mg / kg, or about 1 mg / kg of the compound.

9. 3. The dosage form of claim 2, comprising about 0.5, 0.63, 2.0, or 2.5 mg of the compound.

10. 10. The dosage form of any one of claims 2 to 9, which is a solid dosage form.

11. 10. The dosage form of any one of claims 2 to 9, which is a liquid dosage form.

12. 10. The dosage form of any one of claims 2 to 9, which is an oral dosage form.

13. 10. The dosage form of any one of claims 2 to 9, contained in at least one container.

14. 14. A method comprising administering to a subject in need thereof a therapeutically effective amount of the dosage form of any one of claims 2 to 13.

15. 15. The method of claim 14, wherein the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered a comparable (e.g., equimolar) dose of lorazepam.

16. administering to a subject in need thereof a therapeutically effective amount of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof; the subject does not experience a decrease in the time to non-REM onset of sleep compared to a subject administered an equivalent dose of lorazepam. method.

17. 17. The method of any one of claims 14 to 16, wherein delta, theta, or delta and theta electroencephalogram (EEG) oscillatory power from the subject is reduced by about 20% or more during non-REM sleep compared to a subject administered an equivalent dose of lorazepam.

18. 18. The method of claim 17, wherein the delta, theta, or delta and theta EEG oscillatory power is measured in the frontal cortex, parietal cortex, or frontal and parietal cortex of the subject's brain.

19. The subject is GABA Ａ 19. The method of any one of claims 14 to 18, wherein the patient is suffering from a receptor-related disease or a disease or disorder of the central nervous system.

20. GABA Ａ 14. A method of treating a receptor-related disease or a disease or disorder of the central nervous system in a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a dosage form according to any one of claims 2 to 13, optionally, the subject does not experience a decrease in time to non-REM onset of sleep compared to a subject administered a comparable dose of lorazepam. method.

21. GABA Ａ 1. A method of treating a receptor-related disease or a disease or disorder of the central nervous system in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof; the subject does not experience a decrease in the time to non-REM onset of sleep compared to a subject administered an equivalent dose of lorazepam. method.

22. 14. A method comprising administering to a subject the dosage form of any one of claims 2 to 13, further comprising generating pharmacokinetic parameters for the compound in the subject; said administration of said dosage form is once daily; the dosage form comprises about 0.5, 1.0, 1.5, or 2.0 mg of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate; The pharmacokinetic parameter has a T of about 3 hours ｍａｘ Or about 60 to 70 hours T １／２ or both, method.

23. 14. A method comprising administering to a subject the dosage form of any one of claims 2 to 13, further comprising generating pharmacokinetic parameters for the compound in the subject; said administration of said dosage form is once daily; the dosage form comprises about 1, 2, 3, 4, or 5 μmol of 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile phosphate; The pharmacokinetic parameter has a T of about 3 hours ｍａｘ Or about 60 to 70 hours T １／２ or both, method.

24. 14. A method of treating an anxiety disorder in a subject in need thereof, comprising administering to said subject a dosage form according to any one of claims 2 to 13.

25. 25. The method of claim 24, wherein the administration is oral once daily.

26. 26. The method of claim 25, wherein the dosage form comprises 1, 2, or 3 tablets or capsules containing the compound.

27. 28. The method of any one of claims 14 to 27, wherein the dosage form comprises about 1.0, 1.3, 2.0, 2.6, 3.0, 3.1, 3.8, 4.0, 4.1, 5.0, or 5.1 μmol of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile monophosphate.

28. 28. The method of any one of claims 14 to 27, wherein the dosage form comprises about 2 mg of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile monophosphate.

29. 29. The method of any one of claims 14 to 28, wherein 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile or a pharmaceutically acceptable salt thereof is present at steady state in the plasma of the subject when a once-daily dose of 2',6-difluoro-5'-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1'-biphenyl]-2-carbonitrile phosphate is administered, and wherein the once-daily dose comprises at least six consecutive days of administration.

30. a C of the compound having a steady state of about 10 to 50 ng / mL in the plasma of the subject; ｍａｘ 30. The method of claim 29, comprising:

31. 14. A method of treating anxiety in a subject in need thereof, comprising administering to said subject a dosage form according to any one of claims 2 to 13, said administration of said dosage form is once daily; the dosage form comprises about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, or 13 μmol of 2′,6-difluoro-5′-(3-(2-hydroxypropan-2-yl)imidazo[1,2-b][1,2,4]triazin-7-yl)-[1,1′-biphenyl]-2-carbonitrile phosphate; said once-daily administration comprising administration of said dosage form for at least 12 consecutive days; and the subject experiences reduced mydriasis upon administration of the dosage form compared to administration of the dosage form once daily for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 consecutive days; method.

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