Methods and compositions for treating sleep apnea

Abstract

Disclosed herein are methods of treating obstructive sleep apnea using aldosterone synthase inhibitors, optionally in combination with norepinephrine reuptake inhibitors or other active agents, and related pharmaceutical compositions and therapeutic combinations.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 403,469, filed September 2, 2022, the entire contents of which are incorporated herein by reference.

[0002] The present invention relates to methods of treating obstructive sleep apnea using aldosterone synthase inhibitors, optionally in combination with norepinephrine reuptake inhibitors or other active agents, and to related pharmaceutical compositions and therapeutic combinations. [Background technology]

[0003] Obstructive sleep apnea (OSA) is a common disorder caused by the collapse of the pharyngeal airway during sleep. OSA can have serious health consequences. Summary of the Invention

[0004] One aspect of the present invention is a method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof an effective amount of baxdrostat, having the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0005] Embodiments of this aspect of the invention may include one or more of the following optional features: In some embodiments, the method further comprises administering a norepinephrine reuptake inhibitor (NRI) to the subject. In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a nonselective norepinephrine reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethilphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protryptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is selected from the group consisting of atomoxetine or a pharmaceutically acceptable salt thereof and reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a muscarinic receptor antagonist (MRA), e.g., in combination with baxdrostat and the NRI.In some embodiments, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is racemic oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering to the subject a hypnotic agent, e.g., in combination with baxdrostat and, optionally, an NRI. In some embodiments, the hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharmaceutically acceptable salt thereof. In some embodiments, the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 500 mg.In some embodiments, baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 to about 250 mg. In some embodiments, atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 200 mg. In some embodiments, atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 to about 100 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered at a dose of about 12.5 mg to about 200 mg. In some embodiments, baxdrostat or a pharmaceutically acceptable salt thereof is administered as monotherapy. In some embodiments, the NRI and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the NRI, MRA, and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic agent and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic agent, the NRI, and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the single composition is an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring.In some embodiments, the subject is in a non-fully conscious state, such as sleep. In some embodiments, the subject has hypertension. In some embodiments, the subject has OSA accompanied by hypertension.

[0006] Also provided herein is baxdrostat, or a pharmaceutically acceptable salt thereof, for use in the treatment of obstructive sleep apnea.

[0007] Also provided herein is baxdrostat, or a pharmaceutically acceptable salt thereof, for use in the treatment of obstructive sleep apnea associated with hypertension.

[0008] Also provided herein is a therapeutic combination of baxdrostat or a pharmaceutically acceptable salt thereof with (a) a norepinephrine reuptake inhibitor (NRI) and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent and optionally a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea.

[0009] Also provided herein is a therapeutic combination of baxdrostat or a pharmaceutically acceptable salt thereof and (a) a norepinephrine reuptake inhibitor (NRI), optionally with a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent, optionally with a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea associated with hypertension.

[0010] Another aspect of the present invention is a method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof an effective amount of a compound of formula (A) having the following structure: [ka] or a pharmaceutically acceptable salt thereof.

[0011] Embodiments of this aspect of the invention may include one or more of the following optional features: In some embodiments, the method further comprises administering a norepinephrine reuptake inhibitor (NRI) to the subject. In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talopram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is selected from the group consisting of atomoxetine or a pharmaceutically acceptable salt thereof, and reboxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering to the subject a muscarinic receptor antagonist (MRA), e.g., in combination with a compound of Formula (A) and an NRI. In some embodiments, the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharmaceutically acceptable salt thereof.In some embodiments, the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, difenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexetyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the MRA is racemic oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the method further comprises administering a hypnotic agent to the subject, e.g., in combination with a compound of Formula (A), optionally in combination with an NRI. In some embodiments, the hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharmaceutically acceptable salt thereof. In some embodiments, the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 500 mg. In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 200 mg. In some embodiments, atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 200 mg. In some embodiments, atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 to about 100 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 15 mg. In some embodiments, oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 2 mg to about 10 mg. In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 10 mg.In some embodiments, (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered in a dose of about 1 mg to about 5 mg. In some embodiments, trazodone or a pharmaceutically acceptable salt thereof is administered in a dose of about 12.5 mg to about 200 mg. In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is administered as monotherapy. In some embodiments, the NRI and the compound of Formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the NRI, the MRA, and the compound of Formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic agent and the compound of Formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic agent, the NRI, and the compound of Formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the single composition is an oral dosage form. In some embodiments, the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch. In some embodiments, the condition associated with pharyngeal airway collapse is sleep apnea. In some embodiments, the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA). In some embodiments, the condition associated with pharyngeal airway collapse is snoring. In some embodiments, the condition associated with pharyngeal airway collapse is simple snoring. In some embodiments, the subject is in a state of non-consciousness, such as sleep. In some embodiments, the subject has hypertension. In some embodiments, the subject has OSA accompanied by hypertension.

[0012] Also provided herein is a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for use in the treatment of obstructive sleep apnea.

[0013] Also provided herein is a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for use in the treatment of obstructive sleep apnea associated with hypertension.

[0014] Also provided herein is a therapeutic combination of a compound of Formula (A) or a pharmaceutically acceptable salt thereof and (a) a norepinephrine reuptake inhibitor (NRI) and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent and optionally a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea.

[0015] Also provided herein is a therapeutic combination of a compound of Formula (A) or a pharmaceutically acceptable salt thereof and (a) a norepinephrine reuptake inhibitor (NRI), optionally with a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent, optionally with a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea associated with hypertension.

[0016] Another aspect of the present invention provides a pharmaceutical composition comprising baxdrostat or a pharmaceutically acceptable salt thereof, a norepinephrine reuptake inhibitor, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition further comprises a hypnotic agent. In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA).

[0017] Another aspect of the present invention provides a pharmaceutical composition comprising baxdrostat or a pharmaceutically acceptable salt thereof, a hypnotic agent, and a pharmaceutically acceptable carrier or excipient.

[0018] Another aspect of the present invention provides pharmaceutical compositions comprising a compound of Formula (A) or a pharmaceutically acceptable salt thereof, a norepinephrine reuptake inhibitor, and a pharmaceutically acceptable carrier or excipient. In some embodiments, the pharmaceutical composition further comprises a hypnotic agent. In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA).

[0019] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a hypnotic agent, and a pharmaceutically acceptable carrier or excipient.

[0020] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Methods and materials for use in the present invention are described herein. Other suitable methods and materials known in the art can also be used. The materials, methods, and examples are for illustrative purposes only and are not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0021] Other features and advantages of the invention will become apparent from the following detailed description and drawings, and from the claims. [Brief explanation of the drawings]

[0022] The following figures are provided as examples and are not intended to limit the scope of the claimed invention.

[0023] [Figure 1] Graphical representation of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel represents airflow. The next three channels show ventilator effort due to thoracic and abdominal movement and esophageal pressure changes, all of which reflect the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation. DETAILED DESCRIPTION OF THE INVENTION

[0024] In humans, the pharyngeal airway region lacks bony or cartilaginous support and is held open by muscles. When these muscles relax during sleep, the pharynx can collapse and airflow can cease. As shown in Figure 1, ventilatory efforts continue and increase to overcome the obstruction, as indicated by increasing esophageal pressure changes. The diaphragm contracts against the obstructed airway, the abdominal wall expands, and the chest wall retracts inward, resulting in opposing movements of the thorax and abdomen.

[0025] Increasing respiratory effort leads to arousal from sleep, which can be visualized on EEG (Figure 1), resulting in airway re-opening and resumption of normal breathing. The lack of airflow during apnea also causes hypoxia, indicated by a decrease in oxyhemoglobin saturation (Figure 1). Severity is commonly measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (absence of breathing for at least 10 seconds) and hypopneas (decrease in airflow and oxygen saturation) occurring per hour of sleep (Ruehland et al., The new AASM criteria for scoring hypopneas: Impact on the apnea-hypopnea index. SLEEP 2009;32(2):150-157).

[0026] Figure 1 is a graphical representation of obstructive apnea. The top channel shows the electroencephalogram (EEG) pattern of sleep. The next channel represents airflow. The next three channels show ventilatory effort due to thoracic and abdominal movement and changes in esophageal pressure, all of which reflect the effort of breathing into an obstructed upper airway. The final channel shows oxyhemoglobin saturation.

[0027] If a strict definition of OSA is used (AHI > 15 beats per hour or AHI > 5 beats per hour with daytime sleepiness), the estimated prevalence is approximately 15% in men and 5% in women. An estimated 30 million people in the United States suffer from OSA, of which approximately 6 million have been diagnosed. The prevalence of OSA in the United States appears to be increasing due to an aging population and rising obesity rates. OSA is associated with major comorbidities and economic costs, including: hypertension, diabetes, cardiovascular disease, motor vehicle accidents, workplace accidents, and fatigue / loss of productivity. (Young et al., WMJ 2009;108:246; Peppard et al., Am J Epidemiol 2013;177:1006.)

[0028] The current primary treatment is continuous positive airway pressure (CPAP). CPAP is effective for virtually all patients, with approximately 85% of diagnosed patients being prescribed CPAP, but compliance is low. Patients find CPAP uncomfortable and often intolerable. At least 30% (and up to 80%) of patients are non-adherent and therefore untreated (Weaver, Proc Am Thorac Soc. 2008 Feb 15;5(2):173-178). Other treatments with varying success rates include oral appliances (10%) and surgery (5%), neither of which are effective in the general population.

[0029] The search for drugs that activate pharyngeal muscles in humans during sleep has met with disappointing results: drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective in reducing the severity of OSA. For example, Proia and Hudgel,Chest.1991 Aug;100(2):416-21, Brownell et al.,N Engl J Med 1982,307:1037-1042, Sangal et al.,Sleep Med.2008 Jul;9(5):506-10.Epub 2007 Sep 27, Marshall et al. See al.p.2008 Jun;31(6):824-31, Eckert et al., Clin Sci(Lond).2011 Jun;120(12);505-14, Taranto-Montemurro et al., Sleep.2017 Feb 1;40(2).

[0030] Recent studies have shown that a combination of atomoxetine and oxybutynin, known as "ato-oxy," administered before bedtime, reduces obstructive sleep apnea (OSA) in patients with a wide range of severity. The overnight atomoxetine combination reduced the number of obstructive events, improved overnight oxygen desaturations, and increased genioglossus activity in an unselected group of patients with OSA. Data collected in proof-of-concept trials demonstrate that it is possible to improve or eliminate OSA using drugs with specific neurotransmitter profiles administered systemically. See Taranto-Montemurro, Luigi et al., "The Combination of Atomoxetine and Oxybutynin Greatly Reduces Obstructive Sleep Apnea Severity. A Randomized, Placebo-Controlled, Double-Blind Crossover Trial," American Journal of Respiratory and Critical Care Medicine, vol. 199, 10 (2019): 1267-1276.

[0031] There remains a need for additional therapies to treat conditions associated with pharyngeal airway collapse, such as sleep apnea.

[0032] Treatment methods The methods described herein include methods for treating disorders associated with collapse of pharyngeal airway muscles during sleep. In some embodiments, the disorder is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). In some embodiments, the subject has hypertension or OSA accompanied by hypertension. Generally, the methods include administering a therapeutically effective amount of an aldosterone synthase inhibitor selected from baxdrostat or a compound of Formula (A), or a pharmaceutically acceptable salt thereof, optionally with other active agents, to a subject in need of such treatment or determined to be in need of such treatment.

[0033] As used in this context, "treating" means improving at least one symptom of a disorder associated with pharyngeal airway collapse. Often, pharyngeal airway collapse during sleep leads to snoring and / or interruptions in breathing (apnea or hypopnea), arousals from sleep, and reduced oxygenation (hypoxemia). Thus, treatment can result in a reduction in snoring, apnea / hypopnea, sleep fragmentation, and hypoxemia. Administration of a therapeutically effective amount of a compound described herein for treating a subject with OSA can result in a reduction in AHI. Measurement of OSA disease and symptoms can be performed, for example, by polysomnography (PSG).

[0034] In general, an "effective amount" of a compound refers to an amount sufficient to induce a desired biological response, for example, to treat a condition associated with pharyngeal airway collapse, for example, to treat sleep apnea or snoring. As will be appreciated by those skilled in the art, the effective amount of a compound of the present invention may vary depending on factors such as the desired biological endpoint, the pharmacokinetics of the compound, the disease being treated, the mode of administration, and the age, weight, health, and condition of the subject. An effective amount encompasses both therapeutic and prophylactic treatments.

[0035] An effective amount can be administered in one or more administrations, applications, or dosages. The compositions can be administered one or more times daily to one or more times weekly, including once every other day. In some embodiments, the compositions are administered daily. In some embodiments, the compositions are administered daily before sleep time, e.g., just before sleep time or 15-60 minutes before sleep time. One of skill in the art will appreciate that certain factors can affect the dosage and timing required to effectively treat a subject, including, but not limited to, the severity of the disease or disorder, previous treatments, the general health and / or age of the subject, and other diseases present. Furthermore, treatment of a subject with a therapeutically effective amount of a therapeutic compound described herein can include a single treatment or a series of treatments.

[0036] As used herein, and unless otherwise specified, a "therapeutically effective amount" of a compound is an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or to delay or minimize one or more symptoms associated with the disease, disorder, or condition. A therapeutically effective amount of a compound means an amount of a therapeutic agent that, alone or in combination with other therapies, provides a therapeutic benefit in the treatment of a disease, disorder, or condition. The term "therapeutically effective amount" can encompass an amount that improves overall therapy, reduces or avoids the symptoms or causes of a disease or condition, or enhances the therapeutic effectiveness of another therapeutic agent.

[0037] As used herein, the terms "subject" and "patient" are used interchangeably. The terms "subject" and "patient" refer to animals (e.g., birds such as chickens, quails, or turkeys, or mammals), specifically "mammals," including non-primates (e.g., cows, pigs, horses, sheep, rabbits, guinea pigs, rats, cats, dogs, and mice) and primates (e.g., monkeys, chimpanzees, and humans), more specifically humans. In one embodiment, the subject is a non-human animal, such as a farm animal (e.g., a horse, cow, pig, or sheep), or a pet (e.g., a dog, cat, guinea pig, or rabbit). In a preferred embodiment, the subject is a human.

[0038] As used herein, "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal government, or a state government, or a corresponding agency in a country other than the United States, or listed in the United States Pharmacopoeia or other generally recognized pharmacopeia for use in animals, and more specifically, in humans.

[0039] As used herein, the term "unit dosage form" is defined to refer to the form in which a compound is administered to a subject. Specifically, the unit dosage form can be, for example, a pill, capsule, or tablet. In some embodiments, the unit dosage form is a capsule.

[0040] As used herein, "solid dosage form" means a pharmaceutical dose in solid form, for example, tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.

[0041] With respect to the compounds disclosed herein, single stereochemical isomers as well as enantiomers, diastereomers, cis / trans stereoisomers, and rotamers, as well as racemic and non-racemic mixtures thereof, are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds disclosed herein are within the scope of the invention.

[0042] Baxdrostat and its synthesis method are known in the art. See U.S. Patent No. 9,353,081, the entire contents of which are incorporated herein by reference. Baxdrostat is an aldosterone synthase inhibitor. The structure of baxdrostat is shown below: [ka]

[0043] The compound of formula (A) and its synthesis method are known in the art. See U.S. Patent No. 10,029,993, U.S. Patent No. 11,339,135, and WIPO Publication No. 2022 / 093714A1, the entire contents of each of which are incorporated herein by reference. The compound of formula (A) is an aldosterone synthase inhibitor. The compound of formula (A) is shown below. [ka]

[0044] In some embodiments, the compound of Formula (A) is in the form of a free base. In some embodiments, the compound of Formula (A) is in the form of a pharmaceutically acceptable salt. In some embodiments, the compound of Formula (A) is in the form of a monohydrobromide salt.

[0045] Atomoxetine is the generic name for the drug having the chemical name (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine and its pharmaceutical salts. Atomoxetine is the R(-) isomer as determined by X-ray diffraction. In some embodiments, atomoxetine can be atomoxetine hydrochloride.

[0046] Oxybutynin is the generic name for a pharmaceutical substance with the chemical name 4-diethylamino-2-butynylphenylcyclohexylglycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenylacetate, and its pharmaceutically acceptable salts. In various embodiments, oxybutynin can be a racemic mixture of R- and S-enantiomers, or an isolated enantiomer, for example, the R-enantiomer. In various embodiments, oxybutynin can be oxybutynin hydrochloride or (R)-oxybutynin hydrochloride.

[0047] In some embodiments, baxdrostat or a pharmaceutically acceptable salt thereof can be administered orally at a daily dose of about 0.1 mg to 20 mg per kg body weight, preferably about 0.5 mg to 4 mg per kg body weight (e.g., about 300 mg per person), preferably divided into one to three individual doses, each consisting of the same amount. For example, the daily dose can be about 1 mg to about 2000 mg, preferably about 5 mg to about 500 mg, or about 25 mg to about 250 mg. However, it will be apparent that the upper limits set forth herein may be exceeded if so indicated.

[0048] In some embodiments, the compound of Formula (A) or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.001 mg to about 1,000 mg. In some embodiments, the dose is about 0.01 mg to about 900 mg. In some embodiments, the dose is about 0.1 mg to about 800 mg. In some embodiments, the dose is about 1 mg to about 700 mg. In some embodiments, the dose is about 1 mg to about 600 mg. In some embodiments, the dose is about 1 mg to about 500 mg. In some embodiments, the dose is about 1 mg to about 400 mg. In some embodiments, the compound of Formula (A) is administered according to one of the following: (i) Orally administered twice daily, for example, at 5 mg to 100 mg every 12 hours; (ii) Orally administered twice daily, for example, at 10 mg to 50 mg every 12 hours; (iii) 5 mg to 100 mg orally administered once daily; (iv) 10 mg to 50 mg orally administered once daily; (v) 12.5 mg orally twice daily, e.g., 12 hours apart; or (vi) 25 mg orally twice daily, e.g., 12 hours apart; or (vii) 12.5 mg orally once daily; (viii) 50 mg orally once daily; or (ix) 100 mg is administered orally once daily.

[0049] In some embodiments, the method comprises administering a dose of about 20 mg to about 200 mg of atomoxetine or a pharmaceutically acceptable salt thereof (or the dose equivalent of another NRI). In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 25 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 40 mg to about 80 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 20 mg to about 50 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 50 mg to about 100 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 40 mg. In some embodiments, the dose of atomoxetine or a pharmaceutically acceptable salt thereof is about 80 mg.

[0050] In methods involving administration of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof (or another MRA), the dose of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof can be about 1 mg to about 25 mg (or the dose equivalent of another MRA), or in some embodiments, about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or a pharmaceutically acceptable salt thereof is about 2.5 mg to about 10 mg, e.g., 5 mg. In some embodiments, the dose of (R)-oxybutynin or a pharmaceutically acceptable salt thereof is about 1 mg to about 5 mg, e.g., 2.5 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof is about 1 mg to about 10 mg.

[0051] Pharmaceutical Compositions Also provided herein are pharmaceutical compositions comprising, as an active ingredient, an aldosterone synthase inhibitor selected from baxdrostat or a compound of Formula (A), or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises one or more additional active ingredients selected from an NRI, an MRA, and a hypnotic agent. The active ingredients may be in a single composition or in separate compositions. In certain embodiments, the pharmaceutical composition comprises, as active ingredients, atomoxetine or a pharmaceutically acceptable salt thereof, and optionally oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof. In certain embodiments, the pharmaceutical composition comprises, as active ingredients, trazodone or a pharmaceutically acceptable salt thereof, and optionally atomoxetine or a pharmaceutically acceptable salt thereof.

[0052] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs, such as amedalin (UK-3540-1), atomoxetine (Strattera), CP-39,332, daredalin (UK-3557-15), edivoxetine (LY-2216684), esreboxetine, lortalamine (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), talsupram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan); and non-selective NRIs such as amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxin (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine (GW-353,162), tapentadol (Nucynta), teniloxazine (Lucelan, Metatone), and venlafaxine; and pharmaceutically acceptable salts thereof.

[0053] In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof.

[0054] Exemplary muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, as well as pharmaceutically acceptable salts thereof, which have activity at the M2 receptor. Other exemplary antimuscarinic agents include anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, as well as pharmaceutically acceptable salts thereof.

[0055] In some embodiments, the muscarinic receptor antagonist is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, the oxybutynin is racemic oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof. As used herein, (R)-oxybutynin refers to the (R)-oxybutynin stereoisomer substantially free of other stereoisomers of oxybutynin. In some embodiments, the muscarinic receptor antagonist is fesoterodine.

[0056] Exemplary hypnotics include zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, and pharmaceutically acceptable salts thereof.

[0057] In some embodiments, the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof.

[0058] Pharmaceutical compositions typically contain a pharmaceutically acceptable carrier. As used herein, the term "pharmaceutically acceptable carrier" includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc., that are compatible with pharmaceutical administration.

[0059] The active ingredients for use in the present invention may be provided as a free base or a pharmaceutically acceptable salt. For example, in some embodiments, oxybutynin is oxybutynin hydrochloride. In some embodiments, (R)-oxybutynin is (R)-oxybutynin hydrochloride. In some embodiments, racemic oxybutynin is racemic oxybutynin hydrochloride. In some embodiments, atomoxetine is atomoxetine hydrochloride.

[0060] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration, examples of which include systemic oral or transdermal administration.

[0061] Methods for formulating suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005, and Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions generally include an inert diluent or an edible carrier. For oral therapeutic administration, the active compound can be incorporated with an excipient and used in the form of pills, tablets, lozenges, or capsules, such as gelatin capsules. Oral compositions can also be prepared using a fluid carrier. In some embodiments, the compositions according to the present invention can be in unit dosage form. In some embodiments, the compositions according to the present invention can be in solid dosage form, such as tablets or capsules.

[0062] Pharmaceutically compatible binding agents and / or adjuvant materials can be included as part of the composition. Tablets, pills, capsules, troches and the like can contain any of the following ingredients, or compounds of a similar nature: binders such as microcrystalline cellulose, tragacanth or gelatin; excipients such as starch or lactose; disintegrating agents such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or Sterot, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin, or flavoring agents such as peppermint, methyl salicylate, or orange flavor.

[0063] Systemic administration of the compounds described herein can also be by transdermal means, for example, using a patch, gel, or lotion applied to the skin. For transdermal administration, a penetrant suitable for permeating the epithelial barrier can be used in the formulation. Such penetrants are generally known to those skilled in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salve, gel, or cream, as is generally known in the art. Gels and / or lotions can be provided in individual sachets or via a metered pump that is applied daily. See, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0064] In one embodiment, therapeutic compounds are prepared with carriers that protect the therapeutic compounds from rapid elimination from the body, such as controlled-release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid can be used. Such formulations can be prepared using standard techniques or are commercially available, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions can also be used as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0065] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0066] In some embodiments, the pharmaceutical composition is for use in treating a condition associated with pharyngeal airway collapse, hi some embodiments, the condition is sleep apnea (e.g., OSA) or snoring (e.g., simple snoring).

[0067] Kits and Combinations Also provided herein is a kit comprising an aldosterone synthase inhibitor selected from baxdrostat or a compound of formula (A) and one or more additional active ingredients selected from NRIs, MRAs, and hypnotics. For example, the kit may include separate pharmaceutical compositions, each containing a single active ingredient. The kit may be used to treat a subject with a condition associated with pharyngeal airway collapse. Various embodiments of the kit will become apparent from the detailed description provided herein.

[0068] Also provided herein is an aldosterone synthase inhibitor selected from baxdrostat or a compound of Formula (A) and one or more additional active ingredients selected from an NRI, an MRA, and a hypnotic agent for use in treating a subject having a condition associated with pharyngeal airway collapse. Additionally, provided herein is a therapeutic combination of an aldosterone synthase inhibitor selected from baxdrostat or a compound of Formula (A) and one or more additional active ingredients selected from an NRI, an MRA, and a hypnotic agent for use in treating a subject having a condition associated with pharyngeal airway collapse. Various embodiments of the combinations and therapeutic combinations will become apparent from the detailed description provided herein. In certain embodiments of the kits, combinations, and therapeutic combinations of the present invention, the NRI, if present, is atomoxetine or a pharmaceutically acceptable salt thereof, the hypnotic, if present, is trazodone or a pharmaceutically acceptable salt thereof, and the MRA, if present, is oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof.

[0069] Other embodiments While the present invention has been described in conjunction with its detailed description, it should be understood that the foregoing description is intended to illustrate, but not limit, the scope of the invention, which is defined by the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.

Claims

1. 1. A method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof an effective amount of baxdrostat: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. 10. The method of claim 1, further comprising administering to the subject a norepinephrine reuptake inhibitor (NRI).

3. 3. The method of claim 2, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

4. 4. The method of claim 3, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof.

5. The NRI may be amitriptyline, amoxapine, bupropion, ciclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenide, or the like.

3. The method of claim 2, wherein the active ingredient is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of benzodiazepine, benzodiazepine, benzophenone, benzocaine, benzoyl peroxidase ...

6. 3. The method of claim 2, wherein the NRI is selected from the group consisting of atomoxetine or a pharmaceutically acceptable salt thereof, and reboxetine or a pharmaceutically acceptable salt thereof.

7. 7. The method of claim 6, wherein the NRI is atomoxetine or a pharmaceutically acceptable salt thereof.

8. The method of any one of claims 2 to 7, further comprising administering to the subject a muscarinic receptor antagonist (MRA).

9. 9. The method of claim 8, wherein the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharmaceutically acceptable salt thereof.

10. The MRA is anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, or the like.

9. The method of claim 8, wherein the active ingredient is selected from the group consisting of methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.

11. 10. The method of claim 9, wherein the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.

12. 12. The method of claim 11, wherein the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

13. 12. The method of claim 11, wherein the MRA is racemic oxybutynin or a pharmaceutically acceptable salt thereof.

14. The method of any one of claims 1 to 7, further comprising administering a hypnotic agent to the subject.

15. 15. The method of claim 14, wherein the hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharmaceutically acceptable salt thereof.

16. 16. The method of claim 15, wherein the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof.

17. 17. The method of any one of claims 1 to 16, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 500 mg.

18. 18. The method of claim 17, wherein the baxdrostat or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 to about 250 mg.

19. 19. The method of any one of claims 1 to 18, wherein the atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 200 mg.

20. 20. The method of claim 19, wherein the atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 25 to about 100 mg.

21. 14. The method of any one of claims 8 to 13, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 15 mg.

22. 22. The method of claim 21, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered in a dose of about 2 mg to about 10 mg.

23. 13. The method of any one of claims 8 to 12, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 10 mg.

24. 24. The method of claim 23, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg.

25. 17. The method of any one of claims 14 to 16, wherein the trazodone or a pharmaceutically acceptable salt thereof is administered in a dose of about 12.5 mg to about 200 mg.

26. 20. The method of claim 1, 17, or 18, wherein baxdrostat or a pharmaceutically acceptable salt thereof is administered as monotherapy.

27. 26. The method of any one of claims 2 to 25, wherein the NRI and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition.

28. The method of any one of claims 8 to 13, wherein the NRI, MRA, and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition.

29. The method of any one of claims 14 to 16, wherein the hypnotic agent and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition.

30. 17. The method of any one of claims 14 to 16, wherein the hypnotic agent, the NRI, and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition.

31. The method of any one of claims 27 to 30, wherein the single composition is in an oral dosage form.

32. 32. The method of claim 31, wherein the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch.

33. 33. The method of any one of claims 1 to 32, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

34. 34. The method of claim 33, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

35. 33. The method of any one of claims 1 to 32, wherein the condition associated with pharyngeal airway collapse is snoring.

36. 36. The method of claim 35, wherein the condition associated with pharyngeal airway collapse is simple snoring.

37. 37. The method of any one of claims 1 to 36, wherein the subject is in a non-fully conscious state, such as sleep.

38. 38. The method of any one of claims 1 to 37, wherein the subject has hypertension.

39. 39. The method of claim 38, wherein the subject has OSA accompanied by hypertension.

40. Baxdrostat or a pharmaceutically acceptable salt thereof for use in the treatment of obstructive sleep apnea.

41. Baxdrostat or a pharmaceutically acceptable salt thereof for use in the treatment of obstructive sleep apnea associated with hypertension.

42. A therapeutic combination of baxdrostat or a pharmaceutically acceptable salt thereof with (a) a norepinephrine reuptake inhibitor (NRI) and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent and optionally a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea.

43. A therapeutic combination of baxdrostat or a pharmaceutically acceptable salt thereof and (a) a norepinephrine reuptake inhibitor (NRI), optionally with a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent, optionally with a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea associated with hypertension.

44. A method of treating a subject having a condition associated with pharyngeal airway collapse, comprising administering to a subject in need thereof an effective amount of a compound of formula (A): 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

45. 45. The method of claim 44, further comprising administering to the subject a norepinephrine reuptake inhibitor (NRI).

46. 46. ​​The method of claim 45, wherein the NRI is a norepinephrine selective reuptake inhibitor (NSRI).

47. 47. The method of claim 46, wherein the NSRI is selected from the group consisting of amedalin, atomoxetine, CP-39,332, daredalin, edivoxetine, esreboxetine, lortalamine, nisoxetine, reboxetine, talopram, talsupram, tandamine, and viloxazine, or a pharmaceutically acceptable salt thereof.

48. 46. ​​The method of claim 45, wherein the NRI is a norepinephrine nonselective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, cyclazindol, desipramine, desvenlafaxine, dexmethylphenidate, diethylpropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phenmetrazine, protriptyline, radafaxine, tapentadol, teniloxazine, and venlafaxine, or a pharmaceutically acceptable salt thereof.

49. 46. ​​The method of claim 45, wherein the NRI is selected from the group consisting of atomoxetine or a pharmaceutically acceptable salt thereof, and reboxetine or a pharmaceutically acceptable salt thereof.

50. 50. The method of claim 49, wherein the NRI is atomoxetine or a pharmaceutically acceptable salt thereof.

51. 51. The method of any one of claims 45 to 50, further comprising administering to the subject a muscarinic receptor antagonist (MRA).

52. 52. The method of claim 51, wherein the MRA is selected from the group consisting of atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium, and oxybutynin, or a pharmaceutically acceptable salt thereof.

53. 52. The method of claim 51, wherein the MRA is selected from the group consisting of anisotropine, benztropine, biperiden, clidinium, cyclimine, dicyclomine, diphemanil, diphenidol, ethopropazine, glycopyrrolate, hexocyclium, isopropamide, mepenzolate, methixene, methscopolamine, oxyphencyclimine, oxyphenonium, procyclidine, scopolamine, tridihexethyl, and trihexyphenidyl, or a pharmaceutically acceptable salt thereof.

54. 53. The method of claim 52, wherein the MRA is oxybutynin or a pharmaceutically acceptable salt thereof.

55. 55. The method of claim 54, wherein the MRA is (R)-oxybutynin or a pharmaceutically acceptable salt thereof.

56. 55. The method of claim 54, wherein the MRA is racemic oxybutynin or a pharmaceutically acceptable salt thereof.

57. 51. The method of any one of claims 44 to 50, further comprising administering a hypnotic agent to the subject.

58. 58. The method of claim 57, wherein the hypnotic agent is selected from the group consisting of zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate, or a pharmaceutically acceptable salt thereof.

59. 59. The method of claim 58, wherein the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof.

60. 60. The method of any one of claims 44 to 59, wherein the compound of formula (A) or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 500 mg.

61. 61. The method of claim 60, wherein the compound of formula (A) or a pharmaceutically acceptable salt thereof is administered at a dose of about 5 to about 200 mg.

62. 62. The method of any one of claims 44-61, wherein the atomoxetine or a pharmaceutically acceptable salt thereof is administered at a dose of about 20 to about 200 mg.

63. 63. The method of claim 62, wherein the atomoxetine or a pharmaceutically acceptable salt thereof is administered in a dose of about 25 to about 100 mg.

64. 57. The method of any one of claims 51 to 56, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 to about 15 mg.

65. 65. The method of claim 64, wherein the oxybutynin or a pharmaceutically acceptable salt thereof is administered in a dose of about 2 mg to about 10 mg.

66. 56. The method of any one of claims 51 to 55, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 0.5 to about 10 mg.

67. 67. The method of claim 66, wherein the (R)-oxybutynin or a pharmaceutically acceptable salt thereof is administered at a dose of about 1 mg to about 5 mg.

68. 60. The method of any one of claims 57 to 59, wherein the trazodone or a pharmaceutically acceptable salt thereof is administered in a dose of about 12.5 mg to about 200 mg.

69. 62. The method of claim 44, 60, or 61, wherein the compound of formula (A) or a pharmaceutically acceptable salt thereof is administered as monotherapy.

70. 69. The method of any one of claims 45 to 68, wherein the NRI and the compound of formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition.

71. 57. The method of any one of claims 51 to 56, wherein the NRI, MRA, and the compound of formula (A), or a pharmaceutically acceptable salt thereof, are administered in a single composition.

72. 60. The method of any one of claims 57 to 59, wherein the hypnotic agent and the compound of formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition.

73. 60. The method of any one of claims 57 to 59, wherein the hypnotic agent, the NRI, and the compound of formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition.

74. 74. The method of any one of claims 70 to 73, wherein the single composition is an oral dosage form.

75. 75. The method of claim 74, wherein the oral dosage form is a syrup, pill, tablet, lozenge, capsule, or patch.

76. 76. The method of any one of claims 44 to 75, wherein the condition associated with pharyngeal airway collapse is sleep apnea.

77. 77. The method of claim 76, wherein the condition associated with pharyngeal airway collapse is obstructive sleep apnea (OSA).

78. 76. The method of any one of claims 44 to 75, wherein the condition associated with pharyngeal airway collapse is snoring.

79. 79. The method of claim 78, wherein the condition associated with pharyngeal airway collapse is simple snoring.

80. 80. The method of any one of claims 44 to 79, wherein the subject is in a non-fully conscious state, such as sleep.

81. 81. The method of any one of claims 44 to 80, wherein the subject has hypertension.

82. 82. The method of claim 81, wherein the subject has OSA accompanied by hypertension.

83. A compound of formula (A) or a pharmaceutically acceptable salt thereof for use in the treatment of obstructive sleep apnea.

84. A compound of formula (A) or a pharmaceutically acceptable salt thereof for use in the treatment of obstructive sleep apnea associated with hypertension.

85. A therapeutic combination of a compound of formula (A) or a pharmaceutically acceptable salt thereof with (a) a norepinephrine reuptake inhibitor (NRI) and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent and optionally a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea.

86. A therapeutic combination of a compound of formula (A) or a pharmaceutically acceptable salt thereof and (a) a norepinephrine reuptake inhibitor (NRI), optionally with a muscarinic receptor antagonist (MRA), or (b) a hypnotic agent, optionally with a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea associated with hypertension.

87. A pharmaceutical composition comprising baxdrostat or a pharmaceutically acceptable salt thereof, a norepinephrine reuptake inhibitor, and a pharmaceutically acceptable carrier or excipient.

88. 88. The pharmaceutical composition of claim 87, further comprising a hypnotic agent.

89. 88. The pharmaceutical composition of claim 87, further comprising a muscarinic receptor antagonist (MRA).

90. A pharmaceutical composition comprising baxdrostat or a pharmaceutically acceptable salt thereof, a hypnotic agent, and a pharmaceutically acceptable carrier or excipient.

91. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a norepinephrine reuptake inhibitor, and a pharmaceutically acceptable carrier or excipient.

92. 92. The pharmaceutical composition of claim 91, further comprising a hypnotic agent.

93. 92. The pharmaceutical composition of claim 91, further comprising a muscarinic receptor antagonist (MRA).

94. A pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a hypnotic agent, and a pharmaceutically acceptable carrier or excipient.

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