Methods and compositions for treating sleep apnea

Abstract

Disclosed herein are methods of treating obstructive sleep apnea using an aldosterone synthase inhibitor, optionally in combination with a noradrenaline reuptake inhibitor or other active agent, and related pharmaceutical compositions and therapeutic combinations.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS

[0002] This application claims priority to and the benefit of U.S. Provisional Patent Application No. 63 / 403,469, filed on September 2, 2022, the entire contents of which are incorporated herein by reference. Technical Field

[0003] 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 related pharmaceutical and therapeutic compositions. Background Art

[0004] 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

[0005] One aspect of the present invention provides a method of treating a subject suffering from a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of baxdrostat or a pharmaceutically acceptable salt thereof having the following structure:

[0006]

[0007] 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 to the subject a norepinephrine reuptake inhibitor (NRI). In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of aminometadaline, atomoxetine, CP-39,332, dalaidarine, edexetine, oxepoxetine, chlortalamin, nisoxetine, reboxetine, talopram, tassopram, tandamine and viloxazine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, ciratindol, desipramine, desvenlafaxine, dexmethilphenidate, bupropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetholine, phendimetholine, protriptyline, redafaxin, tapentadol, tenisazine 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), for example, in combination with baxdrostat 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 cintropine, benztropine, biperiden, cyclamate, cyclamine, dicyclomine, diphenylmanil, diphenidol, profenamide, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methylthioxanthene, methylscopolamine, hydroxybenzylamine, orphenamium, procyclidine, scopolamine, trimethoprim 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 to the subject, for example in combination with baxdrostat and optionally with an NRI. In some embodiments, the hypnotic 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 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, the 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 a monotherapy. In some embodiments, NRI and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, NRI, MRA and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, hypnotic and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, hypnotic, NRI and baxdrostat or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the single composition is an oral administration form. In some embodiments, the oral administration form is a syrup, a pill, a tablet, a lozenge, a capsule or a 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-full consciousness, such as sleep. In some embodiments, the subject suffers from hypertension. In some embodiments, the subject suffers from OSA with hypertension.

[0008] Also provided herein is baxdrostat or a pharmaceutically acceptable salt thereof for use in treating obstructive sleep apnea.

[0009] Also provided herein is baxdrostat or a pharmaceutically acceptable salt thereof for use in treating obstructive sleep apnea associated with hypertension.

[0010] Also provided herein are therapeutic combinations of baxdrostat, or a pharmaceutically acceptable salt thereof, and (a) a norepinephrine reuptake inhibitor (NRI), and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic, and optionally a norepinephrine reuptake inhibitor (NRI) for treating obstructive sleep apnea.

[0011] 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, optionally with a norepinephrine reuptake inhibitor (NRI), for use in treating obstructive sleep apnea with hypertension.

[0012] Another aspect of the present invention provides a method for treating a subject suffering from a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (A) or a pharmaceutically acceptable salt thereof, wherein the compound of formula (A) has the following structure:

[0013]

[0014] 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 to the subject a norepinephrine reuptake inhibitor (NRI). In some embodiments, the NRI is a norepinephrine selective reuptake inhibitor (NSRI). In some embodiments, the NSRI is selected from the group consisting of aminometadaline, atomoxetine, CP-39,332, dalaidarine, edexetine, oxepoxetine, chlortalamin, nisoxetine, reboxetine, talopram, tassopram, tandamine and viloxazine or a pharmaceutically acceptable salt thereof. In some embodiments, the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, ciratindol, desipramine, desvenlafaxine, dexmethilphenidate, bupropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetholine, phendimetholine, protriptyline, redafaxin, tapentadol, tenisazine 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), for example, 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 cintropine, benztropine, biperiden, cyclamate, cyclamine, dicyclomine, diphenylmanil, diphenidol, profenamide, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methylthiothixene, methylscopolamine, hydroxybenzylamine, orphenamium, procyclidine, scopolamine, trimethoprim 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 to the subject, for example in combination with a compound of formula (A) and an optional NRI. In some embodiments, the hypnotic is selected from the group consisting of zolpidem, zopiclone, dexzopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine and sodium oxybate or a pharmaceutically acceptable salt thereof. In some embodiments, the hypnotic 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 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, the compound of formula (A) or a pharmaceutically acceptable salt thereof is administered as a 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, MRA and the compound of formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic and the compound of formula (A) or a pharmaceutically acceptable salt thereof are administered in a single composition. In some embodiments, the hypnotic, 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 administration form. In some embodiments, the oral administration form is a syrup, a pill, a tablet, a lozenge, a capsule or a 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 suffers from hypertension. In some embodiments, the subject suffers from OSA with hypertension.

[0015] Also provided herein is a compound of formula (A) or a pharmaceutically acceptable salt thereof for use in treating obstructive sleep apnea.

[0016] Also provided herein is a compound of formula (A) or a pharmaceutically acceptable salt thereof for use in treating obstructive sleep apnea associated with hypertension.

[0017] Also provided herein are therapeutic combinations 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 and optionally a norepinephrine reuptake inhibitor (NRI) for use in treating obstructive sleep apnea.

[0018] 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, optionally with a norepinephrine reuptake inhibitor (NRI), for use in the treatment of obstructive sleep apnea with hypertension.

[0019] 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. In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA).

[0020] Another aspect of the present invention provides a pharmaceutical composition comprising baxdrostat or a pharmaceutically acceptable salt thereof, a hypnotic and a pharmaceutically acceptable carrier or excipient.

[0021] Another aspect of the present invention provides 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. In some embodiments, the pharmaceutical composition further comprises a hypnotic. In some embodiments, the pharmaceutical composition further comprises a muscarinic receptor antagonist (MRA).

[0022] Another aspect of the present invention provides a pharmaceutical composition comprising a compound of formula (A) or a pharmaceutically acceptable salt thereof, a hypnotic and a pharmaceutically acceptable carrier or excipient.

[0023] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the invention belongs. Methods and materials for use in the present invention are described herein; other suitable methods and materials known in the art may also be used. The materials, methods, and examples are illustrative only and not restrictive. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a conflict, the present specification (including definitions) shall prevail.

[0024] Other features and advantages of the invention will be apparent from the following detailed description and drawings, and from the claims. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The following drawings are provided by way of illustration and are not intended to limit the scope of the claimed invention.

[0026] Figure 1 is a graphic illustration 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 through chest and abdominal movements and changes in esophageal pressure, all of which reflect respiratory effort against a blocked upper airway. The last channel shows blood oxygen saturation. DETAILED DESCRIPTION

[0027] In humans, the pharyngeal airway area has no bone or cartilage support and is held open by muscles. When these muscles relax during sleep, the pharynx collapses, causing airflow to cease. Figure 1 As shown, ventilation continues and increases in an attempt to overcome the obstruction, as evidenced by increased esophageal pressure changes. The chest and abdomen move in opposite directions as a result of the diaphragm contracting to block the airway, forcing the abdominal wall to expand outward and the chest wall to collapse inward.

[0028] Increased respiratory activity leads to arousals from sleep, which are visible on the EEG ( Figure 1 ) and leads to opening of the airway and resumption of normal breathing. Insufficient airflow during apnea also leads to hypoxia, which is manifested by a decrease in blood oxygen saturation ( Figure 1 Severity is usually measured using the apnea-hypopnea index (AHI), which is the combined average number of apneas (cessation of breathing for at least 10 seconds) and hypopneas (decreases in airflow and oxygen saturation) that occur 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).

[0029] Figure 1 is a graphic illustration 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 through chest and abdominal movements and changes in esophageal pressure, all of which reflect respiratory effort against a blocked upper airway. The last channel shows blood oxygen saturation.

[0030] When a strict definition of OSA is used (AHI>15 events / hour or AHI>5 events / 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 have OSA, of whom approximately 6 million have been diagnosed. The prevalence of OSA appears to be increasing in the United States due to aging and increasing obesity rates. OSA is associated with major complications 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.)

[0031] The main treatment is continuous positive airway pressure (CPAP). CPAP is effective for almost all patients, and about 85% of diagnosed patients use CPAP, but compliance is low. Patients find CPAP uncomfortable and often cannot tolerate it; at least 30% of patients (up to 80%) often do not follow their doctor's orders and therefore do not receive treatment (Weaver, Proc Am Thorac Soc. 2008 Feb 15; 5(2): 173-178). Other treatments have varying success rates and include oral appliances (10%) and surgery (5%), but neither is likely to be effective in the general population.

[0032] Drug research to activate the human pharyngeal muscles during sleep has been frustrating. Drugs such as serotonin reuptake inhibitors, tricyclic antidepressants, and sedatives have all been tested in humans and shown to be ineffective in reducing OSA severity. See, e.g., 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. 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).

[0033] In a recent study, the combination of atomoxetine and oxybutynin before bed, called "ato-oxy," has been shown to reduce OSA in patients of varying severity. In an unselected group of OSA patients, administration of the ato-oxy combination for one night reduced the number of obstructive events, improved nocturnal oxygen desaturation, and enhanced genioglossus muscle activity. Data collected in a proof-of-concept trial suggest that systemic administration of drugs with specific neurotransmitter profiles may improve or eliminate OSA. 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.

[0034] There remains a need for further therapies to treat conditions associated with pharyngeal airway collapse, such as sleep apnea.

[0035] Treatment

[0036] The methods described herein include methods for treating diseases associated with collapse of pharyngeal airway muscles during sleep. In some embodiments, the disease is sleep apnea (e.g., obstructive sleep apnea (OSA)) or snoring (e.g., simple snoring). In some embodiments, the subject suffers from hypertension or OSA with hypertension. Typically, the method comprises 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 together with other active agents, to a subject in need or determined to be in need of such treatment.

[0037] As used herein, "treating" refers to improving at least one symptom of a disease associated with pharyngeal airway collapse. Typically, pharyngeal airway collapse during sleep leads to snoring and / or interrupted breathing (apnea or hypopnea), sleep arousals, and reduced oxygenation (hypoxemia); therefore, treatment can reduce 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. For example, OSA disease and symptoms can be measured by polysomnography (PSG).

[0038] In general, an "effective amount" of a compound refers to an amount sufficient to elicit the desired biological response, e.g., to treat a condition associated with pharyngeal airway collapse, e.g., to treat sleep apnea or snoring. As will be appreciated by those of ordinary skill in the art, an effective amount of a compound of the 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 includes both therapeutic and prophylactic treatments.

[0039] The effective amount can be administered in one or more administrations, applications or doses. The composition can be administered once or more per day to once or more per week; including once every other day. In some embodiments, the composition is administered daily. In some embodiments, the composition is administered daily before bedtime, for example, immediately before bedtime or 15-60 minutes before bedtime. Those skilled in the art will appreciate that certain factors may affect the dose and time required to effectively treat the subject, including but not limited to the severity of the disease or condition, previous treatment, the overall health and / or age of the subject, and other diseases present. In addition, treating a subject with a therapeutically effective amount of a therapeutic compound described herein may include a single treatment or a series of treatments.

[0040] Unless otherwise indicated, a "therapeutically effective amount" of a compound as used herein refers to an amount sufficient to provide a therapeutic benefit in the treatment of a disease, disorder, or condition, or sufficient to delay or minimize one or more symptoms associated with a disease, disorder, or condition. A therapeutically effective amount of a compound refers to an amount of a therapeutic agent, alone or in combination with other therapies, that 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, alleviates or avoids symptoms or causes of a disease or condition, or enhances the therapeutic efficacy of another therapeutic agent.

[0041] 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, quail or turkeys, or mammals), particularly "mammals", including non-primates (e.g., cattle, 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, cattle, pig or sheep), or a pet (e.g., a dog, cat, guinea pig or rabbit). In a preferred embodiment, the subject is a human.

[0042] As used herein, "pharmaceutically acceptable" means approved or approvable by a regulatory agency of the Federal or a state government or equivalent in a country other than the United States, or listed in the U.S. Pharmacopeia or other generally recognized pharmacopeia, for use in animals, and more particularly, in humans.

[0043] As used herein, the term "unit dosage form" is defined as the form in which the 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.

[0044] As used herein, "solid dosage form" refers to a pharmaceutical dosage form in solid form, such as tablets, capsules, granules, powders, sachets, reconstitutable powders, dry powder inhalers, and chewables.

[0045] For the compounds disclosed herein, single stereochemical isomers, as well as enantiomers, diastereomers, cis / trans conformers and rotational isomers, and racemic and non-racemic mixtures thereof are within the scope of the present invention. Unless otherwise specified, all tautomeric forms of the compounds disclosed herein are within the scope of the present invention.

[0046] Baxdrostat and its synthesis methods are known in the art. See U.S. Pat. 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.

[0047]

[0048] Compounds of formula (A) and methods for synthesizing them are known in the art. See U.S. Patent No. 10,029,993, U.S. Patent No. 11,339,13 and WIPO Publication No. WO 2022 / 093714 A1, the entire contents of each of which are incorporated herein by reference. Compounds of formula (A) are aldosterone synthase inhibitors. Compounds of formula (A) are shown below.

[0049]

[0050] 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.

[0051] Atomoxetine is the common name for a drug with the chemical name (-)-N-methyl-3-phenyl-3-(o-tolyloxy)-propylamine and its pharmaceutically acceptable salts. According to x-ray diffraction, atomoxetine is the R(-) isomer. In some embodiments, atomoxetine can be atomoxetine hydrochloride.

[0052] Oxybutynin is the common name for a drug with the chemical name 4-diethylamino-2-butynylphenylcyclohexyl glycolate or 4-(diethylamino)but-2-ynyl 2-cyclohexyl-2-hydroxy-2-phenyl acetate and its pharmaceutically acceptable salts. In various embodiments, oxybutynin can be a racemic mixture of R- and S-enantiomers, or a separated enantiomer, such as the R-enantiomer. In various embodiments, oxybutynin can be oxybutynin chloride or (R)-oxybutynin chloride.

[0053] In some embodiments, baxdrostat or a pharmaceutically acceptable salt thereof can be administered in the form of oral administration, with a daily dose of about 0.1 mg to 20 mg per kilogram of body weight, preferably about 0.5 mg to 4 mg per kilogram of body weight (e.g., about 300 mg per person), preferably divided into 1-3 separate doses, which can be composed of, for example, 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 clear that when this is shown as an indication, the upper limit given here can be exceeded.

[0054] 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:

[0055] (i) 5 mg to 100 mg orally, twice a day, for example, 12 hours apart;

[0056] (ii) 10 mg to 50 mg orally, twice a day, for example, 12 hours apart;

[0057] (iii) 5 mg to 100 mg orally, once a day;

[0058] (iv) 10 mg to 50 mg orally, once a day.

[0059] (v) 12.5 mg orally twice a day, for example, 12 hours apart;

[0060] (vi) 25 mg orally twice a day, for example, 12 hours apart;

[0061] (vii) 12.5 mg orally, once a day;

[0062] (viii) 50 mg orally once a day; or

[0063] (ix) 100 mg orally, once a day.

[0064] 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.

[0065] In methods comprising administering 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 from about 1 mg to about 25 mg (or the dose equivalent of another MRA), or in some embodiments, from about 2 mg to about 15 mg. In some embodiments, the dose of oxybutynin or a pharmaceutically acceptable salt thereof is from about 2.5 mg to about 10 mg, for example, 5 mg. In some embodiments, the dose of (R)-oxybutynin or a pharmaceutically acceptable salt thereof is from about 1 mg to about 5 mg, for example, 2.5 mg. In some embodiments, the dose of oxybutynin or (R)-oxybutynin or a pharmaceutically acceptable salt thereof is from about 1 mg to about 10 mg.

[0066] Pharmaceutical composition

[0067] Also provided herein is a pharmaceutical composition comprising an aldosterone synthase inhibitor selected from baxdrostat or a compound of formula (A) or a pharmaceutically acceptable salt thereof as an active ingredient. In certain embodiments, the pharmaceutical composition further comprises one or more additional active ingredients selected from NRIs and MRAs and hypnotic drugs. The active ingredient can be in a single composition or in a separate composition. In certain embodiments, the pharmaceutical composition comprises atomoxetine or a pharmaceutically acceptable salt thereof and optionally oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof as an active ingredient. In certain embodiments, the pharmaceutical composition comprises trazodone or a pharmaceutically acceptable salt thereof and optionally atomoxetine or a pharmaceutically acceptable salt thereof as an active ingredient.

[0068] Exemplary norepinephrine reuptake inhibitors (NRIs) include selective NRIs such as aminometadaline (UK-3540-1), atomoxetine (Stratter), CP-39,332, daredaline (UK-3557-15), edexetine (LY-2216684), oxepoxetine, chlortalamin (LM-1404), nisoxetine (LY-94,939), reboxetine (Edronax, Vestra), talopram (Lu 3-010), tassopram (Lu 5-005), tandamine (AY-23,946), viloxazine (Vivalan); and non-selective NRIs such as amitriptyline, amoxapine, bupropion, cilatindol, desipramine, desvenlafaxine, dexmethylphenidate, bupropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine (GW-320,659), maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phendimetrazine, protriptyline, redafaxine (GW-353,162), tapentadol (Nucynta), tenisazine (Lucelan, Metatone) and venlafaxine; and pharmaceutically acceptable salts thereof.

[0069] In some embodiments, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof.

[0070] Exemplary muscarinic receptor antagonists (MRAs) include atropine, propantheline, bethanechol, solifenacin, darifenacin, tolterodine, fesoterodine, trospium and oxybutynin and pharmaceutically acceptable salts thereof, which are active at M2 receptors. Other exemplary antimuscarinic drugs include cintropine, benztropine, biperiden, cyclamate, cyclimine, dicyclomine, diphenylmanil, diphenidol, profenamide, glycopyrrolate, hexacycline, isopropylamide, mepentyl bromide, methylthioxanthene, methylscopolamine, hydroxybenzylamine, orphenamium, procyclidine, scopolamine, trimethoprim and trihexyphenidyl and pharmaceutically acceptable salts thereof.

[0071] In some embodiments, the muscarinic receptor antagonist is oxybutynin or a pharmaceutically acceptable salt thereof. In some embodiments, oxybutynin is racemic oxybutynin or (R)-oxybutynin, or a pharmaceutically acceptable salt thereof. As used herein, (R)-oxybutynin refers to a stereoisomer of (R)-oxybutynin that is substantially free of other stereoisomers of oxybutynin. In some embodiments, the muscarinic receptor antagonist is fesoterodine.

[0072] Exemplary hypnotic drugs include zolpidem, zopiclone, eszopiclone, trazodone, zaleplon, benzodiazepines, gabapentin, tiagabine, and sodium oxybate and pharmaceutically acceptable salts thereof.

[0073] In some embodiments, the hypnotic agent is trazodone or a pharmaceutically acceptable salt thereof.

[0074] Pharmaceutical compositions generally include a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" as used herein includes saline, solvents, dispersion media, diluents, fillers, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are compatible with pharmaceutical administration.

[0075] The active ingredients used in the present invention can be provided in the form of a free base or a pharmaceutically acceptable salt. For example, in some embodiments, oxybutynin is oxybutynin chloride. In some embodiments, (R)-oxybutynin is (R)-oxybutynin chloride. In some embodiments, racemic oxybutynin is racemic oxybutynin chloride. In some embodiments, atomoxetine is atomoxetine hydrochloride.

[0076] A pharmaceutical composition is typically formulated to be compatible with its intended route of administration. Examples of routes of administration include systemic oral or transdermal administration.

[0077] Methods for preparing suitable pharmaceutical compositions are known in the art, see, for example, Remington: The Science and Practice of Pharmacy, 21st ed., 2005; and the books in the series Drugs and the Pharmaceutical Sciences: a Series of Textbooks and Monographs (Dekker, NY). For example, oral compositions typically include an inert diluent or an edible carrier. For the purpose of oral therapeutic administration, the active compound can be mixed with an excipient and used in the form of a pill, tablet, lozenge, or capsule (e.g., gelatin capsule). Oral compositions can also be prepared using fluid carriers. In some embodiments, the composition according to the present invention can be a unit dosage form. In some embodiments, the composition according to the present invention can be a solid dosage form, for example, a tablet or capsule.

[0078] Pharmaceutically compatible binders and / or adjuvant materials may be included as part of the composition. Tablets, pills, capsules, lozenges, etc. may 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, disintegrants such as alginic acid, Primogel or corn starch; lubricants such as magnesium stearate or Sterotes; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as mint, methyl salicylate or orange flavor.

[0079] Systemic administration of the compounds described herein can also be by transdermal means, for example, using a patch, gel or lotion for application to the skin. For transdermal administration, penetrants suitable for penetration of the epidermal barrier can be used in the formulation. Such penetrants are well known in the art. For example, for transdermal administration, the active compound can be formulated into an ointment, salves, gel or cream as is well known in the art. The gel and / or lotion can be provided in a separate pouch or by a metered-dose pump for daily administration; see, for example, Cohn et al., Ther Adv Urol. 2016 Apr; 8(2): 83-90.

[0080] In one embodiment, the therapeutic compound is prepared with a carrier that will protect the therapeutic compound from rapid elimination from the body, such as a controlled release formulation, 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 preparations can be prepared using standard techniques, or commercially available from, for example, 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. Patent No. 4,522,811.

[0081] The pharmaceutical compositions can be included in a container, pack, or dispenser together with instructions for administration or use in the methods described herein.

[0082] In some embodiments, the pharmaceutical composition is used to treat a condition associated with pharyngeal airway collapse. In some embodiments, the condition is sleep apnea (eg, OSA) or snoring (eg, simple snoring).

[0083] Kits and Combos

[0084] 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 hypnotic drugs. For example, the kit can include separate pharmaceutical compositions, each of which has a single active ingredient. The kit can be used to treat a subject suffering from a condition associated with pharyngeal airway collapse. Various embodiments of the kit will be apparent from the detailed description provided herein.

[0085] Also provided herein are aldosterone synthase inhibitors selected from baxdrostat or a compound of formula (A) and one or more additional active ingredients selected from NRIs, MRAs, and hypnotics for use in treating a subject suffering from a condition associated with pharyngeal airway collapse. Also provided herein are therapeutic combinations of aldosterone synthase inhibitors selected from baxdrostat or a compound of formula (A) and one or more additional active ingredients selected from NRIs, MRAs, and hypnotics for use in treating a subject suffering from a condition associated with pharyngeal airway collapse. Various embodiments of the combinations and therapeutic combinations will be apparent from the detailed description provided herein. In certain embodiments of the kits, combinations, and therapeutic combinations of the present invention, if an NRI is present, the NRI is atomoxetine or a pharmaceutically acceptable salt thereof, if a hypnotic is present, the hypnotic is trazodone or a pharmaceutically acceptable salt thereof, and if an MRA is present, the MRA is oxybutynin (e.g., (R)-oxybutynin) or a pharmaceutically acceptable salt thereof.

[0086] Other Implementations

[0087] It should be understood that although the invention has been described in conjunction with the detailed description of the invention, the foregoing description is intended to illustrate rather than limit the scope of the invention, which is defined by the scope of the appended claims. Other aspects, advantages and modifications are within the scope of the appended claims.

Claims

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

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

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

4. The method of claim 3, wherein the NSRI is selected from the group consisting of aminomethadrine, atomoxetine, CP-39,332, daredarine, edexetine, oxepoxetine, chlortalamin, nisoxetine, reboxetine, talopram, tassopram, tandamine and viloxazine or a pharmaceutically acceptable salt thereof.

5. The method of claim 2, wherein the NRI is a norepinephrine non-selective reuptake inhibitor (NNRI) selected from the group consisting of amitriptyline, amoxapine, bupropion, ciratindol, desipramine, desvenlafaxine, dexmethylphenidate, bupropion, doxepin, duloxetine, imipramine, levomilnacipran, manifaxine, maprotiline, methylphenidate, milnacipran, nefazodone, nortriptyline, phendimetrazine, phendimetrazine, protriptyline, redafaxine, tapentadol, tenisazine and venlafaxine or a pharmaceutically acceptable salt thereof.

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

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

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 method of claim 8, wherein the MRA is selected from the group consisting of cintropine, benztropine, biperiden, cyclidine, cyclimine, dicyclomine, diphenylmanil, diphenidol, profenamide, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methylthioxanthene, methylscopolamine, hydroxybenzylamine, orphenadrine, procyclidine, scopolamine, trimethoprim-sulfamethoxazole and trihexyphenidyl or a pharmaceutically acceptable salt thereof.

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

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

13. 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 1-7, further comprising administering a hypnotic to the subject.

15. The method of claim 14, wherein the hypnotic 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. The method of claim 15, wherein the hypnotic is trazodone or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

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

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

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

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

27. The method of any one of claims 2-25, 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 8-13, wherein the NRI, MRA, and baxdrostat, or a pharmaceutically acceptable salt thereof, are administered as a single composition.

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

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

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

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

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

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

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

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

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

38. The method of any one of claims 1-37, wherein the subject suffers from hypertension.

39. The method of claim 38, wherein the subject suffers from OSA with hypertension.

40. Baxdrostat or a pharmaceutically acceptable salt thereof for use in treating obstructive sleep apnea.

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

42. A therapeutic combination of baxdrostat, or a pharmaceutically acceptable salt thereof, and (a) a norepinephrine reuptake inhibitor (NRI), and optionally a muscarinic receptor antagonist (MRA), or (b) a hypnotic, 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, 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 suffering from a condition associated with pharyngeal airway collapse, the method comprising administering to a subject in need thereof an effective amount of a compound of formula (A): or a pharmaceutically acceptable salt thereof.

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

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

47. The method of claim 46, wherein the NSRI is selected from the group consisting of methadone, atomoxetine, CP-39,332, daredaline, edexetine, oxepoxetine, chlortalamin, nisoxetine, reboxetine, talopram, tassopram, tandamine and viloxazine or a pharmaceutically acceptable salt thereof.

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

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

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

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 pharmaceutically acceptable salts thereof.

53. The method of claim 51, wherein the MRA is selected from the group consisting of cintropine, benztropine, biperiden, cyclamate, cyclimine, dicyclomine, diphenylmanil, diphenidol, profenamide, glycopyrrolate, hexacycline, isopropylamide, mepenzolate, methylthioxanthene, methylscopolamine, hydroxybenzylamine, orphenadrine, procyclidine, scopolamine, trimethoprim-sulfamethoxazole and trihexyphenidyl or a pharmaceutically acceptable salt thereof.

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

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

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

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

58. The method of claim 57, wherein the hypnotic 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. The method of claim 58, wherein the hypnotic is trazodone or a pharmaceutically acceptable salt thereof.

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

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 mg to about 200 mg.

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 mg to about 200 mg.

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

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

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

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

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

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

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

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

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

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

74. The method of any one of claims 70-73, wherein the single composition is in an oral administration form.

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

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

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

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

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

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

81. The method of any one of claims 44-80, wherein the subject suffers from hypertension.

82. The method of claim 81, wherein the subject suffers from OSA with hypertension.

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

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

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

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

93. 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 and a pharmaceutically acceptable carrier or excipient.

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