2,3-Dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives for treating sleep apnea

Abstract

The present invention relates to alpha2-adrenergic receptor subtype C (alpha-2C) antagonists, in particular 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

Description

[Technical field]

[0001] The present invention relates to alpha2-adrenergic receptor subtype C (alpha-2C) antagonists, in particular 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring. [Background technology]

[0002] Obstructive sleep apnea (OSA) is a sleep-related breathing disorder characterized by repeated episodes of upper airway obstruction. During inspiration, upper airway patency is ensured by the interplay of two opposing forces. The dilator action of the upper airway musculature counteracts the negative intraluminal pressure that constricts the lumen. Active contraction of the diaphragm and other accessory respiratory muscles generates negative pressure in the airway and constitutes the drive for breathing. Upper airway stability is substantially determined by the coordination and contractile properties of the upper airway dilator muscles.

[0003] It is believed that upper airway collapse in OSA occurs at sleep onset because of reduced activity of several upper airway dilator muscles, resulting in an inability to maintain the anatomically vulnerable airway open. However, several upper airway dilator muscles, including the most important of the upper airway dilator muscles, the genioglossus, innervated by the hypoglossal nerve, can increase their activity during sleep in response to respiratory stimuli, potentially counteracting some of these changes at sleep onset. It has been observed that OSA patients have apnea-free intervals in which genioglossus muscle activity is only 25-40% higher compared to sleep phases with a higher frequency of obstructive sleep apnea (Jordan AS, White DP, Lo YL et al., Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32(3): 361-8). Noradrenaline is one of the most potent neuromodulators of hypoglossal motoneuron activity (Horner RL Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196). A reduction in noradrenergic drive is thought to lead to a sleep-dependent decrease in hypoglossal motoneuron excitability that leads to reduced upper airway dilator muscle activity, particularly genioglossus muscle activity.

[0004] Alpha 2C-adrenergic receptors regulate the release of noradrenaline from central noradrenergic neurons. They are autoreceptors involved in presynaptic feedback inhibition of noradrenaline (Hein L. et al, Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402(6758): 181-184). Increasing the activity of hypoglossal motor neurons via alpha 2c-adrenergic receptor antagonism stabilizes the upper airway and protects it from collapse and obstruction. Furthermore, snoring can be suppressed via a mechanism of stabilizing the upper airway.

[0005] In simple snoring, there is no obstruction of the upper airway. The narrowing of the upper airway increases the inspiratory and expiratory flow rates. This, along with the relaxed muscles, causes fluttering of the soft tissues of the mouth and throat in the airstream. This slight vibration produces the typical snoring sound.

[0006] Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by recurrent partial obstruction of the upper airway during sleep. This results in increased airway resistance and increased work of breathing with significant intrathoracic pressure fluctuations. Negative intrathoracic pressure development during inspiration can reach values ​​that result from complete airway obstruction in OSA. The pathophysiological effects on the heart, circulation, and sleep quality are the same as in obstructive sleep apnea. The etiology is likely to be the same as in OSA. Obstructive snoring is often a precursor to OSA. (Hollandt JH et al., Upper airway resistance syndrome (UARS)-obstructive snoring. HNO 2000, 48(8): 628-634).

[0007] Central sleep apnea (CSA) occurs as a result of impaired brain function or respiratory control. CSA is characterized by recurrent periods of insufficient respiratory drive, insufficient or absent ventilation, and impaired gas exchange during sleep. CSA has several manifestations. These include high altitude-induced periodic breathing, idiopathic CSA (ICSA), opiate-induced central apnea, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes respiration (CSB). Although the exact triggering mechanisms involved in the various types of CSA may differ considerably, unstable ventilatory drive during sleep is the main underlying feature (Eckert DJ et al., Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607).

[0008] US 2018 / 0235934 A1 describes a method for treating disorders such as obstructive sleep apnea using an agent for promoting excitability of hypoglossal motoneurons. As an agent for promoting excitability of hypoglossal motoneurons, a disinhibitor and / or stimulator of central noradrenergic neurons is described. In some embodiments, the disinhibitor of central noradrenergic neurons is an alpha2-adrenergic receptor antagonist, such as yohimbine or an alpha2-adrenergic receptor subtype A (alpha-2A) antagonist or an alpha2-adrenergic receptor subtype C (alpha-2C) antagonist. The alpha2-adrenergic receptor antagonist is selected from the group consisting of atipamezole, MK-912, RS-79948, RX821002, [3H]2-methoxy-idazoxan, and JP-1302.

[0009] The α2C-adrenergic receptor belongs to the G protein-coupled receptor family. Besides the different α1-adrenergic receptors, there are three different α2-adrenergic receptor subtypes (α2A, α2B, α2C). They are involved in mediating several diverse physiological actions in different tissues upon stimulation by endogenous catecholamines (epinephrine, norepinephrine) induced via synapses or blood. The α2-adrenergic receptors play an important physiological role mainly in the cardiovascular and central nervous systems. The α2A- and α2C-adrenergic receptors are the main autoreceptors involved in the presynaptic feedback inhibition of noradrenaline in the central nervous system. The potency and affinity of noradrenaline at the α2C-adrenergic receptors is higher than that at the α2A-adrenergic receptors. α2C-adrenoceptors inhibit noradrenaline release at low concentrations of endogenous noradrenaline, whereas α2A-adrenoceptors inhibit noradrenaline release at high concentrations of endogenous noradrenaline (Uys MM et al. Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia - New Developments and Future Perspective. Frontiers in Psychiatry 2017, Aug 14;8:144. doi: 10.3389 / fpsyt.2017.00144. eCollection 2017).

[0010] Arylpiperazines as α2-adrenergic receptor subtype C (α-2C) antagonists and their preparations and uses are known from WO 03 / 082866 A1, which discloses that the compounds are useful for treating disorders such as stress, Parkinson's disease, depression, schizophrenia, attention deficit hyperactivity disorder, post-traumatic stress disorder, obsessive-compulsive disorder, Tourette's syndrome, blepharospasm or other focal dystonia, temporal lobe epilepsy with psychosis, drug-induced psychosis, Huntington's disease, disorders caused by fluctuations in the levels of sex hormones, panic disorder, Alzheimer's disease or mild cognitive impairment.No use of these compounds is disclosed for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring.

[0011] The current gold standard treatment for patients with OSA is continuous positive airway pressure (CPAP). Positive airflow generated by an airflow turbine splint opens the upper airway and reverses all potential causes of pharyngeal collapse, thereby preventing hypopnea, apnea, and sleep fragmentation. Unfortunately, up to 50% of all patients with OSA cannot tolerate CPAP for extended periods of time (M. Kohler, D. Smith, V. Tippett et al., Thorax 2010 65(9):829-32: Predictors of long-term compliance with continuous positive airway pressure). [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US 2018 / 0235934 A1 [Patent Document 2] WO 03 / 082866 A1 [Non-patent literature]

[0013] [Non-Patent Document 1] Jordan AS, White DP, Lo YL et al., Airway dilator muscle activity and lung volume during stable breathing in obstructive sleep apnea. Sleep 2009, 32(3): 361-8 [Non-Patent Document 2] Horner RL Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196 [Non-Patent Document 3] Hein L. et al, Two functionally distinct alpha2-adrenergic receptors regulate sympathetic neurotransmission Nature 1999, 402(6758): 181-184 [Non-Patent Document 4] Hollandt JH et al., Upper airway resistance syndrome (UARS)-obstructive snoring. HNO 2000, 48(8): 628-634 [Non-Patent Document 5] Eckert DJ et al., Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607 [Non-Patent Document 6] Uys MM et al. Therapeutic Potential of Selectively Targeting the α2C-Adrenoceptor in Cognition, Depression, and Schizophrenia - New Developments and Future Perspective. Frontiers in Psychiatry 2017, Aug 14;8:144. doi: 10.3389 / fpsyt.2017.00144. eCollection 2017 [Non-Patent Document 7] M. Kohler, D. Smith, V. Tippett et al., Thorax 2010 65(9):829-32: Predictors of long-term compliance with continuous positive airway pressure Summary of the Invention [Problem to be solved by the invention]

[0014] Thus, there remains a need to find effective therapeutic agents for the treatment and / or prevention of sleep-related breathing disorders such as obstructive sleep apnea. It is therefore an object of the present invention to provide effective therapeutic agents for the treatment and / or prevention of sleep-related breathing disorders, such as obstructive sleep apnea, central sleep apnea and snoring. [Means for solving the problem]

[0015] Surprisingly, it has been found that the 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) of the present invention inhibit upper airway collapsibility and are therefore suitable for producing medicaments for use in the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0016] The present invention relates to a compound of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring. [ka] [During the ceremony, A is a 5-membered unsaturated heterocyclic ring containing 1, 2 or 3 ring heteroatoms each independently selected from N, O and S, where the heterocyclic ring is unsubstituted, or the heterocyclic ring is substituted with 1 substituent R1, or the heterocyclic ring is substituted with 2 substituents R1 and R2, or the heterocyclic ring is substituted with 3 substituents R1, R2 and R3, or the heterocyclic ring is substituted with 4 substituents R1, R2, R3 and R4; R1 is (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (C1-C6)alkyl-(C=O)-, R5R6N-, R5R6N-(C=O)-, R6(C=O)-R5N-, heterocyclyl, heterocyclyl-N- or phenyl-N-, wherein the heterocyclyl or phenyl is optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6)alkyl, (C1-C6)alkoxy, oxo or phenyl(C1-C6)alkoxy; R2 is (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl; R3 is (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl; R4 is (C1-C6) alkyl; R5 is H or (C1-C6)alkyl; and R6 is H or (C1-C6)alkyl; or R1 and R2 together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms (wherein the heteroatoms are N); However, A is not 1,2,3-oxadiazol-3-ium-3-yl. or a pharma- ceutically acceptable salt or ester thereof.

[0017] In one embodiment, the present disclosure relates to a compound of formula 1, wherein the compound has formula Ia [ka] It is a compound represented by the formula:

[0018] In one embodiment, the present disclosure relates to a compound of formula 1, wherein ring A is [ka] [Where: Z is N, O or S; and Atoms marked with * are attached to the parent molecular moiety. It is one of the following:

[0019] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein R1 is (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (C1-C6)alkyl-(C=O)-, R5R6N-, R5R6N-(C=O)-, R6(C=O)-R5N-, phenyl-N-, or any of the following groups: [ka] [Where: Atoms marked with an * are attached to the parent molecular moiety; and Groups (1') to (11') may be substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6) alkyl, (C1-C6) alkoxy, oxo or phenyl(C1-C6) alkoxy. It is one of the following:

[0020] In one embodiment, the present disclosure relates to a compound of formula 1, wherein ring A is any one of groups (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21), or (22), wherein groups (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), ( 11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21) or (22) is unsubstituted or the group (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21) or (22) is substituted by one substituent R1; or groups (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21) or (22) are substituted with two substituents R1 and R2 or groups (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15) , (16), (17), (18), (19), (20), (21) or (22) is substituted with three substituents R1, R2 and R3, or groups (1), (2), (3), (4), (5), (6), (7), (8), (9), (10), (11), (12), (13), (14), (15), (16), (17), (18), (19), (20), (21) or (22) is substituted with four substituents R1, R2, R3 and R4; R1 is (C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (C1-C6)alkyl-(C=O)-, R5R6N-, R5R6N-(C=O)-, R6(C=O)-R5N-, phenyl-N-, or a group (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8' ), (9'), (10') or (11'), wherein the phenyl or group (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9'), (10') or (11') is optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6)alkyl, (C1-C6)alkoxy, oxo or phenyl(C1-C6)alkoxy; R2 is (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl; R3 is (C1-C6)alkyl, (C1-C6)alkoxy or (C1-C6)alkoxy(C1-C6)alkyl; R4 is (C1-C6) alkyl; R5 is H or (C1-C6)alkyl; and R6 is H or (C1-C6)alkyl; Or, R1 and R2 together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms (wherein the heteroatoms are N).

[0021] In one embodiment, the present disclosure relates to a compound of formula 1, wherein ring A is any one of groups (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10), wherein groups (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10) are unsubstituted or substituted with groups (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) is substituted with one substituent R1, or the group (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) is substituted with two substituents R1 and R2, or the group (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) is substituted with three substituents R1, R2 and R3; R1 is hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (C1-C6)alkyl-(C=O)-, R5R6N-(C=O)-, R6(C=O)-R5N- or a group (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or ( 10'), wherein groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10') are optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6)alkyl, (C1-C6)alkoxy, oxo or phenyl(C1-C6)alkoxy; R2 is (C1-C6) alkyl; R3 is (C1-C6) alkyl; R5 is H or (C1-C6)alkyl; and R6 is H or (C1-C6)alkyl; Or, R1 and R2 together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing one heteroatom (wherein the heteroatom is N).

[0022] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein ring A is any one of groups (1), (2), (4), (7), (8), (9) or (10), wherein group (1), (2), (4), (7), (8), (9) or (10) is substituted with one substituent R1, or group (1), (2), (4), (7), (8), (9) or (10) is substituted with two substituents R1 and R2, or group (1), (2), (4), (7), (8), (9) or (10) is substituted with three substituents R1, R2 and R3; R1 is (C1-C6)alkoxy(C1-C6)alkyl, R5R6N-(C=O)-, or any one of groups (2'), (4'), (5') or (9'), where groups (2'), (4'), (5') or (9') are optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6)alkyl or oxo; R2 is (C1-C6) alkyl; R3 is (C1-C6) alkyl; R5 is (C1-C6) alkyl; and R6 is (C1-C6) alkyl.

[0023] In one embodiment, the present disclosure relates to a compound of formula 1, wherein ring A is [ka] Any one of the following: R1 is hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy-(C=O)-, CN, (C1-C6)alkyl-(C=O)-, R5R6N-(C=O)-, R6(C=O)-R5N- or a group (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or ( 10'), wherein groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10') are optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently (C1-C6)alkyl, (C1-C6)alkoxy, oxo or phenyl(C1-C6)alkoxy; R2 is (C1-C6) alkyl; R3 is (C1-C6) alkyl; R5 is H or (C1-C6)alkyl; and R6 is H or (C1-C6)alkyl; Or, R1 and R2 together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing one heteroatom (wherein the heteroatom is N).

[0024] In one embodiment, the present disclosure relates to a compound of formula 1, wherein ring A is [ka] Any one of the following: R1 is R5R6N-(C=O)- or any one of groups (2'), (4'), (5') or (9'), where groups (2'), (4'), (5') or (9') are optionally substituted with 1, 2 or 3 substituents, each of which is independently (C1-C3) alkyl or oxo; R2 is (C1-C3) alkyl; R3 is (C1-C3) alkyl; R5 is (C1-C3) alkyl; and R6 is (C1-C3) alkyl.

[0025] In one embodiment, the disclosure relates to a compound represented by formula 1, wherein the compound is (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,3-dimethylpyrrolidine-2,5-dione, (S)-2-(3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)isoindoline-1,3-dione, (S)-5-( 4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-2-methyloxazole-4-carbonitrile, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)azetidin-2-one, (S)-3-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)o xazolidin-2-one, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-4,4-dimethylimidazolidin-2-one, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,4,4-trimethylimidazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b] [1,4]dioxin-2-yl)methyl)piperazin-1-yl)-5-(methoxymethyl)thiazole, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)imidazolidin-2-one, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine,4]dioxin-2-yl)methyl)-4-(4-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-3-yl)piperazine, (S)-ethyl 3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate, (S)-2-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)propan-2-ol, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl) (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiazol-4-yl)pyrrolidin-2-one, (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiazol-4-yl)pyrrolidin-2-one, (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiazol-4-yl)pyrrolidin-2-one (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-2-yl)-1,2,5-thiadiazol-3-yl)-3,3-dimethylpyrrolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-2-yl)-1,2,5-thiadiazol-3-amine, (S)-4-(4-((2,3- dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-4-yl)-1,2,5-thiadiazol-3-amine, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)thiazol-4-yl)pyrrolidin-2-one, 1-(4-(4-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-Thiadiazol-3-yl)-3-methylpyrrolidin-2-one, (S)-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazole, (S)-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-5-(methoxymethyl)-1,2,4-oxazin- Azoles, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-piperazin-1-yl)-1,2,5-thiadiazol-3-yl)pyrrolidin-2-ones, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)imidazolides 3-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)oxazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)oxazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-carboxamide, (S )-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)-3-methylimidazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-methyl-1,2,5-thiadiazole-3-carboxamide Hydrochloride, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)imidazolidin-2-one, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-3-methyl-isothiazol-4-yl)pyrrolidin-2-one, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-piperazin-1-yl)-2-methylthiazol-5-yl)-3,3-Dimethylpyrrolidine-2,5-dione hydrochloride, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)ethanone, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N,N-dimethyl-1,2,5-thiadiazole-3-carboxamide, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyridin-4-yl)-1,2,5-thiadiazol-3-amine Dihydrochloride, (S)-3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)isothiazolo[4,5-b]pyridine hydrochloride, (S)-N-(2-(benzyloxy)pyridin-3-yl)-4-(4-((2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-amine The hydrochloride salt is (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(6-methoxypyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine, or (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl)piperazine.

[0026] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0027] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0028] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0029] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0030] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0031] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0032] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0033] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0034] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0035] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] or a pharma- ceutically acceptable salt thereof.

[0036] In one embodiment, the present disclosure relates to a compound represented by formula 1, wherein the compound is [ka] It is.

[0037] Terms used in this specification have the meanings given below.

[0038] As used below, the term "at least one" refers to one or more (eg, 1).

[0039] The term "hydroxy" as used herein by itself or as part of another group refers to an --OH group.

[0040] The term "oxo" as used herein by itself or as part of another group refers to a =O group attached as a substituent.

[0041] The term "(C1-C6) alkyl" as used herein by itself or as part of another group refers to a saturated hydrocarbon group having straight or branched chain portions containing 1, 2, 3, 4, 5, or 6 carbon atoms. Representative examples of (C1-C6) alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, n-pentyl, iso-pentyl, and n-hexyl.

[0042] The term "(C1-C3)alkyl" as used herein by itself or as part of another group refers to a saturated hydrocarbon group having straight or branched chain portions containing 1, 2 or 3 carbon atoms. Representative examples of (C1-C3)alkyl include, but are not limited to, methyl, ethyl, n-propyl and iso-propyl.

[0043] The term "(C1-C6)alkoxy" as used herein by itself or as part of another group refers to a (C1-C6)alkyl group, as defined herein, attached to an oxygen atom. Representative examples of (C1-C6)alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, 2,2-dimethylpropoxy, 3-methylbutoxy, and n-hexoxy.

[0044] The term "hydroxy(C1-C6)alkyl" as used herein by itself or as part of another group refers to at least one hydroxy group, as defined herein, attached to a (C1-C6)alkyl group, as defined herein. Representative examples of hydroxy(C1-C6)alkyl include, but are not limited to, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 2,2-dihydroxyethyl, 1-hydroxypropyl, 3-hydroxypropyl, 1-hydroxy-1-methylethyl, and 1-hydroxy-1-methylpropyl.

[0045] The term "(C1-C6)alkoxy(C1-C6)alkyl" as used herein by itself or as part of another group refers to at least one (C1-C6)alkoxy group, as defined herein, attached to a (C1-C6)alkyl group, as defined herein. When multiple (C1-C6)alkoxy groups are present, the (C1-C6)alkoxy groups can be the same or different. Representative examples of (C1-C6)alkoxy(C1-C6)alkyl include, but are not limited to, methoxymethyl, ethoxymethyl, propoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2,2-dimethoxyethyl, 1-methyl-2-propoxyethyl, 1-methoxy-1-methylethyl, and 4-methoxybutyl.

[0046] The term "(C1-C6)alkyl-(C=O)" as used herein by itself or as part of another group refers to a (C1-C6)alkyl group, as defined herein, attached to a carbonyl group. Representative examples of (C1-C6)alkyl-(C=0) include, but are not limited to, acetyl, ethylcarbonyl, propylcarbonyl, and isopropylcarbonyl.

[0047] The term "(C1-C6)alkoxy-(C=O), as used herein by itself or as part of another group, refers to a (C1-C6)alkoxy group, as defined herein, attached to a carbonyl group. Representative examples of (C1-C6)alkoxy-(C=O) include, but are not limited to, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, and isopropoxycarbonyl.

[0048] The term "phenyl(C1-C6)alkoxy" as used herein by itself or as part of another group refers to a phenyl group linked to a (C1-C6)alkoxy group, as defined herein. Representative examples of phenyl(C1-C6)alkoxy include, but are not limited to, phenylmethoxy, 2-phenylethoxy, and 3-phenylpropoxy.

[0049] The term "heterocyclyl" as used herein by itself or as part of another group refers to a 4-, 5-, or 6-membered saturated or unsaturated monocyclic group containing 1 or 2 ring heteroatoms, each independently selected from N and O, or a 9- or 10-membered saturated or unsaturated bicyclic group containing 1 or 2 ring heteroatoms, each independently selected from N and O. Representative examples of heterocyclyl include, but are not limited to, azetidin-1-yl, pyrrolidin-1-yl, oxazolidin-3-yl, imidazolidin-1-yl, piperidin-1-yl, morpholin-4-yl, pyrazol-1-yl, isoindolin-2-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, pyrimidin-2-yl, and pyrimidin-4-yl.

[0050] As used herein, the phrase "compounds of the disclosure" refers to compounds according to Formula I.

[0051] The compounds of the present invention include compounds represented by formula (I) and salts thereof, solvates and solvates of salts thereof, compounds included in formula (I) and represented by the following formulas and salts thereof, solvates and solvates of salts thereof, and compounds included in formula (I) and cited below as examples and salts thereof, solvates and solvates of salts thereof (unless the compounds included in formula (I) and described below are already salts, solvates or solvates of salts).

[0052] Compounds of the present invention likewise include the N-oxides and S-oxides of compounds of formula (I), as well as the salts, solvates and solvates of the salts thereof.

[0053] In the context of the present invention, preferred salt are physiologically acceptable salts of the compounds according to the invention. Also included are salts which are not themselves suitable for pharmaceutical applications but which can be used, for example, for the isolation, purification or storage of the compounds of the invention.

[0054] Suitable pharma- ceutically acceptable salts of the compounds of the invention can be, for example, acid addition salts of compounds of the invention having a sufficiently basic nitrogen atom in the chain or ring, for example, acid addition salts with inorganic or "mineral acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, bisulfuric acid, phosphoric acid or nitric acid, or with formic acid, acetic acid, acetoacetic acid, pyruvic acid, trifluoroacetic acid, propionic acid, butyric acid, hexanoic acid, heptanoic acid, undecanoic acid, lauric acid, benzoic acid, salicylic acid, 2-(4-hydroxybenzoyl)benzoic acid, camphoric acid, cinnamic acid, cyclopentanepropionic acid, digluconic acid, 3-hydroxy-2-naphthoic acid, nicotinic acid, pamoic acid, benzyl alcohol, ethyl ... and the like. The salts may be acid addition salts with organic acids such as cis acid, 3-phenylpropionic acid, pivalic acid, 2-hydroxyethanesulfonic acid, itaconic acid, trifluoromethanesulfonic acid, dodecylsulfuric acid, ethanesulfonic acid, benzenesulfonic acid, para-toluenesulfonic acid, methanesulfonic acid, 2-naphthalenesulfonic acid, naphthalenedisulfonic acid, camphorsulfonic acid, citric acid, tartaric acid, stearic acid, lactic acid, oxalic acid, malonic acid, succinic acid, malic acid, adipic acid, alginic acid, maleic acid, fumaric acid, D-gluconic acid, mandelic acid, ascorbic acid, glucoheptanoic acid, glycerophosphoric acid, aspartic acid, sulfosalicylic acid, or thiocyanic acid.

[0055] Further suitable pharma- ceutically acceptable salts of the sufficiently acidic compounds of the present invention include alkali metal salts, such as sodium or potassium salts, alkaline earth metal salts, such as calcium, magnesium or strontium salts, or aluminum or zinc salts, or ammonium salts derived from ammonia or from organic primary, secondary or tertiary amines having 1-20 carbon atoms, such as ethylamine, diethylamine, triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine, triethanolamine, dicyclohexylamine, dimethylaminoethanol, diethylaminoethanol, tris(hydroxymethyl)aminomethane, Procaine, dibenzylamine, N-methylmorpholine, arginine, lysine, 1,2-ethylenediamine, N-methylpiperidine, N-methylglucamine, N,N-dimethylglucamine, N-ethylglucamine, 1,6-hexanediamine, glucosamine, sarcosine, serinol, 2-amino-1,3-propanediol, 3-amino-1,2-propanediol, 4-amino-1,2,3-butanetriol, or a salt with a quaternary ammonium ion having 1 to 20 carbon atoms, such as a salt with tetramethylammonium, tetraethylammonium, tetra(n-propyl)ammonium, tetra(n-butyl)ammonium, N-benzyl-N,N,N-trimethylammonium, choline or benzalkonium.

[0056] Those skilled in the art will further recognize that acid addition salts of the claimed compounds can be prepared by reacting the compounds with an appropriate inorganic or organic acid via any of a number of known methods. Alternatively, alkali metal and alkaline earth metal salts of acidic compounds of the invention are prepared by reacting the compounds of the invention with the appropriate base via a variety of known methods.

[0057] The present invention includes all possible salts of the compounds of the present invention, either as single salts or as any mixture of said salts in any ratio.

[0058] Pharmaceutically acceptable esters can be prepared, where applicable, by known methods using pharma- ceutically acceptable acids that are conventional in the pharmaceutical field and that retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols. Representative examples of pharma-ceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl and benzyl esters.

[0059] The present disclosure encompasses all possible geometric isomers (e.g., cis and trans isomers) of the compounds of formula I and all possible optical isomers (e.g., diastereomers and enantiomers) of the compounds of formula I. Furthermore, the present disclosure encompasses all individual isomers and any mixtures thereof (e.g., racemic mixtures). The individual isomers can be obtained using the corresponding isomeric forms of the starting materials or they can be separated after preparation of the final compounds according to conventional separation methods. To separate optical isomers, such as enantiomers, from their mixtures, conventional resolution methods can be used, such as, for example, fractional crystallization or preparative chiral chromatography.

[0060] The compounds of formula (I) and their pharma- ceutically acceptable salts and esters are hereinafter referred to as compounds of the invention, unless otherwise indicated.

[0061] The present invention includes within its scope all possible stereoisomers of the compounds (e.g., geometric isomers, e.g., Z and E isomers (cis and trans isomers), and optical isomers, e.g., diastereomers and enantiomers). Furthermore, the present invention includes within its scope both the individual isomers and any mixtures thereof (e.g., racemic mixtures). The individual isomers can be obtained using the corresponding isomeric forms of the starting materials or they can be separated after preparation of the final compounds according to conventional separation methods. For separating optical isomers, such as enantiomers, from their mixtures, conventional resolution methods, such as, for example, fractional crystallization, can be used.

[0062] Pharmaceutically acceptable salts, such as acid addition salts with both organic and inorganic acids, are well known in the pharmaceutical field. Non-limiting examples of these salts include chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates and ascorbic acid salts. Pharmaceutically acceptable esters, where applicable, can be prepared in known manner using pharmaceutical acceptable acids that are conventional in the pharmaceutical field and retain the pharmacological properties of the free form. Non-limiting examples of these esters include esters of aliphatic or aromatic alcohols, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and tert-butyl esters.

[0063] The compounds of formula (I) and formula (II), their preparation and their action as α2C antagonists for treating diseases or conditions of the peripheral or central nervous system are generally disclosed in WO2016193551, in particular said compounds being an explicit part of the description of the present invention and are incorporated herein by reference.

[0064] As used herein, the term "effective amount" refers to an amount of a compound of formula (I) effective for treating and / or preventing sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0065] The present invention relates to (alpha-2C) antagonists, in particular 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0066] The present invention further relates to the use of compounds of formula (I) for the manufacture of a medicament for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0067] A further object of the present invention is the use of a combination of one or more compounds of formula (I) with one or more other active compounds in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0068] A further object of the present invention is a pharmaceutical composition comprising at least one compound of formula (I) in combination with one or more inert, non-toxic, pharma- ceutical suitable excipients for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0069] The present invention further relates to pharmaceutical compositions comprising the combination with one or more other active compounds in combination with one or more inert, non-toxic, pharma- ceutical suitable excipients for use in methods for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0070] The present invention is further directed to a method for treating and / or preventing sleep-related breathing disorders, wherein the method is by systemic and / or local administration of a therapeutically effective amount of at least one compound of formula (I) or a therapeutically effective amount of a medicament comprising at least one compound of formula (I) in combination with an inert, non-toxic, pharma- ceutical acceptable excipient.

[0071] A further object of the present invention is a combination of one or more compounds of formula (I) with one or more other active compounds for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0072] The 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) according to the present invention can be used alone or, if necessary, in combination with one or more other pharmacologically active substances, provided that the combination does not result in undesirable and unacceptable side effects. Preferred examples of combinations suitable for the purpose of treating sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring, include: Respiratory stimulants such as, by way of example and preferably, theophylline, doxapram, nikethamide or caffeine; psychostimulants, such as, by way of example and preferably, modafinil or armodafinil; Amphetamine and amphetamine derivatives, such as, by way of example and preferably, amphetamine, methamphetamine or methylphenidate; Serotonin reuptake inhibitors, such as, by way of example and preferably, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone; Serotonin precursors, such as, by way of example and preferably, L-tryptophan; selective serotonin-noradrenaline reuptake inhibitors, such as, by way of example and preferably, venlafaxine or duloxetine; noradrenergic and specific serotonergic antidepressants, such as, by way of example and preferably, mirtazapine; selective noradrenaline reuptake inhibitors, such as, by way of example and preferably, reboxetine or atomoxetine; tricyclic antidepressants, such as, by way of example and preferably, amitriptyline, protriptyline, doxepin, trimipramine, imipramine, clomipramine or desipramine; Muscarinic receptor antagonists, for example and preferably oxybutynin; GABAergic drugs, such as, by way of example and preferably, baclofen; Glucocorticoids, such as, by way of example and preferably, fluticasone, budesonide, beclomethasone, mometasone, tixocortol or triamcinolone; · Cannabinoid receptor agonists; TASK channel blockers, for example and preferably generally and in particular those disclosed in WO2017 / 097792A1, WO2017 / 097671A1, WO2018 / 015196A1, WO2018 / 228907A1 and WO2018 / 228909A1; carboanhydrase inhibitors, such as, by way of example and preferably, acetazolamide, methazolamide or diclophenamide; Opioid and benzodiazepine receptor antagonists, such as, by way of example and preferably, flumazenil, naloxone or naltrexone; cholinesterase inhibitors, such as, by way of example and preferably, neostigmine, pyridostigmine, physostigmine, donepezil, galantamine or, by way of example and preferably, rivastigmine; appetite suppressants such as, by way of example and preferably, sibutramine, opiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists; Mineralocorticoid receptor antagonists.

[0073] A preferred subject of the present invention is a combination of one or more compounds of formula (I) or (II) with one or more other active compounds selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, TASK channel blockers, diuretics, corticosteroids, for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

[0074] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a muscarinic receptor antagonist, by way of example and preferably oxybutynin.

[0075] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a TASK channel blocker (for example and preferably in general and in particular WO2017 / 097792A1, WO2017 / 097671A1, WO2018 / 015196A1, WO2018 / 228907A1 and WO2018 / 228909A1).

[0076] In a preferred embodiment of the invention, the inventive compounds are administered in combination with a mineralocorticoid receptor antagonist (by way of example and with preference spironolactone, eplerenone or finerenone).

[0077] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a diuretic (by way of example and with preference furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide, hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, trichlormethiazide, chlorthalidone, indapamide, metolazone, quinethazone, acetazolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol, amiloride or triamterene).

[0078] In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a corticosteroid (by way of example and with preference prednisone, prednisolone, methylprednisolone, triamcinolone, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or fluticasone).

[0079] If necessary, the 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) according to the invention can also be used in conjunction with the use of one or more medical technical devices or auxiliary devices, provided that they do not result in undesirable and unacceptable side effects. Medical devices and auxiliary devices suitable for such combined application are, by way of example and preferably, the following: Devices for positive airway pressure ventilation, such as, by way of example and preferably, CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Bilevel Positive Airway Pressure) devices and IPPV (Intermittent Positive Airway Pressure Ventilation) devices; · Hypoglossal nerve stimulator; Intra-oral appliances, such as, for example and preferably, protrusion braces; · Disposable nasal valves; Nasal stents.

[0080] The 2,3-dihydrobenzo[b][1,4]dioxin-2-ylmethyl)piperazin-1-yl derivatives of formula (I) according to the present invention can act systemically and / or locally.To this end, they can be administered in a suitable manner, for example by oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, cutaneous, transdermal, conjunctival or auricular route, or as an implant or stent.

[0081] A further object of the present invention are pharmaceutical compositions comprising a compound of formula (I) for systemic and / or local administration by oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or auricular routes or as an implant or stent. The preferred administration route is the oral route.

[0082] For these administration routes, the compounds according to the invention can be administered in suitable dosage forms.

[0083] For oral administration, suitable are administration forms which contain the compound according to the invention in crystalline and / or amorphous and / or dissolved form and which release the compound according to the invention rapidly and / or in a modified manner, such as tablets (uncoated or coated, which have a controlled release of the compound according to the invention, e.g. a gastric juice-resistant or slow-dissolving or insoluble coating), tablets which disintegrate quickly in the oral cavity, or films / wafers, films / lyophilisates, capsules (e.g. hard or soft gelatin capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions.

[0084] Parenteral administration can be performed without the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal or intralumbar administration) or with absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration). Suitable dosage forms for parenteral administration include injections and infusions in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

[0085] For other routes of administration, e.g. inhalation formulations (e.g. powder inhalers and nebulizers), nasal solutions, nasal solutions or nasal sprays, lingual, sublingual or buccal tablets, tablets, films / wafers or capsules, suppositories, oral or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shakeable mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. bandages), emulsions, pastes, foams, powders, implants or stents are suitable.

[0086] Oral or parenteral administration, particularly oral and intravenous administration, is preferred.

[0087] The compound according to the present invention can be converted into the described dosage forms.This can be carried out in a manner known per se by mixing with inert, non-toxic, pharma- ceutically suitable additives.These additives include carriers (e.g., microcrystalline cellulose, lactose, mannitol), solvents (e.g., liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g., polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers (e.g., antioxidants, e.g., ascorbic acid), colorants (e.g., inorganic pigments, e.g., iron oxides) and flavors or odor correctors.

[0088] In general, to achieve effective results in parenteral administration, it has proven advantageous to administer amounts of about 0.001 to 10 mg / kg body weight, preferably about 0.01 to 1 mg / kg body weight. In oral administration, the dosage is about 0.01 to 100 mg / kg body weight, preferably about 0.01 to 20 mg / kg body weight, very particularly preferably 0.1 to 15 mg / kg body weight.

[0089] Nevertheless, in some cases, it may be necessary to deviate from the above amounts, i.e. depending on the body weight, the route of administration, the individual response to the active substance, the nature of the formulation, and the time or interval during which the administration takes place. Thus, in some cases, it may be sufficient to administer amounts less than the minimum amounts mentioned, whereas in other cases the upper limits mentioned may have to be exceeded. If larger amounts are administered, it may be advisable to administer them individually in several divided doses throughout the day.

[0090] The following examples are illustrative of the invention, but are not intended to limit the invention. EXAMPLES

[0091] Working Example A. Experimental Method The advantageous pharmacological properties of the compounds of this invention can be confirmed by the following procedures.

[0092] The therapeutic potential of the compounds of formula (I) according to the present invention in sleep apnea can be assessed preclinically in a porcine model of obstructive sleep apnea (OSA).

[0093] By using negative pressure, it is possible to induce collapse and therefore obstruction of the upper airway in anesthetized, spontaneously breathing pigs (Wirth KJ et al., Sleep 36(5) (2013) pp. 699-708).

[0094] The model uses German Landrace pigs. The pigs are anesthetized and the tracheotomy is performed. Two tracheal tubes are inserted into the trachea, one in the rostral part of the trachea and the other in the caudal part. Using a connecting piece, the rostral cannula is connected to a tube to a negative pressure device and to a distal tracheal cannula. The distal tracheal cannula is further connected to a tube with an open end through a connecting piece that serves for free tracheal breathing, bypassing the upper airway. By appropriately opening and clamping these tubes, it is possible to switch breathing from nasal breathing to breathing through the caudal tracheal cannula, thereby bypassing the upper airway and connecting the (separated) upper airway to the negative pressure device, and inducing airflow in the inspiratory direction.

[0095] At specific time points, the collapsibility of the upper airway is tested by having the pigs breathe through a caudal cannula and applying negative pressures of -50, -100, and -150 cm of water (cm H2O) to the upper airway. This causes the upper airway to collapse, which is manifested as an obstruction of airflow and a drop in pressure in the tubing system. This test is performed before and at specific intervals after administration of the test substance. A suitably effective test substance will prevent this airway collapse during the inspiratory phase.

[0096] In this pig model of OSA, the α2-adrenergic receptor subtype C (α2C) antagonist represented by formula (I) was administered at an IC 50 Systemic administration of an appropriate dose reaching 100 mg / kg / day is expected to inhibit upper airway collapse.

Claims

1. A compound of formula (I) for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring. 【Chemistry 1】 [During the ceremony, A is a 5-membered unsaturated heterocyclic ring containing 1, 2 or 3 ring heteroatoms each independently selected from N, O and S, where the heterocyclic ring is unsubstituted or contains one substituent R １ or the heterocyclic ring is substituted with two substituents R １ and R ２ or the heterocyclic ring is substituted with 3 substituents R １ , R ２ and R ３ or the heterocyclic ring is substituted with 4 substituents R １ , R ２ , R ３ and R ４ is substituted with; R １ (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-, CN, (C １ -C ６ ) alkyl-(C=O)-, R ５ R ６ N-, R ５ R ６ N-(C=O)-, R ６ (C=O)-R ５ N-, heterocyclyl, heterocyclyl-N-, or phenyl-N-, wherein the heterocyclyl or phenyl is optionally substituted with 1, 2, 3, or 4 substituents, each of which is independently selected from the group consisting of (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, oxo or phenyl (C １ -C ６ ) alkoxy; R ２ (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy or (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; R ３ (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy or (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl; R ４ (C １ -C ６ ) alkyl; R ５ is H or (C １ -C ６ ) alkyl; and R ６ is H or (C １ -C ６ ) alkyl; Or, R １ and R ２ together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing 1 or 2 heteroatoms, where said heteroatoms are N; However, A is not 1,2,3-oxadiazol-3-ium-3-yl. or a pharma- ceutically acceptable salt or ester thereof.

2. The compound has the formula (Ia) 【Chemistry 2】 2. The compound according to claim 1, or a pharma- ceutically acceptable salt or ester thereof, for use in a method for treating and / or preventing a sleep-related breathing disorder (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being represented by the formula:

3. Ring A is the following group 【Chemistry 3】 [Where: Z is N, O or S; and Atoms marked with an * are attached to the parent molecular moiety.

3. A compound according to claim 1 or 2, or a pharma- ceutically acceptable salt or ester thereof, for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring, the compound being any one of the following:

4. R １ However, (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-, CN, (C １ -C ６ ) alkyl-(C=O)-, R ５ R ６ N-, R ５ R ６ N-(C=O)-, R ６ (C=O)-R ５ N-, phenyl-N-, or 【Chemistry 4】 [Where: The atom marked with an * is attached to the parent molecular moiety; and The groups (1′) to (11′) may be substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, oxo or phenyl (C １ -C ６ ) alkoxy.

4. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof, for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), wherein the compound is any one of

5. Ring A is any one of groups (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10), where group (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10) is unsubstituted or group (1), (2), (3), (4), (5), (6), (7), (8), (9), or (10) is substituted with one substituent R １ or the group (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) is substituted with two substituents R １ and R ２ or the group (1), (2), (3), (4), (5), (6), (7), (8), (9) or (10) is substituted with the substituent R １ , R ２ and R ３ is substituted with; R １ is hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-, CN, (C １ -C ６ ) alkyl-(C=O)-, R ５ R ６ N-(C=O)-, R ６ (C=O)-R ５ N- or any one of the groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10'), wherein the groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10') are optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, oxo or phenyl (C １ -C ６ ) alkoxy; R ２ (C １ -C ６ ) alkyl; R ３ (C １ -C ６ ) alkyl; R ５ is H or (C １ -C ６ ) alkyl; and R ６ is H or (C １ -C ６ ) alkyl; Or, R １ and R ２ together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing one heteroatom, where said heteroatom is N; A compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring).

6. Ring A is any one of groups (1), (2), (4), (7), (8), (9) or (10), where group (1), (2), (4), (7), (8), (9) or (10) is one substituent R １ or the group (1), (2), (4), (7), (8), (9) or (10) is substituted with two substituents R １ and R ２ or the group (1), (2), (4), (7), (8), (9) or (10) is substituted with three substituents R １ , R ２ and R ３ is substituted with; R １ (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, R ５ R ６ N-(C=O)- or any one of groups (2'), (4'), (5') or (9'), wherein group (2'), (4'), (5') or (9') is optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of (C １ -C ６ ) alkyl or oxo; R ２ (C １ -C ６ ) alkyl; R ３ (C １ -C ６ ) alkyl; R ５ (C １ -C ６ ) alkyl; and R ６ (C １ -C ６ ) alkyl; A compound according to any one of claims 1 to 5 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring).

7. Ring A is the following group 【Chemistry 5】 any one of the following: R １ is hydroxy (C １ -C ６ ) alkyl, (C １ -C ６ ) Alkoxy (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy-(C=O)-, CN, (C １ -C ６ ) alkyl-(C=O)-, R ５ R ６ N-(C=O)-, R ６ (C=O)-R ５ N- or any one of the groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10'), wherein the groups (1'), (2'), (3'), (4'), (5'), (6'), (7'), (8'), (9') or (10') are optionally substituted with 1, 2, 3 or 4 substituents, each of which is independently selected from the group consisting of (C １ -C ６ ) alkyl, (C １ -C ６ ) alkoxy, oxo or phenyl (C １ -C ６ ) alkoxy; R ２ (C １ -C ６ ) alkyl; R ３ (C １ -C ６ ) alkyl; R ５ is H or (C １ -C ６ ) alkyl; and R ６ is H or (C １ -C ６ ) alkyl; Or, R １ and R ２ together with the ring atoms to which they are attached form a fused 6-membered unsaturated heterocyclic ring containing one heteroatom, where said heteroatom is N; A compound according to any one of claims 1 to 4 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring).

8. Ring A is the following group 【Chemistry 6】 any one of the following: R １ is R ５ R ６ N-(C=O)- or any one of groups (2'), (4'), (5') or (9'), wherein group (2'), (4'), (5') or (9') is optionally substituted with 1, 2 or 3 substituents, each of which is independently selected from the group consisting of (C １ -C ３ ) alkyl or oxo; R ２ (C １ -C ３ ) alkyl; R ３ (C １ -C ３ ) alkyl; R ５ (C １ -C ３ ) alkyl; and R ６ (C １ -C ３ ) alkyl; 9. A compound according to claim 8 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

9. The compound is, for example, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,3-dimethylpyrrolidine-2,5-dione, (S)-2-(3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)isoindoline-1,3-dione, (S)-5-(4-((2,3-dihydrobenzo[b][1,4 ]dioxin-2-yl)methyl)piperazin-1-yl)-2-methyloxazole-4-carbonitrile, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)azetidin-2-one, (S)-3-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)oxazolidin-2-one, (S) -1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-4,4-dimethylimidazolidin-2-one, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,4,4-trimethylimidazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3,4,4-trimethylimidazolidin-2-one (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)imidazolidin-2-one, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine,4]dioxin-2-yl)methyl)-4-(4-(methoxymethyl)-1,5-dimethyl-1H-pyrazol-3-yl)piperazine, (S)-ethyl 3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazole-4-carboxylate, (S)-2-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)propan-2-ol, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)- (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiazol-4-yl)pyrrolidin-2-one, (S)-1-(3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,5-dimethyl-1H-pyrazol-4-yl)-3-methylimidazolidin-2-one, (S)-N-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiazol-4-yl)pyrrolidin-2-one (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-2-yl)-1,2,5-thiadiazol-3-yl)-3,3-dimethylpyrrolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-2-yl)-1,2,5-thiadiazol-3-amine, (S)-4-(4-((2,3- dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyrimidin-4-yl)-1,2,5-thiadiazol-3-amine, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)thiazol-4-yl)pyrrolidin-2-one, 1-(4-(4-(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-Thiadiazol-3-yl)-3-methylpyrrolidin-2-one, (S)-2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazole, (S)-3-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-5-(methoxymethyl)-1,2,4-oxazin- Azole, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-piperazin-1-yl)-1,2,5-thiadiazol-3-yl)pyrrolidin-2-one, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,3,4-thiadiazol-2-yl)imidazolide (S)-3-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)oxazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)oxazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazole-3-carboxamide, (S )-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)-3-methylimidazolidin-2-one, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-methyl-1,2,5-thiadiazole-3-carboxamide Hydrochloride, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)imidazolidin-2-one, (S)-1-(5-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-3-methyl-isothiazol-4-yl)pyrrolidin-2-one, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-piperazin-1-yl)-2-methylthiazol-5-yl)-3,3-Dimethylpyrrolidine-2,5-dione hydrochloride, (S)-1-(4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-yl)ethanone, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N,N-dimethyl-1,2,5-thiadiazole-3-carboxamide, (S)-4-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-N-(pyridin-4-yl)-1,2,5-thiadiazol-3-amine dihydrochloride, (S)-3-(4-((2,3-dihydrobenzo-[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)isothiazolo[4,5-b]pyridine hydrochloride, (S)-N-(2-(benzyloxy)pyridin-3-yl)-4-(4-((2,3-dihydrobenzo[b][1,4]-dioxin-2-yl)methyl)piperazin-1-yl)-1,2,5-thiadiazol-3-amine hydrochloride, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(pyridin-2-yl)-1H-pyrazol-5-yl)piperazine, (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(1-(6-methoxypyridin-2-yl)-3-methyl-1H-pyrazol-5-yl)piperazine, or (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-methyl-1-(6-methylpyridin-2-yl)-1H-pyrazol-5-yl)piperazine; 2. A compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring.

10. The compound is 【Chemistry 7】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

11. The compound is 【Chemistry 8】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

12. The compound is 【Chemistry 9】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

13. The compound is 【Chemistry 10】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

14. The compound is 【Chemistry 11】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

15. The compound is 【Chemistry 12】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

16. The compound is 【Chemistry 13】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

17. The compound is 【Chemistry 14】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

18. The compound is 【Chemistry 15】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

19. The compound is 【Chemistry 16】 2. The compound according to claim 1 or a pharma- ceutically acceptable salt or ester thereof for use in a method for the treatment and / or prevention of sleep-related breathing disorders (preferably obstructive sleep apnea and central sleep apnea and snoring), the compound being

20. The use of a compound according to any one of claims 1 to 19, wherein said sleep-related breathing disorders are obstructive sleep apnea and central sleep apnea and snoring.

21. A combination of one or more compounds of formula (I) with one or more other active compounds for the use according to any of claims 1 to 19.

22. A pharmaceutical composition for use in a method for the treatment and / or prevention of sleep-related breathing disorders, preferably obstructive sleep apnea and central sleep apnea and snoring, comprising at least one compound of formula (I) according to any one of claims 1 to 19 in combination with one or more inert, non-toxic pharma- ceutical suitable excipients.

23. A pharmaceutical composition for use according to any one of claims 1 to 19, comprising a combination according to claim 21 in combination with one or more inert, non-toxic pharma- ceutically suitable excipients.

24. 20. A method for treating and / or preventing sleep-related breathing disorders by systemic and / or local administration of a therapeutically effective amount of at least one compound according to any one of claims 1 to 19 or a therapeutically effective amount of a medicament comprising at least one compound according to any one of claims 1 to 19 in combination with an inert, non-toxic, pharma- ceutical acceptable excipient.

25. The pharmaceutical agent is a muscarinic receptor antagonist, a mineralocorticoid receptor antagonist, a diuretic, 25. The method of claim 24, further comprising at least one additional active compound selected from the group consisting of corticosteroids.

26. A medicament comprising a compound of formula (I) as defined in any one of claims 1 to 19 in combination with one or more further active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids.

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