Α2-adrenoceptor subtype c (α-2c) antagonists for the treatment of sleep apnea

Abstract

To provide therapeutic agents for the use in a method for the treatment and / or prophylaxis of sleep-related breathing disorders, such as obstructive sleep apnea, central sleep apnea and snoring.SOLUTION: The present invention relates to α2-adrenoceptor subtype C (α-2C) antagonists, in particular substituted piperidinyl-pyrimidinyl-tetrahydrochinolines of formula (I). In formula (I), X is (A) or (B).SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] The present invention relates to a method for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. α2-adrenergic receptor antagonists for use in methods for the treatment and / or prevention of Subtype C (α-2C) antagonists, in particular substituted piperidinyl-pyridinyl compounds of formula (I) Midinyl-tetrahydroquinoline and piperidinyl-pyridinyl-tetrahydroquinoline Regarding . [Background technology]

[0002] Obstructive sleep apnea (OSA) is characterized by repeated episodes of upper airway obstruction. When breathing in, the patency of the upper airway depends on the interaction of two opposing forces. Negative luminal contraction is achieved by the dilatation of the upper airway musculature. Active contraction of the diaphragm and other accessory respiratory muscles creates negative pressure in the airway, It constitutes the driving force for breathing. The stability of the upper airway is determined by the coordination of the dilator muscles of the upper airway and the contractile properties. It is practically decided.

[0003] Upper airway collapse in OSA occurs at the onset of sleep due to reduced activity of some upper airway dilator muscles. This may result in an inability to maintain an open anatomically vulnerable airway. However, the most important dilator muscle of the upper airway, the hypoglossal nerve, controls the otogastric nerve. Several upper airway dilator muscles, including the iliac glossus, increase their activity during sleep in response to respiratory stimuli. This may counter some of these changes in sleep onset. Genioglossus muscle activity was 25-40% higher in this sleep phase than in the sleep phase in which obstructive apnea was more frequent. It was observed that patients had only apnea-free intervals during which they experienced no apnea (Jordan AS, Whi te DP, Lo YL et al;Airway dilator muscle activ ity and lung volume during stable breath ing in obstructive sleep apnea;Sleep 200 9;32(3):361-8). Noradrenaline is the most potent inhibitor of hypoglossal motoneuron activity. It is one of the most powerful neuromodulators (Horner RL; Neuromodulation on of hypoglossal motoneurons during sle ep;Respir Physiol Neurobiol 2008;164(1-2 ):179-196). Decreased noradrenergic drive leads to decreased upper airway dilator activity. In particular, the sleep-dependent decrease in hypoglossal motoneuron excitation, which leads to a decrease in genioglossus muscle activity, It is believed that the

[0004] α2C adrenoceptors mediate noradrenaline release from central noradrenergic neurons. They regulate the release of noradrenaline through presynaptic feedback inhibition of noradrenaline. Hein L. et al.; Two functionally distinct autoreceptors involved in istinct alpha2-adrenergic receptors regu late sympathetic neurotransmission;Natur e 1999;402(6758):181-184). α2c adrenoceptor antagonist Increased activity of motor neurons in the hypoglossal nerve stabilizes the upper airway In addition, snoring also contributes to the mechanisms of stabilization of the upper airway. Thus, it can be suppressed.

[0005] In simple snoring, there is no obstruction of the upper airway. The narrowing of the upper airway makes it difficult to inhale and exhale. The flow rate of the exhaled air increases. This, along with the relaxed muscles, allows the loosening of the soft tissues of the mouth and throat in the airstream. This slight vibration creates the typical snoring sound.

[0006] Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is a recurrent sleep disorder. It is caused by partial obstruction of the upper airway, resulting in increased airway resistance and significant intrathoracic pressure changes. Therefore, the generation of negative intrathoracic pressure during inspiration is a major factor in OSA. This can reach values ​​that would result in complete airway obstruction. The pathophysiological effects on sleep quality are the same as those in obstructive sleep apnea. The causes are likely to be the same as those of OSA. Obstructive snoring is often a precursor to OSA. Hollandt JH et al.;Upper airway resistance e 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 a lack of drive to breathe during sleep, resulting in insufficient ventilation. There are repeated periods of sufficiency or absence and impaired gas exchange. These include high altitude induced periodic breathing, idiopathic CSA (ICSA), opioid-induced Inducible central apnea, Obesity hypoventilation syndrome (OHS), Cheyne-Stokes respiration (CSB) The exact triggering mechanisms involved in the various types of CSA may vary considerably. However, unstable ventilatory drive during sleep is a major underlying feature (Eckert DJ Central sleep apnea: Pathophysiology an d treatment; Chest 2007;131(2):595-607).

[0008] US Patent Application Publication No. 2018 / 0235934 discloses a method for the treatment of hypoglossal motoneuron activation. To treat disorders such as obstructive sleep apnea using drugs to promote excitability The authors described a method for promoting the excitability of hypoglossal motoneurons by using central noradrenaline. Several drugs that disinhibit and / or stimulate adrenergic neurons have been described. In one embodiment, the disinhibitor of central noradrenergic neurons is yohimbine or α2-adrenergic receptor subtype A (α-2A) antagonists or α2- α2-adrenergic receptor subtype C (α-2C) antagonists The α2-adrenergic receptor antagonist is an α2-adrenergic receptor antagonist. Pamezole, MK-912, RS-79948, RX 821002, [3H]2-Methion It is selected from the group consisting of xylidazoxan and JP-1302.

[0009] The α2C-adrenergic receptor belongs to the G protein-coupled receptor family. In addition to the adrenoceptors, there are three distinct α2-adrenergic receptor subtypes These are induced via synapses or blood. When stimulated by endogenous catecholamines (epinephrine, norepinephrine), It is involved in mediating several diverse physiological actions in various tissues. The receptors play important physiological roles, primarily in the cardiovascular and central nervous systems. α2A- and α2C-adrenergic receptors mediate the signaling of noradrenaline in the central nervous system. It is the major autoreceptor involved in prenatal feedback inhibition. α2C-adrenergic The potency and affinity of norepinephrine at the receptor is higher than at the α2A-adrenergic receptor α2C-adrenergic receptors are involved in the regulation of noradrenaline levels when endogenous concentrations of noradrenaline are low. The α2A-adrenergic receptor inhibits the release of noradrenaline, whereas the α2A-adrenergic receptor inhibits the release of noradrenaline at high endogenous concentrations. Sometimes it suppresses noradrenaline release (Uys MM et al.; Therapeutic Potential of Selectively Targeting the α 2C-Adrenoceptor in Cognition,Depression, and Schizophrenia-New Developments and F uture Perspective;Frontiers in Psychiatr y 2017;August 14;8:144;doi:10.3389 / fpsyt.201 7.00144eCollection 2017).

[0010] Substituted pipetamines as α2-adrenergic receptor subtype C (α-2C) antagonists Lysinyl-pyrimidinyl-tetrahydroquinolines and piperidinyl-pyridinyl-tetrahydroquinolines Trahydroquinolines and their preparation and use as medicines are disclosed in WO201 In WO2015 / 091414A1 and WO2015 / 091417A1, primary and secondary diabetic microangiopathy, diabetic wound healing, diabetic ulcers in the extremities, especially the diabetic foot Accelerating wound healing of ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic Heart failure, diabetic coronary heart disease, peripheral and cardiovascular disorders, thromboembolic disorders and ischemia, Peripheral circulatory disorder, Raynaud's phenomenon, CREST syndrome, microcirculatory disorder, intermittent claudication and peripheral It has been disclosed that the compound is useful for treating and / or preventing peripheral and autonomic neuropathy. In the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring No use of these compounds is disclosed.

[0011] The current gold standard treatment for OSA patients is continuous positive airway pressure (CPAP). The positive airflow pressure generated by the airflow turbine pump splint opens the upper airway. It reverses all underlying causes of pharyngeal collapse, thereby preventing hypopnea, apnea and Prevents sleep fragmentation. Unfortunately, up to 50% of all patients with OSA will experience long-term CPAP intolerance (M. Kohler, D. Smith, V. Tippett et al. ;Thorax 2010;65(9):829-32;Predictors of long-term compliance with continuous pos itive airway pressure). [Prior art documents] [Patent documents]

[0012] [Patent Document 1] US Patent Application Publication No. 2018 / 0235934 [Patent Document 2] International Publication No. WO2015 / 091414 Brochure [Patent Document 3] International Publication No. WO2015 / 091417 Brochure [Non-patent literature]

[0013] [Non-Patent Document 1] Jordan AS, White DP, Lo YL et al.;Sleep 2009;32(3):361-8 [Non-Patent Document 2] Horner RL;Respir Physiol Neurobiol 2008;164(1-2):179-196 [Non-Patent Document 3] Hein L. et al.;Nature 1999;402(6758):181-184 [Non-Patent Document 4] Hollandt JH et al;HNO 2000;48(8):628-634 [Non-Patent Document 5] Eckert DJ et al.; Chest 2007; 131(2):595-607 [Non-Patent Document 6] Uys MM et al;Frontiers in Psychiatry 2017;August 14;8:144;doi:10.3389 / fpsyt.2017.00144eCollection 2017 [Non-Patent Document 7] M.Kohler, D.Smith, V.Tippett et al.;Thorax 2010;65(9):829-32 Summary of the Invention [Problem to be solved by the invention]

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

[0015] Surprisingly, the present invention relates to substituted piperidinyl-pyrimidinyl-tetrahydropyridinyl compounds of formula (I) Quinoline and piperidinyl-pyridinyl-tetrahydroquinoline inhibit upper airway collapsibility and therefore, sleep-related breathing disorders, preferably obstructive and central sleep apnea and It has now been found that the compound is suitable for the manufacture of a medicament for use in the treatment and / or prevention of snoring. It was found.

[0016] The present invention relates to a method for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. A compound of formula (I) for use in the treatment and / or prophylaxis of [ka] [In the ceremony X is the following group [ka] {In the formula, R 1 represents C1-C6-alkyl or C3-C5-cycloalkyl, alkyl being One selected from the group consisting of hydroxy, C1-C4-alkoxy and haloalkoxy. is substituted with ~2 independent substituents, and R 2 represents hydrogen or C1-C4-alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocyclic ring Forming wherein the N-heterocycle is oxo, hydroxy, monofluoromethyl, difluoromethyl. aryl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, amino Nocarbonyl, C1-C4-alkyl, C1-C4-alkoxy, C1-C4-alkoxy selected from the group consisting of hydroxyalkyl, halogen and hydroxyalkyl; or The N-heterocycle may have two substituents, which are bonded together. Together with the carbon atom of the N-heterocycle, the heterocycle forms a 4- to 6-membered heterocycle, a part of which is 1 to 3 mutually independent groups selected from the group consisting of oxo, methyl and ethyl; (optionally substituted with an isopropyl group); R 3 represents hydrogen, fluorine, methoxy or ethoxy, and R 4 represents hydrogen, fluorine, methoxy or ethoxy. as well as salts thereof, solvates thereof and solvates of salts thereof. [Brief description of the drawings]

[0017] [Figure 1] Effect of [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-5-yl]methanone administered intravenously at 0.007 mg / kg as an intravenous bolus at 0 min, followed by 0.0025 mg / kg / h for 4 h, on upper airway collapsibility at different levels of negative pressure. Percentage of pigs not exhibiting collapse is shown. Mean values. [Diagram 2]Effect of [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-5-yl]methanone administered intravenously at 0.07 mg / kg as an intravenous bolus at 0 min, followed by 0.025 mg / kg / h for 4 h, on upper airway collapsibility at different levels of negative pressure. Percentage of pigs not exhibiting collapse is shown. Mean values. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0018] In the context of the present invention, unless otherwise stated, the substituents are defined as follows: Alkyl itself as well as alkoxy, alkoxyalkyl, alkylamino and alkoxy. "Alkyl" and "Alkyl" in Alkoxycarbonyl has 1 to 6 carbon atoms, preferably Represents a straight or branched alkyl group having 1 to 4 carbon atoms, for example and preferably methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, te rt-butyl, n-pentyl and n-hexyl.

[0019] Alkoxy are, by way of example and preferably, methoxy, ethoxy, n-propoxy, isopropyl, It represents isopropoxy, n-butoxy and tert-butoxy.

[0020] Alkoxyalkyl are, by way of example and preferably, methoxymethyl, ethoxymethyl , n-propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl oxymethyl, methoxyethyl, ethoxyethyl, n-propoxyethyl, isopropoxy It stands for ethyl, n-butoxyethyl and tert-butoxyethyl.

[0021] base R 1 and R 2 N-heterocycles in the definition ofis a saturated and Partially unsaturated monocyclic groups consisting of a nitrogen heteroatom and S, O, N, SO and SO2 and up to three further heteroatoms and / or hetero groups selected from the group consisting of: represents a monocyclic group which may form an N-oxide, for example and preferably azetidine, Pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-o Oxidothiomorpholine and 1,1-dioxidothiomorpholine, particularly preferably azeti These are dimethylamine, pyrrolidine, morpholine and 1,1-dioxidothiomorpholine.

[0022] base R 1 and R 2 Heterocycles in the definition of and the N-heterocycle to which it is attached Heterocycles with shared carbon atoms have 4-6 ring atoms and S, O, N, SO and SO 2, with up to four heteroatoms and / or hetero groups selected from the group consisting of nitrogen atoms and N -oxides. or azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, piperidine morpholine, thiomorpholine, piperazine, tetrahydropyran and 1,1-dihydropyran Oxidothietanes, particularly preferred are azetidines and oxetanes, even more preferred are Mostly oxetane.

[0023] halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine; be.

[0024] The term "hydroxy" is used herein by itself or as part of another group. When used herein it refers to the -OH group.

[0025] As used herein, the phrase "compounds of the invention" refers to compounds of Formula I.

[0026] Pharmaceutically acceptable salts (e.g., acid addition salts with both organic and inorganic acids) are used in medicine. Representative examples of pharma- ceutically acceptable acid addition salts include the following: salts, bromides, sulfates, nitrates, phosphates, sulfonates, methanesulfonates, formates, Tartrate, maleate, citrate, benzoate, salicylate, ascorbate, These include, but are not limited to, acetate and oxalate salts.

[0027] The hydrates or solvates of the present invention may be formed by hydration with water or solvent molecules in the solid or liquid state. is designated as the form of the compound of formula (I) that forms a molecular compound or complex by coordination with Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Hydrates or solvates of the salts of the compounds of the invention are also suitable.

[0028] Pharmaceutically acceptable esters, where applicable, are conventional in the pharmaceutical field, and in known manner using pharma- ceutical acceptable acids that retain the pharmacological properties of the free form. Non-limiting examples of these esters include aliphatic or aromatic esters. Representative examples of pharma- ceutically acceptable esters include methyl alcohol esters. Chill, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl and benzyl esters.

[0029] The present invention includes within its scope all possible geometric isomers of compounds, e.g., Z and E isomers ( Cis and trans isomers), as well as all possible optical isomers of a compound, e.g., diastereomeric isomers. The present invention further includes within its scope the individual isomers and enantiomers. The individual isomers are the starting material and any mixtures thereof (e.g. racemic mixtures). The corresponding isomeric forms of the compounds may be obtained using conventional separation methods. The optical isomers, e.g., enantiomers, may be separated by the addition of the isomers themselves. To separate the mixture, conventional resolution methods, such as fractional crystallization, can be used. .

[0030] Certain embodiments of the present invention are useful in methods for the treatment and / or prevention of sleep-related breathing disorders. For use in a pharmaceutical composition comprising a compound of formula (I): R 1 is C1-C6-alkyl or C3-C5-cycloalkyl (wherein alkyl are each 1 to 2 independently selected from the group consisting of hydroxy and C1-C4-alkoxy. substituted with independent substituents, and R 2 represents hydrogen or C1-C4-alkyl, or R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocyclic ring Forming wherein the N-heterocycle is oxo, hydroxy, monofluoromethyl, difluoromethyl. aryl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, amino consisting of nocarbonyl, C1-C4-alkyl, C1-C4-alkoxy and halogen or may be substituted with 1 to 3 independent substituents selected from the group The N-heterocycle may have two substituents, which are bonded together. A 4- to 6-membered heterocyclic ring, taken together with the carbon atom of the N-heterocyclic ring, each of the moieties is selected from the group consisting of oxo, methyl and ethyl; and forming a substituted or unsubstituted aryl group, R 3 represents hydrogen, fluorine, methoxy or ethoxy, and R 4 represents hydrogen, fluorine, methoxy or ethoxy; as well as salts thereof, solvates thereof and solvates of salts thereof.

[0031] Further specific embodiments of the present invention provide a method for the treatment and / or prevention of sleep-related breathing disorders. 2. The method of claim 1, wherein the compound is a compound of formula (I): R 1 C2-C6-alkyl (wherein alkyl is hydroxy, methoxy and ethoxy) substituted with a substituent selected from the group consisting of aryl, aryloxy, and R 2 represents hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothio forming omorpholine or 1,1-dioxidothiomorpholine, Here, the azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholino Thiomorpholine, 1-oxide thiomorpholine and 1,1-dioxide thiomorpholine Phosphorus is hydroxy, trifluoromethyl, hydroxycarbonyl, C1-C3-alkyl

[0036] 1 to 2 mutually independent aryl groups selected from the group consisting of aryl, methoxy, and methoxymethyl. may be substituted with a substituent, or The azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine Two substituents that are bonded together are azetidine, pyrrolidine, piperidine, Together with the carbon atom of azetidine, piperazine or morpholine, they form azetidine, oxetidine, or 1,1-dioxidothiethane, where the azetidine, oxetane or 1,1 -dioxide thietane is a 1- and having two substituents forming a ring structure (which may be substituted with two independent substituents). It's okay to be there, R 3 represents hydrogen, and R 4 represents hydrogen, fluorine or methoxy, or R 3 represents hydrogen, fluorine or methoxy, and R 4 represents hydrogen, as well as salts thereof, solvates thereof and solvates of salts thereof.

[0032] Further specific embodiments of the present invention relate to methods for the treatment and / or prevention of sleep-related breathing disorders. For use in the manufacture of a compound of formula (I): R 1 is C2-C4-alkyl (wherein alkyl consists of hydroxy and methoxy) substituted with a substituent selected from the group consisting of: R 2 represents hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, morpholine, 1,1-dioxidothiomorpholine (wherein azetidine, pyrrolidine , morpholine or 1,1-dioxidethiomorpholine is a hydroxycarbonyl, methyl methyl, trifluoromethyl, methoxy, and methoxymethyl; or R 1 and R 2 together with the nitrogen atom to which they are attached to form an azetidine, wherein the azetidine has two substituents that are bonded together at the carbon atom of the azetidine. Two aryl groups that, together with an atom, form an oxetane or a 1,1-dioxidothietane. may have a substituent, R 3 represents hydrogen, fluorine or methoxy, and R 4 represents hydrogen, or R 3 represents hydrogen, and R 4 represents hydrogen, fluorine or methoxy; as well as salts thereof, solvates thereof and solvates of salts thereof.

[0033] Further specific embodiments of the present invention relate to methods for the treatment and / or prevention of sleep-related breathing disorders. For use in the manufacture of a compound of formula (I): R 1 is C2-C4-alkyl (wherein alkyl is composed of hydroxy and methoxy) substituted with a substituent selected from the group R 2 represents hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, morpholine, 1,1-dioxidothiomorpholine (wherein azetidine, pyrrolidine , morpholine or 1,1-dioxidethiomorpholine is a hydroxycarbonyl, methyl methyl, trifluoromethyl, methoxy, and methoxymethyl; or R 1 and R 2 together with the nitrogen atom to which they are attached to form an azetidine, wherein the azetidine has two substituents that are bonded together at the carbon atom of the azetidine. Two substituents that, together with an atomic atom, form an oxetane or a 1,1-dioxidothietane. may have a substituent, R 3 represents hydrogen or fluorine, and R 4 represents hydrogen, fluorine or methoxy; as well as salts thereof, solvates thereof and solvates of salts thereof.

[0034] A further particularly preferred embodiment of the present invention is for the treatment and / or prevention of sleep-related breathing disorders. For use in the method, a compound of formula (I) X is the following group [ka] [In the formula, R 1 is C2-C4-alkyl (wherein alkyl is composed of hydroxy and methoxy) substituted with a substituent selected from the group R 2 represents hydrogen, or R 1 and R 2 together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, morpholine, 1,1-dioxidothiomorpholine (wherein azetidine, pyrrolidine , morpholine or 1,1-dioxidothiomorpholine is a hydroxycarbonyl and methyl), Form or R 1 and R 2 together with the nitrogen atom to which they are attached to form an azetidine, wherein the azetidine has two substituents that are bonded together at the carbon atom of the azetidine. and optionally having two substituents which, together with the atom, form an oxetane; R 3 represents hydrogen, fluoro or methoxy, and R 4 represents hydrogen, or R 3 represents hydrogen, and R 4 represents hydrogen, fluoro or methoxy; as well as salts thereof, solvates thereof and solvates of salts thereof.

[0035] A further particularly preferred embodiment of the present invention is for the treatment and / or prevention of sleep-related breathing disorders. For use in a method for the treatment of a disease comprising administering to said patient a compound of formula (I): X is the following group [ka] [In the formula, R 1 and R 2 together with the nitrogen atom to which they are attached to form azetidine wherein the azetidine is two substituents, each of which is bonded together to form an azetidine group. and having two substituents which, together with the carbon atom of the aryl group, form an oxetane; R 3 represents hydrogen, and R 4 represents hydrogen, as well as salts thereof, solvates thereof and solvates of salts thereof.

[0036] R 2 Also preferred are compounds of formula (I) in which represents hydrogen.

[0037] R 1 and R 2 together with the nitrogen atom to which they are attached, form 2-oxa-6- Also preferred are compounds of formula (I) which represent azaspiro[3.3]hept-6-yl.

[0038] R 1 and R 2 together with the nitrogen atom to which they are attached, form 1,1-dioxy Compounds of formula (I) which represent dothiomorpholin-4-yl are also preferred.

[0039] R 3 Also preferred are compounds of formula (I) in which represents hydrogen.

[0040] R 4 Also preferred are compounds of formula (I) in which represents hydrogen.

[0041] R 3 and R 4 Also preferred are compounds of formula (I) in which represents hydrogen.

[0042] In a preferred embodiment, the present invention relates to a method for treating sleep-related breathing disorders, preferably obstructive and intermediate. For use in a method for the treatment and / or prevention of central sleep apnea and snoring. for the treatment of atopic dermatitis, comprising a compound of formula (I) selected from the group consisting of: [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {2-[(2-methoxyethyl)amino]pyrimidin-5-yl}methanone, [4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl le}methanone, [4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl le}methanone, {2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}[4-( 7-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl Methanone, {2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}[4-( 6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl Methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {2-[(1-methoxybutan-2-yl)amino]pyrimidin-5-yl}methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {2-[(1-hydroxybutan-2-yl)amino]pyrimidin-5-yl}methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-5-yl Methanone, [4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridine [midin-5-yl]methanone, [4-(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridine [midin-5-yl]methanone, 1-(5-{[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidine -1-yl]carbonyl}pyrimidin-2-yl]-D-proline hydrochloride, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [2-(1,1-dioxidethiomorpholin-4-yl)pyrimidin-5-yl]methano hmm, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [2-(2,6-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl]piperidin-1-yl] [2-(2,6-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [2-(2,2-dimethylmorpholin-4-yl)pyrimidin-5-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {6-[(2-methoxyethyl)amino]pyridin-3-yl}methanone, [4-(7-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl {6-[(2-methoxyethyl)amino]pyridin-3-yl}methanone , [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(morpholin-4-yl)pyridin-3-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(1,1-dioxidethiomorpholin-4-yl)pyridin-3-yl]methanone , [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {6-[(2R)-2-(methoxymethyl)pyrrolidin-1-yl]pyridin-3-yl }Methanone, 1-(5-{[4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidine -1-yl]carbonyl}}pyridin-2-yl]-D-proline, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] (6-{[(2S)-1-hydroxybutan-2-yl]amino}pyridin-3-yl) Methanone, [4-(6-fluoro-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]methan No, [4-(6-Methoxy-3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 6-(3-methoxypyrrolidin-1-yl)pyridin-3-yl]methan No, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridin-3-yl ]Methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(2,6-dimethylmorpholin-4-yl)pyridin-3-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(2,2-dimethylmorpholin-4-yl)pyridin-3-yl]methanone, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] {6-[2-(trifluoromethyl)morpholin-4-yl]pyridin-3-yl}meth No, [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl] [6-(2,2-dioxido-2-thia-6-azaspiro[3.3]hept-6-yl) pyridin-3-yl]methanone, as well as their salts, solvates and solvates of their salts.

[0043] In a more preferred embodiment, the present invention relates to a method for treating sleep-related breathing disorders, preferably obstructive and and use in a method for the treatment and / or prevention of central sleep apnea and snoring - Patents.com For the compound [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidinyl 2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyridine 5-(4 ... .

[0044] The compounds of formula (I), their preparation and their action are useful in the treatment of primary and secondary diabetic disorders. Microangiopathy, diabetic wound healing, diabetic ulcers in the extremities, especially diabetic foot ulcers promotion, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetes Coronary heart disease, peripheral and cardiovascular disorders, thromboembolic disorders and ischemia, peripheral circulatory disorders, Raynaud's phenomenon, CREST syndrome, microcirculatory disorders, intermittent claudication and peripheral and autonomic nervous system disorders α2C antagonists for use in a method for treating and / or preventing menstrual disorders and the like, which are publicly disclosed in WO2015 / 091414 and WO2015 / 091417. In particular, said compounds are specifically and expressly part of the description of the present invention and are incorporated herein by reference. This document is incorporated herein by reference.

[0045] As used herein, the term effective amount refers to a dose that is effective for treating sleep-related breathing disorders, preferably obstructive and and compounds of formula (I) useful for the treatment and / or prevention of central sleep apnea and snoring. Refers to the amount of.

[0046] The present invention relates to a method for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and snoring. (α-2C) ANTAGONIST FOR USE IN A METHOD FOR THE TREATMENT AND / OR PROPHYLAXIS In particular, the substituted piperidinyl-pyrimidinyl-tetrahydroquinolines and pyrimidinyl-tetrahydroquinolines of formula (I) Peridinyl-pyridinyl-tetrahydroquinoline.

[0047] The present invention further relates to a method for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and Use of a compound of formula (I) for the manufacture of a medicament for the treatment and / or prevention of snoring Regarding.

[0048] A further subject of the present invention is the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apnea. In a method for treating and / or preventing breathing and snoring, one or more The use of the above compounds in combination with one or more other active compounds.

[0049] A further subject of the present invention is the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apnea. 1 for use in a method for treating and / or preventing breathing and snoring, In combination with one or more inert, non-toxic, pharma- ceutical suitable excipients, I) A pharmaceutical composition comprising the compound of formula I.

[0050] The present invention further relates to a method for treating sleep-related breathing disorders, preferably obstructive and central sleep apnea and For use in a method for treating and / or preventing snoring, With one or more other active compounds in combination with inert, non-toxic, pharma- ceutical suitable excipients. The present invention relates to a pharmaceutical composition comprising the combination.

[0051] The present invention also provides a method for treating a patient having a disease comprising administering to the patient a therapeutically effective amount of at least one compound of formula (I), or ) is administered to a subject in need thereof in an amount of at least one compound selected from the group consisting of: By administering the compound systemically and / or locally in combination with a commercially acceptable excipient. The present invention relates to a method for the treatment and / or prevention of sleep-related breathing disorders.

[0052] A further subject of the present invention is the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apnea. For use in a method for treating and / or preventing breathing and snoring, (I) is a combination of one or more compounds of formula (I) with one or more other active compounds.

[0053] The substituted piperidinyl-pyrimidinyl-tetrahydroquinolines and pyrimidinyl-tetrahydroquinolines of formula (I) of the present invention The peridinyl-pyridinyl-tetrahydroquinolines may be used alone or, if necessary, in combination with one or more It may be used in combination with other pharmacologically active substances listed above, provided that this combination The combination does not result in undesirable and unacceptable side effects. The preferred combinations are suitable for treating obstructive and central sleep apnea and snoring. Good examples include: By way of example and preferably theophylline, doxapram, nikethamide or caffeine respiratory irritants such as nicotine; Psychostimulants, such as by way of example and preferably modafinil or armodafinil; By way of example and preferably amphetamine, methamphetamine or methylphenidamine amphetamine and amphetamine derivatives such as methamphetamine; By way of example and preferably fluoxetine, paroxetine, citalopram, escitabine Serotonin reuptake inhibitors such as lopram, sertraline, fluvoxamine or trazodone Inhibitors; Serotonin precursors, such as, by way of example and preferably, L-tryptophan; By way of example and preferably, selective serotonin receptor antagonists such as venlafaxine or duloxetine Tonin-norepinephrine reuptake inhibitors; Noradrenergic and specific, for example and preferably mirtazapine Serotonergic antidepressants; Selective noradrenaline, such as, for example and preferably, reboxetine or atomoxetine Renaline reuptake inhibitors; By way of example and preferably amitriptyline, protriptyline, doxepin, triptyline tricyclic antidepressants such as mipramine, imipramine, clomipramine or desipramine; Muscarinic receptor antagonists, such as, by way of example and preferably, oxybutynin; GABA agonists, such as, by way of example and preferably, baclofen; By way of example and preferably fluticasone, budesonide, beclomethasone, mometasone , glucocorticoids such as tixocortol or triamcinolone; ·Cannabinoid receptor agonists; By way of example and preferably, acetazolamide, methazolamide or diclophenamide Which carboanhydrase inhibitors; By way of example and preferably, steroids such as flumazenil, naloxone or naltrexone pyoide and benzodiazepine receptor antagonists; By way of example and preferably neostigmine, pyridostigmine, physostigmine, cholinesterase inhibitors such as donepezil, galantamine or rivastigmine; By way of example and preferably, sibutramine, opiramate, phentermine, lipase appetite suppressants, such as inhibitors or cannabinoid receptor antagonists; Mineralocorticoid receptor antagonist.

[0054] A preferred subject of the present invention is muscarinic receptor antagonists, mineralocorticoid receptor antagonists one or more other agents selected from the group consisting of vasopressin antagonists, diuretics, and corticosteroids with one or more compounds of formula (I), Preferably for treating and / or preventing obstructive and central sleep apnea and snoring The combination is for use in a method for

[0055] In a preferred embodiment of the invention, the compounds of the invention are muscarinic receptor antagonists. It is preferably administered in combination with oxybutynin, for example. can be.

[0056] In a preferred embodiment of the present invention, the compounds of the present invention bind to the mineralocorticoid receptor In combination with antagonists, for example and preferably spironolactone, epre It is administered in combination with renone or finerenone.

[0057] In a preferred embodiment of the invention, the compounds of the invention are diuretics, for example and preferably or furosemide, bumetanide, torsemide, bendroflumethiazide, chlorothiazide , hydrochlorothiazide, hydroflumethiazide, methyclothiazide, polythiazide, Lichlormethiazide, Chlorthalidone, Indapamide, Metolazone, Quinethazone, Acetate Zolamide, dichlorphenamide, methazolamide, glycerol, isosorbide, mannitol It is administered in combination with thorax, amiloride or triamterene.

[0058] In a preferred embodiment of the invention, the compounds of the invention are corticosteroids, e.g. , and preferably prednisone, prednisolone, methylprednisolone, triamcinolone Nolon, dexamethasone, betamethasone, beclomethasone, flunisolide, budesonide or or in combination with fluticasone.

[0059] Optionally, the arylpiperazines of formula (I) of the present invention may be modified to reduce undesirable and unacceptable Use in conjunction with one or more medical technical devices or aids, provided this does not result in side effects. Suitable medical devices and aids for such combined use include, for example: , and preferably: By way of example and preferably, CPAP (Continuous Positive Airway Pressure) devices, BiPAP (Biphasic Airway Pressure) devices, Positive airway pressure ventilation devices such as airway pressure (IPPV) devices and intermittent positive pressure ventilation (IPPV) devices; ·Nerve stimulator for the hypoglossal nerve; Oral appliances such as, for example and preferably, mandibular advancement devices; · Disposable nasal valves; Nasal stents.

[0060] The substituted piperidinyl-pyrimidinyl-tetrahydroquinolines and pyrimidinyl-tetrahydroquinolines of formula (I) of the present invention Peridinyl-pyridinyl-tetrahydroquinolines act systemically and / or locally For this purpose, they can be administered in an appropriate manner, for example orally, parenterally, , Pulmonary, Intrapulmonary (inhalation), Nasal, Intranasal, Pharyngeal, Lingual, Sublingual, Buccal, Rectal, Skin, Transdermal It can be administered via the conjunctival or otic routes, or as an implant or stent. do.

[0061] Further subject matter of the present invention are oral, parenteral, pulmonary, intrapulmonary (inhalation), nasal, intranasal, pharyngeal, liningeal, By the gallbladder, sublingual, buccal, rectal, cutaneous, transdermal, conjunctival or auricular routes, or by impingement Compounds of formula (I) for systemic and / or local administration as implants or stents The preferred route of administration is oral.

[0062] For these administration routes, the compounds according to the invention should be administered in suitable dosage forms. can.

[0063] For oral administration, dosage forms functioning according to the state of the art and containing the compounds according to the invention are The compounds according to the invention can be crystallized and / or released in a rapid and / or modified manner. or in an amorphous and / or dissolved form, e.g. tablets (coated Uncoated or coated tablets, e.g. tablets with gastric juice-resistant or slow-dissolving or insoluble coating to control tablets or films / wafers, films / lyophilisates, capsules (e.g. For example, hard or soft gelatin capsules, sugar-coated tablets, granules, pellets, powders, emulsions, Suspensions, aerosols or solutions and the like are suitable.

[0064] Parenteral administration bypasses the absorption step (e.g., intravenous, intraarterial, intracardiac, intraspinal, or lumbar). intrathecal administration), or with absorption (e.g., intramuscular, subcutaneous, intradermal, transdermal or intraperitoneal administration) Suitable dosage forms for parenteral administration include solutions, suspensions, etc. Injectable and infusion preparations in the form of emulsions, lyophilisates or sterile powders. .

[0065] Other routes of administration include, for example, inhaled formulations (including powder inhalers and nebulizers); Nasal drops, solutions or sprays, tablets, pills, fillers for lingual, sublingual or buccal administration tablets / wafers or capsules, suppositories, oral or ophthalmic preparations, vaginal capsules, aqueous suspensions ( lotions, shakeable mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. , plasters), emulsions, pastes, foams, powders, implants or stents are preferred. do.

[0066] Oral or parenteral administration, particularly oral and intravenous administration, is preferred.

[0067] The compounds of the present invention can be converted into the above-mentioned dosage forms. They are inactive and non-toxic. This can be done in a manner known per se by mixing with pharma- ceutically suitable excipients. These excipients include carriers (e.g., microcrystalline cellulose, lactose, mannitol); Solvents (e.g., liquid polyethylene glycol), emulsifying agents and dispersing or wetting agents (e.g., sodium dodecyl sulfate, polyoxysorbitan oleate), binders (e.g. , polyvinylpyrrolidone), synthetic and natural polymers (e.g., albumin), stabilizers ( For example, antioxidants such as ascorbic acid), colorants (for example, inorganic pigments such as iron oxide) , as well as flavor or odor correctors.

[0068] Generally, to achieve effective results in parenteral administration, about 0.001 to 10 mg It is advantageous to administer the compound in an amount of about 0.01 to 1 mg / kg of body weight. It was found that the dose for oral administration is about 0.01 to 100 mg / kg, preferably about 0.0 It is preferably 1 to 20 mg / kg, and very particularly preferably 0.1 to 15 mg / kg of body weight.

[0069] Nevertheless, deviations from the aforementioned amounts are possible, i.e. depending on body weight, route of administration, active ingredient The deviations may vary depending on the individual response to the drug, the nature of the preparation and the time or interval at which the administration takes place. Therefore, in some cases, it may be necessary to maintain the above minimum amount. In other cases the upper limit mentioned above must be exceeded. In some cases it may be advisable to divide these into several individual administrations throughout the day.

[0070] The present invention will be described with reference to the following examples, without however limiting the scope of the invention. EXAMPLES

[0071] A. Experimental Method The advantageous pharmacological properties of the compounds of this invention can be determined by the following methods. The therapeutic potential of the compounds of formula (I) according to the invention in sleep apnea is in the treatment of obstructive sleep apnea. It was evaluated preclinically in a porcine model of OSA.

[0072] The use of negative pressure has been shown to induce upper airway collapse and obstruction in anesthetized, spontaneously breathing pigs. It is possible (Wirth KJ et al.; Sleep 36(5)(2013)pp.6 99-708).

[0073] German Landrace pigs are used in this model. The pigs are anesthetized and tracheotomized. Two tracheal tubes are inserted. The cannulae are inserted into the trachea, one in the rostral part of the trachea and one in the caudal part. Using the connecting piece, the rostral cannula is connected to the negative pressure device and the tubing to the distal tracheal cannula. The distal tracheal cannula also aids in free airway breathing, bypassing the upper airway. Through the connecting pieces, they are connected to tubes having open ends to the atmosphere. By appropriately opening and clamping the nasal passages, breathing can be shifted from nasal breathing to through the caudal tracheal cannula. Bypass the upper airway (isolation) and connect the upper airway to a negative pressure device. This can create an airflow in the intake direction.

[0074] At specific time points, pigs were allowed to breathe through a caudal cannula and were then re-inhaled at −50, −100 and −1 Collapse of the upper airway by applying 50 cm H2O negative pressure to the upper airway This causes the upper airway to collapse, which can lead to airflow obstruction and tubing systems. This test is performed before and after administration of the test substance. An appropriately effective test substance will prevent this airway collapse during the inspiratory phase. It is possible.

[0075] In this pig model of OSA, [4-(3,4-dihydroisoquinoline-2(1H)- yl)piperidin-1-yl][2-(2-oxa-6-azaspiro[3.3]hept- 6-yl)pyrimidin-5-yl]methanone, an α2-adrenergic receptor subtype C-(α-2C) antagonist was administered intravenously in a bolus of 0.007 mg / kg. When administered intravenously for 4 hours at a dose of 100 mg / kg / h, the patient was able to recover from a 2.5 kg / kg drop in blood pressure at a negative pressure of -50 cm head. The upper airway collapse was suppressed for up to 90 minutes with negative pressure of -100cm head pressure. [4-(3 ,4-dihydroisoquinolin-2(1H)-yl)piperidin-1-yl][2-(2- Oxa-6-azaspiro[3.3]hept-6-yl)pyrimidin-5-yl]methanone 0.07mg / kg intravenous bolus injection followed by 0.025mg / kg / h intravenous infusion After 4 hours of treatment, negative pressure of -150cm head pressure was applied for 2 hours, and negative pressure of -50cm head pressure and Upper airway collapse was suppressed by negative pressure of -100cm head for up to 4 hours.

[0076] FIG1: [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-yl [2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidine-5 0.007 mg / kg of 1-ylmethanone was intravenously injected as a bolus at 0 min, and then 0.0 The effect of 100 mg / kg / h intravenous administration for 4 hours on upper airway bypass at different negative pressure levels. Effect on collapse. Percentage of pigs without collapse. Mean values. FIG2: [4-(3,4-dihydroisoquinolin-2(1H)-yl)piperidine-1-yl [2-(2-oxa-6-azaspiro[3.3]hept-6-yl)pyrimidine-5 0.07 mg / kg of 1-ylmethanone was intravenously injected as a bolus at 0 min, followed by 0.02 mg / kg of Upper airway collapsibility at different levels of negative pressure when administered intravenously at 5 mg / kg / h for 4 hours The effect on the survival of pigs. The percentage of pigs without collapse is shown. Mean values.

[0077] From the above data, the α2-adrenergic receptor subtype C (α-2C) agonist of formula (I) The antagonists are used to treat sleep-related breathing disorders, preferably obstructive and central sleep apnea and It can be inferred that it is suitable for treating snoring.

Claims

1. A method for the treatment and / or prevention of sleep-related breathing disorders, comprising administering to said patient a compound of formula (I) Compounds of 【Chemistry 1】 [During the ceremony X is the following group: 【Chemistry 2】 {During the ceremony, R １ is C １ ~C ６ -Alkyl or C ３ ~C ５ -cycloalkyl (wherein alkyl is Hydroxy, C １ ~C ４ - 1 selected from the group consisting of alkoxy and haloalkoxy substituted with up to two independent substituents, R ２ is hydrogen or C １ ~C ４ -alkyl, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocycle. Forming wherein the N-heterocycle is oxo, hydroxy, monofluoromethyl, difluoromethyl. , trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, amino Carbonyl, C １ ~C ４ -Alkyl, C １ ~C ４ -Alkoxy, C １ ~C ４ -Alkoxy -C １ ~C ４ - selected from the group consisting of alkyl, halogen and hydroxyalkyl may be substituted with 1 to 3 independent substituents, or The N-heterocycle may have two substituents, which are linked together by the N - together with the carbon atoms of the heterocycle to form a 4- to 6-membered heterocycle, where the heterocycle is a portion of which is 1 to 3 independently selected from the group consisting of oxo, methyl and ethyl; (optionally substituted with a substituent) R ３ represents hydrogen, fluorine, methoxy or ethoxy, and R ４ represents hydrogen, fluorine, methoxy or ethoxy. or a salt thereof, a solvate thereof, or a solvate of a salt thereof.

2. 2. The method according to claim 1 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: R １ is C １ ~C ６ -Alkyl or C ３ ~C ５ -cycloalkyl (wherein alkyl is Hydroxy and C １ ~C ４ -alkoxy, 1 to 2 independently selected from the group consisting of substituted with an isopropyl group; and R ２ is hydrogen or C １ ~C ４ -alkyl, or R １ and R ２ together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocycle. Forming wherein the N-heterocycle is oxo, hydroxy, monofluoromethyl, difluoromethyl. , trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, amino Carbonyl, C １ ~C ４ -Alkyl, C １ ~C ４ - the group consisting of alkoxy and halogen or The N-heterocycle may have two substituents, which are linked together by the N - a 4- to 6-membered heterocyclic ring together with the carbon atoms of the heterocyclic ring, where the heterocyclic ring is part of 1 to 3 independent substituents selected from the group consisting of oxo, methyl and ethyl; and forming a ring structure, R ３ represents hydrogen, fluorine, methoxy or ethoxy, and R ４ represents hydrogen, fluorine, methoxy or ethoxy; The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

3. 2. The method according to claim 1 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: R １ is C ２ ~C ６ -alkyl (wherein alkyl is hydroxy, methoxy and ethoxy) substituted with a substituent selected from the group consisting of R ２ represents hydrogen, or R １ and R ２ together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothio forming omorpholine or 1,1-dioxidothiomorpholine, Here, the azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholino Thiomorpholine, 1-oxide thiomorpholine and 1,1-dioxide thiomorpholine Phosphorus is hydroxy, trifluoromethyl, hydroxycarbonyl, C １ ~C ３ -Arki [0033] One to two mutually independent aryl groups selected from the group consisting of aryl, methoxy and methoxymethyl. may be substituted with a substituent, or The azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine Two substituents that are bonded together are azetidine, pyrrolidine, piperidine, Together with the carbon atom of azetidine, piperazine or morpholine, they form azetidine, oxetidine, or 1,1-dioxidothiethane (wherein the azetidine, oxetane or 1,1 -dioxidothiethane is one to four of which are selected from the group consisting of methyl and ethyl. and having two substituents forming a ring structure (which may be substituted with two independent substituents). It's okay to be there, R ３ represents hydrogen, and R ４ represents hydrogen, fluorine or methoxy, or R ３ represents hydrogen, fluorine or methoxy, and R ４ represents hydrogen, The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

4. 2. The method according to claim 1 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: R １ is C ２ ~C ４ - alkyl (wherein alkyl consists of hydroxy and methoxy) substituted with a substituent selected from the group R ２ represents hydrogen, or R １ and R ２ together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, azetidine, pyrrole, morpholine or 1,1-dioxidothiomorpholine, Lysine, morpholine or 1,1-dioxidothiomorpholine is a hydroxycarbonyl , methyl, trifluoromethyl, methoxy, and methoxymethyl, optionally substituted with 1 to 2 selected substituents; or R １ and R ２ together with the nitrogen atom to which they are attached to form an azetidine, Here, the azetidine has two substituents, which are bonded together to the carbon atom of the azetidine. Two substituents that, together with the child, form an oxetane or a 1,1-dioxidothietane may have a group, R ３ represents hydrogen, fluorine or methoxy, and R ４ represents hydrogen, or R ３ represents hydrogen, and R ４ represents hydrogen, fluorine or methoxy. The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

5. 2. The method according to claim 1 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: R １ is C ２ ~C ４ - alkyl (wherein alkyl consists of hydroxy and methoxy) substituted with a substituent selected from the group R ２ represents hydrogen, or R １ and R ２ together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, azetidine, pyrrole, morpholine or 1,1-dioxidothiomorpholine, Lysine, morpholine or 1,1-dioxidothiomorpholine is a hydroxycarbonyl , methyl, trifluoromethyl, methoxy, and methoxymethyl, optionally substituted with 1 to 2 selected substituents; or R １ and R ２ together with the nitrogen atom to which they are attached to form an azetidine, Here, the azetidine has two substituents, which are bonded together to the carbon atom of the azetidine. Two substituents that together form an oxetane or a 1,1-dioxidothietane and R ３ represents hydrogen or fluorine, and R ４ represents hydrogen, fluorine or methoxy; The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

6. 2. The method according to claim 1 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: X is the following group: 【Chemistry 3】 [In the formula, R １ is C ２ ~C ４ - alkyl (wherein alkyl consists of hydroxy and methoxy) substituted with a substituent selected from the group R ２ represents hydrogen, or R １ and R ２ together with the nitrogen atom to which they are attached form azetidine, pyrrolidinium, azetidine, pyrrole, morpholine or 1,1-dioxidothiomorpholine, Lysine, morpholine or 1,1-dioxidothiomorpholine is a hydroxycarbonyl and methyl. (b) forming a R １ and R ２ together with the nitrogen atom to which they are attached to form an azetidine, Here, the azetidine has two substituents, which are bonded together to the carbon atom of the azetidine. and optionally having two substituents which together form an oxetane; R ３ represents hydrogen, fluoro or methoxy, and R ４ represents hydrogen, or R ３ represents hydrogen, and R ４ represents hydrogen, fluoro or methoxy; The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

7. 7. The method according to claim 6 for use in the treatment and / or prevention of sleep-related breathing disorders. A compound comprising: R １ and R ２ together with the nitrogen atom to which they are attached to form an azetidine, Here, the azetidine has two substituents, which are bonded together to the carbon atom of the azetidine. has two substituents which together form an oxetane; R ３ represents hydrogen, and R ４ represents hydrogen, The above compound, a salt thereof, a solvate thereof, or a solvate of a salt thereof.

8. 1. The method of claim 1, wherein the sleep-related breathing disorder is obstructive or central sleep apnea or snoring. Use of the compounds according to any one of claims 1 to 7.

9. The use according to any one of claims 1 to 8, comprising one or more compounds of formula (I) and one or more Combination with other active compounds above.

10. A compound of formula (I) according to any one of claims 1 to 7 for the use according to any one of claims 1 to 7. I) at least one of the compounds of formula I, in combination with one or more inert, non-toxic, pharma- ceutically suitable excipients; A pharmaceutical composition comprising the combination.

11. The combination according to claim 9 is administered in one or more combinations according to any one of claims 1 to 8 for use. A pharmaceutical composition comprising the above in combination with an inert, non-toxic, pharma- ceutically suitable excipient.

12. A method for the treatment and / or prevention of sleep-related breathing disorders comprising any one of claims 1 to 7. or any of claims 1 to 7. At least one of the compounds described herein is combined with an inert, non-toxic, pharma- ceutically acceptable excipient. by systemically and / or locally administering a therapeutically effective amount of a drug comprising the compound.

13. The drug is a muscarinic receptor antagonist, a mineralocorticoid receptor antagonist, at least one further agent selected from the group consisting of antidepressants, diuretics, and corticosteroids; 13. The method of claim 12 further comprising an active compound.

14. Muscarinic receptor antagonist, mineralocorticoid receptor antagonist, diuretic In combination with one or more additional active ingredients selected from the group consisting of drugs, corticosteroids, In addition, a medicament comprising a compound of formula (I) as defined in any one of claims 1 to 7.

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