The present invention relates to a2 -Adrenoceptor subtype C (alpha-2C) antagonists, in particular substituted bipiperidinyl derivatives of formula (I) for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

Background of the invention

Obstructive sleep apnoea (OSA) is a sleep-related respiratory disorder which is characterized by repeated episodes of obstruction of the upper airways. When breathing in, the patency of the upper airways is ensured by the interaction of two opposite forces. The dilative effects of the musculature of the upper airways counteract the negative intraluminal pressure, which constricts the lumen. The active contraction of the diaphragm and the other auxiliary respiratory muscles generates a negative pressure in the airways, thus constituting the driving force for breathing. The stability of the upper respiratory tract is substantially determined by the coordination and contraction property of the dilating muscles of the upper airways.

Upper airway collapse in OSA is thought to occur at sleep onset because of the reduction of activity of several upper airway dilator muscles, which as a consequence are unable to maintain the anatomically vulnerable airway open. However, some upper airway dilator muscles, including the genioglossus muscle, which is the most important of the dilating muscles of the upper respiratory airway and which is innervated by the hypoglossal nerve, can increase activity during sleep in response to respiratory stimuli, potentially counteracting some of these changes at sleep onset. It was observed that OSA patients have apnea free intervals in which the genioglossus muscle activity is only 25-40% higher compared with sleep phases with frequent obstructive apneas (. 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 R.L. Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008, 164 (1-2): 179-196). It is thought, that decreased noradrenergic drive leads to sleep-dependent decline of hypoglossal motoneuron excitability resulting in reduced upper airway dilator muscle activity, especially reduced genioglossus muscle activity.

Alpha2C adrenoceptors 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). An increase in the activity of the motoneurons of the hypoglossal nerve through Alpha2c adrenoceptor antagonism can stabilize the upper airways and protect them from collapse and occlusion. Moreover, also snoring can be inhibited through the mechanism of stabilization of the upper respiratory airways.

For simple snoring, there is no obstruction of the upper airways. By the narrowing of the upper airways, the flow velocity of the inhaled and exhaled air increases. This together with the relaxed muscles causes fluttering of the soft tissues of the mouth and throat in the airflow. This slight vibration generated the typical snoring sounds.

Obstructive snoring (upper airway resistance syndrome, heavy snoring, hypopnea syndrome) is caused by a recurrent partial obstruction of the upper airway during sleep. This results in an increase in airway resistance and thus to an increase in work of breathing with significant intrathoracic pressure fluctuations. The negative intrathoracic pressure development during inspiration can thereby reach values as they occur as a result of a complete airway obstruction in OSA. The pathophysiological effects on the heart, circulation and sleep quality are the same as in obstructive sleep apnea. The pathogenesis is likely the same as in OSA. Obstructive snoring often provides the precursor for OSA ( Hollandt J.H. et al, Upper airway resistance syndrome (UARS) -obstructive snoring. HNO 2000, 48(8): 628-634).

Central sleep apnea (CSA) occurs as a result of disturbed brain function or impaired respiratory regulation. CSA is characterized by a lack of drive to breathe during sleep, resulting in repetitive periods of insufficient or absent ventilation and compromised gas exchange. There are several manifestations of CSA. These include high altitude-induced periodic breathing, idiopathic CSA (ICSA), narcotic-induced central apnea, obesity hypoventilation syndrome (OHS), and Cheyne-Stokes breathing (CSB). While the precise precipitating mechanisms involved in the various types of CSA may vary considerably, unstable ventilatory drive during sleep is a principal underlying feature ( Eckert D.J. et al, Central sleep apnea: Pathophysiology and treatment. Chest 2007, 131(2): 595-607).

US 2018/0235934 Al describes methods for treating disorders such as obstructive sleep apnea using agents for promoting hypoglossal motoneuron excitability. As agents for promoting hypoglossal motoneuron excitability a disinhibtor and/or stimulant of central noradrenic neurons is described. In some embodiments the disinhibitor of central noradrenergic neurons is an alpha2-adrenoceptor antagonist such as yohimbine or an alpha2-adrenoceptor subtype A (alpha-2A) antagonists or alpha2-adrenoceptor subtype C (alpha-2C) antagonist. The alpha2-adrenoceptor antagonist are selected from the group consisting of Atipamezole, MK- 912, RS-79948, RX 821002, [3H]2-methoxy-idazoxan and JP-1302.

Alpha2C adrenoceptors belong to the family of G-protein coupled receptors. Beside the different Alphal- adrenoceptors three different Alpha2-adrenoceptor subtypes exist (Alpha2A, Alpha2B and Alpha2C). They are involved in the mediation of several diverse physiologic effects in different tissues upon stimulation by endogeneous catecholamines (epinephrine, norepinephrine), either derived from synapses or via the blood. Alpha2 adrenoceptors plays an important physiological role, mainly in the cardiovascular system and in the central nervous system. Alpha2A- and Alpha2C-adrenoceptors are the main autoreceptors involved in presynaptic feedback inhibition of noradrenaline in the central nervous system. The potency and affinity of noradrenaline at the Alpha2C-adrenoceptor is higher than that for the Alpha2A-adrenoceptor. The Alpha2C-adrenoceptor inhibits noradrenaline release at low endogenous concentrations of noradrenaline, while Alpha2A -adrenoceptors inhibit noradrenaline release at high endogenous noradrenaline concentrations (Uys M.M. et al. Therapeutic Potential of Selectively Targeting the a2C-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).

Substituted bipiperidinyl derivatives as a2 -Adrenoceptor subtype C (alpha-2C) antagonists as well as their preparation and the use thereof as a medicament are known from WO 2015/091415 Al and in WO 2015/091420 Al where the compounds are disclosed as useful for the treatment and/or prophylaxis of diseases, in particular of cardiovascular disorders, diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardiac vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.

There is nothing disclosed about the use of these compounds in the treatment of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The current gold standard treatment for patients with OSA is continuous positive airway pressure (CPAP). The positive airflow pressure that is generated by an airflow turbine pump splints open the upper airway, reversing all potential causes of pharyngeal collapse, thereby preventing hypopneas, apneas and sleep fragmentation. Unfortunately, up to 50% of all patients with OSA do not tolerate CPAP in the long-term (M. Kohler, D. Smith, V. Tippett et al., Thorax 2010 65(9):829-32: Predictors of long-term compliance with continuous positive airway pressure). Therefore, there is still the need to find effective therapeutic agents for the treatment and/or prophalxis of sleep-related breathing disorders such as obstructive sleep apnea. Therefore the object of the present invention is to provide an effective therapeutic agent for the treatment and/or prophalxis of sleep-related breathing disorders, for example of obstructive sleep apnea, central sleep apnea and snoring.

Surprisingly, it has now been found that substituted bipiperidinyl derivatives of formula (1) of the present invention inhibit upper airway collapsibility and are thus suitable for the production of medicaments for the use in the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The present invention relates to compounds of formula (I)

in which Y is a group

R ¹ represents C2-C6-alkyl or benzyl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, Ci-C i-alkoxy, Ci-C _t -cycloalkyloxy and aminocarbonyloxo, where benzyl may be substituted by 1 or 2 substituents independently of one another selected from halogen; and

R ² is selected from the group consisting of hydrogen and Ci-C _t -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, where the N-heterocycle may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C i-alkyl, Ci-C i-alkoxy, Ci-C i-alkoxy-Ci- C i-al yl, halogen, oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl and aminocarbonyl, or where the N-heterocycle may have two substituents which, together with the carbon atom of the N-heterocycle to which they are jointly attached, form a 4- to 6-membered heterocycle, where this N-heterocycle for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, methyl and ethyl;

R' ¹ is selected from the group consisting of C3-C6-alkyl, Ci-C3-alkoxycarbonyl, oxetanyl, 5- or 6- membered heteroaryl, -(CR ⁵ R ⁶ )-R ⁷ and -CONR ⁸ R ⁹ , where oxetanyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of 3-hydroxy and 3-Ci-C ₄ -alkyl, and where

R ⁵ is selected from the group consisting of hydrogen, methyl and ethyl,

R ⁶ is selected from the group consisting of hydrogen, methyl and ethyl, or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a cyclopropyl ring or cyclobutyl ring,

R ⁷ is selected from the group consisting of hydroxy, hydroxymethyl, Ci-C i-alkyl, Ci- C i-alkoxy, Ci-C3-alkoxycarbonyl, Ci-C _t -alkylaminocarbonyl, phenoxy, oxetanyl, 5- or 6-membered heteroaryl and -CH2NR ¹⁰ R ^U , where phenoxy and heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C4-alkyl and Ci-C4-alkoxy, where oxetanyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of 3-Ci-C i-alkyl and 3-OH, and where

R ¹⁰ is selected from the group consisting of hydrogen and Ci-C i-alkyl, and

R ¹¹ is selected from the group consisting of methyl, methylsulphonyl and formyl,

R ⁸ is selected from the group consisting of Ci-C ₆ -alkyl, C3-C6-cycloalkyl and 5- or 6- membered heteroaryl, where heteroaryl may be substituted by Ci-C4-alkyl, where alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, with the proviso that alkyl is C2-C6- alkyl, Ci-C i-alkoxy, Ci-C i-haloalkyl, C3-C6-cycloalkyl, phenyl, oxetanyl and 5- or 6-membered heteroaryl, in which this phenyl heteroaryl for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and Ci-C i-alkyl in which this oxetanyl for its part may be substituted by one or 2 substituents selected from the group consisting of 3-Ci-C ₄ -alkyl and 3- hydroxy

R ⁹ is selected from the group consisting of hydrogen and Ci-C4-alkyl, or

R ⁸ and R ⁹ together with the nitrogen atom to which they are attached form a piperidinyl ring, where the piperidinyl ring may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C i-alkyl,

R' ² is selected from the group consisting of hydrogen and halogen,

R' ³ is selected from the group consisting of hydrogen, halogen, hydroxy and Ci-C i-alkoxy,

R ³ represents Ci-C3-alkyl, Ci-C3-alkoxycarbonyl, C3-C6-cycloalkyl, C3-C6-cycloalkyl-Ci-C3-alkoxy, C3- C ₆ -cycloalkoxy, trifluoromethoxy-Ci-C i-alkoxy, 5- or 6-membered heteroaryl or -OCONR ¹² R ¹³ , where alkyl may be substituted by a substituent selected from the group consisting of Ci- C i-alkoxy, C3-C6-cycloalkoxy, trifluoromethoxy and phenoxy, in which this phenoxy for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, and where heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C i-alkyl and C3-C6-cycloalkyl, where this alkyl for its part may be substituted by a substituent selected from the group consisting of Ci-C3-alkoxy and C3-C6-cycloalkyl,

R ¹² represents Ci-C i-alkyl,

R ¹³ represents hydrogen or Ci-C i-alkyl, or

R ¹² and R ¹³ together with the nitrogen atom to which they are attached form a pyrrolidinyl ring,

A ¹ represents CH and A ² represents N; or

A ¹ represents N and A ² represents CH; or

A ¹ and A ² represent CH; R ⁴ represents hydrogen or Ci-C i-alkyl, or one of the salts thereof, solvates thereof or solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

In the context of the present invention, unless specified otherwise, the substituents are defined as follows:

Alkyl per se and’’Aik ¹ ’ and’’alkyl ¹ ’ in alkoxy. alkoxyalkyl. alkylamino and alkoxycarbonyl represent a straight- chain or branched alkyl radical having 1 to 6 carbon atoms, preferably 1 to 4 carbon atoms, by way of example and with preference methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, sec-pentyl and n- hexyl.

Alkoxy per se and“alkoxy” in alkoxyalkyl, cycloalkoxy, cycloalkylalkoxy, haloalkoxy represents, by way of example and with preference, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy and tert-butoxy.

Alkoxyalkyl. by way of example and with preference, represents methoxymethyl, ethoxymethyl, n- propoxymethyl, isopropoxymethyl, n-butoxymethyl, tert-butoxymethyl, methoxyethyl, ethoxyethyl, n- propoxyethyl, isopropoxyethyl, n-butoxyethyl and tert-butoxyethyl.

Alkoxycarbonyl. by way of example and with preference, represents methoxycarbonyl, ethoxycarbonyl, n- propoxycarbonyl, isopropoxycarbonyl, n-butoxycarbonyl and tert-butoxycarbonyl.

Alkylaminocarbonyl represents an alkylaminocarbonyl radical having one or two (independently selected) alkyl substituents, by way of example and with preference methylaminocarbonyl, ethylaminocarbonyl, n- propylaminocarbonyl, isopropylaminocarbonyl, tert-butylaminocarbonyl, ,V, /V- d i m c t hy 1 a m i n oc a r b o n y 1 , ,V, ,V- d i c t hy 1 a m i n o c a rb o ny 1 , ,V- c t hy 1 - /V- m c t h y 1 a m i n oc a rb o n y 1 , ,V- m c t hy 1 - /V- n - p ro p y 1 a m i n oc a r b o n y 1 , N- isopropyl-iV-n-propylaminocarbonyl and N- 1 c rt - b u ty 1 - ,V- m c t h y 1 a m i n oc a rb o n y 1. C1-C4- Alkylaminocarbonyl represents, for example, a monoalkylaminocarbonyl radical having 1 to 4 carbon atoms or a dialkylaminocarbonyl radical having in each case 1 to 4 carbon atoms per alkyl substituent.

Cvcloalkyl represents a monocyclic cycloalkyl group having generally 3 to 6, preferably 3 or 6, carbon atoms; cycloalkyl groups which may be mentioned by way of example and with preference are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.

Heteroaryl represents an aromatic monocyclic radical having generally 5 or 6 ring atoms and up to 4 heteroatoms from the group consisting of S, O and N, where a nitrogen atom may also form an N-oxide, by way of example and with preference thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, pyrimidyl, pyridazinyl, pyrazinyl. According to one embodiment, heteroaryl is selected from oxazolyl, isoxazolyl, oxadiazolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl and pyrimidyl.

Halogen represents fluorine, chlorine, bromine and iodine, preferably fluorine and chlorine.

Haloalkyl represents an alkyl radical as defined above which is mono- or polyhalogenated up to the maximum possible number of substituents. In the case of polyhalogenation, the halogen atoms can be identical or different. In the context of the present invention, halogen is fluorine, chlorine, bromine or iodine, preferably fluorine or chlorine.

N-Heterocvcle in the definition of the radicals R ¹ and R ² represents a saturated or partially unsaturated monocyclic radical having 4 to 7 ring atoms having a nitrogen heteroatom and up to 3 further heteroatoms and/or hetero groups from the group consisting of S, O, N, SO and SO2, where a nitrogen atom may also form an N- oxide, by way of example and with preference azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothiomorpholine and 1,1-dioxidothiomorpholine, particularly preferably azetidine, pyrrolidine, piperidine, morpholine and 1,1-dioxidothiomorpholine.

Heterocvcle in the definition of the radicals R ¹ and R ² . having a joint carbon atom with the N-heterocycle to which it is attached, represents a saturated and partially unsaturated monocyclic radical having 4 to 6 ring atoms and up to 4 heteroatoms and/or hetero groups from the group consisting of S, O, N, SO and SO2, where a nitrogen atom may also form an N-oxide, by way of example and with preference azetidine, oxetane, thietane, pyrrolidine, tetrahydrofuran, piperidine, morpholine, thiomorpholine, piperazine and tetrahydropyran, particularly preferably azetidine and oxetane and even more preferably oxetane.

The term "hydroxy", as employed herein as such or as part of another group, refers to a -OH group.

When radicals in the compounds of the invention are substituted, the radicals may be mono- or polysubstituted, unless specified otherwise. In the context of the present invention, all radicals which occur more than once are defined independently of one another. Substitution by one, two or three identical or different substituents is preferred.

The expression "compounds of the invention" as employed herein refers to the compounds of formula I.

Pharmaceutically acceptable salts, e.g. acid addition salts, with both organic and inorganic acids, are known in the field of pharmaceuticals. Representative examples of pharmaceutically acceptable acid addition salts include, but are not limited to, chlorides, bromides, sulfates, nitrates, phosphates, sulfonates, methane sulfonates, formates, tartrates, maleates, citrates, benzoates, salicylates, ascorbates, acetates and oxalates. Hydrates or solvates are designated according to the invention as those forms of the compounds of the formula (I) which in the solid or liquid state form a molecular compound or a complex by hydration with water or coordination with solvent molecules. Examples of hydrates are sesquihydrates, monohydrates, dihydrates or trihydrates. Equally, the hydrates or solvates of salts of the compounds according to the invention are also suitable.

Pharmaceutically acceptable esters, when applicable, may be prepared by known methods using pharmaceutically acceptable acids that are conventional in the field of pharmaceuticals and that retain the pharmacological properties of the free form. Nonlimiting examples of these esters include esters of aliphatic or aromatic alcohols. Representative examples of pharmaceutically acceptable esters include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, and benzylesters.

The invention includes within its scope all the possible geometric isomers, e.g. Z and E isomers (cis and trans isomers), of the compounds as well as all the possible optical isomers, e.g. diastereomers and enantiomers, of the compounds. Furthermore, the invention includes in its scope both the individual isomers and any mixtures thereof, e.g. racemic mixtures. The individual isomers may be obtained using the corresponding isomeric forms ofthe starting material or they may be separated after the preparation ofthe end compound according to conventional separation methods. For the separation of optical isomers, e.g. enantiomers, from the mixture thereof, conventional resolution methods, e.g. fractional crystallization, may be used. A particular embodiment of the present invention relates to compounds of the formula (1) in which Y is a group

R ¹ represents C2-C6-alkyl or benzyl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, Ci-C i-alkoxy and aminocarbonyloxo, where benzyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine and chlorine; and

R ² is selected from the group consisting of hydrogen and Ci-C i-alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1 -oxidothiomorpholine or 1,1- dioxidothiomorpholine, where azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1 -oxidothiomorpholine and 1 , 1 -dioxidothiomorpholine may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of C1-C2- alkyl, Ci-C2-alkoxy, Ci-C2-alkoxy-Ci-C2-alkyl and halogen, or where azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1 -oxidothiomorpholine and 1 , 1 -dioxidothiomorpholine may have two substituents which together with the carbon atom of the azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1 -oxidothiomorpholine or 1 , 1 -dioxidothiomorpholine to which they are jointly attached form an azetidine or oxetane, where this azetidine or oxetane for its part may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of 3- methyl and 3 -ethyl,

R ³ is selected from the group consisting of Ci-C i-alkyl and C3-C6-cycloalkyl-Ci-C4-alkoxy;

A ¹ represents CH and A ² represents N; or

A ¹ represents N and A ² represents CH; or

A ¹ and A ² represent CH and

R ⁴ represents hydrogen, and the salts thereof, the solvates thereof and the solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which Y is a group

R ¹ represents C2-C4-alkyl or benzyl, where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, Ci-C2-alkoxy and aminocarbonyloxo, where benzyl may be substituted by 1 or 2 fluorine substituents, and

R ² represents hydrogen or Ci-C2-alkyl; or

R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine, where azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents selected independently from the group consisting of methyl, methoxy, methoxymethyl and fluorine, or where azetidine, pyrrolidine, piperidine, morpholine and 1,1-dioxidothiomorpholine may have two substituents which together with the carbon atom of the azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine to which they are jointly attached form an azetidine or oxetane, where this azetidine or oxetane for its part may be substituted by 1 to 2

substituents independently of one another selected from the group consisting of 3- methyl and 3 -ethyl,

R ³ is selected from the group consisting of methyl and cyclopropylmethoxy; A ¹ represents CH and A ² represents N; or

A ¹ represents N and A ² represents CH; or

A ¹ and A ² represent CH and R ⁴ represents hydrogen, and the salts thereof, the solvates thereof and the solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which Y is a group

R ¹ is selected from the group consisting of methoxyethyl, hydroxy-sec-butyl, sec-butyl carbamate, methoxy-sec-butyl and benzyl, where benzyl may be substituted by 1 to 2 fluorine substituents; and R ² represents hydrogen or methyl; or R ¹ and R ² together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine, where azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents selected independently from the group consisting of methyl, methoxy, methoxymethyl and fluorine, or where azetidine may have two substituents which, together with the carbon atom of the azetidine to which they are jointly attached, form an oxetane,

R ³ is selected from the group consisting of methyl and cyclopropylmethoxy; A ¹ is CH; and

A ² represents N; or

A ¹ represents N; and

A ² represents CH; or

A ¹ and A ² represent CH and R ⁴ represents hydrogen and the salts thereof, the solvates thereof and the solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders.

A further particular embodiment of the present invention relates to compounds of the formula (I) in which Y is a group

R' ¹ represents C3-C4-alkyl, Ci-C3-alkoxycarbonyl, oxetanyl, oxazolyl, -(CR ⁵ R ⁶ )-R ⁷ or -CONR ⁸ R ⁹ , where oxetanyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of 3-hydroxy and 3-Ci-C ₃ -alkyl, and where

R ⁵ is selected from the group consisting of hydrogen, methyl and ethyl,

R ⁶ is selected from the group consisting of hydrogen, methyl and ethyl, or R ⁵ and R ⁶ together with the carbon atom to which they are attached form a cyclopropyl ring or cyclobutyl ring,

R ⁷ is selected from the group consisting of hydroxy, hydroxymethyl, Ci-C3-alkyl, C1-C3- alkoxy, Ci-C3-alkoxycarbonyl, Ci-C3-alkylaminocarbonyl, phenoxy, oxetanyl, pyrazolyl and -CH ₂ NR ¹⁰ R ^U , where phenoxy and pyrazolyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C2-alkyl and Ci-C2-alkoxy, where oxetanyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of 3-Ci-C ₂ -alkyl, and where is selected from the group consisting of hydrogen and Ci-C2-alkyl, and R ¹¹ is selected from the group consisting of methyl, methylsulphonyl and formyl,

R ⁸ is selected from the group consisting of Ci-C _t -alkyl, C ₃ -C ₆ -cycloalkyl and oxazolyl, where alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, with the proviso that alkyl is C ₂ -C ₄ - alkyl, Ci-C ₂ -alkoxy, Ci-C ₂ -haloalkyl, C ₃ -C i-cycloalkyl, phenyl, oxetanyl, oxazolyl, pyrazolyl and pyridyl, in which this phenyl or pyridyl for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, difluoromethoxy, trifluoromethoxy and methyl, in which this oxetanyl for its part may be substituted by 3 -methyl and in which this oxazolyl for its part may be substituted by 1 to 3 methyl substituents,

R ⁹ is selected from the group consisting of hydrogen and Ci-C ₃ -alkyl,

R' ² is selected from the group consisting of hydrogen, fluorine and chlorine,

R' ³ is selected from the group consisting of hydrogen, fluorine, chlorine, hydroxy and Ci-C ₂ -alkoxy,

R ³ is selected from the group consisting of Ci-C ₂ -alkyl, Ci-C ₃ -alkoxycarbonyl, C ₃ -C ₄ -cycloalkyl, C ₃ -C ₄ - cycloalkyl-Ci-C ₃ -alkoxy, C ₃ -C ₄ -cycloalkoxy, trifluoromethoxy-Ci-C ₂ -alkoxy, oxadiazole, triazole and pyrrolidine- 1 -carboxylate, where alkyl may be substituted by a substituent selected from the group consisting of Ci- C ₄ -alkoxy, C ₃ -C ₄ -cycloalkoxy, trifluoromethoxy and phenoxy, in which this phenoxy for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine and chlorine, and where oxadiazole or triazole may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of Ci-C2-alkyl and C3-C4-cycloalkyl, in which this alkyl for its part may be substituted by a substituent selected from the group consisting of Ci-C3-alkoxy and C3-C i-cycloalkyl and R ⁴ represents hydrogen, and the salts thereof, the solvates thereof and the solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders.

A further particular preferred embodiment of the present invention relates to compounds of the formula (I) in which Y is a group

R' ¹ represents C3-C4-alkyl, oxetanyl, -(CR ⁵ R ⁶ )-R ⁷ or -CONR ⁸ R ⁹ , where oxetanyl may be substituted by a substituent selected from the group consisting of 3- hydroxy and 3 -methyl, and where

R ⁵ is selected from the group consisting of hydrogen, methyl and ethyl,

R ⁶ is selected from the group consisting of hydrogen, methyl and ethyl, or

R ⁵ and R ⁶ together with the carbon atom to which they are attached form a cyclobutyl ring,

R ⁷ is selected from the group consisting of hydroxy, methyl, methoxy, oxetanyl, and -CH ₂ NR ¹⁰ R ^u , where oxetanyl may be substituted by a 3 -methyl substituent, and where

R ¹⁰ is selected from the group consisting of hydrogen and methyl, and

R ¹¹ is selected from the group consisting of methyl, methylsulphonyl and formyl,

R ⁸ is selected from the group consisting of Ci-C _t -alkyl and oxazolyl, where alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, with the proviso that alkyl is C2-C6- alkyl, phenyl and pyridyl, in which this phenyl or pyridyl for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of chlorine, fluorine and trifluoromethyl, and where oxazolyl may be substituted by 1 to 3 methyl substituents,

R ⁹ is selected from the group consisting of hydrogen and methyl,

R' ² represents hydrogen,

R' ³ is selected from the group consisting of hydrogen and chlorine,

R ³ is selected from the group consisting of methyl, ethyl, ethoxycarbonyl, cyclopropyl, C3-C4-cycloalkyl-Ci- C2-alkoxy, oxadiazolyl and triazolyl, where methyl or ethyl may be substituted by a substituent selected from the group consisting of methoxy, ethoxy, tert-butoxy, C3-C4-cycloalkoxy and trifluoromethoxy, and where oxadiazolyl or triazolyl may be substituted by 1 to 3 methyl substituents, in which this methyl for its part may be substituted by C3-C4-cycloalkyl and R ⁴ represents hydrogen and the salts thereof, the solvates thereof and the solvates of the salts thereof, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders.

The following preferred embodiments refer to compounds of formula (I) in which

Y is a group

• Preference is also given to compounds of the formula (I) in which R ¹ represents sec-butyl which may be substituted by a substituent selected from the group consisting of hydroxy, methoxy and carbamate.

• Preference is also given to compounds of the formula (I) in which R ¹ represents methoxyethyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents benzyl which may be substituted by 1-2 fluorine substituents.

• Preference is also given to compounds of the formula (I) in which R ² represents hydrogen.

• Preference is also given to compounds of the formula (I) in which R ² represents methyl.

• Preference is also given to compounds of the formula (I) in which R ¹ and R ² together with the nitrogen atom to which they are attached form a 2-methoxymethylpyrrolidine, 3- methoxypyrrolidine, 4,4-difluoropiperidine, 3-methylpiperidine, morpholine, 1,1- dioxidothiomorpholine or 2-oxa-6-azaspiro[3.3]hept-6-yl.

• Preference is also given to compounds of the formula (I) in which R ³ represents methyl.

• Preference is also given to compounds of the formula (I) in which R ³ represents cyclopropylmethoxy.

• Preference is also given to compounds of the formula (I) in which A ¹ represents CH and A ² represents N.

• Preference is also given to compounds of the formula (I) in which A ¹ represents N and A ² represents CH. • Preference is also given to compounds of the formula (I) in which A ¹ and A ² represent CH. The following preferred embodiments refer to compounds of formula (I) in which

Y is a group

· Preference is also given to compounds of the formula (I) in which R ¹ is selected from the group consisting of 1 -hydroxy- 1 -methylethyl, 1-methoxy-l-methylethyl, tert-butylaminocarbonyl, tert-butyl and isobutyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents 1 -hydroxy- 1- methylethyl. · Preference is also given to compounds of the formula (I) in which R ¹ represents tert- butylaminocarbonyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents tert-butyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents oxetanyl, where oxetanyl may be substituted by a substituent selected from the group consisting of 3 -hydroxy and 3- methyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents -(CR ⁶ R ⁷ )-R ⁸ , where

R ⁶ is selected from the group consisting of hydrogen, methyl and ethyl,

R ⁷ is selected from the group consisting of hydrogen, methyl and ethyl, or

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclobutyl ring,

R ⁸ is selected from the group consisting of hydroxy, methoxy, oxetanyl, and -CH2NR ¹³ R ¹⁴ , where oxetanyl may be substituted by a 3 -methyl substituent, and

where

R ¹³ is selected from the group consisting of hydrogen and methyl,

and

R ¹⁴ is selected from the group consisting of methyl, methylsulphonyl and formyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents -(CR ⁶ R ⁷ )-R ⁸ ,

where

R ⁶ and R ⁷ are selected from the group consisting of methyl and ethyl,

R ⁸ is selected from the group consisting of hydroxy and methoxy.

· Preference is also given to compounds of the formula (I) in which R ¹ represents -(CR ⁶ R ⁷ )-R ⁸ ,

where

R ⁶ and R ⁷ are hydrogen,

R ⁸ represents oxetanyl,

where oxetanyl may be substituted by a 3 -methyl substituent.

· Preference is also given to compounds of the formula (I) in which R ¹ represents -(CR ⁶ R ⁷ )-R ⁸ ,

where

R ⁶ and R ⁷ together with the carbon atom to which they are attached form a cyclobutyl ring,

R ⁸ represents -CH ₂ NR ¹³ R ¹⁴ ,

where

R ¹³ is selected from the group consisting of hydrogen and methyl,

and

R ¹⁴ is selected from the group consisting of methyl and methylsulphonyl. • Preference is also given to compounds of the formula (I) in which R ¹ represents -CONR ⁹ R ¹⁰ , where

R ⁹ represents Ci-C i-alkyl, or oxazolyl, where alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, with the proviso that alkyl is C2-C6-alkyl, trifluoromethyl, phenyl and pyridyl, in which this phenyl or pyridyl for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of chlorine, fluorine, trifluoromethyl and methyl, and where oxazolyl may be substituted by a 3 -methyl substituent,

R ¹⁰ is selected from the group consisting of hydrogen and methyl.

• Preference is also given to compounds of the formula (I) in which R ¹ represents -CONR ⁹ R ¹⁰ , where

R ⁹ represents Ci-C i-alkyl, where alkyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of hydroxy, with the proviso that alkyl is C2-C6-alkyl, trifluoromethyl, phenyl and pyridyl, in which this phenyl or pyridyl for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of chlorine, fluorine, trifluoromethyl and methyl,

R ¹⁰ is selected from the group consisting of hydrogen and methyl.

• Preference is also given to compounds of the formula (1) in which R ¹ represents -CONR ⁹ R ¹⁰ , where R ⁹ represents oxazolyl, where oxazolyl may be substituted by a 3 -methyl substituent,

R ¹⁰ is selected from the group consisting of hydrogen and methyl.

• Preference is also given to a compound of the formula (I) in which

R ¹ represents -(CR ⁶ R ⁷ )-R ⁸ , where R ⁶ and R ⁷ represent methyl,

R ⁸ represents hydroxy,

R ² and R ³ represent hydrogen,

R ⁴ represents methyl and

R ⁵ represents hydrogen, or one of the salts thereof, solvates thereof or solvates of the salts thereof.

• Preference is also given to compounds of the formula (I) in which R ² and R ³ represent hydrogen.

• Preference is also given to compounds of the formula (I) in which R ⁴ is selected from the group consisting of methyl, ethyl, methoxymethyl, trifluoromethoxymethyl, ethoxycarbonyl, cyclopropylmethoxy, cyclobutylmethoxy, cyclopropoxymethyl, cyclobutoxymethyl, isopropoxy, methoxy, ethoxy, cyclopropyl and (cyclobutylmethyl)-4H-l,2,4-triazol-3-yl.

• Preference is also given to compounds of the formula (I) in which R ⁴ is selected from the group consisting of methyl and ethyl.

• Preference is also given to compounds of the formula (I) in which R ⁴ represents methoxymethyl.

• Preference is also given to compounds of the formula (I) in which R ⁴ represents trifluoromethoxymethyl. · Preference is also given to compounds of the formula (I) in which R ⁴ represents ethoxycarbonyl.

• Preference is also given to compounds of the formula (I) in which R ⁴ is selected from the group consisting of cyclopropylmethoxy and cyclobutylmethoxy.

• Preference is also given to compounds of the formula (I) in which R ⁴ is selected from the group consisting of cyclopropoxymethyl and cyclobutoxymethyl. • Preference is also given to compounds of the formula (I) in which R ⁴ is selected from the group consisting of isopropoxy, methoxy and ethoxy.

• Preference is also given to compounds of the formula (I) in which R ⁴ represents cyclopropyl.

• Preference is also given to compounds of the formula (I) in which R ⁴ represents triazolyl, where triazolyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of Ci-C _t -alkyl and C3-C6-cycloalkyl, where alkyl may be substituted by a substituent selected from the group consisting of cyclopropyl and cyclobutyl.

• Preference is also given to compounds of the formula (I) in which R ⁴ represents (cyclobutylmethyl)-4H- l,2,4-triazol-3-yl.

• Preference is also given to compounds of the formula (I) in which R ⁵ represents hydrogen.

In a preferred embodiment the present invention relates to a compound of the formula (I) selected from the group consisting of:

[(3R)-3-Methyl-l,4'-bipiperidin-r-yl][6-(morpholin-4-yl)p yridin-3-yl]methanone formic acid salt, [(3R)-3-

Methyl- 1 ,4'-bipiperidin- 1’-yl] [6-(morpholin-4-yl)pyridin-3 -yl]methanone, {6- [(2R)-2-

(Methoxymethyl)pyrrolidin- 1 -yl]pyridin-3 -yl} [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yljmethanone formic acid salt, {6-[(2-Methoxyethyl)amino]pyridin-3-yl} [(3R)-3-methyl-l,4'-bipiperidin-r-yl]methanone, [6-(4,4-

Difluoropiperidin- 1 -yl)pyridin-3 -yl] [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, {6-[(2-

Methoxyethyl)(methyl)amino]pyridin-3 -yl} [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone hydrochloride, [3 -(Cyclopropylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [6-(morpholin-4-yl)pyridin-3 -yl]methanone, {6- [(2,6-

Difluorobenzyl)(methyl)amino]pyridin-3 -yl} [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, [6-( 1 , 1 -

Dioxidothiomorpholin-4-yl)pyridin-3 -yl] [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, (6- {[(2S)-l- Hydroxybutan-2-yl]amino} pyridin-3 -yl) [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, {6- [( 1 -

Hydroxybutan-2-yl)amino]pyridin-3-yl} [(3R)-3-methyl-l,4'-bipiperidin-r-yl]methanone, 2-[(5- {[(3R)-3- Methyl- 1 ,4'-bipiperidin- 1’-yl] carbonyl} pyridin-2-yl)amino]butyl carbamate, [6-(3 -Methoxypyrrolidin- 1 - yl)pyridin-3 -yl] [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, {6- [( 1 -Methoxybutan-2-yl)amino]pyridin- 3 -yl} [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, [(3R)-3 -Methyl- 1 ,4'-bipiperidin- 1’-yl] [6-(3 - methylpiperidin- 1 -yl)pyridin-3 -yl]methanone, [(3R)-3 -Methyl- 1 ,4'-bipiperidin- 1’-yl] [2-(morpholin-4- yl)pyrimidin-5-yl]methanone, [3 -(Cyclopropylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [2-(morpholin-4- yl)pyrimidin-5-yl]methanone, [(3R)-3-Methyl-l,4'-bipiperidin-r-yl][2-(2-oxa-6-azaspiro[3. 3]hept-6- yl)pyrimidin-5-yl]methanone, [2-(4,4-Difluoropiperidin- 1 -yl)pyrimidin-5-yl] [(3R)-3-methyl- 1 ,4'- bipiperidin-r-yl]methanone, {2-[(2R)-2-(Methoxymethyl)pyrrolidin-l-yl]pyrimidin-5-yl} [(3R)-3-methyl- 1 ,4'-bipiperidin- 1 '-yl]methanone, [5-( 1 , 1 -Dioxidothiomorpholin-4-yl)pyrazin-2-yl] [(3R)-3 -methyl- 1,4'- bipiperidin- 1 '-yl]methanone,

Ethyl 1 '- [(4-tert-butylphenyl)carbonyl] - 1 ,4'-bipiperidine-3 -carboxylate, 3 -(Ethoxycarbonyl)- 1 - { 1 - [4- (ethoxycarbonyl)benzoyl]piperidin-4-yl}piperidine trifluoroacetic acid salt, (3-Chloro-4-tert- butylphenyl)(3 -methyl- l,4'-bipiperidin-l'-yl)methanone trifluoroacetic acid salt, (4-Isopropylphenyl)(3- methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, (4-tert-Butylphenyl)(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, (4-tert-Butylphenyl)(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, (-)-enantiomer, [4-( 1 -Hydroxy- 1 - methylethyl)phenyl)] (3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, [4-( 1 -Hydroxy- 1 -methylethyl)phenyl)] (3 - methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, (-)-enantiomer, Ethyl 1 '- [4-(2-hydroxypropan-2-yl)benzoyl] -1,4'- bipiperidine-3 -carboxylate, {4- [(2-Methoxyphenoxy)methyl]phenyl} [3 -methyl- 1 ,4'-bipiperidin- 1 '- yl]methanone, {4- [(3 ,5-Dimethyl- 1 H-pyrazol- 1 -yl)methyl]phenyl} (3 -methyl- 1 ,4'-bipiperidin- 1 '- yl)methanone, (2-Hydroxy-4-tert-butylphenyl)(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, [4-

(Ethoxymethyl)phenyl] (3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, [4-(Phenoxymethyl)phenyl] (3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone, (4-tert-Butyl-2-methoxyphenyl)(3 -methyl- 1 ,4'-bipiperidin- 1 '- yl)methanone, r-(4-tert-Butylbenzoyl)-l,4'-bipiperidin-3-yl cyclopropylcarbamate, l-[l-(4-tert- Butylbenzoyl)piperidin-4-yl]-4,5-dimethyl-l,2,3,6-tetrahydro pyridine, (4-tert-Butylphenyl)[3-(5-methyl- 1 ,3 ,4-oxadiazol-2-yl)- 1 ,4'-bipiperidin- 1 '-yl]methanone, (4-tert-Butylphenyl)[3 -(methoxymethyl)- 1,4'- bipiperidin- 1 '-yl]methanone, cis- 1 - [ 1 -(4-tert-Butylbenzoyl)piperidin-4-yl] -3 ,4-dimethylpiperidine trifluoroacetic acid salt, l-[l-(4-tert-Butylbenzoyl)piperidin-4-yl]-3-(3-methyl-lH-l,2 ,4-triazol-5- yl)piperidine trifluoroacetic acid salt, Methyl 4-[(3-methyl-l,4'-bipiperidin-l'-yl)carbonyl]benzoate, (3- Methyl- 1 ,4'-bipiperidin- 1’-yl) {4- [(3 -methyloxetan-3 -yl)methyl]phenyl}methanone, Ethyl G- {4- [(3 - methyloxetan-3 -yl)methyl]benzoyl} - 1 ,4'-bipiperidine-3 -carboxylate, (3 -Methyl- 1 ,4'-bipiperidin- 1 '-yl)[4-(3 - methyloxetan-3 -yl)phenyl]methanone, Ethyl 1 '- [4-(3 -methyloxetan-3 -yl)benzoyl] - 1 ,4'-bipiperidine-3 - carboxylate, l- {l-[4-(l -Ethoxy-2-methyl- 1 -oxopropan-2-yl)benzoyl]piperidin-4-yl} -3 -methylpiperidine trifluoroacetic acid salt, l- {l-[4-(l -Hydroxy-2-methylpropan-2-yl)benzoyl]piperidin-4-yl} -3 - methylpiperidine trifluoroacetic acid salt, 3-(Ethoxycarbonyl)-l- {l-[4-(l-ethoxy-2-methyl-l-oxopropan-2- yl)benzoyl]piperidin-4-yl}piperidine trifluoroacetic acid salt, l-(l- {4-[l-

(Ethoxycarbonyl)cyclopropyl]benzoyl}piperidin-4-yl)-3-met hylpiperidine trifluoroacetic acid salt, l-(l- {4- [l-(Hydroxymethyl)cyclopropyl]benzoyl}piperidin-4-yl)-3 -methylpiperidine trifluoroacetic acid salt, 1 - { 1 - [4-(Ethoxycarbonyl)benzoyl]piperidin-4-yl} -3 -methylpiperidine trifluoroacetic acid salt, l- {l-[4-(2- Ethoxy-2-oxoethyl)benzoyl]piperidin-4-yl} -3 -methylpiperidine trifluoroacetic acid salt, 3- (Ethoxycarbonyl)- 1 - { 1 -[4-(2-ethoxy-2-oxoethyl)benzoyl]piperidin-4-yl}piperidine trifluoroacetic acid salt, N-Butyl-N-methyl-4-[(3-methyl-l,4'-bipiperidin-l'-yl)carbony l]benzamide, N-(2-Methoxyethyl)-4-[(3- methyl- 1 ,4'-bipiperidin- 1 '-yl)carbonyl]benzamide, 1 -( 1 - {4- [Ethyl-(2- methoxyethyl)carbamoyl]benzoyl}piperidin-4-yl)-3 -methylpiperidine trifluoroacetic acid salt, l- {l-[4-(tert- Butylcarbamoyl)benzoyl]piperidin-4-yl}-3-methylpiperidine trifluoroacetic acid salt, (3 -Methyl- 1,4'- bipiperidin-l'-yl)[4-(l,3-oxazol-5-yl)phenyl]methanone, l'-(4-tert-Butylbenzoyl)-l,4'-bipiperidin-3-yl- pyrrolidin-l-carboxylate trifluoroacetic acid salt, Methyl 2- {3-fluoro-4-[(3-methyl-l,4'-bipiperidin-r- yl)carbonyl]phenyl}-2-methylpropanoate trifluoroacetic acid salt, Ethyl l'-[4-(2-methoxypropan-2- yl)benzoyl]-l,4'-bipiperidine-3-carboxylate, N-Methyl-4- {[(3R)-3-methyl-l,4'-bipiperidin-r-yl]carbonyl}- N-( 1 -phenylethyl)benzamide, 4- [(3 -methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl] -N-(pentan-2-yl)benzamide, 4- [(3 -methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl] -N-(pyridin-4-yl-methyl)benzamide, (2,4-dimethylpiperidin- 1 - yl) {4- [(3 -methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl]phenyl} methanone, 4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '- yl)carbonyl]-N-(3-methylbutan-2-yl)benzamide, N-methyl-4-[(3-methyl-l,4'-bipiperidin-r-yl)carbonyl]-N- (2-methylpropyl)benzamide, N-cyclohexyl-N-methyl-4-[(3-methyl-l,4'-bipiperidin-r- yl)carbonyl]benzamide, N-methyl-4-[(3-methyl-l,4'-bipiperidin-r-yl)carbonyl]-N-[(3- methyl-l,2-oxazol-5- yl)methyl]benzamide, N-(cyclopropylmethyl)-4-[(3-methyl-l,4'-bipiperidin-r-yl)car bonyl]-N- propylbenzamide, N-methyl-4- [(3 -methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl] -N- [(3 -methyloxetan-3 - yl)methyl]benzamide, N- [ 1 -(4-chlorophenyl)-3 -hydroxypropan-2-yl] -4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '- yl)carbonyl]benzamide, 4- [(3 -methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl] -N- [ 1 -( 1 H-pyrazol- 1 -yl)propan-2- yljbenzamide, N-(l-methoxypropan-2-yl)-4-[(3-methyl-l,4'-bipiperidin-r-yl) carbonyl]benzamide, N-(3,5- dimethyl- 1 ,2-oxazol-4-yl)-4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)carbonyl]benzamide, N-Methyl-N- [( 1 - {4- [(3 - methyl- 1 ,4'-bipiperidin- 1 ' yl)carbonyl]phenyl} cyclobutyl)methyl]methanesulphonamide, [4-(2- Hydroxypropan-2-yl)phenyl] [3 -(methoxymethyl)- 1 ,4'-bipiperidin- 1 '-yl] methanone, (4-tert-Butylphenyl)[3 - (5-methyl- 1 ,2,4-oxadiazol-2-yl)- 1 ,4'-bipiperidin- 1’-yl] methanone, [3 -(5-Cyclopropyl-4H- 1 ,2,4-triazol-3 - yl)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, [3 -(5-Cyclobutyl-4H- 1 ,2,4-triazol- 3 -yl)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, [3 -(5-Ethyl- 1 H- 1 ,2,4-triazol-3 - yl)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, [4-(2-Hydroxypropan-2- yl)phenyl] [3 -(3 -methyl- 1 H- 1 ,2,4-triazol-5-yl)- 1 ,4'-bipiperidin- 1’-yl] methanone, [4-(2-Hydroxypropan-2- yl)phenyl][3-(lH-l,2,4-triazol-5-yl)-l,4'-bipiperidin-l'-yl] yl]methanone, N-tert-Butyl-2- {3-fluoro-4-[(3- methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl]phenyl} -2-methylpropanamide, N- [( 1 - {4- [(3 -Methyl- 1,4'- bipiperidin- 1’-yl)carbonyl]phenyl} cyclobutyl)methyl] formamide hydrochloride, N-Methyl-N- [( l- {4-[(3- methyl-l,4'-bipiperidin-r-yl)carbonyl]phenyl}cyclobutyl)meth yl]formamide trifluoroacetic acid salt, (4- { 1 - [(Methylamino)methyl]cyclobutyl}phenyl)(3-methyl- 1 ,4'-bipiperidin- 1 '-yl)methanone trifluoroacetic acid salt, {3-[5-(Cyclobutylmethyl)-4H-l,2,4-triazol-3-yl]-l,4'-bipiper idin-l'-yl} [4-(2-hydroxypropan-2- yl)phenyl]methanone, 4- [(3 -Methyl- 1 ,4'-bipiperidin- 1’-yl)carbonyl] -N- [3 -

(trifluoromethoxy)benzyl]benzamide trifluoroacetic acid salt, 4-[(3-Methyl-l,4'-bipiperidin-l'-yl)carbonyl]- N-(2-phenylpropan-2-yl)benzamide trifluoroacetic acid salt, 4-[(3-Methyl-l,4'-bipiperidin-l'-yl)carbonyl]- N- {2-[4-(trifluoromethyl)phenyl]propan-2-yl}benzamide trifluoroacetic acid salt, N-[2-(3,4- Dichlorophenyl)propan-2-yl] -4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)carbonyl]benzamide trifluoroacetic acid salt, 4- {[4-(3-Methylcyclohexyl)piperidin-l-yl]carbonyl}-N-[(3-methy lpyridin-2-yl)methyl]benzamide trifluoroacetic acid salt, N-[(2-Chloropyridin-4-yl)methyl]-4-[(3-methyl-l,4'-bipiperid in-r- yl)carbonyl]benzamide trifluoroacetic acid salt, N-[(6-Chloropyridin-2-yl)methyl]-4-[(3-methyl-l,4'- bipiperidin-r-yl)carbonyl]benzamide trifluoroacetic acid salt, N-[2-(4-Chlorophenyl)propan-2-yl]-4-[(3- methyl-l,4'-bipiperidin-r-yl)carbonyl]benzamide trifluoroacetic acid salt, N-[2-(2-Chlorophenyl)propan-2- yl]-4-[(3-methyl-l,4'-bipiperidin-r-yl)carbonyl]benzamide trifluoroacetic acid salt, N-[2-(3- Chlorophenyl)propan-2-yl] -4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)carbonyl]benzamide trifluoroacetic acid salt, N-[2-(3,5-Dichlorophenyl)propan-2-yl]-4-[(3-methyl-l,4'-bipi peridin-r-yl)carbonyl]benzamide trifluoroacetic acid salt, 4-[(3-Methyl-l,4'-bipiperidin-l'-yl)carbonyl]-N-[2-

(trifluoromethyl)benzyl]benzamide trifluoroacetic acid salt, (R)-N-[(3,5-Difluoropyridin-2-yl)methyl]-4- {[(3R)-3-methyl-l,4'-bipiperidin-r-yl]carbonyl}benzamide trifluoroacetic acid salt, (R)-N-[(2- Chloropyridin-3-yl)methyl]-4- {[(3R)-3-methyl-l,4'-bipiperidin-r-yl]carbonyl}benzamide trifluoroacetic acid salt, (R)-N-(2,6-Difluorobenzyl)-N-methyl-4- { [(3R)-3-methyl- 1 ,4'-bipiperidin- 1 '- yl]carbonyl}benzamide trifluoroacetic acid salt, 4- {[(3R)-3-Methyl-l,4'-bipiperidin-l'-yl]carbonyl}-N- {2,2,2-trifluoro-l-[4-(trifluoromethyl)phenyl] ethyl} benzamide trifluoroacetic acid salt, (R)-N-[3- (Difluoromethoxy)benzyl] -4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '-yl)carbonyl]benzamide trifluoroacetic acid salt, N-[l-(2,6-Difluorophenyl)ethyl]-4- {[(3R)-3-methyl-l,4'-bipiperidin-r-yl]carbonyl}benzamide

trifluoroacetic acid salt, N-(2,6-Difluorobenzyl)-4- {[(3R)-3-methyl-l,4'-bipiperidin-r- yl]carbonyl}benzamide trifluoroacetic acid salt, N-[l-(2-Fluorophenyl)-3-hydroxypropyl]-4- {[(3R)-3- methyl-l,4'-bipiperidin-r-yl]carbonyl}benzamide trifluoroacetic acid salt, N-[(4-Chloropyridin-2- yl)methyl] -4- { [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1’-yljcarbonyl} benzamide, N- { [5-Chloro-3 -

(trifluoromethyl)pyridin-2-yl]methyl} -4- { [(3R)-3-methyl- 1 ,4'-bipiperidin- 1’-yljcarbonyl} benzamide, N- { [5- Chloro-4-(trifluoromethyl)pyridin-2-yl]methyl} -4- { [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '- yljcarbonyl} benzamide, 4- { [(3R)-3 -Methyl- 1 ,4'-bipiperidin- 1’-yljcarbonyl} -N- [ 1 -(pyridin-4- yl)ethyl]benzamide, N- [ 1 -(2-Fluorophenyl)-2-hydroxyethyl] -4- { [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1 '- yljcarbonyl} benzamide, 4- {[(3R)-3-Methyl-l,4'-bipiperidin-r-yl]carbonyl}-N-[(2-methyl pyridin-3- yl)methyl]benzamide, N-(2,6-Difluorobenzyl)-4- { [3-(methoxymethyl)- 1 ,4'-bipiperidin- 1’-yljcarbonyl} -N- methylbenzamide trifluoroacetic acid salt, N-[(3,5-Difluoropyridin-2-yl)methyl]-4- {[3-(methoxymethyl)- l,4'-bipiperidin-r-yl]carbonyl}benzamide trifluoroacetic acid salt, N-[(3-Fluoropyridin-2-yl)methyl]-4- { [(3R)-3 -methyl- 1 ,4'-bipiperidin- 1’-yljcarbonyl} benzamide, [3 -Chloro-4-(2-hydroxypropan-2- yl)phenyl] [(3R)-3-methyl- 1 ,4'-bipiperidin- 1 '-yljmethanone, N-tert-Butyl-2-chloro-4- { [(3R)-3-methyl- 1 ,4'- bipiperidin-r-yl]carbonyl}benzamide formic acid salt, N-tert-Butyl-3-chloro-4- {[(3R)-3-methyl-l,4'- bipiperidin-r-yl]carbonyl}benzamide formic acid salt, N-tert-Butyl-3-fluoro-4-[(3-methyl-l,4'-bipiperidin- 1 '-yl)carbonyl]benzamide hydrochloride, N-tert-Butyl-2-fluoro-4- [(3 -methyl- 1 ,4'-bipiperidin- 1 '- yl)carbonyl]benzamide, 4- {[4-(4,5-Dimethyl-3,6-dihydropyridin-l(2H)-yl)piperidin-l-yl ]carbonyl}-N-(3,5- dimethyl- 1 ,2-oxazol-4-yl)benzamide, N-(3, 5-Dimethyl- 1 ,2-oxazol-4-yl)-4- { [3-(methoxymethyl)- 1 ,4'- bipiperidin- 1’-yljcarbonyl} benzamide, [3 -(tert-Butoxymethyl)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan- 2-yl)phenyl]methanone, [3-(tert-Butoxymethyl)-l,4'-bipiperidin-r-yl](4-tert-butylph enyl)methanone, {3- [(3 -Fluorophenoxy)methyl] - 1 ,4'-bipiperidin- 1’-yl} [4-(2-hydroxypropan-2-yl)phenyl]methanone, (4-tert- Butylphenyl) {3 - [3 -(2-methoxyethyl)- 1 ,2,4-oxadiazol-5-yl] - 1 ,4'-bipiperidin- 1’-yl} methanone, [4-(2-

Hydroxypropan-2-yl)phenyl] {3 - [(trifluoromethoxy)methyl] - 1 ,4'-bipiperidin- 1’-yl} methanone, [3 -

(Cyclobutylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, 3 -

(Cyclopropyloxy)-l,4'-bipiperidin-l'-yl][4-(2-hydroxyprop an-2-yl)phenyl]methanone formic acid salt, [3- Fluoro-4-(2-hydroxypropan-2-yl)phenyl] [(3 R)-3 -methyl- 1 ,4'-bipiperidin- 1’-yl] methanone, [3 -Ethyl- 1,4'- bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, {3 - [(Cyclobutyloxy)methyl] -1,4'- bipiperidin-r-yl} [4-(2-hydroxypropan-2-yl)phenyl]methanone, {3-[(Cyclopropyloxy)methyl]-l,4'- bipiperidin- 1’-yl} [4-(2-hydroxypropan-2-yl)phenyl]methanone, [3 -(tert-Butoxymethyl)- 1 ,4'-bipiperidin- 1 '- yl] [4-(2-methoxypropan-2-yl)phenyl]methanone, [3 -(Ethoxymethyl)- 1 ,4'-bipiperidin- 1’-yl] [4-(2- hydroxypropan-2-yl)phenyl]methanone, [3 -(Cyclopropylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [4-(2- methoxypropan-2-yl)phenyl]methanone, [4-(2-Hydroxypropan-2-yl)phenyl][(3R)-3-(methoxymethyl)-l,4' - bipiperidin- 1’-yl] methanone, [3 -(Cyclopropylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [4-(3 -hydroxy oxetan-3 - yl)phenyl] methanone, {3-[(Cyclobutyloxy)methyl]-l,4'-bipiperidin-l'-yl} [4-(3-hydroxyoxetan-3- yl)phenyl] methanone, (3-Cyclopropyl-l,4'-bipiperidin-l'-yl)[4-(2-hydroxypropan-2- yl)phenyl]methanone, [4-(2-Hydroxypropan-2-yl)phenyl] {3 - [2-(trifluoromethoxy)ethoxy] - 1 ,4'-bipiperidin- 1’-yl} methanone, [3 - (Cyclopropylmethoxy)- 1 ,4'-bipiperidin- 1’-yl] [4-(2-hydroxypropan-2-yl)phenyl]methanone, and also their salts, solvates, and solvates of the salts, for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The compounds of formula (I), their production and their action as alpha2C antagonists for use in a method for the treatment and/or prophylaxis of primary and secondary forms of diabetic microangiopathies, diabetic wound healing, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic retinopathy, diabetic nephropathy, diabetic erectile dysfunction, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardial vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermitent claudication, and peripheral and autonomous neuropathies are disclosed in WO 2015/091415 and in WO 2015/091420 in general and especially the compounds specifically are an explicit part of the description of the present invention and are hereby incorporated by reference. The term effective amount as used herein refers to an amount of a compound of formula (I) that is effective for treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The present invention relates to (alpha-2C) antagonists, in particular the substituted piperidinyl- pyrimidinyl-tetrahydrochinolines and piperidinyl-pyridinyl-tetrahydrochinolines of formula (I), for the use in a method for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The present invention further relates to the use of compounds of formula (I) for the manufacture of medicaments for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

A further subject of the present invention is the use of a combination of one or more compounds of the formula (1) with one or more other active compounds in a method for the treatment and / or prophylaxis sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

A further subject of the present invention is a pharmaceutical composition comprising at least one compounds of the formula (1) in combination with one or more inert non-toxic pharmaceutically suitable excipients for use in a method for the treatment and / or prophylaxis sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The present invention further relates to pharmaceutical composition comprising a combination with one or more other active compounds in combination with one or more inert non-toxic pharmaceutically suitable excipients for use in a method for the treatment and / or prophylaxis sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

The present invention is also directed to a method for the treatment and/or prophylaxis of sleep-related breathing disorders, by administering systemically and/or locally a therpeutically effective amount of at least one compound of formula (1) or a medicament comprising at least one compound od formula (1) in combination with a inert, non-toxic, pharmaceutically accepable additive.

A further subject of the present invention is a combination of one or more compounds of the formula (1) with one or more other active compounds for use in a method for the treatment and / or prophylaxis sleep- related breathing disorders, preferably obstructive and central sleep apneas and snoring.

Substituted piperidinyl-pyrimidinyl-tetrahydrochinolines and piperidinyl-pyridinyl-tetrahydrochinolines of formula (1) according to the invention can be used alone or, if required, in combination with one or more other pharmacologically active substances, provided that this combination does not lead to undesirable and unacceptable side effects. Preferred examples of combination suitable for the purpose to treat sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring, include:

• respiratory stimulants such as, by way of example and with preference, theophylline, doxapram, nikethamide or caffeine;

• psychostimulants such as, by way of example and with preference, modafinil or armodafinil;

• amphetamines and amphetamine derivatives such as, by way of example and with preference, amphetamine, metamphetamine or methylphenidate;

• serotonin reuptake inhibitors such as, by way of example and with preference, fluoxetine, paroxetine, citalopram, escitalopram, sertraline, fluvoxamine or trazodone;

• serotonin precursors such as, by way of example and with preference, L-tryptophan;

• selective serotonin noradrenaline reuptake inhibitors such as, by way of example and with preference, venlafaxine or duloxetine;

• noradrenergic and specific serotonergic antidepressants such as, by way of example and with preference, mirtazapine;

• selective noradrenaline reuptake inhibitors such as, by way of example and with preference, reboxetine or atomoxetine;

• tricyclic antidepressants such as, by way of example and with preference, amitriptyline, protriptyline, doxepine, trimipramine, imipramine, clomipramine or desipramine;

• muscarinic receptor antagonists, by way of example and with preference oxybutynin;

• GABA agonists such as, by way of example and with preference, baclofen;

• glucocorticoids such as, by way of example and with preference, fluticasone, budesonide, beclometasone, mometasone, tixocortol or triamcinolone; cannabinoid receptor agonists; carboanhydrase inhibitors such as, by way of example and with preference, acetazolamide, methazolamide or diclofenamide; • opioid and benzodiazepine receptor antagonists such as, by way of example and with preference, flumazenil, naloxone or naltrexone;

• cholinesterase inhibitors such as, by way of example and with preference, neostigmine, pyridostigmine, physostigmine donepezil, galantamine or rivastigmine;

• appetite suppressants such as, by way of example and with preference, sibutramin, opiramate, phentermine, lipase inhibitors or cannabinoid receptor antagonists;

• mineralocorticoid receptor antagonists.

A preferred subject of the present invention is a combination of one or more compounds of the formula (I) with one or more other active compounds selected from the groups consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, corticosteroids for use in a method for the treatment and / or prophylaxis sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

In a preferred embodiment of the invention, the compounds of the invention are administered in combination with a muscarinic receptor antagonist, by way of example and with preference oxybutynin.

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

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.

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.

If required, aryl piperazines of formula (I) according to the invention can also be employed in conjunction with the use of one or more medical technical devices or auxiliaries, provided this does not lead to unwanted and unacceptable side-effects. Medical devices and auxiliaries suitable for such a combined application are, by way of example and with preference: • devices for positive airway pressure ventilation such as, by way of example and with preference, CPAP (continuous positive airway pressure) devices, BiPAP (bilevel positive airway pressure) devices and IPPV (intermittent positive pressure ventilation) devices;

• neurostimulators of the Nervus hypoglossus;

• oral appliancessuch as, by way of example and with preference, mandibular advancement devices;

• nasal disposable valves;

• nasal stents.

Substituted piperidinyl-pyrimidinyl-tetrahydrochinolines and piperidinyl-pyridinyl-tetrahydrochinolines of formula (I) according to the invention can act systemically and/or locally. For this purpose, they can be administered in a suitable manner, for example by the oral, parenteral, pulmonal, intrapulmonal (inhalative), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent.

A further subject of the present invention is a pharmaceutical composition comprising a compound of the formula (I) for the systemically and/or locally administration by the oral, parenteral, pulmonal, intrapulmonal (inhalative), nasal, intranasal, pharyngeal, lingual, sublingual, buccal, rectal, dermal, transdermal, conjunctival or otic route, or as an implant or stent. The preferred administration is the oral route.

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

For oral administration, administration forms which function according to the state of the art, releasing the compounds according to the invention rapidly and/or in a modified manner, which contain the compounds according to the invention in crystalline and/or amorphized and/or dissolved form, such as for example tablets (uncoated or coated tablets, for example with gastric juice-resistant or delayed dissolution or insoluble coatings, which control the release of the compound according to the invention), tablets rapidly disintegrating in the oral cavity or films/wafers, films/lyophilisates, capsules (for example hard or soft gelatine capsules), dragees, granules, pellets, powders, emulsions, suspensions, aerosols or solutions are suitable.

Parenteral administration can be effected omitting an absorption step (e.g. intravenous, intra-arterial, intracardial, intraspinal or intralumbar administration) or involving absorption (e.g. intra-muscular, subcutaneous, intracutaneous, percutaneous or intraperitoneal administration). Suitable administration forms for parenteral administration include injection and infusion preparations in the form of solutions, suspensions, emulsions, lyophilisates or sterile powders.

For the other administration routes, for example inhalation formulations (including powder inhalers and nebulisers), nasal drops, solutions or sprays, tablets for lingual, sublingual or buccal administration, tablets, films/wafers or capsules, suppositories, oral or ophthalmic preparations, vaginal capsules, aqueous suspensions (lotions, shakable mixtures), lipophilic suspensions, ointments, creams, transdermal therapeutic systems (e.g. plasters), milk, pastes, foams, dusting powders, implants or stents are suitable.

Oral or parenteral administration, in particular oral and intravenous administration, are preferred.

The compounds according to the invention can be converted into the stated administration forms. This can be effected in a manner known per se by mixing with inert, non-toxic, pharmaceutically suitable additives. These additives include carriers (for example microcrystalline cellulose, lactose, mannitol), solvents (e.g. liquid polyethylene glycols), emulsifiers and dispersants or wetting agents (for example sodium dodecylsulphate, polyoxysorbitan oleate), binders (for example polyvinylpyrrolidone), synthetic and natural polymers (for example albumin), stabilizers (e.g. antioxidants such as for example ascorbic acid), colourants (e.g. inorganic pigments such as for example iron oxides) and flavour or odour correctors.

In general, to achieve effective results in parenteral administration it has been found advantageous to administer quantities of about 0.001 to 10 mg/kg, preferably about 0.01 to 1 mg/kg body weight. In oral administration, the dosage is about 0.01 bis 100 mg/kg, preferably about 0.01 to 20 mg/kg and quite especially preferably 0.1 to 15 mg/kg body weight.

Nonetheless it can sometimes be necessary to deviate from the said quantities, namely depending on body weight, administration route, individual response to the active substance, nature of the preparation and time or interval at which administration takes place. Thus in some cases it can be sufficient to manage with less than the aforesaid minimum quantity, while in other cases the stated upper limit must be exceeded. In the event of administration of larger quantities, it may be advisable to divide these into several individual administrations through the day.