COMBINATION OF AN ?2-ADRENOCEPTOR SUBTYPE C (ALPHA-2C) ANTAGONISTS WITH A TASK1/3 CHANNEL BLOCKER FOR THE TREATMENT OF SLEEP APNEA

Abstract

The present invention relates to a combination of selective blockers of TASK-1 and TASK-3 channels, in particular diazabicyclically substituted imidazo[1,2-a]pyrimidine derivatives and α2-Adrenoceptor subtype C (alpha-2C) antagonists, in particular aryl piperazines of formula (I) for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

Claims

1. A combination comprising a compound of formula (I) ##STR00008## wherein X is O, S or CH.sub.2; Z is —[CH.sub.2].sub.n—; A, B, D and E are independently C or N, provided that at least three of A, B, D and E are C; R.sup.1 is H, halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C═O)—, CN, (R.sub.5).sub.2N—, (R.sub.5).sub.2N—(C.sub.1-C.sub.6)alkyl, (R.sub.5).sub.2N-(C═O)—, SH—(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl-S-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-S—(C.sub.1-C.sub.6)alkyl, hydroxy(C.sub.1-C.sub.6)alkyl-S(Op)-(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl-S(Op)-(C.sub.1-C.sub.6)alkyl or furyl; R.sup.2 is H, halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy or hydroxy(C.sub.1-C.sub.6)alkyl; R.sup.3 is H, halogen, (C.sub.1-C.sub.6)alkyl or phenyl; R.sup.4 is halogen, hydroxy, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, CN or (R.sup.5).sub.2N—; R.sup.5 is, independently at each occurence, H, (C.sub.1-C.sub.6)alkyl or (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl; m is 0, 1 or 2; n is 1 or 2; and p is 1 or 2, or a salt, solvate, or solvate of a salt thereof, and a compound of formula (II) ##STR00009## wherein the ring Q represents a piperazine or a diazaheterobicyclic system of the formula ##STR00010## wherein * denotes a bond to the adjacent CHR′.sup.2 group and ** a bond to the carbonyl group; W.sup.1, W.sup.2 and W.sup.3 are each independently CH or N; R′.sup.1 is halogen, cyano, (C.sub.1-C.sub.4)-alkyl, cyclopropyl or cyclobutyl wherein (C.sub.1-C.sub.4)-alkyl may be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine; and R′.sup.2 is (C.sub.4-C.sub.6)-cycloalkyl in which a ring CH.sub.2 group may be replaced by —O—; or R′.sup.2 a phenyl group of the formula (a), a pyridyl group of the formula (b) or (c) or an azole group of the formula (d), (e), (f) or (g); ##STR00011## wherein *** marks a bond to the adjacent carbonyl group; R′.sup.3 is hydrogen, fluorine, chlorine, bromine or methyl; R′.sup.4 is hydrogen, fluorine, chlorine, bromine, cyano, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy; wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may each be up to trisubstituted by fluorine, R′.sup.5 is hydrogen, fluorine, chlorine, bromine or methyl; R′.sup.6 is hydrogen, (C.sub.1-C.sub.3)-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C.sub.1-C.sub.3)-alkylamino, di-(C.sub.1-C.sub.3)-alkylamino or (C.sub.1-C.sub.3)-alkylsulfanyl[H]; wherein (C.sub.1-C.sub.3)-alkoxy may be up to trisubstituted by fluorine, R.sup.7 is hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl or (C.sub.1-C.sub.3)-alkoxy; R.sup.8A and R.sup.8B are identical or different and independently of one another are hydrogen, fluorine, chlorine, bromine, (C.sub.1-C.sub.3)-alkyl, cyclopropyl or (C.sub.1-C.sub.3)-alkoxy wherein (C.sub.1-C.sub.3)-alkyl and (C.sub.1-C.sub.3)-alkoxy may each be up to trisubstituted by fluorine; R.sup.9 is hydrogen, (C.sub.1-C.sub.3)-alkyl or amino; and wherein in subformula (d) Y is O, S or N(CH.sub.3); wherein in subformula (e) and (f), Y is O or S, or R′.sup.2 is OR.sup.10 or —NR.sup.11R.sup.12, wherein R.sup.10 is (C.sub.1-C.sub.6)-alkyl, (C.sub.4-C.sub.6)-cycloalkyl or [(C.sub.3-C.sub.6)-cycloalkyl]methyl, R.sup.11 is hydrogen or (C.sub.1-C.sub.3)-alkyl and R.sup.12 is (C.sub.1-C.sub.6)-alkyl, (C.sub.3-C.sub.6)-cycloalkyl, phenyl or benzyl, 1-phenylethyl or 2-phenylethyl, wherein (C.sub.1-C.sub.6)-alkyl may be up to trisubstituted by fluorine, and wherein phenyl and a phenyl group in benzyl, 1-phenylethyl and 2-phenylethyl may be up to trisubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy and (trifluoromethyl)sulfanyl, or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a pyrrolidine, piperidine, morpholine or thiomorpholine ring, or R.sup.11 and R.sup.12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a tetrahydroquinoline ring of formula (c) or a tetrahydroisoquinoline ring of formula (d), ##STR00012## wherein ** marks a bond to the carbonyl group, or a salt, solvate, or solvate of a salt thereof.

2. The combination of claim 1, wherein X is O; Z is —[CH.sub.2].sub.n—; A is N; B, D and E are C; R.sup.1 is halogen, (C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy, hydroxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, halo(C.sub.1-C.sub.6)alkoxy, halo(C.sub.1-C.sub.6)alkoxy(C.sub.1-C.sub.6)alkyl, (C.sub.1-C.sub.6)alkoxy-(C═O)—, CN, (R.sub.5).sub.2N-(C.sub.1-C.sub.6)alkyl, (R.sub.5).sub.2N—(C═O)— or furyl; R.sup.2 is H, halogen, (C.sub.1-C.sub.6)alkyl or hydroxy(C.sub.1-C.sub.6)alkyl; R.sup.3 is H, (C.sub.1-C.sub.6)alkyl or phenyl; R.sup.5 is, independently at each occurence, H or (C.sub.1-C.sub.6)alkyl; m is 0; and n is 1 and wherein the ring Q represents a piperazine or a diazaheterobicyclic system of the formula ##STR00013## wherein * denotes a bond to the adjacent CHR.sup.2 group and ** a bond to the carbonyl group, W.sup.2 is CH, W.sup.1 and W.sup.3 are independently CH or N, R′.sup.1 is fluorine, chlorine, bromine, methyl, tert.-butyl, isopropyl, cyclopropyl or cyclobutyl, and R′.sup.2 is cyclobutyl, cyclopentyl or cyclohexyl, or R′.sup.2 is a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d) or formula (g) ##STR00014## wherein *** marks a bond to the adjacent carbonyl group and R′.sup.3 is hydrogen, fluorine or chlorine, R′.sup.4 is fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy, R′.sup.5 is hydrogen, fluorine, chlorine, bromine or methyl, R.sup.6 is methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl, R.sup.8A and R.sup.8B are independently hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl, and R.sup.9 is methyl or amino Y is O or S or N(CH.sub.3) or a salt, solvate, or solvate of a salt thereof.

3. The combination of claim 1, wherein the compound of formula (I) is selected from the group consisting of: (S)-1-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine, (R)-1-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(2-(methoxymethyl)phenyl)piperazine, (2-(4-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)piperazin-1-yl)-6-fluorophenyl)methanol, (S)-1-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(2-(furan-2-yl)phenyl)piperazine, (S)-1-((2,3-Dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-o-tolylpiperazine, methyl 2-(4-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1,4-diazepan-1-yl)benzoate, and (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine and the compound of formula (II) is selected from the group consisting of: (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(cyclopentyl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (4-{[2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3- yl]methyl}piperazin-1yl)(2-fluorophenyl)methanone, (4-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-isopropoxypyridin-2-yl)methanone, (4-{[2-(4-bromophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)[6-(trifluoromethoxy)pyridin-2-yl]methanone, (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, [5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxypyridin-2-yl)methanone, [5-{[2-(4-Isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxypyridin-2-yl)methanone, (3 -Fluoro-6-methoxypyridin-2-yl)[5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl]methanone, [5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}hexahydropyrrolo[3,4-c]pyrrol-2(1H)-yl](6-methoxy-3-methylpyridin-2-yl)methanone, (−)-[(1S,4S)-5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl](6-methoxypyridin-2-yl)methanone, (−)-(3-Chloro-6-methoxypyridin-2-yl)[(1S,4S)-5-{[2-(4-chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl]methanone, (−)-[(1S,4S)-5-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(5-chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone, (−)-(5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)(6-methoxypyridin-2-yl)methanone, (5-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)[6-(difluoromethoxy)pyridin-2-yl]methanone, (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(5-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-2,5-diazabicyclo[2.2.2]oct-2-yl)methanone, (3-Fluoro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone, (3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)(3-fluoro-6-methoxypyridin-2-yl)methanone, (3-chloro-6-methoxypyridin-2-yl)(3-{[2-(4-cyclopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]octan-8-yl)methanone, 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, 3-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-8-oxa-3,10-diazabicyclo[4.3.1]dec-10-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, [3-{[2-(5-Chloropyridin-2-yl)imidazo[1,2-a]pyridin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]non-9-yl](3-fluoro-6-methoxypyridin-2-yl)methanone, and (3-Fluoro-6-methoxypyridin-2-yl)[3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,9-diazabicyclo[4.2.1]nonan-9-yl]methanone.

4. The combination of claim 1, wherein the compound of formula (I) is (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-([.sup.11C]-methoxymethyl)pyridin-2-yl)piperazine and wherein the compound of formula (II) is selected from the group consisting of: (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone and (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone.

5. The combination of claim 1, wherein the compound of formula (I) is (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-([.sup.11C]methoxymethyl)pyridin-2-yl)piperazine and wherein the compound of formula (II) is (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone.

6. The combination of claim 1, wherein wherein the compound of formula (I) is (S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-([.sup.11C]-methoxymethyl)pyridin-2-yl)piperazine and wherein the compound of formula (II) is (3-Chloro-6-methoxypyridin-2-yl)(3-{[2-(4-isopropylphenyl)imidazo[1,2-a]pyrimidin-3-yl]methyl}-3,8-diazabicyclo[3.2.1]oct-8-yl)methanone.

7-8. (canceled)

9. A pharmaceutical composition comprising the combination of claim 1 and one or more inert, nontoxic, pharmaceutically suitable excipients.

10. A pharmaceutical composition comprising the combination of claim 1 and one or more further active ingredients selected from the group consisting of muscarinic receptor antagonists, mineralocorticoid receptor antagonists, diuretics, and corticosteroids.

11. (canceled)

12. A method of treating and/or preventing respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders in humans and animals by administration of an effective amount of the combination of claim 1 to a subject in need thereof.

13. (canceled)

14. A method of treating and/or preventing respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders in humans and animals by administration of an effective amount of the composition of claim 9 to a subject in need thereof.

15. A method of treating and/or preventing respiratory disorders, sleep-related respiratory disorders, obstructive sleep apnoea, central sleep apnoea, snoring, cardiac arrhythmias, neurodegenerative disorders, neuroinflammatory disorders and neuroimmunological disorders in humans and animals by administration of an effective amount of the composition of claim 10 to a subject in need thereof.

Description

EXAMPLES

A. Experimental Methods

[0201] Advantageous pharmacological properties of the combination of an α2-Adrenoceptor subtype C (alpha-2C) antagonists with a TASK1/3 channel blocker can be determined by the following methods.

[0202] The therapeutic potential of the the combination of an α2-Adrenoceptor subtype C (alpha-2C) antagonists with a TASK1/3 channel blocker according to the present invention in sleep apnea has been assessed preclinically in a pig model of obstructive sleep apnea (OSA).

[0203] Using negative pressure. it is possible to induce collapse and thus obstruction of the upper respiratory tract in anaesthetized, spontaneously breathing pigs (Wirth K. J. et al., Sleep 36(5) (2013) pp. 699-708).

[0204] German Landrace pigs are used for the model. The pigs are anaesthetized and tracheotomized. Two tracheal cannulas are inserted into the trachea, one into the rostral part and the other into the caudal part of the trachea. Using a connection piece. the rostral cannula is connected to a tube to the negative pressure device and to the distal tracheal cannula. The distal tracheal cannula is additionally connected to a tube with an open end to atmosphere via a connection piece that served for free tracheal breathing, circumventing the upper airway. By appropriate opening and clamping of those tubes breathing can be switched from nasal breathing to breathing through the caudal tracheal cannula, circumventing the upper airway. and the (isolated) upper airway can be connected to the negative pressure device, causing airflow in the inspiratory direction.

[0205] At certain points in time. the collapsibility of the upper respiratory tract is tested by having the pig breathe via the caudal cannula and applying negative pressures of −50, −100 and −150 cm water head (cm H.sub.2O) to the upper respiratory tract. This causes the upper respiratory tract to collapse, which manifests itself in an interruption of the airflow and a pressure drop in the tube system. This test is conducted prior to the administration of the test substance and at certain intervals after the administration of the test substance. An appropriately effective test substance can prevent this collapse of the respiratory tract in the inspiratory phase.

[0206] In this OSA pig model, systemic application of the a2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine with i.v. bolus injection of 0.3μg/kg followed by an i.v. infusion of 0.13 μg/kg/h for five hours inhibited upper airway collapsibility at all negative pressures of −50, −100 and −150 cm head (cm H.sub.2O) only at time point 30 min after bolus injection and start of infusion. At time point 120 min after bolus injection and start of infusion, upper airway collapsibility was induced at all negative pressures of −50, −100 and −150 cm head (cm H2O). The combination of this non effective dose of the α2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine with the non effective dose of the TASK1/TASK3 channel blocker of 0.3 μg (4-{[2-(4-Chlorophenypimidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at all negative pressures of −50, 100 and −150 cm head (cm H.sub.2O) for more than two hours (see Table 1, 2 and 3 and FIG. 1).

[0207] FIG. 1: Effect of i.v. bolus injection of 0.13 μg/kg followed by an i.v. infusion of 0.13 μg/kg/h for five hours of the α2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine given at time point 0 min in combination with intranasal administration of 0.3 μg of the TASK1/TASK3 channel blocker (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3 -yl]methyl}piperazin-1-yl)(6-methoxypyridin-2-yl)methanone given at time point 160 min after beginning of the experiment on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00001 TABLE 1 Combination of non effective dose of ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2- yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine with the non effective dose of 0.3 μg (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6- methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of −50 cm head (cm H.sub.2O) Percent pigs without Time, min collaps −50 cm H.sub.2O, % 0 0 10 0 30 100 60 100 90 50 120 0 150 0 Nasal application TASK1/3 160 channel blocker 170 100 190 100 220 100 250 100 280 100 300 100

TABLE-US-00002 TABLE 2 Combination of non effective dose of ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2- yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine with the non effective dose of 0.3 μg (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6- methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of −100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps −100 cm H.sub.2O, % 0 0 10 0 30 100 60 100 90 0 120 0 150 0 Nasal application TASK1/3 160 channel blocker 170 100 190 100 220 100 250 100 280 100 300 100

TABLE-US-00003 TABLE 3 Combination of non effective dose of ((S)-1-((2,3-dihydrobenzo[b][1,4]dioxin-2- yl)methyl)-4-(3-(methoxymethyl)pyridin-2-yl)piperazine with the non effective dose of 0.3 μg (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6- methoxypyridin-2-yl)methanone inhibits upper airway collapsibility at negative pressures of −150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps −150 cm H.sub.2O, % 0 0 10 0 30 100 60 50 90 0 120 0 150 0 Nasal application TASK1/3 160 channel blocker 170 100 190 100 220 100 250 100 280 100 300 100

[0208] Table 4, 5 and 6 and FIG. 2: Effect of intranasal administration of 0.3 μg of the TASK1/TASK3 channel blocker (4-{[2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1 -yl)(6-methoxypyridin-2-yl)methanone given at time point 0 min on upper airway collapsibility at different levels of negative pressure. Percentages of pigs with no collapse are given. Mean values.

TABLE-US-00004 TABLE 4 Intranasal administration of 0.3 μg of the TASK1/TASK3 channel blocker (4-{[2-(4- Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2- yl)methanone at negative pressures of −50 cm head (cm H.sub.2O) Time, min Percent pigs without collaps −50 cm H.sub.2O, % 0 0 10 0 30 0 60 0

TABLE-US-00005 TABLE 5 Intranasal administration of 0.3 μg of the TASK1/TASK3 channel blocker (4-{[2-(4- Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2- yl)methanone at negative pressures of −100 cm head (cm H.sub.2O) Time, min Percent pigs without collaps −100 cm H.sub.2O, % 0 0 10 0 30 0 60 0

TABLE-US-00006 TABLE 6 Intranasal administration of 0.3 μg of the TASK1/TASK3 channel blocker (4-{[2-(4- Chlorophenyl)imidazo[1,2-a]pyridin-3-yl]methyl}piperazin-1-yl)(6-methoxypyridin-2- yl)methanone at negative pressures of −150 cm head (cm H.sub.2O) Time, min Percent pigs without collaps −150 cm H.sub.2O, % 0 0 10 0 30 0 60 0

[0209] From the above mentioned data it can be deducted that the combination of an α2-Adrenoceptor subtype C (alpha-2C) antagonists of formula (I) with a TASK 1/3 channel blocker inhibits upper airway collapsibility with improved efficacy compared to each treatment alone and is thus suitable to treat sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.