Combination of a task1/3 channel blocker with a norepinephrine reuptake inhibitor for the treatment of sleep apnea

Patent metadata

Field	Value
Publication number	US-2025049803-A1
Application number	US-202218722227-A
Country	US
Kind code	A1
Filing date	Dec 20, 2022
Priority date	Dec 22, 2021
Publication date	Feb 13, 2025
Grant date	—

Abstract

The present invention relates to a combination of selective blockers of TASK-1 and TASK-3 channels, in particular substituted imidazo[1,2-a]pyrimidine and substituted imidazo[1,2-a]pyridine derivatives of formula (I) and norepinephrine reuptake inhibitors for the treatment and/or prophylaxis of sleep-related breathing disorders, preferably obstructive and central sleep apneas and snoring.

First claim

1 . Combinations of compounds of formula (I)

in which
the ring Q represents a piperazine or a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR′ 2 group and ** the bond to the carbonyl group,
W 1 , W 2 or W 3 represents CH or N,
R′ 1 represents halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl or cyclobutyl
where (C 1 -C 4 )-alkyl may be up to trisubstituted by fluorine and cyclopropyl and cyclobutyl may be up to disubstituted by fluorine,

and
R′ 2 represents (C 4 -C 6 )-cycloalkyl in which a ring CH 2 group may be replaced by —O—,
or
R′ 2 represents 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),

in which *** marks the bond to the adjacent carbonyl group and
R′ 3 represents hydrogen, fluorine, chlorine, bromine or methyl,
R′ 4 represents hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy,
where (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may each be up to trisubstituted by fluorine,

R′ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R′ 6 represents hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, tetrahydro-2H-pyran-4-yloxy, mono-(C 1 -C 3 )-alkylamino, di-(C 1 -C 3 )-alkylamino or (C 1 -C 3 )-alkylsulfanyl,
where (C 1 -C 3 )-alkoxy may be up to trisubstituted by fluorine,

R 7 represents hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl or (C 1 -C 3 )-alkoxy,
R 8A and R 8B are identical or different and independently of one another represent hydrogen, fluorine, chlorine, bromine, (C 1 -C 3 )-alkyl, cyclopropyl or (C 1 -C 3 )-alkoxy
where (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may each be up to trisubstituted by fluorine,

R 9 represents hydrogen, (C 1 -C 3 )-alkyl or amino
and
wherein in subformula (d)
Y represents O, S or N(CH 3 ),

wherein in subformula (e) and (f)
Y represents O or S,

or
R′ 2 represents an —OR 10 or —NR 11 R 12 group in which
R 10 represents (C 1 -C 6 )-alkyl, (C 4 -C 6 )-cycloalkyl or [(C 3 -C 6 )-cycloalkyl]methyl,
R 11 represents hydrogen or (C 1 -C 3 )-alkyl
and
R 12 represents (C 1 -C 6 )-alkyl, (C 3 -C 6 )-cycloalkyl, phenyl or benzyl, 1-phenylethyl or 2-phenylethyl,
where (C 1 -C 6 )-alkyl may be up to trisubstituted by fluorine,
and
where phenyl and the 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 11 and R 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 11 and R 12 are attached to one another and, together with the nitrogen atom to which they are bonded, form a tetrahydroquinoline ring of the formula (c) or a tetrahydroisoquinoline ring of the formula (d),

in which ** marks the bond to the carbonyl group,

and a noradrenaline reuptake inhibitor,
and the salts, solvates and solvates of the salts thereof.

2 . The combinations according to claim 1 of compounds of formula (I),
wherein
the ring Q represents a piperazine or a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group,
W 2 represents CH,
W 1 , W 3 represent CH or N,
R′ 1 represents fluorine, chlorine, bromine, methyl, tert.-butyl, isopropyl, cyclopropyl or cyclobutyl,
and

R′ 2 represents cyclobutyl, cyclopentyl or cyclohexyl,
or
R′ 2 represents 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)

in which *** marks the bond to the adjacent carbonyl group and
R′ 3 represents hydrogen, fluorine or chlorine,
R′ 4 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R′ 5 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 6 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy,
cyclobutyloxy or methylsulfanyl,
R 8A and R 8B are identical or different and independently of one another represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
R 9 represents methyl or amino
Y represents O or S or N(CH 3 )
and a noradrenaline reuptake inhibitor,
and the salts, solvates and solvates of the salts thereof.

3 . The combinations according to claim 1 ,
wherein the ring Q represents a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group,

W 1 represents CH,
W 2 represents CH,
W 3 represents N,
R 1 represents chlorine, bromine, isopropyl or cyclobutyl,
and
R 2 represents cyclopentyl or cyclohexyl,
or
R 2 represents a phenyl group of the formula (a), a pyridyl group of the formula (b) or an azole group of the formula (d), (e) or (f)

in which *** marks the bond to the adjacent carbonyl group and
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents fluorine, chlorine, methyl, isopropyl, methoxy or ethoxy,
R 6 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 7 represents methoxy, difluoromethoxy, trifluoromethoxy, isopropoxy, cyclobutyloxy or methylsulfanyl,
R 9A and R 9B are identical or different and independently of one another and represent hydrogen, methyl, trifluoromethyl, ethyl, isopropyl or cyclopropyl,
and
Y represents O or S,

and a noradrenaline reuptake inhibitor,
and the salts, solvates and solvates of the salts thereof.

4 . The combinations according to claim 1 ,
wherein the ring Q represents a diazaheterobicyclic system of the formula

in which * denotes the bond to the adjacent CHR 2 group and ** the bond to the carbonyl group,

W 1 represents CH,
W 2 represents CH,
W 3 represents N,
R 1 represents chlorine, bromine, isopropyl or cyclobutyl,
and
R 2 represents cyclopentyl or cyclohexyl,
or
R 2 represents a phenyl group of the formula (a), a pyridyl group of the formula

Assignees

• Bayer Ag

Inventors

• Delbeck Martina
• Hahn Michael

Classifications

• A61K45/06

  Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca · CPC title

• A61K31/5377

  not condensed and containing further heterocyclic rings, e.g. timolol · CPC title

• A61K31/138

  Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine (atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377) · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/5383

  ortho- or peri-condensed with heterocyclic ring systems · CPC title