2-phenyl-3-(piperazinomethyl)imidazo[1,2-A]pyridine derivatives as blockers of task-1 and task-2 channels, for the treatment of sleep-related breathing disorders

Patent metadata

Field	Value
Publication number	US-10759794-B2
Application number	US-201615756867-A
Country	US
Kind code	B2
Filing date	Dec 7, 2016
Priority date	Dec 10, 2015
Publication date	Sep 1, 2020
Grant date	Sep 1, 2020

Abstract

The present application relates to novel 2-phenyl-3-(piperazinomethyl)imidazo[1,2-a]pyridine derivatives, to processes for their preparation, to their use alone or in combinations for the treatment and/or prevention of diseases, and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for treatment and/or prevention of respiratory disorders including, sleep-related respiratory disorders such as obstructive sleep apnoeas and central sleep apnoeas and snoring.

First claim

The invention claimed is:

1. A compound of the formula (I)

wherein
R 1 is halogen, cyano, (C 1 -C 4 )-alkyl, cyclopropyl, or cyclobutyl;
R 2 is (C 4 -C 6 )-cycloalkyl, wherein a ring CH 2 group may be replaced by —O—, or
is a phenyl group of the formula (a) or a pyridyl group of the formula (b)

wherein * marks the bond to the adjacent carbonyl group;

R 3 is fluorine, chlorine, bromine, cyano, (C 1 -C 3 )-alkyl, or (C 1 -C 3 )-alkoxy,
wherein (C 1 -C 3 )-alkyl and (C 1 -C 3 )-alkoxy may be substituted up to three times by fluorine;

R 4 is hydrogen, fluorine, chlorine, bromine, or methyl;
R 5 is hydrogen, fluorine, chlorine, bromine or methyl;
and

R 6 is hydrogen, (C 1 -C 3 )-alkoxy, cyclobutyloxy, oxetan-3-yloxy, tetrahydrofuran-3-yloxy, or tetrahydro-2H-pyran-4-yloxy,
wherein (C 1 -C 3 )-alkoxy may be substituted up to three times by fluorine,
or a salt, a solvate, or a solvate of a salt thereof.

2. The compound of the formula (I) according to claim 1 ,
wherein
R 1 is fluorine, chlorine, bromine, methyl, isopropyl, tert-butyl, or cyclopropyl;
R 2 is cyclobutyl, cyclopentyl, or cyclohexyl,
or
is a phenyl group of the formula (a) or a pyridyl group of the formula (b)

wherein * marks the bond to the adjacent carbonyl group;

R 3 is fluorine, chlorine, cyano, (C 1 -C 3 )-alkyl, (C 1 -C 3 )-alkoxy, or trifluoromethoxy,
R 4 is hydrogen, fluorine, or chlorine,
R 5 is hydrogen, fluorine, chlorine, bromine, or methyl;
and

R 6 is hydrogen or (C 1 -C 3 )-alkoxy, which may be substituted up to three times by fluorine,
or a salt, a solvate, or a solvate of a salt thereof.

3. The compound of the formula (I) according to claim 1 ,
wherein
R 1 is chlorine, bromine, isopropyl, or cyclopropyl;
R 2 is cyclobutyl, cyclopentyl, or cyclohexyl,
or
is a phenyl group of the formula (a) or a pyridyl group of the formula (b)

wherein * marks the bond to the adjacent carbonyl group;

R 3 is fluorine, chlorine, cyano, methyl, isopropyl, methoxy, or ethoxy;
R 4 is hydrogen, fluorine, or chlorine;
R 5 is hydrogen, chlorine, or bromine;
and

R 6 is methoxy, difluoromethoxy, trifluoromethoxy, or isopropoxy,
or a salt, a solvate, or a solvate of a salt thereof.

4. A process for preparing a compound of the formula (I) according to claim 1 , comprising reacting a compound of formula (II)

wherein R 1 is as defined in claim 1 ,
in the presence of a suitable reducing agent either
[A] with a compound of formula (III)

wherein R 2 is as defined in claim 1 ,

or
[B] with a protected piperazine derivative of formula (IV)

wherein PG is a suitable amino protective group
to give a compound of formula (V)

wherein PG and R 1 are as defined above,
removing the protective group PG to give a compound of formula (VI)

wherein R 1 is as defined above;
reacting the compound of formula (VI) with a carboxylic acid of formula (VII)

wherein R 2 is as defined in claim 1 ,
with activation of the carboxylic acid function in (VII), or
reacting the compound of formula (VI) with the corresponding acid chloride of formula (VIII)

wherein R 2 is as defined in claim 1 , to give the compound of formula (I),

and optionally converting the compound of formula (I) to a solvate, a salt, or a solvate of a salt thereof.

5. A pharmaceutical composition comprising a compound according to claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

6. A pharmaceutical combination comprising a compound according to claim 1 in combination with one or more further active compounds selected from the group consisting of respiratory stimulants, psychostimulating compounds, serotonin reuptake inhibitors, noradrenergic, serotonergic and tricyclic antidepressants, sGC stimulators, mineralocorticoid receptor antagonists, antiinflammatory drugs, immunomodulators, immunosuppressives and cytotoxic drugs.

7. A method for treatment of sleep-related respiratory disorders, obstructive sleep apneas, central sleep apneas, or snoring, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical composition according to claim 5 .

8. A method for treatment of sleep-related respiratory disorders, obstructive sleep apneas, central sleep apneas, or snoring, comprising administering to a human or animal in need thereof an effective amount of at least one compound according to claim 1 .

9. A method for treatment of sleep-related respiratory disorders, obstructive sleep apneas, central sleep apneas, or snoring, comprising administering to a human or animal in need thereof an effective amount of a pharmaceutical combination according to claim 6 .

10. The compound of claim 1 , wherein the compound is a compound of the formula

or a salt, a solvate, or a solvate of the salt thereof.

11. The compound of claim 10 , wherein the compound is a compound of the formula

12. The compound of claim 1 , wherein the compound is a compound of the formula

or a salt, a solvate, or a solvate of the salt thereof.

13. The compound of claim 12 , wherein the compound is a compound of the formula

14. The compound of claim 1 , wherein the compound is a compound of the formula

or a salt, a solvate, or a solvate of the salt thereof.

15. The compound of claim 14 , wherein the compound is a compound of the formula

Assignees

• Bayer Pharma AG

Inventors

• Delbeck Martina
• Hahn Michael
• Müller Thomas
• Meier Heinrich
• Lustig Klemens
• Mosig Johanna
• Toschi Luisella
• Albus Udo
• Gehring Doris
• Rosenstein Björn

Classifications

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/496

  Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin · CPC title

• A61K31/437

  the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline · CPC title

• A61P11/16

  Central respiratory analeptics · CPC title