Substituted perhydropyrrolo[3,4-c]pyrrole derivatives and the use of same

Patent metadata

Field	Value
Publication number	US-2018370965-A1
Application number	US-201615781848-A
Country	US
Kind code	A1
Filing date	Dec 2, 2016
Priority date	Dec 10, 2015
Publication date	Dec 27, 2018
Grant date	—

Abstract

The present application relates to novel (2-phenylimidazo[1,2-a]pyridin-3-yl)methyl-substituted perhydropyrrolo[3,4-c]pyrrole derivatives, to methods for the preparation thereof, to the use thereof alone or in combinations for treatment and/or prevention of diseases, and to the use thereof for production of medicaments for treatment and/or prevention of diseases, especially for treatment and/or prevention of respiratory disorders including sleep-related respiratory disorders such as obstructive sleep apneas and central sleep apneas and snoring.

First claim

1 : A compound of the formula (I)

in which
R 1 represents halogen, cyano or (C 1 -C 4 )-alkyl,
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) or a pyridyl group of the formula (b)

in which * marks the bond to the adjacent carbonyl group and

R 3 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 be up to trisubstituted by fluorine,
R 4 represents hydrogen, fluorine, chlorine, bromine or methyl,
R 5 represents hydrogen, fluorine, chlorine, bromine or methyl and

R 6 represents hydrogen or (C 1 -C 3 )-alkoxy which may be up to trisubstituted by fluorine,
or
R 2 represents an —OR 7 or —NR 8 R 9 group in which
R 7 and R 8 in each case represent (C 1 -C 4 )-alkyl, (C 4 -C 6 )-cycloalkyl, phenyl, benzyl, 1-phenylethyl or 2-phenylethyl,
where (C 1 -C 4 )-alkyl may be up to trisubstituted by fluorine, and
where phenyl and the phenyl groups in benzyl, 1-phenylethyl and 2-phenylethyl may be up to disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, methoxy and ethoxy,
and
R 9 is hydrogen or methyl,
or

R 8 and R 9 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 the salts, solvates and solvates of the salts thereof.

2 : The compound of claim 1 , in which
R 1 represents chlorine, bromine or isopropyl, and R 2 represents cyclobutyl, cyclopentyl or cyclohexyl or R 2 represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

in which * marks the bond to the adjacent carbonyl group and

R 3 represents fluorine, chlorine, methyl, trifluoromethyl, methoxy or trifluoromethoxy,
R 4 represents hydrogen or fluorine,
R 5 represents hydrogen, fluorine, chlorine or methyl
and

R 6 represents methoxy, difluoromethoxy, trifluoromethoxy or isopropoxy, or
R 2 represents an —OR 7 or —NR 8 R 9 group in which
R 7 represents isopropyl, isobutyl, tert-butyl, cyclopentyl, phenyl or benzyl,
where phenyl and the phenyl group in benzyl may be up to disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,

R 8 represents phenyl, benzyl or 1-phenylethyl,
where phenyl and the phenyl groups in benzyl and 1-phenylethyl may be up to disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,
and
R 9 is hydrogen or methyl,
or

R 8 and R 9 are attached to one another and, together with the nitrogen atom to which they are bonded, form a tetrahydroquinoline ring of the formula (c),

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

and the salts, solvates and solvates of the salts thereof.

3 : The compound of claim 1 , in which
R 1 represents chlorine, bromine or isopropyl, and R 2 represents cyclobutyl or cyclopentyl, or R 2 represents a phenyl group of the formula (a) or a pyridyl group of the formula (b)

in which * marks the bond to the adjacent carbonyl group and

R 3 represents fluorine, chlorine, methyl, trifluoromethyl or methoxy,
R 4 represents hydrogen or fluorine,
R 5 represents hydrogen, fluorine or methyl
and
R 6 represents methoxy,

or
R 2 represents an —OR 7 or —NR 8 R 9 group in which
R 7 represents isopropyl, cyclopentyl, phenyl or benzyl,
where phenyl and the phenyl group in benzyl may be up to disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,

R 8 represents phenyl or 1-phenylethyl,
where phenyl and the phenyl group in 1-phenylethyl may be up to disubstituted by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and ethoxy,
and
R 9 is hydrogen,
or

R 8 and R 9 are attached to one another and, together with the nitrogen atom to which they are bonded, form a tetrahydroquinoline ring of the formula (c),

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

and the salts, solvates and solvates of the salts thereof.

4 : The compound of claim 1 , in which
R 1 represents chlorine or isopropyl, and R 2 represents a pyridyl group of the formula (b)

in which * marks the bond to the adjacent carbonyl group,
R 5 represents hydrogen, fluorine or methyl
and
R 6 represents methoxy,

and the salts, solvates and solvates of the salts thereof.

5 : A method for preparing a compound of the formula (I) as defined in claim 1 , characterized in that a compound of the formula (II)

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

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

or
[B] with a protected perhydropyrrolo[3,4-c]pyrrole of the formula (IV)

in which PG represents a suitable amino protecting group
at first to give a compound of the formula (V)

in which PG is as defined for the compound of formula (IV) and R 1 is as defined in claim 1 ,
then the protecting group PG is cleaved and the resulting compound of the formula (VI)

in which R 1 is as defined in claim 1 ,
is then reacted, depending on the specific definition of the R 2 radical,

[B-1] with a carboxylic acid of the formula (VII)

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

• C07D519/00

  Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00 · 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

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• C07D471/04 Primary

  Ortho-condensed systems · CPC title

• A61K45/06

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