Oxo-heterocyclic substituted carboxylic acid derivatives and the use thereof
View Patent ↗The present application relates to novel carboxylic acid derivatives having an oxo-substituted azaheterocyclic partial structure, processes for their preparation, their use for the treatment and/or prophylaxis of diseases, and their use for producing medicaments for the treatment and/or prophylaxis of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
1. A compound of formula (I)
wherein,
ring A represents an oxo-substituted azaheterocycle of the formula
in which
* denotes the point of attachment to the remainder of the molecule,
R 8 represents trifluoromethyl, (C 3 -C 6 )-cycloalkyl or phenyl, where phenyl for its part may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy and trifluoromethoxy,
and
R 9 represents hydrogen or has the meaning of R 8 given above,
R 1 represents hydrogen or methyl,
R 2 represents hydrogen, fluorine or chlorine,
R 3 represents (C 3 -C 6 )-alkyl or (C 3 -C 6 )-alkenyl, each of which may be substituted up to six times by fluorine,
or
represents (C 3 -C 6 )-cycloalkyl, cyclopentenyl or cyclohexenyl, each of which may be substituted up to two times by identical or different radicals from the group consisting of methyl, ethyl and trifluoromethyl and also up to four times by fluorine,
L 1 represents a bond or represents methylene or ethane-1,2-diyl,
L 2 represents a bond or represents methylene, ethane-1,2-diyl, propane-1,3-diyl or ethene-1,2-diyl, each of which may be substituted up to two times by methyl,
or
represents a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
## denotes the point of attachment to group M,
m represents the number 0 or 1,
n represents the number 1 or 2,
and
R 4A and R 4B independently of one another represent hydrogen or methyl,
M represents phenylene, which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl,
or
represents cyclopentane-1,3-diyl, cyclohexane-1,3-diyl or cyclohexane-1,4-diyl, each of which may be substituted up to two times by identical or different radicals from the group consisting of fluorine and methyl,
or
L 2 and M are attached to one another and together form a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
### denotes the point of attachment to group L 1 ,
R 5 represents hydrogen, methyl or trifluoromethyl
and
R 6 represents hydrogen, fluorine or chlorine.
2. A compound of the formula (I)
wherein
ring A represents an oxo-substituted azaheterocycle of the formula
in which
* denotes the point of attachment to the remainder of the molecule,
R 9 represents hydrogen, methyl or trifluoromethyl
and
R 10A and R 10B independently of one another represent hydrogen or fluorine,
R 1 represents hydrogen or methyl,
R 2 represents hydrogen, fluorine or chlorine,
R 3 represents (C 3 -C 6 )-alkyl or (C 3 -C 6 )-alkenyl, each of which may be substituted up to six times by fluorine,
or
represents (C 3 -C 6 )-cycloalkyl, cyclopentenyl or cyclohexenyl, each of which may be substituted up to two times by identical or different radicals from the group consisting of methyl, ethyl and trifluoromethyl and also up to four times by fluorine,
L 1 represents a bond or represents methylene or ethane-1,2-diyl,
L 2 represents a bond or represents methylene, ethane-1,2-diyl, propane-1,3-diyl or ethene-1,2-diyl, each of which may be substituted up to two times by methyl,
or
represents a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
## denotes the point of attachment to group M,
m represents the number 0 or 1,
n represents the number 1 or 2,
and
R 4A and R 4B independently of one another represent hydrogen or methyl,
M represents phenylene, which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl,
or
represents cyclopentane-1,3-diyl, cyclohexane-1,3-diyl or cyclohexane-1,4-diyl, each of which may be substituted up to two times by identical or different radicals from the group consisting of fluorine and methyl,
or
L 2 and M are attached to one another and together form a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
### denotes the point of attachment to group L 1 ,
R 5 represents hydrogen, methyl or trifluoromethyl
and
R 6 represents hydrogen, fluorine or chlorine.
3. The compound of claim 1 in which
ring A represents an oxo-substituted azaheterocycle of the formula
in which
* denotes the point of attachment to the remainder of the molecule,
R 8 represents trifluoromethyl or phenyl which may be substituted up to two times by identical or different radicals selected from the group consisting of fluorine, chlorine, methyl and trifluoromethyl
and
R 9 represents hydrogen or has the meaning of R 8 given above,
R 1 represents hydrogen,
R 2 represents hydrogen,
R 3 represents propan-2-yl, butan-2-yl, pentan-2-yl, 1,1,1-trifluoropropan-2-yl, 1,1,1-trifluorobutan-2-yl, 4,4,4-trifluorobutan-2-yl, 4,4,4-trifluoro-2-methylbutan-1-yl, cyclopentyl or 3,3-difluorocyclopentyl,
L 1 represents a bond or represents methylene,
L 2 represents a bond, represents methylene or ethane-1,2-diyl, each of which may be substituted up to two times by methyl, or represents ethene-1,2-diyl
or
represents a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping
and
## denotes the point of attachment to group M,
M represents 1,3-phenylene or 1,4-phenylene, each of which may be substituted up to two times by identical or different radicals from the group consisting of fluorine, chlorine, methyl and trifluoromethyl, or represents cyclohexane-1,3-diyl or cyclohexane-1,4-diyl,
or
L 2 and M are attached to one another and together form a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
### denotes the point of attachment to group L 1 ,
R 5 represents hydrogen or methyl
and
R 6 represents hydrogen or fluorine.
4. The compound of claim 2 in which
ring A represents an oxo-substituted azaheterocycle of the formula
in which
* denotes the point of attachment to the remainder of the molecule
and
R 10A and R 10B independently of one another represent hydrogen or fluorine,
R 1 represents hydrogen,
R 2 represents hydrogen,
R 3 represents propan-2-yl, butan-2-yl, pentan-2-yl, 1,1,1-trifluoropropan-2-yl, 1,1,1-trifluorobutan-2-yl, 4,4,4-trifluorobutan-2-yl, 4,4,4-trifluoro-2-methylbutan-1-yl, cyclopentyl or 3,3-difluorocyclopentyl,
L 1 represents a bond,
L 2 represents methylene or ethane-1,2-diyl, each of which may be substituted up to two times by methyl, or represents ethene-1,2-diyl
or
represents a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping
and
## denotes the point of attachment to group M,
M represents 1,3-phenylene or 1,4-phenylene, each of which may be substituted up to two times by identical or different radicals from the group consisting of fluorine, chlorine, methyl and trifluoromethyl,
or
L 2 and M are attached to one another and together form a group of the formula
in which
# denotes the point of attachment to the carboxylic acid grouping,
### denotes the point of attachment to group L 1 ,
R 5 represents hydrogen or methyl
and
R 6 represents hydrogen or fluorine.
5. A process for preparing the compound of the formula (I) as defined in claim 1 , comprising converting a compound of the formula (II)
in which R 1 and R 2 have the meanings given in claim 1
and
T 1 represents (C 1 -C 4 )-alkyl,
in an inert solvent in the presence of a base with a compound of the formula (III)
R 3 —X (III),
in which R 3 has the meaning given in claim 1
and
X represents a leaving group,
into a compound of the formula (IV)
brominating the compound of the formula (IV) in an inert solvent with elemental bromine or with N-bromosuccinimide to give a compound of the formula (V)
reacting the compound of the formula (V) in an inert solvent in the presence of a base with a compound of the formula (VI)
in which ring A represents an oxo-substituted azaheterocycle, as defined in claim 1 ,
to give a compound of the formula (VII)
removing the ester radical T 1 in (VII) under basic or acidic conditions,
to give a carboxylic acid of the formula (VIII)
coupling the carboxylic acid of the formula (VIII) in an inert solvent in the presence of a condensing agent or via the intermediate of the corresponding carbonyl chloride in the presence of a base with an amine of the formula (IX)
in which L 1 , L 2 and M have the meanings given in claim 1
and
T 2 represents (C 1 -C 4 )-alkyl,
to give a compound of the formula (X)
and removing the ester radical T 2 in (X) by further basic or acidic solvolysis to give the carboxylic acid of the formula (I)
and the compounds of the formula (I) are separated where appropriate by methods known to the skilled person into their enantiomers and/or diastereomers, and/or where appropriate reacted with the appropriate (i) solvents and/or (ii) bases or acids to give salts thereof.
6. A pharmaceutical composition comprising the compound of claim 1 and at least one inert, non-toxic, pharmaceutically suitable excipient.
7. A pharmaceutical composition comprising the compound of claim 1 and at least one active ingredient selected from the group consisting of an organic nitrate, an NO donor, a cGMP-PDE inhibitor, a stimulator of guanylate cyclase, an agent having antithrombotic activity, an agent for lowering blood pressure, and an agent for altering lipid metabolism.
8. A process for preparing the compound of the formula (I) as defined in claim 2 , comprising converting a compound of the formula (II)
in which R 1 and R 2 have the meanings given in claim 2
and
T 1 represents (C 1 -C 4 )-alkyl,
in an inert solvent in the presence of a base with a compound of the formula (III)
R 3 —X (III),
in which R 3 has the meaning given in claim 7
and
X represents a leaving group,
into a compound of the formula (IV)
brominating the compound of the formula (IV) in an inert solvent with elemental bromine or with N-bromosuccinimide to give a compound of the formula (V)
reacting the compound of the formula (V) in an inert solvent in the presence of a base with a compound of the formula (VI)
in which ring A represents an oxo-substituted azaheterocycle, as defined in claim 2 ,
to give a compound of the formula (VII)
removing the ester radical T 1 in (VII) under basic or acidic conditions,
to give a carboxylic acid of the formula (VIII)
coupling the carboxylic acid of the formula (VIII) in an inert solvent in the presence of a condensing agent or via the intermediate of the corresponding carbonyl chloride in the presence of a base with an amine of the formula (IX)
in which L 1 , L 2 and M have the meanings given in claim 2
and
T 2 represents (C 1 -C 4 )-alkyl,
to give a compound of the formula (X)
and removing the ester radical T 2 in (X) by further basic or acidic solvolysis to give the carboxylic acid of the formula (I)
and the compounds of the formula (I) are separated where appropriate by methods known to the skilled person into their enantiomers and/or diastereomers, and/or where appropriate reacted with the appropriate (i) solvents and/or (ii) bases or acids to give salts thereof.
9. A pharmaceutical composition comprising a compound as defined in claim 2 and at least one inert, non-toxic, pharmaceutically suitable excipient.
10. A pharmaceutical composition comprising a compound as defined in claim 2 and at least one active ingredient selected from the group consisting of an organic nitrate, an NO donor, a cGMP-PDE inhibitor, a stimulator of guanylate cyclase, an agent having antithrombotic activity, an agent for lowering blood pressure, and an agent for altering lipid metabolism.