Substituted 1-benzylcycloalkylcarboxylic acids and the use thereof
View Patent ↗The present application relates to novel substituted 1-benzylcycloalkylcarboxylic acid derivatives, to processes for their preparation, to their use for the treatment and/or prevention of diseases, and to their use for producing medicaments for the treatment and/or prevention of diseases, especially for the treatment and/or prevention of cardiovascular disorders.
1. A compound of formula (I)
in which
R 1A and R 1B are attached to one another and together with the carbon atom to which they are attached form a cycloalkyl group of the formula
R 2 represents hydrogen, methyl, ethyl, vinyl, hydroxyl, methoxy, trideuteromethoxy, trifluoromethoxy, ethoxy or cyclopropyloxy,
R 3 represents hydrogen, methyl, ethyl, isopropyl or cyclopropyl,
R 4 represents hydrogen, fluorine, chlorine, bromine, cyano, methyl, trifluoromethyl, ethyl, isopropyl, cyclopropyl, cyclobutyl, methoxy or trifluoromethoxy,
R 5 represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy,
R 6 represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl or trifluoromethoxy,
R 7A represents methyl or ethyl,
R 7B represents trifluoromethyl,
or
R 7A and R 7B are attached to one another and together with the carbon atom to which they are attached form an optionally difluoro-substituted cyclopentyl ring of the formula
R 8 represents fluorine, chlorine, bromine, nitro, cyano, trifluoromethoxy, acetyl, 2-cyanovinyl, (C 1 -C 4 )-alkyl, (C 2 -C 4 )-alkenyl, cyclopropyl or cyclobutyl, where
(C 1 -C 4 )-alkyl and (C 2 -C 4 )-alkenyl may be substituted up to three times by fluorine and
cyclopropyl and cyclobutyl may be substituted up to two times by fluorine,
and
R 9 represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl, ethyl, methoxy or trifluoromethoxy,
and salts, solvates and solvates of the salts thereof.
2. The compound of claim 1 , wherein
R 1A and R 1B are attached to one another and together with the carbon atom to which they are attached form a cycloalkyl group of the formula
R 2 represents hydrogen, methyl, ethyl, hydroxyl, methoxy, trideuteromethoxy, ethoxy or cyclopropyloxy,
R 3 represents hydrogen, methyl or ethyl,
R 4 represents hydrogen, fluorine, chlorine, methyl or cyclopropyl,
R 5 represents hydrogen, fluorine, chlorine or methyl,
R 6 represents hydrogen, fluorine, chlorine or methyl,
R 7A represents methyl,
R 7B represents trifluoromethyl,
or
R 7A and R 7B are attached to one another and together with the carbon atom to which they are attached form an optionally difluoro-substituted cyclopentyl ring of the formula
R 8 represents fluorine, chlorine, acetyl, 2-cyanovinyl, (C 1 -C 4 )-alkyl, (C 2 -C 3 )-alkenyl, cyclopropyl or cyclobutyl, where (C 1 -C 4 )-alkyl and (C 2 -C 3 )-alkenyl may be substituted up to three times by fluorine,
and
R 9 represents hydrogen, fluorine, chlorine, methyl, trifluoromethyl or methoxy,
or a salt thereof.
3. The compound of claim 1 , wherein
R 1A and R 1B are attached to one another and together with the carbon atom to which they are attached form an optionally difluoro-substituted cyclopropyl ring of the formula
R 2 represents hydrogen or ethyl,
R 3 represents hydrogen,
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents hydrogen or fluorine,
R 6 represents hydrogen,
R 7A represents methyl,
R 7B represents trifluoromethyl,
or
R 7A and R 7B are attached to one another and together with the carbon atom to which they are attached form a difluoro-substituted cyclopentyl ring of the formula
R 8 represents chlorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, vinyl, 2,2-difluorovinyl or cyclopropyl,
and
R 9 represents hydrogen, fluorine, chlorine or methoxy,
or a salt thereof.
4. The compound of claim 1 , wherein
R 1A and R 1B are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl ring of the formula
R 2 represents hydroxyl, methoxy, trideuteromethoxy, ethoxy or cyclopropyloxy,
R 3 represents hydrogen,
R 4 represents hydrogen, fluorine or chlorine,
R 5 represents hydrogen or fluorine,
R 6 represents hydrogen,
R 7A represents methyl,
R 7B represents trifluoromethyl,
or
R 7A and R 7B are attached to one another and together with the carbon atom to which they are attached form a difluoro-substituted cyclopentyl ring of the formula
R 8 represents chlorine, methyl, trifluoromethyl, ethyl, 1,1-difluoroethyl, 2,2,2-trifluoroethyl, isopropyl, tert-butyl, 1,1,1-trifluoro-2-methylpropan-2-yl, vinyl, 2,2-difluorovinyl or cyclopropyl,
and
R 9 represents hydrogen, fluorine, chlorine or methoxy,
or a salt thereof.
5. A method of making a compound claim 1 , comprising:
coupling a carboxylic acid of the formula (II)
in which R 7A , R 7B , R 8 and R 9 have the meanings given in claim 1 ,
in an inert solvent with the aid 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 (III)
in which R 1A , R 1B , R 2 , R 3 , R 4 , R 5 and R 6 have the meanings given in claim 1
and
T 1 represents (C 1 -C 4 )-alkyl or benzyl,
to give a carboxamide of the formula (IV)
in which R 1A , R 1B , R 2 , R 3 , R 4 , R 5 , R 6 , R 7A , R 7B , R 8 , R 9 and T 1 have the meanings given above,
and removing the ester radical T 1 basic or acidic solvolysis or, in the case that T 1 represents benzyl, also by hydrogenolysis thereby producing a compound of claim 1 .
6. The method of claim 5 , further comprising producing a mixture of compounds of formula (I) and separating the compounds into their enantiomers and/or diastereomers and/or reacting the compounds with an appropriate (i) solvent and/or (ii) base to produce salts thereof.
7. A method of treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, microcirculation impairments, thromboembolic disorders, renal insufficiency, fibrotic disorders and arteriosclerosis comprising administering a compound of claim 1 to a human or animal in need thereof.
8. A pharmaceutical composition comprising a compound of claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.
9. The pharmaceutical composition of claim 8 , further comprising an additional 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.
10. A method of treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, ischaemias, microcirculation impairments, thromboembolic disorders, renal insufficiency, fibrotic disorders and arteriosclerosis comprising administering the pharmaceutical composition to claim 8 to a human or animal in need thereof.