Branched 3-phenylpropionic acid derivatives and their use
View Patent ↗The present application relates to novel 3-phenylpropionic acid derivatives which carry a branched or cyclic alkyl substituent in the 3-position, to processes for their preparation, to their use 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 the treatment and/or prevention of cardiovascular diseases.
1. A process for preparing (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
or a salt, solvate, or solvate of a salt thereof, comprising coupling a carboxylic acid of formula (II)
in which R 8A represents methyl, R 8B represents trifluoromethyl, R 9 represents chlorine and R 10 represents hydrogen,
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 formula (III)
in which L represents a bond,
R 1 , R 2 , R 3 , R 5 , and R 7 independently of one another represent hydrogen,
R 4A and R 4B are attached to one another and together with the carbon atom to which they are attached form a cyclopropyl ring,
R 6 represents chlorine, and
T 1 represents (C 1 -C 4 )-alkyl or benzyl,
to give a carboxamide of the formula (IV)
and removing T 1 from the compound of formula (IV) by basic or acidic solvolysis or, when T 1 represents benzyl, also by hydrogenolysis.
2. The process of claim 1 , wherein the removing of T 1 from the compound of formula (IV) results in formation of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
3. A method for the treatment and/or prevention of heart failure, renal insufficiency, diabetic retinopathy, and vascular dementia comprising administering an effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
or a salt, solvate, or solvate of a salt thereof to a human or animal in need thereof.
4. The method for treatment and/or prevention according to claim 3 , further comprising administering a second active compound selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, agents having antithrombotic activity, agents for lowering blood pressure, and agents for altering lipid metabolisms.
5. A method for the treatment and/or prevention of renal insufficiency comprising administering an effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
or a salt, solvate, or solvate of a salt thereof to a human or animal in need thereof.
6. The method of claim 5 , wherein a therapeutically effective amount of (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
is administered.
7. A method for the treatment and/or prevention of renal insufficiency comprising administering an effective amount of a pharmaceutical composition comprising (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula:
or a salt, solvate, or solvate of a salt thereof and an inert, non-toxic, pharmaceutically suitable excipient to a human or animal in need thereof.
8. The method of claim 7 , wherein the pharmaceutical composition comprises (+)-3-(4-Chloro-3-{[(2S,3R)-2-(4-chlorophenyl)-4,4,4-trifluoro-3-methylbutanoyl]amino}phenyl)-3-cyclopropylpropanoic acid of formula: