Branched 3-phenylpropionic acid derivatives and their use

Patent metadata

Field	Value
Publication number	US-10023528-B2
Application number	US-201615158331-A
Country	US
Kind code	B2
Filing date	May 18, 2016
Priority date	Apr 13, 2011
Publication date	Jul 17, 2018
Grant date	Jul 17, 2018

Abstract

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.

First claim

The invention claimed is:

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:

Assignees

• Bayer Ip Gmbh
• Bayer Pharma AG

Inventors

• Hahn Michael
• Lampe Thomas
• Stasch Johannes-Peter
• Schlemmer Karl-Heinz
• Wunder Frank
• Li Volkhart Min-Jian
• Becker-Pelster Eva-Maria
• Stoll Friederike
• Knorr Andreas
• Woltering Elisabeth

Classifications

• A61P43/00

  Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00 · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title