Substituted aminoindane- and aminotetralinecarboxylic acids and the use thereof

Patent metadata

Field	Value
Publication number	US-9387203-B2
Application number	US-201314414297-A
Country	US
Kind code	B2
Filing date	Jul 16, 2013
Priority date	Jul 20, 2012
Publication date	Jul 12, 2016
Grant date	Jul 12, 2016

Abstract

The present application relates to novel substituted aminoindane- and aminotetralinecarboxylic acids, to processes for preparation thereof, to the use thereof 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 cardiovascular and cardiopulmonary diseases.

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
n represents the number 1 or 2
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 1 represents straight-chain (C 1 -C 5 )-alkanediyl,
x represents the number 1, 2 or 3, where one of these CH 2 groups may be replaced by —O—,
R 1A and R 1B independently of one another represent hydrogen or methyl,
L 2 represents a bond or straight-chain (C 1 -C 5 )-alkanediyl,
Ar represents phenyl or 5- or 6-membered heteroaryl having up to three heteroatoms from the group consisting of N, O and S,
R 2 represents a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and trifluoromethoxy,
p represents the number 0, 1 or 2,
where in the case where the substituent R 2 occurs twice, its respective meanings can be identical or different,

L 3 represents a bond, —O—, —CH 2 —, —CH 2 —CH 2 — or —CH═CH—
and
R 3 and R 4 independently of one another represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy and trifluoromethoxy,

and salts, solvates and solvates of the salts thereof.

2. A compound of the formula (I) according to claim 1 in which
n represents the number 1 or 2
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 1 represents straight-chain (C 2 -C 4 )-alkanediyl,
x represents the number 1 or 2, where one of these CH 2 groups may be replaced by —O—,
L 2 represents a bond or straight-chain (C 1 -C 4 )-alkanediyl,
Ar represents phenyl,
R 2 represents a substituent selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl and trifluoromethyl,
p represents the number 0 or 1,
L 3 represents a bond or —CH 2 —CH 2 —
and
R 3 and R 4 independently of one another represent hydrogen or a substituent selected from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl and trifluoromethyl,

and salts, solvates and solvates of the salts thereof.

3. A compound of the formula (I) according to claim 1 in which
n represents the number 1 or 2
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule
and
R 2 represents methyl, ethyl, isopropyl or tert-butyl,

and salts, solvates and solvates of the salts thereof.

4. A process for preparing the compound of the formula (I) as defined in claim 1 , comprising reacting a compound of the formula (II)

in which n has the meanings given in claim 1
and
T 1 and T 2 are identical or different and represent (C 1 -C 4 )-alkyl
in the presence of a base with a compound of the formula (III)

in which A has the meanings given in claim 1
and
X 1 represents a leaving group
to give a compound of the formula (IV)

in which n, A, T 1 and T 2 each have the meanings given above,
converting the compound of the formula (IV) by hydrolysis of the ester groupings —C(O)OT 1 and —C(O)OT 2 into the corresponding dicarboxylic acid of the formula (I)
and optionally separating the resulting compounds of the formula (I) into the enantiomers and/or diastereomers thereof and/or optionally reacting the resulting compounds of the formula (I) with appropriate (i) solvents and/or (ii) bases or acids to give the solvates, salts and/or solvates of the salts thereof.

5. A medicament comprising the compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.

6. A medicament comprising the compound as defined in claim 1 in combination with one or more further active compounds selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, stimulators of guanylate cyclase, antithrombotic agents, hypotensive agents and lipid metabolism modifiers.

7. A method for treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, thromboembolic disorders, ischaemias, vascular disorders, impaired microcirculation, renal insufficiency, fibrotic disorders and arteriosclerosis in humans and animals by administration of an effective amount of at least one compound as defined in claim 1 to a human or animal in need thereof.

8. A method for the treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, thromboembolic disorders, ischaemias, impaired microcirculation, renal insufficiency, fibrotic disorders and arteriosclerosis in humans and animals by administration of an effective amount of the medicament of claim 5 to a human or animal in need thereof.

9. A method for the treatment of heart failure, angina pectoris, hypertension, pulmonary hypertension, thromboembolic disorders, ischaemias, impaired microcirculation, renal insufficiency, fibrotic disorders and arteriosclerosis in humans and animals by administration of an effective amount of the medicament of claim 6 to a human or animal in need thereof.

Assignees

• Bayer Pharma AG

Inventors

• Hübsch Walter
• Hahn Michael
• Vakalopoulos Alexandros
• Li Volkhart Min-Jian
• Wunder Frank
• Stasch Johannes-Peter
• Schlemmer Karl-Heinz
• Stoll Friederike
• Lindner Niels
• Becker-Pelster Eva Maria

Classifications

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• A61P7/10

  Antioedematous agents; Diuretics · CPC title

• A61K31/197

  the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid (carnitine A61K31/205) · CPC title