5-aminotetrahydroquinoline-2-carboxylic acids and their use

Patent metadata

Field	Value
Publication number	US-10053428-B2
Application number	US-201715600132-A
Country	US
Kind code	B2
Filing date	May 19, 2017
Priority date	Jul 20, 2012
Publication date	Aug 21, 2018
Grant date	Aug 21, 2018

Abstract

The present application relates to novel 5-amino-5,6,7,8-tetrahydroquinoline-2-carboxylic acids, 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 and cardiopulmonary disorders.

First claim

The invention claimed is:

1. A method for the treatment of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, ischaemias, vascular disorders, impaired microcirculation, renal insufficiency, acute respiratory distress syndrome, acute lung injury, chronic-obstructive pulmonary diseases, asthmatic disorders, fibrotic disorders, thromboembolic disorders, and arteriosclerosis comprising administering an effective amount of a compound of formula (I) to a human or animal in need thereof, wherein formula (I) is

in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —O—, —CH 2 —, —CH 2 —CH 2 — or —CH═CH—,
R 3C represents a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy,
and R 3D represents a substituent selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy,
or a salt, solvate or solvate of a salt thereof.

2. The method of claim 1 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —CH 2 —CH 2 — or —CH═CH—,
R 3C represents fluorine, chlorine, methyl or trifluoromethyl,
and
R 3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

3. The method of claim 1 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —CH 2 —CH 2 — or —CH═CH—,
R 3C represents fluorine, chlorine, methyl or trifluoromethyl,
and
R 3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy.

4. The method of claim 1 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond or —CH 2 —CH 2 —,
R 3C represents chlorine,
and
R 3D represents hydrogen, fluorine or trifluoromethyl.

5. The method of claim 1 , wherein the compound is administered by inhalation.

6. The method of claim 1 , wherein the method is for the treatment of acute respiratory distress syndrome.

7. A method for the treatment of primary and secondary forms of pulmonary hypertension, heart failure, angina pectoris, hypertension, ischaemias, vascular disorders, impaired microcirculation, renal insufficiency, acute respiratory distress syndrome, acute lung injury, chronic-obstructive pulmonary diseases, asthmatic disorders, fibrotic disorders and arteriosclerosis comprising administering an effective amount of a compound to a human or animal in need thereof, wherein the compound is a compound having the formula

or a salt, solvate or solvate of the salt thereof.

8. The method of claim 7 , wherein the compound is administered by inhalation.

9. The method of claim 7 , wherein the method is for the treatment of acute respiratory distress syndrome.

10. A method for activating soluble guanylate cyclase in a human or animal comprising administering an effective amount of a compound of formula (I) to the human or animal, wherein formula (I) is

in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —O—, —CH 2 —, —CH 2 —CH 2 — or —CH═CH—,
and
R 3C represents a substituent selected from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy,
and R 3D represents a substituent selected from the group consisting of hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, difluoromethyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, difluoromethoxy and trifluoromethoxy,
or a salt, solvate or solvate of a salt thereof.

11. The method of claim 10 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —CH 2 —CH 2 — or —CH═CH—,
R 3C represents fluorine, chlorine, methyl or trifluoromethyl,
and
R 3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl, methoxy or trifluoromethoxy.

12. The method of claim 10 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond, —CH 2 —CH 2 — or —CH═CH—,
R 3C represents fluorine, chlorine, methyl or trifluoromethyl, and
R 3D represents hydrogen, fluorine, chlorine, cyano, methyl, trifluoromethyl or trifluoromethoxy.

13. The method of claim 10 , in which
R 1 represents hydrogen or fluorine,
L 1 represents ethane-1,2-diyl or 1,4-phenylene,
and
A represents a group of the formula

in which
* denotes the respective point of attachment to the remainder of the molecule,
L 3 represents a bond or —CH 2 —CH 2 —,
R 3C represents chlorine,
and
R 3D represents hydrogen, fluorine or trifluoromethyl.

Assignees

• Bayer Pharma AG

Inventors

• Hahn Michael
• Follmann Markus
• Becker Eva-Maria
• Stasch Johannes-Peter
• Keldenich Joerg
• Delbeck Martina
• Tinel Hanna
• Wunder Frank
• Mittendorf Joachim
• Terebesi Ildiko
• Lang Dieter
• Martin René
• Hübsch Walter

Classifications

• 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

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title