Substituted piperidinyl tetrahydroquinolines

Patent metadata

Field	Value
Publication number	US-9944621-B2
Application number	US-201415106284-A
Country	US
Kind code	B2
Filing date	Dec 16, 2014
Priority date	Dec 19, 2013
Publication date	Apr 17, 2018
Grant date	Apr 17, 2018

Abstract

The present application relates to novel substituted piperidinyltetrahydroquinolines, 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 diabetic microangiopathies, diabetic ulcers on the extremities, in particular for promoting wound healing of diabetic foot ulcers, diabetic heart failure, diabetic coronary microvascular heart disorders, peripheral and cardial vascular disorders, thromboembolic disorders and ischaemias, peripheral circulatory disturbances, Raynaud's phenomenon, CREST syndrome, microcirculatory disturbances, intermittent claudication, and peripheral and autonomous neuropathies.

First claim

The invention claimed is:

1. A compound of the formula (I)

in which
R 1 represents C 1 -C 6 -alkyl or C 3 -C 5 -cycloalkyl,
where alkyl is substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy and haloalkoxy

and
R 2 represents hydrogen or C 1 -C 4 -alkyl,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocycle,
where the N-heterocycle may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, halogen and hydroxyalkyl,
or
where the N-heterocycle may have two substituents which, together with the carbon atom of the N-heterocycle to which they are jointly attached, form a 4- to 6-membered heterocycle,
where this heterocycle for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, methyl and ethyl,

R 3 represents hydrogen, fluorine, methoxy or ethoxy

and
R 4 represents hydrogen, fluorine, methoxy or ethoxy,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

2. The compound of the formula (I) according to claim 1 in which
R 1 represents C 1 -C 6 -alkyl or C 3 -C 5 -cycloalkyl,
where alkyl is substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy and C 1 -C 4 -alkoxy

and
R 2 represents hydrogen or C 1 -C 4 -alkyl,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 7-membered N-heterocycle,
where the N-heterocycle may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl, aminocarbonyl, C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy and halogen,
or
where the N-heterocycle may have two substituents which, together with the carbon atom of the N-heterocycle to which they are jointly attached, form a 4- to 6-membered heterocycle,
where this heterocycle for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, methyl and ethyl,

R 3 represents hydrogen, fluorine, methoxy or ethoxy,

and
R 4 represents hydrogen, fluorine, methoxy or ethoxy,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

3. The compound of the formula (I) according to claim 1 in which
R 1 represents C 2 -C 6 -alkyl,
where alkyl is substituted by a substituent selected from the group consisting of hydroxy, methoxy and ethoxy,

and
R 2 represents hydrogen,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothiomorpholine or 1,1-dioxidothiomorpholine,
where azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothiomorpholine and 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, trifluoromethyl, hydroxycarbonyl, C 1 -C 3 -alkyl, methoxy and methoxymethyl,
or
where azetidine, pyrrolidine, piperidine, azepane, piperazine and morpholine may have two substituents which, together with the carbon atom of the azetidine, pyrrolidine, piperidine, azepane, piperazine or morpholine to which they are jointly attached, form an azetidine, oxetane or 1,1-dioxidothietane,
where this azetidine, oxetane or 1,1-dioxidothietane for its part may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of methyl and ethyl,

R 3 represents hydrogen

and
R 4 represents hydrogen, fluorine or methoxy,

or
R 3 represents hydrogen, fluorine or methoxy

and
R 4 represents hydrogen,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

4. The compound of the formula (I) according to claim 1 in which
R 1 represents C 2 -C 4 -alkyl,
where alkyl is substituted by a substituent selected from the group consisting of hydroxy and methoxy,

and
R 2 represents hydrogen,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, morpholine or 1,1-dioxidothiomorpholine,
where azetidine, pyrrolidine, morpholine or 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents selected independently from the group consisting of hydroxycarbonyl, methyl, trifluoromethyl, methoxy and methoxymethyl,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine,
where the azetidine may have two substituents which, together with the carbon atom of the azetidine to which they are jointly attached, form an oxetane or 1,1-dioxidothietane,

R 3 represents hydrogen, fluorine or methoxy

and
R 4 represents hydrogen,

or
R 3 represents hydrogen,

and
R 4 represents hydrogen, fluorine or methoxy,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

5. The compound of the formula (I) according to claim 1 in which
R 1 represents C 2 -C 4 -alkyl,
where alkyl is substituted by a substituent selected from the group consisting of hydroxy and methoxy,

and
R 2 represents hydrogen,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, morpholine or 1,1-dioxidothiomorpholine,
where azetidine, pyrrolidine, morpholine or 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents selected independently from the group consisting of hydroxycarbonyl and methyl,

or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine,
where the azetidine may have two substituents which, together with the carbon atom of the azetidine to which they are jointly attached, form an oxetane,

R 3 represents hydrogen,

and
R 4 represents hydrogen,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

6. The compound of the formula (I) according to claim 1 in which
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine,
where the azetidine has two substituents which, together with the carbon atom of the azetidine to which they are jointly attached, form an oxetane,

R 3 represents hydrogen,

and
R 4 represents hydrogen,

and the salts thereof, the solvates thereof and the solvates of the salts thereof.

7. A method for preparing a compound of the formula (I) according to claim 1 or one of the salts thereof, solvates thereof or solvates of the salts thereof, wherein
[A] a compound of the formula (II)

is reacted with a compound of the formula (III)

in which R 3 and R 4 have the meanings given in claim 1 ,

in the presence of a reducing agent to give a compound of the formula (IV)

Assignees

• Bayer Pharma AG

Inventors

• Becker-Pelster Eva Maria
• Buchgraber Philipp
• Buchmüller Anja
• Engel Karen
• Geiss Volker
• Göller Andreas
• Himmel Herbert
• Kast Raimund
• Knorr Andreas
• Lang Dieter
• Redlich Gorden
• Schmeck Carsten
• Tinel Hanna
• Wunder Frank

Classifications

• A61P39/06

  Free radical scavengers or antioxidants · CPC title

• A61P7/00

  Drugs for disorders of the blood or the extracellular fluid · CPC title

• A61P9/02

  Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives · 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

• A61P7/06

  Antianaemics · CPC title