Substituted bipiperidinyl derivatives

Patent metadata

Field	Value
Publication number	US-9624199-B2
Application number	US-201415106286-A
Country	US
Kind code	B2
Filing date	Dec 16, 2014
Priority date	Dec 19, 2013
Publication date	Apr 18, 2017
Grant date	Apr 18, 2017

Abstract

The invention relates to novel substituted bipiperidinyl derivatives, 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 2 -C 6 -alkyl or benzyl,
where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy, C 1 -C 4 -cycloalkyloxy and aminocarbonyloxo,
where benzyl may be substituted by 1 or 2 substituents independently of one another selected from halogen;

and
R 2 is selected from the group consisting of hydrogen and 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 C 1 -C 4 -alkyl, C 1 -C 4 -alkoxy, C 1 -C 4 -alkoxy-C 1 -C 4 -alkyl, halogen, oxo, hydroxy, monofluoromethyl, difluoromethyl, trifluoromethyl, hydroxycarbonyl, tert-butoxycarbonyl and aminocarbonyl,
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 N-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 C 1 -C 3 -alkyl, C 1 -C 3 -alkoxycarbonyl, C 3 -C 6 -cycloalkyl, C 3 -C 6 -cycloalkyl-C 1 -C 3 -alkoxy, C 3 -C 6 -cycloalkoxy, trifluoromethoxy-C 1 -C 4 -alkoxy, 5- or 6-membered heteroaryl or —OCONR 4 R 5 ,
where alkyl may be substituted by a substituent selected from the group consisting of C 1 -C 4 -alkoxy, C 3 -C 6 -cycloalkoxy, trifluoromethoxy and phenoxy,
in which this phenoxy for its part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen,

and
where heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of C 1 -C 4 -alkyl and C 3 -C 6 -cycloalkyl,
where this alkyl for its part may be substituted by a substituent selected from the group consisting of C 1 -C 3 -alkoxy and C 3 -C 6 -cycloalkyl,

R 4 represents C 1 -C 4 -alkyl,
R 5 represents hydrogen or C 1 -C 4 -alkyl,
or
R 4 and R 5 together with the nitrogen atom to which they are attached form a pyrrolidinyl ring,
A 1 represents CH and A 2 represents N;
or
A 1 represents N and A 2 represents CH;
or
A 1 and A 2 represent CH;
or one of the salts thereof, solvates thereof or solvates of the salts thereof.

2. The compound of the formula (I) according to claim 1 in which
R 1 represents C 2 -C 6 -alkyl or benzyl,
where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, C 1 -C 4 -alkoxy and aminocarbonyloxo,
where benzyl may be substituted by 1 or 2 substituents independently of one another selected from fluorine and chlorine;

and
R 2 is selected from the group consisting of hydrogen and C 1 -C 4 -alkyl;
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 3 substituents independently of one another selected from the group consisting of C 1 -C 2 -alkyl, C 1 -C 2 -alkoxy, C 1 -C 2 -alkoxy-C 1 -C 2 -alkyl and halogen,
or
where azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothiomorpholine and 1,1-dioxidothiomorpholine may have two substituents which together with the carbon atom of the azetidine, pyrrolidine, piperidine, azepane, piperazine, morpholine, thiomorpholine, 1-oxidothiomorpholine or 1,1-dioxidothiomorpholine to which they are jointly attached form an azetidine or oxetane,
where this azetidine or oxetane for its part may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of 3-methyl and 3-ethyl,

R 3 is selected from the group consisting of C 1 -C 4 -alkyl and C 3 -C 6 -cycloalkyl-C 1 -C 4 -alkoxy;
A 1 represents CH and A 2 represents N;
or
A 1 represents N and A 2 represents CH;
or
A 1 and A 2 represent CH;
or one of the salts thereof, solvates thereof or solvates of the salts thereof.

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

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

R 3 is selected from the group consisting of methyl and cyclopropylmethoxy;
A 1 represents CH and A 2 represents N;
or
A 1 represents N and A 2 represents CH;
or
A 1 and A 2 represent CH;
or one of the salts thereof, solvates thereof or solvates of the salts thereof.

4. The compound of the formula (I) according to claim 1 in which
R 1 is selected from the group consisting of methoxyethyl, hydroxy-sec-butyl, sec-butyl carbamate, methoxy-sec-butyl and benzyl,
where benzyl may be substituted by 1 to 2 fluorine substituents;

and
R 2 represents hydrogen or methyl;
or
R 1 and R 2 together with the nitrogen atom to which they are attached form an azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine,
where azetidine, pyrrolidine, piperidine, morpholine or 1,1-dioxidothiomorpholine may be substituted by 1 to 2 substituents selected independently from the group consisting of methyl, methoxy, methoxymethyl and fluorine,
or
where 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 is selected from the group consisting of methyl and cyclopropylmethoxy;
A 1 is CH;
and
A 2 represents N;
or
A 1 represents N;
and
A 2 represents CH;
or
A 1 and A 2 represent CH;
or one of the salts thereof, solvates thereof or solvates of the salts thereof.

5. A method of making the compound of the formula (I) of claim 1 or the salts thereof, the solvates thereof or the solvates of the salts thereof, where
[A] compounds of the formula (II)

are reacted with compounds of the formula (III)

Assignees

• Bayer Pharma AG

Inventors

• Becker-Pelster Eva Maria
• Buchgraber Philipp
• Buchmüller Anja
• Engel Karen
• Göller Andreas
• Himmel Herbert
• Kast Raimund
• Keldenich Joerg
• Schmeck Carsten
• Tinel Hanna
• Wunder Frank

Classifications

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• 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

• A61P43/00

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