Substituted dihydropyrazolones for treating cardiovascular and hematological diseases

Patent metadata

Field	Value
Publication number	US-8987261-B2
Application number	US-201313769513-A
Country	US
Kind code	B2
Filing date	Feb 18, 2013
Priority date	Oct 26, 2006
Publication date	Mar 24, 2015
Grant date	Mar 24, 2015

Abstract

The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and hematological diseases and kidney diseases, and for promoting wound healing.

First claim

The invention claimed is:

1. A method for treatment of cardiovascular diseases, cardiac insufficiency, anemia, chronic kidney diseases and renal insufficiency in humans and animals using an active amount of at least one compound of formula I:

in which
R 1 represents a heteroaryl group of the formula

wherein
* denotes the linkage point with the dihydropyrazolone ring
and
R 4 denotes hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

R 2 represents a heteroaryl group of the formula

wherein
# denotes the linkage point with the dihydropyrazolone ring
and
R 6 , R 6A and R 6B are identical or different and independently of one another denote hydrogen or a substituent chosen from the group consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein
(C 1 -C 6 )-alkyl in its turn can be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in their turn can in each case be substituted once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl or (C 1 -C 4 )-alkoxy-carbonyl,

and
R 3 represents hydrogen,
or a salt thereof.

2. The method of claim 1 , wherein
R 1 represents a heteroaryl group of the formula

wherein
* denotes the linkage point with the dihydropyrazolone ring
and
R 4 denotes hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

R 2 represents a heteroaryl group of the formula

wherein
# denotes the linkage point with the dihydropyrazolone ring
and
R 6 , R 6A and R 6B are identical or different and independently of one another denote hydrogen or a substituent chosen from the series consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein
(C 1 -C 6 )-alkyl in its turn can be substituted by hydroxyl, (C 1 -C 4 ) -alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in their turn can in each case be substituted once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and/or (C 1 -C 4 )-alkoxy-carbonyl,

and
R 3 represents hydrogen,
or a salt thereof.

3. The method of claim 1 , wherein
R 1 represents a heteroaryl group of the formula

wherein
denotes the linkage point with the dihydropyrazolone ring
and
R 4 denotes hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

R 2 represents a heteroaryl group of the formula

wherein
# denotes the linkage point with the dihydropyrazolone ring
and
R 6 denotes hydrogen or a substituent chosen from the series consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 ) -alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein
(C 1 -C 6 )-alkyl in its turn can be substituted by hydroxyl, (C 1 -C 4 ) -alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in their turn can in each case be substituted once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and/or (C 1 -C4)-alkoxy-carbonyl,

and
R 3 represents hydrogen,
or a salt thereof.

4. The method of claim 1 , wherein,
R 1 represents a heteroaryl group of the formula

wherein
* denotes the linkage point with the dihydropyrazolone ring
and
R 4 denotes hydrogen, fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxymethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, hydroxycarbonyl or (C 1 -C 4 )-alkoxycarbonyl,

R 2 represents a heteroaryl group of the formula

wherein
# denotes the linkage point with the dihydropyrazolone ring
and
R 6 denotes hydrogen or a substituent chosen from the series consisting of fluorine, chlorine, bromine, cyano, (C 1 -C 6 )-alkyl, trifluoro-methyl, hydroxyl, (C 1 -C 6 )-alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl, (C 1 -C 4 )-alkoxycarbonyl, 4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl, wherein
(C 1 -C 6 )-alkyl in its turn can be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or amino
and
4- to 6-membered heterocycloalkyl, phenyl and 5- or 6-membered heteroaryl in their turn can in each case be substituted once or twice in an identical or different manner by fluorine, chlorine, bromine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, oxo, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, hydroxycarbonyl and/or (C 1 -C 4 )-alkoxy-carbonyl,

and
R 3 represents hydrogen,
or a salt thereof.

5. A method for treatment of cardiovascular diseases, cardiac insufficiency, anemia, chronic kidney diseases and renal insufficiency comprising administering to a human o

Assignees

• Bayer Ip Gmbh

Inventors

• Thede Kai
• Flamme Ingo
• Oehme Felix
• Ergüden Jens-Kerim
• Stoll Friederike
• Schuhmacher Joachim
• Wild Hanno
• Kolkhof Peter
• Beck Hartmut
• Keldenich Jörg
• Akbaba Metin
• Jeske Mario

Classifications

• A61P9/04

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

• A61P9/12

  Antihypertensives · CPC title

• A61P7/00

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

• A61P9/00

  Drugs for disorders of the cardiovascular system · 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