Substituted dihydropyrazolones for treating cardiovascular and hematological diseases
View Patent ↗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.
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 or animal in need thereof an active amount of 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H- 1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, a compound having the following formula
or a salt thereof.
6. The method of claim 5 , comprising administering a salt of the compound, having the following formula:
7. A method of treatment of cardiovascular diseases, cardiac insufficiency, anemia, chronic kidney diseases and renal insufficiency comprising administering to a human or animal in need thereof a pharmaceutical formulation comprising an active amount of a compound of formula (I) and an inert, non-toxic, pharmaceutically suitable auxiliary substance, wherein formula (I) is:
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.