Substituted dihydropyrazolones for treating cardiovascular and hematological diseases

1. A compound of the 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. A method of making a compound of claim 1 comprising:

reacting a compound of the formula (V)

in which R 1 has the meaning given in claim 1 and

Z 1 represents methyl or ethyl,

in a condensation reaction with a compound of the formula (VI)

in which

Z 2 represents methyl or ethyl,

to give a compound of the formula (VII)

in which Z 1 represents methyl or ethyl and R 1 has the meaning given in claim 1 ,

and reacting the compound of formula (VII) in the presence of an acid with a compound of the formula (III)

in which R 2 has the meaning given in claim 1 ,

to give compounds of the formula (IV-A)

in which Z 1 represents methyl or ethyl and R 1 and R 2 have the meanings given in claim 1 ,

and allowing a compound of formula (IV-A) to cyclize in the final reaction step given above, or cyclizing a compound of formula (IV-A) in a subsequent reaction step under the influence of a base to give a compound of the formula (I).

3. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with an inert, non-toxic, pharmaceutically suitable auxiliary substance.

4. The pharmaceutical composition of claim 3 , further comprising an active compound selected from the group consisting of an ACE inhibitor, an angiotensin II receptor antagonist, a beta receptor blocker, a calcium antagonist, a PDE inhibitor, a mineralocorticoid receptor antagonist, a diuretic, aspirin, an iron supplement, a vitamin B12 supplement, a folic acid supplement, a statin, a digitalis (digoxin) derivative, a tumor chemotherapeutic, and an antibiotic.

5. A compound of the formula (I) as claimed in claim 1 , 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 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.

6. A compound of the formula (I) as claimed in claim 1 , 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 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.

7. A compound of claim 1 , 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 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.

8. 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.

9. The compound of claim 8 , wherein the compound is 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one having the following formula

10. A salt of the compound of claim 8 , wherein the salt is 2-(6-Morpholin-4-ylpyrimidin-4-yl)-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one hydrochloride having the following formula