Substituted dihydropyrazolones and their use
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 haematological diseases and kidney diseases, and for promoting wound healing.
1. A compound of the formula
in which
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, or a salt thereof.
2. A compound according to claim 1 , wherein
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical is substituted by 1 to 4 fluorine substituents,
or
R 2 represents piperazin-1-yl,
where piperazin-1-yl is substituted by one substituent, where the substituent is selected from the group consisting of C 3 -C 6 -cycloalkyl,
or
R 2 represents azetidin-1-yl,
where azetidin-1-yl is substituted by one substituent, where the substituent is selected from the group consisting of hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
R 2 represents 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl,
or a salt thereof.
3. A compound according to claim 1 , wherein
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents azetidin-1-yl, pyrrolin-1-yl or piperidin-1-yl,
where azetidin-1-yl, pyrrolin-1-yl and piperidin-1-yl are substituted by 1 to 4 fluorine substituents,
or
R 2 represents piperazin-1-yl,
where piperazin-1-yl is substituted in the 4-position by one substituent, where the substituent is selected from the group consisting of C 3 -C 6 -cycloalkyl,
or
R 2 represents azetidin-1-yl,
where azetidin-1-yl is substituted in the 3-position by one substituent, where the substituent is selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,
or
R 2 represents 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl,
or a salt thereof.
4. A method for preparing a compound of the formula (I) or a salt thereof according to claim 1 , wherein
[A] a compound of the formula
in which R 1 has the meaning given in claim 1 , and
Z 1 represents methyl or ethyl,
is reacted in an inert solvent, if appropriate in the presence of an acid, with a compound of the formula
in which R 2 has the meaning given in claim 1 ,
to give a compound of the formula
in which Z 1 , R 1 and R 2 have the meaning given in claim 1 ,
which, already under these reaction conditions or in a subsequent reaction step under the influence of a base, cyclizes to give the compound of the formula (I), and the compound of the formula (I) is, if appropriate with the appropriate (i) solvent and/or (ii) base or acid, converted into one of its salts,
or
[B] a compound of the formula
in which Z 1 and R 1 have the meaning given in claim 1 ,
is condensed with a compound of the formula
in which
Z 2 represents methyl or ethyl,
to give a compound of the formula
in which Z 1 and R 1 have the meaning given in claim 1 ,
and then reacted in the presence of an acid with a compound of the formula (III) to give a compound of the formula (IV), which, already under these reaction conditions or in a subsequent reaction step under the influence of a base, cyclizes to give the compound of the formula (I),
and the compound of the formula (I) is, if appropriate with the appropriate (i) solvent and/or (ii) base or acid, converted into one of its salts,
or
[C] the compound of the formula
is, in water as the solvent in a one-pot process, reacted initially with a compound of the formula
R 1 —H (IX),
in which R 2 has the meaning given in claim 1 ,
and then with a compound of the formula (VII) to give a compound of the formula (I),
and the compound of the formula (I) is, if appropriate with the appropriate (i) solvent and/or (ii) base or acid, converted into one of its salts.
5. A pharmaceutical composition comprising a compound according to claim 1 in combination with an inert, non-toxic, pharmaceutically acceptable excipient.
6. A method for treating anemia in a subject comprising administering a therapeutically effective amount of a compound according to claim 1 .
7. A compound according to claim 1 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents piperazin-1-yl,
wherein piperazin-1-yl is substituted by a substituent selected from the group consisting of C 3 -C 6 -cycloalkyl,
or a salt thereof.
8. A compound according to claim 7 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents piperazin-1-yl,
wherein piperazin-1-yl is substituted in the 4-position by a substituent selected from the group consisting of C 3 -C 6 -cycloalkyl,
or a salt thereof.
9. A compound according to claim 1 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents azetidin-1-yl,
wherein azetidin-1-yl is substituted by a substituent selected from the group consisting of hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or a salt thereof.
10. A compound according to claim 9 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents azetidin-1-yl,
wherein azetidin-1-yl is substituted by a substituent selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,
or a salt thereof.
11. A compound according to claim 10 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents azetidin-1-yl,
wherein azetidin-1-yl is substituted in the 3-position by a substituent selected from the group consisting of hydroxycarbonyl, methyl and dimethylamino,
or a salt thereof.
12. A compound according to claim 1 , characterized in that
X represents N or CH,
R 1 represents hydrogen or cyano, and
R 2 represents 1,2-oxazinan-2-yl or 1,4-oxazepan-4-yl,
or a salt thereof.
13. A compound according to claim 1 , wherein R 2 represents 4-cyclobutyl-piperazin-1-yl.
14. A compound according to claim 1 , wherein the compound is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
or a salt thereof.
15. A compound according to claim 1 , where the compound is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
16. A compound according to claim 1 , where the compound is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
or a salt thereof.
17. A compound according to claim 1 , where the compound is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
18. A compound according to claim 1 , where the compound is 2-[6-(1,2-Oxazinan-2-yl) pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
or a salt thereof.
19. A compound according to claim 1 , where the compound is 2-[6-(1,2-Oxazinan-2-yl) pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
20. A compound according to claim 1 , where the compound is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
or a salt thereof.
21. A compound according to claim 1 , wherein the compound is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: