Substituted triazole derivatives and uses thereof
The present invention relates to novel substituted 1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.
1. A compound of formula (I)
in which
R 1 represents C 1 -C 4 -alkyl, 3,3,3-trifluoro-prop-1-en-1-yl, 2,3,3-trifluoro-prop-2-en-1-yl, cyclopropyl, cyclobutyl, oxetan-2-yl, oxetan-3-yl, azetidin-2-yl, pyrrolidin-2-yl, pyrrolidin-3-yl, 1,1-dioxo-thietan-3-yl, 1,1-dioxo-tetrahydrothiophen-3-yl, 5-chloro-thiophen-2-yl or 2-oxoimidazolidin-4-yl,
where alkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of cyano, fluorine, hydroxy, trifluoromethyl, methoxy, methylsulfonyl, methylcarbonyloxy, methylsulfonylamino and 2-oxo-1,3-oxazolidin-3-yl,
and
where cyclopropyl and cyclobutyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of cyano, fluorine, hydroxy, amino, trifluoromethyl and tert-butoxycarbonylamino,
and
where azetidin-2-yl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine and tert-butoxycarbonyl,
and
where pyrrolidin-2-yl and pyrrolidin-3-yl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, fluorine, trifluoromethyl and tert-butoxycarbonyl,
R 2 represents chlorine, trifluoromethyl or trifluoromethoxy,
And/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.
2. A compound of according to claim 1 , wherein
R 1 represents methyl, ethyl, 3,3,3-trifluoro-prop-1-en-1-yl, 1-trifluoromethylcycloprop-1-yl, 2,2-difluorocycloprop-1-yl, 4-fluoropyrrolidin-2-yl, 5-oxopyrrolidin-2-yl, 1,1-dioxo-thietan-3-yl or 5-chloro-thiophen-2-yl,
where methyl is substituted by one substituent selected from the group consisting of trifluoromethyl, methoxy and methylsulfonyl, and
where ethyl is substituted by one substituent trifluoromethyl,
R 2 represents chlorine or trifluoromethyl,
And/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.
3. A compound of according to claim 1 , wherein
R 1 represents methyl, ethyl, 2,2-difluorocycloprop-1-yl, 4-fluoropyrrolidin-2-yl or 5-oxopyrrolidin-2-yl,
where methyl is substituted by one substituent methylsulfonyl, and
where ethyl is substituted by one substituent trifluoromethyl,
R 2 represents chlorine,
And/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.
4. Process for preparing a compound of the formula (I) and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof according to claim 1 , comprising reacting a compound of formula II
with a compound of formula III
in which
X 1 represents chlorine or hydroxy, and
to give a compound of formula (I),
optionally followed, where appropriate, by (I) separating the compound of the formula (I) thus obtained into a respective diastereomer, and/or (ii) converting the compound of the formula (I) into a respective pharmaceutically acceptable salt thereof, solvate thereof or a solvate of a salt thereof by treatment with a corresponding solvent and/or acid or base.
5. Compound as defined in claim 1 for treatment and/or prevention of one or more diseases.
6. Compound as defined in claim 1 for treatment and/or prevention of one or more acute and chronic kidney diseases optionally including one or more of diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).
7. A product comprising a compound as defined in claim 1 for manufacture of a pharmaceutical composition for treatment and/or prevention of one or more acute and chronic kidney diseases optionally including one or more of diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).
8. Pharmaceutical composition comprising a compound as defined in claim 1 and one or more pharmaceutically acceptable excipients.
9. Pharmaceutical composition of claim 8 comprising one or more first active ingredients, optionally one or more compounds of according to claim 1 , and one or more further active ingredients, optionally one or more additional therapeutic agents selected from the group consisting of diuretics, angiotensin All antagonists, ACE inhibitors, beta-receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, NO donors, activators and stimulators of the soluble guanylate cyclase, and positive-inotropic agents, antiinflammatory agents, immunosuppressive agents, phosphate binders and/or compounds which modulate vitamin D metabolism.
10. The pharmaceutical composition as defined in claim 8 for treatment and/or prevention of one or more acute and chronic kidney diseases optionally including one or more of diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud's syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).
11. Method for treatment and/or prevention of acute and chronic kidney diseases optionally including one or more of diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD) and coronary microvascular dysfunction (CMD), Raynaud's syndrome dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH) in a human or other mammal, said method comprising administering to a human or other mammal in need thereof, a therapeutically effective amount of one or more compounds as defined in claim 1 , or a pharmaceutical composition thereof.