Hydroxyalkyl-substituted phenyltriazole derivatives and uses thereof
The present invention relates to novel 5-(hydroxyalkyl)-1-phenyl-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 cardiovascular and renal diseases.
1. A compound of formula (I)
wherein
R 1 is hydrogen or methyl,
and
R 2A and R 2B are independently selected from the group consisting of hydrogen, fluoro, chloro, cyano, methyl, fluoromethyl, difluoromethyl, trifluoromethyl, ethyl, methoxy, difluoromethoxy and trifluoromethoxy,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
2. The compound of claim 1 , wherein
R 1 is hydrogen or methyl,
and
R 2A and R 2B are independently selected from the group consisting of hydrogen, fluoro, chloro, methyl and methoxy, wherein at least one of R 2A and R 2B is other than hydrogen,
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
3. The compound of claim 1 , wherein the compound is selected from the group consisting of
5-(4-chlorophenyl)-2-{[1-(3-chlorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-{[1-(3-fluorophenyl)-5-(hydroxymethyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5 -(4-chlorophenyl)-2-{[5 -(hydroxymethyl)-1-(2-methylphenyl)-1H-1,2,4-triazol-3-yl]-methyl-}-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-({1-(2-chloro-4-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5 -(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1);
2-{[1-(2-chloro-4-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2);
2-({1-(2-chloro-5-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 1);
2-{[1-(2-chloro-5-fluorophenyl)-5-(1-hydroxyethyl)-1H-1,2,4-triazol-3-yl]methyl}-5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one(diastereomer 2);
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1R)- 1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1R)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
and
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
4. The compound of claim 1 , wherein the compound is selected from the group consisting of
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-fluorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1RS)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
and
5-(4-chlorophenyl)-2-({1-(2-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one;
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
5. 5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, a compound having the following formula
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
6. The compound of claim 5 , wherein the compound is 5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one having the following formula
7. A process for preparing a compound of claim 1 , comprising:
reacting a compound of formula (II)
is with hydrazine to give the hydrazide of formula (III)
condensing the hydrazide of formula (III) with an amidine of formula (IV)
or a salt thereof,
wherein R 1 has the meaning indicated in claim 1 ,
in the presence of a base to give a 1,2,4-triazole derivative of formula (V)
and/or a tautomer thereof,
wherein R 1 has the meaning indicated in claim 1 ,
and coupling the 1,2,4-triazole derivative of formula (V) and/or tautomer thereof with a phenylboronic acid of formula (VI)
wherein R 2A and R 2B have the meanings indicated in claim 1 ,
in the presence of a copper catalyst and an amine base to yield a compound of formula (I)
wherein R 1 , R 2A and R 2B have the meanings indicated in claim 1 , and
when more than one diastereomer, hydrate, solvate, salt, or hydrate or solvate of the salt of the compound of formula (I) is produced they are optionally separated into their respective diastereomers, and/or converted into their respective hydrates, solvates, salts and/or hydrates or solvates of the salts by treatment with the corresponding solvents and/or acids or bases.
8. A pharmaceutical composition comprising a compound of claim 1 and at least one pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8 further comprising at least one therapeutic agent selected from the group consisting of a diuretic, an angiotensin AII antagonist, an ACE inhibitor, a beta-receptor blocker, a mineralocorticoid receptor antagonist, an organic nitrate, an NO donor, an activator of soluble guanylate cyclase, a stimulator of soluble guanylate cyclase, and a positive-inotropic agent.
10. A method of inhibiting the action of vasopressin in a human or other animal comprising administering to the human or the other mammal in need thereof a therapeutically effective amount of at least one compound of claim 1 .
11. A method of inhibiting the action of vasopressin in a human or other animal comprising administering to the human or the other mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 8 .
12. A method for the treatment of acute and chronic heart failure, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of at least one compound of claim 1 .
13. A method for the treatment of acute and chronic heart failure, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of the pharmaceutical composition of claim 8 .
14. A method for treatment of acute and chronic heart failure, comprising administering to a human or other mammal in need thereof a therapeutically effective amount of 5-(4-Chlorophenyl)-2-({1-(3-chlorophenyl)-5-[(1S)-1-hydroxyethyl]-1H-1,2,4-triazol-3-yl}-methyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one, a compound having the following formula
or a pharmaceutically acceptable salt, hydrate and/or solvate thereof.
15. The method of claim 14 , comprising administering the compound, having the following formula