Substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof
View Patent ↗The present application relates to new, substituted 2-acetamido-5-aryl-1,2,4-triazolones, to processes for preparing them, to their use alone or in combinations for the treatment and/or prevention of diseases and also to their use for the production of medicaments for the treatment and/or prevention of diseases, more particularly for the treatment and/or prevention of cardiovascular disorders.
1. A compound of formula (I)
in which
A is —CH 2
Q is N,
R 1 is (C 2 -C 4 ) alkyl, (C 2 -C 4 ) alkenyl or cyclopropyl,
where (C 2 -C 4 ) alkyl and (C 2 -C 4 ) alkenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxyl and trifluoromethyl,
R 2 is phenyl,
where phenyl may be substituted by a substituent selected from the group consisting of fluorine or chlorine,
R 3 is —NR 8 -C(—O)-R 9 , —NR 10 -SO 2 - R 11 , —SO 2 -NR 12 R 13 , —O-C(—O)-NR 14 R 15 , —NR 16 -C(—O)-NR 17 R 18 , —NR 19 -C(—O)-OR 20 , —S(—O) n R 21 or —NR 26 -SO 2 -NR 27 R 28 -,
where
R 8 is hydrogen,
R 9 is methyl,
R 10 is hydrogen,
R 11 is methyl or ethyl,
R 12 is methyl,
R 13 is methyl,
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl,
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl,
or
R 16 and R 17 together with the nitrogen atoms to which they are attached form a 2-oxoimidazolidin-1-yl or a 2-oxotetrahydropyrimidin-1(2H)-yl ring,
R 19 is hydrogen,
R 20 is methyl or ethyl,
or
R 19 and R 20 together with the atoms to which they are attached form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl ring,
n is a number 0 or 2,
R 21 is methyl,
R 26 is hydrogen,
R 27 is hydrogen,
R 28 is hydrogen,
R 4 is a group of the formula
where
# is the attachment site to -C(R 5 )(AR 3 )N-,
R 22 is hydrogen, cyano, methyl, trifluoromethoxy, fluorine, chlorine, tri-fluoromethyl and methoxy,
R 23 is hydrogen, cyano, methyl, trifluoromethoxy, fluorine, chlorine, tri-fluoromethyl and methoxy,
where at least one of the radicals R 22 and R 23 is other than hydrogen,
R 5 is hydrogen or methyl,
R 29 is hydrogen, and also their salts, solvates, and solvates of the salts.
2. The compound of claim 1 , wherein
R 22 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy, and
R 23 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy.
3. The compound of claim 1 , wherein
R 1 is 3,3,3-trifluoroprop-1-en-1-yl; 3,3,3-trifluoropropyl; or 1,1,1-trifluoropropan-2-ol-3-yl
R 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
4. The compound of claim 1 , wherein
R 3 is —NR 8 -C(—O)-R 9 , —NR 10 -SO 2 -R 11 , —O-C(—O)-NR 14 R 15 or —NR 16 -C(—O)-NR 17 R 18,
wherein
R 8 is hydrogen,
R 9 is methyl,
R 10 is hydrogen,
R 11 is methyl or ethyl,
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl,
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl,
R 22 is hydrogen, cyano, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxy, and
R 23 is hydrogen, cyano, methyl, trifluoromethoxy, fluorine, chlorine, trifluoromethyl and methoxy,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
5. The compound of claim 4 , wherein
R 22 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy, and
R 23 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
6. The compound of claim 4 , wherein
R 1 is 3,3,3-trifluoroprop-1-en-1-yl, 3,3,3-trifluoropropyl or 1, 1,1-trifluoropropan-2-ol-3-yl,
R 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
7. The compound of claim 1 , wherein
R 1 is 3,3,3-trifluoroprop-1-en-1-yl, 3,3,3-trifluoropropyl or 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —O-C(—O)-NR 14 R 15 , wherein
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl.
8. The compound of claim 1 , wherein
R 1 is 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —O-C(—O)-NR 14 R 15 , wherein
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl,
R 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
9. The compound of claim 1 , wherein
R 1 is 3,3,3-trifluoroprop-1-en-l-yl, 3,3,3-trifluoropropyl or 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is NH-C(—O)-CH 3 .
10. The compound of claim 1 , wherein
R 1 is 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is NH-C(—O)-CH 3,
R 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
11. The compound of claim 1 , wherein
R 1 3,3,3-trifluoroprop-1-en-l-yl, 3,3,3-trifluoropropyl or 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —NR 10 -SO 2 -R 11 , wherein
R 10 is hydrogen,
R 11 is methyl or ethyl.
12. The compound of claim 1 , wherein
R 1 is 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —NR 10 -o 2 -r 11 , wherein
r 10 is hydrogen,
r 11 is methyl or ethyl,
r 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
13. The compound of claim 1 , wherein
R 1 is 3,3,3-trifluoroprop-1-en-l-yl, 3,3,3-trifluoropropyl or 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —NR 16 -C(—O)-NR 17 R 18,
wherein
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl.
14. The compound of claim 1 , wherein
R 1 is 1,1,1-trifluoropropan-2-ol-3-yl,
R 3 is —NR 16 -C(—O)-NR 17 R 18,
wherein
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl,
R 22 is hydrogen, fluorine, chlorine or trifluoromethyl, and
R 23 is hydrogen, fluorine, chlorine or trifluoromethyl,
wherein at least one of the radicals R 22 and R 23 is other than hydrogen.
15. The compound of claim 1 , wherein
R 1 is S-1,1,1-trifluoropropan-2-ol-3-yl.
16. An enantiomer or diastereomer compound of claim 7 or mixture thereof, selected from the group consisting of:
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-nitro-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer I),
N-{2-(Acetylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide (diastereomer mixture),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S )-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1 ,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[3-trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol- 1-yl}-N-{2-[(methylsulphonyl)amino]-1-[2-trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{1-(2,3-dichlorophenyl)-2-[(ethylsulphonyl)amino]ethyl}acetamide (diastereomer II),
(2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3 -trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]propyl carbamate,
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3 -trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3 -(trifluoromethyl)phenyl]ethyl carbamate (diastereomer II),
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1 -yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethyl carbamate (diastereomer II),
2-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethyl carbamate (diastereomer mixture),
N-{2-(Carbamoylamino)-1-[3-(trifluoromethyl)phenyl]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro- 1H-1,2,4-triazol-1-yl}acetamide (diastereomer I),
N-{2-(Carbamoylamino)-1-[2-(trifluoromethyl)phenyl]ethyl}-2- 55 3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide (diastereomer II),
N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide (diastereomer II),
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(1E)-3,3,3-trifluoroprop- 1-en-1-yl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3-(trifluoromethyl)phenyl]ethyl carbamate (Enantiomer II),
Methyl [2-({[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol- 1-yl]acetyl}amino)-2-(2,3-dichlorophenyl)ethyl]carbamate (enantiomer 2),
N-[2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2-[3-(4-chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetamide (enantiomer 2),
N-{1-(2-Chlorophenyl)-2-[(methylsulphonyl)amino]ethyl}-2-{3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}cetamide (diastereomer 1),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphonyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(dimethylsulphamoyl)- 1[3-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer I),
2-({[3-(4-Chlorophenyl)-5-oxo-4-(3,3,3-trifluoropropyl)-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethyl carbamate (enantiomerically pure),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(2-oxo- 1,3-oxazolidin-3-yl)-1-[3-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer I),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N- {2-(2-oxoimidazolidin-1-yl)-1[3-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer I),
2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-(methylsulphanyl)-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II), p 1 2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[3(trifluoromethyl)phenyl]ethyl sulphamate (diastereomer mixture),
2-(3-chloro-2-fluorophenyl)-2-R {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]ethyl carbamate (diastereomer mixture),
2-({[3-(4-Chlorophenyl)-4-(2-fluorobenzyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethyl carbamate (enantiomer II),
2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-(2,3-dichlorophenyl)ethyl carbamate (diastereomer II),
2-({[4-(4-Chlorophenyl)-2-oxo-3-(3,3,3-trifluoro-2-hydroxypropyl)-2,3-dihydro-1H-imidazol-1-yl]acetyl}amino)-2-[2-(trifluoromethyl)phenyl]ethyl carbamate (diastereomer mixture)
or a salt, solvate, or solvate of a salt thereof.
17. 2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[(methylsulphonyl)amino]-1-[3(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II)
or a salt, solvate, or solvate of a salt thereof.
18. 2-{3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}-N-{2-[methylsulphonyl)amino]-1-[2-(trifluoromethyl)phenyl]ethyl}acetamide (diastereomer II)
or a salt, solvate, or solvate of a salt thereof.
19. (2R)-2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]- 2 -[ 3-(trifluoromethyl)phenyl]propyl carbamate
or a salt, solvate, or solvate of a salt thereof.
20. 2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2- [3-(trifluoromethyl)phenyl]ethyl carbamate (diastereomer II)
21. 2-[({3-(4-Chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetyl)amino]-2-[2-(trifluoromethyl)phenyl]ethyl carbamate (diastereomer II)
or a salt, solvate, or solvate of a salt thereof.
22. N- [2-(Carbamoylamino)-1-(2,3-dichlorophenyl)ethyl]-2- {3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-yl}acetamide (diastereomer II)
or a salt, solvate, or solvate of a salt thereof.
23. 2-(2-Chlorophenyl)-2-[({3-(4-chlorophenyl)-5-oxo-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-4,5-dihydro-1H-1,2,4-triazol-1-l}acetyl)amino]ethyl carbamate (diastereomer mixture).
or a salt, solvate, or solvate of a salt thereof.
24. A compound of the formula
5-(4-chlorophenyl)-4-[(2S)-3,3,3-trifluoro-2-hydroxypropyl]-2,4-dihydro-3H-1,2,4-triazol-3-one.
25. Compound of the formula (III)
wherein
A is CH 2 ,
R 3 is is —NR 8 -C(—O)-R 9 , —NR 10 -SO 2 -R 11 , —SO 2 —NR 12 R 13 , —O-C(—O)-NR 14 R 15 , —NR 16 -C(—O)NR 17 R 18 , —NR 19 -C(—O)-OR 20 ,S(—O) n R 21 or —NR 26 -SO 2 -NR 27 R 28 -,
where
R 8 is hydrogen,
R 9 is methyl,
R 10 is hydrogen,
R 11 is methyl or ethyl,
R 12 is methyl,
R 13 is methyl,
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl,
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl,
or
R 16 and R 17 together with the nitrogen atoms to which they are attached form a 2-oxoimidazolidin-1-yl or a 2-oxotetrahydropyrimidin- 1(2H)-yl ring,
R 19 is hydrogen,
R 20 is methyl or ethyl,
or
R 19 and R 20 together with the atoms to which they are attached form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl ring,
n is a number 0 or 2,
R 21 is methyl,
R 26 is hydrogen,
R 27 is hydrogen,
R 28 is hydrogen,
R 4 is a group of the formula
where
# is the attachment site to -C(R 5 )(AR 3 )N-,
R 22 is hydrogen, fluorine, chlorine and trifluoromethyl,
R 23 is hydrogen, fluorine, chlorine and trifluoromethyl,
where at least one of the radicals R 22 and R 23 is other than hydrogen,
R 5 is hydrogen or methyl, and
R 29 is hydrogen
or a salt, solvate, or solvate of a salt thereof.
26. A compound of formula (V)
wherein
A is CH 2,
R 3 is —NR 8 -C(—O)-R 9 , —NR 10 -SO 2 -R 11 , —S 0 2 -NR 12 Rhu 13 , —O-C(—O)-NR 14 R 15 , —NR 16 -C(—O)-NR 17 R 18 , —NR 19 - C(—O)-OR 20 , —S(—O) n R 21 or —NR 26 -SO 2 -NR 27 R 28 -,
where
R 8 is hydrogen,
R 9 is methyl,
R 10 is hydrogen,
R 11 is methyl or ethyl,
R 12 is methyl,
R 13 is methyl,
R 14 is hydrogen or methyl,
R 15 is hydrogen, methyl or ethyl,
R 16 is hydrogen,
R 17 is hydrogen or methyl,
R 18 is hydrogen, methyl or ethyl,
or
R 16 and R 17 together with the nitrogen atoms to which they are attached form a 2-oxoimidazolidin-1-yl or a 2-oxotetrahydropyrimidin- 1(2H)-yl ring,
R 19 is hydrogen,
R 20 is methyl or ethyl,
or
R 19 and R 20 together with the atoms to which they are attached form a 2-oxo-1,3-oxazolidin-3-yl or 2-oxo-1,3-oxazinan-3-yl ring,
n is a number 0 or 2,
R 21 is methyl,
R 26 is hydrogen,
R 27 is hydrogen,
R 28 is hydrogen,
R 4 is a group of the formula
where
# is the attachment site to -C(R 5 )(AR 3 )N-,
R 22 is hydrogen, fluorine, chlorine and trifluoromethyl,
R 23 is hydrogen, fluorine, chlorine and trifluoromethyl,
where at least one of the radicals R 22 and R 23 is other than hydrogen,
R 5 is hydrogen or methyl, and
R 29 is hydrogen
x 1 is a leaving group.
27. The compound of claim 26 , wherein the leaving group is selected from the group consisting of halogen, mesylate, and tosylate.
28. A process for preparing compounds of the formula (I) as defined in claim 1 , comprising the steps of:
[A] coupling a compound of the formula (II)
in which Q, R 1 , and R 2 are each as defined in claim 1 , in an inert solvent, with activation of the carboxylic acid function, to a compound of the formula (III)
in which A, R 3 , R 4 , R 5 , and R 29 are each as defined in claim 1 ; or
[B] reacting a compound of the formula (IV)
in which Q, R 1 , and R 2 are each as defined in claim 7 , in an inert solvent, in the presence of a base, with a compound of the formula (V)
in which A, R 3 , R 4 , R 5 , and R 29 are each as defined in claim 7 , and X 1 is a leaving group; and optionally converting the resulting compound into a salt thereof.
29. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with a pharmaceutically suitable excipient.
30. A method for the treatment of acute and chronic cardiac insufficiency, hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites, oedemas, and the syndrome of inadequate ADH secretion (SIADH) in humans and animals, comprising the step of administering a therapeutically effective amount of a compound of the formula (I) as defined in claim 1 .