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 the formula (I)
in which
A is —C(R 6A R 6B )—* or —C(R 6A R 6B )—C(R 7A R 7B )—*,
where
* is the attachment site to R 3 ,
R 6A is hydrogen, (C 1 -C 4 ) alkyl or trifluoromethyl,
R 6B is hydrogen or (C 1 -C 4 ) alkyl,
R 7A is hydrogen, (C 1 -C 4 ) alkyl or trifluoromethyl,
R 7B is hydrogen or (C 1 -C 4 ) alkyl,
Q is CH or N,
R 1 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 6 ) alkynyl or (C 3 -C 7 ) cycloalkyl,
where (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl and (C 2 -C 6 ) alkynyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of deuterium, halogen, cyano, oxo, hydroxyl, trifluoromethyl, (C 3 -C 7 ) cycloalkyl, (C 1 -C 6 ) alkoxy, trifluoromethoxy and phenyl,
in which (C 3 -C 7 ) cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of (C 1 -C 4 ) alkyl, oxo, hydroxyl, (C 1 -C 4 ) alkoxy and amino, and
in which (C 1 -C 6 ) alkoxy may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of amino, hydroxyl, (C 1 -C 4 ) alkoxy, hydroxycarbonyl and (C 1 -C 4 ) alkoxycarbonyl, and
in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxyl, hydroxymethyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, (C 1 -C 4 ) alkoxymethyl, hydroxycarbonyl, (C 1 -C 4 ) alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 ) alkylaminocarbonyl and di-(C 1 -C 4 ) alkylaminocarbonyl, and
where (C 3 -C 7 ) cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, hydroxy, amino and oxo,
R 2 is benzothienyl, phenyl, thienyl or furyl,
where benzothienyl, phenyl, thienyl and furyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 ) alkoxy and trifluoromethoxy,
R 3 is hydroxyl, trifluoromethoxy, (C 1 -C 4 ) alkoxy, (C 3 -C 7 ) cycloalkoxy, nitro, amino, —O—SO 2 —NR 24 R 25 , or —NR 30 R 31 ,
where
R 24 is hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl,
R 25 is hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl, or
R 24 and R 25 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxyl, (C 1 -C 4 ) alkyl and trifluoromethyl,
R 30 is hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl,
R 31 is (C 1 -C 4 ) alkyl or (C 3 -C 7 ) cycloalkyl, or
R 30 and R 31 together with the nitrogen atom to which they are attached form a 4- to 7-membered heterocycle,
where the 4- to 7-membered heterocycle may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, oxo, hydroxyl, (C 1 -C 4 ) alkyl and trifluoromethyl,
R 4 is phenyl, naphthyl or 5- to 10-membered heteroaryl,
where phenyl, naphthyl and 5- to 10-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, cyano, nitro, (C 1 -C 4 ) alkyl, difluoromethyl, trifluoromethyl, hydroxyl, (C 1 -C 4 ) alkoxy, difluoromethoxy and trifluoromethoxy,
R 5 is hydrogen, deuterium, trifluoromethyl or (C 1 -C 4 ) alkyl,
R 29 is hydrogen or (C 1 -C 4 ) alkyl,
or a salt thereof.
2. The compound of claim 1 , in which
A is —C(R 6A R 6B )—* or —C(R 6A R 6B )—C(R 7A R 7B )—*,
where
* is the attachment site to R 3 ,
R 6A is hydrogen, methyl or trifluoromethyl,
R 6B is hydrogen or methyl,
R 7A is hydrogen, methyl or trifluoromethyl,
R 7B is hydrogen or methyl,
Q is CH or N,
R 1 is (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl or (C 3 -C 6 ) cycloalkyl,
where (C 1 -C 6 ) alkyl and (C 2 -C 6 ) alkenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, oxo, hydroxyl, trifluoromethyl, (C 3 -C 6 ) cycloalkyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy and phenyl,
in which (C 3 -C 6 ) cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of methyl, ethyl, oxo, hydroxyl, methoxy, ethoxy and amino, and
in which phenyl may be substituted by a substituent selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methoxymethyl, ethoxymethyl, hydroxycarbonyl, methoxycarbonyl, ethoxycarbonyl and aminocarbonyl, and
where (C 3 -C 6 ) cycloalkyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, methyl, ethyl, methoxy, ethoxy, hydroxyl, amino and oxo,
R 2 is benzothien-2-yl, phenyl or thienyl,
where benzothien-2-yl, phenyl and thienyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,
R 3 is hydroxyl, amino, or —O—SO 2 —NR 24 R 25 ,
where
R 24 is hydrogen or methyl,
R 25 is hydrogen or methyl,
R 4 is phenyl,
where phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, methyl, ethyl, difluoromethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, difluoromethoxy and trifluoromethoxy,
R 5 is hydrogen, deuterium, trifluoromethyl, methyl or ethyl,
R 29 is hydrogen or methyl,
or a salt thereof.
3. The compound of claim 1 , in which
A is —C(R 6A R 6B )—* or —C(R 6A R 6B )—C(R 7A R 7B )—*,
where
* is the attachment site to R 3 ,
R 6A is hydrogen or trifluoromethyl,
R 6B is hydrogen,
R 7A is hydrogen,
R 7B is hydrogen,
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 hydroxyl, amino,
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, trifluoromethyl and methoxy,
R 23 is hydrogen, fluorine, chlorine, trifluoromethyl 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,
or a salt thereof.
4. A process for preparing a compound of claim 1 , comprising
[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 1
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 1 and
X 1 is a leaving group, such as halogen, mesylate or tosylate, for example,
and optionally converting the resulting compound of formula (I) with a (i) solvent and/or (ii) base or acid into a salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.
6. The pharmaceutical composition of claim 5 , further comprising at least one active ingredient 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, and a substance with positive inotropic activity.
7. A method for the treatment and/or prophylaxis of acute and chronic cardiac insufficiency, hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites, oedemas and the syndrome of inadequate ADH secretion (SIADH) comprising administering to a human or animal in need thereof, an effective amount of at least one compound of claim 1 .
8. A method for the treatment and/or prophylaxis of acute and chronic cardiac insufficiency, hypervolaemic and euvolaemic hyponatraemia, liver cirrhosis, ascites, oedemas and the syndrome of inadequate ADH secretion (SIADH), comprising administering to a human or animal in need thereof, an effective amount of at least one pharmaceutical composition of claim 5 .