Heterocyclic-substituted 2-acetamido-5-aryl-1,2,4-triazolones and use thereof
The present application relates to new, heterocyclyl-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
L is a bond or —C(R 6A R 6B )—*,
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 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 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 halogen, (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 phenyl, thienyl or furyl,
where 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 a 5- or 6-membered heterocyclyl or 5- or 6-membered heteroaryl,
where 5- or 6-membered heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 4 ) alkyl, hydroxyl, oxo, trifluoromethoxy, (C 1 -C 4 ) alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, (C 1 -C 4 ) alkylthio and thiooxo,
where 5- or 6-membered heteroaryl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of halogen,
trifluoromethyl, (C 1 -C 4 ) alkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 ) alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino and (C 1 -C 4 ) alkylthio,
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, trifluoro-methyl, hydroxyl, (C 1 -C 4 ) alkoxy, difluoromethoxy and trifluoromethoxy,
R 5 is hydrogen, trifluoromethyl or (C 1 -C 4 ) alkyl,
or a salt thereof.
2 . The compound of claim 1 , in which
L is a bond or —C(R 6A R 6B )—*,
where
* is the attachment site to R 3 ,
R 6A is hydrogen or methyl,
R 6B is hydrogen or methyl,
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 fluorine, 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 phenyl or thienyl,
where phenyl and thienyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,
R 3 is 2-oxo-1,3-oxazolidin-5-yl, 2-oxo-1,3-oxazolidin-4-yl, 2-oxoimidazolidin-4-yl, 2-oxo-2,3-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-1-yl, 2-oxo-2,3-dihydro-1,3-oxazol-4-yl, 2-oxo-2,3-dihydro-1,3-oxazol-5-yl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-1,3-oxazol-5-yl, 4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl, 4,5-dihydro-5-oxo-1H-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl, 4,5-dihydro-5-oxo-1H-1,2,4-thiadiazol-3-yl, 2,3-dihydro-2-oxo-1,3,4-thiadiazol-5-yl, furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl or triazinyl,
it being possible for 2-oxo-1,3-oxazolidin-5-yl, 2-oxo-1,3-oxazolidin-4-yl, 2-oxo-imidazolidin-4-yl, 2-oxo-2,3-dihydro-1H-imidazol-4-yl, 2-oxo-2,3-dihydro-1,3-oxazol-4-yl, 2-oxo-2,3-dihydro-1,3-oxazol-5-yl, 4,5-dihydro-5-oxo-1H-1,2,4-triazol-3-yl, 4,5-dihydro-5-oxo-1H-1,2,4-oxadiazol-3-yl, 4,5-dihydro-5-oxo-1,3,4-oxadiazol-2-yl, 4,5-dihydro-5-oxo-1H-1,2,4-thiadiazol-3-yl, 2,3-dihydro-2-oxo-1,3,4-thiadiazol-5-yl to be substituted by 1 or 2 substituents independently of one another selected from the group consisting of trifluoromethyl, methyl and ethyl,
and
it being possible for 4,5-dihydro-1H-imidazol-2-yl, 4,5-dihydro-1H-imidazol-4-yl, 4,5-dihydro-1H-imidazol-1-yl, 4,5-dihydro-1,3-oxazol-2-yl, 4,5-dihydro-1,3-oxazol-4-yl, 4,5-dihydro-1,3-oxazol-5-yl to be substituted by 1 or 2 substituents independently of one another selected from the group consisting of oxo, methyl and ethyl,
and
it being possible for furyl, thienyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, pyrazolyl, imidazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyridazinyl, pyrazinyl and triazinyl to be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, ethyl, hydroxyl, trifluoromethoxy, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino, methylethylamino and diethylamino,
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, methyl or ethyl,
or a salt thereof.
3 . The compound of claim 1 , in which
L is a bond or —C(R 6A R 6B )—*,
where
* is the attachment site to R 3 ,
R 6A is hydrogen,
R 6B is hydrogen,
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 are substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, hydroxyl, oxo and trifluoromethyl,
R 2 is phenyl,
where phenyl is substituted by a substituent selected from the group consisting of fluorine and chlorine,
R 3 is a group of the formula
where
# is the attachment site to L,
R 9 is hydrogen, trifluoromethyl, methyl or amino,
R 10 is trifluoromethyl, methyl or amino,
R 11 is hydrogen, fluorine, trifluoromethyl or methyl,
R 12 is hydroxyl or methoxy,
R 4 is a group of the formula
where
## is the attachment site to —C(R 5 )(LR 3 )N—,
R 7 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
R 8 is hydrogen, fluorine, chlorine, trifluoromethyl and methoxy,
where at least one of the radicals R 7 and R 8 is other than hydrogen,
R 5 is hydrogen or methyl,
or a salt, solvate, or a solvate of a salt thereof.
4 . A process for preparing a compound of the formula (I) as defined in claim 1 , comprising
[A] coupling a compound of the formula (II)
in which 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 L, R 3 , R 4 and R 5 are each as defined in claim 1 ,
or
[B] reacting a compound of the formula (IV)
in which R 1 and R 2 are each as defined in claims 1 to 3
in an inert solvent, in the presence of a base, with a compound of the formula (V)
in which L, R 3 , R 4 and R 5 are each as defined in claim 1
and
X 1 is a leaving group, such as halogen, mesylate or tosylate, for example,
or
[C] reacting a compound of the formula (VI)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
and
T 1 is hydrogen or (C 1 -C 4 ) alkyl,
in an inert solvent, optionally with activation of the carboxylic acid function with hydrazine, to give a compound of the formula (VII)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
cyclizing the compound of formula (VII) in an inert solvent, optionally in the presence of a suitable base, with cyanogen bromide or a compound of the formula (VIII)
in which
R 9 is (C 1 -C 4 ) alkyl,
and
T 2 is (C 1 -C 4 ) alkyl,
to give a compound of the formula (I-C1) or (I-C2)
in which L, R 1 , R 2 , R 4 , R 5 and R 9 are each as defined in claim 1 ,
or
[D] reacting a compound of the formula (VI) in an inert solvent, optionally with activation of the carboxylic acid function, with a compound of the formula (IX)
in which R 10 is as defined in claim 1 ,
and cyclizing the resulting intermediate in a suitable solvent to give a compound of the formula (I-D)
in which L, R 1 , R 2 , R 4 , R 5 and R 10 are each as defined in claim 1 ,
or
[E] reacting a compound of the formula (X)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
in an inert solvent in the presence of suitable base with hydroxylamine hydrochloride to give a compound of the formula (XI)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
and cyclizing the compound of formula (XI) in an inert solvent with a compound of the formula (XII-1) or (XII-2)
in which
R 11A is trifluoromethyl or (C 1 -C 4 ) alkyl,
R 11B is hydrogen, trifluoromethyl or (C 1 -C 4 ) alkyl,
T 4 is chlorine, hydroxyl, (C 1 -C 4 ) alkoxy, trifluoromethylcarbonyloxy or (C 1 -C 4 ) alkylcarbonyloxy,
T 5 is (C 1 -C 4 ) alkyl,
to give a compound of the formula (I-E1) or (I-E2)
in which L, R 1 , R 2 , R 4 , R 5 , R 11A and R 11B are each as defined in claim 1 ,
or
[F]cyclizing a compound of the formula (X)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
in an inert solvent in the presence of a suitable base with an azide reagent to give a compound of the formula (I-F)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
or
[G] reacting a compound of the formula (XI) in an inert solvent in the presence of a suitable base with phosgene, a phosgene derivative such as di- or triphosgene, N,N-carbonyldiimidazole or a chloroformic ester, to produce an intermediate, and
cyclizing the intermediate is in an inert solvent, optionally in the presence of a suitable base, to give a compound of the formula (I-G)
in which L, R 1 , R 2 , R 4 and R 5 are each as defined in claim 1 ,
and optionally converting the resulting compound of the formula (I), (I-C1), (I-C2), (I-D), (I-E1), (I-E2), (I-F) or (I-G) with a corresponding (i) solvent and/or (ii) base or acid into a salt thereof.
5 . (canceled)
6 . (canceled)
7 . (canceled)
8 . A pharmaceutical composition comprising a compound of claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.
9 . The pharmaceutical composition of claim 8 , further comprising an active ingredients 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.
10 . (canceled)
11 . 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) in a human or animal, comprising administering an effective amount of at least one compound of claim 1 to the human or animal.
12 . The method of claim 11 wherein the compound of claim 1 is administered in the form of the pharmaceutical composition of claim 8 .