Substituted benzyl and phenylsulfonyl triazolones, and use thereof
View Patent ↗The present application relates to new, substituted benzyl-1,2,4-triazolones and phenylsulfonyl-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. Compound of the formula (I)
in which
A is —CH 2 — or —SO 2 —,
R 1 is hydrogen, (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, trifluoromethyl, (C 3 -C 7 ) cycloalkyl, phenyl, —OR 10 , —NR 11 R 12 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 ,
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 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
in which R 10 , R 11 , R 12 , R 13 , R 14 and R 15 are each independently of one another hydrogen or (C 1 -C 6 ) alkyl,
in which (C 1 -C 6 ) alkyl may on its part 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
where (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, (C 1 -C 4 ) alkoxy, hydroxy, amino and oxo,
R 2 is halogen, trifluoromethyl, (C 1 -C 6 ) alkyl, (C 1 -C 6 ) alkoxy, mono-(C 1 -C 6 )-alkylamino, di-(C 1 -C 6 )-alkylamino, (C 3 -C 7 ) cycloalkyl, 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 hydrogen or (C 1 -C 4 ) alkoxy,
R 4 is (C 1 -C 6 ) alkylcarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl or di-(C 1 -C 6 ) alkylaminocarbonyl,
where (C 1 -C 6 )-alkylcarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl and di-(C 1 -C 6 )-alkylaminocarbonyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of halogen, trifluoromethyl, (C 1 -C 6 ) alkyl and phenyl,
in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of halogen, cyano, trifluoromethyl, hydroxyl-(C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkyl, trifluoromethoxy and (C 1 -C 4 ) alkoxy,
R 5 is halogen, trifluoromethyl, (C 1 -C 4 ) alkyl, trifluoromethoxy or (C 1 -C 4 ) alkoxy,
n is a number 0, 1 or 2,
and salts thereof.
2. The compound of claim 1 , in which
A is —CH 2 — or —SO 2 —,
R 1 is hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl or (C 3 -C 6 ) cycloalkyl,
where (C 1 -C 6 ) alkyl and (C 2 -C 4 ) alkenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, oxo, trifluoromethyl, (C 3 -C 6 ) cycloalkyl, phenyl, —OR 10 , —NR 11 R 12 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 ,
in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, hydroxycarbonyl, (C 1 -C 4 ) alkoxycarbonyl, aminocarbonyl, mono-(C 1 -C 4 )-alkylaminocarbonyl and di-(C 1 -C 4 )-alkylaminocarbonyl,
and
in which R 10 , R 11 , R 12 , R 13 , R 14 and R 15 independently of one another are each hydrogen or (C 1 -C 6 ) alkyl,
R 2 is chlorine, bromine, trifluoromethyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, (C 3 -C 6 ) cycloalkyl or 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, trifluoromethyl, hydroxyl, methoxy, ethoxy and trifluoromethoxy,
R 3 is hydrogen or methoxy,
R 4 is (C 1 -C 6 ) alkylcarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl or di-(C 1 -C 6 )-alkylaminocarbonyl,
where mono-(C 1 -C 6 )-alkylaminocarbonyl and di-(C 1 -C 6 )-alkylaminocarbonyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 ) alkyl and phenyl,
in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, trifluormethyl, methyl, ethyl, trifluoromethoxy, methoxy and ethoxy,
R 5 is fluorine, chlorine, trifluoromethyl, methyl, ethyl, trifluoromethoxy, methoxy or ethoxy,
n is a number 0 or 1,
and salts thereof.
3. The compound of claim 1 , in which
A is —CH 2 — or —SO 2 —,
R 1 is hydrogen, (C 1 -C 6 ) alkyl, (C 2 -C 4 ) alkenyl or cyclopropyl,
where (C 1 -C 6 ) alkyl and (C 2 -C 4 ) alkenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, oxo, trifluoromethyl, phenyl, —OR 10 , —NR 11 R 12 , —C(═O)—OR 13 and —C(═O)—NR 14 R 15 ,
in which phenyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, hydroxycarbonyl, methoxycarbonyl and ethoxycarbonyl,
and
in which R 10 , R 11 , R 12 , R 13 , R 14 and R 15 independently of one another are each hydrogen or methyl,
R 2 is chlorine, bromine, trifluoromethyl, (C 1 -C 4 ) alkyl, (C 1 -C 4 ) alkoxy, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, cyclopropyl or phenyl,
where phenyl 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 hydrogen or methoxy,
R 4 is methylcarbonyl, ethylcarbonyl, mono-(C 1 -C 6 )-alkylaminocarbonyl or di-(C 1 -C 6 )-alkylaminocarbonyl,
where mono-(C 1 -C 6 )-alkylaminocarbonyl and di-(C 1 -C 6 )-alkylaminocarbonyl may be substituted by 1 to 4 substituents independently of one another selected from the group consisting of fluorine, trifluoromethyl, methyl, ethyl and phenyl,
in which phenyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine, chlorine, trifluoromethyl, methyl, ethyl, trifluoromethoxy, methoxy and ethoxy,
R 5 is fluorine, chlorine or trifluoromethyl,
n is a number 0 or 1,
and salts thereof.
4. A process for preparing a compound of claim 1 , characterized in that:
[A] a compound of formula (II)
in which R 1 and R 2 are each as defined in claim 1
is reacted in an inert solvent, in the presence of a suitable base, with a compound of the formula (III)
in which A, n, R 3 , R 4 and R 5 are each as defined in claim 1 ,
and
X 1 is halogen, in particular chlorine,
or
[B] from a compound of the formula (IV)
in which A, n, R 2 , R 3 , R 4 and R 5 are each as defined in claim 1 ,
and
PG 1 is a suitable protective group, for example allyl,
in an inert solvent by standard methods the protective group PG 1 is eliminated
and the resulting compound of the formula (V)
in which A, n, R 2 , R 3 , R 4 and R 5 are each as defined in claim 1 ,
is reacted in the presence of a suitable base with a compound of the formula (VI)
R 1 —X 2 (VI),
in which R 1 is as defined in claim 1 ,
and
X′ is a leaving group, such as, for example, halogen, mesylate or tosylate,
and the resulting compound of formula (I) are optionally converted with the corresponding base or acids into a salt thereof.
5. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 in combination with 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 diuretics, angiotensin AII antagonists, ACE inhibitors, beta receptor blockers, mineralocorticoid receptor antagonists, organic nitrates, and NO donors.
7. A method of treatment 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 patient in need thereof a compound of claim 1 or a pharmaceutical composition of claim 5 .