Substituted aryloxazoles and their use
View Patent ↗The present application relates to novel substituted aryloxazole derivatives, to processes for their preparation, to their use for the treatment and/or prophylaxis of diseases and to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, preferably for the treatment and/or prevention of cardiovascular and metabolic disorders.
1. A compound of the formula (I)
in which
A represents O or S,
R 1 represents hydrogen or (C 1 -C 4 )-alkyl,
R 2 represents hydrogen or (C 1 -C 4 )-alkyl which may be substituted by hydroxyl, (C 1 -C 4 )-alkoxy or up to three times by fluorine
or
R 1 and R 2 are attached to one another and together with the carbon atom to which they are attached form a cyclopropane or cyclobutane ring,
R 3 represents hydrogen, halogen or (C 1 -C 4 )-alkyl,
R 4 and R 5 are identical or different and independently of one another represent hydrogen or (C 1 -C 6 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, carboxyl, and (C 1 -C 4 )-alkoxycarbonyl;
and either (i)
R 6 represents (C 6 -C 10 )-aryl which may be mono- to trisubstituted by identical or different substituents from the group consisting of halogen, nitro, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 )-alkoxy, difluoromethoxy, trifluoromethoxy, mono-(C 1 -C 4 )-alkylaminocarbonyl, (C 1 -C 4 )-alkoxycarbonyl and carboxyl,
and
R 7 represents hydrogen, fluorine, chlorine, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxycarbonyl, carboxyl or phenyl, where
the (C 1 -C 4 )-alkyl may be substituted by hydroxyl or (C 1 -C 4 )-alkoxy
and
the phenyl may be substituted by halogen, cyano, (C 1 -C 4 )-alkyl or trifluoromethyl,
or (ii)
R 6 represents hydrogen or (C 1 -C 4 )-alkyl
and
R 7 represents phenyl which may be mono- or disubstituted by identical or different substituents from the group consisting of halogen, cyano, (C 1 -C 4 )-alkyl and trifluoromethyl,
or a salt thereof.
2. The compound of claim 1 in which
A represents O or S,
R 1 represents hydrogen or methyl,
R 2 represents hydrogen, methyl, hydroxymethyl, methoxymethyl or trifluoromethyl,
R 3 represents hydrogen, fluorine or methyl,
R 4 represents hydrogen or (C 1 -C 4 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of hydroxyl, (C 1 -C 4 )-alkoxy, amino, mono-(C 1 -C 4 )-alkylamino, di-(C 1 -C 4 )-alkylamino, and carboxyl,
R 5 represents hydrogen or methyl
and either (i)
R 6 represents phenyl, which may be mono- to trisubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxy, trifluoromethoxy, mono-(C 1 -C 4 )-alkylaminocarbonyl, (C 1 -C 4 )-alkoxycarbonyl and carboxyl,
and
R 7 represents hydrogen, (C 1 -C 4 )-alkyl, trifluoromethyl, (C 1 -C 4 )-alkoxycarbonyl, carboxyl or phenyl which may be substituted by fluorine or chlorine,
or (ii)
R 6 represents hydrogen
and
R 7 represents phenyl which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, cyano, methyl and trifluoromethyl,
or a salt thereof.
3. The compound of claim 1 in which
A represents O or S,
R 1 represents hydrogen or methyl,
R 2 represents hydrogen, methyl, hydroxymethyl or trifluoromethyl,
R 3 represents hydrogen or fluorine,
R 4 represents hydrogen or (C 1 -C 4 )-alkyl which may be mono- or disubstituted by identical or different substituents from the group consisting of hydroxyl, amino, methylamino, ethylamino, dimethylamino and diethylamino,
R 5 represents hydrogen or methyl
R 6 represents phenyl which may be mono- or disubstituted by identical or different substituents from the group consisting of fluorine, chlorine, methyl, trifluoromethyl, methoxy and carboxyl,
and
R 7 represents hydrogen, methyl, trifluoromethyl, methoxycarbonyl or carboxyl,
or a salt thereof.
4. A process for preparing a compound of the formula (I) as defined in claim 1 , comprising the steps of:
reacting a compound of the formula (II)
in which A, R 1 , R 2 , R 3 , R 4 and R 5 each have the meanings given in claim 1 ,
and
R 8 represents hydrogen or a hydroxyl protective group
in an inert solvent in the presence of a base with a compound of the formula (III)
in which R 6 and R 7 have the meanings given in claim 1 and
Q represents a leaving group,
or alternatively, if A represents O, a compound of the formula (IV)
in which R 1 , R 2 , R 3 , R 4 , R 5 and R 8 each have the meanings given above
in an inert solvent in the presence of a base with a compound of the formula (V)
in which R 6 and R 7 have the meanings given in claim 1 ,
removing any protective groups present, and
optionally, reacting the resulting compound of the formula (I) with a base or acid to produce a salt thereof.
5. A pharmaceutical composition comprising a compound of claim 1 and one or more inert nontoxic pharmaceutically suitable auxiliaries.