Substituted heterocyclylbenzylpyrazoles and use thereof
View Patent ↗The present application relates to novel substituted 1-[3-(heterocyclyl)benzyl]-1H-pyrazole derivatives, to processes for preparation thereof, to use thereof for treatment and/or prevention of diseases and to use thereof for production of medicaments for treatment and/or prevention of diseases, more particularly for treatment and/or prevention of hyperproliferative and angiogenic diseases and those diseases which arise from metabolic adaptation to hypoxic states. Such treatments can be effected in the form of monotherapy or else in combination with other medicaments or further therapeutic measures.
1. A compound of the formula (I)
in which
m is 1 or 2,
n is 1, 2 or 3,
R 1 is hydroxyl or cyano,
and
R 2 is trifluoromethoxy, trifluoromethylsulphanyl, trifluoromethylsulphonyl, pentafluorosulphanyl or a group of the formula
in which
* denotes the bonding site to the phenyl ring,
R 3A and R 3B are each independently fluorine or methyl
or
are joined to one another and, together with the carbon atom to which they are bonded, form a cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, cyclopentane-1,1-diyl, cyclohexane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring and
R 4 is hydrogen, fluorine, methyl, trifluoromethyl or methoxy,
and the physiologically acceptable salts thereof.
2. The compound of the formula (I) according to claim 1 , in which
m and n are each independently 1 or 2,
R 1 is hydroxyl or cyano,
and
R 2 is trifluoromethyl, trifluoromethoxy, trifluoromethylsulphanyl or a group of the formula
in which
* denotes the bonding site to the phenyl ring,
R 3A and R 3B are both methyl or are joined to one another and, together with the carbon atom to which they are bonded, form a cyclopropane-1,1-diyl, cyclobutane-1,1-diyl, oxetane-3,3-diyl or tetrahydro-2H-pyran-4,4-diyl ring and
R 4 is hydrogen, fluorine, methyl or trifluoromethyl,
and the physiologically acceptable salts thereof.
3. The compound of the formula (I) according to claim 1 , in which
m and n are both 1 or 2,
R 1 is hydroxyl or cyano,
and
R 2 is trifluoromethoxy or a group of the formula
in which
* denotes the bonding site to the phenyl ring,
and the physiologically acceptable salts thereof.
4. The compound of the formula (I) according to claim 1 , in which
R 1 is hydroxyl,
and
m, n and R 2 are each as defined in claim 1 ,
and the physiologically acceptable salts thereof.
5. A compound of the formula (I-PD)
in which m, n and R 2 are each as defined in claim 1
and
R PD is a prodrug group of the formula
in which
# denotes the bonding site to the oxygen atom,
R 5 is hydrogen or (C 1 -C 4 )-alkyl,
and
R 6A and R 6B are each independently hydrogen or methyl,
and the physiologically acceptable salts thereof.
6. The compound of the formula (I-PD) according to claim 5 , in which
R PD is a prodrug group of the formula
in which
# denotes the bonding site to the oxygen atom,
and the physiologically acceptable salts thereof.
7. A process for preparing a compound of formula (I) as defined in claim 1 , characterized in that a compound of formula (II)
in which R 2 is as defined in claim 1
and
X is bromine or iodine,
in the presence of a suitable palladium catalyst and of a base, is coupled with a compound of formula (III)
in which m, n and R 1 are each as defined in claim 1 ,
and the resulting compound of formula (I) is optionally separated into the enantiomers and/or diastereomers thereof and/or converted using the appropriate (i) solvents and/or (ii) acids to a physiologically acceptable salt thereof.
8. A process for preparing a compound of formula (I-PD) as defined in claim 5 , characterized in that a compound of formula (I-A)
in which m, n and R 2 are each as defined in claim 5
is esterified by customary methods with a compound of the formula (VIII)
R PD —OH (VIII)
or an activated form thereof in which R PD is as defined in claim 5 , and the resulting compound of formula (I-PD) is optionally separated into the enantiomers and/or diastereomers thereof and/or converted using the appropriate (i) solvents and/or (ii) acids to a physiologically acceptable salt thereof.
9. A pharmaceutical composition comprising a compound as defined in claim 1 in combination with one or more inert, nontoxic, pharmaceutically suitable excipients.