Aliphatically substituted pyrazolopyridines, and the use thereof
View Patent ↗The present application relates to novel aliphatically substituted pyrazolopyridines, to processes for their preparation, to their use, alone or in combination, for the treatment and/or prevention of diseases and to their use for preparing medicaments for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of cardiovascular disorders.
1. A compound of the formula (I)
in which
A represents CR 3 or N,
where
R 3 represents hydrogen,
D represents CR 4 or N,
where
R 4 represents hydrogen,
E represents CR 5 or N,
where
R 5 represents hydrogen,
G represents CR 6 or N,
where
R 6 represents hydrogen,
with the proviso that at most 2 of the groups A, D, E and G represent N,
R 1 represents cyclopentyl, cyclohexyl or cycloheptyl,
where cyclopentyl, cyclohexyl or cycloheptyl may be substituted by 1 or 2 substituents independently of one another selected from the group consisting of fluorine and methyl,
R 2 represents a group of the formula
where
# represents the point of attachment to the heterobicycle,
R 10 and R 11 independently represent H or NH 2 ,
K represents CH or N,
J represents CR 12 , N or N + —O − ,
in which
R 12 represents halogen, nitro, cyano, —R 7 , —C(═O)—R 7 , —C(═O)—OR 7 , —C(═O)—NR 7 R 8 , —O—(C═O) n —R 7 , —O—C(═O)—OR 7 , —O—C(═O)—NR 7 R 8 , —S(O) p —R 7 , —SO 2 —OR 7 , —SO 2 —NR 7 R 8 , —NR 7 —(C═O) n —R 8 , —NR 7 —SO 2 —R 8 , —NR 7 —C(═O)—OR 8 , —NR 9 —C(═O)—NR 7 R 8 or —NR 9 —SO 2 —NR 7 R 8 ,
in which
n represents the number 0 or 1,
p represents the number 0 or 2,
R 7 , R 8 and R 9 each independently of one another represent hydrogen, (C 1 -C 6 )-alkyl, (C 2 -C 6 )-alkenyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkenyl, phenyl, 5- to 7-membered heterocyclyl or 5- or 6-membered heteroaryl,
in which R 7 , R 8 and R 9 for their part may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of fluorine, chlorine, cyano, trifluoromethyl, (C 1 -C 4 )-alkyl, hydroxyl, trifluoromethoxy, (C 1 -C 4 )-alkoxy, oxo, amino, mono-(C i -C 4 )-alkylamino and di-(C 1 -C 4 )-alkylamino,
or
R 7 and R 8 together with the radical to which the two are attached form a 5- to 7-membered heterocycle,
or
R 7 and R 9 together with the radical to which the two are attached form a 5- to 7-membered heterocycle,
or an N-oxide, salt, or salt of an N-oxide thereof.
2. The compound of the formula (I) of claim 1 in which
A represents N,
D represents CR 4 ,
where
R 4 represents hydrogen,
E represents CR 5 ,
where
R 5 represents hydrogen,
G represents CR 6 ,
where
R 6 represents hydrogen,
R 1 represents cyclohexyl or cycloheptyl,
R 2 represents a group of the formula
where
# represents the point of attachment to the heterobicycle,
R 10 and R 11 independently represent H or NH 2 ,
K represents N,
J represents CR 12 or N,
in which
R 12 represents hydrogen, —R 7 , —NR 7 —(C═O) n —R 8 , —NR 7 —C(═O)—OR 8 or pyridyl,
in which
n represents the number 1,
R 7 represents hydrogen, trifluoromethyl or (C 1 -C 4 )-alkyl, in which (C 1 -C 4 )-alkyl for its part may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, hydroxyl and methoxy,
R 8 represents (C 1 -C 4 )-alkyl or (C 3 -C 7 )-cycloalkyl, in which (C 1 -C 4 )-alkyl and (C 3 -C 7 )-cycloalkyl for their part may be substituted by a substituent selected from the group consisting of fluorine, trifluoromethyl, (C 1 -C 4 ) -alkyl, hydroxyl, methoxy and oxo,
or
R 7 and R 8 together with the radical to which the two are attached form a 5- to 7-membered heterocycle,
or an N-oxide, salt, or salt of an N-oxide thereof.
3. A process for preparing a compound of the formula (I) as defined in claim 1 , characterized in that a compound of formula (II)
in which A, D, E, G and R 2 each have the meanings given 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 R 1 has the meaning given in claim 2
and
X 1 represents a suitable leaving group, such as tosylate, mesylate or halogen, in particular bromine,
and the resulting compounds of formula (I) is, optionally, converted with an appropriate (i) solvent and/or (ii) base or acids into a salt thereof.
4. A pharmaceutical composition comprising a compound of the formula (I) as defined in claim 1 and an inert, non-toxic, pharmaceutically suitable excipient.
5. The pharmaceutical composition of claim 4 , further comprising an active ingredient selected from the group consisting of organic nitrates, NO donors, cGMP-PDE inhibitors, agents having antithrombotic activity, agents lowering blood pressure, and agents altering lipid metabolism.