Cyclically substituted furopyrimidine derivatives and use thereof
View Patent ↗The present application relates to novel, cyclically substituted furopyrimidine derivatives, methods for their production, their use for the treatment and/or prophylaxis of diseases and their use for the production of medicinal products for the treatment and/or prophylaxis of diseases, in particular for the treatment and/or prophylaxis of cardiovascular diseases.
1. Compound of formula (I)
in which
A stands for O, S or N—R 4 where
R 4 denotes hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl or (C 4 -C 7 ) cycloalkenyl,
L 1 stands for a bond or for (C 1 -C 4 ) alkanediyl,
the Q ring stands for (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be up to disubstituted, identically or differently, by fluorine, chlorine, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 ) alkylamino and/or di-(C 1 -C 4 ) alkylamino,
where (C 1 -C 4 ) alkyl may in turn be substituted by hydroxyl, (C 1 -C 4 ) alkoxy, amino, mono- or di-(C 1 -C 4 ) alkylamino,
L 2 stands for (C 1 -C 4 ) alkanediyl, which is mono- or disubstituted by fluorine and in which one methylene group may be exchanged for O or N—R 5 in which
R 5 denotes hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl,
or stands for (C 2 -C 4 ) alkenediyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L 2 and
R 6 denotes hydrogen or (C 1 -C 4 ) alkyl,
R 1 and R 2 , independently of one another, stand for a substituent selected from the group comprising halogen, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 4 ) alkynyl, (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 ) alkylthio, (C 1 -C 6 ) acyl, amino, mono-(C 1 -C 6 ) alkylamino, di-(C 1 -C 6 ) alkylamino and (C 1 -C 6 ) acylamino,
in which (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy can in their turn each be substituted with cyano, hydroxy, (C 1 -C 4 ) alkoxy, (C 1 -C 4 ) alkylthio, amino, mono- or di-(C 1 -C 4 ) alkylamino, or
two residues R 1 and/or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of formula —O—CH 2 —O—, —O—CHF—O—, —O—CF 2 —O—, —O—CH 2 —CH 2 —O— or —O—CF 2 —CF 2 —O—,
n and o, independently of one another, stand for the number 0, 1, 2 or 3,
and for the case when R 1 or R 2 occurs more than once, their meanings can in each case be identical or different, and
R 3 stands for hydrogen, (C 1 -C 4 ) alkyl or cyclopropyl,
and the salts thereof.
2. Compound of formula (I) according to claim 1 , in which
A stands for O, S or N—R 4 , where
R 4 denotes hydrogen, (C 1 -C 6 ) alkyl, (C 3 -C 7 ) cycloalkyl or (C 4 -C 7 ) cycloalkenyl,
L 1 stands for a bond or for (C 1 -C 4 ) alkanediyl,
the Q ring stands for (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, a 5- to 7-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be up to disubstituted, identically or differently, by fluorine, chlorine, (C 1 -C 4 ) alkyl, trifluoromethyl, hydroxyl, (C 1 -C 4 ) alkoxy, trifluoromethoxy, amino, mono-(C 1 -C 4 ) alkylamino and/or di-(C 1 -C 4 ) alkylamino,
where (C 1 -C 4 ) alkyl may in turn be substituted by hydroxyl, (C 1 -C 4 ) alkoxy, amino, mono- or di-(C 1 -C 4 ) alkylamino,
L 2 stands for (C 1 -C 4 ) alkanediyl, which is mono- or disubstituted by fluorine and in which one methylene group may be exchanged for O or N—R 5 in which
R 5 denotes hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl,
or stands for (C 2 -C 4 ) alkenediyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L 2 and
R 2 denotes hydrogen or (C 1 -C 4 ) alkyl,
R 1 and R 2 , independently of one another, stand for a substituent selected from the group comprising halogen, cyano, nitro, (C 1 -C 6 ) alkyl, (C 2 -C 6 ) alkenyl, (C 2 -C 4 ) alkenyl, (C 3 -C 7 ) cycloalkyl, (C 4 -C 7 ) cycloalkenyl, (C 1 -C 6 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 6 ) alkylthio, (C 1 -C 6 ) acyl, amino, mono-(C 1 -C 6 ) alkylamino, di-(C 1 -C 6 ) alkylamino and (C 1 -C 6 ) acylamino,
and (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy in their turn can each be substituted with hydroxy, (C 1 -C 4 ) alkoxy, amino, mono- or di-(C 1 -C 4 ) alkylamino, or
two residues R 1 and/or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of formula —O—CH 2 —O—, —O—CHF—O—, —O—CF 2 —O—,—O—CH 2 —CH 2 —O— or —O—CF 2 —CF 2 —O—,
n and o, independently of one another, stand for the number 0, 1, 2 or 3,
and for the case when R 1 or R 2 occurs more than once, their meanings can in each case be identical or different, and
R 3 stands for hydrogen, (C 1 -C 4 ) alkyl or cyclopropyl.
3. Compound of formula (I) according to claim 1 , in which
A stands for O or N—R 4 , where
R 4 denotes hydrogen, (C 1 -C 4 ) alkyl or (C 3 -C 6 ) cycloalkyl,
L 1 stands for a bond or (C 1 -C 3 ) alkanediyl,
the Q ring stands for (C 3 -C 6 ) cycloalkyl, (C 4 -C 6 ) cycloalkenyl, a 5- or 6-membered heterocycle, phenyl or 5- or 6-membered heteroaryl, each of which may be up to disubstituted, identically or differently, by fluorine, chlorine, (C 1 -C 3 ) alkyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and/or diethylamino,
where (C 1 -C 3 ) alkyl may in turn be substituted by hydroxyl, methoxy, ethoxy, amino, methylamino, ethylamino, dimethylamino or diethylamino,
L 2 stands for (C 1 -C 3 ) alkanediyl which may be mono- or disubstituted by fluorine, (C 2 -C 3 ) alkenediyl or a group of the formula *-M-CR 7 R 8 —, *-M-CH 2 —CR 7 R 8 — or *—CH 2 —M—CR 7 R 8 —, in which denotes the point of linkage with the Q ring,
M is O or N—R 5 in which
R 5 is hydrogen, (C 1 -C 3 ) alkyl or cyclopropyl, and
R 7 and R 8 , independently of one another, are hydrogen or fluorine,
Z stands for a group of formula
where
# denotes the point of linkage with group L 2 and
R 6 denotes hydrogen, methyl or ethyl,
R 1 and R 2 , independently of one another, stand for a substituent selected from the group comprising fluorine, chlorine, cyano, (C 1 - 5 ) alkyl, (C 2 - 5 ) alkenyl, (C 3 -C 6 ) cycloalkyl, (C 4 -C 6 ) cycloalkenyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 ) alkylthio, (C 1 - 5 ) acyl, amino, mono-(C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino and (C 1 -C 4 ) acylamino or
two residues R 1 and/or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of formula —O—CH 2 —O—, —O—CHF—O— or —O—CF 2 —O—,
n and o, independently of one another, stand for the number 0, 1, 2 or 3,
and for the case when R 1 or R 2 occurs more than once, their meanings can in each case be identical or different, and
R 3 stands for hydrogen or (C 1 -C 3 ) alkyl.
4. Compound of formula (I) according to claim 1 , in which
A stands for O or N—R 4 in which
R 4 is hydrogen or (C 1 -C 4 ) alkyl,
L 1 stands for a bond or (C 1 -C 3 ) alkanediyl,
the Q ring stands for (C 4 -C 6 ) cycloalkyl, (C 5 -C 6 ) cycloalkenyl, a 5- or 6-membered heterocycle or phenyl, each of which may be up to disubstituted, identially or differently, by fluorine, chlorine, (C 1 -C 3 ) alkyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, trifluoromethoxy, amino, methylamino, ethylamino, dimethylamino and/or diethylamino,
L 2 stands for (C 1 -C 3 ) alkanediyl which may be mono- or disubstituted by fluorine, (C 2 -C 3 ) alkenediyl or a group of the formula *-M—CR 7 R 8 —, *-M—CH 2 —CR 7 R 8 — or *—CH 2 —M—CR 7 R 8 —, in which
denotes the point of linkage with the Q ring,
M is O or N—R 5 in which
R 5 is hydrogen or (C 1 -C 3 ) alkyl, and
R 7 and R 8 , independently of one another, denote hydrogen or fluorine,
Z stands for a group of the formula
where
# denotes the point of linkage with group L 2 and
R 6 denotes hydrogen, methyl or ethyl,
R 1 and R 2 , independently of one another, stand for a substituent selected from the group comprising fluorine, chlorine, cyano, (C 1 -C 5 ) alkyl, (C 2 -C 5 ) alkenyl, (C 3 -C 6 ) cycloalkyl, (C 4 -C 6 ) cycloalkenyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 ) alkylthio, (C 1 -C 5 ) acyl, amino, mono-(C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino and (C 1 -C 4 ) acylamino or
two residues R 1 and/or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of formula —O—CH 2 —O—, —O—CHF—O or —O—CF 2 —O—,
n and o, independently of one another, stand for the number 0, 1 or 2,
and for the case when R 1 or R 2 occurs twice, their meanings can in each case be identical or different, and
R 3 stands for hydrogen or (C 1 -C 3 ) alkyl.
5. Compound of formula (I) according to claim 1 , in which
A stands for O or NH,
L 1 stands for a bond, methylene, ethane-1,1-diyl or ethane-1,2-diyl,
the Q ring stands for cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl, tetrahydrofuranyl, tetrahydropyranyl, morpholinyl or phenyl, each of which may be up to disubstituted, identically or differently, by fluorine, methyl, ethyl, trifluoromethyl, hydroxyl, methoxy, ethoxy, amino, methylamino and/or dimethylamino,
L 2 stands for (C 1 -C 3 ) alkanediyl, (C 2 -C 3 ) alkenediyl or a group of the formula *-M-CH 2 — or *-M-CH 2 —CH 2 —, in which
denotes the point of linkage to the Q ring and
M denotes O or N—R 5 , in which
R 5 is hydrogen or (C 1 -C 3 ) alkyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L 2 and
R 6 denotes hydrogen, methyl or ethyl,
R 1 and R 2 , independently of one another, stand for a substituent selected from the group comprising fluorine, chlorine, cyano, (C 1 -C 5 ) alkyl, (C 2 -C 5 ) alkenyl, (C 3 -C 6 ) cycloalkyl, (C 4 -C 6 ) cycloalkenyl, (C 1 -C 4 ) alkoxy, trifluoromethyl, trifluoromethoxy, (C 1 -C 4 ) alkylthio, (C 1 -C 5 ) acyl, amino, mono-(C 1 -C 4 ) alkylamino, di-(C 1 -C 4 ) alkylamino and (C 1 -C 4 ) acylamino or
two residues R 1 and/or R 2 bound to adjacent carbon atoms of the respective phenyl ring together form a group of formula —O—CH 2 —O—, —O—CHF—O— or —O—CF 2 —O—,
n and o, independently of one another, stand for the number 0, 1 or 2,
and for the case when R 1 or R 2 occurs twice, their meanings can in each case be identical or different, and
R 3 stands for hydrogen.
6. Compound of formula (I) according to claim 1 , in which
A stands for O or NH,
L 1 stands for a bond, methylene or ethane-1,1-diyl,
the Q ring stands for cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, pyrrolidinyl, piperidinyl or phenyl, each of which may be up to disubstituted, identically or differently, by fluorine, methyl, hydroxyl and/or methoxy,
L 2 is (C 1 -C 3 ) alkanediyl, (C 2 -C 3 ) alkenediyl or a group of the formula *-M-CH 2 — or *-M-CH 2 —CH 2 —, in which
denotes the point of linkage with the Q ring, and
M denotes O or NH,
Z stands for a group of formula
where
# denotes the point of linkage with group L 2 and
R 6 denotes hydrogen, methyl or ethyl,
R 1 stands for a substituent selected from the group comprising fluorine, chlorine, methyl, ethyl, vinyl, trifluoromethyl and methoxy,
R 2 stands for a substituent selected from the group comprising fluorine, chlorine, cyano, methyl, ethyl, n-propyl, vinyl, trifluoromethyl, methoxy, ethoxy, trifluoromethoxy, methylthio, ethylthio, amino, methylamino and ethylamino,
n and o, independently of one another, stand for the number 0, 1 or 2,
and for the case when R 1 or R 2 occurs twice, their meanings can in each case be identical or different, and
R 3 stands for hydrogen.
7. A method for producing compounds of formula (I), as defined in claim 1 , in which Z stands for —COOH or —C(═O)—COOH, characterized in that either
[A] Compounds of formula (II)
in which R 1 , R 2 , R 3 , n and o have the respective meanings given in claim 1 and
X 1 stands for a leaving group,
in the presence of a base if necessary in an inert solvent with a compound of formula (III)
in which A, L 1 , L 2 and Q have the respective meanings given in claim 1 and
Z 1 stands for cyano or a group of formula —[C(O)] y —COOR 6A , where
y denotes the number 0 Or 1 and
R 6A denotes (C 1 -C 4 ) alkyl, to form compounds of formula (IV)
in which A, L 1 , L 2 , Q, Z 1 , R 1 , R 2 , R 3 , n and o have the respective meanings given in claim 1 , or
[B] Compounds of formula (V-1)
R 1 , R 3 , X 1 and n have the respective meanings given in claim 1 ,
optionally, in the presence of a base, and an inert solvent are reacted with a compound of formula (III) to form compounds of formula (VI-1)
in which A, L 1 , L 2 , Q, Z 1 , R 1 , R 3 and n have the respective meanings given in claim 1 , then brominated in an inert solvent to form compounds of formula (VII-1)
A, L 1 , L 2 , Q, Z 1 , R 1 , R 3 and n have the respective meanings given in claim 1 ,
and these are then coupled in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of formula (VIII-1)
in which R 2 and o have the meanings given in claim 1 , to form compounds of formula (IV) or
[C] Compounds of formula (V-2)
in which R 2 , R 3 , X 1 and o have the respective meanings given in claim 1 ,
are reacted optionally, in the presence of a base, and an inert solvent is reacted with a compound of formula (III) to form compounds of formula (VI-2)
in which A, L 1 , L 2 , Q, Z 1 , R 2 , R 3 and o have the respective meanings given in claim 1 ,
then brominated in an inert solvent to compounds of formula (VII-2)
in which A, L 1 , L 2 , Q, Z 1 , R 2 , R 3 and o have the respective meanings given in claim 1 ,
and these are then coupled in an inert solvent in the presence of a base and a suitable palladium catalyst with a phenylboronic acid of formula (VIII-2)
in which R 1 and n have the meanings given in claim 1 , to form compounds of formula (IV), and in each case the resultant compounds of formula (IV) are then converted by hydrolysis of the ester or cyano group Z 1 to the carboxylic acids of formula (I-A)
in which A, L 1 , L 2 , Q, R 1 , R 2 , R 3 , n, o and y have the respective meanings given in claim 1 , and these are converted if necessary with the corresponding (i) solvents and/or (ii) bases or acids to their salts.
8. A medicinal product comprising a compound of formula (I), as defined in claim 1 in combination with an inert, nontoxic, pharmaceutically acceptable excipient.