Acyclically substituted furopyrimidine derivatives and use thereof
View Patent ↗The present application relates to novel, acyclically 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. A compound of formula (I)
in which
A stands for O,
L stands for (C 1 -C 7 ) alkanediyl or (C 2 -C 7 ) alkenediyl, which can be substituted singly or doubly with fluorine, or for a group of formula *-L 1 -Q-L 2 , where
* denotes the point of linkage with the CHR 3 group,
L 1 denotes (C 1 -C 5 ) alkanediyl, which can be substituted with (C 1 -C 4 ) alkyl or (C 1 -C 4 ) alkoxy,
L 2 denotes a bond or (C 1 -C 3 ) alkanediyl, which can be substituted singly or doubly with fluorine,
and
Q denotes O or N—R 6 , where
R 6 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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 ) alkinyl, (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,
R 3 stands for hydrogen or (C 1 -C 4 ) alkyl, which can be substituted with hydroxy or amino,
and
R 4 stands for hydrogen, (C 1 -C 4 ) alkyl or cyclopropyl,
or a salt thereof.
2. The compound of claim 1 , in which
A stands for O,
L stands for (C 1 -C 7 ) alkanediyl or (C 2 -C 7 ) alkenediyl, which can be substituted singly or doubly with fluorine, or for a group of formula *-L 1 -Q-L 2 , where
* denotes the point of linkage with the CHR 3 group,
L 1 denotes (C 1 -C 5 ) alkanediyl,
L 2 denotes a bond or (C 1 -C 3 ) alkanediyl, which can be substituted singly or doubly with fluorine,
and
Q denotes O or N—R 6 , where
R 6 represents hydrogen, (C 1 -C 6 ) alkyl or (C 3 -C 7 ) cycloalkyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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 ) alkinyl, (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,
R 3 stands for hydrogen or (C 1 -C 4 ) alkyl, which can be substituted with hydroxy or amino,
and
R 4 stands for hydrogen, (C 1 -C 4 ) alkyl or cyclopropyl,
or a salt thereof.
3. The compound of claim 1 , in which
A stands for O
L stands for (C 3 -C 7 ) alkanediyl or (C 3 -C 7 ) alkenediyl, which can be substituted singly or doubly with fluorine, or for a group of formula *-L 1 -Q-L 2 , where
* denotes the point of linkage with the CHR 3 group,
L 1 denotes (C 1 -C 3 ) alkanediyl,
L 2 denotes (C 1 -C 3 ) alkanediyl, which can be substituted singly or doubly with fluorine,
and
Q denotes O or N—R 6 , where
R 6 represents hydrogen, (C 1 -C 3 ) alkyl or cyclopropyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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, trifluorometh-oxy, (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, 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,
R 3 stands for hydrogen or (C 1 -C 3 ) alkyl, which can be substituted with hydroxy or amino,
and
R 4 stands for hydrogen or (C 1 -C 3 ) alkyl,
or a salt thereof.
4. The compound of claim 1 , in which
A stands for O,
L stands for (C 3 -C 7 ) alkanediyl, (C 3 -C 7 ) alkenediyl or for a group of formula *−L 1 −O−L 2 , where
* denotes the point of linkage with the CHR 3 group
and
L 1 and L 2 , independently of one another, denote (C 1 -C 3 ) alkanediyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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, trifluorometh-oxy, (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,
R 3 stands for hydrogen, methyl or ethyl
and
R 4 stands for hydrogen,
or a salt thereof.
5. The compound of claim 1 , in which
A stands for O,
L stands for a group of formula *-L 1 -N(CH 3 )-L 2 , where
* denotes the point of linkage with the CHR 3 group
and
L 1 and L 2 , independently of one another, denote (C 1 -C 3 ) alkanediyl,
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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, trifluorometh-oxy, (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,
R 3 stands for hydrogen, methyl or ethyl
and
R 4 stands for hydrogen, or a salt thereof.
6. The compound of claim 1 , in which
A stands for O,
L stands for (C 3 -C 7 ) alkanediyl, (C 3 -C 7 ) alkenediyl or for a group of formula *-L 1 -Q-L 2 , where
* denotes the point of linkage with the CHR 3 group,
L 1 and L 2 , independently of one another, denote (C 1 -C 3 ) alkanediyl
and
Q denotes O or N(CH 3 ),
Z stands for a group of formula
where
# denotes the point of linkage with group L
and
R 7 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,
R 3 stands for hydrogen, methyl or ethyl
and
R 4 stands for hydrogen,
and their salts, solvates and solvates of the salts.
7. A method of making a compound of claim 1 , comprising either
[A] reacting a compound of formula (II)
in which R 1 , R 2 , R 4 , n and o have the respective meanings given in claim 1
and
X 1 stands for a leaving group such as halogen, especially for chlorine,
in the presence of a base if necessary in an inert solvent with a compound of formula (III)
in which A, L and R 3 have the respective meanings given in claim 1
and
Z 1 stands for cyano or a group of formula —[C(O)] y —COOR 7A , where
y denotes the number 0 or 1
and
R 7A denotes (C 1 -C 4 ) alkyl,
to produce a compounds of formula (IV)
in which A, L, Z 1 , R 1 , R 2 , R 3 , R 4 , n and o have the respective meanings given above,
or
[B] reacting a compound of formula (V-1)
in which R 1 , R 4 , X 1 and n have the respective meanings given in claim 1 ,
in the presence of a base if necessary in an inert solvent with a compound of formula (III) to produce a compound of formula (VI-1)
in which A, L, Z 1 , R 1 , R 3 , R 4 and n have the respective meanings given above,
brominating the compound of formula (VI-1) in an inert solvent, to produce a compounds of formula (VII-1)
in which A, L, Z 1 , R 1 , R 3 , R 4 and n have the respective meanings given above,
and coupling the compound of formula (VII-1) 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 produce the compound of formula (IV)
or
[α] reacting a compound of formula (V-2)
in which R 2 , R 4 , X 1 and o have the respective meanings given in claim 1 ,
in the presence of a base if necessary in an inert solvent with a compound of formula (III), to produce a compounds of formula (VI-2)
in which A, L, Z 1 , R 2 , R 3 , R 4 and o have the respective meanings given above,
brominating the compound of formula (VI-2) in an inert solvent to produce a compounds of formula (VII-2)
in which A, L, Z 1 , R 2 , R 3 , R 4 and o have the respective meanings given above,
and coupling the compound of formula (VII-2) 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 produce the compound of formula (IV),
and converting the compounds of formula (IV) produced in [A], [B], or [C] by hydrolysis of the ester or cyano group Z 1 to produce at carboxylic acid of formula (I-A)
in which A, L, R 1 , R 2 , R 3 , R 4 , n, o and y have the respective meanings given above,
and optionally converting the carboxylic acid of formula (I-A) with a corresponding (i) solvents and/or (ii) base or acid to a salt thereof.
8. A pharmaceutical composition comprising a compound of claim 1 , and an inert, nontoxic, pharmaceutically acceptable excipient.
9. The pharmaceutical composition of claim 8 , further comprising another active substance selected from the group consisting of an organic nitrate and NO-donor, a compound that inhibits the degradation of cyclic guanosine monophosphate and/or cyclic adenosine monophosphate, an NO-independent but haem-dependent stimulator of guanylate cyclase, an NO- and haem-independent activator of guanylate cyclise, a compound which inhibits human neutrophilic elase, a compound which inhibits the signal transduction cascade, a compound which influences the energy metabolism of the heart, an antithrombotic agent, an active substance for lowering blood pressure, and an active substance that modifies lipid metabolism.