Heterocyclyl-substituted dihydroquinazolines and their use as antiviral agents
View Patent ↗The invention relates to heterocyclyl-substituted dihydroquinazolines of formula (I), to processes for their preparation, to medicaments containing them, and to methods for the treatment and/or prophylaxis of diseases, in particular, for use as anti-viral agents, in particular, against cytomegaloviruses.
1. A compound of the formula (I)
in which
represents a single or double bond,
R 1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 2 represents hydrogen, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl
or
one of the radicals R 1 , R 2 and R 3 represents hydrogen, alkyl, alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two together with the carbon atoms to which they are attached form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring,
R 4 represents hydrogen or alkyl,
R 5 represents hydrogen, alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl or nitro,
where alkyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl,
R 6 represents hydrogen, alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl or nitro,
where alkyl may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of halogen, amino, alkylamino, hydroxyl and aryl
or
R 5 and R 6 together with the carbon atoms to which they are attached form a 1,3-dioxolane, a cyclopentane ring or a cyclohexane ring,
R 7 represents hydrogen or alkyl,
R 8 represents hydrogen, alkyl, alkoxy, alkylamino, alkylthio, formyl, carboxyl, aminocarbonyl, alkylaminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, nitro or a 5- to 7-membered heterocycle which is attached via nitrogen,
R 9 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R 10 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
or a salt thereof.
2. The compound according to claim 1 , wherein:
represents a single or double bond,
R 1 represents hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, fluorine or chlorine,
R 2 represents hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, fluorine or chlorine,
R 3 represents C 1 -C 4 -alkyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
or
one of the radicals R 1 , R 2 and R 3 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, cyano, halogen, nitro or trifluoromethyl and the other two together with the carbon atoms to which they are attached form a cyclopentane ring or a cyclohexane ring,
R 4 represents hydrogen,
R 5 represents hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C 1 -C 6 -alkylamino or nitro,
R 6 represents hydrogen, C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy, carboxyl, C 1 -C 6 -alkylcarbonyl, C 1 -C 6 -alkoxycarbonyl, trifluoromethyl, fluorine, chlorine, bromine, cyano, hydroxyl, amino, C 1 -C 6 -alkylamino or nitro
or
R 5 and R 6 together with the carbon atoms to which they are attached form a 1,3-dioxolane,
R 7 represents hydrogen or methyl,
R 8 represents C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, carboxyl, aminocarbonyl, C 1 -C 3 -alkylaminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,
R 9 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluorine, chlorine, cyano or hydroxyl
and
R 10 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluorine, chlorine, cyano or hydroxyl.
3. The compound according to claim 1 or 2 , wherein:
represents a single or double bond,
R 1 represents hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,
R 2 represents hydrogen,
R 3 represents methyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
R 4 represents hydrogen,
R 5 represents hydrogen, methyl, methoxy, fluorine or chlorine,
R 6 represents hydrogen, methyl, methoxy, fluorine or chlorine,
R 7 represents hydrogen,
R 8 represents aminocarbonyl, fluorine, chlorine, cyano or hydroxyl,
R 9 represents hydrogen
and
R 10 represents hydrogen.
4. The compound according to claim 1 , wherein represents a single bond.
5. The compound according to claim 1 , wherein R 1 represents hydrogen, methyl, methoxy or fluorine.
6. The compound according to claim 1 , wherein R 1 represents methoxy.
7. The compound according to claim 1 , wherein R 1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring.
8. The compound according to claim 1 , wherein R 2 represents hydrogen.
9. The compound according to claim 1 , wherein R 3 represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.
10. The compound according to claim 1 , wherein R 3 represents trifluoromethyl, chlorine or methyl.
11. The compound according to claim 1 , wherein R 1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring and R 3 is attached to the phenyl ring via the position meta to the point of attachment of the phenyl ring, which position is opposite to that of R 1 .
12. The compound according to claim 1 , wherein R 4 represents hydrogen.
13. The compound according to claim 1 , wherein R 5 represents hydrogen, methyl, methoxy, fluorine or chlorine.
14. The compound according to claim 1 , wherein R 6 represents hydrogen, methyl, methoxy or fluorine.
15. The compound according to claim 1 , wherein R 7 represents hydrogen.
16. The compound according to claim 1 , wherein R 8 represents fluorine.
17. The compound according to claim 1 , wherein R 9 represents hydrogen.
18. The compound according to claim 1 , wherein R 10 represents hydrogen, methyl or fluorine.
19. A process for preparing a compound of the formula (I) according to claim 1 , wherein:
according to process [P], a compound of the formula
in which
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1 ,
and
R 11 represents alkyl,
is reacted with a base,
or,
according to process [Q], a compound of the formula
in which
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1 is,
by reaction with reducing agent, converted into a compound of the formula
in which
R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 and R 10 are as defined in claim 1 .
20. A medicament comprising a compound according to claim 1 or a salt thereof in combination with an inert nontoxic pharmaceutically acceptable auxiliary.
21. A method for preparing a medicament comprising bringing a compound according to claim 1 or a salt thereof into a pharmaceutically acceptable administration form.
22. A method for-treating a viral infection in a human, or the prophylaxis, or treatment and prophylaxis of a viral infection in an immuno-compromised human, comprising administering an antivirally effective amount of at least one compound according to claim 1 or a salt thereof to a human in need thereof, wherein the viral infection is an infection with the human cytomegalovirus (HCMV) or another representative of the group Herpes viridae.
23. The process of claim 19 , wherein in subprocess [P], R 11 represents methyl or ethyl.