Substituted dihydroquinazolines
View Patent ↗The invention relates to substituted dihydroquinazolines and to processes for their preparation and also to their use for preparing medicaments for the treatment and/or prophylaxis of diseases, in particular for use as antiviral agents, in particular against cytomegalo viruses.
1. A compound of the formula
in which
Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and 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 1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl
R 4 represents hydrogen or alkyl,
R 5 represents hydrogen or alkyl
or
the radicals R 4 and R 5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups,
R 6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R 7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro, and
R 8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
wherein R 1 is attached to the phenyl ring via the position ortho to the point of attachment of the phenyl ring,
or a salt, solvate, or solvate of a salt thereof.
2. A compound according to claim 1 , wherein
Ar represents phenyl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of 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 and nitro,
R 1 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylthio, fluorine or chlorine,
R 2 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, C 1 -C 3 -alkylthio, fluorine or chlorine,
R 3 represents C 1 -C 4 -alkyl, cyano, fluorine, chlorine, nitro, trifluoromethyl or C 1 -C 3 -alkylsulphonyl,
R 4 represents hydrogen or methyl,
R 5 represents hydrogen,
R 6 represents C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro,
R 7 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluorine, chlorine, cyano or hydroxyl
and
R 8 represents hydrogen, C 1 -C 3 -alkyl, C 1 -C 3 -alkoxy, fluorine, chlorine, cyano or hydroxyl.
3. A compound according to claim 1 wherein
Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine,
R 1 represents hydrogen, methyl, methoxy, methylthio, fluorine or chlorine,
R 2 represents hydrogen,
R 3 represents methyl, isopropyl, tert-butyl, cyano, fluorine, chlorine, nitro or trifluoromethyl,
R 4 represents hydrogen,
R 5 represents hydrogen,
R 6 represents aminocarbonyl, fluorine, chlorine, cyano or hydroxyl,
R 7 represents hydrogen
and
R 8 represents hydrogen, fluorine or chlorine.
4. A compound according to claim 1 , wherein R 1 represents hydrogen, methyl, methoxy or fluorine.
5. A compound according to claim 1 , wherein R 1 represents methoxy.
6. A 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.
7. A compound according to claim 1 , wherein R 2 represents hydrogen.
8. A compound according to claim 1 , wherein R 3 represents trifluoromethyl, chlorine, methyl, isopropyl or tert-butyl.
9. A compound according to claim 1 , wherein R 3 represents trifluoromethyl, chlorine or methyl.
10. A 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 .
11. A compound according to claim 1 , wherein R 4 and R 5 represent hydrogen.
12. A compound according to claim 1 , wherein R 6 represents fluorine.
13. A compound according to claim 1 , wherein R 7 represents hydrogen.
14. A compound according to claim 1 , wherein R 8 represents hydrogen, methyl or fluorine.
15. A compound according to claim 1 , wherein Ar represents phenyl which may be substituted by 1 or 2 substituents, where the substituents are selected independently of one another from the group consisting of methyl, methoxy, fluorine and chlorine.
16. A process for preparing a compound of the formula (I) according to claim 1 , wherein or a salt, solvate, or solvate of a salt thereof
in which
Ar represents aryl which may be substituted by 1 to 3 substituents, where the substituents are selected independently of one another from the group consisting of alkyl, alkoxy, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl, amino, alkylamino, aminocarbonyl and 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 1 represents hydrogen, amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 2 represents hydrogen, alkyl, alkoxy, alkylthio, cyano, halogen, nitro or trifluoromethyl,
R 3 represents amino, alkyl, alkoxy, alkylamino, alkylthio, cyano, halogen, nitro, trifluoromethyl, alkylsulphonyl or alkylaminosulphonyl
R 4 represents hydrogen or alkyl,
R 5 represents hydrogen or alkyl
or
the radicals R 4 and R 5 are attached to carbon atoms directly opposing each other in the piperazine ring and form a methylene bridge which is optionally substituted by 1 or 2 methyl groups,
R 6 represents alkyl, alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
R 7 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro, and
R 8 represents hydrogen, alkyl, alkoxy, alkylthio, formyl, carboxyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro,
said process comprising:
reacting a compound of the formula II
in which
Ar, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and R 8 are as defined in claim 1
and
R 9 represents alkyl selected from the group consisting of methyl, ethyl, and tert-butyl,
is reacted with a base or an acid.
17. A medicament comprising a compound according to claim 1 in combination with an inert non-toxic pharmaceutically acceptable auxiliary.
18. A method for treating infection by Herpes viridae in humans and animals by administering an antivirally effective amount of at least one compound according to claim 1 , or a medicament according to claim 17 .
19. The method according to claim 18 , wherein the Heprpes Herpes viridae is selected form the group consisting of cytomegalovirus a cytomegalovirus (CMV) and human cytomegalovirus (HCMV) or another representative of the group of the Herpes viridae.
20. The method according to claim 18, wherein the Herpes viridae is human cytomegalovirus (HCMV).
21. A method for treating infection by HCMV in humans by administering an antiviral effective amount of the compound:
or a physiologically acceptable salt thereof.
22. The method according to claim 21, wherein said compound is:
or a physiologically acceptable salt thereof.
23. The compound of claim 1, wherein said compound is:
or a physiologically acceptable salt thereof.
24. The compound of claim 1, wherein said compound is:
25. The compound of claim 1, wherein said compound is a physiologically acceptable salt of:
26. The compound of claim 1, wherein said compound is:
or a physiologically acceptable salt thereof.
27. The compound of claim 1, wherein said compound is:
28. The compound of claim 1, wherein said compound is a physiologically acceptable salt of the compound:
29. The compound of claim 1, wherein said compound is of the formula:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and Ar are as defined in claim 6, and R 6 is fluorine; or a physiologically acceptable salt thereof.
30. The compound of claim 3, wherein said compound is of the formula:
wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 7 , R 8 , and Ar are as defined in claim 3, and R 6 is fluorine; or a physiologically acceptable salt thereof.
31. The medicament of claim 17, wherein said compound is:
or a physiologically acceptable salt thereof.
32. The medicament of claim 17, wherein said compound is:
or a physiologically acceptable salt thereof.
33. The compound of claim 1, which is the compound of formula (I) or a physiologically acceptable salt thereof.
34. A compound according to claim 1, wherein R 6 represents alkoxy, alkylthio, formyl, carboxyl, aminocarbonyl, alkylcarbonyl, alkoxycarbonyl, trifluoromethyl, halogen, cyano, hydroxyl or nitro.
35. A compound according to claim 30, wherein R 1 is methoxy.
36. A compound according to claim 30, wherein R 3 is trifluoromethyl, chlorine or methyl.
37. A compound according to claim 36, wherein R 3 is trifluoromethyl.
38. A compound according to claim 30, wherein R 8 is hydrogen.
39. A compound according to claim 30, wherein R 1 is methoxy and wherein R 3 is trifluoromethyl, chlorine or methyl.
40. A compound according to claim 30, wherein R 3 is trifluoromethyl and 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 .
41. A compound according to claim 26, having an enantiomeric excess of more than 90%.
42. A compound according to claim 27, having an enantiomeric excess of more than 90%.
43. A compound according to claim 28, having an enantiomeric excess of more than 90%.
44. A compound according to claim 2, wherein R 6 represents C 1 -C 3 -alkoxy, carboxyl, aminocarbonyl, trifluoromethyl, fluorine, chlorine, cyano, hydroxyl or nitro.