Substituted dihydroquinazolines
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,
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 a compound of the formula
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 viridae is selected form the group consisting of cytomegalovirus (CMV) and human cytomegalovirus (HCMV) or another representative of the group of the Herpes viridae.
20. A process for preparing a compound of formula (I) 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:
(a) reacting a compound of formula (III)
wherein R 6 , R 7 , and R 8 are as defined above and R 9 is methyl or ethyl, in a two-step reaction initially with a compound of formula (IV)
in which R 1 , R 2 and R 3 are as defined above, and then with a compound of formula (V)
in which Ar, R 4 and R 5 are as defined above,
to obtain a compound of 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 above, and
R 9 is methyl or ethyl; and
(b) reacting the compound of formula (II) with a base in an inert solvent wherein the base is an alkali metal hydroxide or alkali metal carbonate, and the inert solvent is an ether or alcohol.
21. The process according to claim 20, wherein said base is sodium hydroxide, lithium hydroxide, potassium hydroxide, caesium carbonate, sodium carbonate or potassium carbonate.
22. The process according to claim 20, wherein said base is sodium hydroxide in water.
23. The process according to claim 20, wherein said inert solvent is 1,2-dimethoxyethane, dioxane, tetrahydrofuran, glycol dimethyl ether, diethylene glycol dimethyl ether, methanol, ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, or mixtures thereof.
24. The process according to claim 20, wherein said inert solvent is dioxane or tetrahydrofuran.
25. A process for preparing a compound of formula (I) 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:
(a) reacting a compound of formula (III)
wherein R 6 , R 7 , and R 8 are as defined above and R 9 is methyl or ethyl, in a two-step reaction initially with a compound of formula (IV)
in which R 1 , R 2 and R 3 are as defined above, and then with a compound of formula (V)
in which Ar, R 4 and R 5 are as defined above,
to obtain a compound of 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 above, and
R 9 is tert-butyl, and
(b) reacting a compound of formula (II) with an acid in an inert solvent.
26. The process according to claim 25, wherein the reaction is carried out in a temperature range of from 0° C. to 40° C. at atmospheric pressure.
27. The process according to claim 25, wherein the acid is hydrogen chloride in dioxane, hydrogen bromide in acetic acid, or trifluoroacetic acid in methylene chloride.