Sodium and calcium salts of dihydroquinazoline derivative and use thereof as antiviral agents
View Patent ↗The invention relates to sodium and calcium salts of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and solvates thereof, to the use thereof in a method of treatment and/or prophylaxis of virus infections and to the use thereof for producing drugs for use in methods of treatment and/or prophylaxis of diseases, more particularly the use thereof as antiviral agents, more particularly against cytomegaloviruses.
1. A salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5 (trifluoromethyl) phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or a solvate thereof selected from the group consisting of crystalline sodium salts of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, crystalline calcium salts of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid and solvates thereof.
2. The salt according to claim 1 , which is the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or a solvate thereof.
3. The salt according to claim 2 , which is the 2.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine- 1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid.
4. The salt according to claim 3 , which shows X-ray powder diffractogram characteristic peaks at about 6.1, 9.2 and 15.5 degrees 2theta.
5. The salt according to claim 2 , which is the 3.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid.
6. The salt according to claim 5 , which shows X-ray powder diffractogram characteristic peaks at about 6.2, 12.4 and 22.4 degrees 2theta.
7. The salt according to claim 1 , which is the monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or a solvate thereof.
8. The salt according to claim 7 , which is the 3-hydrate of the monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid.
9. The salt according to claim 8 , which shows X-ray powder diffractogram characteristic peaks at about 6.2, 20.9 and 22.4 degrees 2theta.
10. A pharmaceutical composition containing a salt according to claim 1 in combination with at least one pharmaceutically acceptable excipient.
11. A process for preparing a salt according to claim 1 , comprising the following steps:
a) dissolving {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or a solvate thereof in a mixture of at least one (C 1 -C 4 ) dialkyl ether and at least one (C 1 -C 4 ) alcohol, optionally under heat,
b) adding NaOH or Ca(OH) 2 to the solution obtained in step a),
c) removing a portion of the solvent from the solution obtained in step b) and inoculate, optionally with seed crystals in order to initiate the crystallization of the salt or of a solvate of a salt,
d) separating the crystallized-out salt or solvate thereof obtained in step c),
e) optionally stirring the salt or solvate obtained in step d) in a solvent in order to obtain a solvate, and
f) drying the salt or solvate obtained in step d) or e).
12. The process according to claim 11 , wherein the solvent in step e) is a mixture of water and at least one (C 1 -C 4 ) alcohol.
13. A method for the treatment and/or prophylaxis of a virus infection, comprising administering an effective amount of a salt according to claim 1 to a human or an animal who or which is in need of such a treatment.
14. A method for the treatment of a virus infection, comprising administering an effective amount of a salt according to claim 1 to a human or an animal who or which is in need of such a treatment.
15. The method according to claim 13 , wherein the virus infection is by a member of the herpes viridae group of viruses.
16. The method according to claim 13 , wherein the virus infection is by human cytomegalovirus.
17. The method according to claim 16 , wherein the 2.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, the 3.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or the 3-hydrate of the monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid is administered.
18. The method according to claim 14 , wherein the virus infection is by a member of the herpes viridae group of viruses.
19. The method according to claim 14 , wherein the virus infection is by human cytomegalovirus.
20. The method according to claim 19 , wherein the 2.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, the 3.5-hydrate of the monocalcium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid or the 3-hydrate of the monosodium salt of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid is administered.