Salts of a dihydroquinazoline derivative

Abstract

The invention relates to besylate and tosylate salts of {8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazolin-4-yl} acetic acid and solvates thereof, to the use thereof in a method of treating and/or preventing virus infections, and to the use thereof to produce drugs for use in treating and/or preventing diseases, in particular use as antiviral agents, in particular against cytomegaloviruses (FIG. 1).

The invention claimed is: 
     
       1. A method for purifying {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid using the following steps:
 1.) Reacting {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid in a solvent with benzenesulfonic acid or toluenesulfonic acid to obtain a crystalline salt, 
 2.) Isolating the salt obtained in step 1.), 
 3.) Treating the isolated salt obtained in step 2.) with a buffer solution at a pH in the range of 5 to 7 to release a zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, and 
 4). Isolating the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid obtained in step 3.). 
 
     
     
       2. A method according to  claim 1 , wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.1% impurities. 
     
     
       3. A method according to  claim 1 , wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.08% impurities. 
     
     
       4. A method according to  claim 1 , wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid comprises less than 0.05% impurities. 
     
     
       5. The method according to  claim 1 , wherein the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid is suitable for preparation of the crystalline besylate 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 crystalline tosylate 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 solvates thereof. 
     
     
       6. A method according to  claim 5 , wherein a salt or solvate prepared from the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, is suitable for use in a method of treatment and/or prophylaxis of human cytomegalovirus (HCMV) infections or infections with another representative of the herpes viridae group. 
     
     
       7. The method according to  claim 6 , wherein the said infection of the herpes viridae group is human cytomegalovirus (HCMV). 
     
     
       8. A method according to  claim 5 , wherein a salt or solvate prepared from the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid, is suitable for combination with at least one pharmaceutically acceptable excipient for use in a method of treatment and/or prophylaxis of human cytomegalovirus (HCMV) infections or infections with another representative of the herpes viridae group. 
     
     
       9. A method for purifying {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4- dihydroquinazoline-4-yl}acetic acid using the following steps:
 1.) reacting {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4- dihydroquinazoline-4-yl}acetic acid in a solvent with benzenesulfonic acid or toluenesulfonic acid, 
 2.) cooling the reaction from step 1) to initiate the crystallization of the salt obtained in step 1.), 
 3.) treating the isolated salt obtained in step 2.) with a buffer to release a zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4- yl}acetic acid, and 
 4). isolating the zwitterionic form of {8-fluoro-2-[4-(3-methoxyphenyl)piperazine-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-3,4-dihydroquinazoline-4-yl}acetic acid obtained in step 3.). 
 
     
     
       10. The method according to claim 1, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       11. The method according to claim 2, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       12. The method according to claim 3, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       13. The method according to claim 4, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       14. The method according to claim 5, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       15. The method according to claim 6, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       16. The method according to claim 7, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       17. The method according to claim 8, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration. 
     
     
       18. The method according to claim 9, wherein the carbon in position 4 of the dihydroquinazoline ring has an (S)-configuration.