Potassium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid
The present invention relates to potassium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)-piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid and solvates thereof. The invention further relates to methods of preparation of said potassium salt of 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)-phenyl]-4H-quinazolin-4-yl]acetic acid or solvates thereof as well as pharmaceutical compositions comprising said salt.
1 . A crystalline potassium salt of letermovir (potassium 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetate) of formula (I)
or a solvate thereof.
2 . The crystalline potassium salt of letermovir or the solvate thereof according to claim 1 , wherein the solvate is a hydrate.
3 . The crystalline potassium salt of letermovir or the solvate thereof according to claim 1 , wherein the solvate is a 2.5-hydrate.
4 . The crystalline potassium salt of letermovir or the solvate thereof according to claim 1 , wherein the solvate is a mixed water-ethanol solvate.
5 . The crystalline potassium salt of letermovir or the solvate thereof according to claim 3 , wherein said 2.5-hydrate shows characteristic peaks at about 6.1, 9.5, 10.7, 11.3, 12.4, 12.9, 15.6, 16.4, 16.8, 17.9, 19.0, 20.0, 20.9, 21.7, 22.4, 23.6, 25.2, 26.0, 26.7, 27.3, 28.2, 28.7, 29.6, 30.2, 30.9, 31.4, 32.2, 32.8 and 33.4 degrees 2theta in an X-ray powder diffractogram.
6 . The crystalline potassium salt of letermovir or the solvate thereof according to claim 4 , wherein said mixed water-ethanol solvate shows characteristic peaks at about 6.1, 9.4, 10.6, 11.2, 12.3, 12.8, 15.5, 16.3, 16.7, 17.8, 18.9, 19.9, 20.8, 21.7, 22.3, 23.5, 25.1, 25.9, 26.6, 27.1, 28.1, 28.5, 29.4, 30.1, 30.8, 31.2, 32.0, 32.6 and 33.3, degrees 2theta in an X-ray powder diffractogram.
7 . A method of producing the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 , wherein the method comprises:
a) Dissolving 2-[(4S)-8-fluoro-2-[4-(3-methoxyphenyl)piperazin-1-yl]-3-[2-methoxy-5-(trifluoromethyl)phenyl]-4H-quinazolin-4-yl]acetic acid or a salt or a solvate thereof in a first solvent, wherein said first solvent comprises at least one C1-C6-dialkyl ether and at least one C1-C6 alcohol, optionally under heating;
b) Adding potassium hydroxide to the solution obtained in a) to provide a first mixture;
c) Stirring said first mixture obtained in b) at a temperature in the range of from 25° C. to 80° C. for at least 5 minutes;
d) Cooling said first mixture to a temperature in the range of from 0° C. to 30° C. and stirring said first mixture at said temperature for at least 10 minutes;
e) Removing said first solvent to provide a first solid;
f) Contacting said first solid with a second solvent comprising at least one C1-C6-dialkyl ether to provide a second mixture;
g) Stirring said second mixture at a temperature in the range of from 0° C. to 30° C. for at least 1 hour; and
h) Removing said second solvent to provide a second solid.
8 . The method according to claim 7 , further comprising keeping the second solid at a temperature in the range of from 20° C. to 30° C. and at a relative humidity of at least 60% for at least 1 hour.
9 . The method according to claim 7 , wherein said C1-C6-dialkyl ether is diisopropyl ether.
10 . The method according claim 7 , wherein said C1-C6-alcohol is ethanol.
11 . The method according to claim 7 , wherein the ratio of volumes of C1-C6-dialkyl ether and C1-C6 alcohol in a) is in the range of from 3:1 to 1:3.
12 . The method according to claim 7 , wherein said first mixture is stirred in c) at a temperature in the range of from 45° C. to 55° C. for at least 30 minutes.
13 . The method according to claim 7 , wherein said first mixture is cooled in d) to a temperature in the range of from 20° C. to 30° C. and stirred at said temperature for at least 30 minutes.
14 . The method according to claim 7 , wherein said first solvent is removed in e) by evaporation.
15 . The method according to claim 7 , wherein said second solvent is removed in h) by filtration.
16 . A crystalline potassium salt of letermovir or a solvate thereof which is obtainable by the method as defined in claim 7 .
17 . A pharmaceutical composition comprising the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 and at least one pharmaceutically acceptable excipient and/or diluent.
18 . A method for treatment of a virus infection comprising administering to an infected subject a pharmaceutical composition as defined in claim 17 .
19 . A method for treatment of a virus infection comprising administering to an infected subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 .
20 . A method for prevention of a virus infection comprising administering to a subject a pharmaceutical composition as defined in claim 17 .
21 . A method for treatment of a virus infection by a member of the herpes viridae group comprising administering to an infected subject a pharmaceutical composition as defined in claim 17 .
22 . A method for treatment of a human cytomegalovirus (HCMV) infection comprising administering to an infected subject a pharmaceutical composition as defined in claim 17 .
23 . A method for treatment of a virus infection by a member of the herpes viridae group comprising administering to an infected subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 .
24 . A method for treatment of a human cytomegalovirus (HCMV) infection comprising administering to an infected subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 to the subject.
25 . A method for prevention of a virus infection by a member of the herpes viridae group comprising administering to a subject a pharmaceutical composition as defined in claim 17 .
26 . A method for prevention of a human cytomegalovirus (HCMV) infection comprising administering to a subject a pharmaceutical composition as defined in claim 17 .
27 . A method for prevention of a virus infection comprising administering to a subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 .
28 . A method for prevention of a virus infection by a member of the herpes viridae group comprising administering to a subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 .
29 . A method for prevention of a human cytomegalovirus (HCMV) infection comprising administering to a subject the crystalline potassium salt of letermovir or the solvate thereof as defined in claim 1 .