HYDROCHLORIDE SALTS OF 8-[1-(3,5-BIS-(TRIFLUOROMETHYL)PHENYL)-ETHOXYMETHYL]-8-PHENYL-1,7-DIAZASPIRO[4,5]DECAN-2-ONE AND PREPARATION PROCESS THEREFOR
Disclosed are hydrochloride and tosylate crystalline salt forms of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one, represented by Formula I and methods of preparing the same.
1 ) An isolated crystalline Form I monohydrate hydrochloride salt form of the compound (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I)
which yields an x-ray powder diffraction pattern having characteristic peaks at diffraction angles (in 2 θ) of: 16.1 (M); 18.4 (M); 21.6 (S); and 23.5 (M).
2 ) The Form I hydrochloride salt form of claim 1 yielding an x-ray powder diffraction pattern having additional characteristic peaks present at diffraction angles (in 2 θ) of: 12.9 (S); 15.4 (S); 17.3 (S); 20.2 (S).
3 ) A crystalline anhydrous Form II hydrochloride salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I)
characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 7.0 (M); 9.0 (S); 12.6 (VS); and 20.2 (S).
4 ) A crystalline Form I tosylate salt form of 8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I)
characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 9.4 (M); 20.0 (VS); 21.0 (MS); and 25.3 (MS).
5 ) A crystalline Form II Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy]-methyl}-8-phenyl-1,7-diazaspiro[4.5]decan-2-one characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 5.0 (VS); 10.0 (S); 13.6 (M); and 19.7 (VS).
6 ) A crystalline Form III Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 6.3 (M); 9.7 (VS); 20.2 (S); and 22.2 (S).
7 ) A crystalline Form IV Tosylate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one which is characterized by an x-ray powder diffraction pattern having peaks present at diffraction angles (in 2 θ) of: 6.1 (S); 9.6 (S); 20.9 (S); and 22.0 (S).
8 ) A crystalline Form I hydrochloride monohydrate salt form of (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I)
characterized by the following x-ray powder diffraction pattern expressed in terms of lattice “d” spacing (in angstroms) and relative peak intensities (“RI”, denoted as S=strong, M=medium, and W=weak, each of which may be modified by V=very and D=diffuse, for example, VS=Very Strong, VWD=very weak diffuse):
d
relative
spacing
intensity
6.85
WD
5.49
M
4.83
M
4.74
WD
4.48
W
4.11
S
3.89
WD
3.78
M
3.70
WD
3.16
W
2.62
VW
2.56
W
9 ) A pharmaceutical composition comprising the crystalline salt of claim 1 and a pharmaceutically acceptable carrier and optionally one or more additional therapeutic agents.
10 ) A combination comprising the composition of claim 9 and a chemotherapeutic agent.
11 ) The combination of claim 10 wherein the chemotherapeutic agent is temozolomide.
12 ) A pharmaceutical composition comprising the crystalline salt of claim 2 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
13 ) A pharmaceutical composition comprising the crystalline salt of claim 3 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
14 ) A pharmaceutical composition comprising the crystalline salt of claim 4 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
15 ) A pharmaceutical composition comprising the crystalline salt of claim 5 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
16 ) A pharmaceutical composition comprising the crystalline salt of claim 6 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
17 ) A pharmaceutical composition comprising the crystalline salt of claim 7 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
18 ) A pharmaceutical composition comprising the crystalline salt of claim 8 and a pharmaceutically acceptable carrier optionally in combination with one or more additional therapeutic agents.
19 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a medicament comprising a therapeutically effective amount of the crystalline salt of claim 1 .
20 ) The method of claim 19 further comprising administering said medicament in combination with a therapeutically effective amount of a chemotherapeutic agent.
21 ) The method of claim 20 wherein said chemotherapeutic agent is temozolomide.
22 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of claim 2 optionally administered in combination with one or more additional therapeutic agents.
23 ) A method of treating and/or preventing emesis in a mammal a therapeutically effective amount of which comprises administering to said mammal the crystalline salt of claim 3 optionally administered in combination with one or more additional therapeutic agents.
24 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of claim 4 optionally administered in combination with one or more additional therapeutic agents.
25 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of claim 5 optionally administered in combination with one or more additional therapeutic agents.
26 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of claim 6 optionally administered in combination with one or more additional therapeutic agents.
27 ) A method of treating and/or preventing emesis in a mammal which comprises administering to said mammal a therapeutically effective amount of the crystalline salt of claim 7 optionally administered in combination with one or more additional therapeutic agents.
28 ) A method of treating and/or preventing emesis in a mammal which comprises to administering to said mammal a therapeutically effective amount of the crystalline salt of claim 8 optionally administered in combination with one or more additional therapeutic agents.
29 ) A salt of the compound (5S,8S)-8-[{(1R)-1-(3,5-Bis-(trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diazaspiro[4.5]decan-2-one (Formula I)
prepared by treating an ethanol solution of the compound of Formula I with an acid selected from the group consisting of hydrochloric acid and p-toluene-sulfonic acid.
30 ) A method of providing therapy for delayed onset emesis and/or delayed onset nausea along with chemotherapy by administering the combination of claim 10 to a patient in need of chemotherapy.
31 ) The treatment method of claim 19 further comprising contemporaneous administration of a chemotherapeutic agent
32 ) The treatment method of claim 31 wherein the chemotherapeutic agent is temozolomide.
33 ) The treatment method of claim 22 wherein said salt is administered in combination with a chemotherapeutic agent.
34 ) The treatment method of claim 23 wherein said salt is administered in combination with a chemotherapeutic agent.
35 ) The treatment method of claim 24 wherein said salt is administered in combination with a chemotherapeutic agent.
36 ) The treatment method of claim 25 wherein said salt is administered in combination with a chemotherapeutic agent.
37 ) The treatment method of claim 26 wherein said salt is administered in combination with a chemotherapeutic agent.
38 ) The treatment method of claim 27 wherein said salt is administered in combination with a chemotherapeutic agent.
39 ) The treatment method of claim 28 wherein said salt is administered in combination with a chemotherapeutic agent.