Hydrochloride salts of 8-[{1-(3,5-Bis-trifluoromethyl)phenyl)-ethoxy}-methyl]-8-phenyl-1,7-diaza-spiro[4.5]decan-2-one and preparation process therefor
View Patent ↗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. A method of treating or delaying the onset of chemotherapy-induced nausea and/or chemotherapy-induced emesis in a mammal receiving chemotherapy which comprises administering to said mammal a medicament comprising a therapeutically effective amount of a 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):
wherein the crystalline Form I monohydrate hydrochloride salt form is characterized by an x-ray powder diffraction pattern including at least a strong peak having a diffraction angle (in 2θ) of 21.6±0.2 and lattice spacing (in Å) of 4.11±0.04.
2. The method of claim 1 further comprising administering said medicament in combination with a therapeutically effective amount of a chemotherapeutic agent.
3. The method of claim 2 wherein said chemotherapeutic agent is temozolomide.
4. The method of claim 1 , wherein one or more additional therapeutic agents are administered in combination with the 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.
5. The method of claim 1 further comprising contemporaneous administration of a chemotherapeutic agent.
6. The method of claim 5 wherein the chemotherapeutic agent is temozolomide.
7. The method of claim 1 , wherein the crystalline Form I monohydrate 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 is characterized by an x-ray powder diffraction pattern having at least one additional peak selected from
Diffraction angle (2Θ ± 0.2)
RI
Lattice Spacing (Å ± 0.04)
16.1
Medium
5.49
18.4
Medium
4.83
23.5
Medium
3.78.
8. The method of claim 1 , wherein the crystalline Form I monohydrate 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 is characterized by an x-ray powder diffraction pattern having at least two additional peaks selected from
Diffraction angle (2Θ ± 0.2)
RI
Lattice Spacing (Å ± 0.04)
16.1
Medium
5.49
18.4
Medium
4.83
23.5
Medium
3.78.
9. The method of claim 1 , wherein the crystalline Form I monohydrate 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 is characterized by an x-ray powder diffraction pattern which includes the following peaks:
Diffraction angle (2Θ ± 0.2)
RI
Lattice Spacing (Å ± 0.04)
16.1
Medium
5.49
18.4
Medium
4.83
21.6
Strong
4.11
23.5
Medium
3.78.
10. A method of treating or delaying the onset of nausea and/or emesis in a mammal which comprises administering to said mammal a medicament comprising a therapeutically effective amount of a 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):
characterized by an x-ray powder diffraction pattern substantially as shown in FIG. 1 .
11. The method of claim 4 , wherein the one or more additional therapeutic agents are selected from a 5HT 3 inhibitor and a corticosteroid.
12. The method of claim 11 , wherein the 5HT 3 inhibitor is selected from ondensetron, granisetron, palonosetron, dolasetron and tropisetron.
13. The method of claim 11 , wherein the corticosteroid is dexamethasone.
14. The method of claim 5 , wherein the medicament is administered contemporaneously with the chemotherapeutic agent such that the medicament is administered before administration of the chemotherapeutic agent.
15. The method according to claim 5 , wherein the medicament is administered contemporaneously with the chemotherapeutic agent such that the medicament is administered during administration of the chemotherapeutic agent.
16. The method according to claim 5 , wherein the medicament is administered contemporaneously with the chemotherapeutic agent such that the medicament is administered after administration of the chemotherapeutic agent.