Crystal of salt of novel 3-azabicyclo[3.1.0]hexane derivative and pharmaceutical use thereof
View Patent ↗Disclosed herein are a crystal comprising a compound, which has μ-opioid receptor antagonistic action, few side effects, and high safety, and having high purity and excellent physical properties (stability, solubility, etc.), and a method for producing the crystal. The crystal is a crystal of a salt comprising: a compound represented by a formula (I) [wherein R 2 is a hydrogen atom or a halogen atom, and R 1 is a group selected from the group consisting of and an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, and oxalic acid, or a hydrate thereof.
1. A crystal of a salt comprising: a compound represented by a formula (I)
wherein R 2 is a hydrogen atom or a halogen atom, and R 1 is a group selected from the group consisting of
and an acid selected from the group consisting of hydrochloric acid, hydrobromic acid, and oxalic acid.
2. The crystal of a salt of claim 1 , wherein the salt is N-(3 {(1R,5S,6r)-6-ethyl-3-[(2-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide hydrochloride.
3. The crystal according to claim 2 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 8.3°, 13.6°, 17.4°, and 24.3° in powder X-ray diffraction.
4. The crystal of a salt of claim 1 , wherein the salt is N-(3 {(1R,5S,6r)-6-ethyl-3-[2-hydroxy-2,3-dihydro-1H-inden-2-yl)methyl]-3-azabicyclo[3.1.0]hexan-6-yl}-4-fluorophenyl)cyclopropanesulfonamide hydrobromide.
5. The crystal according to claim 4 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 9.1° 14.1°, 17.3°, and 24.2° in powder X-ray diffraction.
6. The crystal of a salt of claim 1 , wherein the salt is N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoro-1-methoxycyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide hydrochloride.
7. The crystal according to claim 6 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 8.6°, 16.2°, 23.9°, and 27.4° in powder X-ray diffraction.
8. The crystal of a salt of claim 1 , wherein the salt is N-(3-{(1R,5S,6r)-3-[3-(4,4-difluoro-1-methoxycyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide oxalate.
9. The crystal according to claim 8 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 9.5°, 10.3°, 23.8°, and 25.1° in powder X-ray diffraction.
10. The crystal of a salt of claim 1 , wherein the salt is N-(3-{(1R,5S,6r)-3-[3-(4,4-difluorocyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide hydrobromide.
11. The crystal according to claim 10 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 9.1°, 14.5°, 17.1°, and 25.2° in powder X-ray diffraction.
12. The crystal of a salt of claim 1 , wherein the salt is N-(3-{(1R,5S,6r)-3-[3-(4,4-difluorocyclohexyl)propyl]-6-ethyl-3-azabicyclo[3.1.0]hexan-6-yl}phenyl)cyclopropanesulfonamide oxalate.
13. The crystal according to claim 12 , which has a diffraction peak(s) at a diffraction angle(s) (2θ±0.2°) of 9.7°, 14.5°, 17.3°, and 26.0° in powder X-ray diffraction.
14. A pharmaceutical composition comprising the crystal according to claim 1 as an active ingredient.
15. The crystal according to claim 2 , which has a diffraction peak(s) at a d-spacing(s) of 10.6 Å, 6.50 Å, 5.09 Å, and 3.66 Å in powder X-ray diffraction.
16. The crystal according to claim 2 , which has absorption peaks at wave numbers (ν max ±18 cm −1 ) of 737 cm −1 , 800 cm −1 , 1150 cm −1 , 1466 cm −1 , and 3219 cm −1 in its infrared absorption spectrum.
17. The crystal according to claim 4 , which has a diffraction peak(s) at a d-spacing(s) of 9.71 Å, 6.27 Å, 5.12 Å, and 3.67 Å in powder X-ray diffraction.
18. The crystal according to claim 4 , which has absorption peaks at wave numbers (ν max ±18 cm) of 737 cm −1 , 797 cm −1 , 1148 cm −1 , 1460 cm −1 , and 3277 cm −1 in its infrared absorption spectrum.
19. The crystal according to claim 6 , which has a diffraction peak(s) at a d-spacing(s) of 10.3 Å, 5.46 Å, 3.72 Å, and 3.25 Å in powder X-ray diffraction.
20. The crystal according to claim 6 , which has absorption peaks at wave numbers (ν max ±18 cm −1 ) of 706 cm −1 , 1148 cm −1 , 1477 cm −1 , 1607 cm −1 , and 2941 cm −1 in its infrared absorption spectrum.
21. The crystal according to claim 8 , which has a diffraction peak(s) at a d-spacing(s) of a 9.30 Å, 8.58 Å, 3.73 Å, and 3.54 Å in powder X-ray diffraction.
22. The crystal according to claim 8 , which has absorption peaks at wave numbers (ν max ±18 cm −1 ) of 712 cm −1 , 1157 cm −1 , 1458 cm −1 , 1607 cm −1 , and 3254 cm −1 its infrared absorption spectrum.
23. The crystal according to claim 10 , which has a diffraction peak(s) at a d-spacing(s) of 9.71 Å, 6.10 Å, 5.18 Å, and 3.53 Å in powder X-ray diffraction.
24. The crystal according to claim 10 , which has absorption peaks at wave numbers (ν max ±18 cm −1 ) of 733 cm −1 , 889 cm −1 , 1152 cm −1 , 1605 cm −1 , and 3071 cm −1 in its infrared absorption spectrum.
25. The crystal according to claim 12 , which has a diffraction peak(s) at a d-spacing(s) of 9.11 Å, 6.10 Å, 5.12 Å, and 3.42 Å; in powder X-ray diffraction.
26. The crystal according to claim 12 , which has absorption peaks at wave numbers (ν max ±18 cm −1 ) of 704 cm −1 , 889 cm −1 , 1152 cm −1 , 1609 cm −1 , and 3244 cm −1 in its infrared absorption spectrum.