Addition salt of S1P1 receptor agonist and crystal form thereof, and pharmaceutical composition
Disclosed in the present application are a salt form and a crystal form of an S1P1 receptor mediated disease or symptom drug 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl]benzyl}-3-azetidinecarboxylic acid (formula A). Also disclosed in the present invention are a preparation method for the salt form or the crystal form, a pharmaceutical composition of the salt form or the crystal form, and use of the salt form or the crystal form in the preparation of a drug for treating and/or preventing an S1P1 receptor mediated disease or symptom.
1. A sulfate of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid, having a structure represented by the following formula:
2. The sulfate according to claim 1 , wherein the sulfate is substantially a crystal form, wherein with Cu—Kα radiation, the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 16.7±0.2°, and 18.3±0.2°.
3. The sulfate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 5.4±0.2°, 8.1±0.2°, 14.8±0.2°, 15.6±0.2°, 16.7±0.2°, 18.3±0.2°, 21.0±0.2°, 22.0±0.2°, 22.9±0.2°, 25.2±0.2°, and 26.3±0.2°.
4. The sulfate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions with relative intensities as follows:
2θ
Relative intensity %
5.4 ± 0.2°
62.3
8.1 ± 0.2°
47.3
10.9 ± 0.2°
9.9
14.8 ± 0.2°
100
15.6 ± 0.2°
12.5
16.7 ± 0.2°
58.6
18.3 ± 0.2°
18.2
19.7 ± 0.2°
15.5
20.5 ± 0.2°
10.1
21.0 ± 0.2°
17.4
22.0 ± 0.2°
18.1
22.9 ± 0.2°
39.3
25.2 ± 0.2°
37.4
26.3 ± 0.2°
36.5.
5. The sulfate according to claim 2 , wherein the crystal form has an X-ray powder diffraction pattern substantially as illustrated in FIG. 6 .
6. The sulfate according to claim 2 , wherein the crystal form has a Fourier transform infrared spectrum having characteristic peaks at wavenumbers 1733 cm −1 , 1438 cm −1 , 1346 cm −1 , 1230 cm −1 , 1184 cm −1 , 1109 cm −1 , 1063 cm −1 , 1009 cm −1 , 885 cm −1 , 854 cm −1 , and 758 cm −1 .
7. The sulfate according to claim 1 , wherein the sulfate is an anhydrate, a hydrate, or a nonsolvate.
8. A pharmaceutical composition comprising: a) an effective amount of the sulfate according to claim 1 ; and b) at least one pharmaceutically acceptable carrier or excipient.
9. A method for preparing the sulfate according to claim 1 , comprising the following steps:
forming a suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid in a solvent selected from the group consisting of a C 1 -C 4 alcohol, a C 3 -C 4 ketone, a cyclic ether, a nitrile, water, and mixtures thereof, and a suspension or solution of sulfuric acid in a solvent selected from the group consisting of a C 1 -C 4 alcohol, a C 3 -C 4 ketone, a cyclic ether, a nitrile, water, and mixtures thereof;
mixing the suspension or solution of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid and the suspension or solution of sulfuric acid in a molar ratio of 1:0.4 to 1:10 of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid to sulfuric acid for reaction;
removing the solvent after the reaction is complete; and
performing drying; wherein
preferably, the solvent is selected from the group consisting of methanol, ethanol, n-propanol, acetone, tetrahydrofuran, water, acetonitrile, and mixtures thereof;
preferably, the molar ratio of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid to sulfuric acid is 1:0.4 to 1:7.9;
preferably, the reaction is performed at −10 to 60° C., the reaction is performed under stirring, and the stirring time is 1 to 72 hours, more preferably 1 to 24 hours;
preferably, the drying temperature is 10 to 60° C.,
preferably, the drying time is 1 to 48 hours;
preferably, the ratio of mass of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid to volume of the solvent in the method is 1 mg: 1 mL to 50 mg: 1 mL.
10. A sodium salt of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid, having a structure represented by the following formula:
11. The sodium salt according to claim 10 , wherein the sodium salt is substantially a crystal form, wherein with Cu—Kα radiation, the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions: 4.4±0.2°, 6.6±0.2°, 14.7±0.2°, and 17.2±0.2°.
12. The sodium salt according to claim 11 , wherein the crystal form has an X-ray powder diffraction pattern characterized by angle 2θ having characteristic peaks at the following positions with relative intensities as follows:
2θ
Relative intensity %
4.4 ± 0.2°
100
6.6 ± 0.2°
80.8
14.7 ± 0.2°
11.5
15.4 ± 0.2°
2.6
17.2 ± 0.2°
8.6.
13. The sodium salt according to claim 11 , wherein the crystal form has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2 .
14. The sodium salt according to claim 11 , wherein the crystal form has a Fourier transform infrared spectrum having characteristic peaks at wavenumbers 1560 cm −1 , 1505 cm −1 , 1476 cm −1 , 1417 cm −1 , 1365 cm −1 , 1276 cm −1 , 885 cm −1 , 849 cm −1 , and 756 cm −1 .
15. The sodium salt according to claim 10 , wherein the sodium salt is an anhydrate, a hydrate, or a nonsolvate.
16. A pharmaceutical composition comprising: a) an effective amount of the sodium salt according to claim 10 ; and b) at least one pharmaceutically acceptable carrier or excipient.
17. A method for preparing the sodium salt according to claim 10 , comprising the following steps:
mixing the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid and sodium hydroxide in a molar ratio of 1:1 to 1:5 in a solvent selected from the group consisting of a C 1 -C 4 alcohol, a C 3 -C 4 ketone, a C 4 -C 6 ether, water, a nitrile, and mixtures thereof for reaction;
removing the solvent after the reaction is complete; and
performing drying; wherein
preferably, the solvent is selected from the group consisting of methanol, ethanol, acetone, diethyl ether, water, acetonitrile, and mixtures thereof;
preferably, the molar ratio of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid to sodium hydroxide is 1:1.0 to 1:1.3;
preferably, the reaction is performed at 10 to 60° C.; preferably, the reaction is performed under stirring, and the stirring time is 1 to 48 hours;
preferably, the drying is performed under vacuum, and the drying temperature is 10 to 60° C.;
preferably, the drying time is 1 to 48 hours;
preferably, the ratio of mass of the compound 1-{2-fluoro-4-[5-(4-isobutylphenyl)-1,2,4-oxadiazole-3-yl] benzyl}-3-azetidinecarboxylic acid to volume of the solvent in the method is 1 mg: 1 mL to 50 mg: 1 mL.