Crystalline form of GnRH receptor antagonist and preparation method therefor
10787451 ยท 2020-09-29
Assignee
- JIANGSU HENGRUI MEDICINE CO., LTD. (Lianyungang, Jiangsu, CN)
- Suncadia Pharmaceuticals Co., Ltd. (Chengdu, Sichuan, CN)
Inventors
- Quanliang Zhang (Jiangsu, CN)
- Junlei Jia (Jiangsu, CN)
- Lin Bian (Jiangsu, CN)
- Xiaohui Gao (Jiangsu, CN)
Cpc classification
A61K31/519
HUMAN NECESSITIES
International classification
A61P15/00
HUMAN NECESSITIES
A61K31/519
HUMAN NECESSITIES
Abstract
Provided are a crystalline form of a GnRH receptor antagonist and a preparation method therefor. Specifically, provided are a crystalline form I of 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dicarbonyl-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxy urea (a compound of formula I) and a preparation method, the use of same in a pharmaceutical composition and the use of the crystalline form I and the composition in the preparation of a drug for treating diseases associated with a GnRH receptor antagonist.
Claims
1. Crystal form I of a compound of formula (I), characterized by an X-ray powder diffraction spectrum comprising diffraction peaks at diffraction angles 20.2 of 5.56, 9.15, 9.79, 11.08, 19.59, 20.25 and 22.16: ##STR00003##
2. The crystal form I according to claim 1, wherein the X-ray powder diffraction spectrum comprises diffraction peaks at diffraction angles 20.2 of 5.56, 9.15, 9.79, 10.29, 11.08, 14.21, 16.61, 19.59, 20.25, 22.16 and 25.69.
3. The crystal form I according to claim 2, wherein the X-ray powder diffraction spectrum comprises diffraction peaks at diffraction angles 20.2 of 5.22, 5.56, 9.15, 9.79, 10.29, 11.08, 13.38, 13.81, 14.21, 14.89, 16.61, 17.19, 18.47, 19.59, 20.25, 22.16, 23.32, 24.67, 25.69, 26.72, 28.73, 29.38, 31.78, 34.02 and 36.95.
4. A method for preparing the crystal form I of the compound of formula (I) according to claim 1, comprising dissolving the compound of formula (I) in an organic solvent to precipitate a crystal, filtering, washing and drying the crystal to obtain the desired crystal form I, wherein the organic solvent is selected from the group consisting of an alcohol, ketone, ester, ether, a mixed solvent of an ether and an alcohol, and a mixed solvent of a ketone and water; and the alcohol solvent is selected from the group consisting of methanol, ethanol and isopropanol.
5. The crystal form I according to claim 1, characterized by a DSC spectrum comprising a melting endothermic peak of 160 C. to 175 C.
6. A pharmaceutical composition comprising the crystal form I according to claim 1, and one or more pharmaceutically acceptable carriers, diluents or excipients.
7. A method for preparing the crystal form I of the compound of formula (I) according to claim 1, comprising adding the compound of formula (I) into an organic solvent to obtain a mixture; pulping the mixture; and filtering, washing and drying a crystal to obtain the desired crystal form I, wherein the organic solvent is selected from the group consisting of an alcohol, ketone, ester, ether, a mixed solvent of an ether and an alcohol, and a mixed solvent of a ketone and water; and the alcohol solvent is selected from the group consisting of methanol, ethanol, and isopropanol.
8. The method according to claim 4, wherein the ketone solvent is acetone.
9. The method according to claim 4, wherein the ester solvent is ethyl acetate.
10. The method according to claim 4, wherein the ether solvent is tetrahydrofuran.
11. The method according to claim 4, wherein the mixed solvent of the ether and the alcohol is tetrahydrofuran/ethanol or tetrahydrofuran/isopropanol.
12. The method according to claim 4, wherein the mixed solvent of the ketone and water is acetone/water.
13. The method according to claim 7, wherein the ketone solvent is acetone.
14. The method according to claim 7, wherein the ester solvent is ethyl acetate.
15. The method according to claim 7, wherein the ether solvent is tetrahydrofuran.
16. The method according to claim 7, wherein the mixed solvent of the ether and the alcohol is tetrahydrofuran/ethanol or tetrahydrofuran/isopropanol.
17. The method according to claim 7, wherein the mixed solvent of the ketone and water is acetone/water.
18. The crystal form I according to claim 5, wherein the DSC spectrum comprises a melting endothermic peak of from 165 C. to 170 C.
19. The crystal form I according to claim 5, wherein the DSC spectrum comprises a melting endothermic peak of 168.71 C.
20. A method for treating a disease associated with GnRH receptor antagonist, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition according to claim 6, wherein the disease is selected from the group consisting of endometriosis, uterine leiomyoma, and prostate cancer.
Description
DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF THE INVENTION
(11) The present invention will be illustrated by the following examples in detail. The examples of the present invention are merely intended to describe the technical solution of the present invention, and should not be considered as limiting the spirit and scope of the present invention.
(12) Test conditions for the instruments used in the experiments:
(13) 1. Differential Scanning Calorimeter, DSC
(14) Instrument type: Mettler Toledo DSC 1 STAR.sup.e System
(15) Purging gas: Nitrogen
(16) Heating rate: 10.0 C./min
(17) Temperature range: 40-300 C.
(18) 2. X-Ray Powder Diffraction, XRPD
(19) Instrument type: Bruker D8 Focus X-ray powder diffractometer
(20) Ray: monochromatic Cu-K ray (=1.5406)
(21) Scanning mode: /2, Scanning range: 2-40
(22) Voltage: 40 kV, Electric current: 40 mA
Example 1
(23) The crude 1-(4-(7-(2,6-difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxyurea (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, a mixed solvent of acetone/water (5 mL, V:V=5:1) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved completely, and the solution was cooled to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 212 mg of a solid. The crystal sample was determined by XRPD, and there are characteristic peaks at diffraction angle 2 of 5.19 (17.02), 5.48 (16.10), 9.08 (9.73), 9.73 (9.08), 10.24 (8.63), 11.01 (8.03), 13.80 (6.41), 14.13 (6.26), 14.82 (5.97), 15.35 (5.77), 16.56 (5.35), 18.31 (4.84), 18.65 (4.75), 19.50 (4.55), 20.18 (4.40), 22.07 (4.03), 23.26 (3.82), 24.59 (3.62), 25.61 (3.48), 26.66 (3.34), 28.69 (3.11), 29.30 (3.05), 33.96 (2.64) and 36.91 (2.43). The crystal form was defined as crystal form I.
Example 2
(24) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, acetone (6 mL) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 221 mg of a solid. The XRPD spectrum of the crystal sample is shown in
(25) TABLE-US-00001 TABLE 1 Characteristic peaks of crystal form I Peak No. 2 [] d [] Peak 1 5.22 16.92 Peak 2 5.56 15.88 Peak 3 9.15 9.66 Peak 4 9.79 9.03 Peak 5 10.29 8.59 Peak 6 11.08 7.98 Peak 7 13.38 6.61 Peak 8 13.81 6.41 Peak 9 14.21 6.23 Peak 10 14.89 5.94 Peak 11 16.61 5.33 Peak 12 17.19 5.16 Peak 13 18.47 4.80 Peak 14 19.59 4.53 Peak 15 20.25 4.38 Peak 16 22.16 4.01 Peak 17 23.32 3.81 Peak 18 24.67 3.61 Peak 19 25.69 3.47 Peak 20 26.72 3.33 Peak 21 28.73 3.11 Peak 22 29.38 3.04 Peak 23 31.78 2.81 Peak 24 34.02 2.63 Peak 25 36.95 2.43
Example 3
(26) The crude compound of formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, methanol (50 mL) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved, and the solution was stirred to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 350 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 4
(27) The crude compound of formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, ethanol (125 mL) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved, and the solution was stirred to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 406 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 5
(28) The crude compound of formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, isopropanol (10 mL) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 445 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 6
(29) The crude compound of formula (I) (500 mg, 0.82 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, acetone (25 mL) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved, and the solution was stirred to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 251 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 7
(30) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, ethyl acetate (9 mL) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 224 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 8
(31) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, tetrahydrofuran/ethanol (8 mL, V:V=1:1) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved, and the solution was stirred to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 197 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 9
(32) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, tetrahydrofuran/isopropanol (12 mL, V:V=1:1) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved, and the solution was stirred to precipitate a crystal. The mixture was filtered and dried under vacuum to obtain 182 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 10
(33) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, methanol (6 mL) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 239 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 11
(34) The crude compound of formula (I) (300 mg, 0.49 mmol) (prepared according to the method of Example 11 of WO2015062391A1) was added to a reaction flask, ethanol (6 mL) was added, and the resulting mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 231 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 12
(35) 1-(4-(7-(2,6-Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxy urea (500 mg, 0.82 mmol) (prepared according to Example 1) was added to a reaction flask, purified water (10 mL) was added, and the resulting mixture was pulped for 5 hours at room temperature. The mixture was filtered and dried to obtain 369 mg of a solid. The crystal form was identified as crystal form A by XRPD and DSC spectra.
(36) The resulting crystal form A was added to a reaction flask, ethanol (4 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 89 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 13
(37) 1-(4-(7-(2,6-Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxy urea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to a reaction flask, acetonitrile (9 mL) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved completely, and the solution was cooled to precipitate a crystal. The mixture was filtered and dried to obtain 243 mg of a solid. The crystal form was identified as crystal form B by XRPD and DSC spectra.
(38) The resulting crystal form B was added to a reaction flask, ethanol (4 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 80 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 14
(39) 1-(4-(7-(2,6-Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxy urea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to a reaction flask, 1,4-dioxane (15 mL) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved completely, and the solution was cooled to precipitate a crystal. The mixture was filtered and dried to obtain 205 mg of a solid. The crystal form was identified as crystal form C by XRPD and DSC spectra.
(40) The resulting crystal form C was added to a reaction flask, ethanol (10 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 78 mg of a solid (yield: 78.0%). The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 15
(41) 1-(4-(7-(2,6-Difluorobenzyl)-3-((dimethylamino)methyl)-5-(6-methoxypyridazin-3-yl)-4,6-dioxo-4,5,6,7-tetrahydro-2H-pyrazolo[3,4-d]pyrimidin-2-yl)phenyl)-3-methoxy urea (300 mg, 0.49 mmol) (prepared according to Example 1) was added to a reaction flask, tetrahydrofuran/water (15 mL, V:V=1:1) was added, and the resulting mixture was heated to reflux. The heating was stopped when the solid was dissolved completely, and the solution was cooled to precipitate a crystal. The mixture was filtered and dried to obtain 205 mg of a solid. The crystal form was identified as crystal form D by XRPD and DSC spectra.
(42) The resulting crystal form D was added to a reaction flask, ethanol (10 mL) was added, and the mixture was stirred overnight at room temperature. The mixture was filtered and dried under vacuum to obtain 78 mg of a solid. The product was identified as crystal form I after studying and comparing the XRPD and DSC spectra of the crystal sample.
Example 16
(43) The product sample of crystal form I prepared in Example 1 and the product samples of crystal forms A, B, C and D prepared in Examples 12, 13, 14 and 15 were spread flat in the air to test sample stability under conditions of lighting (4500 Lux), heating (40 C., 60 C.), and high humidity (RH 75%, RH 90%). Samplings were carried out on Day 5 and Day 10. The purity as detected by HPLC is shown in Table 2.
(44) Test Results:
(45) TABLE-US-00002 TABLE 2 Stability comparison of crystal form I of the compound of formula (I) of the present invention and crystal forms A, B, C and D of the compound of formula (I) Batch Time number (day) Lighting 40 C. 60 C. RH 75% RH 90% Crystal 0 99.36% 99.36% 99.36% 99.36% 99.36% form I 5 99.26% 99.33% 99.24% 99.22% 99.27% 10 99.20% 99.41% 99.30% 99.31% 99.27% Crystal 0 97.86% 97.86% 97.86% 97.86% 97.86% form A 5 97.27% 97.50% 97.62% 97.61% 97.59% 10 97.13% 97.52% 97.50% 97.65% 97.79% Crystal 0 99.69% 99.69% 99.69% 99.69% 99.69% form B 5 99.39% 99.45% 99.45% 99.52% 99.47% 10 99.19% 99.03% 99.34% 99.34% 99.34% Crystal 0 99.75% 99.75% 99.75% 99.75% 99.75% form C 5 98.30% 99.57% 99.53% 99.51% 99.54% 10 96.83% 99.35% 99.47% 99.48% 99.38% Crystal 0 99.67% 99.67% 99.67% 99.67% 99.67% form D 5 99.43% 99.44% 99.48% 99.57% 99.57% 10 99.22% 99.31% 99.40% 99.34% 99.39%
(46) Test Conclusion
(47) The results of the stability test in Table 2 showed that:
(48) When being spread in the air under conditions of lighting, high humidity and high temperature, the decrease of HPLC purity data of crystal form I of the compound of formula (I) were less than that of crystal forms A, B, C and D, and the crystal form was not changed by XRPD test, indicating that the stability of crystal form I of the present invention is significantly better than that of crystal forms A, B, C and D.
Example 17
(49) The sample of crystal form I of the compound of formula (I) prepared according to the method of Example 1 was ground, heated and tableted. The results of crystal form stability, XRPD test and DSC test of the sample are shown in Table 3.
(50) Test Results:
(51) TABLE-US-00003 TABLE 3 Special stability study of crystal form I of the compound of formula (I) XRPD Sample Treatment Process Experimental procedure test DSC peak Crystal Grinding treatment for 1 g of the sample of crystal form I Crystal 166.16 C. form I 10 minutes of the compound of formula (I) form I was ground for 10 minutes in a mortar under nitrogen atmosphere. Crystal Heating treatment for 3 1 g of the sample of crystal form I Crystal 168.36 C. form I hours at 80 C. of the compound of formula (I) form I was spread flat and heated at 80 C. for 3 hours. Crystal Tableting treatment The sample of crystal form I of the Crystal 168.97 C. form I compound of formula (I) was form I tableted.
(52) Test Conclusion:
(53) The results of the stability study in Table 3 showed that the crystal form was not changed during the grinding, heating and tableting procedure, indicating that the crystal form I of the present invention is stable.