SALT OF 2-(SUBSTITUTED PYRIMIDINYL) THIAZOLE CARBOXAMIDE COMPOUND, AND COMPOSITION AND USE THEREOF
20230312551 · 2023-10-05
Assignee
Inventors
Cpc classification
C07C309/29
CHEMISTRY; METALLURGY
C07C309/30
CHEMISTRY; METALLURGY
A61K31/506
HUMAN NECESSITIES
International classification
Abstract
A salt of a 2-(substituted pyrimidinyl)thiazole carboxamide compound, and a composition and use thereof, and also a crystal form of the salt. Specifically, a pharmaceutical composition includes the salt, and a use of the salt or pharmaceutical composition in the preparation of a drug for preventing, treating or alleviating central nervous system dysfunction, particularly depression.
Claims
1-17. (canceled)
18. A salt of the compound having formula (I), ##STR00003## wherein, the salt is phosphate, L-tartrate, benzenesulfonate, p-toluenesulfonate or sulfate.
19. The salt of claim 18, wherein the phosphate is phosphate crystal form A, and its X-ray powder diffraction pattern comprises peaks expressed as 2θ at: 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.38°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°; or the phosphate is phosphate crystal form A, and its X-ray powder diffraction pattern comprises peaks expressed as 2θ at: 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.28°± 0.2°, 16.38°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°.
20. The salt of claim 19, wherein the X-ray powder diffraction pattern of the phosphate crystal form A comprises peaks expressed as 2θ at: 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.38°± 0.2°, 19.36°± 0.2°, 20.31°± 0.2°, 20.79°± 0.2°, 20.93°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°; or the X-ray powder diffraction pattern of the phosphate crystal form A comprises peaks expressed as 2θ at: 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.28°± 0.2°, 16.38°± 0.2°, 19.36°± 0.2°, 20.31°± 0.2°, 20.79°± 0.2°, 20.93°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°.
21. The salt of claim 19, wherein the X-ray powder diffraction pattern of the phosphate crystal form A comprises peaks expressed as 2θ at: 9.65°± 0.2°, 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.38°± 0.2°, 16.86°± 0.2°, 19.36°± 0.2°, 20.31°± 0.2°, 20.79°± 0.2°, 20.93°± 0.2°, 21.68°± 0.2°, 22.52°± 0.2°, 24.73°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°, 29.82°± 0.2°, 30.58°± 0.2°, 31.43°± 0.2°, 32.14°± 0.2°; or the X-ray powder diffraction pattern of the phosphate crystal form A comprises peaks expressed as 2θ at: 9.65°± 0.2°, 11.14°± 0.2°, 12.25°± 0.2°, 13.50°± 0.2°, 15.98°± 0.2°, 16.28°± 0.2°, 16.38°± 0.2°, 16.86°± 0.2°, 19.36°± 0.2°, 20.31°± 0.2°, 20.79°± 0.2°, 20.93°± 0.2°, 21.68°± 0.2°, 22.52°± 0.2°, 24.73°± 0.2°, 25.26°± 0.2°, 25.98°± 0.2°, 26.82°± 0.2°, 29.82°± 0.2°, 30.58°± 0.2°, 31.43°± 0.2°, 32.14°± 0.2°.
22. The salt of claim 19, wherein the phosphate crystal form A has an X-ray powder diffraction pattern substantially as shown in Figure 1.
23. The salt of claim 19, wherein the differential scanning calorimetry diagram of the phosphate crystal form A comprises an endothermic peak at 200.43° C. ± 3° C.
24. The salt of claim 19, wherein the phosphate crystal form A has a differential scanning calorimetry diagram substantially as shown in Figure 2.
25. A pharmaceutical composition comprising the salt of claim 18, and a pharmaceutically acceptable carrier, excipient, diluent, adjuvant or a combination thereof.
26. A method of preventing, treating or alleviating central nervous system dysfunction in a subject, comprising contacting the subject with a therapeutically effective amount of the salt of claim 18.
27. The method of claim 26, wherein, the central nervous system dysfunction comprises depression, anxiety disorder, mania, schizophrenia, bipolar disorder, sleep disorder, obsession and behavior disorder, panic disorder, post-traumatic stress disorder, movement disorders, sexual dysfunction, musculoskeletal pain disorder, cognitive impairment, memory impairment, Parkinson’s disease, Huntington’s disease, phobias, substance abuse or addiction, drug addiction withdrawal symptoms or premenstrual stress syndrome.
28. A method of preventing, treating or alleviating central nervous system dysfunction in a subject, comprising contacting the subject with a therapeutically effective amount of the pharmaceutical composition of claim 25.
29. The method of claim 28, wherein, the central nervous system dysfunction comprises depression, anxiety disorder, mania, schizophrenia, bipolar disorder, sleep disorder, obsession and behavior disorder, panic disorder, post-traumatic stress disorder, movement disorders, sexual dysfunction, musculoskeletal pain disorder, cognitive impairment, memory impairment, Parkinson’s disease, Huntington’s disease, phobias, substance abuse or addiction, drug addiction withdrawal symptoms or premenstrual stress syndrome.
30. A method of selectively inhibiting 5-hydroxytryptamine reuptake and/or agonizing 5-HT.sub.1A receptor, comprising using the salt of claim 18.
31. A method of selectively inhibiting 5-hydroxytryptamine reuptake and/or agonizing 5-HT.sub.1A receptor, comprising using the pharmaceutical composition of claim 25.
Description
DESCRIPTION OF THE DRAWINGS
[0133]
[0134]
[0135]
[0136]
[0137]
[0138]
[0139]
[0140]
[0141]
[0142]
[0143]
[0144]
[0145]
[0146]
[0147]
[0148]
[0149]
[0150]
[0151]
[0152]
[0153]
[0154]
[0155]
[0156]
[0157]
[0158]
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0159] The invention will now be further described by way of example without limiting the invention to the scope of the invention.
[0160] The X-ray powder diffraction analysis method used in the present invention was an Empyrean diffractometer, and an X-ray powder diffraction pattern was obtained using Cu-Kα radiation (45 KV, 40 mA). The powdery sample was prepared as a thin layer on a monocrystalline silicon sample rack or domestic silicon wafers, and placed on a rotating sample stage, analyzed with a step size of 0.0167° in the range of 3°-40° or 3°-60°. Data Collector software was used to collect data, HighScore Plus software was used to process data, Data Viewer software was used to read data. It should be noted that when using domestic silicon wafers for testing, there is a diffraction peak at 32.97° in the XRPD pattern of the tested sample, which is a background peak.
[0161] The differential scanning calorimetry (DSC) analysis method used in the present invention is a differential scanning calorimeter using a TA Q2000 module with a thermal analysis controller. Data were collected and analyzed using TA Instruments Thermal Solutions software. Approximately 1-5 mg of the sample was accurately weighed into a specially crafted aluminum crucible with a lid and analyzed from room temperature to about 300° C.-350° C. using a linear heating device at 10° C./min. During use, the DSC chamber was purged with dry nitrogen.
EXAMPLES
[0162] For the specific synthesis method of the compound 2-(2-(4-(3-(5-cyano-1H-indol-3-yl)propyl)piperazin-1-yl)pyrimidin-5-yl)-4-methylthiazol-5-carboxamide of formula (I) in free form, refer to Example 8 in the international application WO 2019062662 A1.
Examples
Example 1 Phosphate Crystal Form A1 of the Present Invention
1. Preparation of Phosphate Crystal Form A1
[0163] The compound of formula (I) in free form (2.01 g) and DMF (40 mL) were added in a 250 mL round-bottom flask, and stirred to dissolve at room temperature. Then 1 mmol/mL phosphoric acid solution (4.8 mL) and acetone (50 mL) were added in turn. The mixture was stirred at room temperature for 24 h, and a large amount of solid was precipitated. The mixture was suction filtered, and the solid was dried in vacuo to obtain a light yellow solid with a yield of about 85%, which is the phosphate crystal form A1.
2. Characterization of Phosphate Crystal Form A1
[0164] Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 5.67°, 7.23°, 11.22°, 12.55°, 13.64°, 14.43°, 16.12°, 17.16°, 19.71°, 20.49°, 21.35°, 21.96°, 22.94°, 24.56°, 25.45°, 27.69°, 28.41°. There is an error tolerance of ± 0.2°.
[0165] Specifically, the XRPD pattern of the phosphate crystal form Al prepared according to the method of Example 1 of the present invention is substantially as shown in
Example 2 Phosphate Crystal Form A of the Present Invention
1. Preparation of Phosphate Crystal Form A
[0166] The compound of formula (I) in free form (2.01 g) and DMF (40 mL) were added in a 250 mL round-bottom flask, and stirred to dissolve at room temperature. Then 1 mmol/mL phosphoric acid solution (4.8 mL) and acetone (50 mL) were added in turn. The mixture was stirred at room temperature for 24 h, and a large amount of solid was precipitated. The mixture was suction filtered, and purified water (50 mL) was added to the dried solid. The resulting mixture was heated to 80° C. and stirred for 8 h, suction filtered, and dried in vacuo to obtain a pale yellow solid with a yield of about 85%, which is phosphate crystal form A.
2. Characterization of Phosphate Crystal Form A
[0167] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 9.65°, 11.14°, 12.25°, 13.50°, 15.98°, 16.28°, 16.38°, 16.86°, 17.20°, 19.36°, 20.31°, 20.79°, 20.93°, 21.68°, 22.52°, 24.73°, 25.26°, 25.98°, 26.82°, 29.82°, 30.58°, 31.43°, 32.14°, 36.35°. There is an error tolerance of ± 0.2°.
[0168] Specifically, the XRPD pattern of the phosphate crystal form A prepared according to the method of Example 2 of the present invention is substantially as shown in
[0169] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 200.43° C. There is an error tolerance of ± 3° C.
[0170] Specifically, the DSC diagram of the phosphate crystal form A prepared according to the method of Example 2 of the present invention is substantially as shown in
Example 3 Phosphate Crystal Form B of the Present Invention
1. Preparation of Phosphate Crystal Form B
[0171] The phosphate crystal form Al (500.50 mg) of the compound of formula (I) and methanol (10 mL) were sequentially added to a 25 mL round-bottom flask, and the mixture was suspended and stirred at 50° C. for 24 h. The mixture was suction filtered, and the solid was dried in vacuo at 50° C. to obtain a light yellow solid with a yield of about 80%, which is the phosphate crystal form B.
2. Characterization of Phosphate Crystal Form B
[0172] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 8.17°, 10.08°, 12.38°, 14.82°, 16.55°, 17.77°, 19.18°, 20.52°, 22.36°, 23.67°, 25.89°, 26.39°, 28.13°, 28.91°. There is an error tolerance of ± 0.2°.
[0173] Specifically, the XRPD pattern of the phosphate crystal form B prepared according to the method of Example 3 of the present invention is substantially as shown in
[0174] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises endothermic peaks of 120.04° C. and 244.33° C. There is an error tolerance of ± 3° C.
[0175] Specifically, the DSC diagram of the phosphate crystal form B prepared according to the method of Example 3 of the present invention is substantially as shown in
Example 4 Phosphate Crystal Form C of the Present Invention
1. Preparation of Phosphate Crystal Form C
[0176] The phosphate crystal form Al (500.50 mg) of the compound of formula (I) and n-propanol (10 mL) were sequentially added to a 25 mL round-bottom flask, and the mixture was suspended and stirred at 50° C. for 24 h. The mixture was suction filtered, and the solid was dried in vacuo at 50° C. to obtain a light yellow solid with a yield of about 90%, which is the phosphate crystal form C.
2. Characterization of Phosphate Crystal Form C
[0177] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 5.69°, 6.99°, 10.57°, 10.97°, 12.37°, 13.03°, 14.05°, 15.55°, 15.95°, 16.76°, 17.24°, 18.82°, 19.13°, 19.43°, 20.23°, 20.75°, 21.40°, 22.58°, 23.04°, 24.91°, 25.60°, 25.90°, 26.67°, 27.10°, 27.90°, 28.93°, 29.19°, 32.21°. There is an error tolerance of ± 0.2°.
[0178] Specifically, the XRPD pattern of the phosphate crystal form C prepared according to the method of Example 4 of the present invention is substantially as shown in
[0179] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 178.53° C. There is an error tolerance of ± 3° C.
[0180] Specifically, the DSC diagram of the phosphate crystal form C prepared according to the method of Example 4 of the present invention is substantially as shown in
Example 5 Phosphate Crystal Form G of the Present Invention
1. Preparation of Phosphate Crystal Form G
[0181] The phosphate crystal form Al (501 mg) of the compound of formula (I) and N-methylpyrrolidone (NMP, 7 mL) were added to a 50 mL round-bottom flask, and stirred to dissolve at 60° C. Then the anti-solvent toluene (30 mL) was added, and the mixture was stirred at room temperature for 24 h. The mixture was suction filtered, and the solid was dried in vacuo at 50° C. to obtain a light yellow solid with a yield of about 85%, which is the phosphate crystal form G
2. Characterization of Phosphate Crystal Form G
[0182] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 6.59°, 7.72°, 13.23°, 13.72°, 14.95°, 15.49°, 18.07°, 18.99°, 20.78°, 21.90°, 23.29°, 24.97°, 25.49°, 26.30°, 26.94°, 27.26°, 27.86°. There is an error tolerance of ± 0.2°.
[0183] Specifically, the XRPD pattern of the phosphate crystal form G prepared according to the method of Example 5 of the present invention is substantially as shown in
[0184] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises endothermic peaks of 97.41° C., 136.32° C. and 183.12° C. There is an error tolerance of ± 3° C.
[0185] Specifically, the DSC pattern of the phosphate crystal form G prepared according to the method of Example 5 of the present invention is substantially as shown in
Example 6 Phosphate Crystal Form H of the Present Invention
1. Preparation of Phosphate Crystal Form H
[0186] The phosphate crystal form Al (500.50 mg) of the compound of formula (I) and ethyl formate (10 mL) were sequentially added to a 25 mL round-bottom flask, and the mixture was suspended and stirred at 50° C. for 48 h; then the temperature was raised to 55° C. and the mixture was continuously stirred for 24 h. The mixture was suction filtered, and the solid was dried in vacuo at 50° C. to obtain a light yellow solid with a yield of about 88%, which is the phosphate crystal form H.
2. Characterization of Phosphate Crystal Form H
[0187] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 7.31°, 8.95°, 11.81°, 12.03°, 13.45°, 14.65°, 14.74°, 16.21°, 16.48°, 18.16°, 18.98°, 20.09°, 23.17°, 23.64°, 24.66°, 25.19°, 27.50°, 29.69°. There is an error tolerance of ± 0.2°.
[0188] Specifically, the XRPD pattern of the phosphate crystal form H prepared according to the method of Example 6 of the present invention is substantially as shown in
[0189] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 176.45° C. There is an error tolerance of ± 3° C.
[0190] Specifically, the DSC diagram of the phosphate crystal form H prepared according to the method of Example 6 of the present invention is substantially as shown in
Example 7 L-tartrate Crystal Form A of the Present Invention
1. Preparation of L-Tartrate Crystal Form A
[0191] The compound of formula (I) in free form (501 mg) and DMSO (5 mL) were added to a 10 mL round-bottom flask, and stirred to dissolve at room temperature. Then L-tartaric acid (200 mg) and acetone (10 mL) were added to the above solution. The mixture was stirred for 24 h. The mixture was filtered, and the solid was dried in vacuo to obtain a light yellow solid with a yield of about 88%, which is the L-tartrate crystal form A.
2. Characterization of L-Tartrate Crystal Form A
[0192] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 5.39°, 6.72°, 14.01°, 14.61°, 15.24°, 15.46°, 17.11°, 18.46°, 18.66°, 19.21°, 20.33°, 21.20°, 21.75°, 22.81°, 23.85°, 24.55°, 25.65°, 26.70°, 27.23°, 27.50°, 29.34°. There is an error tolerance of ± 0.2°.
[0193] Specifically, the XRPD pattern of the L-tartrate crystal form A prepared according to the method of Example 7 of the present invention is substantially as shown in
[0194] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 255.02° C. There is an error tolerance of ± 3° C.
[0195] Specifically, the DSC diagram of the L-tartrate crystal form A prepared according to the method of Example 7 of the present invention is substantially as shown in
Example 8 Benzenesulfonate Crystal Form A of the Present Invention
1. Preparation of Benzenesulfonate Crystal Form A
[0196] The compound of formula (I) in free form (501 mg) and DMF (10 mL) were added to a 50 mL round-bottom flask, and stirred to dissolve at room temperature. Then 75% aqueous solution of benzenesulfonic acid (192 .Math.L) and acetone (7.5 mL) were added in turn. The mixture was stirred for 24 h. The mixture was suction filtered, rinsed with acetone (2 mL), and the obtained pale yellow solid was dried in vacuo, the yield was about 89%, and it is benzenesulfonate crystal form A.
2. Characterization of Benzenesulfonate Crystal Form A
[0197] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 5.69°, 10.45°, 11.37°, 11.72°, 14.18°, 15.14°, 15.58°, 17.05°, 17.82°, 18.63°, 19.26°, 19.67°, 20.36°, 20.98°, 23.21°, 24.23°, 24.54°, 25.00°, 25.74°, 26.36°, 27.41°, 27.81°, 28.52°, 29.65°, 30.53°, 31.09°, 31.55°, 32.19°, 33.43°, 38.98°. There is an error tolerance of ± 0.2°.
[0198] Specifically, the XRPD pattern of the benzenesulfonate crystal form A prepared according to the method of Example 8 of the present invention is substantially as shown in
[0199] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 275.40° C. There is an error tolerance of ± 3° C.
[0200] Specifically, the DSC diagram of the benzenesulfonate crystal form A prepared according to the method of Example 8 of the present invention is substantially as shown in
Example 9 p-Toluenesulfonate Crystal Form A of the Present Invention
1. Preparation of Benzenesulfonate Crystal Form A
[0201] The compound of formula (I) in free form (501 mg) and DMF (10 mL) were added to a 50 mL round-bottom flask, and stirred to dissolve at room temperature. Then p-toluenesulfonic acid (240 mg) and acetone (5 mL) were added in turn. The mixture was stirred for 24 h. The mixture was suction filtered, rinsed with acetone (2 mL), and the obtained pale yellow solid was dried in vacuo, the yield was about 89%, and it is p-toluenesulfonate crystal form A.
2. Characterization of P-toluenesulfonate Crystal Form A
[0202] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 4.68°, 9.30°, 11.60°, 13.74°, 13.94°, 15.22°, 15.57°, 16.37°, 16.73°, 17.70°, 18.26°, 19.55°, 19.88°, 24.33°. There is an error tolerance of ± 0.2°.
[0203] Specifically, the DSC diagram of the p-toluenesulfonate crystal form A prepared according to the method of Example 9 of the present invention is substantially as shown in
[0204] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 251.27° C. There is an error tolerance of ± 3° C.
[0205] Specifically, the DSC diagram of the p-toluenesulfonate crystal form A prepared according to the method of Example 9 of the present invention is substantially as shown in
Example 10 Sulfate Crystal Form A of the Present Invention
1. Preparation of Sulfate Crystal Form A
[0206] The compound of formula (I) in free form (501 mg) and DMF (10 mL) were added to a 50 mL round-bottom flask, and stirred to dissolve at room temperature. Then 1 mmol/mL dilute sulfuric acid (0.6 mL) and acetone (7 mL) were added in turn. The mixture was stirred for 24 h. The mixture was suction filtered, rinsed with acetone (2 mL), and the obtained pale yellow solid was dried in vacuo to obtain sulfate crystal form A with a yield of about 90%.
2. Characterization of Sulfate Crystal Form A
[0207] (1) Analysis and identification by Empyrean X-ray powder diffraction (XRPD): Cu-Kα radiation was used and the pattern comprises the following characteristic peaks expressed as 2θ at: 11.29°, 13.77°, 14.64°, 16.15°, 18.23°, 19.82°, 20.67°, 22.14°, 23.90°, 24.96°, 25.84°, 27.65°, 29.39°, 31.80°, 39.33°. There is an error tolerance of ± 0.2°.
[0208] Specifically, the XRPD pattern of the sulfate crystal form A prepared according to the method of Example 10 of the present invention is substantially as shown in
[0209] (2) Analysis and identification by TA Q2000 Differential Scanning Calorimetry: the scanning speed was 10° C./min and the diagram comprises an endothermic peak of 269.17° C. There is an error tolerance of ± 3° C.
[0210] Specifically, the DSC diagram of the sulfate crystal form A prepared according to the method of Example 10 of the present invention is substantially as shown in
Example 11 The Pharmacokinetics Test of the Salt of the Present Invention
[0211] The test samples were filled into capsules for oral administration.
[0212] Three 8-12 kg male Beagle dogs were taken orally administered capsules containing the test sample at a dose of 5 mg/kg, and blood was collected at time points of 0.25, 0.5, 1.0, 2.0, 4.0, 6.0, 8.0 and 24 h. Standard curve was plotted based on concentrations of the samples in a suitable range, the concentration of the test sample in the plasma sample was measured and quantified by AB SCIEX API4000 LC-MS / MS at MRM mode. Pharmacokinetic parameters were calculated according to drug concentration -time curve using a noncompartmental method by WinNonLin 6.3 software. Results are as shown in Table 1.
TABLE-US-00001 Pharmacokinetic data of the salt of the present invention Test sample T.sub.max (h) C.sub.max (ng/ml) AUC.sub.last (h.sup.∗ng/ml) Example 2 1.67 496 5240
Conclusion:
[0213] It can be seen from Table 1 that the phosphate crystal form A described in Example 2 of the present invention has a large exposure in beagle dogs and has good pharmacokinetic properties.
Example 12 The Stability Test of the Salt of the Present Invention
1. Stability Test Experiment A
[0214] At room temperature, the test samples (50 mg) were added into EP tubes, water (1 mL) was added respectively. The mixture was suspended and stirred at room temperature for 24 h, then suction filtered, and dried for X-ray powder diffraction (XRPD) analysis and identification. Among them, the experimental results of phosphate crystal form A, phosphate crystal form B, phosphate crystal form C, phosphate crystal form G and phosphate crystal form H are shown in
[0215] It can be seen from
2. Stability Test Experiment B
[0216] (1) High temperature test: the test samples were taken into the flat weighing bottle, spread into a thin layer of ≤ 5 mm thick, and stored for 30 days at a humidity of 75% ± 5%, 40° C. ± 2° C. and/or 60° C. ± 2° C. On the 5th, 10th, and 30th days, samples were taken for detection according to the key stability inspection items: the color change of the sample was observed, the purity of the sample was determined by HPLC, and the crystal structure of the sample was determined by XRPD.
[0217] (2) High humidity test: the test samples were taken into the flat weighing bottle, spread into a thin layer of ≤ 5 mm thick, and stored for 30 days at 25° C., RH 90% ± 5% and/or RH 75% ± 5%. On the 5th, 10th, and 30th days, samples were taken for detection according to the key stability inspection items: the color change of the sample was observed, the purity of the sample was determined by HPLC, and the crystal structure of the sample was determined by XRPD.
[0218] (3) Light test: the test samples were taken into the flat weighing bottle, spread into a thin layer of ≤ 5 mm thick, and placed in a light box (with an ultraviolet lamp) with an open mouth. The test samples were stored under the condition of illuminance of 4500 ± 5001x and ultraviolet light ≥ 0.7w/m.sup.2 for 30 days. Samples were taken on the 5th, 10th and 30th days. The color change of the sample was observed, the purity of the sample was determined by HPLC, and the crystal structure of the sample was determined by XRPD.
[0219] The experimental results are shown in Table 2 and
TABLE-US-00002 The stability test results 1 of the salt of the present invention No. Condition High temperature (60° C., RH 75%±5%) High humidity (25° C., RH 90% ± 5%) Light Project 0 day 5 days 10 days 30 days 5 days 10 days 30 days 5 days 10 days 30 days Example 2 Outward Light yellow solid Light yellow solid Light yellow solid Light yellow solid Light yellow solid Light yellow solid Light yellow solid Yellow solid Yellow solid Yellow solid Purity (%) 99.24 99.26 99.23 99.24 99.27 99.21 99.22 99.25 99.21 99.10
[0220] Experimental conclusion: It can be seen from the experimental results that under high temperature (60° C., RH 75% ± 5%), high humidity (25° C., RH 90% ± 5%) or light conditions, the appearance and purity of the phosphate crystal form A of the present invention have no obvious changes; at the same time, the XRPD pattern of the phosphate crystal form A is also basically unchanged. That is, the phosphate crystal form A of the present invention has good stability under various setting conditions, and is suitable for pharmaceutical use.
3. Stability Test Experiment C
[0221] 1.0 g of the test samples were packaged in a single-layer PE bag and aluminum foil, and fasten with cable ties. 6 packs were prepared in total and put in a stable box (40° C. ± 2° C., RH 75% ± 5%, or 25° C. ± 2° C., RH 60% ± 10%). Test samples were taken at 0, 3, and 6 months for HPLC and XRPD detection, respectively. The experimental results are shown in Table 3 and
TABLE-US-00003 The stability test results 2 of the salt of the present invention No. Condition 40° C. ± 2° C., RH 75% ±5% 25° C. ± 2° C., RH 60% ±10% Project 0 month 3 months 6 months 3 months 6 months Example 2 Outward Light yellow solid Light yellow solid Light yellow solid Light yellow solid Light yellow solid Purity (%) 99.62 99.63 99.64 99.63 99.64
[0222] Experimental conclusion: It can be seen from the experimental results that the phosphate crystal form A of the present invention is stored for a long time under simple and conventional packaging conditions, and the purity and crystal structure have not changed, indicating the properties of the phosphate crystal form A of the present invention is stable, does not require high packaging, and is suitable for medical purposes.
Example 13 The Hygroscopicity Test of the Salt of the Present Invention
Test Method
[0223] 1) A dry stoppered glass weighing bottle was placed in a suitable constant temperature desiccator (RH 80% ± 2%) at 25° C. + 1° C. the day before, and accurately weighed (m1).
[0224] 2) An appropriate amount of the test sample was taken and spread in the above weighing bottle. The thickness of the test sample was generally about 1 mm, and it was precisely weighed (m2).
[0225] 3) The weighing bottle was opened and placed together with the bottle cap under the above constant temperature and humidity conditions for 24 hours.
[0226] 4) The weighing bottle was closed with the bottle cap, and accurately weighed (m3). Calculate: weight gain % = (m3-m2) / (m2-m1) × 100%.
[0227] 5) Judgment of hygroscopicity results (Chinese Pharmacopoeia 2015 Edition Appendix 9103 Guidelines for the hygroscopicity test of drugs, experimental conditions: 25° C.±1° C., 80%±2% relative humidity):
TABLE-US-00004 The hygroscopicity feature The hygroscopicity gain 1 Deliquescence Absorb enough water to form a liquid 2 Highly hygroscopicity Not less than 15% 3 Hygroscopicity Less than 15% but not less than 2% 4 Slightly hygroscopicity Less than 2% but not less than 0.2% 5 No or almost none hygroscopicity Less than 0.2%
[0228] Results are as shown in Table 4.
TABLE-US-00005 The hygroscopicity test results of the salts of the present invention No. The hygroscopicity gain(%) Conclusion Example 2 0.32 Slightly hygroscopicity
[0229] It can be seen from the experimental results that the phosphate crystal form A of the present invention is not easily affected by high humidity to deliquescence.
[0230] The foregoing description is merely a basic illustration of the present invention and any equivalent transformation made in accordance with the technical solution of the present invention is intended to be within the scope of the present invention.
[0231] Reference throughout this specification to “an embodiment”, “some embodiments”, “one embodiment”, “another example”, “an example”, “a specific example”, or “some examples” means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present disclosure. Thus, the appearances of the above terms throughout this specification are not necessarily referring to the same embodiment or example of the present disclosure. Furthermore, the particular features, structures, materials, or characteristics may be combined in any suitable manner in one or more embodiments or examples. In addition, those skilled in the art can integrate and combine different embodiments, examples or the features of them as long as they are not contradictory to one another.
[0232] Although explanatory embodiments have been shown and described, it would be appreciated by those skilled in the art that the above embodiments cannot be construed to limit the present disclosure, and changes, alternatives, and modifications can be made in the embodiments without departing from spirit, principles and scope of the present disclosure.