SALT AND CRYSTAL FORM OF HA INHIBITOR COMPOUND
20240043416 ยท 2024-02-08
Assignee
Inventors
- Yao Li (Chengdu, CN)
- Guobiao ZHANG (Chengdu, CN)
- Xiaobo ZHANG (Chengdu, CN)
- Pingming Tang (Chengdu, CN)
- Chen Zhang (Chengdu, CN)
- Pangke Yan (Chengdu, CN)
Cpc classification
A61K31/4545
HUMAN NECESSITIES
C07C309/29
CHEMISTRY; METALLURGY
C07C309/30
CHEMISTRY; METALLURGY
International classification
Abstract
Disclosed are a pharmaceutically acceptable salt of an HA inhibitor (1S,2S)-2-fluoro-N-(2-(2-(4-((R)-(5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidine-1-formyl)pyridine-4-yl)benzo[d]oxazol-5-yl)cyclopropyl-1-carboxamide, or a hydrate or solvate of a salt thereof, a preparation method therefor, and a use thereof.
Claims
1. A compound A or a hydrate or solvate of a salt thereof, ##STR00007## wherein the salt is hydrochloride, hydrobromide, 2-naphthalenesulfonate, benzenesulfonate, methanesulfonate, p-toluenesulfonate, hemi-1,5-naphthalene disulfonate, succinate, citrate or malate.
2. The salt or the hydrate or solvate of the salt thereof according to claim 1, wherein the salt is hydrochloride, hydrobromide, 2-naphthalenesulfonate or hemi-1,5-naphthalene disulfonate.
3. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is hemi-1,5-naphthalene disulfonate of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 5.30.2, 13.40.2, 17.40.2, 18.50.2, 20.40.2 and 23.60.2 2, as determined by using Cu-K radiation.
4. The salt or the hydrate or solvate of the salt thereof according to claim 3, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 7.00.2, 9.80.2, 10.60.2, 12.70.2, 14.80.2, 22.20.2 and 23.10.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 14.10.2, 16.00.2 and 21.50.2 2.
5. (canceled)
6. (canceled)
7. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is hydrochloride of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 5.90.2, 11.20.2, 11.70.2, 17.60.2, 18.20.2, 21.90.2 and 26.80.2 2, as determined by using Cu-K radiation.
8. The salt or the hydrate or solvate of the salt thereof according to claim 7, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 7.10.2, 16.30.2, 18.60.2, 22.30.2 and 23.80.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 13.30.2, 14.20.2, 15.70.2, 20.30.2, 21.30.2, 24.80.2, 25.40.2, 27.20.2 and 27.70.2 2.
9. (canceled)
10. (canceled)
11. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is hydrobromide of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 6.00.2, 7.20.2, 9.00.2, 12.00.2, 14.80.2 and 17.60.2 2, as determined by using Cu-K radiation.
12. The salt or the hydrate or solvate of the salt thereof according to claim 11, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 17.30.2, 18.00.2, 21.20.2, 21.50.2, 24.20.2 and 26.50.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 16.90.2, 18.60.2, 19.00.2, 20.20.2 and 28.00.2 2.
13. (canceled)
14. (canceled)
15. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is hydrobromide of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 6.50.2, 7.30.2, 12.20.2, 12.90.2 and 16.00.2 2, as determined by using Cu-K radiation.
16. The salt or the hydrate or solvate of the salt thereof according to claim 15, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 6.10.2, 17.40.2, 18.30.2, 20.40.2, 22.40.2, 24.80.2 and 28.20.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 13.80.2, 14.50.2, 15.20.2, 19.10.2, 19.90.2, 21.40.2, 21.80.2, 23.10.2, 23.60.2, 25.50.2, 26.00.2 and 26.50.2 2.
17. (canceled)
18. (canceled)
19. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is 2-naphthalenesulfonate of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 4.70.2, 9.40.2, 17.20.2, 21.20.2 and 23.40.2 2, as determined by using Cu-K radiation.
20. The salt or the hydrate or solvate of the salt thereof according to claim 19, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 6.30.2, 6.80.2, 7.80.2, 13.40.2, 16.50.2, 19.20.2 and 20.10.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 14.90.2, 15.30.2, 15.70.2, 24.30.2, 25.10.2 and 26.10.2 2.
21. (canceled)
22. (canceled)
23. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is 2-naphthalenesulfonate of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern comprising characteristic diffraction peaks at 5.60.2, 11.20.2, 14.10.2, 16.00.2, 22.80.2 and 26.80.2 2, as determined by using Cu-K radiation.
24. The salt or the hydrate or solvate of the salt thereof according to claim 23, having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 4.50.2, 6.20.2, 6.80.2, 8.40.2, 10.40.2, 15.30.2, 15.60.2, 19.00.2, 19.60.2 and 25.50.2 2, and/or having an X-ray powder diffraction pattern further comprising characteristic diffraction peaks at 12.40.2, 12.70.2, 16.70.2, 17.20.2, 17.50.2, 18.00.2, 20.80.2, 21.80.2, 23.50.2 and 24.30.2 2.
25. (canceled)
26. The salt or the hydrate or solvate of the salt thereof according to claim 2, wherein the salt is hemi-1,5-naphthalene disulfonate of compound A, which is in the form of a crystal and has an X-ray powder diffraction pattern substantially as shown in
27. A method for preparing the hemi-1,5-naphthalene disulfonate of compound A according to claim 3, comprising the steps of (1) dissolving amorphous compound A in solvent 1; (2) dissolving 1,5-naphthalene disulfonic acid in solvent 2; (3) adding dropwise a solution obtained in step (2) to a solution obtained in step (1) at room temperature with stirring; and stirring a reaction; wherein the solvent 1 is selected from one of isopropanol, acetone or tetrahydrofuran, and the solvent 2 is a single-solvent system or a double-solvent mixed system, wherein the single-solvent system is selected from one of isopropanol, acetone or tetrahydrofuran, and the double-solvent mixed system is a tetrahydrofuran-water mixed liquid.
28. A method for preparing the 2-naphthalenesulfonate of compound A, comprising the steps of (1) dissolving amorphous compound A in solvent 3; (2) dissolving 2-naphthalenesulfonic acid in solvent 4; (3) adding dropwise a solution obtained in step (2) to a solution obtained in step (1) at room temperature with stirring; and carrying out stirring, crystallization, centrifugation and drying; wherein the solvent 3 is selected from one of isopropanol, acetone, tetrahydrofuran, isopropyl acetate, 1,4-dioxane, toluene or dimethyl sulfoxide, and the solvent 4 is a single-solvent system or a double-solvent mixed system, wherein the single-solvent system is selected from one of isopropanol, acetone, tetrahydrofuran, isopropyl acetate, 1,4-dioxane, toluene or dimethyl sulfoxide, and the double-solvent mixed system is a toluene-methanol mixed liquid.
29. A method for preparing the hydrochloride of compound A according to claim 7, comprising the steps of (1) dissolving amorphous compound A in solvent 5; (2) dissolving hydrochloric acid in solvent 6; (3) adding dropwise a solution obtained in step (2) to a solution obtained in step (1) at room temperature with stirring; and stirring a reaction; wherein the solvent 5 and solvent 6 are each independently selected from one of isopropanol, acetone and tetrahydrofuran.
30. A method for preparing the hydrobromide of compound A, comprising the steps of (1) dissolving amorphous compound A in solvent 7; (2) dissolving hydrobromic acid in solvent 8; (3) adding dropwise a solution obtained in step (2) to a solution obtained in step (1) at room temperature with stirring; and stirring a reaction; wherein the solvent 7 and solvent 8 are each independently selected from one of isopropanol, acetone and tetrahydrofuran.
31. A pharmaceutical composition comprising a therapeutically effective amount of the salt or the hydrate or solvate of the salt thereof according to claim 1, and a pharmaceutically acceptable carrier or excipient.
32. (canceled)
33. A method for preventing and/or treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of the salt or the hydrate or solvate of the salt thereof according to claim 1.
34. (canceled)
35. (canceled)
Description
BRIEF DESCRIPTION OF THE DRAWINGS
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DETAILED DESCRIPTION OF EMBODIMENTS
[0177] The implementation process and beneficial effects of the present application are described in detail below through specific examples, which are intended to help readers better understand the essence and characteristics of the present application and are not intended to limit the scope of implementation of the present application.
[0178] The structure of the compound is determined by nuclear magnetic resonance (NMR) and/or mass spectrometry (MS).
[0179] NMR is determined with Bruker ADVANCE III 400; the solvent for determination is deuterated dimethyl sulfoxide (DMSO-d.sub.6), deuterated chloroform (CDCl.sub.3) and deuterated methanol (CD.sub.3OD); and the internal standard is tetramethylsilane (TMS).
[0180] MS is determined with Agilent 6120B (ESI).
[0181] HPLC is determined with Agilent 1260DAD high pressure liquid chromatograph (ZorbaSB-C18 1004.6 mm).
[0182] For the column chromatography, Yantai Huanghai silica gel of 200-300 mesh silica gel is generally used as a carrier.
[0183] Instrument:
TABLE-US-00007 X-ray powder diffractometer (XRPD) and hot-stage XRPD Instrument Model Bruker D8 Advance Diffractometer No. LY-01-034 Technical K radiation (40 KV, 40 mA) with a indicator copper target wavelength of 1.54 , a -2 goniometer, nickel filtration and a Lynxeye detector Acquisition Diffrac Plus XRD Commander software Calibration Corundum (Al.sub.2O.sub.3) material Analysis MDI Jade software Accessory Non-reflective Specification 24.6 mm diameter sample plate 1.0 mm thickness Manufacturer MTI corporation Differential scanning calorimeter (DSC) Instrument Model METTLER TOLEDO DSC 3 No. LY-01-167 Control software STARe software Analysis STARe software software Sample tray Aluminium crucible (with a cover and with perforation) Parameter Sample size 0.5 mg-5 mg Protective gas Nitrogen gas Gas flow rate 50 mL/min Detection Segment 1 method Start temp 25 C. End temp 350 Heating rate 10.0 k/min Thermal gravimetric analyser (TGA) Instrument Model METTLER TOLEDO TGA/DSC 3.sup.+ No. LY-01-166 Control software STARe software Analysis STARe software software Sample tray 70 L ceramic crucible Parameter Sample size 1 mg-10 mg Protective gas Nitrogen gas Gas flow rate 50 mL/min Detection Segment 1 (MaxRes) method Start temp 25.0 C. End temp 120.0 C. Heating rate 10.0 k/min Segment 2 Start temp 120.0 C. End temp 350.0 C. Heating rate 10.0 k/min
[0184] Unless otherwise specified in the examples, a solution refers to an aqueous solution.
[0185] Unless otherwise specified in the examples, a reaction is performed at room temperature, [0186] and room temperature refers to 10 C.-30 C.
DESCRIPTION OF ABBREVIATIONS
[0187] DDQ: 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; [0188] Pd(dppf)Cl.sub.2: 1,1-bis(diphenylphosphino)ferrocene dichloropalladium (II); [0189] EA: ethyl acetate; [0190] PE: petroleum ether; [0191] THF: tetrahydrofuran; [0192] DEAD: diethyl azodicarboxylate; [0193] DMF: N, N-dimethylformamide; [0194] HATU: 2-(7-azobenzotriazole)-N,N,N,N-tetramethyluronium hexafluorophosphate; [0195] DIEA: N,N-diisopropylethylamine; [0196] SBE--CD: sulfobutyl ether -cyclodextrin; [0197] DMA: dimethylacetamide; [0198] MC: methylcellulose; [0199] DMSO: dimethyl sulfoxide.
Intermediate 1: methyl 4-(5-((tert-butoxycarbonyl)amino)benzo[d]oxazol-2-yl)picolinate (Intermediate 1)
[0200] ##STR00004##
Step 1: Preparation of tert-butyl-(4-hydroxy-3-nitrophenyl)carbamate (1b)
[0201] Tetrahydrofuran (50 mL) and di-tert-butyl dicarbonate (10.6 g, 48.7 mmol) were successively added to known compound 1a (5.0 g, 32.5 mmol). After the addition, the mixture was warmed to 70 C., reacted for 16 h and concentrated under reduced pressure to remove tetrahydrofuran. The resulting mixture was slurried with petroleum ether (100 mL) for 1 h and then filtered. The filter cake was collected and dried to obtain compound 1b (6.1 g, 74%).
[0202] .sup.1H NMR (400 MHz, CD.sub.3OD) 8.25 (d, 1H), 7.56 (d, 1H), 7.06 (d, 1H) ,1.52 (s, 9H).
[0203] LC-MS (ESI): m/z=255.1[M+H].sup.+.
Step 2: Preparation of tert-butyl-(3-amino-4-hydroxyphenyl)carbamate (1c)
[0204] At room temperature, compound 1b (6.1 g, 24.0 mmol) was dissolved in anhydrous methanol (60 mL). Pd/C (2.1 g, with Pd content of 10% and water content of 50%) was added. Hydrogen was introduced. The mixture was warmed to 45 C. and reacted for 5 h. After filtration, the filtrate was concentrated to obtain compound 1c (4.3 g, 80%).
[0205] LC-MS (ESI): m/z=225.1[M+H].sup.+.
Step 3: Preparation of tert-butyl (2-(2-bromopyridin-4-yl)-2,3-dihydrobenzo[d]oxazol-5-yl)carbamate (1d)
[0206] Compound 1c (4.3 g, 19.2 mmol) was dissolved in methanol (50 mL). 2-bromopyridine-4-carboxaldehyde (3.6 g, 19.2 mmol) was added. The mixture was warmed to 70 C. and stirred for 15 h. The reaction solution was cooled to room temperature and concentrated under reduced pressure to remove methanol. Then dichloromethane (200 mL) and DDQ (5.3 g, 23.0 mmol) were successively added to the residue. After the addition, the mixture was stirred for 2 h at room temperature, and a saturated aqueous sodium carbonate solution (100 mL) was added. The resulting solution was stirred for 10 min and filtered. The filtrate was extracted with dichloromethane (200 mL2). The combined organic phase was washed with water (100 mL), dried over anhydrous sodium sulphate and filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography (eluent: EA/PE=10%-50%) to obtain compound 1d (4.1 g, 54%).
[0207] LC-MS (ESI): m/z=392.1[M+H].sup.+.
Step 4: Preparation of methyl 4-(5-((tert-butoxycarbonyl)amino)benzo[d]oxazol-2-yl)picolinate (Intermediate 1)
[0208] Methanol (25 mL), dichloromethane (25 mL), Pd(dppf)Cl.sub.2 (804.0 mg, 1.1 mmol) and triethylamine (4.24 g, 42.0 mmol) were successively added to compound 1d (4.1 g, 10.5 mmol). Carbon monoxide was introduced; and then the reaction solution was warmed to 120 C., stirred for 14 h, cooled to room temperature and then filtered. The filtrate was concentrated under reduced pressure, and then the residue was separated and purified by column chromatography (eluent: EA/PE=10%-50%) to obtain intermediate 1 (3.5 g, 90%).
[0209] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.95 (d, 1H), 8.89 (d, 1H), 8.26 (d, 1H), 7.86 (s, 1H), 7.54-7.47 (m, 2H) , 6.67 (s, 1H), 4.08 (s, 3H), 1.55 (s, 9H).
[0210] LC-MS (ESI): m/z=370.1[M+H].sup.+.
Intermediate 2: (R)-4-4-((5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Intermediate 2)
[0211] ##STR00005##
Step 1: Preparation of tert-butyl 4-4-((5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidine-1-carboxylate (2b)
[0212] At room temperature, compound 2a (580 mg, 2.0 mmol), 5-methyltetrazole (185 mg, 2.2 mmol) and triphenylphosphine (787 mg, 3.0 mmol) were dissolved in anhydrous THF (20 mL). The mixture was cooled to 0 C. under nitrogen protection, and then DEAD (520 mg, 3.0 mmol) was added dropwise. The mixture was allowed to naturally warm to room temperature, reacted overnight, concentrated under reduced pressure and subjected to column chromatography to obtain compound 2b (440 mg, 61.0%).
[0213] LC-MS (ESI): m/z=358.3[M+H].sup.+.
Step 2: Preparation of (R)-tert-butyl 4-((5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidine-1-carboxylate (2c)
[0214] Compound 2b was resolved by chiral HPLC to obtain compound 2c (tR=1.78 min, 200 mg, 45.5%).
[0215] Resolution conditions were as follows:
[0216] instrument: MG II preparative SFC (SFC-1); column type: ChiralCel OJ, 25030 mm I.D., 5 m; mobile phase: A: CO.sub.2, B: ethanol; gradient: B 15%; flow rate: 60 mL/min; back pressure: 100 bar; column temperature: 38 C.; column length: 220 nm; time cycle: about 5 min; sample preparation: 0.44 g of compound 2b was dissolved in a mixed solvent (4 mL) of dichloromethane and methanol; sample injection: 2 mL/injection.
Step 3: Preparation of (R)-4-((5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidin-1-ium 2,2,2-trifluoroacetate (Intermediate 2)
[0217] At room temperature, compound 2c (200 mg, 0.55 mmol) was dissolved in dichloromethane (10 mL). Trifluoroacetic acid (2.5 mL) was added dropwise, and the mixture was stirred for another 2 h. The reaction solution was subjected to rotary evaporation to obtain a crude of intermediate 2 (300 mg), which was directly used in the next reaction without purification.
[0218] LC-MS (ESI): m/z=258.2[M+H].sup.+.
Compound A: (1S,2S)-2-fluoro-N-(2-(2-(4-((R)-(5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidine-1-carbonyl)pyridin-4-yl)benzo[d]oxazol-5-yl)cyclopropane-1-carboxamide
[0219] ##STR00006##
Step 1: Preparation of methyl-4-(5-aminobenzo[d]oxazol-2-yl)picolinate (3a)
[0220] Intermediate 1 (600.0 mg, 1.62 mmol) was dissolved in dichloromethane (5 mL), and trifluoroacetic acid (2 mL) was added. After the addition, the mixture was stirred for 2 h at room temperature, adjusted to pH=8-9 with a saturated aqueous sodium carbonate solution and extracted with dichloromethane (50 mL2). The organic phases were combined, dried and filtered. The filtrate was concentrated to obtain compound 3a (396.0 mg, 90%).
[0221] LC-MS (ESI): m/z=270.1[M+H].sup.+.
Step 2: Preparation of methyl-4-(5-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]oxazol-2-yl)picolinate (3b)
[0222] DMF (50 mL), (1S,2S)-2-fluorocyclopropanecarboxylic acid (425 mg, 4.1 mmol), HATU (2.1 g, 5.58 mmol) and DIEA (1.44 g, 11.16 mmol) were successively added to compound 3a (1.0 g, 3.71 mmol), and the mixture was stirred at room temperature for 5 h. The reaction was quenched by adding water, extracted 3 times with ethyl acetate and washed twice with saturated brine. The organic phase was dried and concentrated, and the residue was separated and purified by silica gel column chromatography (eluent: EA/PE=1/2) to obtain compound 3b (1.1 g, 83.4%).
[0223] LC-MS (ESI): m/z=356.3 [M+H].sup.+.
Step 3: Preparation of 4-(5-((1S,2S)-2-fluorocyclopropane-1-carboxamido)benzo[d]oxazol-2-yl)picolinic acid (3c)
[0224] At room temperature, compound 3b (1 g, 3.1 mmol) was dissolved in methanol (15 mL), and lithium hydroxide (700 mg) was dissolved in 20 mL of pure water. An aqueous solution of lithium hydroxide was added to the reaction solution. The mixture was stirred at 40 C. for 0.5 h and then adjusted to pH=6-7 with 2N hydrochloric acid. A large amount of solid was precipitated out, filtered by suction and washed with water (10 mL3). The filter cake was dried at 50 C. to obtain compound 3c (1.0 g, 94.6%).
[0225] LC-MS (ESI): m/z=342.1 [M+H].sup.+.
Step 4: Preparation of (1S,2S)-2-fluoro-N-(2-(2-(4-((R)-(5-methyl-2H-tetrazol-2-yl)(phenyl)methyl)piperidine-1-carbonyl)pyridin-4-yl)benzo[d]oxazol-5-yl)cyclopropane-1-carb oxamide (Compound A)
[0226] At room temperature, compound 3c (170 mg, 0.5 mmol) and DIPEA (130 mg, 1.0 mmol) were dissolved in DMF (5 mL), and then HATU (230 mg, 0.6 mmol) was added. The mixture was stirred for 3 min, and then intermediate 2 (300 mg, approximately 0.55 mmol) was added. The mixture was reacted for another 30 min at room temperature. 30 mL of water was added, and the reaction solution was extracted with ethyl acetate (30 mL3). The organic phases were combined, washed with saturated sodium chloride (30 mL1), dried over anhydrous sodium sulphate and concentrated under reduced pressure, and then the residue was subjected to column chromatography (DCM:MeOH=30:1-15:1) to obtain compound A (130 mg, 44.8%), which was an amorphous form as identified by XPRD.
[0227] LC-MS (ESI): m/z=581.3 [M+H].sup.+.
[0228] .sup.1H NMR (400 MHz, CDCl.sub.3) 8.74-8.71(m, 1H), 8.31(s, 1H), 8.12-8.10(m, 1H), 8.01(s, 1H), 7.90-7.87(m, 1H), 7.56-7.51(m,4H), 7.41-7.31(m, 3H), 5.55-5.52(m, 1H), 4.93-4.75(m, 2H), 3.91-3.88(m, 1H), 3.20-3.11(m, 1H), 2.91-2.80 (m, 2H), 2.56-2.50 (m, 3H), 1.94-1.84 (m, 2H), 1.61-1.23 (m, 5H).
EXAMPLE 1 PREPARATION OF HEMI-1,5-NAPHTHALENE DISULFONATE OF COMPOUND A
[0229] At room temperature, 200 mg of the amorphous compound A was dissolved in 16.60 mL of isopropanol to obtain solution 1a; 150.94 mg of 1,5-naphthalene disulfonic acid was dissolved in 1.80 mL of isopropanol to obtain solution 1b; at room temperature with stirring, solution 1b was added dropwise to solution 1a to obtain solution 1c; solution 1c was continuously stirred, and a solid was precipitated immediately to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the hemi-1,5-naphthalene disulfonate of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form I of hemi-1,5-naphthalene disulfonate of compound A.
[0230] .sup.1H NMR (400 MHz, DMSO-d6) 10.48 (s, 1H), 8.92-8.85 (m, 1H), 8.84-8.77 (m, 1H), 8.25 (d, 1H), 8.18-8.11 (m, 2H), 7.95 (dd, 1H), 7.80 (d, 1H), 7.69-7.53 (m, 3H), 7.48-7.30 (m, 4H), 5.93 (dd, 1H), 5.07-4.82 m, 1H), 4.50 (d, 1H), 3.75-3.68 (m, 1H), 3.08 (t, 1H), 2.86 (d, 2H), 2.46 (d, 3H), 2.10-2.00 (m, 1H), 1.75-1.60 (m, 1H), 1.46-1.13 (m, 5H).
[0231] The crystal form I of hemi-1,5-naphthalene disulfonate of compound A obtained in example 1 is a crystalline form as identified by XRPD. Table 1 shows the XRPD peak list;
EXAMPLE 2: PREPARATION OF HYDROCHLORIDE OF COMPOUND A
[0232] At room temperature, 100 mg of the amorphous compound A was ultrasonically dissolved in 2.40 mL of acetone to obtain a clear solution, i.e., solution 2a; 20.17 mg of hydrochloric acid was dissolved in 2.66 mL of acetone to obtain solution 2b; at room temperature with stirring, solution 2b was added dropwise to solution 2a to obtain solution 2c; solution 2c was continuously stirred overnight, and then a solid was precipitated to obtain a suspension; the suspension was centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the hydrochloride of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form I of hydrochloride of compound A.
[0233] .sup.1H NMR (400 MHz, DMSO-d6) 10.54 (s, 1H), 8.80 (t, 1H), 8.25 (d, 1H), 8.19-8.10 (m, 2H), 7.80 (d, 1H), 7.67-7.53 (m, 3H), 7.47-7.28 (m, 3H), 5.93 (dd, 1H), 5.10-4.85 (m, 1H), 4.50 (d, 1H), 3.72 (d, 1H), 3.08 (t, 1H), 2.89-2.79 (m, 2H), 2.45 (d, 3H), 2.07-1.93 (m, 1H), 1.75-1.60 (m, 1H), 1.44-1.10 (m, 5H).
[0234] The crystal form I of hydrochloride of compound A obtained in example 2 is a crystalline form as identified by XRPD. Table 2 shows the XRPD peak list;
EXAMPLE 3: PREPARATION OF HYDROBROMIDE OF COMPOUND A
Method I
[0235] At room temperature, 100 mg of the amorphous compound A was ultrasonically dissolved in 2.40 mL of acetone to obtain a clear solution, i.e., solution 3a; 40.50 mg of hydrobromic acid was dissolved in 2.33 mL of acetone to obtain solution 3b; at room temperature with stirring, solution 3b was added dropwise to solution 3a to obtain solution 3c; solution 3c was continuously stirred for 1 h, and then a solid was precipitated to obtain a suspension; the suspension was stirred and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the hydrobromide of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form I of hydrobromide of compound A.
Method II
[0236] At room temperature, 30 mg of the amorphous compound A was ultrasonically dissolved in 0.2 mL of acetone to obtain a clear solution, i.e., solution 3a-1; 12.32 mg of hydrobromic acid was dissolved in 0.7 mL of acetone to obtain solution 3b-1; at room temperature with stirring, solution 3b-1 was added dropwise to solution 3a-1 to obtain solution 3c-1; solution 3c-1 was continuously stirred for a few minutes, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the hydrobromide of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form II of hydrobromide of compound A.
[0237] .sup.1H NMR (400 MHz, DMSO-d6) 10.50 (s, 1H), 8.81 (t, 1H), 8.25 (d, 1H), 8.19-8.10 (m, 2H), 7.80 (d, 1H), 7.69-7.51 (m, 3H), 7.46-7.27 (m, 3H), 5.93 (dd, 1H), 5.10-4.86 (m, 1H), 4.50 (d, 1H), 3.72 (d, 1H), 3.08 (t, 1H), 2.86 (d, 2H), 2.45 (d, 3H), 2.08-1.98 (m, 1H), 1.75-1.61 (m, 1H), 1.45-1.10 (m, 5H).
[0238] The crystal form I of hydrobromide of compound A obtained in example 3 is a crystalline form as identified by XRPD. Table 3 shows the XRPD peak list;
[0239] The crystal form II of hydrobromide of compound A obtained in example 3 is a crystalline form as identified by XRPD. Table 4 shows the XRPD peak list; and
EXAMPLE 4: PREPARATION OF 2-NAPHTHALENESULFONATE OF COMPOUND A
Method I
[0240] At room temperature, approximately 100 mg of the amorphous compound A was dissolved in 0.67 mL of tetrahydrofuran to obtain solution 4a; 40.27 mg of 2-naphthalenesulfonic acid was dissolved in 2.16 mL of tetrahydrofuran to obtain solution 4b; at room temperature with stirring, solution 4b was added dropwise to solution 4a to obtain solution 4c; solution 4c was continuously stirred for a few minutes, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the 2-naphthalenesulfonate of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form I of 2-naphthalenesulfonate of compound A.
Method II
[0241] At room temperature, 30 mg of the amorphous compound A was ultrasonically dissolved in 0.20 mL of 1,4-dioxane to obtain a clear solution, i.e., solution 4d; 12.0 mg of 2-naphthalenesulfonic acid was ultrasonically dissolved in 1.00 mL of 1,4-dioxane to obtain a clear solution, i.e., solution 4e; at room temperature with stirring, solution 4e was added dropwise to solution 4d to obtain solution 4f; solution 4f was continuously stirred, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the 2-naphthalenesulfonate of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form I of 2-naphthalenesulfonate of compound A.
Method III
[0242] At room temperature, 30 mg of the amorphous compound A was ultrasonically dissolved in 0.20 mL of tetrahydrofuran to obtain a clear solution, i.e., solution 4a-1; 12.10 mg of 2-naphthalenesulfonic acid was dissolved in 0.65 mL of tetrahydrofuran to obtain solution 4b-1; at room temperature with stirring, solution 4b-1 was added dropwise to solution 4a-1 to obtain solution 4c-1; solution 4c-1 was continuously stirred for 2 h, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the 2-naphthalenesulfonate of compound A. The compound was identified as a crystalline form by XRPD and named as crystal form II of 2-naphthalenesulfonate of compound A.
[0243] .sup.1H NMR (400 MHz, DMSO-d6) 10.48 (s, 1H), 8.84-8.77 (m, 1H), 8.24 (d, 1H), 8.19-8.10 (m, 3H), 7.96 (t, 1H), 7.93-7.84 (m, 2H), 7.80 (d, 1H), 7.72 (dd, 1H), 7.66-7.49 (m, 5H), 7.47-7.28 (m, 3H), 5.93 (d, 1H), 5.05-4.85 (m, 1H), 4.50 (d, 1H), 3.72 (d, 1H), 3.08 (t, 1H), 2.86 (d, 2H), 2.45 (d, 3H), 2.12-1.94 (m, 1H), 1.76-1.60 (m, 1H), 1.45-1.00 (m, 5H).
[0244] The crystal form I of 2-naphthalenesulfonate of compound A obtained in example 4 is a crystalline form as identified by XRPD. Table 5 shows the XRPD peak list;
[0245] The crystal form I of 2-naphthalenesulfonate of compound A obtained in example 4 is a crystalline form as identified by XRPD. Table 6 shows the XRPD peak list; and
EXAMPLE 5: PREPARATION OF BENZENESULFONATE OF COMPOUND A
[0246] At room temperature, 90 mg of the amorphous compound A was dissolved in 7.50 mL of isopropanol to obtain solution 5a; 30.0 mg of benzenesulfonic acid was dissolved in 0.48 mL of isopropanol to obtain solution 5b; at room temperature with stirring, solution 5b was added dropwise to solution 5a to obtain solution 5c; solution was continuously stirred for 1 h, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the benzenesulfonate of compound A.
[0247] .sup.1H NMR (500 MHz, DMSO-d6) 10.50 (s, 1H), 8.80 (t, 1H), 8.25 (d, 1H), 8.19-8.11 (m, 2H), 7.80 (d, 1H), 7.67-7.53 (m, 5H), 7.46-7.25 (m, 6H), 5.93 (dd, 1H), 5.02-4.74 (m, 1H), 4.49 (s, 1H), 3.71 (d, 1H), 3.07 (t, 1H), 2.84 (d, 2H), 2.46 (d, 3H), 2.09-1.98 (m, 1H), 1.76-1.61 (m, 1H), 1.45-1.11 (m, 5H).
EXAMPLE 6: PREPARATION OF METHANESULFONATE OF COMPOUND A
[0248] At room temperature, 90 mg of the amorphous compound A was dissolved in 0.60 mL of acetone to obtain solution 6a; 18.0 mg of methanesulfonic acid was dissolved in 1.80 mL of acetone to obtain solution 6b; at room temperature with stirring, solution 6b was added dropwise to solution 6a to obtain solution 6c; solution 6c was continuously stirred for a few minutes, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the methanesulfonate of compound A.
[0249] .sup.1H NMR (500 MHz, DMSO-d6) 10.50 (s, 1H), 8.80 (t, 1H), 8.25 (d, 1H), 8.18-8.11 (m, 2H), 7.80 (d, 1H), 7.66-7.53 (m, 3H), 7.46-7.29 (m, 3H), 5.93 (dd, 1H), 5.05-4.85 (m, 1H), 4.49 (s, 1H), 3.71 (d, 1H), 3.07 (t , 1H), 2.84 (d, 2H), 2.45 (d, 3H), 2.38 (s, 3H), 2.11-2.00 (m, 1H), 1.72-1.62 (m, 1H), 1.44-1.11 (m, 5H).
EXAMPLE 7: PREPARATION OF P-TOLUENESULFONATE OF COMPOUND A
[0250] At room temperature, approximately 90 mg of the amorphous compound A was dissolved in 0.60 mL of acetone to obtain solution 7a; 29.58 mg of p-toluenesulfonic acid was dissolved in 2.04 mL of acetone to obtain solution 7b; at room temperature with stirring, solution 7b was added dropwise to solution 7a to obtain solution 7c; solution 7c was continuously stirred, and then a solid was precipitated to obtain a suspension; the suspension was stirred overnight and then centrifuged; and the resulting solid was dried under vacuum at room temperature to obtain the p-toluenesulfonate of compound A.
[0251] .sup.1H NMR (500 MHz, DMSO-d6) 10.50 (s, 1H), 8.80 (t, 1H), 8.25 (d, 1H), 8.18-8.11 (m, 2H), 7.80 (d, 1H), 7.65-7.59 (m, 2H), 7.56 (d, 1H), 7.51-7.45 (m, 2H), 7.45-7.30 (m, 3H), 7.12 (d, 2H), 5.93 (dd, 1H), 5.02-4.73 (m, 1H), 4.49 (s, 1H), 3.71 (d, 1H), 3.07 (t, 1H), 2.84 (d, 2H), 2.46 (d, 3H), 2.29 (s, 3H), 2.08-2.00 (m, 1H), 1.72-1.62 (m, 1H), 1.46-1.07 (m, 5H).
EXAMPLE 8: PREPARATION OF ACETATE, FUMARATE, MALONATE, SUCCINATE, BENZOATE, CITRATE, MALATE AND L-TARTRATE OF COMPOUND A
[0252] With reference to the methods in Examples 1-7, according to the feeding ratios in Table 7, the corresponding salts were prepared.
TABLE-US-00008 TABLE 7 Salt formation from compound A with different acids Feeding Solvent molar for free Solvent ratio Anti- Acid compound A for acid (base:acid) solvent Acetic Isopropanol Isopropanol 1:1.2 acid Methanol Methanol 1:1.2 Acetic acid:water = 1:1.2 Acetic acid:methyl tert-butyl ether = 1:2 Fumaric Isopropanol Isopropanol 1:1.2 Isopropyl acid ether Acetone Acetone, water 1:1.2 Isopropyl ether Tetrahydrofuran Tetrahydrofuran, 1:1.2 n-Heptane water Ethanol Ethanol 1:1.2 Malonic Isopropanol Isopropanol 1:1.2 acid Acetone Acetone 1:1.2 Isopropyl ether Tetrahydrofuran Tetrahydrofuran 1:1.2 n-Heptane Ethanol Ethanol 1:1.2 Methanol Methanol 1:1.2 Acetone Acetone 1:1.2 Tetrahydrofuran Tetrahydrofuran/ 1:1.2 n-Heptane water Ethanol Ethanol 1:1.2 Acetone Acetone 1:1.2 Methanol Methanol 1:1.2 Benzoic Isopropanol Isopropanol 1:1.2 Isopropyl acid ether Acetone Acetone 1:1.2 Isopropyl ether Tetrahydrofuran Tetrahydrofuran 1:1.2 n-Heptane Ethanol Ethanol 1:1.2 Acetone Acetone 1:1.2 Methanol Methanol 1:1.2 Acetone Acetone 1:1.2 Tetrahydrofuran Tetrahydrofuran 1:1.2 n-Heptane Ethanol Ethanol 1:1.2 Tetrahydrofuran Tetrahydrofuran 1:1.2 n-Heptane Ethanol Ethanol 1:1.2 L-tartaric Isopropanol Isopropanol 1:1.2 Isopropyl acid ether Acetone Acetone 1:1.2 Isopropyl ether Tetrahydrofuran Tetrahydrofuran 1:1.2 n-Heptane
[0253] Test results: no salt form or stable salt form was prepared.
1. Characterization of Salt Form of Compound A
[0254] The properties of various salts of compound A are shown in Table 8.
TABLE-US-00009 TABLE 8 Properties of various salts of compound A Molar ratio for salt Melting Crystal form PLM (hot-stage Characterization formation point at high polarized light Name of crystal form Crystallinity Category (base:acid) ( C.) humidity microscopy) Free base Amorphous Low Tabular particles Hemi-1,5- Crystal form 1 High Anhydride 1:0.5 189 Crystal form Agglomerated naphthalene unchanged particles disulfonate Hydrochloride Crystal form 1 High Solvate 1:1 119 Crystal form Agglomerated unchanged particles Hydrobromide Crystal form 1 High Solvate 1:1 180 Agglomerated particles Crystal form 2 High 2-naphthalenesulfonate Crystal form 1 High Anhydride 1:1 143 Agglomerated particles Crystal form 2 High Benzenesulfonate Relatively 1:1 Tabular particles p-toluenesulfonate Relatively 1:1 Blocky particles low Methanesulfonate Low 1:1 Blocky particles Notes: crystallinity is determined by the height of the strongest peak in XRPD; and melting points are determined by DSC and expressed as onset values.
2. Stability Study
[0255] Samples: crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1, crystal form I of hydrochloride of compound A in Example 2, crystal form I of hydrobromide of compound A in Example 3, and crystal form I of 2-naphthalenesulfonate of compound A in Example 4.
[0256] Experiments: the crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1, crystal form I of hydrochloride of compound A in Example 2, crystal form I of hydrobromide of compound A in Example 3, and crystal form I of 2-naphthalenesulfonate of compound A in Example 4 were respectively placed at an accelerated condition (open, 40 C., 75% RH (relative humidity)), a light condition (open, 25 C., total illuminance not less than 1.2106 Lux.Math.hr, near-ultraviolet energy not less than 200 w.Math.hr/m2), a high humidity condition (open, drying oven) and a long-term condition (open, 25 C.-60% RH) for stability experiments. On day 0, day 5, day 10 and day 15, the samples were taken and detected for purity by HPLC (expressed as a percentage). The experimental results are shown in Table 9.
[0257] Conditions for detecting purity by HPLC: chromatographic column: ChromCore 120 C18 5 m (4.6 mm*100); column temperature: 35 C.; detection wavelength: 220 nm; mobile phase: 10 mmol/L ammonium formate aqueous solution: acetonitrile=55:45 (v/v); flow rate: 1.0 mL/min.
TABLE-US-00010 TABLE 9 HPLC results of experiments for solid state stability study Sample/influencing factor High Initial Long-term temperature Accelerated Light value condition condition condition condition Time Day 0 Day 5 Day 10 Day 5 Day 10 Day 5 Day 10 Day 15 Day 5 Day 10 Crystal form I of 98.80 98.50 98.47 98.52 98.28 98.90 98.62 hemi-1,5- naphthalene disulfonate of compound A in Example 1 Crystal form I of 98.95 98.42 98.12 98.57 98.53 99.00 98.91 hydrochloride of compound A in Example 2 Crystal form I of 99.35 99.32 99.25 99.27 99.29 99.10 98.83 hydrobromide of compound A in Example 3 Crystal form I of 2- 99.46 99.41 99.39 99.36 99.38 98.94 98.43 97.82 99.45 99.37 naphthalenesulfonate of compound A in Example 4
[0258] Conclusion: after placed at a high temperature condition, a long-term condition or a light condition for 10 days, the compounds of Examples 1-4 have basically no change in purity and little change in single impurity content, indicating good stability; in addition, a stability test at an accelerated condition was performed on the crystal form I of 2-naphthalenesulfonate of compound A in Example 4, which showed good stability.
3. Pharmacokinetics of Example Compounds
3.1. Pharmacokinetic Test in Rats
[0259] Test objective: by giving test compounds to SD rats via single-dose intravenous and intragastric administration and measuring the concentrations of the test compounds in plasma of rats, the pharmacokinetic characteristics and bioavailability of the test compounds in rats were evaluated.
[0260] Test compound: compound A, crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1 and crystal form I of 2-naphthalenesulfonate of compound A in Example 4.
[0261] Test animal: male SD rats, about 220 g, 6-8 weeks old, 6 rats/compound, purchased from Chengdu Ddossy Experimental Animals Co., Ltd.
[0262] Test method: on the day of the test, 6 SD rats were randomly grouped according to their body weight; the animals were fasted with water available for 12 to 14 h one day before the administration, and were fed 4 h after the administration; and the administration was performed according to Table 10.
TABLE-US-00011 TABLE 10 Administration information Administration information Administration Administration Administration Number Test dosage* concentration volume Collected Mode of Group Male compound (mg/kg) (mg/mL) (mL/kg) sample administration Vehicle G1 3 Compound 2 0.4 5 Plasma Intravenously 5% DMA + A or a salt 95% (20% thereof SBE--CD) G2 3 Compound 10 1 10 Plasma Intragastrically 0.5% MC A or a salt thereof *Dosage is calculated on the basis of free base.
Biological Sample Collection
[0263] Before and after the administration, 0.1 mL of blood samples were drawn from the orbits of the animals under isoflurane anaesthesia, and placed in an EDTAK2 centrifuge tube. Centrifugation was performed at 5000 rpm at 4 C. for 10 min, and plasma was collected.
[0264] Time points for sample collection in G1 and G2 groups comprise 0, 5 min, 15 min, 30 min, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h.
[0265] Before analysis and detection, all samples were stored at 80 C.
Pretreatment of Samples
[0266] 30 L of each of plasma samples, standard curve samples and quality control samples was taken, and 200 L of acetonitrile solution containing an internal standard was added. The resulting mixture was homogeneously mixed by vortex and centrifuged at 4 C. at 12000 rpm for 10 min. 170 L of the supernatant was taken and placed to a 96-well plate, and LC-MS/MS analysis was performed, wherein the sample size was 0.2 L.
[0267] The main pharmacokinetic parameters were analysed by a non-compartmental model using WinNonlin 8.0 software. The test results were as shown in Table 11.
TABLE-US-00012 TABLE 11 Pharmacokinetic parameters in rats Mode of C0 or Cmax AUC T.sub.1/2 Tmax Test compound administration (ng/ml) (h*ng/ml) (h) (h) F % Compound A IV 2 mg/kg 1460 134 2006 396 0.897 0.013 PO 10 mg/kg 715 127 2614 620 1.04 0.099 1.67 0.58 26.1 6.2 Crystal form I of IV 2 mg/kg 1729 215 2157 509 1.18 0.36 hemi-1,5- naphthalene disulfonate of PO 10 mg/kg 1393 497 4521 1682 1.38 0.079 1.00 0.0 41.9 16 compound A in Example 1 Crystal form I of 2- IV 2 mg/kg 1408 83 1909 846 1.05 0.42 naphthalenesulfonate of compound PO 10 mg/kg 1190 430 4209 2090 1.42 0.30 1.33 0.58 44.1 22 A in Example 4
[0268] Conclusion: the salt forms of the compounds of the present application, such as crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1 and crystal form I of 2-naphthalenesulfonate of compound A in Example 4, have good pharmacokinetics in rats and significantly improved bioavailability compared with compound A in a free state.
3.2. Pharmacokinetic Test in Ferrets
[0269] Test objective: by giving test compounds to ferrets via single-dose intragastric administration, collecting plasma at different time points and measuring the concentrations of the test compounds in plasma of ferrets, the absorption of the test compounds in ferrets was evaluated in this test.
[0270] Test compound: crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1.
[0271] Test animal: 6 healthy adult male ferrets, about 800-1500 g, 6-10 months old, purchased from Wuxi Sangosho Biotechnology Co., Ltd.
[0272] Test method: the male ferrets selected for the test were fasted with water available for 12-14 h one day before the administration, and were fed 4 h after the administration; and the administration was performed according to Table 12.
TABLE-US-00013 TABLE 12 Administration information Administration information Administration Administration Administration Number Test dosage concentration volume Collected Mode of Group M compound (mg/kg) (mg/mL) (mL/kg) sample administration Vehicle G1 3 Crystal form 15 1.5 10 Plasma Intragastrically 20% SBE--CD I of hemi-1,5- naphthalene disulfonate of compound A in Example 1 G2 3 Crystal form 15 1.5 10 Plasma Intragastrically 5% DMSO + I of hemi-1,5- 5% Solutol + naphthalene 90% (0.5% MC) disulfonate of compound A in Example 1 *Administration dosage is calculated on the basis of free base.
[0273] Time points for blood collection: before the administration and 0.0833 h, 0.25 h, 0.5 h, 1 h, 2 h, 4 h, 6 h, 8 h and 24 h after the administration (10 time points in total), venous blood samples were collected into centrifuge tubes and centrifuged within 30 minutes, and the centrifuged plasma samples were stored in a refrigerator at 80 C. for PK analysis.
[0274] The test results were as shown in Table 13.
TABLE-US-00014 TABLE 13 Pharmacokinetic parameters in ferrets Mode of C0 or Cmax AUC T.sub.1/2 Tmax Example no. administration (ng/ml) (h*ng/ml) (h) (h) Vehicle Crystal form I PO 15 mg/kg 314 32 393 76 1.13 0.43 0.583 0.38 20% SBE--CD of hemi-1,5- naphthalene disulfonate of compound A in Example 1 Crystal form I PO 15 mg/kg 942 1354 0.705 0.750 5% DMSO + of hemi-1,5- 5% Solutol + naphthalene 90% (0.5% MC) disulfonate of compound A in Example 1
[0275] Conclusion: the salt forms of the compounds of the present application, such as crystal form I of hemi-1,5-naphthalene disulfonate of compound A in Example 1, have good pharmacokinetics in ferrets.