WO2025237335A1 - 一种葫芦脲衍生物的可药用盐、其结晶形式及用途 - Google Patents

一种葫芦脲衍生物的可药用盐、其结晶形式及用途

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Publication number
WO2025237335A1
WO2025237335A1 PCT/CN2025/094868 CN2025094868W WO2025237335A1 WO 2025237335 A1 WO2025237335 A1 WO 2025237335A1 CN 2025094868 W CN2025094868 W CN 2025094868W WO 2025237335 A1 WO2025237335 A1 WO 2025237335A1
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WIPO (PCT)
Prior art keywords
crystal form
compound
formula
ray powder
salt
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PCT/CN2025/094868
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English (en)
French (fr)
Inventor
尚婷婷
石巾艺
杨俊然
杜振兴
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Jiangsu Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Pharmaceutical Co Ltd
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Publication of WO2025237335A1 publication Critical patent/WO2025237335A1/zh
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4188—1,3-Diazoles condensed with other heterocyclic ring systems, e.g. biotin, sorbinil
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings

Definitions

  • This disclosure belongs to the field of pharmaceutical technology and relates to a free alkali crystal form of a cucurbituril derivative, a pharmaceutically acceptable salt, its crystal form and uses.
  • Muscle relaxation is one of the three essential elements of general anesthesia. While muscle relaxants meet the needs of endotracheal intubation and surgery, they also bring safety risks—residual muscle relaxation. This can lead to subjective discomfort in patients and a series of pulmonary complications such as hypoxemia, regurgitation, and aspiration. To reduce the incidence of residual muscle relaxation, measures such as the use of intermediate- and short-acting muscle relaxants, optimized intraoperative muscle relaxation management, postoperative antagonism of muscle relaxant effects, and perioperative objective muscle relaxation monitoring have made continuous progress in addressing this clinical challenge.
  • Postoperative muscle relaxant antagonism refers to the use of muscle relaxant antagonists to reverse the residual effects of non-depolarizing muscle relaxants.
  • muscle relaxant antagonists can be broadly classified into two categories: competitive muscle relaxant antagonists, including neostigmine as an acetylcholine inhibitor; and selective muscle relaxant antagonists, including sugambogia sodium as a steroid muscle relaxant antagonist and cysteine as a benzylisoquinoline muscle relaxant antagonist.
  • PCT/CN2023/131007 discloses a non-closed-ring CB[n] type molecular container with a cucurbituril structure, having the structure shown in Formula 1. It can bind efficiently to benzyl isoquinoline and steroid muscle relaxants, and by covering the quaternary ammonium sites of benzyl isoquinoline and steroid muscle relaxants, it prevents the muscle relaxants from binding to neuromuscular cholinergic receptors, thereby rapidly reversing the muscle relaxant effect.
  • Salt formation can improve certain undesirable physicochemical or biological properties of drugs.
  • Developing salts with superior physicochemical or pharmaceutical properties compared to compounds of Formula 1 is of great significance. Given the importance of the crystal form and stability of solid drugs in clinical treatment, in-depth research into the polymorphisms of pharmaceutically viable salts of Formula 1 compounds is also crucial for developing drugs suitable for industrial production and possessing good biological activity.
  • This disclosure provides a pharmaceutically acceptable salt of a compound of formula 1, wherein the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, calcium salts, choline salts, ethanolamine salts, diethanolamine salts, diethylamine salts, tromethamine salts, arginine salts, lysine salts, meglumine salts, and ammonium salts.
  • the pharmaceutically acceptable salt is selected from sodium salts, potassium salts, calcium salts, choline salts, ethanolamine salts, diethanolamine salts, diethylamine salts, tromethamine salts, arginine salts, lysine salts, meglumine salts, and ammonium salts.
  • This disclosure also provides a method for preparing a pharmaceutically acceptable salt of a compound of formula 1, comprising the step of reacting the compound of formula 1 with a base, wherein the base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, choline hydroxide, tromethamine, arginine, lysine, ethanolamine, diethylamine, meglumine, diethanolamine, and ammonia.
  • a base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, choline hydroxide, tromethamine, arginine, lysine, ethanolamine, diethylamine, meglumine, diethanolamine, and ammonia.
  • the solvents used in the salt formation of this disclosure are selected from, but are not limited to, acetone, acetonitrile, water, ethanol, 2-methyltetrahydrofuran, ethyl acetate, isopropanol, cyclohexane, n-heptane, 1,4-dioxane, 2-butanone, tetrahydrofuran, and methanol.
  • the method for preparing the aforementioned pharmaceutically usable salt also includes steps such as crystallization, filtration, washing, or drying.
  • the chemical ratio of the compound of Formula 1 to the base is 3:1 to 1:8, including but not limited to 3:1, 2:1, 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, and 1:8.
  • the chemical ratio of the compound of formula 1 to the base is 2:1 to 1:8.
  • the chemical ratio of the compound of Formula 1 to sodium ions is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to potassium ions is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to calcium ions is 1:2 or 1:4.
  • the chemical ratio of the compound of Formula 1 to ammonium ions is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to choline is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to tromethamine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to arginine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to lysine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to ethanolamine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to diethanolamine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to meglumine is 1:2, 1:4, 1:6, or 1:8.
  • the chemical ratio of the compound of Formula 1 to diethylamine is 1:2, 1:4, 1:6, or 1:8.
  • the crystal form A of the compound of Formula 1 provided in this disclosure has characteristic peaks at 9.195, 14.303, 18.343, and 21.652 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of crystal form A of compound of formula 1, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 17.
  • This disclosure also provides a method for preparing crystal form A of compound of formula 1, the method comprising any of the following methods:
  • Method 1 Add the compound of Formula 1 to solvent I and stir.
  • Solvent I is selected from 7% water/ethanol, 10% water/isopropanol, 10% water/acetone, and tetrahydrofuran.
  • Method 2 Dissolve the compound of Formula 1 in water, add solvent II and stir; the solvent II is selected from acetone and acetonitrile.
  • the disodium salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 3-50° at the diffraction angle 2 ⁇ .
  • this disclosure provides a method for preparing a disodium salt of a compound of formula 1, the method comprising dissolving the compound of formula 1 in water and then adding 2 equivalents of sodium hydroxide.
  • the disodium salt crystal form A of the compound of formula 1 disclosed herein has characteristic peaks at 9.720, 11.232, 14.901, 15.811, and 19.759 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the disodium salt of Formula 1, crystal form A, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 18.
  • This disclosure also provides a method for preparing disodium salt of Formula 1, crystal form A, the method comprising adding disodium salt of Formula 1 to solvent II and stirring.
  • the disodium salt crystal form B of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.654, 8.040, 8.883, 11.778, 14.719, and 21.649 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the disodium salt B of Formula 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 19.
  • This disclosure also provides a method for preparing disodium salt of Formula 1, crystal form B, the method comprising dissolving disodium salt of Formula 1 in water, adding solvent III, and stirring, wherein solvent III is selected from acetone, acetonitrile, and tetrahydrofuran.
  • the tetrasodium salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2 ⁇ range of 3-50°.
  • this disclosure provides a method for preparing a tetrasodium salt of Formula 1 compound, the method comprising dissolving the Formula 1 compound in water and then adding 4 equivalents of sodium hydroxide.
  • the tetrasodium salt crystal form A of the compound of formula 1 provided in this disclosure has characteristic peaks at 8.334, 9.972, 15.260, 17.155, 20.557, and 22.867 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the tetrasodium salt A of Formula 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 20.
  • This disclosure also provides a method for preparing the tetrasodium salt of compound 1, crystal form A, the method comprising any of the following methods:
  • Method 1 Add the tetrasodium salt of compound 1 to 10% water/isopropanol or 10% water/acetone and stir;
  • Method 2 Dissolve the tetrasodium salt of compound 1 in water, add acetone or tetrahydrofuran, and stir.
  • the hexasodium salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 3-50° at the diffraction angle 2 ⁇ .
  • this disclosure provides a method for preparing the hexasodium salt of Formula 1 compound, the method comprising dissolving the Formula 1 compound in water and then adding 6 equivalents of sodium hydroxide.
  • the octasodium salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2 ⁇ range of 3-50°.
  • this disclosure provides a method for preparing an octasodium salt of Formula 1 compound, the method comprising dissolving the Formula 1 compound in water and then adding 8 equivalents of sodium hydroxide.
  • the octasodium salt crystal form A of the compound of Formula 1 provided in this disclosure has characteristic peaks at 5.052, 7.543, 11.974, 21.775, and 23.581 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the octasodium salt crystal form A of the compound of formula 1, as expressed in X-ray powder diffraction patterns at diffraction angles of 2 ⁇ , has characteristic peaks at 5.052, 5.598, 7.543, 10.955, 11.974, 17.533, 18.583, 21.775, 23.581, and 25.051.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form A of the compound of Formula 1, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.052, 5.598, 7.543, 10.268, 10.955, 11.400, 11.974, 12.912, 15.139, 17.533, 18.583, 21.775, 23.581, and 25.051.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form A of compound of formula 1, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 3.
  • This disclosure also provides a method for preparing the octasodium salt crystal form A of compound of formula 1, the method comprising any of the following methods:
  • Method 1 Dissolve the octasodium salt of compound 1 in water, add methanol, and stir;
  • Method 2 Add the octasodium salt of Formula 1 to 10% water/methanol (v/v), add seed crystals, and stir.
  • the octasodium salt crystal form B of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.402, 8.124, 12.072, 16.357, 19.255, 21.775, and 27.109 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt B of compound 1, expressed as a diffraction angle 2 ⁇ has characteristic peaks at 5.310, 6.402, 8.124, 10.434, 12.072, 14.845, 16.357, 19.255, 20.599, 21.775, 22.573, 23.917, 27.109, and 29.461.
  • the X-ray powder diffraction pattern of the octasodium salt B of compound 1, expressed as a diffraction angle 2 ⁇ has characteristic peaks at 5.310, 6.402, 8.124, 10.434, 12.072, 14.089, 14.845, 16.357, 19.255, 20.599, 21.775, 22.573, 23.917, 24.589, 27.109, 28.285, and 29.461.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form B of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 4.
  • This disclosure also provides a method for preparing the octasodium salt crystal form B of compound 1, the method comprising the steps of dissolving the octasodium salt of compound 1 in water and adding tetrahydrofuran while stirring.
  • the octasodium salt crystal form C of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.772, 6.738, 8.166, 9.888, and 21.901 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the octasodium salt crystal form C of compound 1 as expressed in X-ray powder diffraction patterns at diffraction angles 2 ⁇ , has characteristic peaks at 5.772, 6.738, 8.166, 9.888, 12.912, 14.761, 16.693, and 21.901.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form C of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 5.
  • This disclosure also provides a method for preparing the octasodium salt crystal form C of compound 1, the method comprising dissolving the octasodium salt of compound 1 in water and adding acetonitrile while stirring.
  • the octasodium salt crystal form D of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.100, 8.544, 12.744, 15.391, and 21.397 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the octasodium salt crystal form D of the compound of formula 1, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.100, 6.528, 8.544, 12.744, 15.391, 16.567, 19.885, 21.397, and 27.235.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form D of compound 1, expressed as a diffraction angle 2 ⁇ has characteristic peaks at 5.100, 6.528, 8.544, 12.744, 15.391, 16.567, 19.885, 21.397, 23.329, 24.547, 26.185, and 27.235.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form D of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 6.
  • This disclosure also provides a method for preparing the octasodium salt crystal form D of compound 1, the method comprising adding the octasodium salt of compound 1 to solvent I and stirring for 3 days; wherein solvent I is selected from 10% water/isopropanol (v/v) and 10% water/acetone (v/v).
  • the octasodium salt crystal form E of the compound of formula 1 provided in this disclosure has characteristic peaks at 8.082, 9.762, 16.525, and 20.599 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt E of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 7.
  • This disclosure also provides a method for preparing the octasodium salt of Formula 1, crystal form E, the method comprising dissolving the octasodium salt of Formula 1 in water and adding acetone while stirring.
  • the octasodium salt crystal form F of the compound of formula 1 provided in this disclosure has characteristic peaks at 13.543, 15.055, 17.701, 21.691, and 25.933 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt crystal form F of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 8.
  • This disclosure also provides a method for preparing the octasodium salt crystal form F of compound of formula 1, the method comprising the step of subjecting the octasodium salt crystal form A to a DVS cycle.
  • the octasodium salt crystal form G of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.515, 13.061, 14.807, 17.854, and 21.703 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the octasodium salt crystal form G of compound 1 as expressed in X-ray powder diffraction patterns at diffraction angles 2 ⁇ , has characteristic peaks at 5.946, 6.515, 12.036, 13.061, 14.807, 17.854, 21.703, 24.406, and 27.046.
  • the octasodium salt crystal form G of compound 1 as expressed in X-ray powder diffraction patterns at diffraction angles 2 ⁇ , exhibits characteristic peaks at 5.946, 6.515, 11.521, 12.036, 13.061, 14.807, 17.854, 20.952, 21.703, 24.406, and 27.046.
  • the X-ray powder diffraction pattern of the octasodium salt crystal form G of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 9.
  • This disclosure also provides a method for preparing the octasodium salt crystal form G of compound formula 1, the method comprising any of the following methods:
  • Method 1 Dissolve the octasodium salt of Formula 1 in water and add methanol while stirring.
  • Method 2 The procedure of placing the octasodium salt crystal form E of compound 1 at 92.5% RH for 7 days.
  • the octasodium salt crystal form H of the compound of formula 1 provided in this disclosure has characteristic peaks at 9.132, 10.921, 12.786, and 14.845 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt H of Formula 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 10.
  • This disclosure also provides a method for preparing the octasodium salt of Formula 1, crystal form H, comprising adding the octasodium salt of Formula 1 to 10% water/methanol (v/v) and stirring for 1 day.
  • the octasodium salt crystal form I of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.402, 11.274, 17.743, and 25.219 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt crystal form I of compound 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 11.
  • This disclosure also provides a method for preparing octasodium salt crystal form I of compound 1, comprising the step of placing octasodium salt crystal form B of compound 1 at room temperature with 75% RH for 7 days.
  • the octasodium salt crystal form J of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.436, 9.048, 11.232, 12.618, 13.374, 16.693, 17.995, and 21.019 in its X-ray powder diffraction pattern expressed as a diffraction angle of 2 ⁇ .
  • the X-ray powder diffraction pattern of the octasodium salt crystal form J of Formula 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 12.
  • This disclosure also provides a method for preparing the octasodium salt crystal form J of compound 1, comprising the step of placing the octasodium salt of compound 1 at room temperature with 75% RH for 7 days.
  • the ammonium salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2 ⁇ range of 3-50°.
  • this disclosure provides a method for preparing an ammonium salt of a compound of formula 1, the method comprising adding the compound of formula 1 to acetone and then adding ammonia.
  • the ammonium salt crystal form a of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.523, 7.155, 13.226, 14.686, 19.621, and 20.993 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the ammonium salt crystal form a of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.523, 7.155, 7.971, 11.199, 13.226, 14.686, 15.132, 16.170, 18.285, 19.621, and 20.993.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form a of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.523, 7.155, 7.971, 11.199, 13.226, 14.686, 15.132, 16.170, 18.285, 19.621, 20.993, 22.218, 22.997, and 25.742.
  • This disclosure also provides a method for preparing ammonium salt crystal form a of compound of formula 1, the method comprising the steps of dissolving compound of formula 1 in ethanol and adding ammonia water and stirring.
  • the ammonium salt crystal form b of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.524, 7.489, 8.342, 15.057, 19.992, and 24.295 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the ammonium salt crystal form b of the compound of formula 1 provided in this disclosure expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 6.524, 7.489, 8.342, 11.978, 14.278, 15.057, 17.877, 19.992, 21.661, 22.589, and 24.295.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form b of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.524, 7.489, 8.342, 10.680, 11.978, 14.278, 15.057, 16.541, 17.877, 19.101, 19.992, 21.661, 22.589, 24.295, and 26.336.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form b of Formula 1, expressed in terms of the diffraction angle 2 ⁇ , is shown in Figure 22.
  • This disclosure also provides a method for preparing ammonium salt crystal form b of compound of formula 1, the method comprising adding compound of formula 1 to acetone, and then adding ammonia water and stirring.
  • the method for preparing the ammonium salt crystal form b of compound formula 1 includes dissolving the compound of formula 1 in ethanol and then adding ammonia and stirring.
  • the ammonium salt crystal form c of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.225, 8.214, 14.872, 17.803, and 22.700 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the ammonium salt crystal form c of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.225, 6.042, 6.858, 8.214, 14.872, 15.725, 16.912, 17.803, and 22.700.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form c of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.225, 6.042, 6.858, 8.214, 10.049, 10.568, 14.872, 15.725, 16.912, 17.803, 22.700, and 23.665.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form c of Formula 1, expressed in terms of the diffraction angle 2 ⁇ , is shown in Figure 23.
  • This disclosure also provides a method for preparing ammonium salt crystal form c of compound of formula 1, the method comprising adding compound of formula 1 to 2-methyltetrahydrofuran, and then adding ammonia water and stirring.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form d of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 7.378, 8.231, 9.881, 14.977, 19.918, and 22.403.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form d of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 6.228, 7.378, 8.231, 9.881, 13.726, 14.303, 14.977, 16.756, 19.918, 22.403, 24.258, and 26.076.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form d of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 6.228, 7.378, 8.231, 9.881, 11.199, 11.570, 12.117, 12.906, 13.726, 14.303, 14.977, 16.756, 19.064, 19.918, 20.548, 20.956, 22.403, 24.258, and 26.076.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form d of Formula 1, expressed in terms of the diffraction angle 2 ⁇ , is shown in Figure 24.
  • This disclosure also provides a method for preparing ammonium salt crystal form d of compound of formula 1, the method comprising dissolving compound of formula 1 in ethanol and then adding ammonia water and stirring.
  • the ammonium salt crystal form e of the compound of formula 1 provided in this disclosure has characteristic peaks at 7.266, 8.445, 12.043, 13.253, 16.216, 20.851, and 24.365 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the ammonium salt crystal form e of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.152, 7.266, 8.445, 9.805, 10.309, 12.043, 13.253, 14.872, 16.216, 19.880, 20.851, 21.587, 22.552, and 24.365.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form e of the compound of formula 1 provided in this disclosure, expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.152, 7.266, 8.445, 9.805, 10.309, 11.607, 12.043, 12.831, 13.253, 14.204, 14.872, 16.216, 17.283, 19.509, 19.880, 20.851, 21.587, 22.552, 23.628, and 24.365.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form e of Formula 1, expressed in terms of the diffraction angle 2 ⁇ , is shown in Figure 25.
  • This disclosure also provides a method for preparing ammonium salt crystal form e of compound of formula 1, the method comprising placing ammonium salt crystal form d of compound of formula 1 at 75% RH for 7 days.
  • the ammonium salt crystal form f of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.337, 9.752, 10.531, 12.460, and 18.879 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the ammonium salt crystal form f of the compound of formula 1 provided in this disclosure expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.337, 9.752, 10.531, 11.385, 12.460, 13.573, 14.353, 15.354, 17.914, and 18.879.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form f of the compound of formula 1 provided in this disclosure expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 5.337, 9.752, 10.531, 11.385, 12.460, 13.573, 14.353, 15.354, 17.914, 18.879, 19.880, and 21.327.
  • the X-ray powder diffraction pattern of the ammonium salt crystal form f of Formula 1, expressed in terms of the diffraction angle 2 ⁇ , is shown in Figure 26.
  • This disclosure also provides a method for preparing ammonium salt crystal form f of Formula 1, the method comprising placing ammonium salt crystal form d of Formula 1 at 92.5% RH for 7 days.
  • the aminobutadiene triol salt of Formula 1 is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2 ⁇ range of 3-50°.
  • this disclosure provides a method for preparing a tromethamine salt of Formula 1 compound, the method comprising adding a Formula 1 compound to solvent IV, and then adding tromethamine, wherein solvent IV is selected from acetone, ethanol, and ethyl acetate.
  • the compound of Formula 1, meglumine salt is amorphous, and its X-ray powder diffraction pattern has no obvious characteristic peaks in the diffraction angle 2 ⁇ range of 3-50°.
  • this disclosure provides a method for preparing a meglumine salt of Formula 1, the method comprising adding a compound of Formula 1 to solvent IV, and then adding meglumine, wherein solvent IV is selected from acetone, ethanol, and ethyl acetate.
  • the crystal form B of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.629, 14.555, 17.926, 19.716, and 24.300 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the crystal form B of the compound of formula 1 provided in this disclosure has characteristic peaks at 6.629, 9.243, 13.425, 14.555, 17.926, 19.716, 21.879, 24.300, 26.117, and 27.220 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of crystal form B of the compound of formula 1 provided in this disclosure has characteristic peaks at 5.857, 6.629, 9.243, 11.440, 12.097, 13.425, 14.555, 16.096, 17.926, 19.716, 21.879, 22.440, 22.883, 24.300, 24.666, 26.117, 27.220, and 29.030.
  • the X-ray powder diffraction pattern of compound B of Formula 1, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 27.
  • This disclosure also provides a method for preparing crystal form B of compound of formula 1, the method comprising any of the following methods:
  • Method 1 Dissolve the compound of Formula 1 in solvent V, and evaporate the solvent, wherein solvent V is selected from one or more of water, methanol, ethanol, isopropanol, acetonitrile, and cyclohexane;
  • Method 2 Add the compound of Formula 1 to solvent VI and stir.
  • Solvent VI is selected from 1,4-dioxane, n-heptane, and 10% water/acetone.
  • Method 3 Dissolve the compound of formula 1 in water, add 1,4-dioxane, and stir.
  • the crystal form C of the compound of Formula 1 provided in this disclosure has characteristic peaks at 6.487, 11.433, 16.309, 20.956, and 23.613 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form C of the compound of Formula 1 provided in this disclosure expressed in terms of diffraction angle 2 ⁇ , has characteristic peaks at 6.487, 11.433, 16.309, 17.543, 17.988, 18.767, 19.695, 20.956, 23.613, 24.963, and 27.597.
  • the X-ray powder diffraction pattern of the crystal form C of the compound of Formula 1 provided in this disclosure has characteristic peaks at 6.487, 11.433, 16.309, 17.543, 17.988, 18.767, 19.695, 20.956, 23.613, 24.963, 25.631, 26.076, and 27.597.
  • the X-ray powder diffraction pattern of compound C of Formula 1, expressed as a diffraction angle 2 ⁇ , is shown in Figure 28.
  • This disclosure also provides a method for preparing crystal form C of compound of formula 1, the method comprising the steps of adding compound of formula 1 to acetone and stirring.
  • the crystal form D of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.454, 11.607, 16.073, 18.174, 21.105, and 22.218 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the crystal form D of the compound of formula 1 provided in this disclosure has characteristic peaks at 8.454, 11.607, 14.204, 16.073, 18.174, 20.103, 21.105, 22.218, 23.294, and 25.631 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form D of the compound of Formula 1 provided in this disclosure has characteristic peaks at 8.454, 11.607, 12.535, 13.054, 14.204, 16.073, 17.543, 18.174, 20.103, 21.105, 22.218, 23.294, and 25.631.
  • the X-ray powder diffraction pattern of the compound of Formula 1, crystal form D, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 29.
  • This disclosure also provides a method for preparing crystal form D of compound of formula 1, the method comprising the steps of adding compound of formula 1 to acetonitrile and stirring.
  • the crystal form E of the compound of Formula 1 provided in this disclosure has characteristic peaks at 4.715, 7.118, 7.637, 9.270, 12.052, and 20.214 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the crystal form E of the compound of formula 1 provided in this disclosure has characteristic peaks at 4.715, 6.005, 7.118, 7.637, 9.270, 12.052, 13.796, 15.132, and 20.214 in its X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ .
  • the X-ray powder diffraction pattern of the crystal form E of the compound of Formula 1 provided in this disclosure expressed as a diffraction angle 2 ⁇ , has characteristic peaks at 4.715, 6.005, 7.118, 7.637, 9.270, 12.052, 13.796, 15.132, 17.654, 20.214, and 22.886.
  • the X-ray powder diffraction pattern of the compound of Formula 1, crystal form E, expressed in terms of diffraction angle 2 ⁇ , is shown in Figure 30.
  • This disclosure also provides a method for preparing crystal form E of compound of formula 1, the method comprising placing crystal form B of compound of formula 1 at 40°C/75% RH for 14 days.
  • This disclosure also provides a pharmaceutical composition
  • a pharmaceutical composition comprising any of the aforementioned pharmaceutically acceptable salts, free acid crystal forms A, B, C, D, and E, ammonium salt crystal forms a, b, c, d, e, and f, disodium salt crystal form A, disodium salt crystal form B, tetrasodium salt crystal form A, octasodium salt crystal forms A, B, C, D, E, F, G, H, I, or J, and pharmaceutical excipients optionally selected from pharmaceutically acceptable excipients.
  • This disclosure also provides a pharmaceutical composition prepared from optionally the aforementioned pharmaceutically acceptable salts, free acid crystal forms A, B, C, D, and E, ammonium salt crystal forms a, b, c, d, e, and f, disodium salt crystal form A, disodium salt crystal form B, tetrasodium salt crystal form A, octasodium salt crystal forms A, B, C, D, E, F, G, H, I, or J, and optionally a pharmaceutically acceptable excipient.
  • This disclosure also provides a method for preparing a pharmaceutical composition, comprising the step of mixing any of the aforementioned pharmaceutically acceptable salts, free acid crystal forms A, B, C, D, and E, ammonium salt crystal forms a, b, c, d, e, and f, disodium salt crystal form A, disodium salt crystal form B, tetrasodium salt crystal form A, octasodium salt crystal forms A, B, C, D, E, F, G, H, I, or J with a pharmaceutically acceptable excipient.
  • This disclosure also provides the use of any of the aforementioned pharmaceutically acceptable salts, free acid crystal forms A, B, C, D, and E, ammonium salt crystal forms a, b, c, d, e, and f, disodium salt crystal form A, disodium salt crystal form B, tetrasodium salt crystal form A, octasodium salt crystal forms A, B, C, D, E, F, G, H, I, or J, or the use of the aforementioned compositions in the preparation of medicaments for reversing drug-induced neuromuscular blockade and/or anesthesia.
  • the "2 ⁇ or 2 ⁇ angle" mentioned in this disclosure refers to the diffraction angle, where ⁇ is the Bragg angle, and the unit is ° or degree; the error range of 2 ⁇ for each characteristic peak is ⁇ 0.20 (including the case where the number has more than one decimal place after rounding), specifically -0.20, -0.19, -0.18, -0.17, -0.16, -0.15, -0.14, -0.13, -0.12, -0.11, -0.10, -0.09, -0.08, -0.07, -0.06, -0.05, -0.04, -0.03, -0.02, -0.01, 0.00, 0.01, 0.02, 0.03, 0.04, 0.05, 0.06, 0.07, 0.08, 0.09, 0.10, 0.11, 0.12, 0.13, 0.14, 0.15, 0.16, 0.17, 0.18, 0.19, 0.20.
  • the numerical values in this disclosure are calculated data and inevitably contain a certain degree of error. Generally, ⁇ 10% is within the reasonable error range. The error may vary to some extent depending on the context in which it is used, but this variation shall not exceed ⁇ 10%, and may be ⁇ 9%, ⁇ 8%, ⁇ 7%, ⁇ 6%, ⁇ 5%, ⁇ 4%, ⁇ 3%, ⁇ 2%, or ⁇ 1%, preferably ⁇ 5%.
  • the starting material used in the crystal form preparation method disclosed herein can be any form of compound, including but not limited to: amorphous, arbitrary crystal form, hydrate, solvate, etc.
  • the drying temperature described in this disclosure is generally 25°C-100°C, preferably 40°C-70°C, and can be dried under normal pressure or reduced pressure.
  • the crystallization methods described in this disclosure include room temperature crystallization, cooling crystallization, solvent evaporation crystallization, and seed crystallization induction.
  • the cooling temperature is selected from below 65°C, preferably from -10°C to 60°C. Stirring can also be performed during the crystallization process.
  • the “differential scanning calorimetry or DSC” described in this disclosure refers to measuring the temperature difference and heat flow difference between the sample and the reference material during the sample heating or isothermal process, in order to characterize all physical and chemical changes related to thermal effects and obtain phase transition information of the sample.
  • Deliquescence Absorbs sufficient moisture to form a liquid
  • the weight gain due to hygroscopic absorption is not less than 15%;
  • the weight gain due to hygroscopic absorption is less than 15% but not less than 2%;
  • the weight gain due to moisture absorption is less than 2% but not less than 0.2%;
  • the weight gain due to moisture absorption is less than 0.2%.
  • excipients include, but are not limited to, any adjuvants, carriers, flow aids, sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, or emulsifiers that have been approved by the U.S. Food and Drug Administration for use in humans or livestock.
  • NMR nuclear magnetic resonance
  • MS mass spectrometry
  • ⁇ NMR shifts ( ⁇ ) are given in units of 10 ⁇ 6 (ppm).
  • NMR measurements were performed using a Bruker AVANCE NEO 500M NMR spectrometer with deuterated dimethyl sulfoxide (DMSO- d6 ), deuterated chloroform ( CDCl3 ), and deuterated methanol ( CD3OD ) as solvents, and tetramethylsilane (TMS) as the internal standard.
  • DMSO- d6 deuterated dimethyl sulfoxide
  • CDCl3 deuterated chloroform
  • CD3OD deuterated methanol
  • TMS tetramethylsilane
  • MS measurements were performed using an Agilent 1200/1290DAD-6110/6120 Quadrupole MS LC-MS system (manufacturer: Agilent, MS model: 6110/6120 Quadrupole MS), a Waters ACQuity UPLC-QD/SQD system (manufacturer: Waters, MS model: Waters ACQuity Qda Detector/Waters SQ Detector), or a THERMO Ultimate 3000-Q Exactive system (manufacturer: THERMO, MS model: THERMO Q Exactive).
  • HPLC High-performance liquid chromatography
  • HPLC High performance liquid chromatography
  • Silica gel column chromatography generally uses Yantai Huanghai silica gel with a mesh size of 200-300 as the carrier.
  • XRPD X-ray Powder Diffraction
  • DSC Differential Scanning Calorimetry: Measurements were performed using a METTLER TOLEDO DSC 3+ differential scanning calorimeter with a heating rate of 10°C/min. The specific temperature range was referenced from the corresponding spectra (mostly 25-300°C or 350°C), and the nitrogen purging rate was 50mL/min.
  • TGA thermogravimetric analysis: the test was performed using a METTLER TOLEDO TGA 2 thermogravimetric analyzer, with a heating rate of 10°C/min, and the specific temperature range was referenced from the corresponding spectrum (mostly 30-400°C). The nitrogen purging rate was 50mL/min.
  • DVS Dynamic Moisture Adsorption: The detection method used is SMSDVS Advantage. At 25°C, the humidity changes from 50% to 95% to 0% to 95% to 50%, with a step of 10% (the last step is 5%). (The specific humidity range is subject to the corresponding spectrum. The method listed here is the most commonly used method.) The judgment criterion is that dm/dt is not greater than 0.002%/min.
  • the known starting materials disclosed herein can be synthesized using or in accordance with methods known in the art, or can be purchased from companies such as ABCR GmbH & Co. KG, Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., and Darui Chemicals.
  • Argon or nitrogen atmosphere refers to a reaction flask connected to an argon or nitrogen gas balloon with a volume of approximately 1L.
  • the reaction process in the examples was monitored using thin-layer chromatography (TLC).
  • TLC thin-layer chromatography
  • the volume ratio of the solvent was adjusted according to the polarity of the compounds, and small amounts of basic or acidic reagents such as triethylamine and acetic acid could also be added for adjustment.
  • Step 1 Urea (38.89 g, 647.46 mmol), 0.3 M dilute hydrochloric acid (80 mL), and 1,2-cyclohexanedione 1a (22.0 g, 196.20 mmol) were added to a 500 mL three-necked flask. The mixture was heated to 50 °C and stirred for 16 hours. The reaction mixture was cooled to room temperature, filtered, and the filter cake was washed with 100 mL of water and 100 mL of anhydrous ethanol. After drying, cyclohexylglycerol, compound 1b (pale yellow body, 27.4 g, yield: 71%) was obtained.
  • Step 2 Add compound 1b (27.4 g, 139.65 mmol), 140 mL of 9 M hydrochloric acid, and paraformaldehyde (20.9 g, 698.23 mmol) to a 1 L three-necked flask. Stir the reaction mixture at room temperature for 24 hours. Add 500 mL of water to the reaction system and continue stirring at room temperature for 16 hours. Filter the reaction mixture, wash, and dry to obtain cyclohexylglycerol diether and compound 1c (white solid, 20.2 g, yield: 52%).
  • Step 3 Compound 1c (2.73 g, 9.73 mmol) was weighed into a dry three-necked flask, purged with argon, dissolved in methanesulfonic acid (10 mL), and then glycourea dimer 1d (1 g, 3.24 mmol, prepared using the known method "WO2012051407A2" was added. The mixture was stirred at room temperature for 24 hours. The reaction solution was slowly added to 100 mL of water (cooled in an ice-water bath), and then brought to room temperature. The mixture was filtered. 1.77 g of crude product was obtained by drying. The crude product was heated and dissolved in TFA (4 mL), then 16 mL of water was added, stirred, filtered, and dried under vacuum to obtain compound 1e (1.21 g, yield: 44.9%).
  • Step 4 In a three-necked flask, add methyl 3-bromo-2-(bromomethyl)propionate, compound 1f (25 g, 96 mmol), and anhydrous THF (70 mL). Replace the air with nitrogen, then cool to -78°C using a dry ice-acetone bath. Slowly add DIBAL-H (135 mL, 202 mmol, 1.5 M toluene). After addition, raise the temperature to 0°C and stir the reaction at 0°C for 45 minutes. Quench the reaction by adding HCl (1 M, 500 mL) dropwise at 0°C.
  • Step 5 Weigh 1 g (7 g, 30.4 mmol) of compound 1,4-dihydroxynaphthalene, 1.62 g (10.1 mmol) of compound 1h, and 1.4 mL of MeSO3H into a dry three-necked flask. Purge with nitrogen and heat the reaction mixture to 100 °C with stirring for 3 hours. Cool to room temperature, then pour the reaction mixture into ice water and extract with ethyl acetate (50 mL ⁇ 3). Wash the combined organic phases successively with NaHCO3 solution and saturated brine, dry, filter, and evaporate to dryness with solvent.
  • Step 6 Add compound 1i (2.25 g, 3.83 mmol) and sodium sulfite (4.91 g, 38.9 mmol) to a three-necked flask, replace the air with nitrogen, and then add 42 mL of isopropanol and 42 mL of water. Heat the reaction to 100 °C and stir for 24 hours.
  • Step 7 Weigh compound 1j (1.57 g, 2.37 mmol) into a dry three-necked flask, replace with argon gas, add TFA (15 mL) to dissolve, then add compound 1e (0.79 g, 0.95 mmol). After addition, heat the reaction to 70 °C and stir for 3 hours. Evaporate the TFA under reduced pressure, add 40 mL of ethanol to the obtained solid, heat under reflux for 2 hours, cool to room temperature, and filter. Wash the filter cake with ethanol and dry.
  • Step 8 Compound 1k (2.34 g) was subjected to a single acidic high-performance liquid chromatography (HPLC) treatment to remove Na ions (mobile phase: 0.1% TFA aqueous solution/methanol). The prepared solution was concentrated, then evaporated three times under reduced pressure with water to remove residual trifluoroacetic acid. After lyophilization, water was added again for three more evaporations, followed by lyophilization again to obtain 2.0 g of free acid, a pink solid compound 1 with a purity of 98.2%. X-ray powder diffraction analysis showed that the product was amorphous, as shown in Figure 13. TGA analysis showed a weight loss of 10.34% from 30°C to 185°C.
  • Test Example 1 Test of the in vitro binding activity of the disclosed compounds against muscle relaxants.
  • the in vitro binding activity of the disclosed compound with the muscle relaxant was tested by isothermal titration calorimetry (ITC), and the Kd value of the binding was evaluated.
  • Isothermal titration calorimeter including computer host and supporting software
  • CB2 compound 1, cisatracurium ammonium, deionized water.
  • the Kd value of the combination of the test compound and cisatracurium is calculated by thermal curve.
  • the tubing, sample cell and titration needle are then washed using a washing procedure before testing the next compound.
  • Test Example 2 Test on the antagonistic effect of the disclosed compound on muscle relaxants.
  • SPF grade male SD rats SPF grade male SD rats, BL-420A biological function experimental system (main unit, stimulator, tension transducer), ventilator, electronic scale, surgical instruments, syringe, clippers, electronic scale, iron stand, foam board, urethane, sodium chloride, CB2, compound 1, cisatracurium, succinylcholine, neostigmine, sterile water, 95% alcohol.
  • SPF-grade male SD rats that have passed quarantine were used and housed in an environment with a room temperature of 22 ⁇ 0.5°C, an air exchange rate of 20-50/h, an airflow velocity of 0.05-0.18m/s, and a 12/12-hour day/night light/dark cycle.
  • the rats were allowed to acclimatize in the facility for at least 3 days, with 6 rats per cage, until their weight reached 220g-250g before the start of the experiment.
  • test sample was reconstituted using 0.9% sodium chloride. After calculating the content, the required amount of test sample was weighed, dissolved in 0.9% sodium chloride injection (within 30 minutes), and then mixed thoroughly using a vortex mixer. CB2 was reconstituted with purified water.
  • Rats were randomly divided into CB2, compound 1, and neostigmine groups, with 5 rats in each group (based on the actual number of rats in each group).
  • the drug administration volume was 2 mL/kg for each group.
  • a muscle relaxant cistracurium
  • ED90 dose 0.8 mg/kg
  • an antagonist the test drug and neostigmine
  • muscle tone should be observed at this point.
  • the experiment was stopped once muscle tone naturally recovered to above 95%. Muscle tone signals were continuously recorded throughout the experiment. The onset time and clinical efficacy were statistically analyzed. By comparing muscle tone signals after drug administration, the reversal effect of the antagonist was assessed and compared.
  • the rats were weighed and, once they were in a stable mood, 25% urethane was prepared from ethyl carbamate and anesthetized by intraperitoneal injection at a rate of 1 mL/100 g. After the pain reflex disappeared, the rats were fixed in a prone position on a foam board, and hair was removed from the buttocks and the outer side of the right thigh.
  • the gastrocnemius muscle ligation suture was connected to the tension transducer, and the stimulator was connected to the sciatic nerve.
  • the input signal was set to tension, and the parameters were set as square wave, fine voltage, series stimulation, delay 0.05ms, pulse width 0.2ms, frequency 2Hz, intensity 0.225 ⁇ 0.025V, intensity increment 0, series length 4, main period 12s, and number of stops 30000.
  • the muscle contraction curve was recorded. During the measurement, the muscle nerve was kept moist with physiological saline every 3-5 minutes.
  • administer medication via the jugular vein.
  • administer twice the ED 90 dose of muscle relaxant cistracurium
  • the muscle tone curve should decrease. 30-60 seconds after administration, inject the antagonist (test sample or neostigmine).
  • administer the ED 90 dose of muscle relaxant succinylcholine. Wait again for the muscle tone curve to recover to above 95% before stopping the experiment. Continuously record the muscle tone curve throughout the experiment.
  • the onset time and secondary muscle relaxation onset time were statistically analyzed using a biological function experimental system, and the statistical standards are as follows.
  • TOF 0.9 The time for the T4 / T1 value of TOF string stimulation to recover to approximately 90% - the time of antagonist administration.
  • compound 1 can achieve the efficacy level of neostigmine at 20 mg/kg, which is superior to CB2.
  • Example 2 Five mg of the sodium salt obtained in Example 2 was added to 0.5 mL of solvent, as shown in Table 7. The mixture was stirred overnight at room temperature, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as disodium salt crystal form A. The XRPD spectrum is shown in Figure 18, and the positions of its characteristic peaks are shown in Table 8. Ionic results showed a sodium ion content of 2.36%.
  • Example 2 Six mg of the sodium salt obtained in Example 2 was dissolved in 0.06 mL of water, and 0.3 mL of solvent (as shown in Table 9) was added. The mixture was stirred overnight at room temperature, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis identified the product as disodium salt crystal form B. The XRPD spectrum is shown in Figure 19, and the positions of its characteristic peaks are shown in Table 10. Ionic results showed that the sodium ion content was 2.47%.
  • Example 3 Five mg of the sodium salt obtained in Example 3 was added to 0.5 mL of solvent, as shown in Table 11. The mixture was stirred overnight at room temperature, centrifuged, and vacuum dried to obtain a solid product. X-ray powder diffraction analysis identified the product as tetrasodium salt crystal form A. The XRPD spectrum is shown in Figure 20, and the positions of its characteristic peaks are shown in Table 12. Ionic results showed a sodium ion content of 4.29%.
  • Example 3 Six mg of the sodium salt obtained in Example 3 was dissolved in 0.06 mL of water, and 0.3 mL of solvent (as shown in Table 13) was added. The mixture was stirred overnight at room temperature, centrifuged, and vacuum dried to obtain a solid. X-ray powder diffraction analysis showed that the product was a tetrasodium salt of crystal form A.
  • Example 5 Five mg of the sodium salt obtained in Example 5 was added to 0.5 mL of solvent, as shown in Table 14. The mixture was stirred at room temperature for two days, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was amorphous, and the XRPD pattern is shown in Figure 2. Ion chromatography results showed that the sodium ion content was 8.93%.
  • Example 5 5 mg of the sodium salt obtained in Example 5 was dissolved in 0.05 mL of water and allowed to evaporate and solidify at room temperature to obtain the product.
  • Example 5 100 mg of the sodium salt obtained in Example 5 was added to 3 mL of 10% water/methanol (v/v), seed crystals were added, and the mixture was stirred at room temperature for 1 day. After centrifugation and vacuum drying, a solid was obtained.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form A.
  • the XRPD spectrum is shown in Figure 3, and the positions of its characteristic peaks are shown in Table 15. TGA spectroscopy showed a weight loss of 11.04% from 31°C to 175°C. Ionic analysis revealed a sodium ion content of 8.4%.
  • Example 5 5 mg of the sodium salt obtained in Example 5 was dissolved in 0.025 mL of water, and 0.125 mL of methanol was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and dried under vacuum to obtain a solid. X-ray powder diffraction analysis showed that the product was an octasodium salt of crystal form A.
  • Example 5 5 mg of the sodium salt obtained in Example 5 was dissolved in 0.05 mL of water, and 0.25 mL of tetrahydrofuran was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and vacuum dried to obtain a solid.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form B.
  • the XRPD spectrum is shown in Figure 4, and the positions of its characteristic peaks are shown in Table 16.
  • TGA spectroscopy showed a weight loss of 13.05% from 31°C to 176°C.
  • Ionic analysis revealed a sodium ion content of 8.12%.
  • DVS testing showed that under normal storage conditions (i.e., 25°C, 60% RH), the sample gained approximately 14.71% more weight due to moisture absorption; under accelerated testing conditions (i.e., 70% RH), the weight gain was approximately 16.66%; and under extreme conditions (90% RH), the weight gain was approximately 25.95%. Retesting of the crystal form after DVS testing showed no change in crystal form.
  • Example 5 5 mg of the sodium salt obtained in Example 5 was dissolved in 0.05 mL of water, and 0.25 mL of acetonitrile was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and vacuum dried to obtain a solid.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form C.
  • the XRPD spectrum is shown in Figure 5, and the positions of its characteristic peaks are shown in Table 17. TGA spectroscopy showed a weight loss of 10.00% from 31°C to 169°C.
  • Example 5 Five mg of the sodium salt obtained in Example 5 was added to 0.5 mL of 10% water/isopropanol (v/v), stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain the product.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form D.
  • the XRPD spectrum is shown in Figure 6, and the positions of its characteristic peaks are shown in Table 18.
  • TGA spectroscopy showed a weight loss of 9.65% from 31°C to 164°C.
  • Ion analysis revealed a sodium ion content of 8.14%.
  • Example 5 Five mg of the sodium salt obtained in Example 5 was added to 0.5 mL of 10% water/acetone (v/v), stirred at room temperature for 3 days, centrifuged, and dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was an octasodium salt of crystal form D.
  • Example 5 5 mg of the sodium salt obtained in Example 5 was dissolved in 0.025 mL of water, and 0.125 mL of acetone was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and then dried under vacuum to obtain the product.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form E.
  • the XRPD spectrum is shown in Figure 7, and the characteristic peak positions are shown in Table 19.
  • TGA spectroscopy showed a weight loss of 11.35% from 31°C to 190°C.
  • Ionic analysis revealed a sodium ion content of 8.7%.
  • Example 5 90 mg of the sodium salt obtained in Example 5 was dissolved in 0.45 mL of water, and 2.25 mL of methanol was added. The mixture was stirred at room temperature to induce crystallization, centrifuged, and the solid was dried under vacuum to obtain the product. X-ray powder diffraction analysis showed that the product was an octasodium salt with crystal form E.
  • the sodium salt crystal form A from Example 14 was subjected to DVS cycling to obtain the product.
  • X-ray powder diffraction analysis identified this product as the octasodium salt crystal form F.
  • the XRPD spectrum is shown in Figure 8, and the positions of its characteristic peaks are shown in Table 20.
  • TGA spectroscopy showed a weight loss of 10.12% at 30°C-222°C.
  • Example 5 100 mg of the sodium salt obtained in Example 5 was dissolved in 0.5 mL of water, and 2.5 mL of methanol was added. The mixture was stirred at room temperature to induce crystallization, yielding a solid.
  • X-ray powder diffraction analysis identified the product as the octasodium salt G.
  • the XRPD spectrum is shown in Figure 9, and the positions of its characteristic peaks are shown in Table 21. Ionic results showed a sodium ion content of 8.26%.
  • the sodium salt crystal form E from Example 21 was placed at room temperature (92.5% RH) for 7 days to obtain the product.
  • X-ray powder diffraction analysis confirmed that the product was an octasodium salt crystal form G.
  • Example 5 100 mg of the sodium salt obtained in Example 5 was added to 3 mL of 10% water/methanol (v/v) and stirred at room temperature for 1 day to obtain a solid.
  • X-ray powder diffraction analysis identified the product as octasodium salt crystal form H.
  • the XRPD spectrum is shown in Figure 10, and the positions of its characteristic peaks are shown in Table 22.
  • the sodium salt crystal form B of Example 16 was placed at room temperature (75% RH) for 7 days to obtain the product.
  • X-ray powder diffraction analysis determined the product to be octasodium salt crystal form I.
  • the XRPD spectrum is shown in Figure 11, and the positions of its characteristic peaks are shown in Table 23.
  • the sodium salt amorphous product from Example 5 was placed at room temperature (75% RH) for 7 days to obtain the product.
  • X-ray powder diffraction analysis determined the product to be octasodium salt crystal form J.
  • the XRPD spectrum is shown in Figure 12, and the positions of its characteristic peaks are shown in Table 24.
  • X-ray powder diffraction analysis identified the product as ammonium salt crystal form c.
  • the XRPD spectrum is shown in Figure 23, and the positions of its characteristic peaks are listed in Table 27.
  • the DSC spectrum shows endothermic peaks at 75.47°C and 292.08°C.
  • the TGA spectrum shows a weight loss of 10.62% between 30°C and 162°C. Ion detection results indicate an ammonium ion content of 4.8%.
  • X-ray powder diffraction analysis identified the product as ammonium salt crystal form d.
  • the XRPD spectrum is shown in Figure 24, and the positions of its characteristic peaks are listed in Table 28.
  • the DSC spectrum shows endothermic peaks at 82.15°C and 294.41°C.
  • the TGA spectrum shows a weight loss of 13.17% between 30°C and 215°C. Ion detection results indicate an ammonium ion content of 4.9%.
  • ammonium salt crystal form d of Example 34 was placed at 75% RH for 7 days. After X-ray powder diffraction, the product was defined as ammonium salt crystal form e.
  • the XRPD spectrum is shown in Figure 25, and the positions of its characteristic peaks are shown in Table 29.
  • ammonium salt crystal form d from Example 34 was placed at 92.5% RH for 7 days to obtain a solid product.
  • X-ray powder diffraction analysis identified this product as ammonium salt crystal form f.
  • the XRPD spectrum is shown in Figure 26, and the positions of its characteristic peaks are shown in Table 30.
  • XRPD X-ray powder diffraction
  • X-ray powder diffraction analysis identified the product as free crystalline form C.
  • the XRPD spectrum is shown in Figure 28, and the positions of its characteristic peaks are shown in Table 39.
  • the DSC spectrum shows endothermic peaks at 94.76°C and 105.74°C.
  • the TGA spectrum shows a weight loss of 17.36% between 30°C and 189°C.
  • X-ray powder diffraction analysis identified the product as free-state crystalline form D.
  • the XRPD spectrum is shown in Figure 29, and the positions of its characteristic peaks are shown in Table 40.
  • the DSC spectrum shows endothermic peaks at 108.40°C and 115.28°C.
  • the TGA spectrum shows a weight loss of 15.38% between 30°C and 186°C.
  • the free crystal form B of Example 45 was placed at 40°C/75%RH for 14 days to obtain a solid product.
  • X-ray powder diffraction analysis determined the product to be free crystal form E.
  • the XRPD spectrum is shown in Figure 30, and the positions of its characteristic peaks are shown in Table 41.

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Abstract

本公开涉及一种葫芦脲类化合物的可药用盐、其结晶形式及用途。具体而言，本公开提供式（1）化合物的可药用盐、晶型及其制备方法，相应盐具有良好的稳定性，可更好地用于临床治疗。

Description

一种葫芦脲衍生物的可药用盐、其结晶形式及用途 技术领域
本公开属于医药技术领域，涉及一种葫芦脲衍生物的游离碱晶型、可药用盐、其结晶形式及用途。
背景技术
肌松是全身麻醉中三大基本要素之一。肌松药在满足气管插管和手术需要的同时也带来了安全隐患——肌松残余，这会导致患者主观上不适感受以及低氧血症、反流误吸等一系列肺部并发症。了降低肌松残余发生率，往往通过使用中短效肌松药、优化术中肌松管理、术毕拮抗肌松药效应、围术期客观肌松监测等措施，使得肌松残余这一临床难题不断取得进展。
术毕拮抗肌松，是指通过采用肌松药拮抗剂，来逆转非去极化肌松药的残留作用。目前，常用的肌松药拮抗剂大致可分为两类：一类是竞争性肌松拮抗剂，包括作为乙酰胆碱抑制剂的新斯的明等；另一类是选择性肌松拮抗剂，包括作为甾类肌松药拮抗剂的舒更葡萄钠、作为苄异喹啉类肌松药拮抗剂的半胱氨酸等。
PCT/CN2023/131007公开了一种具有葫芦脲结构的非闭合环CB[n]型的分子容器，具有式1所示结构其可与苄异喹啉类和甾类肌松药高效结合，通过覆盖苄异喹啉类和甾类肌松药的季铵位点，以阻止肌松药与神经肌肉胆碱受体的结合，从而迅速实现逆转肌松作用。
成盐可改善药物某一些不理想的物理化学或生物学性质。开发出相对于式1化合物在理化性质或药学性质方面具有更优异的性质的盐是具有重要意义的。鉴于固体药物晶型及其稳定性对其在临床治疗中的重要性，深入研究式1化合物的可药用盐的多晶型，对开发适合工业生产且生物活性良好的药物也是具有重要意义。
发明内容
本公开提供一种式1化合物的可药用盐，所述可药用盐选自钠盐、钾盐、钙盐、胆碱盐、乙醇胺盐、二乙醇胺盐、二乙胺盐、氨丁三醇盐、精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐，
本公开还提供一种式1化合物可药用盐的制备方法，包括将式1化合物与碱反应的步骤，所述碱选自氢氧化钠、氢氧化钾、氢氧化钙、氢氧化胆碱、氨丁三醇、精氨酸、赖氨酸、乙醇胺、二乙胺、葡甲胺、二乙醇胺、氨水。
本公开成盐所用溶剂选自但不限于丙酮、乙腈、水、乙醇、2-甲基四氢呋喃、乙酸乙酯、异丙醇、环己烷、正庚烷、1，4-二氧六环、2-丁酮、四氢呋喃、甲醇。
进一步地，在可选实施方案中，制备前述可药用盐的方法还包括析晶，过滤、洗涤或干燥等步骤。
在可选实施方案中，式1化合物与碱的化学配比为3:1-1:8，包括但不限于3:1、2:1、1:1、1:2、1:3、1:4、1:5、1:6、1:7、1:8。
在另一实施方案中，式1化合物与碱的化学配比为2:1-1:8。
在可选实施方案中，所述式1化合物与钠离子的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与钾离子的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与钙离子的化学配比为1:2或1:4。
在可选实施方案中，所述式1化合物与铵离子的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与胆碱的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与氨丁三醇的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与精氨酸的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与赖氨酸的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与乙醇胺的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与二乙醇胺的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与葡甲胺的化学配比为1:2或1:4或1:6或1:8。
在可选实施方案中，所述式1化合物与二乙胺的化学配比为1:2或1:4或1:6或1:8。
在一些实施方案中，本公开提供的式1化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在9.195、14.303、18.343、21.652处有特征峰。
在一些实施方案中，式1化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
本公开还提供一种制备式1化合物的晶型A的方法，所述方法包括以下任一方法：
方法一：将式1化合物加入溶剂I中搅拌，所述溶剂I选自7％水/乙醇、10％水/异丙醇、10％水/丙酮、四氢呋喃；
方法二：将式1化合物溶于水，加入溶剂II搅拌；所述溶剂II选自丙酮、乙腈。
在一些实施方案中，式1化合物二钠盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物二钠盐的制备方法，所述制备方法包括将式1化合物溶于水后，加入2当量的氢氧化钠的步骤。
本公开提供的式1化合物的二钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在9.720、11.232、14.901、15.811、19.759处有特征峰。
在一些实施方案中，式1化合物二钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
本公开还提供一种制备式1化合物二钠盐晶型A的方法，所述方法包括将式1化合物二钠盐加入溶剂II，搅拌的步骤。
本公开提供的式1化合物的二钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在6.654、8.040、8.883、11.778、14.719、21.649处有特征峰。
在一些实施方案中，式1化合物二钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
本公开还提供一种制备式1化合物二钠盐晶型B的方法，所述方法包括将式1化合物二钠盐溶于水，加入溶剂III，搅拌，所述溶剂III选自丙酮、乙腈、四氢呋喃。
在一些实施方案中，式1化合物四钠盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物四钠盐的制备方法，所述制备方法包括将式1化合物溶于水后，加入4当量的氢氧化钠的步骤。
本公开提供的式1化合物的四钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在8.334、9.972、15.260、17.155、20.557、22.867处有特征峰。
在一些实施方案中，式1化合物四钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
本公开还提供一种制备式1化合物四钠盐晶型A的方法，所述方法包括以下任一方法：
方法一：将式1化合物四钠盐加入10％水/异丙醇或10％水/丙酮，搅拌；
方法二：将式1化合物四钠盐溶于水，加入丙酮或四氢呋喃，搅拌。
在一些实施方案中，式1化合物六钠盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物六钠盐的制备方法，所述制备方法包括将式1化合物溶于水后，加入6当量的氢氧化钠的步骤。
在一些实施方案中，式1化合物八钠盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物八钠盐的制备方法，所述制备方法包括将式1化合物溶于水后，加入8当量的氢氧化钠的步骤。
本公开提供的式1化合物的八钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在5.052、7.543、11.974、21.775、23.581处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在5.052、5.598、7.543、10.955、11.974、17.533、18.583、21.775、23.581、25.051处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在5.052、5.598、7.543、10.268、10.955、11.400、11.974、12.912、15.139、17.533、18.583、21.775、23.581、25.051处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
本公开还提供一种制备式1化合物八钠盐晶型A的方法，所述方法包括以下任一方法：
方法一：将式1化合物八钠盐溶于水，加入甲醇，搅拌；
方法二：将式1化合物八钠盐加入10％水/甲醇(v/v)中，加入晶种，搅拌。
本公开提供的式1化合物的八钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在6.402、8.124、12.072、16.357、19.255、21.775、27.109处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在5.310、6.402、8.124、10.434、12.072、14.845、16.357、19.255、20.599、21.775、22.573、23.917、27.109、29.461处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在5.310、6.402、8.124、10.434、12.072、14.089、14.845、16.357、19.255、20.599、21.775、22.573、23.917、24.589、27.109、28.285、29.461处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
本公开还提供一种制备式1化合物八钠盐晶型B的方法，所述方法包括将式1化合物八钠盐溶于水，加入四氢呋喃搅拌的步骤。
本公开提供的式1化合物的八钠盐晶型C，以衍射角2θ角度表示的X-射线粉末衍射图，在5.772、6.738、8.166、9.888、21.901处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型C，以衍射角2θ角度表示的X-射线粉末衍射图，在5.772、6.738、8.166、9.888、12.912、14.761、16.693、21.901处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱如图5所示。
本公开还提供一种制备式1化合物八钠盐晶型C的方法，所述方法包括将式1化合物八钠盐溶于水中，加入乙腈搅拌的步骤。
本公开提供的式1化合物的八钠盐晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在5.100、8.544、12.744、15.391、21.397处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在5.100、6.528、8.544、12.744、15.391、16.567、19.885、21.397、27.235处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在5.100、6.528、8.544、12.744、15.391、16.567、19.885、21.397、23.329、24.547、26.185、27.235处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱如图6所示。
本公开还提供一种制备式1化合物八钠盐晶型D的方法，所述方法包括将式1化合物八钠盐加入溶剂I中，搅拌3天的步骤；所述溶剂I选自10％水/异丙醇(v/v)、10％水/丙酮(v/v)。
本公开提供的式1化合物的八钠盐晶型E，以衍射角2θ角度表示的X-射线粉末衍射图，在8.082、9.762、16.525、20.599处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型E，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
本公开还提供一种制备式1化合物八钠盐晶型E的方法，所述方法包括将式1化合物八钠盐溶于水，加入丙酮搅拌的步骤。
本公开提供的式1化合物的八钠盐晶型F，以衍射角2θ角度表示的X-射线粉末衍射图，在13.543、15.055、17.701、21.691、25.933处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型F，以衍射角2θ角度表示的X-射线粉末衍射图谱如图8所示。
本公开还提供一种制备式1化合物八钠盐晶型F的方法，所述方法包括将八钠盐晶型A经DVS循环的步骤。
本公开提供的式1化合物的八钠盐晶型G，以衍射角2θ角度表示的X-射线粉末衍射图，在6.515、13.061、14.807、17.854、21.703处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型G，以衍射角2θ角度表示的X-射线粉末衍射图，在5.946、6.515、12.036、13.061、14.807、17.854、21.703、24.406、27.046处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型G，以衍射角2θ角度表示的X-射线粉末衍射图，在5.946、6.515、11.521、12.036、13.061、14.807、17.854、20.952、21.703、24.406、27.046处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型G，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
本公开还提供一种制备式1化合物八钠盐晶型G的方法，所述方法包括以下任一方法：
方法一：将式1化合物八钠盐溶于水，加入甲醇搅拌的步骤。
方法二：将式1化合物八钠盐晶型E于92.5％RH放置7天的步骤。
本公开提供的式1化合物的八钠盐晶型H，以衍射角2θ角度表示的X-射线粉末衍射图，在9.132、10.921、12.786、14.845处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型H，以衍射角2θ角度表示的X-射线粉末衍射图谱如图10所示。
本公开还提供一种制备式1化合物八钠盐晶型H的方法，包括将式1化合物八钠盐加入10％水/甲醇(v/v)，搅拌1天的步骤。
本公开提供的式1化合物的八钠盐晶型I，以衍射角2θ角度表示的X-射线粉末衍射图，在6.402、11.274、17.743、25.219处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型I，以衍射角2θ角度表示的X-射线粉末衍射图谱如图11所示。
本公开还提供一种制备式1化合物八钠盐晶型I的方法，包括将式1化合物八钠盐晶型B于75％RH室温放置7天的步骤。
本公开提供的式1化合物的八钠盐晶型J，以衍射角2θ角度表示的X-射线粉末衍射图，在5.436、9.048、11.232、12.618、13.374、16.693、17.995、21.019处有特征峰。
在一些实施方案中，式1化合物的八钠盐晶型J，以衍射角2θ角度表示的X-射线粉末衍射图谱如图12所示。
本公开还提供一种制备式1化合物八钠盐晶型J的方法，包括将式1化合物八钠盐于75％RH室温放置7天的步骤。
在一些实施方案中，式1化合物铵盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物铵盐的制备方法，所述制备方法包括将式1化合物加入丙酮，再加入氨水的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型a，以衍射角2θ角度表示的X-射线粉末衍射图，在5.523、7.155、13.226、14.686、19.621、20.993处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型a，以衍射角2θ角度表示的X-射线粉末衍射图，在5.523、7.155、7.971、11.199、13.226、14.686、15.132、16.170、18.285、19.621、20.993处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型a，以衍射角2θ角度表示的X-射线粉末衍射图，在5.523、7.155、7.971、11.199、13.226、14.686、15.132、16.170、18.285、19.621、20.993、22.218、22.997、25.742处有特征峰。
在一些实施方案中，式1化合物铵盐晶型a，以衍射角2θ角度表示的X-射线粉末衍射图谱如图21所示。
本公开还提供一种制备式1化合物铵盐晶型a的方法，所述方法包括将式1化合物溶于乙醇，加入氨水搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型b，以衍射角2θ角度表示的X-射线粉末衍射图，在6.524、7.489、8.342、15.057、19.992、24.295处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型b，以衍射角2θ角度表示的X-射线粉末衍射图，在6.524、7.489、8.342、11.978、14.278、15.057、17.877、19.992、21.661、22.589、24.295处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型b，以衍射角2θ角度表示的X-射线粉末衍射图，在6.524、7.489、8.342、10.680、11.978、14.278、15.057、16.541、17.877、19.101、19.992、21.661、22.589、24.295、26.336处有特征峰。
在一些实施方案中，式1化合物铵盐晶型b，以衍射角2θ角度表示的X-射线粉末衍射图谱如图22所示。
本公开还提供一种制备式1化合物铵盐晶型b的方法，所述方法包括将式1化合物加入丙酮，再加入氨水搅拌的步骤。
在一些实施方案中，制备式1化合物铵盐晶型b的方法包括将式1化合物溶于乙醇，再加入氨水搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型c，以衍射角2θ角度表示的X-射线粉末衍射图，在5.225、8.214、14.872、17.803、22.700处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型c，以衍射角2θ角度表示的X-射线粉末衍射图，在5.225、6.042、6.858、8.214、14.872、15.725、16.912、17.803、22.700处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型c，以衍射角2θ角度表示的X-射线粉末衍射图，在5.225、6.042、6.858、8.214、10.049、10.568、14.872、15.725、16.912、17.803、22.700、23.665处有特征峰。
在一些实施方案中，式1化合物铵盐晶型c，以衍射角2θ角度表示的X-射线粉末衍射图谱如图23所示。
本公开还提供一种制备式1化合物铵盐晶型c的方法，所述方法包括将式1化合物加入2-甲基四氢呋喃，再加入氨水搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型d，以衍射角2θ角度表示的X-射线粉末衍射图，在7.378、8.231、9.881、14.977、19.918、22.403处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型d，以衍射角2θ角度表示的X-射线粉末衍射图，在6.228、7.378、8.231、9.881、13.726、14.303、14.977、16.756、19.918、22.403、24.258、26.076处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型d，以衍射角2θ角度表示的X-射线粉末衍射图，在6.228、7.378、8.231、9.881、11.199、11.570、12.117、12.906、13.726、14.303、14.977、16.756、19.064、19.918、20.548、20.956、22.403、24.258、26.076处有特征峰。
在一些实施方案中，式1化合物铵盐晶型d，以衍射角2θ角度表示的X-射线粉末衍射图谱如图24所示。
本公开还提供一种制备式1化合物铵盐晶型d的方法，所述方法包括将式1化合物溶于乙醇，再加入氨水搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型e，以衍射角2θ角度表示的X-射线粉末衍射图，在7.266、8.445、12.043、13.253、16.216、20.851、24.365处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型e，以衍射角2θ角度表示的X-射线粉末衍射图，在5.152、7.266、8.445、9.805、10.309、12.043、13.253、14.872、16.216、19.880、20.851、21.587、22.552、24.365处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型e，以衍射角2θ角度表示的X-射线粉末衍射图，在5.152、7.266、8.445、9.805、10.309、11.607、12.043、12.831、13.253、14.204、14.872、16.216、17.283、19.509、19.880、20.851、21.587、22.552、23.628、24.365处有特征峰。
在一些实施方案中，式1化合物铵盐晶型e，以衍射角2θ角度表示的X-射线粉末衍射图谱如图25所示。
本公开还提供一种制备式1化合物铵盐晶型e的方法，所述方法包括将式1化合物的铵盐晶型d置于75％RH下7天的步骤。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型f，以衍射角2θ角度表示的X-射线粉末衍射图，在5.337、9.752、10.531、12.460、18.879处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型f，以衍射角2θ角度表示的X-射线粉末衍射图，在5.337、9.752、10.531、11.385、12.460、13.573、14.353、15.354、17.914、18.879处有特征峰。
在一些实施方案中，本公开提供的式1化合物的铵盐晶型f，以衍射角2θ角度表示的X-射线粉末衍射图，在5.337、9.752、10.531、11.385、12.460、13.573、14.353、15.354、17.914、18.879、19.880、21.327处有特征峰。
在一些实施方案中，式1化合物铵盐晶型f，以衍射角2θ角度表示的X-射线粉末衍射图谱如图26所示。
本公开还提供一种制备式1化合物铵盐晶型f的方法，所述方法包括将式1化合物铵盐晶型d置于92.5％RH下7天的步骤。
在一些实施方案中，式1化合物氨丁三醇盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物氨丁三醇盐的制备方法，所述制备方法包括将式1化合物加入溶剂IV，再加入氨丁三醇的步骤，所述溶剂IV选自丙酮、乙醇、乙酸乙酯。
在一些实施方案中，式1化合物葡甲胺盐为无定形，其X-射线粉末衍射图谱的衍射角2θ角在3-50°范围内没有明显特征峰。
在一些实施方案中，本公开提供式1化合物葡甲胺盐的制备方法，所述制备方法包括将式1化合物加入溶剂IV，再加入葡甲胺的步骤，所述溶剂IV选自丙酮、乙醇、乙酸乙酯。
在一些实施方案中，本公开提供的式1化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在6.629、14.555、17.926、19.716、24.300处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在6.629、9.243、13.425、14.555、17.926、19.716、21.879、24.300、26.117、27.220处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型B，以衍射角2θ角度表示的X-射线粉末衍射图，在5.857、6.629、9.243、11.440、12.097、13.425、14.555、16.096、17.926、19.716、21.879、22.440、22.883、24.300、24.666、26.117、27.220、29.030处有特征峰。
在一些实施方案中，式1化合物晶型B，以衍射角2θ角度表示的X-射线粉末衍射图谱如图27所示。
本公开还提供一种制备式1化合物晶型B的方法，所述方法包括以下任一方法：
方法一：将式1化合物溶于溶剂V中，挥发溶剂，所述溶剂V选自水、甲醇、乙醇、异丙醇、乙腈、环己烷中的一种或多种；
方法二：将式1化合物加入溶剂VI中，搅拌，所述溶剂VI选自1,4-二氧六环、正庚烷、10％水/丙酮中的一种；
方法三：将式1化合物溶于水，加入1，4-二氧六环，搅拌。
在一些实施方案中，本公开提供的式1化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图，在6.487、11.433、16.309、20.956、23.613处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图，在6.487、11.433、16.309、17.543、17.988、18.767、19.695、20.956、23.613、24.963、27.597处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型C，以衍射角2θ角度表示的X-射线粉末衍射图，在6.487、11.433、16.309、17.543、17.988、18.767、19.695、20.956、23.613、24.963、25.631、26.076、27.597处有特征峰。
在一些实施方案中，式1化合物晶型C，以衍射角2θ角度表示的X-射线粉末衍射图谱如图28所示。
本公开还提供一种制备式1化合物晶型C的方法，所述方法包括将式1化合物加入丙酮，搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在8.454、11.607、16.073、18.174、21.105、22.218处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在8.454、11.607、14.204、16.073、18.174、20.103、21.105、22.218、23.294、25.631处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型D，以衍射角2θ角度表示的X-射线粉末衍射图，在8.454、11.607、12.535、13.054、14.204、16.073、17.543、18.174、20.103、21.105、22.218、23.294、25.631处有特征峰。
在一些实施方案中，式1化合物晶型D，以衍射角2θ角度表示的X-射线粉末衍射图谱如图29所示。
本公开还提供一种制备式1化合物晶型D的方法，所述方法包括将式1化合物加入乙腈，搅拌的步骤。
在一些实施方案中，本公开提供的式1化合物的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图，在4.715、7.118、7.637、9.270、12.052、20.214处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图，在4.715、6.005、7.118、7.637、9.270、12.052、13.796、15.132、20.214处有特征峰。
在一些实施方案中，本公开提供的式1化合物的晶型E，以衍射角2θ角度表示的X-射线粉末衍射图，在4.715、6.005、7.118、7.637、9.270、12.052、13.796、15.132、17.654、20.214、22.886处有特征峰。
在一些实施方案中，式1化合物晶型E，以衍射角2θ角度表示的X-射线粉末衍射图谱如图30所示。
本公开还提供一种制备式1化合物晶型E的方法，所述方法包括将式1化合物晶型B放置于40℃/75％RH条件下14天的步骤。
本公开还提供了一种药物组合物，其含有前述任一可药用盐，游离酸晶型A、晶型B、晶型C、晶型D、晶型E，铵盐晶型a、晶型b、晶型c、晶型d、晶型e、晶型f，二钠盐晶型A，二钠盐晶型B，四钠盐晶型A，八钠盐晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I或晶型J，和任选自药学上可接受的赋形剂中的药用辅料。
本公开还提供了一种药物组合物，其由任选地前述可药用盐，游离酸晶型A、晶型B、晶型C、晶型D、晶型E，铵盐晶型a、晶型b、晶型c、晶型d、晶型e、晶型f，二钠盐晶型A，二钠盐晶型B，四钠盐晶型A，八钠盐晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I或晶型J，和任选药学上可接受的赋形剂制备而成。
本公开还提供了一种药物组合物的制备方法，包括将前述任一可药用盐，游离酸晶型A、晶型B、晶型C、晶型D、晶型E，铵盐晶型a、晶型b、晶型c、晶型d、晶型e、晶型f，二钠盐晶型A，二钠盐晶型B，四钠盐晶型A，八钠盐晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I或晶型J，与药学上可接受的赋形剂混合的步骤。
本公开还提供了前述任一可药用盐，游离酸晶型A、晶型B、晶型C、晶型D、晶型E，铵盐晶型a、晶型b、晶型c、晶型d、晶型e、晶型f，二钠盐晶型A，二钠盐晶型B，四钠盐晶型A，八钠盐晶型A、晶型B、晶型C、晶型D、晶型E、晶型F、晶型G、晶型H、晶型I或晶型J或由前述组合物在制备逆转药物诱导的神经肌肉阻滞和/或麻醉的药物的用途。
本公开所述的“2θ或2θ角度”是指衍射角，θ为布拉格角，单位为°或度；每个特征峰2θ的误差范围为±0.20(包括超过1位小数的数字经过四舍五入后的情况)，具体为-0.20、-0.19、-0.18、-0.17、-0.16、-0.15、-0.14、-0.13、-0.12、-0.11、-0.10、-0.09、-0.08、-0.07、-0.06、-0.05、-0.04、-0.03、-0.02、-0.01、0.00、0.01、0.02、0.03、0.04、0.05、0.06、0.07、0.08、0.09、0.10、0.11、0.12、0.13、0.14、0.15、0.16、0.17、0.18、0.19、0.20。
本公开中数值如有关物质含量为测定计算的数据，不可避免存在一定程度的误差。一般而言，±10％均属于合理误差范围内。随其所用之处的上下文而有一定程度的误差变化，该误差变化不超过±10％，可以为±9％、±8％、±7％、±6％、±5％、±4％、±3％、±2％或±1％，优选±5％。
本公开晶型制备方法中所用的起始原料可以是任意形式的化合物，具体形式包括但不限于：无定形、任意晶型、水合物、溶剂合物等。
本公开中所述干燥温度一般为25℃-100℃，优选40℃-70℃，可以常压干燥，也可以减压干燥。
本公开中所述的析晶的方法有室温析晶、冷却析晶、挥发溶剂析晶、加入晶种诱导析晶等，所述冷却的温度选自65℃以下，优选-10℃至60℃，所述析晶过程中还可以搅拌。
本公开中所述的“差示扫描量热分析或DSC”是指在样品升温或恒温过程中，测量样品与参考物之间的温度差、热流差，以表征所有与热效应有关的物理变化和化学变化，得到样品的相变信息。
依据《中国药典》2015年版四部中“9103药物引湿性指导原则”中引湿性特征描述与引湿性增重的界定，
潮解：吸收足量水分形成液体；
极具引湿性：引湿增重不小于15％；
有引湿性：引湿增重小于15％但不小于2％；
略有引湿性：引湿增重小于2％但不小于0.2％；
无或几乎无引湿性：引湿增重小于0.2％。
本公开中所述的“赋形剂”包括但不限于任何已经被美国食品和药物管理局批准对于人类或家畜动物使用可接受的任何助剂、载体、助流剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增香剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂或乳化剂。
附图说明
图1.顺阿曲库铵给与肌松药拮抗剂的TOF0.9时间，其中***p<0.001。
图2.式1化合物八钠盐无定形的XRPD谱图。
图3.式1化合物八钠盐晶型A的XRPD谱图。
图4.式1化合物八钠盐晶型B的XRPD谱图。
图5.式1化合物八钠盐晶型C的XRPD谱图。
图6.式1化合物八钠盐晶型D的XRPD谱图。
图7.式1化合物八钠盐晶型E的XRPD谱图。
图8.式1化合物八钠盐晶型F的XRPD谱图。
图9.式1化合物八钠盐晶型G的XRPD谱图。
图10.式1化合物八钠盐晶型H的XRPD谱图。
图11.式1化合物八钠盐晶型I的XRPD谱图。
图12.式1化合物八钠盐晶型J的XRPD谱图。
图13.式1化合物无定形的XRPD谱图。
图14.式1化合物二钠盐无定形的XRPD谱图。
图15.式1化合物四钠盐无定形的XRPD谱图。
图16.式1化合物六钠盐无定形的XRPD谱图。
图17.式1化合物游离态晶型A的XRPD谱图。
图18.式1化合物二钠盐晶型A的XRPD谱图。
图19.式1化合物二钠盐晶型B的XRPD谱图。
图20.式1化合物四钠盐晶型A的XRPD谱图。
图21.式1化合物铵盐晶型a的XRPD谱图。
图22.式1化合物铵盐晶型b的XRPD谱图。
图23.式1化合物铵盐晶型c的XRPD谱图。
图24.式1化合物铵盐晶型d的XRPD谱图。
图25.式1化合物铵盐晶型e的XRPD谱图。
图26.式1化合物铵盐晶型f的XRPD谱图。
图27.式1化合物游离态晶型B的XRPD谱图。
图28.式1化合物游离态晶型C的XRPD谱图。
图29.式1化合物游离态晶型D的XRPD谱图。
图30.式1化合物游离态晶型E的XRPD谱图。
具体实施方式
以下将结合实施例或实验例更详细地解释本公开，本公开中的实施例或实验例仅用于说明本公开中的技术方案，并非限定本公开中的实质和范围。
实验所用仪器的测试条件：
化合物的结构是通过核磁共振(NMR)或/和质谱(MS)来确定的。NMR位移(δ)以10-6(ppm)的单位给出。NMR的测定是用Bruker AVANCE NEO 500M核磁仪，测定溶剂为氘代二甲基亚砜(DMSO-d6)、氘代氯仿(CDCl3)、氘代甲醇(CD3OD)，内标为四甲基硅烷(TMS)。
MS的测定用Agilent 1200/1290DAD-6110/6120Quadrupole MS液质联用仪(生产商：Agilent，MS型号：6110/6120Quadrupole MS)、waters ACQuity UPLC-QD/SQD(生产商：waters，MS型号：waters ACQuity Qda Detector/waters SQ Detector)、THERMO Ultimate 3000-Q Exactive(生产商：THERMO，MS型号：THERMO Q Exactive)。
高效液相色谱法(HPLC)分析使用Agilent HPLC 1200DAD、Agilent HPLC 1200VWD和Waters HPLC e2695-2489高效液相色谱仪。
高效液相制备使用Waters 2767、Waters 2767-SQ Detecor2、Shimadzu LC-20AP和Gilson-281制备型色谱仪。
硅胶柱色谱法一般使用烟台黄海硅胶200～300目硅胶为载体。
XRPD为X射线粉末衍射检测：测定使用BRUKER D8型X射线衍射仪进行，具体采集信息：Cu阳极(40kV，40mA)，Cu-Kα1射线Kα2射线Kβ射线扫描方式：θ/2θ，扫描范围(2θ范围)：3°～45°。
DSC为差示扫描量热：测定采用METTLER TOLEDO DSC 3+示差扫描量热仪，升温速率10℃/min，温度具体范围参照相应图谱(多为25-300℃或350℃)，氮气吹扫速度50mL/min。
TGA为热重分析：检测采用METTLER TOLEDO TGA 2型热重分析仪，升温速率10℃/min，温度具体范围参照相应图谱(多为30-400℃)，氮气吹扫速度50mL/min。
DVS为动态水分吸附：检测采用SMSDVS Advantage，在25℃，湿度变化为50％-95％-0％-95％-50％，步进为10％(最后一步为5％)(湿度具体范围以相应图谱为准，此处所列为大多使用方法)，判断标准为dm/dt不大于0.002％/min。
本公开的已知的起始原料可以采用或按照本领域已知的方法来合成，或可购买自ABCR GmbH&Co.KG，Acros Organics，Aldrich Chemical Company，韶远化学科技(Accela ChemBio Inc)、达瑞化学品等公司。
实施例中无特殊说明，反应均能够在氩气氛或氮气氛下进行。
氩气氛或氮气氛是指反应瓶连接一个约1L容积的氩气或氮气气球。
实施例中的反应进程的监测采用薄层色谱法(TLC)，反应所使用的展开剂，纯化化合物采用的柱层析的洗脱剂的体系和薄层色谱法的展开剂体系包括：A：正己烷/乙酸乙酯体系，B：二氯甲烷/甲醇体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺和醋酸等碱性或酸性试剂进行调节。
实施例1式1化合物的制备

步骤1：向500mL三口瓶中加入尿素(38.89g，647.46mmol)、0.3M的稀盐酸(80mL)和1,2-环己二酮1a(22.0g,196.20mmol)，加热至50℃搅拌16小时。反应冷却至室温，过滤，滤饼用100mL水淋洗，100mL无水乙醇淋洗，干燥，得环己基甘脲，化合物1b(浅黄色体，27.4g，产率：71％)。
MS m/z(ESI):197.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ7.02(s,4H),1.72-1.68(m,4H),1.42-1.35(m,4H)。
步骤2：向1L三口瓶中加入化合物1b(27.4g,139.65mmol)、140mL 9M的盐酸和多聚甲醛(20.9g，698.23mmol)，反应液室温搅拌24小时，向反应体系中加入500mL水，室温搅拌继续16小时，将反应液过滤，洗涤，干燥，得到环己基甘脲二醚，化合物1c(白色固体，20.2g,收率：52％)。
MS(ESI):281.1[M+1]+。
1H NMR(400MHz,DMSO-d6):δ5.20(d,4H,J＝11.6),4.91(d,4H,J＝11.2),2.25-2.18(m,4H),1.56-1.50(m,4H)。
步骤3：将化合物1c(2.73g,9.73mmol)称入干燥三口烧瓶中，置换氩气，加入甲磺酸(10mL)溶解，加入甘脲二聚体1d(1g，3.24mmol，采用公知的方法“WO2012051407A2”制备而得)后室温搅拌反应24小时，将反应液慢慢加入100mL水中(冰水浴冷却)，加完后恢复到室温。过滤。干燥得粗品产物1.77g，将上述粗产物加热溶于TFA中(4mL)，然后加入16mL水，搅拌，过滤，真空干燥得到化合物1e(1.21g，产率：44.9％)。
MS(ESI):837.3[M+1]+。
1H NMR(400MHz,CDCl3):δ5.72-5.37(m,10H),5.15(d,4H),4.75(d,4H),4.15-4.11(m,6H),2.28(br,4H),2.05(br,4H),1.45(br,8H)。
步骤4：在三口瓶里加入3-溴-2-(溴甲基)丙酸甲酯，化合物1f(25g,96mmol)和无水THF(70mL)，然后用氮气置换其中的空气，然后用干冰丙酮浴冷却至-78℃，接着慢慢滴加DIBAL-H(135mL,202mmol，1.5M甲苯)，滴毕，升温到0℃，反应在0℃搅拌45分钟。然后在0℃下滴加HCl(1M,500mL)淬灭反应，加入200mL乙酸乙酯，用乙酸乙酯萃取(50mL×3)。合并的有机相用饱和食盐水洗(100mL)，干燥，过滤，溶剂旋干。粗产品过柱(PE:EA＝5:1)得15.8g淡黄色油状物3-溴-2-溴甲基-1-丙醇，化合物1g(产率：71.5％)。
1H NMR(400MHz,CDCl3):δ3.77-3.75(m,2H),3.62-3.53(m,4H),2.46(br,1H),2.29-2.22(m,1H)。
步骤5：将化合物1g(7g,30.4mmol)，1,4-二羟基萘，化合物1h(1.62g,10.1mmol)和MeSO3H(1.4mL)称入干燥三口烧瓶中，置换氮气，将反应加热到100℃搅拌3小时。冷却到室温，然后将反应液倒入冰水中，用乙酸乙酯萃取(50mL×3),合并的有机相依次用NaHCO3溶液和饱和食盐水洗，干燥，过滤，溶剂旋干。粗产品过柱(PE:EA＝50:1)得2.74g淡黄色固体1,4-双(3-溴-2-(溴甲基)丙氧基)萘，化合物1i(产率：46％)。
1H NMR(400MHz,CDCl3):δ8.16(q,2H),7.54(q,2H),6.74(s,2H),4.23(d,4H),3.81-3.71(m,8H),2.73-2.70(m,2H)。
步骤6：向三口瓶中加入化合物1i(2.25g，3.83mmol)和亚硫酸钠(4.91g,38.9mmol),用氮气置换其中的空气，然后加入42mL异丙醇和42mL水。反应加热至100℃搅拌24小时。反应冷却至室温，浓缩得到粗品，再加入83mL甲醇，打浆搅拌1小时，过滤，收集所得固体，送HPLC制备(流动相：20mM NH4HCO3水溶液/甲醇，梯度配比：水相93％)，得1.62g白色固体2,2'-((萘-1,4-二氧基)亚甲基)双(丙烷-1,3-二磺酸)铵，化合物1j(产率：64％)。
MS m/z(ESI):331.8[M/2+1]+。
1H NMR(400MHz,D2O):δ8.23-8.22(m,2H),8.57-7.55(m,2H),6.90-6.88(m,2H),4.40-4.39(m,4H),3.33-3.31(m,8H),2.94-2.92(m,2H)。
步骤7：将化合物1j(1.57g,2.37mmol)称入干燥三口烧瓶中，置换氩气，加入TFA(15mL)溶解，然后加入化合物1e(0.79g,0.95mmol)。加完后将反应加热到70℃搅拌反应3小时。减压蒸掉TFA，向所得固体中加入40mL乙醇加热回流2小时，冷到室温，过滤。滤饼用乙醇洗涤，干燥。所得固体用12mL水溶解，然后用1M氢氧化钠水溶液将体系pH值调为约为7，加入50mL乙醇，析出粘稠物，倒掉上清液，残余物旋干，然后用高效液相色谱法(流动相：20mM NH4HCO3水溶液/乙腈，梯度配比：水相25％-42％)纯化，最后用氢氧化钠成盐得到299mg白色固体化合物1k(产率：12％)。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图无明显特征峰。
MS m/z(ESI):990.6[(M-8Na+8H)/2]+。
1H NMR(400MHz,D2O):δ7.96-7.93(m,4H),7.32-7.33(m,4H),5.57-5.44(m,6H),5.35-5.31(m,4H),5.09-5.05(m,4H),4.54-4.50(m,4H),4.27-4.23(m,4H),4.10-4.01(m,10H),3.52-3.31(m,16H),2.98-2.92(m,4H),2.19-2.17(m,4H),2.01-1.98(m,4H),1.47-1.45(m,8H)。
步骤8：将化合物1k(2.34g)，经过一次酸性高效液相制备去除Na离子(流动相：0.1％TFA水溶液/甲醇)，制备液浓缩，然后用水减压带蒸3次去除残留三氟醋酸，冻干，再加入水带蒸3次，再次冻干得到2.0g的游离酸，粉红色固体化合物1，纯度：98.2％。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图13。TGA谱图显示，30℃-185℃失重10.34％。
MS m/z(负离子ESI):989.2[(M/2-1]-。
1H NMR(400MHz,D2O):δ7.93-7.91(m,4H),7.32-7.30(m,4H),5.55-5.43(m,6H),5.33-5.27(m,4H),5.18-5.15(d,4H),4.50-4.46(d,4H),4.24-4.23(m,4H),4.09-4.04(m,10H),3.53-3.42(m,8H),3.37-3.32(m,8H),2.96-2.93(m,4H),2.19-2.14(m,4H),2.05-2.01(m,4H),1.55-1.39(m,8H)。
实施例2式1化合物二钠盐的制备
取化合物1(200mg)，用4ml的水溶解，加入氢氧化钠(8.07mg，2.0eq)超声溶解，过滤，滤液冻干，得到式1化合物二钠盐(白色固体，210mg)。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图14。TGA谱图显示，30℃-157℃失重9.69％。离子结果显示，钠离子含量2.73％。
实施例3式1化合物四钠盐的制备
取化合物1(200mg)，用4ml的水溶解，加入氢氧化钠(16.14mg，4.0eq)超声溶解，过滤，滤液冻干，得到式1化合物四钠盐(白色固体，222mg)。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图15。TGA谱图显示，30℃-204℃失重8.94％。离子结果显示，钠离子含量4.66％。
实施例4式1化合物六钠盐的制备
取化合物1(200mg)，用4ml的水溶解，加入氢氧化钠(24.21mg，6.0eq)超声溶解，过滤，滤液冻干，得到式1化合物六钠盐(白色固体，229mg)。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图16。TGA谱图显示，30℃-206℃失重10.24％。离子结果显示，钠离子含量6.78％。
实施例5式1化合物八钠盐的制备
取化合物1(200mg)，用4ml的水溶解，加入氢氧化钠(32.29mg，8.0eq)超声溶解，过滤，滤液冻干，得到式1化合物八钠盐(白色固体，237mg)。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图2所示。实施例1至5钠离子含量如下表1所示。
表1
*经离子色谱检测的钠离子含量；**离子色谱检测背景值；***消除背景值的钠离子含量；#QNMR折算的钠离子含量。
测试例1.本公开化合物对肌松药体外结合活性的测试
一、试验目的：
通过等温滴定量热法(ITC)测试本公开化合物与肌松药的体外结合活性，评价结合的Kd值。
二、试验材料：
等温滴定量热仪(含电脑主机及配套软件)、CB2、化合物1、顺阿曲库铵、去离子水。
三、试验方法与步骤：
利用预设的洗涤程序，使用去离子水洗涤等温滴定量热系统的管路、样品池与滴定针。配置顺阿曲库铵水溶液与待测化合物的水溶液，顺阿曲库铵：待测化合物＝10:1～20:1。以加样针将CB2与待测化合物加满样品池中，以加样程序将顺阿曲库铵吸取到滴定针中。将滴定针置入样品池中，启动搅拌，平衡系统5～10min。设置滴定参数：每滴样品2.5μL，共20滴，滴定间隔150s。开始滴定，记录热曲线。
滴定完毕后，通过热曲线计算待测化合物与顺阿曲库铵结合的Kd值，利用洗涤程序洗涤管路、样品池与滴定针，进行下一个化合物的测试。
CB2(采用公知方法“WO2012051407A2”制备而得)，其结构如下所示：
四、试验结果：
以ITC的方法检测了CB2、化合物1在体外结合顺阿曲库铵的结合能力，其解离常数Kd值如表1所示，结果表明，化合物1体外结合顺阿曲库铵的能力强于CB2。
表2：待测化合物与顺阿曲库铵的体外结合力
测试例2.本公开化合物对肌松药拮抗的效果测试
一、实验目的
测试本公开提供的化合物在大鼠神经肌肉模型中对腓肠肌的肌松药效逆转作用，评价起效时间、TOF等指标，并与CB2和新斯的明进行比较。
二、实验材料
SPF级SD雄性大鼠，BL-420A生物机能实验系统(主机、刺激器、张力换能器)，呼吸机，电子称，手术器械，注射器，剪毛器，电子秤，铁架台，泡沫板，氨基甲酸乙酯，氯化钠，CB2，化合物1，顺阿曲库铵，琥珀酰胆碱，新斯的明，无菌水，95％酒精。
三、实验方法
取检疫合格的SPF级雄性SD大鼠，饲养环境为室温22±0.5℃，换气次数20-50/h，气流速度0.05-0.18m/s 12/12小时昼夜明暗交替。动物设施中适应3天以上，6只/笼饲养，待体重范围在220g～250g开始试验。
利用0.9％氯化钠复溶供试品。按含量折算后，称取所需量的供试品，用0.9％氯化钠注射液溶解后(30min以内)，再用涡旋混匀器混匀震荡。其中，CB2用纯净水复溶。
实际称药重量(mg)＝给药制剂浓度A(mg/mL)×溶媒体积(mL)/含量(％)
将大鼠随机分成CB2、化合物1、新斯的明组，每组5只(以实际入组只数为准)，给药体积均为2mL/kg。
CB2(采用公知方法“WO2012051407A2”制备而得)，其结构如下所示：
大鼠麻醉后，分离坐骨神经和腓肠肌，刺激坐骨神经并通过张力换能器记录肌张力信号。气管插管通过小动物呼吸机给予机械通气。稳定记录肌张力信号一段时间后给予药物：首次给予2倍ED90剂量(0.8mg/kg)的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品和新斯的明)，待肌张力曲线恢复至95％以上后，给ED90剂量(0.9mg/kg)的肌松药(琥珀酰胆碱)，此时应观察到肌张力的下降，待肌张力自然恢复至95％以上即可停止实验。期间持续记录肌张力信号，统计分析起效时间和临床时效等指标，通过给药后肌张力信号的比较，判断并比较拮抗药的肌松逆转作用。
四、实验步骤
4.1大鼠称重、麻醉
将大鼠进行称重，待大鼠情绪稳定，将氨基甲酸乙酯配制成25％的乌拉坦，按照1mL/100g进行腹腔注射麻醉，待疼痛反射消失后将大鼠俯卧位固定于泡沫板上，对臀部和右大腿外侧区域脱毛处理。
4.2分离坐骨神经
在髋关节后，大腿中部股骨外缘切开皮肤，掀开皮肤、浅筋膜层，钝性分离肌肉，暴露坐骨神经。注意分离时使用玻璃分针，防止金属器械损伤神经。
4.3分离腓肠肌
从踝关节处剪开小腿皮肤，剪断踝关节前部韧带，分离腓肠肌，在踝部的腓肠肌肌腱处扎线，于结扎线远端切断肌腱。
4.4收集信号
将腓肠肌结扎线与张力换能器连接，刺激器与坐骨神经相连接。设定输入信号为张力，参数设定为方波，细电压，串刺激，延时0.05ms，波宽0.2ms，频率2Hz，强度0.225±0.025V，强度增量0，串长4，主周期12s，停止次数30000，记录肌肉收缩曲线。测量期间通过生理盐水始终保持肌肉神经处于湿润状态，每3-5分钟润湿一次。
4.5连接呼吸机，注射肌松药、拮抗药
酒精擦拭呼吸机管口，切开颈部皮肤，找到颈静脉和气管，将气管剪开，连接呼吸机，参数设定为潮气量6mL，呼吸时比5:4，呼吸频率80次/min。稳定5分钟左右经颈静脉给药，结合参考文献设定，首次给予2倍ED90剂量的肌松药(顺阿曲库铵)，此时肌张力曲线应当下降，给药30-60s后注射拮抗药(供试品或新斯的明)，待肌张力曲线恢复至95％以上后，给予ED90剂量的肌松药(琥珀酰胆碱)，再次等待肌张力曲线恢复至95％以上后即可停止实验。期间持续记录肌张力曲线。
表3
4.6时效指标统计
利用生物机能实验系统统计起效时间、二次肌松起效时间等指标，统计标准如下。
1)TOF恢复90％时间(TOF0.9)：TOF串刺激的T4/T1值恢复至90％左右的时间-拮抗剂给药时间
2)琥珀酰胆碱肌松作用时间：肌张力下降到最低值的时间-琥珀酰胆碱给药时间
五、实验结论
由图1可知，化合物1在20mg/kg可达到新斯的明的药效水平，优于CB2。
实施例6游离态晶型A制备
将实施例1所得游离酸(化合物1)5mg，加入0.5mL溶剂，所述溶剂如表4所示，室温搅拌过夜，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为游离态晶型A，XRPD谱图如图17，其特征峰位置如表5所示。
表4
表5
实施例7游离态晶型A制备
将实施例1所得游离酸(化合物1)6mg，溶于0.06mL水，加入0.3mL溶剂，所述溶剂如表6所示，室温搅拌过夜，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物为游离态晶型A
表6
实施例8二钠盐晶型A制备
将实施例2所得钠盐5mg，加入0.5mL溶剂，所述溶剂如表7所示，室温搅拌过夜，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为二钠盐晶型A，XRPD谱图如图18，其特征峰位置如表8所示。离子结果显示，钠离子含量2.36％。
表7
表8
实施例9二钠盐晶型B制备
将实施例2所得钠盐6mg，溶于0.06mL水，加入0.3mL溶剂，所述溶剂如表9所示，室温搅拌过夜，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为二钠盐晶型B，XRPD谱图如图19，其特征峰位置如表10所示。离子结果显示，钠离子含量2.47％。
表9
表10
实施例10四钠盐晶型A制备
将实施例3所得钠盐5mg，加入0.5mL溶剂，所述溶剂如表11所示，室温搅拌过夜，离心，真空干燥，得到产物固体。经X-射线粉末衍射检测，将该产物定义为四钠盐晶型A，XRPD谱图如图20，其特征峰位置如表12所示。离子结果显示，钠离子含量4.29％。
表11
表12
实施例11四钠盐晶型A制备
将实施例3所得钠盐6mg，溶于0.06mL水，加入0.3mL溶剂，所述溶剂如表13所示，室温搅拌过夜，离心，真空干燥，得到固体。经X-射线粉末衍射检测，该产物为四钠盐晶型A
表13
实施例12八钠盐无定形制备
将实施例5所得钠盐5mg，加入0.5mL溶剂，所述溶剂如表14所示，室温搅拌2天，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图2。离子色谱结果显示，钠离子含量8.93％。
表14

实施例13八钠盐无定形制备
将实施例5所得钠盐5mg，溶于0.05mL水中，室温挥发固化，得到产物。
实施例14八钠盐晶型A
将实施例5所得钠盐100mg，加入3mL 10％水/甲醇(v/v)，加晶种，室温搅拌1天，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型A，XRPD谱图如图3，其特征峰位置如表15所示。TGA谱图显示，31℃-175℃失重11.04％。离子结果显示，钠离子含量8.4％。
表15
实施例15八钠盐晶型A制备
将实施例5所得钠盐5mg，溶于0.025mL水，加入0.125mL甲醇，室温搅拌析晶，离心，真空干燥，得到固体。经X-射线粉末衍射检测，该产物为八钠盐晶型A。
实施例16八钠盐晶型B制备
将实施例5所得钠盐5mg，溶于0.05mL水，加入0.25mL四氢呋喃，室温搅拌析晶，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型B，XRPD谱图如图4，其特征峰位置如表16所示。TGA谱图显示，31℃-176℃失重13.05％。离子结果显示，钠离子含量8.12％。
DVS检测显示在正常存储条件下(即25℃、60％RH)，该样品吸湿增重约14.71％；加速实验条件(即70％RH)，吸湿增重约为16.66％；极端条件下(90％RH)，吸湿增重约为25.95％；DVS检测后复测晶型，晶型未转变。
表16
实施例17八钠盐晶型C制备
将实施例5所得钠盐5mg，溶于0.05mL水，加入0.25mL乙腈，室温搅拌析晶，离心，真空干燥，得到固体。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型C，XRPD谱图如图5，其特征峰位置如表17所示。TGA谱图显示，31℃-169℃失重10.00％。
表17
实施例18八钠盐晶型D制备
将实施例5所得钠盐5mg，加入0.5mL 10％水/异丙醇(v/v)，室温搅拌3天，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型D，XRPD谱图如图6，其特征峰位置如表18所示。TGA谱图显示，31℃-164℃失重9.65％。离子结果显示，钠离子含量8.14％。
表18
实施例19八钠盐晶型D制备
将实施例5所得钠盐5mg，加入0.5mL 10％水/丙酮(v/v)，室温搅拌3天，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，该产物为八钠盐晶型D。
实施例20八钠盐晶型E制备
将实施例5所得钠盐5mg，溶于0.025mL水，加入0.125mL丙酮，室温搅拌析晶，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型E，XRPD谱图如图7，其特征峰位置如表19所示。TGA谱图显示，31℃-190℃失重11.35％。离子结果显示，钠离子含量8.7％。
表19
实施例21八钠盐晶型E制备
将实施例5所得钠盐90mg，溶于0.45mL水，加入2.25mL甲醇，室温搅拌析晶，离心，固体真空干燥，得到产物。经X-射线粉末衍射检测，该产物为八钠盐晶型E
实施例22八钠盐晶型F制备
将实施例14钠盐晶型A经DVS循环后，得到产物。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型F，XRPD谱图如图8，其特征峰位置如表20所示。TGA谱图显示，30℃-222℃失重10.12％。
表20
实施例23八钠盐晶型G制备
将实施例5所得钠盐100mg，溶于0.5mL水，加入2.5mL甲醇，室温搅拌析晶，得到固体。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型G，XRPD谱图如图9，其特征峰位置如表21所示。离子结果显示，钠离子含量8.26％。
表21
实施例24八钠盐晶型G制备
将实施例21中钠盐晶型E于92.5％RH室温放置7天，得到产物。经X-射线粉末衍射检测，该产物为八钠盐晶型G
实施例25八钠盐晶型H制备
将实施例5所得钠盐100mg，加入3mL 10％水/甲醇(v/v)，室温搅拌1天，得到固体。经X-射线粉末衍射检测，将该产物定义为八钠盐晶型H，XRPD谱图如图10，其特征峰位置如表22所示。
表22
实施例26八钠盐晶型I制备
将实施例16钠盐晶型B于75％RH室温放置7天，得到产物。
经X-射线粉末衍射检测，将该产物定义为八钠盐晶型I，XRPD谱图如图11，其特征峰位置如表23所示。
表23
实施例27八钠盐晶型J制备
将实施例5钠盐无定形于75％RH室温放置7天，得到产物。
经X-射线粉末衍射检测，将该产物定义为八钠盐晶型J，XRPD谱图如图12，其特征峰位置如表24所示。
表24
实施例28铵盐无定形的制备
将化合物1 30mg，依次加入2mL丙酮，30.4μL 2M氨水水溶液，室温搅拌过夜，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为铵盐无定形。TGA谱图显示，30℃-222℃失重11.16％。离子检测结果显示，铵根离子含量为4.7％。
实施例29铵盐晶型a制备
将化合物1 7mg，溶解于0.15mL乙醇中，加入7.1μL 2M氨水水溶液，室温搅拌过夜，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，将该产物定义为铵盐晶型a，XRPD谱图如图21，其特征峰位置如表25所示。DSC谱图显示，吸热峰峰值87.47℃、291.39℃。TGA谱图显示，30℃-185℃失重10.80％。
表25
实施例30铵盐晶型b制备
将化合物1 7mg，依次加入0.15mL丙酮，7.1μL 2M氨水水溶液，室温搅拌过夜，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，将该产物定义为铵盐晶型b，XRPD谱图如图22，其特征峰位置如表26所示。DSC谱图显示，吸热峰峰值91.96℃、305.23℃。TGA谱图显示，30℃-184℃失重11.39％。
表26

实施例31铵盐晶型b制备
将化合物1 7mg，溶于0.15mL乙醇中，加入17.5μL 2M氨水水溶液，室温搅拌过夜，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为铵盐晶型b。
实施例32铵盐晶型c制备
将化合物1 7mg，依次加入0.15mL 2-甲基四氢呋喃，17.5μL 2M氨水水溶液，室温搅拌过夜，离心，固体真空干燥，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为铵盐晶型c，XRPD谱图如图23，其特征峰位置如表27所示。DSC谱图显示，吸热峰峰值75.47℃、292.08℃。TGA谱图显示，30℃-162℃失重10.62％。离子检测结果显示，铵根离子含量为4.8％。
表27
实施例33铵盐晶型c制备
将化合物1 30mg，依次加入1mL 2-甲基四氢呋喃，30.4μL 2M氨水水溶液，室温搅拌过夜，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为铵盐晶型c。
实施例34铵盐晶型d制备
将化合物1 30mg，溶于0.8mL乙醇，加入101.4μL 2M氨水水溶液，室温搅拌过夜，离心，固体真空干燥，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为铵盐晶型d，XRPD谱图如图24，其特征峰位置如表28所示。DSC谱图显示，吸热峰峰值82.15℃、294.41℃。TGA谱图显示，30℃-215℃失重13.17％。离子检测结果显示，铵根离子含量为4.9％。
表28
实施例35铵盐晶型e制备
将实施例34铵盐晶型d置于75％RH下7天，经X-射线粉末衍射检测，将该产物定义为铵盐晶型e，XRPD谱图如图25，其特征峰位置如表29所示。
表29

实施例36铵盐晶型f制备
将实施例34铵盐晶型d置于92.5％RH下7天，得到固体产物。经X-射线粉末衍射检测，将该产物定义为铵盐晶型f，XRPD谱图如图26，其特征峰位置如表30所示。
表30
实施例37氨丁三醇盐无定形的制备
将化合物1 7mg，依次加入0.15mL丙酮，1.7mg氨丁三醇，室温搅拌过夜，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为无定形。离子检测结果显示，氨丁三醇离子含量为5.4％。
实施例38氨丁三醇盐无定形的制备
将化合物1 7mg，加入0.15mL表31溶剂，1.7mg氨丁三醇，室温搅拌过夜，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为无定形。
表31
实施例39葡甲胺盐无定形的制备
将化合物1 7mg，依次加入0.15mL乙酸乙酯，2.8mg葡甲胺，室温搅拌过夜，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为无定形。核磁检测结果显示，葡甲胺子含量为9.0％。
实施例40葡甲胺盐无定形的制备
将化合物1 7mg，依次加入0.15mL表32溶剂，2.8mg葡甲胺，室温搅拌过夜，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为无定形。
表32
实施例41游离态无定形的制备
将化合物1 5mg，加入0.5mL表33溶剂，室温搅拌3d，离心，固体真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为无定形，XRPD谱图如图1。TGA谱图显示，30℃-161℃失重17.0％。
表33
实施例42游离态无定形的制备
将化合物1 5mg，溶于表34溶剂中，室温挥发固化，得到固体产物。经X-射线粉末衍射检测，该产物为无定形。
表34
实施例43游离态无定形的制备
将化合物1 5mg，溶于0.05mL表35良溶剂，室温加入0.25mL表35反溶剂，室温搅拌析晶，离心，固体真空干燥，得到固体产物。
表35
实施例44游离态晶型A的制备
将化合物1 5mg，加入0.5mL四氢呋喃，室温搅拌2天，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为游离态晶型A。
实施例45游离态晶型B的制备
将化合物1 5mg，溶于0.025mL甲醇中，室温挥发溶剂，得到固体产物。经X-射线粉末衍射检测，将该产物定义为游离态晶型B，XRPD谱图如图27，其特征峰位置如表36所示。DSC谱图显示，吸热峰峰值82.85、197.62、226.64℃。TGA谱图显示，30℃-91℃失重13.40％；91℃-219℃失重14.76％。
表36

实施例46游离态晶型B的制备
将化合物1 5mg，溶于表37溶剂中，室温挥发溶剂，得到固体产物。经X-射线粉末衍射检测，该产物为游离态晶型B。
表37
实施例47游离态晶型B的制备
将化合物1 5mg，加入0.5mL表38溶剂，室温搅拌3天，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为游离态晶型B。
表38
实施例48游离态晶型B的制备
将化合物1 5mg，溶于0.025mL水，室温加入0.125mL1，4-二氧六环，室温搅拌析晶，离心，真空干燥，得到固体产物。经X-射线粉末衍射检测，该产物为游离态晶型B。
实施例49游离态晶型C的制备
将化合物1 5mg，加入0.5mL丙酮，室温搅拌3天，离心，真空干燥，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为游离态晶型C，XRPD谱图如图28，其特征峰位置如表39所示。DSC谱图显示，吸热峰峰值94.76℃、105.74℃。TGA谱图显示，30℃-189℃失重17.36％。
表39
实施例50游离态晶型D的制备
将化合物1 5mg，加入0.5mL乙腈，室温搅拌3天，离心，真空干燥，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为游离态晶型D，XRPD谱图如图29，其特征峰位置如表40所示。DSC谱图显示，吸热峰峰值108.40℃、115.28℃。TGA谱图显示，30℃-186℃失重15.38％。
表40
实施例51游离态晶型E的制备
将实施例45游离态晶型B放置于40℃/75％RH条件下14天，得到固体产物。
经X-射线粉末衍射检测，将该产物定义为游离态晶型E，XRPD谱图如图30，其特征峰位置如表41所示。
表41
实施例52：长期/加速稳定性
将八钠盐晶型A、晶型B、晶型E和晶型G分别放置25℃/60％RH和40℃/75％RH条件考察稳定性。
表42
结论：长期加速实验表明：八钠盐晶型A和晶型B在长期(25℃/60％RH)和加速(40℃/75％RH)条件下12个月，物理和化学稳定性良好。八钠盐晶型E和晶型G在长期(25℃/60％RH)和加速(40℃/75％RH)条件下3个月，物理和化学稳定性良好。

Claims (32)

  1. 一种式1所示的化合物的可药用盐，所述可药用盐选自钠盐、钾盐、钙盐、胆碱盐、乙醇胺盐、二乙醇胺盐、二乙胺盐、氨丁三醇盐、精氨酸盐、赖氨酸盐、葡甲胺盐、铵盐，
  2. 根据权利要求1所述的可药用盐，其特征在于，所述式1化合物与碱的化学配比为8:1-1:8，优选3:1-1:8，更优选1:2或1:4或1:6或1:8。
  3. 根据权利要求1或2所述的可药用盐，所述可药用盐选自二钠盐、四钠盐、六钠盐、八钠盐。
  4. 根据权利要求1-3任一项所述可药用盐的制备方法，包括式1化合物与碱反应的步骤，所述的碱选自氢氧化钠、氢氧化钾、氢氧化钙、氢氧化胆碱、氨丁三醇、精氨酸、赖氨酸、乙醇胺、二乙胺、葡甲胺、二乙醇胺、氨水。
  5. 一种式1化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图，在9.195、14.303、18.343、21.652处有特征峰，
  6. 根据权利要求5所述的式1化合物的晶型A，以衍射角2θ角度表示的X-射线粉末衍射图谱如图17所示。
  7. 一种如权利要求5或6所述的式1化合物的晶型A的制备方法，所述方法包括以下任一方法：
    方法一：将式1化合物加入溶剂I中搅拌，所述溶剂I选自7％水/乙醇、10％水/异丙醇、10％水/丙酮、四氢呋喃中的一种或多种；
    方法二：将式1化合物溶于水，加入溶剂II搅拌；所述溶剂II选自丙酮、乙腈中的一种或多种。
  8. 一种式1化合物的二钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在9.720、11.232、14.901、15.811、19.759处有特征峰。
  9. 根据权利要求8所述的二钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图18所示。
  10. 一种如权利要求8或9所述的二钠盐晶型A的制备方法，所述方法包括将式1化合物二钠盐加入溶剂II，搅拌的步骤，所述溶剂II选自丙酮、乙腈中的一种或多种。
  11. 一种式1化合物的二钠盐晶型B，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.654、8.040、8.883、11.778、14.719、21.649处有特征峰。
  12. 根据权利要求11所述的二钠盐晶型B，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图19所示。
  13. 一种如权利要求11或12所述的二钠盐晶型B的制备方法，所述方法包括将式1化合物二钠盐溶于水，加入溶剂III，搅拌的步骤，所述溶剂III选自丙酮、乙腈、四氢呋喃中的一种或多种。
  14. 一种式1化合物的四钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在8.334、9.972、15.260、17.155、20.557、22.867处有特征峰。
  15. 根据权利要求14所述的四钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图20所示。
  16. 一种如权利要求14或15所述的四钠盐晶型A的制备方法，所述方法包括以下任一方法：
    方法一：将式1化合物四钠盐加入10％水/异丙醇或10％水/丙酮，搅拌；
    方法二：将式1化合物四钠盐溶于水，加入丙酮或四氢呋喃，搅拌。
  17. 一种式1化合物的八钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在5.052、7.543、11.974、21.775、23.581处有特征峰，优选在5.052、5.598、7.543、10.955、11.974、17.533、18.583、21.775、23.581、25.051处有特征峰，更优选在5.052、5.598、7.543、10.268、10.955、11.400、11.974、12.912、15.139、17.533、18.583、21.775、23.581、25.051处有特征峰。
  18. 根据权利要求17所述的八钠盐晶型A，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图3所示。
  19. 一种如权利要求17或18所述的八钠盐晶型A的制备方法，所述方法包括以下任一方法：
    方法一：将式1化合物八钠盐溶于水，加入甲醇，搅拌；
    方法二：将式1化合物八钠盐加入10％水/甲醇(v/v)中，加入晶种，搅拌。
  20. 一种式1化合物的八钠盐晶型B，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.402、8.124、12.072、16.357、19.255、21.775、27.109处有特征峰，优选在5.310、6.402、8.124、10.434、12.072、14.845、16.357、19.255、20.599、21.775、22.573、23.917、27.109、29.461处有特征峰，更优选在5.310、6.402、8.124、10.434、12.072、14.089、14.845、16.357、19.255、20.599、21.775、22.573、23.917、24.589、27.109、28.285、29.461处有特征峰。
  21. 根据权利要求20所述的八钠盐晶型B，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图4所示。
  22. 一种如权利要求20或21所述的八钠盐晶型B的制备方法，所述方法包括将式1化合物八钠盐溶于水，加入四氢呋喃搅拌的步骤。
  23. 一种式1化合物的八钠盐晶型E，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在8.082、9.762、16.525、20.599处有特征峰。
  24. 根据权利要求23所述的八钠盐晶型E，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图7所示。
  25. 一种如权利要求23或24所述的八钠盐晶型E的制备方法，所述方法包括将式1化合物八钠盐溶于水，加入丙酮搅拌的步骤。
  26. 一种式1化合物的八钠盐晶型G，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图，在6.515、13.061、14.807、17.854、21.703处有特征峰，优选在5.946、6.515、12.036、13.061、14.807、17.854、21.703、24.406、27.046处有特征峰，更优选在5.946、6.515、11.521、12.036、13.061、14.807、17.854、20.952、21.703、24.406、27.046处有特征峰。
  27. 根据权利要求26所述的八钠盐晶型G，其特征在于，以衍射角2θ角度表示的X-射线粉末衍射图谱如图9所示。
  28. 一种如权利要求26或27所述的八钠盐晶型G的制备方法，所述方法包括以下任一方法：
    方法一：将式1化合物八钠盐溶于水，加入甲醇搅拌的步骤；
    方法二：将式1化合物八钠盐晶型E于92.5％RH放置7天的步骤。
  29. 根据权利要求5-6、8-9、11-12、14-15、17-18、20-21、23-24、26-27任一项所述的晶型，所述2θ角误差范围为±0.20。
  30. 一种药物组合物，含有权利要求1-3中任一项所述的式1化合物的可药用盐，或者权利要求5-6、8-9、11-12、14-15、17-18、20-21、23-24、26-27任一项所述的晶型和任选自药学上可接受的赋形剂。
  31. 一种药物组合物的制备方法，包括以下步骤：将权利要求1-3中任一项所述的可药用盐，或者权利要求5-6、8-9、11-12、14-15、17-18、20-21、23-24、26-27任一项所述的晶型和药学上可接受的赋形剂混合的步骤。
  32. 权利要求1-3中任一项所述的可药用盐，或者权利要求5-6、8-9、11-12、14-15、17-18、20-21、23-24、26-27任一项所述的晶型，或权利要求30所述的药物组合物在制备逆转药物诱导的神经肌肉阻滞和/或麻醉的药物中的用途。
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