Crystal forms of tetrahydrothiophene derivative as well as preparation method therefor and use thereof

Abstract

The present invention provides crystal forms of a compound shown as formula (I), a preparation method therefor, and the use thereof in the preparation of related drugs.

Description

A crystal form of a tetrahydrothiophene derivative and a preparation method and application thereof TECHNICAL FIELD

[0001] The present application relates to a plurality of crystal forms of a compound and a preparation method and application thereof, in particular to a plurality of crystal forms of a tetrahydrothiophene derivative and a preparation method and application thereof, and belongs to the technical field of pharmaceutical chemistry. BACKGROUND

[0002] Pain originates from nociceptors in the peripheral nervous system. It can convert the perceived heat, mechanical or chemical stimulation into nerve impulses (action potentials) and transmit to its soma part located in the dorsal root ganglion (DRG) via afferent nerve fibers, and ultimately to the high-level nerve center, causing pain. The generation and conduction of action potential in neurons also depend on the voltage-gated sodium channels (VGSCS) on the cell membrane. When the cell membrane is depolarized, the sodium ion channel is activated, the channel is opened, causing sodium ion influx, further depolarizing the cell membrane, leading to the generation of action potential.

[0003] VGSCS is composed of a pore-forming alpha-subunit (about 260kDa) and associated smaller size (30-40kDa) beta-subunit. The associated alpha-subunit family consists of 10 members, of which 9 (Nav1.1-1.9) are voltage-gated. Nav1.8 is encoded by the gene SCN10A and preferentially expressed in peripheral sensory neurons. It has been shown to shape action potentials in these neurons. Nav1.8 transcripts and proteins have been found in dorsal root ganglion (DRG) neurons. Nav1.8 is not detected in non-neuronal tissues (such as heart and skeletal muscle) or central nervous system (including brain and spinal cord).

[0004] The key role of Nav1.8 in pain signaling has been supported by multiple lines of evidence. According to a series of animal experiments and human genetic evidence, selective inhibition of Nav1.8 has the potential to become a new analgesic therapy. Currently, drugs targeting this site have entered clinical studies.

[0005] A compound of formula (I) is described in PCT / CN2024 / 070802 patent, which has good Nav1.8 inhibitory activity.

[0006] A crystal form of a compound of formula (I) is described in the present application, which is a Nav1.8 inhibitor and is intended to treat pain, and a preparation method thereof is also disclosed. SUMMARY

[0007] The advantages of the crystalline form or amorphous form of the compound of formula (I) include, but are not limited to, easy to process and crystallize, convenient to handle, easy to purify, easy to industrialize, low hygroscopicity, good flowability, easy to micronize, higher solubility, better pharmacokinetic characteristics and good stability, suitable for preparing pharmaceutical preparations.

[0008] The present application provides a pharmaceutically acceptable crystalline form of the compound of formula (I).

[0009] The present application provides a crystalline form A of the compound of formula (I); in any embodiment, the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 13.20°±0.2°, 14.64°±0.2°, 14.90°±0.2°, 15.08°±0.2°, 17.16°±0.2°; in any embodiment, the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ positions using Cu-Kα radiation: 11.70°±0.2°, 13.20°±0.2°, 14.64°±0.2°, 14.90°±0.2°, 15.08°±0.2°, 17.16°±0.2°, 18.32°±0.2°, 24.25°±0.2°; in any embodiment, the X-ray powder diffraction pattern thereof has characteristic diffraction peaks at the following 2θ positions: 11.70°±0.2°, 13.20°±0.2°, 14.64°±0.2°, 14.90°±0.2°, 15.08°±0.2°, 16.80°±0.2°, 17.16°±0.2°, 17.51°±0.2°, 18.32°±0.2°, 19.17°±0.2°, 21.07°±0.2°, 21.86°±0.2°, 24.25°±0.2°; in any embodiment, the X-ray powder diffraction pattern thereof is shown in Figure 1 using Cu-Kα radiation.

[0010] In any embodiment, the differential scanning calorimetric curve (DSC) of the crystalline form A shows peak temperatures of 169.66℃, respectively; the thermogravimetric curve (TGA) thereof shows a weight loss of about 0.25% before 100℃; the isothermal adsorption curve thereof shows a weight gain of 0.055% in the range of 0-80% RH, no hygroscopicity;

[0011] In any embodiment, the differential scanning calorimetric curve, the thermogravimetric curve and the isothermal adsorption curve of the crystalline form A are shown in Figures 2, 3 and 4, respectively.

[0012] The present application provides a crystalline form B of a compound of formula (I); in any embodiment, an X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2-theta positions: 14.07° ± 0.2°, 19.08° ± 0.2°, 19.67° ± 0.2°, 22.94° ± 0.2°, 31.15° ± 0.2°; in any embodiment, an X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2-theta positions: 14.07° ± 0.2°, 15.92° ± 0.2°, 16.78° ± 0.2°, 19.08° ± 0.2°, 19.67° ± 0.2°, 22.94° ± 0.2°, 28.84° ± 0.2°, 31.15° ± 0.2°; in any embodiment, an X-ray powder diffraction pattern using Cu-Ka radiation having characteristic diffraction peaks at the following 2-theta positions: 14.07° ± 0.2°, 15.92° ± 0.2°, 16.78° ± 0.2°, 18.41° ± 0.2°, 19.08° ± 0.2°, 19.67° ± 0.2°, 22.94° ± 0.2°, 28.84° ± 0.2°, 29.25° ± 0.2°, 30.36° ± 0.2°, 31.15° ± 0.2°, 36.46° ± 0.2°, 38.84° ± 0.2°; in any embodiment, an X-ray powder diffraction pattern using Cu-Ka radiation is shown in Figure 5.

[0013] The present application provides a crystalline form C of a compound of formula (I); in any embodiment, the X-ray powder diffraction pattern using Cu-Ka radiation has characteristic diffraction peaks at the following 2-theta positions: 10.59°±0.2°, 13.20°±0.2°, 19.28°±0.2°, 21.93°±0.2°, 29.30°±0.2°; in any embodiment, the X-ray powder diffraction pattern using Cu-Ka radiation has characteristic diffraction peaks at the following 2-theta positions: 10.59°±0.2°, 11.42°±0.2°, 13.20°±0.2°, 19.13°±0.2°, 19.28°±0.2°, 21.30°±0.2°, 21.93°±0.2°, 29.30°±0.2°; in any embodiment, the X-ray powder diffraction pattern using Cu-Ka radiation has characteristic diffraction peaks at the following 2-theta positions: 10.59°±0.2°, 11.42°±0.2°, 11.68°±0.2°, 13.20°±0.2°, 14.84°±0.2°, 16.86°±0.2°, 19.13°±0.2°, 19.28°±0.2°, 21.30°±0.2°, 21.93°±0.2°, 23.75°±0.2°, 24.85°±0.2°, 29.30°±0.2°; in any embodiment, the X-ray powder diffraction pattern using Cu-Ka radiation is shown in Figure 6.

[0014] The present application also provides a pharmaceutical composition, wherein the pharmaceutical composition contains a therapeutically effective amount of any of the crystalline forms described above, and a pharmaceutically acceptable carrier and / or excipient, preferably the therapeutically effective amount is 1-1500 mg. The pharmaceutical composition can be in the form of a unit formulation (unit formulation is also referred to as "formulation specification").

[0015] The present application also provides the use of any of the crystalline forms or compositions described above in the preparation of a medicament for the treatment of a Nav1.8 related pain disease. Further, the Nav1.8 mediated disease is pain.

[0016] The present application also provides a method for treating a Nav1.8 related pain disease, the method comprising administering to a subject a therapeutically effective amount of any of the crystalline forms or compositions described above, preferably the therapeutically effective amount is 1-1500 mg. In some embodiments, the mammal described in the present application includes a human.

[0017] An "effective amount" or "therapeutically effective amount" as described herein refers to an amount of a crystalline form disclosed herein that is sufficient to alleviate, to some extent, one or more symptoms of the disease or condition being treated. In any embodiment, the result is a reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an "effective amount" for therapeutic uses is the amount of a composition comprising a crystalline form disclosed herein that is needed to provide a clinically significant decrease in disease symptoms. Examples of a therapeutically effective amount include, but are not limited to, 1-1500 mg, 1-1400 mg, 1-1300 mg, 1-1200 mg, 1-1000 mg, 1-900 mg, 1-800 mg, 1-700 mg, 1-600 mg, 1-500 mg, 1-400 mg, 1-300 mg, 1-250 mg, 1-200 mg, 1-150 mg, 1-125 mg, 1-100 mg, 1-80 mg, 1-60 mg, 1-50 mg, 1-40 mg, 1-25 mg, 1-20 mg, 5-1500 mg, 5-1000 mg, 5-900 mg, 5-800 mg, 5-700 mg, 5-600 mg, 5-500 mg, 5-400 mg, 5-300 mg, 5-250 mg, 5-200 mg, 5-150 mg, 5-125 mg, 5-100 mg, 5-90 mg, 5-70 mg, 5-80 mg, 5-60 mg, 5-50 mg, 5-40 mg, 5-30 mg, 5-25 mg, 5-20 mg, 10-1500 mg, 10-1000 mg, 10-900 mg, 10-800 mg, 10-700 mg, 10-600 mg, 10-500 mg, 10-450 mg, 10-400 mg, 10-300 mg, 10-250 mg, 10-200 mg, 10-150 mg, 10-125 mg, 10-100 mg, 10-90 mg, 10-80 mg, 10-70 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-30 mg, 10-20 mg; 20-1500 mg, 20-1000 mg, 20-900 mg, 20-800 mg, 20-700 mg, 20-600 mg, 20-500 mg, 20-400 mg, 20-350 mg, 20-300 mg, 20-250 mg, 20-200 mg, 20-150 mg, 20-125 mg, 20-100 mg, 20-90 mg, 20-80 mg, 20-70 mg, 20-60 mg, 20-50 mg, 20-40 mg, 20-30 mg;50-1500 mg, 50-1000 mg, 50-900 mg, 50-800 mg, 50-700 mg, 50-600 mg, 50-500 mg, 50-400 mg, 50-300 mg, 50-250 mg, 50-200 mg, 50-150 mg, 50-125 mg, 50-100 mg; 100-1500 mg, 100-1000 mg, 100-900 mg, 100-800 mg, 100-700 mg, 100-600 mg, 100-500 mg, 100-400 mg, 100-300 mg, 100-250 mg, 100-200 mg;

[0018] In any embodiment, the pharmaceutical composition or formulation of the present application contains a therapeutically effective amount of the crystalline form described above.

[0019] The present application relates to a pharmaceutical composition or a pharmaceutical formulation comprising a therapeutically effective amount of the crystalline form described above and a carrier and / or excipient. The pharmaceutical composition can be in the form of a unit formulation (the amount of the main drug in the unit formulation is also referred to as "formulation specification"). In any embodiment, the pharmaceutical composition includes, but is not limited to, 1 mg, 1.25 mg, 2.5 mg, 5 mg, 10 mg, 12.5 mg, 15 mg, 20 mg, 25 mg, 30 mg, 35 mg, 40 mg, 45 mg, 50 mg, 55 mg, 60 mg, 65 mg, 70 mg, 75 mg, 80 mg, 85 mg, 90 mg, 95 mg, 100 mg, 110 mg, 120 mg, 125 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, 250 mg, 275 mg, 300 mg, 325 mg, 350 mg, 375 mg, 400 mg, 425 mg, 450 mg, 475 mg, 500 mg, 525 mg, 550 mg, 575 mg, 600 mg, 625 mg, 650 mg, 675 mg, 700 mg, 725 mg, 750 mg, 775 mg, 800 mg, 850 mg, 900 mg, 950 mg, 1000 mg, 1100 mg, 1200 mg, 1300 mg, 1400 mg, 1500 mg of the crystalline form of the present application.

[0020] A method for treating a disease in a mammal, the method comprising administering to the subject a therapeutically effective amount of the crystalline form of the present application, and a pharmaceutically acceptable carrier and / or excipient, the therapeutically effective amount preferably being 1-1500 mg, the disease preferably being pain.

[0021] A method for treating a disease in a mammal, the method comprising administering to the subject a pharmaceutical crystalline form of the present invention, and a pharmaceutically acceptable carrier and / or excipient, in a daily dose of 1-1500 mg / day, which can be in a single dose or divided doses, in any embodiment the daily dose includes but is not limited to 10-1500 mg / day, 20-1500 mg / day, 25-1500 mg / day, 50-1500 mg / day, 75-1500 mg / day, 100-1500 mg / day, 200-1500 mg / day, 10-1000 mg / day, 20-1000 mg / day, 25-1000 mg / day, 50-1000 mg / day, 75-1000 mg / day, 100-1000 mg / day, 200-1000 mg / day, 25-800 mg / day, 50-800 mg / day, 100-800 mg / day, 200-800 mg / day, 25-400 mg / day, 50-400 mg / day, 100-400 mg / day, 200-400 mg / day, in any embodiment the daily dose includes but is not limited to 1 mg / day, 5 mg / day, 10 mg / day, 20 mg / day, 25 mg / day, 50 mg / day, 75 mg / day, 100 mg / day, 125 mg / day, 150 mg / day, 200 mg / day, 400 mg / day, 600 mg / day, 800 mg / day, 1000 mg / day, 1200 mg / day, 1400 mg / day, 1500 mg / day.

[0022] The present invention relates to a kit which can comprise the crystalline form in single or multiple dose forms, the kit comprising the crystalline form of the present invention, the amount of the crystalline form of the present invention being the same as in the above pharmaceutical composition.

[0023] The amount of the crystalline form of the present invention in the present invention is in each case calculated as the free base.

[0024] "Formulation strength" means the weight of the principal drug contained in each unit of preparation, tablet or other.

[0025] The crystalline forms described herein are present in about 5% to about 100% by weight of the drug substance; in certain embodiments, about 10% to about 100% by weight of the drug substance; in certain embodiments, about 15% to about 100% by weight of the drug substance; in certain embodiments, about 20% to about 100% by weight of the drug substance; in certain embodiments, about 25% to about 100% by weight of the drug substance; in certain embodiments, about 30% to about 100% by weight of the drug substance; in certain embodiments, about 35% to about 100% by weight of the drug substance; in certain embodiments, about 40% to about 100% by weight of the drug substance; in certain embodiments, about 45% to about 100% by weight of the drug substance; in certain embodiments, about 50% to about 100% by weight of the drug substance; in certain embodiments, about 55% to about 100% by weight of the drug substance; in certain embodiments, about 60% to about 100% by weight of the drug substance; in certain embodiments, about 65% to about 100% by weight of the drug substance; in certain embodiments, about 70% to about 100% by weight of the drug substance; in certain embodiments, about 75% to about 100% by weight of the drug substance; in certain embodiments, about 80% to about 100% by weight of the drug substance; in certain embodiments, about 85% to about 100% by weight of the drug substance; in certain embodiments, about 90% to about 100% by weight of the drug substance; in certain embodiments, about 95% to about 100% by weight of the drug substance; in certain embodiments, about 98% to about 100% by weight of the drug substance; in certain embodiments, about 99% to about 100% by weight of the drug substance; in certain embodiments, substantially all of the drug substance is substantially pure crystalline.

[0026] The crystalline forms of the present application can be prepared by the following methods:

[0027] 1. Evaporation experiment: the compound of formula (I) is added to a selected single solvent or binary solvent to form a clear solution, which is then evaporated at different temperatures to dryness with the solution open to the air.

[0028] 2. Suspension method: the compound of formula (I) is added to a selected single solvent or binary solvent until a suspension is formed, which is then stirred at room temperature to 50°C for a certain period of time (for example, 1 h to 3 days, or 2 h to 24 h, or 2 h to 12 h, or 3 to 5 h), after which the suspension is centrifuged and dried to obtain the product.

[0029] 3. Solvent evaporation method: dissolve the compound of formula (I) in a good solvent, take a certain amount of the solution and drop it into a poor solvent, or take a certain amount of the solution and drop it into a poor solvent, stir to precipitate the solid, separate and dry.

[0030] 4. Cooling method: dissolve a certain amount of sample in the corresponding solvent at high temperature, transfer the solution to room temperature, precipitate the crystal by standing or stirring, separate and dry.

[0031] 5. Hot method experiment: take a certain amount of sample and place it on a glass sheet on a hot stage, heat it to the target temperature at a certain rate (such as 5-20℃ / min, or 10-15℃ / min), and keep it at a constant temperature for a period of time (such as 0.5-5min, or 1-3min, or 1-2min), then naturally cool to room temperature to obtain a solid.

[0032] 6. Gas phase diffusion experiment: take a certain amount of compound of formula (I) and drop it into a certain amount of good solvent at room temperature to completely dissolve the sample or prepare a saturated solution of good solvent; take a certain amount of solution respectively, and place the clear solution in a poor solvent atmosphere at room temperature until solid precipitates, separate and dry.

[0033] The good solvent and the poor solvent described in the present application are relative. In a pair of solvents, the one with higher solubility is the good solvent, and the one with lower solubility is the poor solvent. In some embodiments, the good solvent is selected from the one with higher solubility in ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF (N,N-dimethylformamide), DMSO (dimethyl sulfoxide), methanol, ethanol, n-propanol, butyl formate, 4-methyl-2-pentanone, tetrahydrofuran, isopropanol, ethyl acetate, dichloromethane, n-heptane, diethyl ether, water, acetonitrile, toluene, chloroform, acetone, butyl formate, MTBE (methyl tert-butyl ether), MIBK (methyl isobutyl ketone), cyclohexane, and the poor solvent is selected from the one with lower solubility in the above-mentioned solvents. In some embodiments, the good solvent is selected from ethylene glycol methyl ether, ethylene glycol dimethyl ether, dioxane, DMF, DMSO, methanol, ethanol, n-propanol, butyl formate, 4-methyl-2-pentanone, tetrahydrofuran, dichloromethane, or a mixed solvent thereof. In some embodiments, the poor solvent is selected from isopropanol, ethyl acetate, n-heptane, diethyl ether, water, acetonitrile, toluene, chloroform, acetone, butyl formate, MTBE, cyclohexane, or a mixed solvent thereof.

[0034] In any embodiment, the solvent of the evaporation method is water and acetone.

[0035] In any embodiment, the solvent employed in the method of solvent evaporation is ethanol; in any embodiment, the solvent employed in the method of solvent evaporation is ethyl acetate and n-heptane; in any embodiment, the solvent employed in the method of solvent evaporation is DMSO and water; in any embodiment, the solvent employed in the method of solvent evaporation is dichloromethane and MIBK; in any embodiment, the solvent employed in the method of solvent evaporation is dioxane and n-heptane;

[0036] The good solvent and the poor solvent described in the present application are relative. In a pair of solvents, the one with higher solubility is the good solvent, and the one with lower solubility is the poor solvent.

[0037] The solvent employed in the above preparation method, when not specified, can be a single solvent, or a combination of two or more solvents.

[0038] The X-ray powder diffraction or DSC pattern, TGA pattern disclosed in the present application, and those substantially the same as them also belong to the scope of the present application.

[0039] Unless otherwise stated, the terms used in the specification and claims have the following meanings.

[0040] "IC 50 " refers to the half maximal inhibitory concentration, which refers to the concentration at which the maximum inhibitory effect is halved.

[0041] As used herein, "crystal of the present application", "crystal form of the present application", "crystal form of the present application", and the like are used interchangeably.

[0042] The "room temperature" described in the present application generally refers to 4-30°C, preferably 20±5°C.

[0043] The crystal form structure of the present application can be analyzed using various analytical techniques known to those of ordinary skill in the art, including but not limited to X-ray powder diffraction (XRD), differential scanning calorimetry (DSC), and / or thermogravimetric analysis (TGA), also known as thermogravimetry (TG).

[0044] The "2θ or 2θ angle" described in the present application refers to the peak position expressed in degrees (°) based on the experimental setting in X-ray diffraction experiments, and is generally the unit of the abscissa in the diffraction pattern. If the reflection is diffracted when the incident beam forms a θ angle with a certain lattice plane, the experimental setting needs to record the reflected beam with a 2θ angle. It should be understood that the specific 2θ value mentioned herein for a specific crystal form is intended to represent the 2θ value measured using the X-ray diffraction experimental conditions described herein (expressed in degrees), and the error range of the 2θ can be ±0.3, ±0.2 or ±0.1.

[0045] It is understood that the numerical values described and claimed herein are approximations. Variations in the numerical values can be attributed to differences in equipment, instrument calibration, purity of the crystalline form, crystal size, sample size, and other factors.

[0046] It is understood that the crystalline forms of the present application are not limited to those having exactly the same characteristic pattern as described in the figures disclosed herein, such as XRD, DSC, TGA, DVS, any crystalline form having substantially the same or essentially the same characteristic pattern as those described in the figures disclosed herein fall within the scope of the present application.

[0047] It is understood that, as is well known in the art of differential scanning calorimetry (DSC), the height of the melting peak of a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in any embodiment, the crystalline compound of the present application has a DSC pattern with a characteristic peak position having substantially the same properties as the DSC pattern provided in the figures disclosed herein, with a tolerance of ± 5 °C, and typically ± 3 °C.

[0048] "Carriers" refer to a system that does not cause significant irritation to an organism, does not eliminate the biological activity and characteristics of the given compound, and can change the way the drug enters the human body and its distribution in the body, control the release rate of the drug and deliver the drug to the target organ, non-limiting examples include microcapsules and microspheres, nanoparticles, liposomes, etc.

[0049] "Excipient" refers to a substance, not itself a therapeutic agent, used as a diluent, adjuvant, binder, and / or vehicle, for adding to a pharmaceutical composition to improve its handling or storage properties or to allow or facilitate formation of a compound or pharmaceutical composition into a unit dosage form for administration. Pharmaceutical excipients can serve various functions and can be described as wetting agents, buffering agents, suspending agents, lubricating agents, emulsifiers, disintegrants, absorbents, preservatives, surfactants, colorants, flavorants, and sweeteners, as known to those skilled in the art. Examples of pharmaceutical excipients include, but are not limited to: (1) sugars, such as lactose, dextrose, and sucrose; (2) starches, such as corn starch and potato starch; (3) cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, cellulose acetate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, microcrystalline cellulose, and crosscarmellose (e.g., crosscarmellose sodium); (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol, and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laureate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer's solution; (19) ethyl alcohol; (20) pH buffered solutions; (21) polyesters, polycarbonates and / or polyanhydrides; and (22) other non-toxic compatible substances used in pharmaceutical formulations. BRIEF DESCRIPTION OF DRAWINGS

[0050] FIG. 1 is an X-ray powder diffraction pattern of crystalline Form A of the compound of Formula (I).

[0051] FIG. 2 is a differential scanning calorimetry profile of crystalline Form A of the compound of Formula (I).

[0052] FIG. 3 is a thermogravimetric analysis plot of crystalline Form A of the compound of Formula (I).

[0053] FIG. 4 is an isothermic adsorption plot of crystalline Form A of the compound of Formula (I).

[0054] FIG. 5 is an X-ray powder diffraction pattern of crystalline Form B of the compound of Formula (I).

[0055] FIG. 6 is an X-ray powder diffraction pattern of crystalline Form C of the compound of Formula (I). DETAILED DESCRIPTION

[0056] The structure of a compound is determined by nuclear magnetic resonance (NMR) or (and) mass spectrometry (MS). NMR shifts (δ) are given in parts per million (ppm) using residual solvent as an internal standard (δ 7.26 for1H NMR and δ 66.1 for13C NMR in CDCl3). -6The unit of ppm is given. NMR measurements were performed using a Bruker Avance 111 400 and Bruker Avance 300 NMR spectrometer. The solvents used were deuterated dimethyl sulfoxide (DMSO-d6), deuterated chloroform (CDCl3), and deuterated methanol (CD3OD). The internal standard was tetramethylsilane (TMS).

[0057] MS was measured using (Ag1lent 6120B (ES1) and Ag1lent 6120B (APC1)).

[0058] HPLC determination was performed using an Agilent 1260DAD high pressure liquid chromatograph (Eclipse Plus C18, 150×4.6 mm).

[0059] The known starting materials of the present invention can be synthesized by methods known in the art, or can be purchased from companies such as Titan Technology, Anage Chemical, Shanghai Demer, Chengdu Kelon Chemical, Shaoyuan Chemical Technology, and Bailingwei Technology.

[0060] The following describes in detail the implementation process of the present invention and the beneficial effects produced by specific embodiments, which is intended to help readers better understand the essence and characteristics of the present invention and is not intended to limit the scope of implementation of this case.

[0061] Example 1: Preparation of compound of formula (I)

[0062] Step 1: Preparation of compound 1b

[0063] 1a-1 (30.96 g, 129.95 mmol) was dissolved in tetrahydrofuran (130 mL) under an ice bath. Sodium hydride (5.20 g, 130 mmol) was added portionwise. The mixture was reacted under a nitrogen atmosphere and ice bath for 30 minutes. 1a (11.20 g, 100 mmol) was dissolved in tetrahydrofuran (20 mL) and added dropwise to the reaction system. The temperature was naturally raised to room temperature under a nitrogen atmosphere and the reaction was allowed to proceed for 18 hours. Under an ice bath, 1N hydrochloric acid was slowly added dropwise to the reaction system until the pH reached 7-8. The reaction system was extracted with diethyl ether (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated (at room temperature) to obtain the crude product. The crude product was purified by silica gel column chromatography to afford 1b (14.1 g, 71.88% yield, E / Z configuration mixture).

[0064] Step 2: Preparation of compound 1c

[0065] Under ice-bath, 1b-1 (8.63 g, 71.88 mmol) was added into a round bottom flask, piperidine (1.22 g, 14.38 mmol) was added into the system dropwise, 1b (6.0 g, 71.88 mmol) was added into the system, and the reaction was carried out at 50 °C for 24 h under nitrogen protection. Under ice-bath, 0.1 N hydrochloric acid (100 mL) was added into the reaction system to quench the reaction, and ether (100 mL x 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated (concentrated at 25 °C) to obtain 1c crude product. The 1c crude product was purified by silica gel column chromatography to obtain 1c (6.3 g, yield 27.96%).

[0066] LC-MS m / z = 317.1 [M+H] +

[0067] Third step: preparation of compound 1d

[0068] Under ice-bath, 1c (6.3 g, 19.92 mmol) was dissolved in ether (120 mL), and potassium tert-butoxide (2.91 g, 25.90 mmol) was slowly added into the system under nitrogen protection. The reaction was carried out at ice-bath for 2 h. Under ice-bath, glacial acetic acid (1.56 mL) and water (100 mL) were added into the reaction system to quench the reaction, and ether (100 mL x 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain 1d.

[0069] Fourth step: preparation of compound 1e

[0070] 1d (4.05 g, 15 mmol) was dissolved in dichloromethane (40 mL), and N, N- diisopropylethylamine (2.32 g, 17.99 mmol) was added into the system dropwise under nitrogen atmosphere at -78 °C for 15 min. Trifluoromethanesulfonic anhydride (4.23 g, 15 mmol) was dissolved in dichloromethane (10 mL) and slowly added into the system. After the addition was completed, the reaction was continued at -78 °C for 2 h. Under ice-bath, saturated sodium bicarbonate aqueous solution (50 mL) was slowly added into the reaction system to quench the reaction, and dichloromethane (50 mL x 3) was used for extraction. The combined organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 1e (5.2 g, yield 86.16%).

[0071] Fifth step: preparation of compound 1f

[0072] To a solution of 1e (5.2 g, 12.92 mmol) in toluene (50 mL) was added 1e-1 (2.67 g, 14.21 mmol) and Pd(PPh3)4 (0.75 g, 0.65 mmol) successively, and a 2 M aqueous solution of potassium phosphate (8.23 g, 38.71 mmol) was added to the system. The reaction was carried out at 100°C for 6 h under a nitrogen atmosphere. The reaction was cooled to room temperature, the reaction system was filtered, and the filter cake was washed with ethyl acetate (10 mL x 2). The filtrate was separated into layers, and the organic phase was collected. The aqueous phase was extracted with ethyl acetate (30 mL x 3), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain 1f (5.1 g, yield 99.59%).

[0073] LC-MS m / z = 397.1 [M+H] +

[0074] Sixth step: Preparation of compounds 1f-2a and 1f-2b

[0075] 1f (3.7 g, 9.33 mmol) was dissolved in methanol (50 mL), and palladium-carbon (1.99 g, 18.56 mmol) was added. After the addition was completed, the reaction was carried out at room temperature for 24 h under a hydrogen atmosphere with a pressure of 2 Mpa. The reaction was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 1g-1a and 1g-1b (1.02 g, yield 27.44%), and a mixture of unreacted 1f-2a and 1f-2b (0.148 g, yield 4.00%) was recovered.

[0076] Mixture of 1g-1a and 1g-1b:

[0077] LC-MS m / z = 399.4 [M+H] +

[0078] 1 H NMR (400 MHz, CDCl3): δ 6.96-6.90 (m, 1H), 6.88-6.79 (m, 1H), 4.08-4.01 (m, 4H), 3.94-3.80 (m, 2H), 3.77-3.68 (m, 1H), 3.49-3.37 (m, 1H), 1.59 (s, 3H), 1.02 (t, 3H), 0.96 (d, 3H).

[0079] Mixture of 1f-2a and 1f-2b:

[0080] LC-MS m / z = 397.1 [M+H] +

[0081] 1H NMR (400 MHz, CDC13): δ 6.90-6.81 (m, 1H), 6.77-6.71 (m, 1H), 4.13-4.04 (m, 2H), 3.92 (d, 3H), 3.42-3.34 (m, 1H), 1.77 (s, 3H), 1.13 (t, 3H), 1.09-1.04 (m, 3H).

[0082] Step 7: Preparation of compounds 1g-2a and 1g-2b

[0083] A mixture of 1f-2a and 1f-2b (0.148 g, 0.38 mmol) was dissolved in methanol (10 mL), and palladium on carbon (0.15 g, 1.41 mmol) was added. After the addition was completed, the reaction was pressurized to 2.5 MPa under a hydrogen atmosphere and reacted at 90 °C for 24 h. The reaction was filtered, and the filtrate was concentrated to obtain a crude product. The crude product was purified by silica gel column chromatography to obtain a mixture of 1g-2a and 1g-2b (0.052 g, yield 34.35%).

[0084] Step 8: Preparation of compounds 1h-2a and 1h-2b

[0085] A mixture of 1g-2a and 1g-2b (0.052 g, 0.13 mmol) was dissolved in tetrahydrofuran (5 mL) under a nitrogen atmosphere and ice bath. Potassium tert-butoxide (0.048 g, 0.43 mmol) was slowly added dropwise to the system (internal temperature < 13 °C). After the addition was completed, the reaction was reacted under an ice bath for 2 h. Under an ice bath, 1N hydrochloric acid was slowly added dropwise to the system (internal temperature < 13 °C) until the pH was 1. Water (5 mL) was added, and ethyl acetate (10 mL x 3) was extracted. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a mixture of 1h-2a and 1h-2b.

[0086] LC-MS m / z = 369.0 [M-H] -

[0087] Step 9: Preparation of 1h-2a

[0088] A mixture of compounds 1h-2a and 1h-2b 3.0 g was prepared by SFC, and after freeze-drying, compound 1h-2a (1.28 g, chiral HPLC retention time: 0.760 min) and compound 1h-2b (1.11 g, chiral HPLC retention time: 0.966 min) were obtained. The chiral HPLC test method: (instrument: SHIMADZU LC-30AD, chiral column: Chiralcel IG column. Preparation method: the crude product was dissolved in acetonitrile to prepare a sample solution. Mobile phase system: carbon dioxide / 0.05% DEA in ethanol. Elution gradient: 5%-40%; elution time: 3 min).

[0089] SFC preparation condition: instrument: Waters 150Prep-SFC A, preparation column: Chiralcel IG column. Preparation method: the crude product was dissolved in acetonitrile to prepare a sample solution with a concentration of 2 mg / mL. Mobile phase system: carbon dioxide / ethanol, ethanol content 10%; flow rate: 100 mL / min, elution time: 2 min.

[0090] Compound 1h-2a:

[0091] 1 HNMR (400 MHz, CDC13): δ 6.91-6.78 (m, 2H), 4.53 (d, 1H), 4.46-4.34 (m, 1H), 4.02 (d, 3H), 2.68-2.54 (m, 1H), 1.85 (s, 3H), 0.88-0.75 (m, 3H).

[0092] Step 10: Preparation of the compound of formula (I)

[0093] Compound 1h-2a (0.037 g, 0.1 mmol) was dissolved in tetrahydrofuran (3 mL), and triethylamine (0.061 g, 0.60 mmol), T3P (50% wt in EtOAc 0.26 g, containing 1-propyl phosphonic anhydride 0.13 g, 0.40 mmol), 6-2a-1 (0.023 g, 0.15 mmol) were added successively, and the reaction was carried out at room temperature for 18 h under nitrogen atmosphere. Sodium bicarbonate aqueous solution (10 mL) was added, and ethyl acetate (10 mL x 3) was extracted, and the organic phase was combined, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a crude product, which was purified by silica gel column chromatography to obtain the compound of formula (I) (0.036 g, yield 71.08%).

[0094] 1 HNMR (400 MHz, CDC13): δ 6.91-6.78 (m, 2H), 4.53 (d, 1H), 4.46-4.34 (m, 1H), 4.02 (d, 3H), 2.68-2.54 (m, 1H), 1.85 (s, 3H), 0.88-0.75 (m, 3H).

[0095] LCMS m / z = 507.2 [M+H] +

[0096] Example 2: Preparation of crystalline form A of the compound of formula (I)

[0097] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, 0.3 mL of ethanol was added to prepare a suspension solvent, and the mixture was slurried for 7 days. Centrifugation was performed, and the solid was vacuum-dried at 50°C to obtain Form A of the compound of formula (I). Its XRD, DSC, TGA, adsorption isotherm, and DVS curves are shown in Figures 1-4, respectively.

[0098] Example 3: Preparation of Form B of the Compound of Formula (I)

[0099] 50 mg of the compound of formula (I) was placed in a 2 mL sample bottle, and 0.3 mL of ethyl acetate / n-heptane (1 / 2) was added to prepare a suspension solvent. The suspension was slurried for 7 days and centrifuged to obtain Form B of the compound of formula (I), whose XRD is shown in Figure 5.

[0100] Example 4: Preparation of Form C of the Compound of Formula (I)

[0101] 50 mg of the compound of formula (I) was placed in a 2 mL sample vial, and 0.3 mL of a 1 / 2 ethyl acetate / n-heptane suspension was added. The suspension was slurried for 7 days. The mixture was centrifuged and the solid was dried under vacuum at 50°C to obtain Form C of the compound of formula (I), whose XRD pattern is shown in Figure 6.

[0102] X-ray powder diffractometer (XRD) / DSC / TGA / DVS / 1C testing

[0103] The XRD / DSC / TGA / DVS test parameters are detailed in Table 1, and the XRD data of the relevant crystal forms are shown in Tables 2 to 8.

[0104] Table 1 XRD / DSC / TGA test instruments and parameters

[0105] Table 2: XRD peak list of Form A of the compound of formula (I)

[0106] Table 3: XRD peak list of Form B of the compound of formula (I)

[0107] Table 4: XRD peak list of Form C of the compound of formula (I)

[0108] Stability data

[0109] Table 5 Crystal stability data of compound of formula (I)

[0110] Sample stability crystallinity comparison of compound of formula (I) under accelerated conditions over 11 days

[0111] Table 6 Crystallinity comparison of compound of formula (I)

[0112] Solid state property comparison

[0113] Table 7 Solid state property comparison of compound of formula (I)

[0114] Conclusion: Compound of formula (I) Form A has good solid state stability.

[0115] Biological test example one

[0116] Nav1.8 manual patch clamp test

[0117] (1) Cell culture

[0118] The CHO cell line stably expressing human Nav1.8 was cultured in Ham's F-12 medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B and 100 μg / mL Zeocin. The cell culture temperature was 37 °C and the carbon dioxide concentration was 5%. The old medium was removed and rinsed once with PBS, then 1 mL of 0.25% -Trypsin-EDTA solution was added, and incubated at 37 °C for about 1.5 min. When the cells were detached from the dish bottom, 37 °C preheated complete medium was added. The cell suspension was gently blown with a pipette to separate the aggregated cells. The cell suspension was transferred to a sterile centrifuge tube, and the cells were collected by centrifugation at 1000 rpm for 5 min. The cells were seeded in 6 cm cell culture dishes, and the amount of cells seeded in each cell culture dish was 2.5 x 10 5 cells (final volume 5 mL) for expansion or maintenance culture. To maintain the electrophysiological activity of the cells, the cell density should not exceed 80%. Before patch clamp detection, the cells were separated by 0.25% -Trypsin-EDTA, and 6.5 x 10 3 The cells were plated on coverslips and cultured in 24-well plates (final volume 500 μL), and detected after 18 hours.

[0119] (2) Compound preparation

[0120] The compounds were dissolved in dimethyl sulfoxide (DMSO) and made into a DMSO stock solution with a concentration of 30 mM. The stock solution was diluted with extracellular solution (140 mM NaCl, 3.5 mM KCl, 1 mM MgCl2-6H2O, 2 mM CaCl2-2H2O, 10 mM D-Glucose, 10 mM HEPES and 1.25 mM NaH2PO4-2H2O, pH adjusted to 7.4 with NaOH) to the test concentration, and the final DMSO concentration of all test samples was 0.1%.

[0121] (3) Electrophysiological test

[0122] First, the capillary glass tube was drawn into a recording electrode by a microelectrode puller, and then the electrode filled with intracellular solution (50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 60 mM CsF and 20 mM EGTA, pH adjusted to 7.2 with CsOH) was loaded into a microelectrode holder. Under an inverted microscope, the microelectrode manipulator was operated to immerse the electrode into extracellular solution and record the electrode resistance (Rpip). Then the electrode was slowly contacted to the cell surface, and a negative pressure was applied to form a GΩ seal. At this time, fast capacitance compensation was performed, and a negative pressure was continuously applied to break the cell membrane and form a whole-cell recording mode. Finally, slow capacitance compensation was performed and experimental parameters such as series resistance (Rs) were recorded. No leakage compensation was given. When the Nav1.8 current of the whole-cell recording was stable, the drug was administered, and each drug concentration was allowed to act for about 5 min (or the current was stable). The coverslipped cells were placed in a recording bath under an inverted microscope, and the blank control extracellular solution and the working solution of the test compound were allowed to flow through the recording bath to act on the cells by gravity perfusion, and the liquid exchange was performed by using a peristaltic pump. The current detected in the extracellular solution without the compound was used as the control group. All electrophysiological tests were performed at room temperature. The inhibition rate of the compound on Nav1.8 was determined by calculating the relative percentage of the peak current before and after the compound treatment.

[0123] The voltage stimulation protocol for recording Nav1.8 sodium current by whole-cell patch clamp was as follows: after forming a whole-cell seal, the cell voltage was clamped at -120 mV. First, the voltage was stepped from -110 mV to -30 mV at 10 mV, and after maintaining for 5 s, a 0 mV depolarization pulse was given to obtain the half-inactivation voltage (Vhalf). Then, Vhalf was used as the stimulation voltage, and after maintaining for 5 s, the voltage was restored to -120 mV, maintained for 20 ms, and then a depolarization pulse (TP2) was given to 0 mV for 50 ms to detect the sodium current in the half-inactivated state. Finally, it was restored to the clamping voltage -120 mV, and the data was collected every 20 ms to observe the effect of the drug on the peak of the sodium current. The test data was collected by EPC 10 amplifier (HEKA) and stored in PatchMaster (HEKA) software.

[0124] Table 8 Inhibitory activity IC of test compounds on hNav1.8 50

[0125] Conclusion: The compound of formula (I) of the present invention has good Nav1.8 inhibitory activity.

[0126] Biological Test Example 2: Spinal Nerve Ligation (SNL)-Induced Neuropathic Pain Model in Mice

[0127] Male C57BL / 6J mice purchased from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. were adaptively raised for one week before establishing the model. The specific establishment method is as follows:

[0128] (1) Sterilization of surgical instruments and ligatures;

[0129] (2) Mice were anesthetized with isoflurane and placed in the prone position on the operating table;

[0130] (3) The mouse was skinned near the hip bone and an incision of approximately 2 cm was made along the spine.

[0131] (4) Separate the fascia along the spine, bluntly separate the muscles, and expose the L5 transverse process;

[0132] (5) Use forceps to carefully bite off the L5 transverse process and expose the L5 spinal nerve;

[0133] (6) Carefully separate the L5 nerve with a glass needle and ligate it with a 5-0 ligature.

[0134] (7) Suture the muscles and skin and disinfect with iodine;

[0135] The day after modeling, mice with unsuccessful modeling were eliminated (sign of successful modeling: the hind paw of the mouse curled up). After modeling, the mice were stroked for 3 to 5 minutes every day to ensure that the animals were familiar with the experimenter. Then, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. After the third day, after environmental adaptation, the mice were placed on a metal pain test frame to adapt for 40 to 60 minutes. Pre-dose baseline values ​​(Ascending test) were obtained for test animals (0.16, 0.4, 0.6, 1.0, 1.4, and 2.0 g). Each animal was measured twice, with at least 5 minutes between measurements, and the average was calculated. The animals were then grouped according to baseline values ​​(10 animals per group). After grouping, the compound of formula (I) (3 and 30 mg / kg) or vehicle (0.5% methylcellulose) was administered orally. The mechanical pain threshold (MPT) of the mice was measured at various time points after administration. Time-MPT curves were plotted and statistically analyzed using GraphPad 8.3.0.

[0136] Conclusion: According to the area under the time-MPT curve analysis, the compound of formula (I) has significant analgesic effect at the administration dose of 3 mg / kg or 30 mg / kg.

Claims

1. A crystalline form of a compound of Formula (I), ###00001### (I) 2. The crystalline form of claim 1, which is crystalline Form A of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2Θ positions of 13.20°±0.2°, 14.64°±0.2°, 14.90°±0.2°, 15.08°±0.2°, 17.16°±0.2°; or at 2Θ positions of 11.70°±0.2°, 13.20°±0.2°, 14.64°±0.2°, 14.90°±0.2°, 15.08°±0.2°, 17.16°±0.2°, 18.32°±0.2°, 24.25°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 1.

3. The crystalline form of claim 1, which is crystalline Form B of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2Θ positions of 14.07°±0.2°, 19.08°±0.2°, 19.67°±0.2°, 22.94°±0.2°, 31.15°±0.2°; or at 2Θ positions of 14.07°±0.2°, 15.92°±0.2°, 16.78°±0.2°, 19.08°±0.2°, 19.67°±0.2°, 22.94°±0.2°, 28.84°±0.2°, 31.15°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 5.

4. The crystalline form of claim 1, which is crystalline Form C of the compound of formula (I), having an X-ray powder diffraction pattern with characteristic diffraction peaks at 2Θ positions of 10.59°±0.2°, 13.20°±0.2°, 19.28°±0.2°, 21.93°±0.2°, 29.30°±0.2°; or at 2Θ positions of 10.59°±0.2°, 11.42°±0.2°, 13.20°±0.2°, 19.13°±0.2°, 19.28°±0.2°, 21.30°±0.2°, 21.93°±0.2°, 29.30°±0.2°; or an X-ray powder diffraction pattern substantially as shown in Figure 6.

5. A pharmaceutical composition comprising a therapeutically effective amount of the crystalline form of any one of claims 1-4, preferably 1-1500 mg, and a pharmaceutically acceptable carrier and / or excipient.

6. Use of the crystalline form of any one of claims 1-4, or the pharmaceutical composition of claim 5, for the manufacture of a medicament for the treatment or alleviation of pain.

7. A method for the treatment or alleviation of pain, which comprises administering to a subject a therapeutically effective amount of the crystalline form of any one of claims 1-4, or the pharmaceutical composition of claim 5, preferably 1-1500 mg.

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