CN116964065A - Selective Na V Pharmaceutically acceptable salts, crystalline forms and methods of preparing the same - Google Patents

Selective Na V Pharmaceutically acceptable salts, crystalline forms and methods of preparing the same Download PDF

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CN116964065A
CN116964065A CN202280017418.6A CN202280017418A CN116964065A CN 116964065 A CN116964065 A CN 116964065A CN 202280017418 A CN202280017418 A CN 202280017418A CN 116964065 A CN116964065 A CN 116964065A
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formula
compound
salt
characteristic peaks
pharmaceutically acceptable
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祝令建
洪敏�
郑澄
黄建
马亚辉
杨俊然
杜振兴
王捷
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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Jiangsu Hengrui Medicine Co Ltd
Shanghai Hengrui Pharmaceutical Co Ltd
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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
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/553—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having one nitrogen atom as the only ring hetero atom
    • C07F9/576—Six-membered rings

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Abstract

Providing a selective Na V Pharmaceutically acceptable salts, crystalline forms, and methods of preparing the same. Specifically, provided are meglumine salt, ethanolamine salt, potassium salt, amine salt, sodium salt, calcium salt, lysine salt and arginine salt of the compound represented by formula (I), a process for producing the same, and crystalline forms thereof.

Description

Selective Na V Pharmaceutically acceptable salts, crystalline forms and methods of preparing the same
The present application claims priority from China patent application 202110216129.6 with the application date 2021/2/26. The present application incorporates the entirety of the above-mentioned chinese patent application.
Technical Field
The present disclosure relates to pharmaceutically acceptable salts, crystalline forms and methods of preparing prodrugs of selective Nav1.8 inhibitors, and in particular, provides meglumine salts, ethanolamine salts, potassium salts, amine salts, sodium salts, calcium salts, lysine salts and arginine salts of compounds of formula (I), crystalline forms and methods of preparing.
Background
Pain is a common clinical symptom that originates from nociceptors in the peripheral nervous system. The receptors are widely distributed in the skin, muscle, joint and visceral tissues throughout the body, and can convert thermal, mechanical or chemical stimuli into nerve impulses (action potentials) and be transmitted by afferent nerve fibers to their cytoplasmic portions located in dorsal root ganglions (dorsal root ganglia, DRG), ultimately to the higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons in turn depends on voltage gates on cell membranes Sodium control channel (voltage-gated sodium channels, na V ). When the cell membrane depolarizes, sodium ion channels are activated, the channels are opened, sodium ions flow in, and the cell membrane is further depolarized, so that action potential is generated. Thus, inhibition of aberrant sodium channel activity contributes to the treatment, relief of pain.
Local anesthetic lidocaine through inhibition of Na V To relieve pain. Nonselective Na V Inhibitors such as lamotrigine, lacosamide, mexiletine have been successfully used to treat chronic pain. Due to Na used in clinic V Inhibitors lack subtype selectivity and can inhibit sodium ion channels in the heart and central nervous system, so that the treatment window is narrow and the application range is limited. Na (Na) V 1.8 distribution mainly in peripheral nervous system, selectively inhibiting Na V 1.8 can effectively reduce side effects. Therefore, there is a need to develop Na with higher activity, better selectivity, better pharmacokinetic properties and fewer side effects V 1.8 inhibitors. The patent application WO2020140959 of the present inventors provides a selective Na V 1.8 inhibitors of the chemical name 5-chloro-2- (4-fluoro-2- (methoxy-d) 3 ) Phenoxy) -N- (6-oxo-1, 6-dihydropyridazin-4-yl) -4- (trifluoromethyl) benzamide (formula a), which has been found to have better pharmaceutical activity. PCT/CN2021/113504 provides a selective Na V 1.8 inhibitors, which have the structure shown in formula (I),
disclosure of Invention
The present disclosure provides pharmaceutically acceptable salts of compounds of formula (I), wherein the pharmaceutically acceptable salts are selected from meglumine salts, ethanolamine salts, sodium salts, calcium salts, amine salts, potassium salts, lysine salts, and arginine salts.
In certain embodiments, the chemical ratio of the compound of formula (I) to the base molecule or cation is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to meglumine is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to ethanolamine is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to sodium ions is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to potassium ion is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to the ammonia molecule is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to calcium ions is 1:1. In certain embodiments, the chemical ratio of the compound of formula (I) to lysine is 1:1 or 1:2. In certain embodiments, the chemical ratio of the compound of formula (I) to arginine is 1:1 or 1:2.
The present disclosure also provides a process for preparing a pharmaceutically acceptable salt of a compound of formula (I), comprising the step of salifying a compound of formula (1) with a base. In certain embodiments, the solvent used in the salification reaction is selected from at least one of methanol, 2-butanone, ethyl acetate, 1, 4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether, methylene chloride, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene, and water. In certain embodiments, the method of preparing the aforementioned pharmaceutically acceptable salts further comprises the steps of volatilizing the solvent or stirring to crystallize, filtering, drying, and the like.
The present disclosure provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salts.
The present disclosure also provides a pharmaceutical composition comprising a pharmaceutically acceptable salt of the foregoing or a pharmaceutically acceptable salt prepared by the foregoing process, and optionally from a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure provides a process for preparing a pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable salt of the foregoing, or a pharmaceutically acceptable salt of a compound of formula (I) prepared by the foregoing process, with a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure provides a pharmaceutically acceptable salt of a compound of formula (I), or a pharmaceutically acceptable salt prepared by the method, or a composition, or a use of the composition in the manufacture of a medicament for inhibiting a voltage-gated sodium channel in a subject, preferably, the voltage-gated sodium channel is Na V 1.8。
The present disclosure provides a pharmaceutically acceptable salt of a compound of the formula (I) or a pharmaceutically acceptable salt prepared by the process described above, or a composition prepared by the process described above, for use in the manufacture of a medicament for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, sham-equine-figure three-syndrome, incontinence or cardiac arrhythmias, preferably the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
The present disclosure provides meglumine salts of compounds of formula (I).
The present disclosure provides an amorphous form of a dimeglumine salt of a compound represented by formula (I) having an X-ray powder diffraction pattern with a diffraction angle 2 theta in the range of 2-48 deg. without distinct characteristic peaks.
The present disclosure further provides a method for preparing an amorphous form of a meglumine salt of a compound of formula (I), method 1, comprising the steps of: a) mixing a compound shown in a formula (I) with a solvent I, heating, wherein the solvent is at least one selected from tetrahydrofuran, ethanol and DMSO, b) adding meglumine solution for reaction, cooling, separating out, c) adding isopropanol or ethanol, and precipitating out; or method 2, comprising the steps of: a) Mixing a compound shown in a formula (I) and meglumine with a solvent II, heating for reaction, wherein the solvent II is at least one selected from ethanol, acetone and acetonitrile, and b) precipitating and separating out.
In certain embodiments, the solvent I or II of the present disclosure may be used in a volume (μl) that is 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides an amorphous form of a monomethylamine salt of a compound represented by formula (I) having an X-ray powder diffraction pattern with a diffraction angle 2θ of 2 to 48 ° without distinct characteristic peaks.
The present disclosure further provides a method for preparing an amorphous meglumine salt of a compound of formula (I), comprising the steps of: a) Mixing a compound shown in a formula (I) and meglumine with solvent methyl tertiary butyl ether or toluene, b) heating, and precipitating to obtain the product.
In certain embodiments, the volume (μl) used for the solvents described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides crystalline form a of an ethanolamine salt of a compound of formula (I) having characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726 and 27.000 in X-ray powder diffraction patterns expressed in terms of diffraction angle 2θ. In certain embodiments, the ethanolamine salt of the compound of formula (I) has a characteristic peak at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, 24.375, 25.060, 27.000, and 27.847, and in certain embodiments, the ethanolamine salt of the compound has a characteristic peak at 9.857, 13.767, 14.953, 16.243, 16.932, 19.965, 22.654, 23.726, 24.375, 25.060, 26.102, 27.000, and 27.847. In certain embodiments, the X-ray powder diffraction pattern of form a of the ethanolamine salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in figure 2.
The present disclosure further provides a process for preparing form a of the ethanolamine salt of a compound of formula (I) comprising: a) Mixing a compound shown in a formula (I), ethanol and ethanolamine, b) heating, and separating out.
In certain embodiments, the volume (μl) of solvent ethanol described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides an a-form of the sodium salt of the compound of formula (I) having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784 and 23.654. In certain embodiments, form a of the sodium salt of the compound of formula (I) has characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 17.442, 18.354, 20.784 and 23.654. In certain embodiments, form a of the sodium salt of the compound of formula (I) has characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 16.533, 17.442, 18.354, 20.168, 20.784, 22.996 and 23.654. In certain embodiments, the X-ray powder diffraction pattern of form a of the sodium salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 3.
The present disclosure further provides a process for preparing form a of the sodium salt of the compound of formula (I), comprising: a) Mixing the compound shown in the formula (I), isopropanol and sodium hydroxide solution, and b) precipitating.
In certain embodiments, the volume (μl) used for the solvent isopropyl alcohol described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure further provides a b-form of the sodium salt of the compound of formula (I), having characteristic peaks at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301 and 28.642 in X-ray powder diffraction patterns expressed in terms of diffraction angle 2θ. In certain embodiments, form b of the sodium salt of the compound of formula (I) has characteristic peaks at 8.105, 9.016, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428 and 28.642. In certain embodiments, form b of the sodium salt of the compound of formula (I) has characteristic peaks at 8.105, 9.016, 11.816, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, 28.642 and 30.771. In certain embodiments, the X-ray powder diffraction pattern of form b of the sodium salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 4.
The present disclosure further provides a process for preparing form b of the sodium salt of the compound of formula (I), comprising: a) Mixing a compound shown in a formula (I) and sodium hydroxide solution with a solvent, heating, wherein the solvent is at least one selected from EtOH and THF, and b) precipitating.
In certain embodiments, the volume (μl) used for the solvents described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure also provides a form I of the potassium salt of the compound of formula (I), having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044 and 26.297. In certain embodiments, form I of the potassium salt of the compound of formula (I) has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 32.079 and 39.038. In certain embodiments, the potassium salt of the compound of formula (I) in form I has characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 29.594, 30.585, 32.079, 36.429 and 39.038. In certain embodiments, the X-ray powder diffraction pattern of form I of the potassium salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 5.
The present disclosure provides a form II of the potassium salt of the compound of formula (I), having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 7.488, 11.277, 13.394, 15.073, 22.860, 26.219 and 33.298. In certain embodiments, form II of the potassium salt of the compound of formula (I) has characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 33.298 and 38.093. In certain embodiments, form II of the potassium salt of the compound of formula (I) has characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 27.808, 31.943, 33.298, 38.093 and 40.734. In certain embodiments, the X-ray powder diffraction pattern of form II of the potassium salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 6.
The present disclosure further provides a process for preparing crystalline form I or II of the potassium salt of a compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), isopropanol and potassium hydroxide solution, and b) precipitating to obtain the compound.
In certain embodiments, the volume (μl) used for the solvent isopropyl alcohol described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides a form III of the potassium salt of the compound of formula (I) having an X-ray powder diffraction pattern in terms of diffraction angle 2θ, with characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948 and 27.600. In certain embodiments, form III of the potassium salt of the compound of formula (I) has characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, 26.462, 27.600, 30.872 and 34.296. In certain embodiments, form III of the potassium salt of the compound of formula (I) has characteristic peaks at 7.457, 11.223, 13.603, 15.042, 16.970, 19.420, 20.485, 23.948, 25.061, 26.462, 27.600, 30.872 and 34.296. In certain embodiments, the X-ray powder diffraction pattern of form III of the potassium salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 7.
The present disclosure further provides a process for preparing a potassium salt form III of a compound of formula (I), comprising: 1) Mixing at least one solvent selected from the group consisting of ethanol and tetrahydrofuran with a potassium hydroxide solution, and 2) precipitating.
In certain embodiments, the volume (μl) used for the solvents described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides a crystalline form a of an amine salt of a compound of formula (I), having characteristic peaks at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498 and 24.596, in X-ray powder diffraction patterns expressed in terms of diffraction angle 2θ. In certain embodiments, form a of the amine salt of the compound of formula (I) has characteristic peaks at 8.324, 11.597, 12.156, 14.903, 15.445, 17.259, 23.498, 24.596, 28.342 and 31.287. In certain embodiments, form a of the amine salt of the compound of formula (I) has characteristic peaks at 8.324, 11.597, 12.156, 13.808, 14.903, 15.445, 17.259, 19.073, 21.251, 23.498, 24.596, 28.342 and 31.287. In certain embodiments, the X-ray powder diffraction pattern of form a of the amine salt of the compound of formula (I) as represented by the angle of diffraction, 2θ, is shown in fig. 8.
The present disclosure further provides a process for preparing form a of an amine salt of a compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), isopropanol and ammonia water, and b) pulping and crystallizing.
In certain embodiments, the volume (μl) used for the solvent isopropyl alcohol described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides a form B of an amine salt of a compound of formula (I) having characteristic peaks at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052 and 29.047, an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ. In certain embodiments, form B of the amine salt of the compound of formula (I) has characteristic peaks at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208, 21.472, 24.052, 29.047, 29.644. In certain embodiments, form B of the amine salt of the compound of formula (I) has characteristic peaks at 5.263, 8.132, 10.629, 11.886, 16.619, 17.221, 18.848, 20.208, 21.472, 24.052, 27.121, 29.047, 29.644. In certain embodiments, the X-ray powder diffraction pattern of form B of the amine salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 9.
The present disclosure further provides a process for preparing form B of an amine salt of a compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), isopropanol and ammonia water, and b) cooling and crystallizing.
In certain embodiments, the volume (μl) used for the solvents described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure provides a crystalline form a of the calcium salt of a compound of formula (I), having characteristic peaks at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878 and 34.073 in X-ray powder diffraction patterns expressed in terms of diffraction angle 2θ. In certain embodiments, form a of the calcium salt of the compound of formula (I) has characteristic peaks at 8.455, 9.436, 13.657, 16.433, 18.106, 20.756, 26.620, 28.892, 29.878 and 34.073. In certain embodiments, form a of the calcium salt of the compound of formula (I) has characteristic peaks at 8.455, 9.436, 13.657, 16.433, 17.105, 18.106, 20.756, 23.017, 26.620, 27.653, 28.892, 29.878 and 34.073. In certain embodiments, the X-ray powder diffraction pattern of form a of the calcium salt of the compound of formula (I) as represented by the angle of diffraction, 2θ, is shown in figure 10.
The present disclosure further provides a process for preparing form a of the calcium salt of the compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), ethanol and a calcium hydroxide solution, heating, and b) precipitating to obtain the product.
In certain embodiments, the volume (μl) of solvent ethanol described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure further provides a crystalline form a of a lysine salt of the compound of formula (I), having characteristic peaks at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226 and 25.795 in X-ray powder diffraction patterns expressed in terms of diffraction angle 2θ. In certain embodiments, form a of the lysine salt of the compound of formula (I) has characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 25.226, 25.795 and 30.365. In certain embodiments, form a of the lysine salt of the compound of formula (I) has characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 24.450, 25.226, 25.795, 30.365 and 34.619. In certain embodiments, the X-ray powder diffraction pattern of form a of the lysine salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 11.
The present disclosure further provides a process for preparing form a of the lysine salt of the compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), acetone and a lysine solution, heating, and b) precipitating to obtain the product.
In certain embodiments, the solvent acetone described in the present disclosure may be used in a volume (μl) that is 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure further provides a crystalline form a of an arginine salt of a compound of formula (I), having an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618, and 26.485. In certain embodiments, form a of the arginine salt of the compound of formula (I) has characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 23.794, 25.589, and 26.485. In certain embodiments, form a of the arginine salt of the compound of formula (I) has characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 22.911, 23.794, 25.589, 26.485, 29.631, and 37.910. In certain embodiments, the X-ray powder diffraction pattern of form a of the arginine salt of the compound of formula (I) as represented by the angle of diffraction, 2θ, is shown in figure 12.
The present disclosure further provides a method of preparing form a of arginine salt of a compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), acetone and an arginine water solution, and b) stirring for crystallization.
In certain embodiments, the solvent acetone described in the present disclosure may be used in a volume (μl) that is 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure further provides a form B of an arginine salt of a compound of formula (I), having an X-ray powder diffraction pattern, expressed as diffraction angle 2θ, with characteristic peaks at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124, and 33.605. In certain embodiments, form B of the arginine salt of the compound of formula (I) has characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 33.605, and 43.535. In certain embodiments, the arginine salt of the compound of formula (I) has characteristic peaks at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 29.546, 31.433, 33.155, 33.605, 34.490, and 43.535 in form B. In certain embodiments, the X-ray powder diffraction pattern of form B of the arginine salt of the compound of formula (I) as represented by the angle of diffraction 2θ is shown in fig. 13.
The present disclosure further provides a method of preparing form B of an arginine salt of a compound of formula (I), comprising: a) Mixing a compound shown in a formula (I), acetone and arginine, b) heating, cooling and crystallizing.
In certain embodiments, the volume (μl) used for the solvents described in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments may be 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 200. In certain embodiments, the methods of preparation described in the present disclosure further comprise a filtration, washing, or drying step.
The present disclosure also provides pharmaceutical compositions prepared from the crystalline forms of the pharmaceutically acceptable salts of (I) above.
The present disclosure also provides a pharmaceutical composition comprising a crystalline form of a pharmaceutically acceptable salt of the foregoing and optionally a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure also provides a method of preparing a pharmaceutical composition comprising the step of mixing a crystalline form of a pharmaceutically acceptable salt as described above with a pharmaceutically acceptable carrier, diluent or excipient.
The present disclosure also provides the use of a crystalline form of the aforementioned pharmaceutically acceptable salt, or of the aforementioned composition, or of a composition prepared by the aforementioned method, in the manufacture of a medicament for inhibiting a voltage-gated sodium channel in a subject, preferably, the voltage-gated sodium channel is Na V 1.8。
The present disclosure also provides the use of a crystalline form of the foregoing pharmaceutically acceptable salt, or of the foregoing composition, or of a composition prepared by the foregoing process, for the manufacture of a medicament for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, charcot-marie-tooth syndrome, incontinence or cardiac arrhythmias, preferably the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
Certain errors exist in the chemical ratio measurement of the compound of the formula (I) and the alkali molecule in the present disclosure, and in general, both plus and minus 10% are within a reasonable error range. There is a degree of variation in error, depending on the context in which it is used, that is no more than plus or minus 10%, plus or minus 9%, plus or minus 8%, plus or minus 7%, plus or minus 6%, plus or minus 5%, plus or minus 4%, plus or minus 3%, plus or minus 2%, plus or minus 1%, preferably plus or minus 5%.
The "2θ or 2θ angle" described in the present disclosure refers to a diffraction angle, θ is a bragg angle, and the unit is ° or degree; the error range of each characteristic peak 2 theta is + -0.20 (including the case where the numbers of more than 1 decimal place are rounded off), and may be-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 precipitation modes described in the present disclosure include, but are not limited to, stirring, volatilizing, beating, and precipitating.
According to the description of the hygroscopicity characteristic and the definition of the hygroscopicity weight increase in the '9103 medicine hygroscopicity guiding principle' in the fourth part of the 2015 edition of Chinese pharmacopoeia,
deliquescence: absorbing a sufficient amount of moisture to form a liquid;
the moisture absorption performance is very good: the weight gain after moisture absorption is not less than 15%;
moisture permeability: the weight gain of the wet-drawing is less than 15 percent but not less than 2 percent;
slightly hygroscopic: the weight gain of the wet-drawing is less than 2 percent but not less than 0.2 percent;
no or little hygroscopicity: the weight gain caused by moisture is less than 0.2 percent.
The term "differential scanning calorimetric analysis or DSC" in the present disclosure refers to measuring the temperature difference and the heat flow difference between a sample and a reference object during the temperature rising or constant temperature process of the sample, so as to characterize all physical changes and chemical changes related to thermal effects, and obtain phase change information of the sample.
The drying temperature in the present disclosure is generally 25 to 100 ℃, preferably 40 to 70 ℃, and the drying temperature can be either normal pressure drying or reduced pressure drying.
"pharmaceutical composition" means a mixture comprising one or more compounds of formula (I) as described herein or a pharmaceutically acceptable salt thereof, and other chemical components, such as pharmaceutically acceptable carriers and excipients. The purpose of the pharmaceutical composition is to promote the administration to organisms, facilitate the absorption of active ingredients and thus exert biological activity.
The crystal forms disclosed in the disclosure comprise but are not limited to solvates of meglumine salts of the compounds shown in formula (I), and the solvents comprise but are not limited to tetrahydrofuran/ethanol, DMSO, ethanol, acetonitrile, acetone, methyl tertiary butyl ether and toluene. The crystal forms described in the present disclosure include, but are not limited to, solvates of the ethanolamine salt of the compound of formula (I), including, but not limited to, ethanol. The crystal forms disclosed in the present disclosure include, but are not limited to, solvates of sodium salts of the compounds of formula (I), including, but not limited to, isopropanol, etOH/THF. The crystal forms disclosed in the present disclosure include, but are not limited to, solvates of potassium salts of the compounds of formula (I), including, but not limited to, isopropanol, etOH/THF. The crystal forms described in the present disclosure include, but are not limited to, solvates of amine salts of the compounds of formula (I), including, but not limited to, isopropanol. The crystal forms disclosed in the present disclosure include, but are not limited to, solvates of the calcium salt of the compound of formula (I), including, but not limited to, ethanol. The crystal forms described in the present disclosure include, but are not limited to, solvates of the compound lysine of formula (I), including, but not limited to, acetone. The crystal forms described in the present disclosure include, but are not limited to, solvates of arginine as a compound of formula (I), including, but not limited to, acetone.
"solvates" as described in this disclosure include, but are not limited to, complexes formed by the combination of a compound of formula I with a solvent.
Drawings
Fig. 1: XRPD pattern of amorphous crystals of dimeglumine salt of compound of formula (I).
Fig. 2: XRPD pattern of the ethanolamine salt form a of the compound of formula (I).
Fig. 3: XRPD pattern of the crystalline form a of the sodium salt of the compound of formula (I).
Fig. 4: XRPD pattern of crystalline form b of the sodium salt of the compound of formula (I).
Fig. 5: XRPD pattern of potassium salt form I of compound of formula (I).
Fig. 6: XRPD pattern of the potassium salt form II of the compound of formula (I).
Fig. 7: XRPD pattern of potassium salt form III of compound of formula (I).
Fig. 8: XRPD pattern of the salt of the compound of formula (I) form a.
Fig. 9: XRPD pattern of the salt B crystalline form of the compound of formula (I).
Fig. 10: XRPD pattern of calcium salt form a of compound of formula (I).
Fig. 11: XRPD pattern of lysine salt form a of compound of formula (I).
Fig. 12: XRPD pattern of arginine salt form a of compound of formula (I).
Fig. 13: XRPD pattern of compound arginine salt form B of formula (I).
Detailed Description
The present disclosure will be explained in more detail below with reference to examples or experimental examples, which are only for illustrating technical solutions in the present disclosure, and do not limit the spirit and scope in the present disclosure.
The reagents used in the present invention are commercially available.
Test conditions of the instrument used for the experiment in the invention:
1. differential scanning calorimeter (Differential Scanning Calorimeter DSC)
Instrument model: mettler Toledo DSC 3+STARe System
Sweep gas: nitrogen gas; nitrogen purge rate: 50mL/min
Rate of temperature rise: 10.0 ℃/min
Temperature range: 25-350 DEG C
2. X-ray powder diffraction spectrum (X-ray Powder Diffraction, XRPD)
Instrument model: BRUKER D8 Discover A25X-ray powder diffractometer
Rays: monochromatic Cu-ka radiation (λ=1.5406)
Scanning mode: θ/2θ, scan range (2θ range): 3-50 DEG
Voltage: 40kV, current: 40mA
3. Thermogravimetric analyzer (Thermogravimetric Analysis, TGA)
Instrument model: mettler Toledo TGA2
Sweep gas: nitrogen gas; nitrogen purge rate: 50mL/min
Rate of temperature rise: 10.0 ℃/min
Temperature range: 25-350 DEG C
4. DVS is dynamic moisture adsorption
Surface Measurement Systems advantage 2 is adopted for detection, the humidity is increased from 50% -95% -0% -95% -50% RH to 10% at 25 ℃, and the judgment standard is that the quality change dM/dT of each gradient is smaller than 0.002%, TMAX is 360min, and the two circles are circulated. 5. The average inhibition rate of kinase and IC50 value were measured by NovoStar microplate reader (BMG, germany).
6. The monitoring of the progress of the reaction in the examples employed Thin Layer Chromatography (TLC), the developing reagent used for the reaction, the system of eluent for column chromatography employed for purifying the compound and the developing reagent system of thin layer chromatography included: a: dichloromethane/methanol system, B: n-hexane/ethyl acetate system. The thin layer chromatography silica gel plate uses a smoke table yellow sea HSGF254 or Qingdao GF254 silica gel plate, the specification of the silica gel plate used by the Thin Layer Chromatography (TLC) is 0.15 mm-0.2 mm, and the specification of the thin layer chromatography separation and purification product is 0.4 mm-0.5 mm. The silica gel column chromatography generally uses 200-300 mesh silica gel of yellow sea of the tobacco stand as a carrier.
7. The structure of the compounds is determined by Nuclear Magnetic Resonance (NMR) or/and Mass Spectrometry (MS). NMR shift (. Delta.) is given in units of 10-6 (ppm).
The NMR was performed using Bruker AVANCE NEO M with a solvent of deuterated dimethyl sulfoxide (DMSO-d 6), deuterated chloroform (CDCl 3), deuterated methanol (CD 3 OD) and an internal standard of Tetramethylsilane (TMS).
MS was determined using an Agilent 1200/1290DAD-6110/6120 Quadrapol MS liquid chromatography-mass spectrometry (manufacturer: agilent, MS model: 6110/6120 Quadrapol MS). waters ACQuity UPLC-QD/SQD (manufacturers: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). Thermo Ultimate3000-Q actual (manufacturer: thermo, MS model: THERMO Q Exactive)
8. The known starting materials of the present invention may be synthesized using or following methods known in the art, or may be purchased from the companies ABCR GmbH & Co.KG, acros Organics, aldrich Chemical Company, shaog chemical technology (Accela ChemBio Inc), dary chemical, and the like.
9. HPLC was determined using agilent 1260DAD high performance liquid chromatography (ACE Excel c18×4.6mm column) and Thermo Dionex Ultimate 3000 high pressure liquid chromatography (Waters Xbridge c18×4.6mm column).
Example 1: preparation of Compounds of formula I
The first step: compounds of formula III
The compound of formula IV (1.5 g,3.26mmol,1.0 eq) was stirred with aqueous formaldehyde (10 mL), heated and filtered to give a white solid 1.5g, ms (ESI): m/z 491.00[ M+1] +.1H-NMR (400 MHz, DMSO-d 6) δ11.11 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.26-7.30 (m, 2H), 7.16-7.14 (d, 1H), 7.01 (s, 1H), 6.88-6.83 (m, 1H), 6.72-6.88 (m, 1H), 5.29-5.27 (d, 2H).
And a second step of: compounds of formula II
The compound of formula III (1 g,2.04mmol,1.0 eq) was added to anhydrous THF (10 mL) and stirred. And (5) nitrogen ventilation protection and cooling. 1.0M solution of sodium bis (trimethylsilyl) amide (NaHMDS)/(tetrahydrofuran) in THF (3.05 mL,3.05mmol,1.5 eq) was added, and then solution of tetrabenzyl pyrophosphate (1.09 g,2.04mmol,1.0 eq) in THF (2 mL) was added dropwise, and after the addition was completed, the reaction was stirred at room temperature. Ethyl acetate EA was added to the reaction solution to dilute it, then 0.5M aqueous NaOH solution was added dropwise thereto, the organic phases were combined, dried, filtered and concentrated to dryness to give a crude pale yellow oil, which was purified to yield 1.25g, yield 81.69%, ms (ESI) M/z 750.95[ M+1] +.1H-NMR (400 MHz, DMSO-d 6) δ11.19 (s, 1H), 8.07 (s, 1H), 7.98 (s, 1H), 7.34-7.31 (m, 12H), 7.17-7.14 (d, 1H), 7.01 (s, 1H), 6.89-6.85 (m, 1H), 5.83-5.81 (d, 2H), 5.05-5.03 (d, 4H).
And a third step of: a compound of formula (I)
Trifluoroacetic acid (TFA) (10.34 mL,139.14mmol,95.0 eq) was added to the starting compound of formula II (1.10 g,1.46mmol,1.0 eq) and the reaction was stirred. Concentrating and drying to obtain crude product. Purification gave 0.77g of a white solid, yield: 92.11%, ms (ESI) m/z 570.90[ M+1] +.1H-NMR (400 MHz, DMSO-d 6) δ11.17 (s, 1H), 8.06 (s, 1H), 8.00 (s, 1H), 7.33 (s, 1H), 7.39-7.26 (m, 1H), 7.15-7.13 (d, 1H), 7.01 (s, 1H), 6.87-6.83 (m, 1H), 5.63-5.61 (d, 2H).
Test example 1: the compound of formula I is against Na V 1.8 determination of inhibitory Activity
The purpose of the experiment was to investigate the compound of formula I for Na in an ex vivo experiment V 1.8 influence of ion channel, na V 1.8 ion channels were stably expressed on HEK293 cells. At Na (Na) V 1.8 comparison of Na before and after Compound application after current stabilization V 1.8 current to obtain the compound with Na V 1.8 influence of ion channels.
1 Experimental materials and instruments
1) Patch clamp amplifier: latch clamp PC-505B (WARNER instruments)/MultiClamp 700A (Axon instrument)
2) A digital-to-analog converter: digidata 1440A (Axon CNS)/Digidata 1550A (Axon instruments)
3) Micro-controller: MP-225 (SUTTER instrument)
4) Inverted microscope: TL4 (Olympus)
5) Glass microelectrode drawing instrument: PC-10 (NARISHIGE)
6) Microelectrode glass capillary: B12024F (Wuhan micro-detection science instruments Co., ltd.)
7) Dimethyl sulfoxide (DMSO) D2650 (Sigma-Aldrich)
8)TTX AF3014(Affix Scientific)
2 experimental procedure
2.1 test Compounds
Compounds I and VX-150 (prepared by the method described in WO 2015089361).
2.1 Compound formulation
Compounds for preparing extracellular and intracellular fluids were purchased from Sigma (St. Louis, MO) company, except NaOH and KOH for acid-base titration.Extracellular fluid (mM) is NaCl,137; KCl,4; caCl (CaCl) 2 ,1.8；MgCl 2, 1, a step of; HEPES,10; glucose 10; pH 7.4 (NaOH titration). Intracellular fluid (mM) is Aspartic acid,140; mgCl2,2; EGTA 11; HEPES,10; pH7.2 (CsOH titration). All test compound and control compound solutions contained 1. Mu.M TTX.
The test compound was stored at a concentration of 9mM and dissolved in dimethyl sulfoxide (DMSO). The test day is dissolved in extracellular fluid again to prepare the required concentration.
2.2 Manual patch clamp test procedure
1) After the compound is prepared into a solution with a specified concentration, the liquid medicine is sequentially added into each pipeline according to the sequence from low concentration to high concentration, and each pipeline is marked.
2) Transferring the cells into a perfusion groove, applying positive pressure in the electrode, enabling the tip of the electrode to be in contact with the cells, adjusting a three-way valve of an air extractor to be in a three-way state, and then applying negative pressure to the electrode to enable the electrode and the cells to form high-resistance sealing. Continuing to apply negative pressure, the cell membrane breaks, forming a current path.
3) And after the cell rupture current is stable, sequentially carrying out perfusion with different concentrations. And if the current is stable for at least one minute, the next concentration can be replaced for perfusion. Each concentration was perfused for no more than five minutes.
4) And cleaning the perfusion groove. The washing is carried out according to the concentration of the liquid medicine from high to low, and the washing is carried out for 20 seconds for each concentration of the liquid medicine. Finally, the cells were rinsed with extracellular fluid for 1min.
2.3 test Voltage equation (holding) and results
The cells were clamped at-80 mV and then depolarized to 10mV with a square wave for 10 ms to give Na V 1.8 current. This procedure was repeated every 5 seconds. The maximum current induced by the square wave is detected, after which the test compound is perfused and after the reaction is stable, the intensity of the blockage is calculated.
3. Data analysis
The data is stored in the computer system for analysis. Data collection and analysis will be performed using pCLAMP 10 (Molecular Devices, union City, calif.), and the manager will review the results of the analysis. Current stabilization refers to a current that varies over time within a limited range. The magnitude of the stabilized current was used to calculate the effect of the compound on this solubility.
The inhibitory Activity of Compound (I) of the present disclosure on Nav1.8 IC was determined by the above assay 50 The value was 2.80nM and VX-150 was 17.71nM.
Test example 2: in vivo pharmacokinetic studies in rats
1. Summary
The concentration of the drug in plasma at various times after intravenous injection of the compounds of the present disclosure was determined using LC/MS method using CD rats as the test animals. Pharmacokinetic behavior of the compounds of the present disclosure in mice was studied and their pharmacokinetic profile was assessed.
2. Test protocol
2.1 test drug
A compound of formula I: sodium chloride injection is used for preparing;
a compound of formula IV: is prepared by 1% DMSO+5% HS15+94% physiological saline.
2.2 test animals
SD rats, male and female halves, weighing 190-230 g, purchased from Shanghai Jieshijie laboratory animals Inc., produced license number SCXK (Shanghai) 2018-0004, pass number 20180004038484.
2.3 administration of drugs
The rats were divided into 2 groups of 6 animals each, each male and female half. Fasted before administration is not less than 12 hours, drinking water is free, and the administration is carried out for 4 hours after administration, so that the administration is unified. The specific arrangement is as follows:
TABLE 2
3. Operation of
Sample collection and processing:
before and after administration for 5min, 0.25, 0.5, 1.0, 2.0, 4.0, 7.0, 10, 24 and 48h blood is taken from the retrobulbar venous plexus for 0.2ml, the sample is placed into an EDTA-K2 anticoagulant tube containing 10 mu L of 100mM BNPP, centrifuged at 11000rpm for 5min (4 ℃), plasma is separated for 30min, and the sample is stored at-70 ℃.
The concentration of the compound of formula I and the compound of formula IV in plasma at various time points after rat dosing was determined using the LC-MS/MS method. Pharmacokinetic parameters were calculated following administration in rats using a non-compartmental model of Phoenix WinNonlin 7.0.0 software (Pharsight, USA).
Peak time T max Peak concentration C of sum-of-arrival max The actual measurement values are adopted;
area under the curve AUC 0-t Value: calculating by adopting a trapezoid method; AUC (AUC) 0-∞ ＝AUC 0-t +C t /k e ，C t For the blood concentration, k, at the last measurable time point e To eliminate the rate constant;
elimination half-life t 1/2 ＝0.693/k e ；
Mean residence time mrt=aumc/AUC;
clearance cl=d/AUC 0-∞ (D is the dosage administered);
steady state distribution volume V ss ＝CL×MRT。
4. Pharmacokinetic parameter results
TABLE 3 Table 3
Conclusion:
after intravenous administration of the compound of formula I to SD rats, no compound of formula I was detected in the plasma (below the lower limit of quantitation of 7.50 ng/mL), the plasma concentration of the compound of formula IV peaked at the first sampling point (5 min) after administration, suggesting that the compound of formula I can be rapidly converted to the parent compound of formula IV in vivo after administration.
At equimolar doses, the peak concentration (C 5min ) Peak concentration of group for administration of compound of formula IV (C 5min ) Presumably following intravenous administration, of a compound of formula IThe rapid distribution of the substance into the tissue and the conversion into the compound of formula IV; exposure AUC 0-t 77% of the compound of formula IV; plasma clearance CL and steady state distribution volume V ss 1.40 and 1.77 times the group to which the compound of formula IV was administered, respectively.
Test example 3: in vivo pharmacokinetic studies in beagle dogs
1. Summary
The concentration of the drug in plasma at various times after intravenous injection of the compounds of the present disclosure was determined using LC/MS method using beagle dogs as the test animals. Pharmacokinetic behavior of the compounds of the present disclosure in mice was studied and their pharmacokinetic profile was assessed.
2. Test protocol
2.1 test drug
A compound of formula I: sodium chloride injection is used for preparing;
a compound of formula IV: formulated with 2% dmso+10% hs15 (polyethylene glycol (PEG) dodecahydroxystearate) +88% physiological saline.
2.2 test animals
Beagle, each half of male and female, has a weight of about 9-11 kg, and is purchased from Jiangsu eastern laboratory animal institute, inc., and has a production license number SCXK (Shanghai) 2016-0009 and a license number 202020255.
2.3 administration of drugs
The six beagle dogs are 6, the male and the female are half, and fasted for not less than 12 hours before administration, and the beagle dogs drink water freely. 4 hours after administration, the food is taken uniformly. The washing period was 1 week.
TABLE 4 beagle pharmacokinetic test schedule
3. Operation of
1ml of blood was collected via the limb veins 5min, 15min, 0.5, 1.0, 2.0, 4.0, 7.0, 10, 24 and 48h before and after administration, and EDTA-K containing 50. Mu.L of 100mM BNPP was added after sampling 2 In the anticoagulation tube, the blood plasma was separated by centrifugation at 3500rpm for 10min (4 ℃) for 1h, -70Preserving at the temperature of the test piece.
The concentration of the compound of formula I and the compound of formula IV in plasma at various time points after administration to beagle dogs was determined using the LC-MS/MS method. Pharmacokinetic parameters were calculated following beagle administration using a non-compartmental model of Phoenix WinNonlin 7.0.0 software (Pharsight, usa).
Peak time T max Peak concentration C of sum-of-arrival max The actual measurement values are adopted;
area under the curve AUC 0-t Value: calculating by adopting a trapezoid method; AUC (AUC) 0-∞ ＝AUC 0-t +C t /k e ，C t For the blood concentration, k, at the last measurable time point e To eliminate the rate constant;
elimination half-life t 1/2 ＝0.693/k e ；
Mean residence time mrt=aumc/AUC;
clearance cl=d/AUC 0-∞ (D is the dosage administered);
steady state distribution volume V ss ＝CL×MRT。
4. Pharmacokinetic parameter results
TABLE 5
After intravenous injection of the compound of formula I, no compound of formula I was detected in the plasma (below the lower limit of quantitation of 7.50 ng/mL), the plasma concentration of the compound of formula IV peaked at the first sampling point (5 min) after administration, suggesting that the compound of formula I may be rapidly converted to the parent compound of formula IV in vivo after administration.
Peak concentration of compound of formula IV after injection of compound of formula I into beagle at equimolar dose (C 5min ) Peak concentration of group for administration of compound of formula IV (C 5min ) 100.4% of (3); AUC (AUC) 0-t 96.3% of the group to which the compound of formula IV was administered. Plasma scavenging of compounds of formula IVRate CL, steady state distribution volume V ss Half-life t 1/2 No significant differences were shown between the two groups.
Example 2: amorphous preparation of meglumine salt of Compound of formula (I)
100mg of the compound of formula (I) at 3mL of 1:1 in Tetrahydrofuran (THF)/ethanol (EtOH), dissolving at 50 ℃, adding 684mg/mL meglumine aqueous solution to react with 0.1mL, cooling to precipitate, adding 3mL of precooled isopropanol, precipitating, centrifuging, and drying the solid in vacuum. The product was amorphous as measured by X-ray powder diffraction and the XRPD pattern is shown in figure 1.
Nuclear Magnetic (HNMR) detection of the resulting product: meglumine content was 43.2%, indicating a molar ratio of compound to meglumine in the salt of about 1:2.
Example 3: amorphous preparation of meglumine salt of Compound of formula (I)
100mg of the compound shown in the formula (I) is dissolved in 3mL of THF/EtOH (1:1) at 50 ℃, and then 684mg/mL of meglumine aqueous solution is added for 0.1mL reaction, and the temperature is reduced for precipitation. Pre-chilled EtOH 3mL was added and the precipitate separated out and the centrifuged solid dried in vacuo. The product was amorphous as measured by X-ray powder diffraction.
Example 4: amorphous preparation of meglumine salt of Compound of formula (I)
After 100mg of the compound shown in the formula (I) is dissolved in 0.5mL of DMSO, 684mg/mL of meglumine aqueous solution is added for reaction at 50 ℃, the temperature is reduced to room temperature, the reaction solution is dripped into 10mL of precooled EtOH, precipitation is carried out, and centrifugal solid is dried in vacuum. The product was amorphous as measured by X-ray powder diffraction.
Example 5: amorphous preparation of meglumine salt of Compound of formula (I)
10.0mg of the compound of formula (I) and 7.8mg of meglumine, 0.2mL of ethanol are added, the mixture is heated at 50 ℃ and reacted, stirred at room temperature, and the centrifuged solid is dried under vacuum. The product was amorphous as measured by X-ray powder diffraction.
Example 6: amorphous preparation of meglumine salt of Compound of formula (I)
10.0mg of the compound of formula (I) and 7.8mg of meglumine are reacted with 0.2mL of acetone at 50℃under stirring at room temperature, and the solid is centrifuged and dried under vacuum. The product was amorphous as measured by X-ray powder diffraction.
Example 7: amorphous preparation of meglumine salt of Compound of formula (I)
10.0mg of the compound of formula (I) and 7.8mg of meglumine are reacted with 0.2mL of acetonitrile, heated at 50℃and stirred at room temperature, and the centrifuged solid is dried under vacuum. The product was amorphous as measured by X-ray powder diffraction.
Example 8: preparation of meglumine salt of Compound of formula (I) amorphous form
10.4mg of the compound of formula (I) and 3.9mg of meglumine, 0.2mL of methyl tert-butyl ether are added, the temperature is reduced after heating reaction at 50 ℃, and the centrifugal solid is dried in vacuum. The product was amorphous as measured by X-ray powder diffraction.
Nuclear Magnetic (HNMR) detection of the resulting product: meglumine content was 26.6%, indicating a molar ratio of compound to meglumine in the salt of about 1:1.
Example 9: preparation of meglumine salt of Compound of formula (I) amorphous form
10.3mg of the compound represented by the formula (I) and 3.9mg of meglumine are reacted with 0.3mL of toluene at 50℃and then cooled, and the centrifuged solid is dried under vacuum. The product was amorphous as measured by X-ray powder diffraction.
Example 10: preparation of the ethanolamine salt A form of the Compound of formula (I)
11.2mg of the compound represented by the formula (I) is added with 0.2mL of ethanol, 19.3 mu L of ethanol amine aqueous solution with 1mol/L of solution is added, and the mixture is heated for precipitation, and the centrifugal solid is dried in vacuum. The product was form a as measured by X-ray powder diffraction, the XRPD pattern is shown in figure 2, and the characteristic peak positions are shown in table 1. The DSC profile showed an endothermic peak at 105.27 ℃. TGA profile shows a weight loss of 6.64% at 25-110 ℃, 6.36% at 110-255 ℃. Nuclear Magnetism (HNMR) detection of the obtained product shows that the salt forming ratio of the compound to the ethanolamine is about 1:1.1.
TABLE 1
Example 11: preparation of sodium salt form a of Compound of formula (I)
10.35mg of the compound shown in the formula (I) is added with 0.2mL of isopropanol at room temperature, 19.3 mu L of 1mol/L sodium hydroxide aqueous solution is added, the mixture is heated at 45 ℃ for reaction, cooled to room temperature for pulping, 0.1mL of isopropanol is added for precipitation, and centrifugal solid is dried in vacuum. The product was crystalline form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 3 and the characteristic peak positions shown in table 2. DSC spectra showed an endothermic peak at 57.49 ℃, 97.49 ℃, 162.79 ℃, 241.94 ℃ and an exothermic peak at 197.83 ℃. TGA spectrum shows that the weight loss is 5.47% at 25-105 ℃ and 3.49% at 105-190 ℃.
TABLE 2
Example 12: preparation of sodium salt b Crystal form of Compound of formula (I)
10.1mg of the compound of formula (I) are heated by adding 0.2mL of EtOH/THF (1:1), 19.3. Mu.L of 1mol/L aqueous sodium hydroxide solution are added, the precipitate is separated out, and the solid is dried by centrifugation under vacuum. The product was form b as measured by X-ray powder diffraction, the XRPD pattern shown in figure 4 and the characteristic peak positions shown in table 3. Ion chromatography of the resulting product gave a salt formation ratio of compound to sodium ion of about 1:1.
TABLE 3 Table 3
Example 13: preparation of Potassium salt form I of Compounds of formula (I)
10.1mg of the compound represented by the formula (I) was reacted by adding 0.2mL of isopropyl alcohol, adding 19.3. Mu.L of 1mol/L aqueous potassium hydroxide solution, heating at 45℃to react, cooling to room temperature, beating for 3 days, centrifuging, and drying the solid in vacuo. The product was form I as measured by X-ray powder diffraction, the XRPD pattern shown in figure 5 and the characteristic peak positions shown in table 4. DSC spectra showed an endothermic peak at 80.79℃and 166.10 ℃and 241.89 ℃and an exothermic peak at 203.52 ℃. TGA profile shows a weight loss of 9.15% at 25-130 ℃, 5.25% at 130-235 ℃.
TABLE 4 Table 4
Example 14: preparation of Potassium salt form II of the Compound of formula (I)
49.72mg of the compound of formula (I) was reacted with 1.0mL of isopropyl alcohol and 49.7. Mu.L of 1mol/L aqueous potassium hydroxide at 45℃under heating, cooled to room temperature, slurried for 1 day, centrifuged, and the solid was dried under vacuum. The product was form II as measured by X-ray powder diffraction, the XRPD pattern shown in figure 6 and the characteristic peak positions shown in table 5. DSC spectra showed an endothermic peak at 68.80 ℃, 167.05 ℃, 240.18 ℃, and an exothermic peak at 197.03 ℃. TGA spectrum shows that the weight loss is 3.94% at 25-140 ℃ and 4.63% at 140-235 ℃.
TABLE 5
Example 15: preparation of Potassium salt III Crystal form of Compound of formula (I)
10mg of the compound shown in the formula (I) is added with 0.3mL of ethanol/tetrahydrofuran, dissolved at 50 ℃, cooled to room temperature, added with 19.3 mu L of 1M potassium hydroxide aqueous solution, cooled, precipitated, centrifuged and dried to obtain solid. The product was in form III as measured by X-ray powder diffraction, the XRPD pattern is shown in FIG. 7 and the characteristic peak positions are shown in Table 6. DSC spectra showed an endothermic peak at 72.31℃and 186.68 ℃and 244.60 ℃and an exothermic peak at 202.45 ℃. TGA profile shows a weight loss of 2.64% at 25-145 ℃ and 4.31% at 145-230 ℃. Ion chromatography of the resulting product gave a salt formation ratio of compound to potassium ion of about 1:0.9.
TABLE 6
Example 16: preparation of amine salt form A of the Compound of formula (I)
10.3mg of the compound represented by the formula (I) is added with 0.2mL of isopropanol, 19.3 mu L of 1mol/L ammonia water solution is added, the mixture is heated at 45 ℃ for reaction, beating is carried out at room temperature for 3 days, white solid is separated out, and the solid is centrifuged and dried in vacuum. X-ray powder diffraction detection shows that the product is A crystal form, the XRPD spectrum is shown in figure 8, and the characteristic peak positions are shown in table 7. DSC spectra showed an endothermic peak at 76.96℃and 138.8 ℃. TGA profile showed a weight loss of 13.27% at 25-240 ℃. The resulting product was tested by ion chromatography and the salt formation ratio of the compound to the amine was about 1:1.
TABLE 7
Example 17: preparation of amine salt B Crystal form of Compound of formula (I)
202.9mg of the compound of formula (I) are added to 4ml of isopropanol, 385.4ul of aqueous 1M ammonia solution are added, the temperature is raised (50 ℃ C. -5 ℃ C.), the mixture is centrifuged, and the solid is dried in vacuo. X-ray powder diffraction detection shows that the product is B crystal form, the XRPD spectrum is shown in figure 9, and the characteristic peak positions are shown in table 8. The DSC spectrum shows an endothermic peak 173.34 ℃and an exothermic peak 188.10 ℃. TGA profile showed a weight loss of 5.00% at 25-230 ℃. The resulting product was tested by ion chromatography and the salt formation ratio of the compound to the amine was about 1:0.8.
TABLE 8
Example 18: preparation of calcium salt form a of the Compound of formula (I)
10.1mg of the compound represented by the formula (I) is reacted by adding 1.6mg of calcium hydroxide, adding 0.2mL of ethanol and heating at 45 ℃, white suspended solid is separated out, and the centrifugal solid is dried in vacuum. The product was crystalline form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 10 and the characteristic peak positions shown in table 9. The DSC profile showed an endothermic peak at 204.14 ℃. TGA spectrum shows that the weight loss is 2.15% at 25-170 ℃ and 3.50% at 170-235 ℃.
TABLE 9
Example 19: preparation of lysine salt form A of Compound of formula (I)
10.4mg of the compound of formula (I) was added with 0.2mL of acetone, 19.3. Mu.L of 1mol/L of lysine aqueous solution was added, heated, precipitated and dried. The product was form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 11 and the characteristic peak positions shown in table 10. DSC spectra showed an endothermic peak at 175.18 ℃and 193.83 ℃and an exothermic peak at 179.36 ℃. TGA profile shows a weight loss of 11.50% at 25-170 ℃.
Table 10
Example 20: preparation of arginine salt A crystal form of compound shown in formula (I)
10.1mg of the compound represented by the formula (I) was reacted by adding 0.2mL of acetone, adding 19.3uL of 1mol/L of arginine aqueous solution, heating, stirring for 3 days, precipitating a solid, centrifuging, and drying the solid. The product was form a as measured by X-ray powder diffraction, the XRPD pattern shown in figure 12 and the characteristic peak positions shown in table 11. DSC spectra showed an endothermic peak at 72℃and 86.16 ℃and 155.82 ℃and 181.49 ℃. The TGA spectrum shows that the weight loss is 6.70% at 25-140 ℃ and 8.00% at 140-240 ℃. Nuclear Magnetism (HNMR) detection of the obtained product shows that the salt forming ratio of the compound to arginine is about 1:1.
TABLE 11
Example 21: preparation of arginine salt B form of Compound of formula (I)
200.7mg of the compound represented by the formula (I) and 70.1mg of arginine, 2ml of acetone and 100ul of pure water are added to raise and lower the temperature (50 ℃ -5 ℃), the solid is separated out, and the solid is centrifuged and dried. The product was form B as measured by X-ray powder diffraction, the XRPD pattern shown in figure 13 and the characteristic peak positions shown in table 12. The DSC profile showed an endothermic peak at 118.02 ℃. TGA profile showed a weight loss of 5.63% at 25-145 ℃. Nuclear Magnetism (HNMR) detection of the obtained product shows that the salt forming ratio of the compound to arginine is about 1:1.
Table 12
Example 22: preparation of arginine salt of Compound of formula (I)
10mg of the compound shown in the formula (I) is added with 3.5mg of arginine, 0.2mL of ethanol is added, the mixture is heated to react at 45 ℃, cooled to room temperature, stirred, centrifuged and dried to obtain the product. The product was amorphous as measured by X-ray powder diffraction. Nuclear Magnetism (HNMR) detection of the obtained product shows that the salt forming ratio of the compound to arginine is about 1:1.
Example 23: amorphous preparation of lysine salt of Compound of formula (I)
10mg of the compound shown in the formula (I) is added with 6mg of lysine, 0.2mL of isopropyl acetate is added for reaction by heating at 45 ℃, and the mixture is cooled to room temperature, stirred, centrifuged and dried to obtain the product. The product was amorphous as measured by X-ray powder diffraction. Nuclear Magnetism (HNMR) detection of the obtained product shows that the salt forming ratio of the compound to lysine in the salt is about 1:0.9.
Example 24: solubility and stability testing of different salts
1. Solubility of
The solubility of the compounds of formula (I) and their different salt forms in phosphate buffer solution was measured by HPLC as follows:
solubility (mg/ml) pH 4 pH 6 pH 7.4 pH 9 Water and its preparation method 0.9％NaCl
Free form A crystal form 0.39 0.51 0.84 1.50 0.13 0.28
Amorphous dimeglumine salt 0.34 ＞130 ＞154 ＞194 ＞226 ＞238
Potassium salt III crystal form 0.13 0.33 0.15 1.84 1.88 0.01
Sodium salt form b 0.03 0.01 2.18 ＞10.2 ＞4.6 0.02
Calcium salt form a 0.23 0.01 0.07 0.01 0.02 0.05
Ethanol amine salt A crystal form 0.02 0.04 / 0.48 23-30.7 0.32
Amine salt A crystal form 0.11 0.11 5.44 11.70 6.73 0.27
Amine salt B crystal form 1.23 0.19 0.33 0.54 0.66 0.20
Arginine salt form A 2.83 0.39 ＞28 ＞24.5 0.19 1.92
Arginine salt B crystal form 0.27 0.26 25-50 ＞50 1.29 0.36
Amorphous arginine salt 0.83 0.37 1.95 ＞148 ＞37.5 1.23
Amorphous lysine salt 0.41 0.33 0.90 2.22 9.01 0.20
The results show that: the meglumine salt has a greater advantage in solubility than other salts of the compound of formula I.
2. Stability:
the solid stability of the compounds of formula 1 and salts thereof is shown in the following table:
the results show that: meglumine salts are better stable than sodium salts at room temperature.
Example 25: amorphous stability study of Dimeglumine salt of Compounds of formula I
The stability under light (4500 Lux), high temperature (40 ℃ C., 60 ℃ C.), high humidity (RH 75%, RH 92.5%) and sample inspection period of 30 days were examined by placing the dimethylamine salt of the compound of formula I in an amorphous open place, and the results are shown in the following table,
TABLE 13
The influence factor experiment shows that the amorphous form of the compound dimeglumine salt shown in the formula I has better physical stability under the conditions of illumination, high temperature (40 ℃ and 60 ℃) and high humidity (RH 75 percent and RH 92.5 percent) for 1 month; besides high temperature of 60 ℃ and illumination, the chemical stability is good under other conditions.
Example 26: amorphous long-term/accelerated stability studies of meglumine salts of compounds of formula I
The meglumine salt of the compound of formula I was amorphous and its stability was examined under conditions of-20 ℃, 4 ℃, 25 ℃ and 60% rh, 40 ℃ and 75% rh, respectively, and the results are shown in the following table:
TABLE 14
Long term/accelerated stability experiments showed that: the meglumine salt of the compound of formula I is better in physical stability when placed for 3 months under amorphous long-term/accelerated stability conditions, and is still amorphous; besides the acceleration condition, the chemical stability is good when the material is placed for 3 months at the temperature of minus 20 ℃ and 4 ℃ under the long-term condition.
Example 27: hygroscopicity study of different salt forms of Compounds of formula I
Surface Measurement Systems advantage 2, at 25deg.C, humidity from 50%, humidity range of 0% -95%, step of 10%, and judging whether each gradient quality change dM/dT is less than 0.002%, TMAX is less than 360min, and circulating for two circles. The hygroscopicity of different salt crystal forms of the compound shown in the formula I is respectively examined, and the experimental results are shown in the following table:
under normal storage conditions (25 ℃, RH 60%), potassium salt form III, amine salt form B, arginine salt form B, and ethanolamine salt form a absorb about 2.80%, 1.25%, 0.20%, and 7.49%, respectively; at accelerated test conditions (RH 70%), water absorption was about 2.91%, 1.78%, 0.27%, and 8.58%, respectively; at extreme conditions (RH 90%), the water absorption was about 3.37%, 9.90%, 0.60% and 13.95%, respectively.
Example 28: stability study of different salt forms of Compounds of formula I
The compound shown in the formula I is placed in an open and flat way, and the stability of the sample under the conditions of illumination (4500 Lux), high temperature (40 ℃ and 60 ℃) and high humidity (RH 75% and RH 92.5%) is respectively examined, the sampling examination period is 30 days, and the experimental results are shown in the following table:
experimental results table: the potassium salt III crystal form of the compound shown in the formula I is basically stable physically and chemically under the condition of influencing factors; the arginine salt B crystal form and the amine salt B crystal form have good physical stability, the arginine salt A crystal form and the ethanolamine salt A crystal form are subjected to crystal transformation under the high-humidity condition, and the physical stability is good under other conditions; besides high temperature of 60 ℃ and illumination, arginine salt B crystal form, A crystal form, amine salt B crystal form and ethanolamine salt A crystal form have good chemical stability under other conditions.
Experimental example 29: long term/accelerated stability of different salts of the compounds of formula I
Samples of different salt forms of the compound shown in formula I are placed at 4 ℃, 25 ℃ and 60% RH, 40 ℃ and 75% RH to examine the stability, the sampling examination period is 2 months, and the experimental results are shown in the following table:
the results show that: besides slightly poor physical stability of arginine salt A crystal form and ethanolamine salt A crystal form, other crystal forms have good physical stability. Besides the purity reduction under the acceleration condition, the potassium salt III crystal form, the amine salt A crystal form, the amine salt B crystal form, the arginine salt A crystal form, the arginine salt B crystal form and the ethanolamine salt A crystal form have good chemical stability under other conditions.

Claims (28)

  1. Pharmaceutically acceptable salts of the compounds of formula (I), wherein the pharmaceutically acceptable salts are selected from meglumine salts, ethanolamine salts, sodium salts, potassium salts, amine salts, calcium salts, lysine salts and arginine salts,
  2. the pharmaceutically acceptable salt according to claim 1, wherein the chemical ratio of the compound of formula (I) to the base molecule or cation is 1:0.5 to 1:3, preferably 1:0.5, 1:1, 1:2 or 1:3, most preferably 1:1 or 1:2.
  3. The pharmaceutically acceptable salt according to claim 1 or 2, which is a dimeglumine salt.
  4. A process for preparing a pharmaceutically acceptable salt according to any one of claims 1-3, comprising: a step of salifying the compound represented by formula (1) with a base.
  5. The method according to claim 4, wherein the solvent used in the salification reaction is at least one selected from the group consisting of methanol, 2-butanone, ethyl acetate, 1, 4-dioxane, methyl isobutyl ketone, methyl t-butyl ether, methylene chloride, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water.
  6. A pharmaceutical composition prepared from the pharmaceutically acceptable salt of any one of claims 1-3.
  7. A pharmaceutical composition comprising a pharmaceutically acceptable salt according to any one of claims 1 to 3, or a pharmaceutically acceptable salt prepared by the process of claim 4 or 5, and optionally from a pharmaceutically acceptable carrier, diluent or excipient.
  8. A process for the preparation of a pharmaceutical composition comprising the step of mixing a pharmaceutically acceptable salt according to any one of claims 1 to 3, or a pharmaceutically acceptable salt prepared by a process according to claim 4 or 5, with a pharmaceutically acceptable carrier, diluent or excipient.
  9. Use of a pharmaceutically acceptable salt according to any one of claims 1 to 3, or a pharmaceutically acceptable salt prepared by a method according to claim 4 or 5, or a composition according to claim 6 or 7, or a composition prepared by a method according to claim 8, in the manufacture of a medicament for inhibiting a voltage-gated sodium channel in a subject, preferably Na V 1.8。
  10. Use of a pharmaceutically acceptable salt according to any one of claims 1-3, or a pharmaceutically acceptable salt prepared by the process of claim 4 or 5, or a composition according to claim 6 or 7, or a composition prepared by the process of claim 8, in the manufacture of a medicament for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, charles-Marsh-Santa syndrome, incontinence or cardiac arrhythmias, preferably the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
  11. A crystalline form a of an ethanolamine salt of a compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726 and 27.000, preferably at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, 24.375, 25.060, 27.000 and 27.847, more preferably at 9.857, 13.767, 14.953, 16.243, 16.932, 19.965, 22.654, 23.726, 24.375, 25.060, 26.102, 27.000 and 27.847, and most preferably by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, as shown in fig. 2.
  12. A crystal form a of a sodium salt of a compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784 and 23.654, preferably having characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 17.442, 18.354, 20.784 and 23.654, more preferably having characteristic peaks at 7.242, 7.497, 9.934, 12.281, 13.600, 15.002, 16.533, 17.442, 18.354, 20.168, 20.784, 22.996 and 23.654, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 3.
  13. A b crystal form of a sodium salt of the compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301 and 28.642, preferably at 8.105, 9.016, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428 and 28.642, more preferably at 8.105, 9.016, 11.816, 14.259, 15.193, 16.945, 21.259, 24.629, 25.301, 27.428, 28.642 and 30.771, most preferably in terms of diffraction angle 2θ, as shown in fig. 4.
  14. A potassium salt of the compound of formula (I) in crystalline form I,
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044 and 26.297, preferably having characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 32.079 and 39.038, more preferably having characteristic peaks at 7.910, 11.916, 15.916, 16.931, 21.885, 22.433, 24.044 and 26.297, 29.594, 30.585, 32.079, 36.429 and 39.038, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 5.
  15. A crystal form II of the potassium salt of the compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 7.488, 11.277, 13.394, 15.073, 22.860, 26.219 and 33.298, preferably having characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 33.298 and 38.093, more preferably having characteristic peaks at 7.488, 11.277, 13.394, 15.073, 17.102, 19.915, 22.860, 26.219, 27.808, 31.943, 33.298, 38.093 and 40.734, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 6.
  16. A crystalline form III of the potassium salt of the compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948 and 27.600, preferably at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, 26.462, 27.600, 30.872 and 34.296, more preferably at 7.457, 11.223, 13.603, 15.042, 16.970, 19.420, 20.485, 23.948, 25.061, 26.462, 27.600, 30.872 and 34.296, and most preferably by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as shown in fig. 7.
  17. A crystal form a of an amine salt of a compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498 and 24.596, preferably having characteristic peaks at 8.324, 11.597, 12.156, 14.903, 15.445, 17.259, 23.498, 24.596, 28.342 and 31.287, more preferably having characteristic peaks at 8.324, 11.597, 12.156, 13.808, 14.903, 15.445, 17.259, 19.073, 21.251, 23.498, 24.596, 28.342 and 31.287, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 8.
  18. A B crystal form of an amine salt of the compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052 and 29.047, preferably having characteristic peaks at 5.263, 8.132, 10.629, 16.619, 18.848, 20.208, 21.472, 24.052, 29.047 and 29.644, more preferably having characteristic peaks at 5.263, 8.132, 10.629, 11.886, 16.619, 17.221, 18.848, 20.208, 21.472, 24.052, 27.121, 29.047 and 29.644, most preferably by terms of diffraction angle 2θ, as shown in fig. 9.
  19. A crystal form a of a calcium salt of a compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878 and 34.073, preferably having characteristic peaks at 8.455, 9.436, 13.657, 16.433, 18.106, 20.756, 26.620, 28.892, 29.878 and 34.073, more preferably having characteristic peaks at 8.455, 9.436, 13.657, 16.433, 17.105, 18.106, 20.756, 23.017, 26.62, 27.653, 28.892, 29.878 and 34.073, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 10.
  20. A lysine salt of the compound of formula (I) in crystalline form A,
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226 and 25.795, preferably having characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 25.226, 25.795 and 30.365, more preferably having characteristic peaks at 8.493, 14.946, 17.127, 18.633, 21.196, 23.020, 23.926, 24.450, 25.226, 25.795, 30.365 and 34.619, and most preferably by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ, as shown in fig. 11.
  21. An arginine salt of a compound of formula (I) form A,
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618 and 26.485, preferably having characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 23.794, 25.589 and 26.485, more preferably having characteristic peaks at 7.780, 10.847, 14.639, 15.726, 18.634, 20.265, 21.618, 22.911, 23.794, 25.589, 26.485, 29.631 and 37.910, most preferably an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ is shown in fig. 12.
  22. A B crystal form of an arginine salt of the compound of formula (I),
    characterized by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ having characteristic peaks at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124 and 33.605, preferably at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 33.605 and 43.535, more preferably at 8.097, 15.541, 16.329, 19.256, 19.883, 22.111, 24.679, 27.124, 29.546, 31.433, 33.155, 33.605, 34.490 and 43.535, and most preferably by an X-ray powder diffraction pattern expressed in terms of diffraction angle 2θ as shown in fig. 13.
  23. The crystalline form of any one of claims 11-22, wherein the 2Θ angle error range is ± 0.20.
  24. A pharmaceutical composition prepared from the crystalline form of the pharmaceutically acceptable salt of any one of claims 11-23.
  25. A pharmaceutical composition comprising a crystalline form of a pharmaceutically acceptable salt according to any one of claims 11-23 and optionally from a pharmaceutically acceptable carrier, diluent or excipient.
  26. A method of preparing a pharmaceutical composition comprising the step of mixing a crystalline form of a pharmaceutically acceptable salt as defined in any one of claims 11-23 with a pharmaceutically acceptable carrier, diluent or excipient.
  27. Use of a crystalline form of a pharmaceutically acceptable salt according to any one of claims 11-23, or a composition according to claim 24 or 25, or a composition prepared by a method according to claim 26, in the manufacture of a medicament for inhibiting a voltage-gated sodium channel in a subject, preferably wherein the voltage-gated sodium channel is Na V 1.8。
  28. Use of a crystalline form of a pharmaceutically acceptable salt according to any one of claims 11 to 23, or a composition according to claim 24 or 25, or a composition prepared by a process according to claim 26, for the manufacture of a medicament for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, sham-horse-figure three's syndrome, incontinence or cardiac arrhythmias, preferably the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.
CN202280017418.6A 2021-02-26 2022-02-25 Selective Na V Pharmaceutically acceptable salts, crystalline forms and methods of preparing the same Pending CN116964065A (en)

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