WO2022179624A1 - Sel pharmaceutiquement acceptable d'un inhibiteur sélectif de nav et forme cristalline de ce dernier, et procédé de préparation associé - Google Patents
Sel pharmaceutiquement acceptable d'un inhibiteur sélectif de nav et forme cristalline de ce dernier, et procédé de préparation associé Download PDFInfo
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- WO2022179624A1 WO2022179624A1 PCT/CN2022/078026 CN2022078026W WO2022179624A1 WO 2022179624 A1 WO2022179624 A1 WO 2022179624A1 CN 2022078026 W CN2022078026 W CN 2022078026W WO 2022179624 A1 WO2022179624 A1 WO 2022179624A1
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- salt
- formula
- characteristic peaks
- ray powder
- pharmaceutically acceptable
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- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 238000005086 pumping Methods 0.000 description 1
- 238000012797 qualification Methods 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
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- 238000011160 research Methods 0.000 description 1
- 230000000284 resting effect Effects 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 238000001179 sorption measurement Methods 0.000 description 1
- 238000012430 stability testing Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- CZDYPVPMEAXLPK-UHFFFAOYSA-N tetramethylsilane Chemical compound C[Si](C)(C)C CZDYPVPMEAXLPK-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
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Images
Classifications
-
- 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
Definitions
- the present disclosure relates to a pharmaceutically acceptable salt, a crystalline form and a preparation method of a selective Nav1.8 inhibitor prodrug, and specifically, provides compounds represented by formula (I) meglumine salt, ethanolamine salt, potassium salt, Amine salts, sodium salts, calcium salts, lysine salts and arginine salts, crystalline forms and methods of preparation.
- formula (I) meglumine salt, ethanolamine salt, potassium salt, Amine salts, sodium salts, calcium salts, lysine salts and arginine salts, crystalline forms and methods of preparation.
- Pain is a common clinical symptom that originates from nociceptors in the peripheral nervous system. This receptor is widely distributed in skin, muscles, joints, and visceral tissues throughout the body and converts thermal, mechanical, or chemical stimuli into nerve impulses (action potentials) that are transmitted by afferent nerve fibers to their dorsal root ganglia (dorsal root ganglia). ganglia, DRG), which is ultimately transmitted to higher nerve centers, causing pain sensation. The generation and conduction of action potentials in neurons in turn depend on voltage-gated sodium channels (Na V ) on the cell membrane.
- Na V voltage-gated sodium channels
- the sodium ion channel When the cell membrane is depolarized, the sodium ion channel is activated, the channel opens, and the sodium ion flows inward, which further depolarizes the cell membrane, resulting in the generation of action potentials. Therefore, inhibiting abnormal sodium channel activity is helpful for the treatment and relief of pain.
- the local anesthetic lidocaine relieves pain by inhibiting Na V.
- Nonselective Na V inhibitors such as lamotrigine, lacosamide, and mexiletine, have been successfully used to treat chronic pain. Due to the lack of subtype selectivity of Na V inhibitors used in the clinic and their ability to inhibit sodium ion channels in the heart and central nervous system, the therapeutic window is narrow and the scope of application is limited.
- Na V 1.8 is mainly distributed in the peripheral nervous system, and selective inhibition of Na V 1.8 can effectively reduce side effects. Therefore, it is necessary to develop Na V 1.8 inhibitors with higher activity, better selectivity, better pharmacokinetic properties and fewer side effects.
- the present disclosure provides a pharmaceutically acceptable salt of the compound represented by formula (I), wherein the pharmaceutically acceptable salt is selected from meglumine salt, ethanolamine salt, sodium salt, calcium salt, amine salt, potassium salt, lysine salt salts and arginine salts.
- the stoichiometric ratio of the compound represented by the 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.
- the stoichiometric ratio of the compound represented by the formula (I) and meglumine is 1:1 or 1:2.
- the stoichiometric ratio of the compound represented by the formula (I) and ethanolamine is 1:1 or 1:2.
- the stoichiometric ratio of the compound represented by the formula (I) to the sodium ion is 1:1 or 1:2.
- the stoichiometric ratio of the compound represented by the formula (I) and potassium ion is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to the ammonia molecule is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to calcium ions is 1:1. In certain embodiments, the stoichiometric ratio of the compound represented by formula (I) to lysine is 1:1 or 1:2. In certain embodiments, the stoichiometric ratio of the compound represented by the formula (I) to arginine is 1:1 or 1:2.
- the present disclosure also provides a method for preparing a pharmaceutically acceptable salt of the compound represented by formula (I), comprising the step of forming a salt of the compound represented by formula (1) with a base.
- the solvent used in the salt-forming reaction is selected from methanol, 2-butanone, ethyl acetate, 1,4-dioxane, methyl isobutyl ketone, methyl tert-butyl ether , at least one of dichloromethane, ethanol, isopropanol, tetrahydrofuran, dimethyl sulfoxide, acetone, acetonitrile, toluene and water.
- the method for preparing the aforementioned pharmaceutically acceptable salt further comprises the steps of volatilizing the solvent or stirring for crystallization, filtering, drying, and the like.
- the present disclosure provides a pharmaceutical composition prepared from the aforementioned pharmaceutically acceptable salt.
- the present disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising the aforementioned pharmaceutically acceptable salt or a pharmaceutically acceptable salt prepared by the aforementioned method, and optionally a pharmaceutically acceptable carrier, diluent or excipient.
- the present disclosure provides a preparation method of a pharmaceutical composition, comprising mixing the aforementioned pharmaceutically acceptable salt, or the pharmaceutically acceptable salt of the compound of formula (I) prepared by the aforementioned method, with a pharmaceutically acceptable carrier, diluent or excipient. The step of mixing the excipients.
- the present disclosure provides a pharmaceutically acceptable salt of the compound of the former formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or a composition prepared by the aforementioned method.
- the present disclosure provides a pharmaceutically acceptable salt of a compound of the former formula (I), or a pharmaceutically acceptable salt prepared by the aforementioned method, or the aforementioned composition, or a composition prepared by the aforementioned method in the preparation of therapeutic and /or use in a medicament for alleviating pain and pain-related diseases, multiple sclerosis, Sharma- Figure 3 syndrome, incontinence or arrhythmia, preferably the pain is selected from chronic pain, acute pain, inflammatory Pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, bowel pain and idiopathic pain.
- the present disclosure provides dimeglumine salts of compounds represented by formula (I).
- the present disclosure provides the amorphous form of dimeglumine salt of the compound represented by formula (I), and the diffraction angle 2 ⁇ of its X-ray powder diffraction pattern has no obvious characteristic peaks in the range of 2-48°.
- the present disclosure further provides an amorphous method for preparing the dimeglumine salt of the compound represented by formula (I), method 1, comprising the steps of: a) mixing the compound represented by formula (I) with solvent I, heating, and the solvent Be selected from at least one in tetrahydrofuran, ethanol, DMSO, b) add meglumine solution reaction, cool down, separate out, c) add isopropanol or ethanol, precipitate out;
- method 2 comprises steps: a) formula (I) ), the meglumine is mixed with solvent II, and the solvent II is heated for reaction, and the solvent II is selected from at least one of ethanol, acetone and acetonitrile, and b) is precipitated.
- the volume ( ⁇ l) used for solvent I or II 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides the amorphous form of the compound represented by formula (I), a meglumine salt, the X-ray powder diffraction pattern of which has no obvious characteristic peaks in the diffraction angle 2 ⁇ of the powder diffraction pattern in the range of 2-48°.
- the present disclosure further provides a method for preparing the amorphous monomeglumine salt of the compound represented by the formula (I), comprising the steps of: a) the compound represented by the formula (I), meglumine and a solvent methyl tert-butyl ether or toluene Mix, b) heat, and precipitate out.
- the volume ( ⁇ l) of the solvent 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of the ethanolamine salt of the compound represented by formula (I), Form A, expressed as a diffraction angle 2 ⁇ , characterized at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, and 27.000 peak.
- Form A of the ethanolamine salt of the compound of formula (I) has characteristic peaks at 9.857, 13.767, 14.953, 19.965, 22.654, 23.726, 24.375, 25.060, 27.000 and 27.847, and in some In embodiments, Form A of the ethanolamine salt of the compound shown has characteristic peaks 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.
- the X-ray powder diffraction pattern of Form A of the ethanolamine salt of the compound represented by formula (I) in terms of diffraction angle 2 ⁇ is shown in FIG. 2 .
- the present disclosure further provides a method for preparing Form A of the ethanolamine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), ethanol and ethanolamine, and b) heating and precipitation.
- the used volume ( ⁇ l) of the 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) in form a, expressed as a diffraction angle 2 ⁇ , characterized at 7.242, 7.497, 9.934, 12.281, 18.354, 20.784, and 23.654 peak.
- the crystalline 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.
- the crystalline form a of the sodium salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of crystal form a, represented by the diffraction angle 2 ⁇ , is shown in FIG. 3 .
- the present disclosure further provides a method for preparing crystal form a of the sodium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and sodium hydroxide solution, and b) precipitating.
- the volume ( ⁇ l) of the solvent isopropanol used in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments, it 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure further provides an X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of form b, expressed as a diffraction angle 2 ⁇ , characterized at 8.105, 9.016, 15.193, 16.945, 21.259, 25.301 and 28.642 peak.
- crystal 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.
- the crystalline 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.
- the X-ray powder diffraction pattern of the sodium salt of the compound represented by formula (I) of crystal form b, expressed as a diffraction angle 2 ⁇ , is shown in FIG. 4 .
- the present disclosure further provides a method for preparing the b crystal form of the sodium salt of the compound represented by the formula (I), comprising: a) mixing the compound represented by the formula (I), a sodium hydroxide solution and a solvent, and heating, and the solvent is selected from EtOH , at least one of THF, b) precipitation.
- the volume ( ⁇ l) of the solvent 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure also provides an X-ray powder diffraction pattern of Form I of the potassium salt of the compound represented by formula (I), expressed in diffraction angle 2 ⁇ , at 7.910, 11.916, 15.916, 16.931, 22.433, 24.044 and 26.297. Characteristic peaks. 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.
- Form I of the potassium salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of Form I of the potassium salt of the compound represented by formula (I) is shown in FIG. 5 as a diffraction angle 2 ⁇ .
- the present disclosure provides an X-ray powder diffraction pattern of the potassium salt of the compound represented by formula (I), Form II, characterized by 7.488, 11.277, 13.394, 15.073, 22.860, 26.219, and 33.298, in terms of diffraction angle 2 ⁇ peak.
- 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.
- Form II of the potassium salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of Form II of the potassium salt of the compound represented by formula (I) is shown in FIG. 6 as a diffraction angle 2 ⁇ .
- the present disclosure further provides a method for preparing the I or II crystal form of the potassium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and potassium hydroxide solution, b) precipitating out .
- the volume ( ⁇ l) of the solvent isopropanol used in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments, it 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of the potassium salt of the compound represented by formula (I), Form III, characterized at 7.457, 11.223, 13.603, 15.042, 20.485, 23.948, and 27.600, as an X-ray powder diffraction pattern at diffraction angles 2 theta peak.
- 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.
- Form III of the potassium salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of Form III of the potassium salt of the compound represented by formula (I) in terms of diffraction angle 2 ⁇ is shown in FIG. 7 .
- the present disclosure further provides a method for preparing the potassium salt III crystal form of the compound represented by formula (I), comprising: 1) the compound represented by formula (I), at least one solvent in ethanol and tetrahydrofuran, mixed with potassium hydroxide solution, 2) Precipitation.
- the volume ( ⁇ l) of the solvent 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of the amine salt of the compound represented by formula (I) of Form A, expressed as a diffraction angle 2 ⁇ , characterized at 8.324, 11.597, 14.903, 15.445, 17.259, 23.498, and 24.596 peak.
- 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.
- Form A of the amine salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of Form A of the amine salt of the compound represented by formula (I) in terms of diffraction angle 2 ⁇ is shown in FIG. 8 .
- the present disclosure further provides a method for preparing Form A of the amine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and ammonia water, and b) beating and crystallization.
- the volume ( ⁇ l) of the solvent isopropanol used in the present disclosure may be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments, it 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of an amine salt of a compound represented by formula (I), Form B, expressed as a diffraction angle 2 ⁇ , characterized at 5.263, 10.629, 16.619, 20.208, 21.472, 24.052, and 29.047 peak.
- 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.
- Form B of the amine salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of the amine salt of the compound represented by formula (I) of Form B is shown in FIG. 9 .
- the present disclosure further provides a method for preparing the B crystal form of the amine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), isopropanol and ammonia water, and b) cooling and crystallization.
- the volume ( ⁇ l) of the solvent 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure provides an X-ray powder diffraction pattern of a calcium salt of a compound represented by formula (I), characterized at 8.455, 9.436, 13.657, 18.106, 28.892, 29.878, and 34.073, as an X-ray powder diffraction pattern expressed as a diffraction angle 2 ⁇ peak.
- the crystalline 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.
- the crystalline form a of the calcium salt of the compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of the calcium salt form a of the compound represented by formula (I) in terms of diffraction angle 2 ⁇ is shown in FIG. 10 .
- the present disclosure further provides a method for preparing a crystal form of calcium salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), ethanol and calcium hydroxide solution, heating, and b) precipitating.
- the used volume ( ⁇ l) of the 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure further provides the X-ray powder diffraction pattern of Form A of the lysine salt of the compound represented by formula (I), expressed in diffraction angle 2 ⁇ , at 8.493, 17.127, 18.633, 21.196, 23.020, 25.226 and 25.795 There are characteristic peaks.
- 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.
- Form A of the lysine salt of a compound of formula (I) is characterized 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 peak.
- the X-ray powder diffraction pattern of Form A of the lysine salt of the compound represented by formula (I), represented by the diffraction angle 2 ⁇ is shown in FIG. 11 .
- the present disclosure further provides a method for preparing the crystal form A of the lysine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), acetone and lysine solution, heating, and b) precipitating out .
- the volume ( ⁇ l) of the solvent acetone used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments can 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure further provides an X-ray powder diffraction pattern of Form A of the arginine salt of the compound represented by formula (I), expressed as diffraction angle 2 ⁇ , at 7.780, 10.847, 15.726, 18.634, 20.265, 21.618 and 26.485 There are characteristic peaks.
- 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.
- Form A of the arginine salt of the compound of formula (I) is 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 There are characteristic peaks.
- the X-ray powder diffraction pattern of the crystal form A of the arginine salt of the compound represented by formula (I) is shown in FIG. 12 as a diffraction angle 2 ⁇ .
- the present disclosure further provides a method for preparing Form A of the arginine salt of the compound represented by formula (I), comprising: a) mixing the compound represented by formula (I), acetone and an aqueous arginine solution, and b) stirring and crystallization.
- the volume ( ⁇ l) of the solvent acetone used in the present disclosure can be 1-200 times the mass (mg) of the compound of formula I, and in non-limiting embodiments can 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure further provides an X-ray powder diffraction pattern of Form B of the arginine salt of the compound represented by formula (I), expressed as diffraction angle 2 ⁇ , at 8.097, 15.541, 19.256, 22.111, 24.679, 27.124 and 33.605 There are characteristic peaks.
- 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.
- Form B of the arginine salt of the compound of formula (I) is 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 There is a characteristic peak at 43.535.
- the X-ray powder diffraction pattern of the crystal form B of the arginine salt of the compound represented by formula (I) is shown in FIG.
- the present disclosure further provides a method for preparing the crystal form B of the arginine salt of the compound represented by the formula (I), comprising: a) mixing the compound represented by the formula (I), acetone and arginine, b) heating, cooling down for crystallization .
- the volume ( ⁇ l) of the solvent 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.
- the preparation methods described in the present disclosure further comprise filtering, washing or drying steps.
- the present disclosure also provides a pharmaceutical composition
- a pharmaceutical composition comprising the aforementioned crystalline form of the pharmaceutically acceptable salt and optionally a pharmaceutically acceptable carrier, diluent or excipient.
- the present disclosure also provides a preparation method of a pharmaceutical composition, comprising the step of mixing the aforementioned crystalline form of the pharmaceutically acceptable salt with a pharmaceutically acceptable carrier, diluent or excipient.
- the present disclosure also provides the use of the crystalline form of the aforementioned pharmaceutically acceptable salt, or the aforementioned composition, or the composition prepared by the aforementioned method in the preparation of a medicament for inhibiting voltage-gated sodium channels in a subject, preferably, The voltage-gated sodium channel is Na V 1.8.
- the present disclosure also provides the crystalline forms of the aforementioned pharmaceutically acceptable salts, or the aforementioned compositions, or the compositions prepared by the aforementioned methods in preparation for the treatment and/or alleviation of pain and pain-related diseases, multiple sclerosis, summer- Use in the medicament of Horse- Figure 3 syndrome, incontinence or arrhythmia, preferably, the pain is selected from chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain Pain, bowel pain and idiopathic pain.
- the “2 ⁇ or 2 ⁇ angle” mentioned in this disclosure refers to the diffraction angle, and ⁇ is the Bragg angle, in degrees or degrees; the error range of each characteristic peak 2 ⁇ is ⁇ 0.20 (including rounded numbers with more than 1 decimal place).
- the precipitation methods described in the present disclosure include, but are not limited to, stirring, volatilization, beating, and precipitation.
- Deliquescence Absorbs sufficient water to form a liquid
- the weight gain of moisture is not less than 15%;
- Moisture gain is less than 15% but not less than 2%
- wet weight gain is less than 2% but not less than 0.2%
- hygroscopic weight gain is less than 0.2%.
- DSC Different Scanning Calorimetry or DSC refers to the measurement of the temperature difference, heat flow difference between a sample and a reference during the heating or constant temperature of the sample to characterize all physical changes related to thermal effects and Chemical changes to obtain phase transition information of the sample.
- the drying temperature mentioned in the present disclosure is generally 25°C to 100°C, preferably 40°C to 70°C, and can be dried under normal pressure or under reduced pressure.
- “Pharmaceutical composition” means a mixture containing one or more compounds of formula (I) described herein, or a pharmaceutically acceptable salt thereof, and other chemical components, together with other components such as pharmaceutically acceptable carriers and excipients.
- the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
- the crystal forms described in the present disclosure include but are not limited to the solvate of the compound meglumine salt of formula (I), and the solvents include but are not limited to tetrahydrofuran/ethanol, DMSO, ethanol, acetonitrile, acetone, methyl tertiary Butyl ether, toluene.
- the crystal form described in the present disclosure includes but is not limited to the solvate of the ethanolamine salt of the compound represented by formula (I), and the solvent includes but is not limited to ethanol.
- the crystal form described in the present disclosure includes but is not limited to the solvate of the sodium salt of the compound represented by formula (I), and the solvent includes but is not limited to isopropanol, EtOH/THF.
- the crystal form described in the present disclosure includes but is not limited to the solvate of the potassium salt of the compound represented by formula (I), and the solvent includes but not limited to isopropanol, EtOH/THF.
- the crystal form described in the present disclosure includes, but is not limited to, the solvate of the amine salt of the compound represented by formula (I), and the solvent includes but is not limited to isopropanol.
- the crystal forms described in the present disclosure include, but are not limited to, the solvate of the calcium salt of the compound represented by formula (I), and the solvent includes, but is not limited to, ethanol.
- the crystal form described in the present disclosure includes, but is not limited to, a solvate of lysine of the compound represented by formula (I), and the solvent includes but is not limited to acetone.
- the crystal form described in the present disclosure includes, but is not limited to, a solvate of the compound represented by formula (I), arginine, and the solvent includes, but is not limited to, acetone.
- Solids as used in this disclosure include, but are not limited to, complexes formed by combining a compound of formula I with a solvent.
- Fig. 1 XRPD pattern of amorphous crystal of dimeglumine salt of compound represented by formula (I).
- Figure 2 XRPD pattern of the ethanolamine salt form A of the compound represented by formula (I).
- Figure 4 XRPD pattern of the sodium salt form b of the compound represented by formula (I).
- Figure 8 XRPD pattern of amine salt form A of the compound represented by formula (I).
- Figure 9 XRPD pattern of the amine salt form B of the compound represented by formula (I).
- Figure 11 XRPD pattern of the lysine salt form A of the compound represented by formula (I).
- Figure 12 The XRPD pattern of the crystalline form A of arginine salt of the compound represented by formula (I).
- Figure 13 XRPD pattern of the crystalline form B of arginine salt of the compound represented by formula (I).
- the reagents used in the present invention are commercially available.
- test conditions of the instrument used in the experiment in the present invention are identical to the test conditions of the instrument used in the experiment in the present invention:
- DVS dynamic moisture adsorption
- the detection adopts Surface Measurement Systems advantage 2, at 25°C, the humidity is from 50%-95%-0%-95%-50%RH, the step is 10%, and the judgment standard is that each gradient mass change dM/dT is less than 0.002% , TMAX360min, cycle twice. 5.
- the average inhibition rate and IC50 value of kinases were measured with NovoStar microplate reader (BMG, Germany).
- the monitoring of the reaction progress in the embodiment adopts thin layer chromatography (TLC), and the developing agent used in the reaction, the eluent system of the column chromatography adopted for the purification compound and the developing agent system of thin layer chromatography include: A: dichloromethane/methanol system, B: n-hexane/ethyl acetate system.
- the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the size of the silica gel plate used for thin layer chromatography (TLC) is 0.15mm ⁇ 0.2mm, and the size of the TLC separation and purification products is 0.4mm ⁇ 0.5mm.
- Silica gel column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
- NMR nuclear magnetic resonance
- MS mass spectrometry
- the MS was measured using an Agilent 1200/1290DAD-6110/6120Quadrupole MS LC/MS instrument (manufacturer: Agilent, MS model: 6110/6120Quadrupole MS). waters ACQuity UPLC-QD/SQD (manufacturer: waters, MS model: waters ACQuity Qda Detector/waters SQ Detector). THERMO Ultimate3000-Q Exactive (Manufacturer: THERMO, MS Model: THERMO Q Exactive)
- the known starting materials of the present invention can be synthesized by adopting or according to methods known in the art, or can be purchased from ABCR GmbH & Co.KG, Acros Organics, Aldrich Chemical Company, Shaoyuan Chemical Technology (Accela ChemBio Inc. ), Darui Chemicals and other companies.
- HPLC HPLC
- the compound of formula III (1 g, 2.04 mmol, 1.0 eq) was added to dry THF (10 mL) and stirred. Nitrogen ventilation protection, cooling. 1.0M sodium bis(trimethylsilyl)amide (NaHMDS)/(tetrahydrofuran) THF solution (3.05mL, 3.05mmol, 1.5eq) was added, followed by dropwise addition of tetrabenzyl pyrophosphate (1.09g, 2.04mmol, 1.0 eq) in THF (2 mL), after the addition was complete, the reaction was stirred at room temperature.
- NaHMDS sodium bis(trimethylsilyl)amide
- THF solution 3.05mL, 3.05mmol, 1.5eq
- Test Example 1 Determination of the Inhibitory Activity of Compounds of Formula I on Na V 1.8
- the purpose of the experiment was to investigate the effect of compound formula I on the Na V 1.8 ion channel in vitro, which was stably expressed on HEK293 cells. After the Na V 1.8 current was stable, comparing the magnitude of the Na V 1.8 current before and after the application of the compound, the effect of the compound on the Na V 1.8 ion channel could be obtained.
- Patch clamp amplifier patch clamp PC-505B(WARNER instruments)/MultiClamp 700A(Axon instruments)
- D/A converter Digidata 1440A(Axon CNS)/Digidata 1550A(Axon instruments)
- Extracellular fluid was: NaCl, 137; KCl, 4; CaCl2 , 1.8; MgCl2 , 1; HEPES, 10; glucose 10; pH 7.4 (NaOH titration).
- Intracellular fluid was Aspartic acid, 140; MgCl2,2; EGTA 11; HEPES, 10; pH 7.2 (CsOH titration). All test compound and control compound solutions contained 1 ⁇ M TTX.
- Test compounds were stored at 9 mM in dimethyl sulfoxide (DMSO). On the test day, it was redissolved in extracellular fluid to prepare the required concentration.
- DMSO dimethyl sulfoxide
- the data will be stored in a computer system for analysis. Data collection and analysis will use pCLAMP 10 (Molecular Devices, Union City, CA), and management will review the analysis results.
- Current stabilization refers to the fact that the current varies with time within a limited range. The magnitude of the current after stabilization is used to calculate the effect of the compound's solubility here.
- the inhibitory activity of compound (I) of the present disclosure on Nav1.8 was determined by the above test, and the IC 50 value was 2.80 nM, and the VX-150 value was 17.71 nM.
- LC/MS/MS method was used to determine the drug concentration in plasma at different times after intravenous injection of the compounds of the present disclosure.
- the pharmacokinetic behavior of the disclosed compounds in mice was studied, and their pharmacokinetic characteristics were evaluated.
- 0.2ml of blood was collected from the retrobulbar venous plexus, and 10 ⁇ L of 100mM BNPP in EDTA-K2 was added after sampling In an anticoagulant tube, centrifuge at 11,000 rpm for 5 min (4°C), separate plasma within 30 min, and store at -70°C for testing.
- the LC-MS/MS method was used to determine the concentration of the compound of formula I and the compound of formula IV in the plasma of rats at different time points after administration.
- the non-compartmental model of Phoenix WinNonlin 7.0 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters of rats after administration.
- the time to peak Tmax and the peak concentration Cmax are all measured values
- AUC 0-t value of the area under the drug-time curve calculated by trapezoidal method;
- AUC 0- ⁇ AUC 0-t +C t / ke ,
- C t is the blood drug concentration at the last measurable time point, and
- ke is elimination rate constant;
- Average residence time MRT AUMC/AUC
- the compound of formula I After intravenous injection of the compound of formula I to SD rats, the compound of formula I was not detected in the plasma (below the lower limit of quantification of 7.50 ng/mL), and the plasma concentration of the compound of formula IV reached the peak at the first sampling point (5min) after administration, It is suggested that the compound of formula I can be rapidly converted into the parent compound of formula IV in vivo after administration.
- the peak concentration (C 5min ) of the compound of formula IV in the compound of formula I administration group was 38.3% of the peak concentration (C 5min ) of the compound of formula IV administration group. It is related to rapid distribution into tissues and then converted to the compound of formula IV; exposure AUC 0-t is 77% of the compound of formula IV administration group; plasma clearance CL and steady-state volume of distribution Vss are the same as those of the compound of formula IV administration group, respectively 1.40 and 1.77 times.
- Compound of formula IV formulated with 2% DMSO + 10% HS15 (polyethylene glycol (PEG) dodecyl stearate) + 88% normal saline.
- HS15 polyethylene glycol (PEG) dodecyl stearate
- the LC-MS/MS method was used to determine the concentrations of the compounds of formula I and IV in plasma at different time points after administration to beagle dogs.
- the non-compartmental model of Phoenix WinNonlin 7.0 software (Pharsight, USA) was used to calculate the pharmacokinetic parameters of beagle dogs after administration.
- the time to peak Tmax and the peak concentration Cmax are all measured values
- AUC 0-t value of the area under the drug-time curve calculated by trapezoidal method;
- AUC 0- ⁇ AUC 0-t +C t / ke ,
- C t is the blood drug concentration at the last measurable time point, and
- ke is elimination rate constant;
- Average residence time MRT AUMC/AUC
- the compound of formula I After intravenous injection of the compound of formula I to beagle dogs, the compound of formula I was not detected in the plasma (below the lower limit of quantification of 7.50 ng/mL), and the plasma concentration of the compound of formula IV reached a peak at the first sampling point (5min) after administration, It is suggested that the compound of formula I can be rapidly converted into the parent compound of formula IV in vivo after administration.
- the peak concentration (C 5min ) of the compound of formula IV after injection of the compound of formula I in beagle dogs is 100.4% of the peak concentration (C 5min ) of the compound of formula IV administration group;
- AUC 0-t is the administration of the compound of formula IV 96.3% of the group.
- the plasma clearance CL, steady state volume of distribution V ss and half-life t 1/2 of the compounds of formula IV did not show significant differences between the two groups.
- Example 3 Amorphous preparation of dimeglumine salt of compound represented by formula (I)
- Example 8 Amorphous preparation of monomeglumine salt of compound represented by formula (I)
- Example 9 Amorphous preparation of monomeglumine salt of compound represented by formula (I)
- the DSC spectrum shows that the endothermic peaks are 57.49°C, 97.49°C, 162.79°C, and 241.94°C, and the exothermic peaks are 197.83°C.
- the TGA spectrum showed that the weight loss was 5.47% at 25-105°C and 3.49% at 105-190°C.
- the TGA spectrum showed that the weight loss was 2.64% at 25-145°C and 4.31% at 145-230°C.
- the ion chromatography of the obtained product shows that the salt-forming ratio of the compound and potassium ion in the salt is about 1:0.9.
- Adopt HPLC to detect the solubility of the compound shown in formula (I) and its different salt forms in phosphate buffer solution, as shown in the following table:
- Example 25 Amorphous stability study of dimglumine salt of compound represented by formula I
- the dimeglumine salt amorphous of the compound shown in formula I was placed in an open mouth, and the stability under the conditions of illumination (4500Lux), high temperature (40°C, 60°C), and high humidity (RH 75%, RH 92.5%) was investigated respectively.
- the sampling period is 30 days. The results are shown in the following table.
- Example 26 Amorphous long-term/accelerated stability study of dimeglumine salt of compound represented by formula I
- the amorphous dimeglumine salt of the compound represented by formula I was placed under conditions of -20°C, 4°C, 25°C and 60% RH, 40°C and 75% RH to investigate its stability.
- the results are shown in the following table. :
- the dimeglumine salt of the compound described in formula I is amorphous and has good physical stability for 3 months under long-term/accelerated stability conditions, and is still amorphous; except for accelerated conditions,- Good chemical stability after 3 months at 20°C, 4°C and long-term conditions.
- Example 27 Study on the hygroscopicity of different salt crystal forms of the compound represented by formula I
- the crystal form of potassium salt III of the compound represented by formula I is basically stable physically and chemically under the conditions of influencing factors; the crystal form of arginine salt and the crystal form of amine salt B have good physical stability, and the crystal form of arginine salt A , Ethanolamine salt crystal form A is crystallized under high humidity conditions, and has good physical stability under other conditions; except for high temperature of 60 ° C and light, arginine salt crystal form B and A crystal form, amine salt B crystal form, ethanolamine salt Form A has good chemical stability under other conditions.
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Abstract
L'invention concerne un sel pharmaceutiquement acceptable d'un inhibiteur sélectif de NaV et une forme cristalline de ce dernier, et un procédé de préparation associé. Plus précisément, l'invention porte sur un sel de méglumine, un sel d'éthanolamine, un sel de potassium, un sel d'amine, un sel de sodium, un sel de calcium, un sel de lysine et un sel d'arginine d'un composé tel que représenté par la formule (I), un procédé de préparation associé et une forme cristalline de ce composé.
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Citations (7)
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CN105814067A (zh) * | 2013-12-13 | 2016-07-27 | 沃泰克斯药物股份有限公司 | 作为钠通道调节剂的吡啶酮酰胺的前药 |
WO2017075222A1 (fr) * | 2015-10-30 | 2017-05-04 | Lieber Institute For Brain Development | Traitement de maladies et de troubles neurologiques et neurdéveloppementaux associés à une expression et à une activité aberrante des canaux ioniques |
CN110740993A (zh) * | 2017-05-16 | 2020-01-31 | 沃泰克斯药物股份有限公司 | 用作钠通道调节剂的氘代吡啶酮酰胺及其前药 |
WO2020140959A1 (fr) * | 2019-01-04 | 2020-07-09 | 江苏恒瑞医药股份有限公司 | Dérivé de 6-oxo-1,6-dihydropyridazine, son procédé de préparation et son utilisation médicale |
WO2020169042A1 (fr) * | 2019-02-20 | 2020-08-27 | 江苏恒瑞医药股份有限公司 | Dérivé de promédicament de 6-oxo -1,6-dihydropyridazine, son procédé de préparation et son application en médecine |
CN113880771A (zh) * | 2020-07-03 | 2022-01-04 | 江苏恒瑞医药股份有限公司 | 一种选择性Nav抑制剂的结晶形式及其制备方法 |
WO2022037641A1 (fr) * | 2020-08-19 | 2022-02-24 | 江苏恒瑞医药股份有限公司 | Promédicament d'un inhibiteur sélectif de nav et forme cristalline de celui-ci |
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- 2022-02-25 TW TW111106947A patent/TW202302118A/zh unknown
- 2022-02-25 WO PCT/CN2022/078026 patent/WO2022179624A1/fr active Application Filing
- 2022-02-25 CN CN202280017418.6A patent/CN116964065A/zh active Pending
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105814067A (zh) * | 2013-12-13 | 2016-07-27 | 沃泰克斯药物股份有限公司 | 作为钠通道调节剂的吡啶酮酰胺的前药 |
WO2017075222A1 (fr) * | 2015-10-30 | 2017-05-04 | Lieber Institute For Brain Development | Traitement de maladies et de troubles neurologiques et neurdéveloppementaux associés à une expression et à une activité aberrante des canaux ioniques |
CN110740993A (zh) * | 2017-05-16 | 2020-01-31 | 沃泰克斯药物股份有限公司 | 用作钠通道调节剂的氘代吡啶酮酰胺及其前药 |
WO2020140959A1 (fr) * | 2019-01-04 | 2020-07-09 | 江苏恒瑞医药股份有限公司 | Dérivé de 6-oxo-1,6-dihydropyridazine, son procédé de préparation et son utilisation médicale |
WO2020169042A1 (fr) * | 2019-02-20 | 2020-08-27 | 江苏恒瑞医药股份有限公司 | Dérivé de promédicament de 6-oxo -1,6-dihydropyridazine, son procédé de préparation et son application en médecine |
CN113880771A (zh) * | 2020-07-03 | 2022-01-04 | 江苏恒瑞医药股份有限公司 | 一种选择性Nav抑制剂的结晶形式及其制备方法 |
WO2022037641A1 (fr) * | 2020-08-19 | 2022-02-24 | 江苏恒瑞医药股份有限公司 | Promédicament d'un inhibiteur sélectif de nav et forme cristalline de celui-ci |
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