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WO2022188872A1 - 吡啶氮氧化合物晶型及其应用 - Google Patents

吡啶氮氧化合物晶型及其应用 Download PDF

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Publication number
WO2022188872A1
WO2022188872A1 PCT/CN2022/080430 CN2022080430W WO2022188872A1 WO 2022188872 A1 WO2022188872 A1 WO 2022188872A1 CN 2022080430 W CN2022080430 W CN 2022080430W WO 2022188872 A1 WO2022188872 A1 WO 2022188872A1
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Prior art keywords
crystal form
ray powder
powder diffraction
diffraction pattern
pain
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2022/080430
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English (en)
French (fr)
Inventor
张勇
曹程
万清卫
程宏明
彭建彪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
Original Assignee
Jiangxi Jemincare Group Co Ltd
Shanghai Jemincare Pharmaceuticals Co Ltd
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Publication date
Priority to JP2023555355A priority Critical patent/JP2024509939A/ja
Priority to CN202280013148.1A priority patent/CN116829539B/zh
Priority to BR112023018348A priority patent/BR112023018348A2/pt
Priority to PE2023002566A priority patent/PE20250414A1/es
Priority to US18/549,984 priority patent/US20240208908A1/en
Priority to MX2023010704A priority patent/MX2023010704A/es
Priority to CA3211594A priority patent/CA3211594A1/en
Priority to KR1020237034827A priority patent/KR20240019064A/ko
Application filed by Jiangxi Jemincare Group Co Ltd, Shanghai Jemincare Pharmaceuticals Co Ltd filed Critical Jiangxi Jemincare Group Co Ltd
Priority to EP22766394.5A priority patent/EP4306511A4/en
Priority to AU2022233221A priority patent/AU2022233221A1/en
Publication of WO2022188872A1 publication Critical patent/WO2022188872A1/zh
Anticipated expiration legal-status Critical
Priority to CONC2023/0013445A priority patent/CO2023013445A2/es
Priority to ZA2023/09462A priority patent/ZA202309462B/en
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/89—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4425—Pyridinium derivatives, e.g. pralidoxime, pyridostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • 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]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a crystal form, a pharmaceutical composition of a compound represented by formula (I), and its application as a voltage-gated sodium channel (NaV) blocker.
  • the global analgesic market was approximately US$36 billion in 2018 and is expected to reach US$56 billion in 2023.
  • acute moderate to severe patients mainly rely on opioids, which account for about two-thirds of the analgesic market share, and will grow steadily at a compound annual growth rate of 2.5% in the future.
  • the number of chronic pain patients, mainly neuropathic pain and arthritis pain is increasing year by year, and the market is expected to show a compound annual growth rate of about 18%, which will be the main driving force for the continued growth of the global pain market in the next decade. .
  • Neuropathic pain is a chronic pain caused by damage or disease of the peripheral somatosensory nervous system, and its symptoms include spontaneous pain and hyperalgesia to normal innocuous stimuli.
  • Common causes of neuropathic pain include: diabetes mellitus, herpes zoster, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical radiculopathy, and trauma or post-operative nerve damage.
  • Osteoarthritis also known as degenerative arthritis, is the degeneration of bone and articular cartilage caused by a variety of factors, which can lead to uneven surface of joint bones, and may form bone spurs. The clinical manifestations are mainly joint pain and joint stiffness. Long-term pain not only affects the patient's ability to sleep, work and live, but also increases the incidence of emotional disorders such as depression or anxiety, thus bringing a heavy economic burden to the patient's family and society.
  • Neuropathic Pain Task Force (NeuPSIG) of the International Pain Society
  • the prevalence of neuropathic pain is approximately 3.3%-8.2%.
  • Neuropathic pain is one of the most difficult diseases to treat, and most current treatment options are still unsatisfactory. It is reported that only 14.9% of outpatients can get timely pain relief through drug treatment, that is, about 85% of pain patients do not receive timely and effective drug treatment, so some patients have to seek surgical intervention.
  • the first-line drugs used in the clinical treatment of neuropathic pain are mainly calcium channel modulators (such as pregabalin, gabapentin), tricyclic antidepressants and serotonin, norepinephrine reuptake inhibitors (such as Anticonvulsants and antidepressants such as loxetine and venlafaxine). These drugs have limited efficacy and are associated with various adverse reactions.
  • Duloxetine is one of the first-line drugs for the treatment of neuropathic pain.
  • the main side effects include gastrointestinal reactions, nausea, drowsiness, dry mouth, hyperhidrosis and dizziness. The resulting drug discontinuation rate reaches 15%-20%.
  • the antiepileptic drugs gabapentin and pregabalin are the main drugs for the treatment of neuropathic pain, causing dizziness, somnolence, peripheral edema, weight gain, weakness, headache and dry mouth and many other adverse effects.
  • pregabalin has also been found to cause drug use-related suicidal ideation and self-injury behavior in a very small number of patients.
  • Opioid analgesics are used for severe pain, but have obvious side effects such as nausea and vomiting, constipation and drug dependence, and are not suitable for long-term use. Therefore, it is of great economic and social significance to develop new mechanisms for targeting new targets, as well as safe and effective analgesics to meet unmet clinical needs.
  • NaV1.8 sodium channel subtype 1.8
  • afferent neurons including sensory neurons afferent neurons including sensory neurons. It plays an important role in the regulation of release and persistence and pain sensitivity.
  • Diseases such as chronic inflammation and diabetes can cause increased expression or altered properties of NaV1.8 to sensitize nociceptive neurons, causing a variety of pain.
  • the NaV1.8 knockout mice were insensitive to pain.
  • NaV1.8 is a potential target for analgesia.
  • the mechanism of action and phase II clinical trials of NaV1.8 blockers show that they have a wide range of applications, including neuropathic pain, osteoarthritis pain, acute injury pain and other pains; and they are relatively safe and non-addictive , and there are no gastrointestinal side effects and cardiovascular and cerebrovascular side effects of non-steroidal anti-inflammatory drugs; it can be used in combination with other analgesics to enhance efficacy and reduce side effects.
  • NaV1.8 sodium channel subtype 1.8
  • the present invention provides crystal form A of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 16.63 ⁇ 0.2°, 18.04 ⁇ 0.2°, 20.59 ⁇ 0.2°, 23.38 ⁇ 0.2°, 23.96 ⁇ 0.2°, 29.19 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form A has characteristic diffraction peaks at the following 2 ⁇ angles: 12.46 ⁇ 0.2°, 13.11 ⁇ 0.2°, 16.63 ⁇ 0.2°, 18.04 ⁇ 0.2°, 20.59 ⁇ 0.2 °, 23.38 ⁇ 0.2°, 23.96 ⁇ 0.2°, 27.66 ⁇ 0.2°, 29.19 ⁇ 0.2°, 29.82 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form A has an X-ray powder diffraction pattern substantially as shown in FIG. 1 .
  • the crystal form A when the above crystal form A is subjected to thermogravimetric analysis (TGA), the crystal form A has a weight loss of 3.9% when heated to 150° C., with an error tolerance of ⁇ 0.2%.
  • TGA thermogravimetric analysis
  • the above-mentioned Form A has a thermogravimetric analysis substantially as shown in FIG. 2 .
  • the differential scanning calorimetry (DSC) of the above-mentioned Form A has an endothermic peak at 101.1°C ⁇ 3°C.
  • the above-mentioned Form A has a DSC differential scanning calorimetry curve substantially as shown in FIG. 3 .
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 2.0wt%-6.0wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form A is a hydrate, and the moisture content of the hydrate is 3.0wt%-5.0wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form A is a hydrate
  • the moisture content of the hydrate is 2.1wt%, 2.3wt%, 2.5wt%, 2.8wt%, 3.1wt%, 3.2wt%, 3.5wt% , 3.8wt%, 4.1wt%, 4.2wt%, 4.5wt%, 4.8wt%, 5.1wt%, 5.2wt%, 5.5wt%, 5.8wt% or 6.1wt% with a ⁇ 0.02% error tolerance.
  • the present invention provides crystal form B of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 12.28 ⁇ 0.2°, 14.47 ⁇ 0.2°, 18.86 ⁇ 0.2°, 23.09 ⁇ 0.2°, 25.50 ⁇ 0.2°, 27.58 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form B has characteristic diffraction peaks at the following 2 ⁇ angles: 12.28 ⁇ 0.2°, 14.47 ⁇ 0.2°, 16.81 ⁇ 0.2°, 18.86 ⁇ 0.2°, 19.78 ⁇ 0.2 °, 23.09 ⁇ 0.2°, 25.09 ⁇ 0.2°, 25.50 ⁇ 0.2°, 27.58 ⁇ 0.2°, 28.19 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form B has an X-ray powder diffraction pattern substantially as shown in FIG. 4 .
  • the crystal form B when the above-mentioned crystal form B is subjected to thermogravimetric analysis (TGA), the crystal form B has a weight loss of 1.2% when heated to 150° C., with an error tolerance of ⁇ 0.1%.
  • TGA thermogravimetric analysis
  • the above-mentioned Form B has a thermogravimetric analysis substantially as shown in FIG. 5 .
  • the differential scanning calorimetry (DSC) of the above-mentioned Form B has an endothermic peak at 148.4°C ⁇ 3°C.
  • the above-mentioned Form B has a DSC differential scanning calorimetry curve substantially as shown in FIG. 6 .
  • the above-mentioned crystal form B is an anhydrous crystal form.
  • the present invention provides crystal form C of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 8.22 ⁇ 0.2°, 17.33 ⁇ 0.2°, 19.55 ⁇ 0.2°, 20.27 ⁇ 0.2°, 21.99 ⁇ 0.2°, 24.90 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form C has characteristic diffraction peaks at the following 2 ⁇ angles: 8.22 ⁇ 0.2°, 13.80 ⁇ 0.2°, 17.33 ⁇ 0.2°, 19.55 ⁇ 0.2°, 20.27 ⁇ 0.2 °, 21.99 ⁇ 0.2°, 23.00 ⁇ 0.2°, 23.95 ⁇ 0.2°, 24.90 ⁇ 0.2°, 26.10 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form C has an X-ray powder diffraction pattern substantially as shown in FIG. 7 .
  • the crystal form C when the above-mentioned crystal form C is subjected to thermogravimetric analysis (TGA), the crystal form C has a weight loss of 1.2% when heated to 80°C, and has a 7.0% step weight loss when heated from 80°C to 150°C. ⁇ 0.1% error tolerance.
  • TGA thermogravimetric analysis
  • the above-mentioned Form C has a thermogravimetric analysis substantially as shown in FIG. 8 .
  • the differential scanning calorimetry (DSC) of the above-mentioned Form C has overlapping endothermic peaks at 106.6°C ⁇ 3°C and 111.3°C ⁇ 3°C.
  • the above-mentioned Form C has a DSC differential scanning calorimetry curve substantially as shown in FIG. 9 .
  • the above-mentioned crystal form C is a 1,4-dioxane solvate, and the content of the 1,4-dioxane is 3wt%-17wt%, with an error tolerance of ⁇ 0.2% limit.
  • the above-mentioned crystal form C is a 1,4-dioxane solvate, and the content of the 1,4-dioxane is 6wt%-16wt%, with an error tolerance of ⁇ 0.2% limit.
  • the above-mentioned crystal form C is a 1,4-dioxane solvate, and the content of the 1,4-dioxane is 3.1 wt %, 3.3 wt %, 3.5 wt %, 3.8 wt % wt%, 4.1wt%, 4.3wt%, 4.5wt%, 4.8wt%, 5.1wt%, 5.3wt%, 5.5wt%, 5.8wt%, 6.1wt%, 6.3wt%, 6.5wt%, 6.8wt% , 7.1wt%, 7.3wt%, 7.5wt%, 7.8wt%, 8.1wt%, 8.3wt%, 8.5wt%, 8.8wt%, 9.1wt%, 9.3wt%, 9.5wt%, 9.7wt%, 10.1 wt%, 10.3wt%, 10.5wt%, 10.8wt%,
  • the present invention provides crystal form D of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.63 ⁇ 0.2°, 16.81 ⁇ 0.2°, 20.40 ⁇ 0.2°, 21.50 ⁇ 0.2°, 22.23 ⁇ 0.2°, 26.08 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above crystal form D has characteristic diffraction peaks at the following 2 ⁇ angles: 5.63 ⁇ 0.2°, 11.02 ⁇ 0.2°, 16.81 ⁇ 0.2°, 19.58 ⁇ 0.2°, 20.40 ⁇ 0.2 °, 21.50 ⁇ 0.2°, 22.23 ⁇ 0.2°, 24.17 ⁇ 0.2°, 26.08 ⁇ 0.2°, 28.44 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form D has an X-ray powder diffraction pattern substantially as shown in FIG. 10 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form D are shown in Table 4 below. Table 4
  • the crystal form D when the above crystal form D is subjected to thermogravimetric analysis (TGA), the crystal form D has a weight loss of 0.9% when heated to 80°C, and has a weight loss of 7.0% when heated from 80°C to 150°C, and there is ⁇ 0.1 % error tolerance.
  • TGA thermogravimetric analysis
  • the above-mentioned Form D has a thermogravimetric analysis substantially as shown in FIG. 11 .
  • the differential scanning calorimetry (DSC) of the above-mentioned Form D has two endothermic peaks at 97.8°C ⁇ 3°C and 149.2°C ⁇ 3°C.
  • the above-mentioned Form D has a DSC differential scanning calorimetry curve substantially as shown in FIG. 12 .
  • the above-mentioned crystal form D is a methyl ethyl ketone solvate, and the content of the methyl ethyl ketone is 4wt%-14wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form D is a methyl ethyl ketone solvate, and the content of the methyl ethyl ketone is 6wt%-14wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form D is methyl ethyl ketone solvate, and the content of the methyl ethyl ketone is 4.1 wt %, 4.3 wt %, 4.5 wt %, 4.8 wt %, 5.1 wt % , 5.3wt%, 5.5wt%, 5.8wt%, 6.1wt%, 6.3wt%, 6.5wt%, 6.8wt%, 7.1wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.8wt%, 8.1 wt%, 8.3wt%, 8.5wt%, 8.8wt%, 9.1wt%, 9.3wt%, 9.5wt%, 9.8wt%, 10.1wt%, 10.3wt%, 10.5wt%, 10.7wt%, 10.9wt% , 11.1wt%, 11.3wt%, 1
  • the present invention provides crystal form E of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 5.75 ⁇ 0.2°, 13.71 ⁇ 0.2°, 18.29 ⁇ 0.2°, 20.18 ⁇ 0.2°, 22.92 ⁇ 0.2°, 23.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form E has characteristic diffraction peaks at the following 2 ⁇ angles: 5.75 ⁇ 0.2°, 13.71 ⁇ 0.2°, 16.65 ⁇ 0.2°, 17.17 ⁇ 0.2°, 18.29 ⁇ 0.2 °, 20.18 ⁇ 0.2°, 22.92 ⁇ 0.2°, 23.96 ⁇ 0.2°, 24.76 ⁇ 0.2°, 29.18 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form E has an X-ray powder diffraction pattern substantially as shown in FIG. 13 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form E are shown in Table 5 below.
  • the crystal form E when the above crystal form E is subjected to thermogravimetric analysis (TGA), the crystal form E has a weight loss of 1.9% when heated to 80°C, and has a weight loss of 4.9% when heated from 80°C to 150°C. % error tolerance.
  • TGA thermogravimetric analysis
  • the above-mentioned Form E has a thermogravimetric analysis substantially as shown in FIG. 14 .
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form E has a broad endothermic peak at 94.1°C ⁇ 3°C.
  • the above-mentioned Form E has a DSC differential scanning calorimetry curve substantially as shown in FIG. 15 .
  • the above-mentioned crystal form E is a tetrahydrofuran solvate, and the content of the tetrahydrofuran is 2wt%-14wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form E is a tetrahydrofuran solvate, and the content of the tetrahydrofuran is 2.1wt%, 2.3wt%, 2.5wt%, 2.8wt%, 3.1wt%, 3.3wt%, 3.5wt% , 3.8wt%, 4.1wt%, 4.3wt%, 4.5wt%, 4.8wt%, 5.1wt%, 5.3wt%, 5.5wt%, 5.8wt%, 6.1wt%, 6.3wt%, 6.5wt%, 6.8 wt%, 7.1wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.8wt%, 8.1wt%, 8.3wt%, 8.5wt%, 8.8wt%, 9.1wt%, 9.3wt%, 9.5wt% , 9.8wt%, 10.1wt%, 10.3
  • the present invention provides crystal form F of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 17.24 ⁇ 0.2°, 20.28 ⁇ 0.2°, 23.03 ⁇ 0.2°, 23.96 ⁇ 0.2°, 24.89 ⁇ 0.2°, 28.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned crystal form F has characteristic diffraction peaks at the following 2 ⁇ angles: 5.78 ⁇ 0.2°, 14.31 ⁇ 0.2°, 17.24 ⁇ 0.2°, 20.28 ⁇ 0.2°, 22.06 ⁇ 0.2 °, 23.03 ⁇ 0.2°, 23.96 ⁇ 0.2°, 24.89 ⁇ 0.2°, 26.27 ⁇ 0.2°, 28.96 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form F has an X-ray powder diffraction pattern substantially as shown in FIG. 16 .
  • the analytical data of the X-ray powder diffraction pattern of the above-mentioned crystal form F are shown in Table 6 below.
  • the crystal form F when the above-mentioned crystal form F is subjected to thermogravimetric analysis (TGA), the crystal form F has a weight loss of 11.5% when heated to 150° C., with an error tolerance of ⁇ 0.1%.
  • TGA thermogravimetric analysis
  • the above-mentioned Form F has a thermogravimetric analysis substantially as shown in FIG. 17 .
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form F has an endothermic peak at 105.2°C ⁇ 3°C.
  • the above-mentioned Form F has a DSC differential scanning calorimetry curve substantially as shown in FIG. 18 .
  • the above-mentioned crystal form F is a chloroform solvate, and the content of the chloroform is 5wt%-21wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form F is a chloroform solvate, and the content of the chloroform is 11wt%-21wt%, with an error tolerance of ⁇ 0.2%.
  • the above-mentioned crystal form F is a chloroform solvate, and the content of the chloroform is 5.1 wt %, 5.3 wt %, 5.5 wt %, 5.8 wt %, 6.1 wt %, 6.3 wt %, 6.5 wt % , 6.8wt%, 7.1wt%, 7.3wt%, 7.4wt%, 7.5wt%, 7.8wt%, 8.1wt%, 8.3wt%, 8.5wt%, 8.8wt%, 9.1wt%, 9.3wt%, 9.5 wt%, 9.8wt%, 10.1wt%, 10.3wt%, 10.5wt%, 10.7wt%, 10.9wt%, 11.1wt%, 11.3wt%, 11.5wt%, 11.8wt%, 12.1wt%, 12.3wt% , 12.5wt%, 12.8w
  • the present invention provides crystal form G of the compound represented by formula (I), whose X-ray powder diffraction pattern has characteristic diffraction peaks at the following 2 ⁇ angles: 15.53 ⁇ 0.2°, 17.08 ⁇ 0.2°, 21.41 ⁇ 0.2°, 23.23 ⁇ 0.2°, 26.00 ⁇ 0.2°, 28.49 ⁇ 0.2°
  • the X-ray powder diffraction pattern of the above-mentioned crystal form G has characteristic diffraction peaks at the following 2 ⁇ angles: 10.54 ⁇ 0.2°, 13.02 ⁇ 0.2°, 15.53 ⁇ 0.2°, 17.08 ⁇ 0.2°, 21.41 ⁇ 0.2 °, 23.23 ⁇ 0.2°, 25.10 ⁇ 0.2°, 26.00 ⁇ 0.2°, 27.17 ⁇ 0.2°, 28.49 ⁇ 0.2°.
  • the X-ray powder diffraction pattern of the above-mentioned Form G has an X-ray powder diffraction pattern substantially as shown in FIG. 19 .
  • the analytical data of the X-ray powder diffraction pattern of the above crystal form G are shown in Table 7 below.
  • the crystal form G when the above crystal form G is subjected to thermogravimetric analysis (TGA), the crystal form G has a weight loss of 2.3% when heated to 160° C., with an error tolerance of ⁇ 0.1%.
  • TGA thermogravimetric analysis
  • the above-mentioned Form G has a thermogravimetric analysis substantially as shown in FIG. 20 .
  • the differential scanning calorimetry (DSC) of the above-mentioned crystal form G has an endothermic peak at 149.0°C ⁇ 3°C.
  • the above-mentioned Form G has a DSC differential scanning calorimetry curve substantially as shown in FIG. 21 .
  • the above-mentioned crystal form G is an anhydrous crystal form.
  • the present invention also discloses a pharmaceutical composition.
  • the above-mentioned pharmaceutical composition comprises the aforementioned crystal forms A to G.
  • the above-mentioned pharmaceutical composition further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.
  • the present invention also discloses the use of the aforementioned crystal forms A to G or the aforementioned pharmaceutical composition in the preparation of a medicament for inhibiting a voltage-gated sodium channel of an individual.
  • the voltage-gated sodium channel described above is Navl.8.
  • the present invention also discloses the use of the aforementioned crystal forms A to G in the preparation of a medicament for treating and/or preventing pain, cough or reducing the severity of pain in an individual.
  • the aforementioned pain is selected from the group consisting of chronic pain, bowel pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple pain Sclerosis, Cha-Ma-Tuo III syndrome, incontinence, and cardiac arrhythmias.
  • the above-mentioned bowel pain is selected from the group consisting of inflammatory bowel disease pain, Crohn's disease pain, and interstitial cystitis pain.
  • the neuropathic pain is selected from the group consisting of post-herpetic neuralgia, diabetic neuralgia, pain HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful Neuroma, traumatic neuroma, Morto neuroma, nerve crush injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion, brachial plexus avulsion, complex regional pain syndrome , neuralgia from drug therapy, neuralgia from cancer chemotherapy, neuralgia from antiretroviral therapy, pain after spinal cord injury, primary small fiber neuropathy, primary sensory neuropathy, and trigeminal autonomic headache.
  • the aforementioned musculoskeletal pain is selected from the group consisting of osteoarthritis pain, back pain, cold pain, burn pain, and toothache.
  • the aforementioned inflammatory pain is selected from rheumatoid arthritis pain and vulvodynia.
  • the above-mentioned primary pain is selected from fibromyalgia.
  • the present invention also provides a method of treating or alleviating pain in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of the aforementioned Forms A-G or the aforementioned pharmaceutical composition.
  • pain in the above-mentioned subject is as defined herein.
  • the present invention also provides a method for inhibiting a voltage-gated sodium channel in a subject.
  • the method comprises administering to the subject a therapeutically effective amount of the aforementioned Forms A-G or the aforementioned pharmaceutical composition.
  • the voltage-gated sodium channel described above is Navl.8.
  • Crystalline refers to a solid with a highly regular chemical structure, including, but not limited to, single-component or multi-component crystals, and/or polymorphs, solvates, hydrates, Inclusion compounds, co-crystals, salts, solvates of salts, hydrates of salts. Crystalline forms of materials can be obtained by a number of methods known in the art.
  • Such methods include, but are not limited to, melt crystallization, melt cooling, solvent crystallization, crystallization in confined spaces, e.g., in nanopores or capillaries, crystallization on surfaces or templates, e.g., on polymers, Crystallization, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, antisolvent addition, grinding, and solvent drop grinding in the presence of additives such as co-crystallizing anti-molecules, among others.
  • Amorphous or “amorphous form” refers to a substance formed when its particles (molecules, atoms, ions) are arranged aperiodically in three-dimensional space, characterized by a diffuse X-ray powder diffraction pattern without sharp peaks. Amorphous is a special physical form of solid matter, and its locally ordered structural features suggest that it is inextricably linked with crystalline matter. Amorphous forms of substances can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, antisolvent flocculation, ball milling, spray drying, freeze drying, wet granulation, and solid dispersion techniques, among others.
  • Solvent refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid).
  • Solvents used in the practice of the present invention include, but are not limited to, water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol , ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, Methyl ethyl ketone, 1-methyl-2-pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran
  • Antisolvent refers to a fluid that facilitates precipitation of a product (or product precursor) from a solvent.
  • the antisolvent may comprise a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that reduces the solubility of the product in the solvent; it may be the same liquid as the solvent but at a different temperature, or it may be a different liquid than the solvent.
  • Solidvate means that the crystal has a solvent on the surface, or in the lattice, or both on the surface and in the lattice, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, tetrachloride Carbon, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, tert-butanol, N,N-dimethylacetamide, N,N- Dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methyl pyrrolidone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene and mixtures thereof and
  • a specific example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both on the surface and in the lattice is water. Hydrates may or may not have solvents other than water on the surface of the substance, or in the lattice, or both on the surface and in the lattice.
  • Crystalline or amorphous form can be identified by various techniques, such as X-ray powder diffraction (XRPD), infrared absorption spectroscopy (IR), melting point method, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) ), nuclear magnetic resonance, Raman spectroscopy, X-ray single crystal diffraction, dissolution calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, etc.
  • XRPD X-ray powder diffraction
  • IR infrared absorption spectroscopy
  • DSC differential scanning calorimetry
  • TGA thermogravimetric analysis
  • Raman spectroscopy X-ray single crystal diffraction
  • dissolution calorimetry dissolution calorimetry
  • SEM scanning electron microscopy
  • X-ray powder diffraction can detect the change of crystal form, crystallinity, crystal structure and other information, and is a common method to identify crystal form.
  • the peak positions of the XRPD patterns depend primarily on the structure of the crystal form and are relatively insensitive to experimental details, while their relative peak heights depend on many factors related to sample preparation and instrument geometry. Accordingly, in some embodiments, the crystalline forms of the present invention are characterized by XRPD patterns having certain peak positions substantially as shown in the XRPD patterns provided in the accompanying drawings of the present invention.
  • DSC Differential Scanning Calorimetry
  • an inert reference commonly ⁇ -Al 2 O 3
  • the melting peak heights of DSC curves depend on many factors related to sample preparation and instrument geometry, while peak positions are relatively insensitive to experimental details. Accordingly, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions substantially as shown in the DSC patterns provided in the accompanying drawings of the present invention.
  • the DSC spectrum may have experimental errors, and the peak positions and peaks of the DSC spectrum may be slightly different between different instruments and different samples, so the peak position or peak value of the DSC endothermic peak cannot be regarded as absolute. According to the conditions of the apparatus used in the experiments of the present invention, there is an error tolerance of ⁇ 3°C for the melting peak.
  • the glass transition refers to the transition of an amorphous substance between a highly elastic state and a glass state, which is an inherent property of the substance; its corresponding transition temperature is the glass transition temperature (Tg), which is an important part of the amorphous substance. physical properties. Glass transition is a phenomenon related to molecular motion, therefore, the glass transition temperature (Tg) mainly depends on the structure of the substance, and is relatively insensitive to experimental details and the like.
  • the amorphous glass transition temperature (Tg) of the present invention is determined by differential scanning calorimetry (DSC) and is characterized by having a glass transition temperature of 107.44°C. Depending on the condition of the instrumentation used in the experiments of the present invention, there is a tolerance of ⁇ 3°C for the glass transition temperature.
  • DSC Differential scanning calorimetry
  • Crystal transformation Due to the transformation of the crystal form, the mechanical, electrical, magnetic and other properties of the crystal will undergo great changes.
  • DSC differential scanning calorimetry
  • the transformation process can be observed on a differential scanning calorimetry (DSC) pattern, which is characterized in that the DSC pattern has an exothermic peak reflecting the transformation process, and There are two or more endothermic peaks at the same time, which are the characteristic endothermic peaks of different crystal forms before and after transformation.
  • DSC differential scanning calorimetry
  • Thermogravimetric analysis is a technique for measuring the change of the mass of a substance with temperature under program control. It is suitable for checking the loss of solvent in the crystal or the process of sublimation and decomposition of the sample. It can be speculated that the crystal contains water of crystallization or crystallization solvent. Case.
  • the mass change shown by the TGA curve depends on many factors such as sample preparation and instrument; the mass change detected by TGA varies slightly between different instruments and between different samples.
  • the calcium salt crystal form A of the present invention loses about 5.1% in weight at a temperature of about 150°C. There is an error tolerance of ⁇ 0.3% for mass variation depending on the condition of the instrumentation used for the experiments of the present invention.
  • the 2 ⁇ values in an X-ray powder diffraction pattern are all in degrees (°).
  • wt% refers to the mass ratio (g/g), for example, in a hydrate, the moisture content of crystal form A is 3.0wt%, which means the mass of water in the crystal form A and the crystal form
  • the mass ratio (g/g) of A is 3.0; for another example, in the solvate, the content of 1,4-dioxane in the crystal form C is 3.1 wt %, which means that the 1,4-dioxane in the crystal form C is 3.1 wt %.
  • the ratio (g/g) of the mass of dioxane to the mass of the crystal form C was 3.1.
  • substantially as shown means at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95% of the X-ray powder diffraction pattern or DSC pattern or TGA result %, or at least 99% of the peaks are shown in its graph.
  • a peak refers to a feature that would be recognized by those skilled in the art that would not be attributed to background noise.
  • substantially pure means that a crystalline form is substantially free of one or more other crystalline forms, ie, the crystalline form is at least 80% pure, or at least 85% pure, or at least 90% pure, or at least 93% pure, or At least 95%, or at least 98%, or at least 99%, or at least 99.5%, or at least 99.6%, or at least 99.7%, or at least 99.8%, or at least 99.9%, or the crystal form contains other crystal forms, said The percentage of other crystal forms in the total volume or total weight of the crystal form is less than 20%, or less than 10%, or less than 5%, or less than 3%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • substantially free means that the percentage of one or more other crystalline forms in the total volume or total weight of the crystalline form is less than 20%, or less than 10%, or less than 5%, or less than 4% , or less than 3%, or less than 2%, or less than 1%, or less than 0.5%, or less than 0.1%, or less than 0.01%.
  • Relative intensity refers to the ratio of the intensity of the other peaks to the intensity of the first intense peak when the intensity of the first intense peak is 100% among all diffraction peaks in an X-ray powder diffraction pattern (XRPD).
  • Fig. 1 is the X-ray powder diffraction (XRPD) pattern of crystal form A;
  • Fig. 2 is the thermogravimetric analysis (TGA) figure of crystal form A
  • FIG. 3 is a differential scanning calorimetry (DSC) diagram of Form A
  • Fig. 4 is the X-ray powder diffraction (XRPD) pattern of crystal form B;
  • Fig. 5 is the thermogravimetric analysis (TGA) figure of crystal form B;
  • Figure 6 is a differential scanning calorimetry (DSC) diagram of Form B
  • Fig. 7 is the X-ray powder diffraction (XRPD) pattern of crystal form C;
  • Fig. 8 is the thermogravimetric analysis (TGA) figure of crystal form C
  • Figure 9 is a differential scanning calorimetry (DSC) diagram of Form C
  • Figure 10 is an X-ray powder diffraction (XRPD) pattern of Form D;
  • FIG. 11 is a thermogravimetric analysis (TGA) diagram of Form D
  • Figure 12 is a differential scanning calorimetry (DSC) chart of Form D;
  • FIG. 14 is a thermogravimetric analysis (TGA) diagram of Form E
  • Figure 15 is a differential scanning calorimetry (DSC) chart of Form E;
  • Figure 16 is an X-ray powder diffraction (XRPD) pattern of Form F;
  • FIG. 17 is a thermogravimetric analysis (TGA) diagram of Form F
  • Figure 18 is a differential scanning calorimetry (DSC) chart of Form F;
  • Figure 19 is an X-ray powder diffraction (XRPD) pattern of Form G;
  • FIG. 20 is a thermogravimetric analysis (TGA) diagram of crystal form G
  • Figure 21 is a differential scanning calorimetry (DSC) chart of Form G
  • Figure 22 is the 1 H NMR chart of Form B
  • Figure 23 is the 1 H NMR chart of Form C
  • Figure 24 is the 1 H NMR chart of Form E
  • Figure 25 is the 1 H NMR chart of Form F
  • Figure 26 is the 1 H NMR chart of Form G
  • Figure 27 is the XRPD overlay (I/III) of the solid after suspension competition
  • Figure 28 is an XRPD overlay (II/III) of the solid after suspension competition
  • Figure 29 is an XRPD stack of solids after suspension competition (III/III).
  • TGA and DSC diagrams of the present invention are collected on a TA Q5000/Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter respectively, and table 9 lists the test parameters.
  • the dynamic moisture adsorption (DVS) curve of the present invention was collected on the DVS Intrinsic of SMS (Surface Measurement Systems). The relative humidity at 25°C was corrected for the deliquescence points of LiCl, Mg( NO3 ) 2 and KCl. DVS test parameters are listed in Table 10.
  • the liquid nuclear magnetic spectrum of the hydrogen spectrum of the present invention is collected on a Bruker 400M nuclear magnetic resonance apparatus, and DMSO-d 6 is used as a solvent.
  • HPLC high performance liquid chromatography
  • the embodiments of the present invention disclose the crystalline forms of the compounds of formula (I) and their preparation methods. Those skilled in the art can learn from the content of the present invention and appropriately improve the process parameters to achieve. It should be particularly pointed out that all similar substitutions and modifications will be apparent to those skilled in the art, and they are deemed to be included in the present invention.
  • the method of the present invention has been described through the preferred embodiments, and it is obvious that relevant persons can make changes or appropriate changes and combinations of the methods described herein without departing from the content, spirit and scope of the present invention, so as to realize and apply the technology of the present invention .
  • Intermediate D5 was synthesized and prepared with reference to the method in WO2019014352.
  • 200 mL of dichloromethane was added to the reaction flask, and under stirring conditions, 40 g of D5, 53.8 g of HATU, and 19.1 g of D6 were added to the reaction flask, and the stirring was continued.
  • DIPEA 42.2g was slowly added dropwise to the reaction flask, and the temperature in the reaction flask was controlled not to be higher than 35°C during the dropping process. After the addition was completed, the temperature in the reaction flask was kept at 30-35°C and stirring was continued for 16 hours.
  • reaction system was cooled to 25-30° C., 100 mL of dichloromethane was added, and 240 mL of a prepared 5% potassium carbonate aqueous solution was added to the system, stirred for 0.5 hours, and allowed to stand for liquid separation.
  • the organic phase was washed successively with 5% aqueous citric acid, 7% aqueous sodium bicarbonate and purified water, and then concentrated under reduced pressure to obtain the compound of formula (I).
  • the crystalline form of AXRPD was obtained by beating 20.2 mg of the compound represented by formula (I) in 0.3 mL of MTBE for 10 days at room temperature.
  • the results are shown in Figure 1, the TGA results are shown in Figure 2, and the DSC results are shown in Figure 3.
  • the TGA results show that the sample has a weight loss of 3.9% when heated to 150°C (the theoretical content of a crystal water is about 3.8%).
  • DSC results show that the sample has a broad endothermic peak at 86.3 °C (onset temperature).
  • Form B was obtained by beating 19.9 mg of the compound represented by formula (I) in 0.3 mL of Acetone at room temperature for 10 days.
  • the XRPD results are shown in Figure 4, the TGA results are shown in Figure 5, and the DSC results are shown in Figure 6.
  • the TGA results showed a 1.2% weight loss at 150°C.
  • the DSC results showed that the sample had an endothermic peak at 146.6°C (onset temperature).
  • Form C was obtained by beating 20.0 mg of the compound represented by formula (I) in 0.5 mL 1,4-Dioxane/Toluene (1:4, v/v) at room temperature for 10 days.
  • the XRPD results are shown in Figure 7, the TGA results are shown in Figure 8, and the DSC results are shown in Figure 9.
  • the TGA results show that the sample has a weight loss of 1.2% when heated to 80°C, and a stepwise weight loss of 7.0% when heated from 80°C to 150°C.
  • the DSC results showed that the sample observed overlapping endothermic peaks at 106.6°C and 111.3°C (peak temperature).
  • 1 H NMR results showed ( FIG. 23 ) that 6.3 wt % of 1,4-dioxane was detected.
  • Form D was obtained by gas-solid diffusion of 15.0 mg of the compound represented by formula (I) in 4 mL of MEK for one week.
  • the XRPD results are shown in Figure 10
  • the TGA results are shown in Figure 11
  • the DSC results are shown in Figure 12.
  • the TGA results show that the sample has a weight loss of 0.9% when heated to 80°C, and a weight loss of 7.0% when heated from 80°C to 150°C.
  • the DSC results showed that the sample had two endothermic peaks at 97.8°C and 149.2°C (peak temperature).
  • Form E was obtained by gas-solid diffusion of 15.0 mg of the compound represented by formula (I) in 4 mL of THF at room temperature for one week.
  • the XRPD results are shown in Figure 13
  • the TGA results are shown in Figure 14, and the DSC results are shown in Figure 15.
  • the TGA results showed that the sample weight loss was 1.9% from room temperature to 80°C, and the sample weight loss was 4.9% from 80°C to 150°C.
  • DSC results show that the sample has a broad endothermic peak at 85.1 °C (onset temperature).
  • ⁇ 1 >H NMR results showed ( Figure 24) that 3.8 wt% THF was detected.
  • Form F was obtained by gas-solid diffusion of 15.1 mg of the compound represented by formula (I) in 4 mL of CHCl 3 at room temperature for one week.
  • the XRPD results are shown in Figure 16, the TGA results are shown in Figure 17, and the DSC results are shown in Figure 18.
  • the TGA results showed a weight loss of 11.5% when heated to 150°C.
  • the DSC results showed that the sample had an endothermic peak at 95.7°C (onset temperature).
  • 1 H NMR results showed (FIG. 25) that 11.1 wt% CHCl3 was detected (consistent with TGA weight loss).
  • Form G is obtained by diffusing about 20 mg of the compound represented by formula (I) in DMSO at room temperature for about 4 days at room temperature, heating to 100° C. under nitrogen protection, and then cooling to room temperature.
  • the XRPD results are shown in Figure 19, the TGA results are shown in Figure 20, and the DSC results are shown in Figure 21.
  • the TGA results show that the sample of crystal form G has a weight loss of 2.3% when heated to 160°C.
  • the DSC results showed that the sample had an endothermic peak at 146.8°C (onset temperature). ⁇ 1 >H NMR results showed (FIG. 26) that 1.0 wt% DMSO solvent residue was detected.
  • the free anhydrous crystal form B can exist stably under certain water activity conditions, and the hydrate crystal form may have the risk of dehydration in the subsequent development, so the stability of the anhydrous crystal form B and the subsequent drugability are better.
  • Test method patch clamp technique to detect the effect of compounds on the current of voltage-gated sodium channel (NaV) 1.1-1.8 subtypes
  • Control Weigh an appropriate volume of DMSO as a stock solution.
  • Control and test compound stock solutions were diluted into 10 mL of extracellular fluid as working solutions and sonicated for 20 min prior to NaV channel current testing.
  • the cell density must not exceed 80%.
  • the voltage stimulation protocol for whole-cell patch-clamp recording of Nav channel currents was as follows: firstly, the membrane potential of the cell was clamped at -130mV, and then the voltage was stepped to -40mV or -20mV at 10mV step intervals for 8s. The clamping voltage was maintained at -120 mV, and data acquisition was repeated every 20 seconds. The peak amplitude of its inward current was measured to determine its half-inactivation voltage.
  • the cell clamp potential was set at -120mV. Resting and half-inactivating inhibition of sodium currents were measured using double-pulse mode.
  • the double-pulse mode is accomplished by two 0 mV depolarizing test pulses (TP1 and TP2) lasting 50 ms. Conditioning voltage between two depolarizing pulses, set around the half-inactivation voltage (duration 8s). Before a second depolarizing pulse was given, the cell membrane potential was clamped to -120 mV for 20 ms to allow compound unbound and inactive channels to be restored. Data acquisition was repeated at 20 s intervals, and current peaks at two test pulses were measured.
  • Experimental data were acquired by an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software (software version: v2x73.2).
  • Capillary glass tubes (BF150-86-10, Sutter Instruments) were drawn into recording electrodes using a microelectrode drawer (P97, Sutter Instruments).
  • the microelectrode manipulator (MP285) was operated under an inverted microscope (IX71) to contact the recording electrode on the cells, and suction was given under negative pressure to form a G ⁇ seal. After forming the G ⁇ seal, perform fast capacitance compensation, and then continue to give negative pressure to break the cell membrane to form a whole-cell recording mode. Then compensate for the slow capacitance and record the film capacitance and series resistance, and no leakage compensation is given.
  • the drug is administered, and each drug concentration is applied for 5 minutes (or the current is stable), and then the next concentration is detected, and each test compound is detected at multiple concentrations.
  • the cell-coated coverslip was placed in the recording bath of the inverted microscope, and the test compound and the compound-free external solution flowed through the recording chamber sequentially from low concentration to high concentration by gravity perfusion to act on the cells. Liquid exchange was performed using a vacuum pump during the recording. The current detected by each cell in the compound-free exosome served as its own control. Multiple cells were independently replicated. All electrophysiological experiments were performed at room temperature.
  • the current after each drug concentration was normalized to the blank control current, and then the blocking rate corresponding to each drug concentration was calculated.
  • the mean and standard error were calculated for each concentration, all of the above values were calculated using Microsoft Excel 2013.
  • the compound of formula (I) has obvious blocking effect on NaV1.8 channel activity.
  • mice Male Sprague Dawley rats, all animals were fasted overnight, and were given a single dose of the test compound 1 mg/Kg (intravenous injection, solvent 5% DMSO/10% Solutol/85% Saline) and 10 mg/Kg (infusion).
  • Stomach administration blood was collected from the submandibular vein at 5, 15, 30 min, 1, 2, 4, 6, 8 and 24 hr after administration, each sample was collected about 0.20 mL, anticoagulated with heparin sodium, placed on ice after collection, Plasma was centrifuged within 1 hour for testing. The plasma concentration of the drug was detected by liquid tandem mass spectrometry (LC/MS/MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Table 17 and Table 18 below.
  • the compound of formula (I) has good pharmacokinetic absorption in rats and has a pharmacokinetic advantage.

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Abstract

一种吡啶氮氧化合物晶型及其应用，具体地，涉及式(I)所示化合物的晶型、药物组合物及其用途。

Description

吡啶氮氧化合物晶型及其应用
本发明要求如下优先权：
申请号：CN202110265997.3，申请日：2021年03月11日；
申请号：CN202210195905.3，申请日：2022年03月01日。
技术领域
本发明涉及式(Ⅰ)所示化合物的晶型、药物组合物，以及其作电压门控钠离子通道(Voltage-gated sodium channels，NaV)阻滞剂的应用。
背景技术
疼痛是临床上最常见的症状之一，是继呼吸、脉搏、血压和体温之后的第五生命体征，严重影响患者的生活质量。据统计，2018年全球镇痛药市场约为360亿美元，预计2023年将达到560亿美元。其中急性中重度主要依赖于阿片类药物，占镇痛药市场份额的三分之二左右，未来将以2.5％的年复合增长率稳定增长。而以神经病理性疼痛(neuropathic pain)和关节炎疼痛为主的慢性疼痛患者数量逐年增加，预计市场将呈现18％左右的年复合增长率，是驱动未来十年全球疼痛市场持续增长的主要推动力。
神经病理性疼痛是由于外周躯体感觉神经系统的损伤或疾病导致的一种慢性疼痛，其症状包括自发性疼痛以及对正常无害刺激产生的痛觉超敏。诱发神经病理性疼痛的常见病因包括：糖尿病、带状疱疹、脊髓损伤、脑卒中、多发性硬化、癌症、HIV感染、腰或颈神经根性神经病变和创伤或术后神经损害等等。骨关节炎又称退化性关节炎，是由多种因素引起的骨关节软骨退化，能导致关节骨表面凸凹不平，并有可能形成骨刺，临床表现主要是关节疼痛和关节僵硬。长期疼痛不但影响患者睡眠、工作和生活能力，还会增加抑郁或焦虑等感情障碍的发病率，因此给患者家庭及社会带来沉重的经济负担。
根据国际疼痛学会神经病理性疼痛特别小组(NeuPSIG)发布的数据，神经病理性疼痛患病率约3.3％-8.2％。据此推算，仅我国国内就有至少5千万以上患者。2017年，美国、日本和欧盟五大市场(法国、德国、意大利、西班牙和英国)共有3050万例神经病理性疼痛患者，并呈逐年上升趋势。神经病理性疼痛是最难治疗的疾病之一，目前大多数治疗方案仍不能达到令人满意的效果。有报道指出，能通过药物治疗而及时止痛的门诊患者仅有14.9％，即约85％的疼痛病人并没有得到及时有效的药物治疗，因而一些病人不得不寻求手术介入性治疗。目前临床上用于神经病理性疼痛治疗的一线药物主要是钙离子通道调节剂(如普瑞巴林、加巴喷丁)、三环类抗抑郁药和5-羟色胺、去甲肾上腺素再摄取抑制药(如度洛西汀、文拉法辛等抗惊厥、抗抑郁的药物)。这些药疗效有限并伴随有各种不良反应。度洛西汀是神经病理性疼痛治疗的一线用药之一，主要副作用包括胃肠道反应、恶心、嗜睡、口干、多汗和头晕等，由此导致的停药率到达15％-20％。抗癫痫药物加巴喷丁和普瑞巴林是治疗神经病理性疼痛的主要药物，会引起头晕、嗜睡、周围性水肿、体重增加、虚弱、头痛和口干等诸多不良反应。近年来还发现普瑞巴林会导致极少部分患者出现药物使用相关的自杀观念和自伤行为。
骨关节炎患者数量庞大，预计目前全世界骨关节炎患者超过4亿，中国患者人数已过亿。骨关节炎疼痛目前也没有有效的治疗方法。临床上有物理疗法和药物疗法和手术治疗。物理疗法包括热疗，水疗，超声和按摩等，另外辅助用具减少关节压力缓解疼痛，但效果均有限，大部分依然需要依赖药物进行治疗。这些药物均存在不同程度的副作用。非甾体类抗炎药只适用于轻中度疼痛，而且有胃肠道副作用和心脑血管方面的风险。阿片类镇痛药用于重度疼痛，但有明显的恶心呕吐、便秘和药物依赖等副作用，不适合长期服用。因此，研发靶向新靶点新机制以及安全有效的镇痛药物，满足未被满足的临床需求，具有重要的经济意义和社会意义。
近年来的研究成果逐步揭示了钠离子通道亚型1.8(NaV1.8)在痛觉的发生和传递方面起重要作用。 NaV1.8是一种电压门控钠离子通道，主要表达在包括感觉神经元在内的传入神经元上，通过控制钠离子进出细胞，在维持伤害性感觉神经元的兴奋性、动作电位的发放和持续以及痛觉敏感性的调节等方面，发挥着重要作用。NaV1.8激活性突变病人出现小纤维神经病变(主要负责痛觉传递的Aδ纤维和无髓纤维C型纤维受损)导致的阵发性疼痛。慢性炎症和糖尿病等疾病会引起NaV1.8表达增加或性质改变从而敏化伤害感受神经元，引起多种疼痛。而NaV1.8基因敲除小鼠对痛觉不敏感。
随着Nav1.8在慢性疼痛中地位的确定，基于此靶点的药物研究也日益火热，目前国际上有一个小分子阻滞剂处于临床2期，其他多个小分子阻滞剂及抗体在进行临床前开发，国内尚无其他针对该靶点的新药研发。处于研发前端的是美国福泰(Vertex)公司的小分子NaV1.8阻滞剂VX-150,目前已在骨性关节炎、急性疼痛及小纤维神经病变导致疼痛的患者中进行了2期临床试验，并且所有三项研究均获得阳性结果，表明抑制NaV1.8活性可以缓解包括神经病理性疼痛在内的多种疼痛。目前VX-150获得了美国FDA突破性疗法认定，用于治疗中度至重度疼痛，再次证明NaV1.8是镇痛很有潜力的靶点。另外，NaV1.8阻滞剂的作用机理及二期临床实验表明，其适应广泛，包括神经病理性疼痛、骨关节炎疼痛和急性损伤疼痛等多种疼痛；且安全性相对高，没有成瘾性，也没有非甾体类抗炎药的胃肠道副作用及心脑血管方面的副作用；可以与其他镇痛药联用，增强疗效，降低副作用。
近年来还有研究表明钠离子通道亚型1.8(NaV1.8)对咳嗽有一定的调控作用，NaV1.8阻滞剂可能作为治疗咳嗽的有潜力药物。
申请号为PCT/CN2020/114700(申请日为2020年09月11日)的申请中提供了一种NaV1.8阻滞剂，结构如下所示：
Figure PCTCN2022080430-appb-000001
发明内容
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型A，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：16.63±0.2°、18.04±0.2°、20.59±0.2°、23.38±0.2°、23.96±0.2°、29.19±0.2°。
Figure PCTCN2022080430-appb-000002
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.46±0.2°、13.11±0.2°、16.63±0.2°、18.04±0.2°、20.59±0.2°、23.38±0.2°、23.96±0.2°、27.66±0.2°、29.19±0.2°、29.82±0.2°。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型A的X射线粉末衍射图谱解析数据如下表1所示。
表1
Figure PCTCN2022080430-appb-000003
Figure PCTCN2022080430-appb-000004
本发明的一些方案中，当上述晶型A进行热重分析(TGA)时，晶型A加热至150℃有3.9％的失重，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型A具有基本上如图2所示的热重分析。
本发明的一些方案中，上述晶型A的差示扫描量热分析(DSC)在101.1℃±3℃处具有吸热峰。
本发明的一些方案中，上述晶型A具有基本上如图3所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为2.0wt％-6.0wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为3.0wt％-5.0wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型A为水合物，所述水合物的水分含量为2.1wt％、2.3wt％、2.5wt％、2.8wt％、3.1wt％、3.2wt％、3.5wt％、3.8wt％、4.1wt％、4.2wt％、4.5wt％、4.8wt％、5.1wt％、5.2wt％、5.5wt％、5.8wt％或6.1wt％，存在±0.02％的误差容限。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型B，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.28±0.2°、14.47±0.2°、18.86±0.2°、23.09±0.2°、25.50±0.2°、27.58±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.28±0.2°、14.47±0.2°、16.81±0.2°、18.86±0.2°、19.78±0.2°、23.09±0.2°、25.09±0.2°、25.50±0.2°、27.58±0.2°、28.19±0.2°。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱具有基本上如图4所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型B的X射线粉末衍射图谱解析数据如下表2所示。
表2
Figure PCTCN2022080430-appb-000005
Figure PCTCN2022080430-appb-000006
Figure PCTCN2022080430-appb-000007
本发明的一些方案中，当上述晶型B进行热重分析(TGA)时，晶型B加热至150℃有1.2％的失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型B具有基本上如图5所示的热重分析。
本发明的一些方案中，上述晶型B的差示扫描量热分析(DSC)在148.4℃±3℃处具有吸热峰。
本发明的一些方案中，上述晶型B具有基本上如图6所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型B为无水晶型。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型C，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.22±0.2°、17.33±0.2°、19.55±0.2°、20.27±0.2°、21.99±0.2°、24.90±0.2°。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.22±0.2°、13.80±0.2°、17.33±0.2°、19.55±0.2°、20.27±0.2°、21.99±0.2°、23.00±0.2°、23.95±0.2°、24.90±0.2°、26.10±0.2°。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型C的X射线粉末衍射图谱解析数据如下表3所示。
表3
Figure PCTCN2022080430-appb-000008
Figure PCTCN2022080430-appb-000009
本发明的一些方案中，当上述晶型C进行热重分析(TGA)时，晶型C加热至80℃有1.2％的失重，从80℃加热至150℃有7.0％的台阶式失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型C具有基本上如图8所示的热重分析。
本发明的一些方案中，上述晶型C的差示扫描量热分析(DSC)在106.6℃±3℃和111.3℃±3℃有重叠的吸热峰。
本发明的一些方案中，上述晶型C具有基本上如图9所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型C为1,4-二氧六环溶剂合物，所述1,4-二氧六环的含量为3wt％-17wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型C为1,4-二氧六环溶剂合物，所述1,4-二氧六环的含量为6wt％-16wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型C为1,4-二氧六环溶剂合物，所述1,4-二氧六环的含量为3.1wt％、3.3wt％、3.5wt％、3.8wt％、4.1wt％、4.3wt％、4.5wt％、4.8wt％、5.1wt％、5.3wt％、5.5wt％、5.8wt％、6.1wt％、6.3wt％、6.5wt％、6.8wt％、7.1wt％、7.3wt％、7.5wt％、7.8wt％、8.1wt％、8.3wt％、8.5wt％、8.8wt％、9.1wt％、9.3wt％、9.5wt％、9.7wt％、10.1wt％、10.3wt％、10.5wt％、10.8wt％、11.1wt％、11.3wt％、11.5wt％、11.8wt％、12.1wt％、12.3wt％、12.5wt％、12.8wt％、13.1wt％、13.3wt％、13.5wt％、13.8wt％、14.1wt％、14.3wt％、14.5wt％、14.8wt％、15.1wt％、15.3wt％、15.5wt％、15.8wt％、16.1wt％、16.3wt％、16.5wt％、16.8wt％或17.1wt％，存在±0.02％的误差容限。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型D，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.2°、16.81±0.2°、20.40±0.2°、21.50±0.2°、22.23±0.2°、26.08±0.2°。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.2°、11.02±0.2°、16.81±0.2°、19.58±0.2°、20.40±0.2°、21.50±0.2°、22.23±0.2°、24.17±0.2°、26.08±0.2°、28.44±0.2°。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱具有基本上如图10所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型D的X射线粉末衍射图谱解析数据如下表4所示。 表4
Figure PCTCN2022080430-appb-000010
Figure PCTCN2022080430-appb-000011
本发明的一些方案中，当上述晶型D进行热重分析(TGA)时，晶型D加热至80℃有0.9％的失重，从80℃加热至150℃有7.0％的失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型D具有基本上如图11所示的热重分析。
本发明的一些方案中，上述晶型D的差示扫描量热分析(DSC)在97.8℃±3℃和149.2℃±3℃处有两个吸热峰。
本发明的一些方案中，上述晶型D具有基本上如图12所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型D为甲基乙基酮溶剂合物，所述甲基乙基酮的含量为4wt％-14wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型D为甲基乙基酮溶剂合物，所述甲基乙基酮的含量为6wt％-14wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型D为甲基乙基酮溶剂合物，所述甲基乙基酮的含量为4.1wt％、4.3wt％、4.5wt％、4.8wt％、5.1wt％、5.3wt％、5.5wt％、5.8wt％、6.1wt％、6.3wt％、6.5wt％、6.8wt％、7.1wt％、7.3wt％、7.4wt％、7.5wt％、7.8wt％、8.1wt％、8.3wt％、8.5wt％、8.8wt％、9.1wt％、9.3wt％、9.5wt％、9.8wt％、10.1wt％、10.3wt％、10.5wt％、10.7wt％、10.9wt％、11.1wt％、11.3wt％、11.5wt％、11.8wt％、12.1wt％、12.3wt％、12.5wt％、12.8wt％、13.1wt％、13.3wt％、13.5wt％、13.6wt％、13.8wt％或14.1wt％，存在±0.02％的误差容限。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型E，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.75±0.2°、13.71±0.2°、18.29±0.2°、20.18±0.2°、22.92±0.2°、23.96±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.75±0.2°、13.71±0.2°、16.65±0.2°、17.17±0.2°、18.29±0.2°、20.18±0.2°、22.92±0.2°、23.96±0.2°、24.76±0.2°、29.18±0.2°。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱具有基本上如图13所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型E的X射线粉末衍射图谱解析数据如下表5所示。
表5
Figure PCTCN2022080430-appb-000012
Figure PCTCN2022080430-appb-000013
本发明的一些方案中，当上述晶型E进行热重分析(TGA)时，晶型E加热至80℃有1.9％的失重，从80℃加热至150℃有4.9％的失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型E具有基本上如图14所示的热重分析。
本发明的一些方案中，上述晶型E的差示扫描量热分析(DSC)在94.1℃±3℃处有一个较宽的吸热峰。
本发明的一些方案中，上述晶型E具有基本上如图15所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型E为四氢呋喃溶剂合物，所述四氢呋喃的含量为2wt％-14wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型E为四氢呋喃溶剂合物，所述四氢呋喃的含量为2.1wt％、2.3wt％、2.5wt％、2.8wt％、3.1wt％、3.3wt％、3.5wt％、3.8wt％、4.1wt％、4.3wt％、4.5wt％、4.8wt％、5.1wt％、5.3wt％、 5.5wt％、5.8wt％、6.1wt％、6.3wt％、6.5wt％、6.8wt％、7.1wt％、7.3wt％、7.4wt％、7.5wt％、7.8wt％、8.1wt％、8.3wt％、8.5wt％、8.8wt％、9.1wt％、9.3wt％、9.5wt％、9.8wt％、10.1wt％、10.3wt％、10.5wt％、10.7wt％、10.9wt％、11.1wt％、11.3wt％、11.5wt％、11.8wt％、12.1wt％、12.3wt％、12.5wt％、12.8wt％、13.1wt％、13.3wt％、13.5wt％、13.6wt％、13.8wt％或14.1wt％，存在±0.02％的误差容限。在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型F，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.24±0.2°、20.28±0.2°、23.03±0.2°、23.96±0.2°、24.89±0.2°、28.96±0.2°。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.78±0.2°、14.31±0.2°、17.24±0.2°、20.28±0.2°、22.06±0.2°、23.03±0.2°、23.96±0.2°、24.89±0.2°、26.27±0.2°、28.96±0.2°。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱具有基本上如图16所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型F的X射线粉末衍射图谱解析数据如下表6所示。
表6
Figure PCTCN2022080430-appb-000014
Figure PCTCN2022080430-appb-000015
本发明的一些方案中，当上述晶型F进行热重分析(TGA)时，晶型F加热至150℃有11.5％的失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型F具有基本上如图17所示的热重分析。
本发明的一些方案中，上述晶型F的差示扫描量热分析(DSC)在105.2℃±3℃处有的吸热峰。
本发明的一些方案中，上述晶型F具有基本上如图18所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型F为氯仿溶剂合物，所述氯仿的含量为5wt％-21wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型F为氯仿溶剂合物，所述氯仿的含量为11wt％-21wt％，存在±0.2％的误差容限。
本发明的一些方案中，上述晶型F为氯仿溶剂合物，所述氯仿的含量为5.1wt％、5.3wt％、5.5wt％、5.8wt％、6.1wt％、6.3wt％、6.5wt％、6.8wt％、7.1wt％、7.3wt％、7.4wt％、7.5wt％、7.8wt％、8.1wt％、8.3wt％、8.5wt％、8.8wt％、9.1wt％、9.3wt％、9.5wt％、9.8wt％、10.1wt％、10.3wt％、10.5wt％、10.7wt％、10.9wt％、11.1wt％、11.3wt％、11.5wt％、11.8wt％、12.1wt％、12.3wt％、12.5wt％、12.8wt％、13.1wt％、13.3wt％、13.5wt％、13.6wt％、13.8wt％、14.1wt％、14.3wt％、14.5wt％、14.8wt％、15.1wt％、15.3wt％、15.5wt％、15.8wt％、16.1wt％、16.3wt％、16.5wt％、16.8wt％、17.1wt％、17.3wt％、17.5wt％、17.8wt％、18.1wt％、18.3wt％、18.5wt％、18.8wt％、19.1wt％、19.3wt％、19.5wt％、19.8wt％、20.1wt％、20.3wt％、20.5wt％、20.6wt％、20.7wt％、20.8wt％或21.1wt％，存在±0.02％的误差容限。
在本发明的一方面，本发明提供了式(Ⅰ)所示化合物晶型G，其X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.53±0.2°、17.08±0.2°、21.41±0.2°、23.23±0.2°、26.00±0.2°、28.49±0.2°
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.54±0.2°、13.02±0.2°、15.53±0.2°、17.08±0.2°、21.41±0.2°、23.23±0.2°、25.10±0.2°、26.00±0.2°、27.17±0.2°、28.49±0.2°。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱具有基本上如图19所示的X射线粉末衍射图谱。
本发明的一些方案中，上述晶型G的X射线粉末衍射图谱解析数据如下表7所示。
表7
Figure PCTCN2022080430-appb-000016
本发明的一些方案中，当上述晶型G进行热重分析(TGA)时，晶型G加热至160℃有2.3％的失重，存在±0.1％的误差容限。
本发明的一些方案中，上述晶型G具有基本上如图20所示的热重分析。
本发明的一些方案中，上述晶型G的差示扫描量热分析(DSC)在149.0℃±3℃处有的吸热峰。
本发明的一些方案中，上述晶型G具有基本上如图21所示的DSC差示扫描量热曲线。
本发明的一些方案中，上述晶型G为无水晶型。
在本发明的再一方面，本发明还公开了一种药物组合物。在本发明的一些方案中，上述药物组合物包含前面所述的晶型A～G。
在本发明的一些方案中，上述药物组合物进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
在本发明的再一方面，本发明还公开了前面所述的晶型A～G或前面所述的药物组合物在制备用于抑制个体的电压门控型钠通道的药物中的用途。
在本发明的一些方案中，上述电压门控型钠通道是Navl.8。
在本发明的再一方面，本发明还公开了前面所述的晶型A～G在制备用于治疗和/或预防个体的疼痛、咳嗽或减轻其严重性的药物中的用途。
在本发明的一些方案中，上述疼痛选自慢性疼痛、肠痛、神经性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原发性疼痛、手术后疼痛、内脏痛、多发性硬化症、夏-马-图三氏综合症、失禁和心律失常。
在本发明的一些方案中，上述肠痛选自炎性肠病疼痛、克罗恩病疼痛和间质性膀胱炎疼痛。
在本发明的一些方案中，上述神经性疼痛选自疱疹后神经痛、糖尿病性神经痛、痛HIV相关性感觉神经病、三叉神经痛、口灼伤综合症、截肢术后疼痛、幻痛、痛性神经瘤、创伤性神经瘤、Morto神经瘤、神经挤压损伤、脊管狭窄、腕管综合症、神经根痛、坐骨神经痛、神经撕脱伤、臂丛撕脱伤、复杂性区域疼痛综合症、药物疗法引起的神经痛、癌症化学疗法引起的神经痛、抗逆转录病毒疗法引起的神经痛、脊髓损伤后疼痛、原发性小纤维神经病、原发性感觉神经病和三叉自主神经性头痛。
在本发明的一些方案中，上述肌肉骨骼痛选自骨关节炎疼痛、背痛、冷痛、烧伤疼痛和牙痛。
在本发明的一些方案中，上述炎性疼痛选自类风湿性关节炎疼痛和外阴痛。
在本发明的一些方案中，上述原发性疼痛选自纤维肌痛。
在本发明的再一方面，本发明还提出了一种治疗或减轻受试者的疼痛的方法。
在本发明的一些方案中，所述方法包含对所述受试者施用治疗有效量的前面所述的晶型A～G或前面所述的药物组合物。在本发明的一些方案中，上述受试者的疼痛如本发明所定义。
在本发明的再一方面，本发明还提出了一种抑制受试者电压门控的钠通道的方法。
在本发明的一些方案中，所述方法包含对所述受试者施用治疗有效量的前面所述的晶型A～G或前面所述的药物组合物。在本发明的一些方案中，上述电压门控型钠通道是Navl.8。
定义和说明
除非另有说明，本发明使用的所有技术和科学术语与本发明所属领域的普通技术人员所通常理解的具有相同含义。本发明涉及的所有专利和公开出版物通过引用方式整体并入本发明。尽管在本发明的实践或者测试中可以使用与本发明所述相似或者相同的任何方法和物质，但是本发明中描述的是优选的方法、设备和物质。
“晶型”或“结晶形式”是指具有高度规则化学结构的固体，包括，但不限于，单组分或者多组分晶体， 和/或化合物的多晶型物、溶剂化物、水合物、包合物、共晶、盐、盐的溶剂化物、盐的水合物。物质的结晶形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，熔体结晶、熔体冷却、溶剂结晶、在限定的空间中结晶，例如，在纳米孔或者毛细管中，在表面或者模板上结晶，例如，在聚合物上，在添加剂如共结晶反分子的存在下结晶、去溶剂、脱水、快速蒸发、快速冷却、缓慢冷却、蒸气扩散、升华、反应结晶、反溶剂添加、研磨和溶剂滴研磨等。
“无定形”或“无定形形式”是指物质的质点(分子、原子、离子)在三维空间排列无周期性时形成的物质，其特征是具有漫射的不具尖峰的X射线粉末衍射图。无定形是固体物质的一种特殊的物理形式，其局部有序的结构特征，提示其与晶型物质有着千丝万缕的联系。物质的无定形形式可通过本领域已知的许多方法得到。这种方法包括，但不限于，骤冷法、反溶剂絮凝法、球磨法、喷雾干燥法、冷冻干燥法、湿法制粒法和固体分散体技术等等。
“溶剂”是指一种物质(典型地是一种液体)，该物质能够完全地或部分地溶解另一种物质(典型地是一种固体)。用于本发明实施的溶剂包括但并不限于，水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯甲烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、l-甲基-2-吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯、它们的混合物等等。
“反溶剂”是指促进产物(或产物前体)从溶剂中沉淀的流体。反溶剂可以包括冷气体、或通过化学反应促进沉淀的流体、或降低产物在溶剂中的溶解度的流体；其可以是与溶剂相同的液体但是处于不同温度，或者它可以是与溶剂不同的液体。
“溶剂化物”是指晶体在表面上、或在晶格中、或者在表面上和在晶格中具有溶剂，其中，所述溶剂可以是水、乙酸、丙酮、乙腈、苯、氯仿、四氯化碳、二氯曱烷、二甲基亚砜、1,4-二氧六环、乙醇、乙酸乙酯、丁醇、叔丁醇、N,N-二甲基乙酰胺、N,N-二甲基甲酰胺、甲酰胺、蚁酸、庚烷、己烷、异丙醇、甲醇、甲基乙基酮、甲基吡咯烷酮、均三甲苯、硝基甲烷、聚乙二醇、丙醇、2-丙酮、吡啶、四氢呋喃、甲苯、二甲苯以及它们的混合物等等。溶剂化物的一个具体例子是水合物，其中在表面上、或在晶格中、或者在表面上和在晶格中的溶剂是水。在物质的表面上、或在晶格中、或者在表面上和在晶格中，水合物可以具有或者不具有除了水以外的其它溶剂。
晶型或无定形可以通过多种技术手段进行鉴别，例如X射线粉末衍射(XRPD)、红外吸收光谱法(IR)、熔点法、差示扫描量热法(DSC)、热重分析法(TGA)、核磁共振法、拉曼光谱、X射线单晶衍射、溶解量热法、扫描电子显微镜(SEM)、定量分析、溶解度和溶解速度等等。
X射线粉末衍射(XRPD)可检测晶型的变化、结晶度、晶构状态等信息，是鉴别晶型的常用手段。XRPD图谱的峰位置主要取决于晶型的结构，对实验细节相对不敏感，而其相对峰高取决于与样品制备和仪器几何形状有关的许多因素。因此，在一些实施例中，本发明的晶型的特征在于具有某些峰位置的XRPD图，其基本上如本发明附图中提供的XRPD图所示。同时，XRPD图谱的2θ的量度可以有实验误差，不同仪器以及不同样品之间，XRPD图谱的2θ的量度可能会略有差别，因此所述2θ的数值不能视为绝对的。根据本发明试验所用仪器状况，衍射峰存在±0.2°的误差容限。
差示扫描量热(DSC)是在程序控制下，通过不断加热或降温，测量样品与惰性参比物(常用α-Al 2O 3)之间的能量差随温度变化的一种技术。DSC曲线的熔化峰高取决于与样品制备和仪器几何形状有关的许多因素，而峰位置对实验细节相对不敏感。因此，在一些实施例中，本发明所述晶型的特征在于具有特征峰 位置的DSC图，其基本上如本发明附图中提供的DSC图所示。同时，DSC图谱可以有实验误差，不同仪器以及不同样品之间，DSC图谱的峰位置和峰值可能会略有差别，因此所述DSC吸热峰的峰位置或峰值的数值不能视为绝对的。根据本发明试验所用仪器状况，熔化峰存在±3℃的误差容限。
玻璃态转变是指非晶态物质在高弹态和玻璃态之间的转变，是该物质的固有性质；它所对应的转变温度为玻璃化转变温度(Tg)，是非晶态物质的一个重要物理性质。玻璃化转变是与分子运动有关的现象，因而，玻璃化转变温度(Tg)主要取决于物质的结构，而对实验细节等相对不敏感。在一些实施例中，本发明所述无定形的玻璃化转变温度(Tg)通过差示扫描量热法(DSC)测定，其特征在于具有107.44℃的玻璃化转变温度。根据本发明试验所用仪器状况，玻璃化转变温度存在±3℃的误差容限。
差示扫描量热(DSC)还可用于检测分析晶型是否有转晶或混晶现象。
化学组成相同的固体，在不同的热力学条件下，常会形成晶体结构不同的同质异构体，或称为变体，这种现象称为同质多晶或同质多相现象。当温度和压力条件变化时，变体之间会发生相互转变，此现象称为晶型转变。由于晶型转变，晶体的力学、电学、磁学等性能会发生巨大的变化。当晶型转变的温度在可测范围内时，在差示扫描量热(DSC)图上可观察到这一转变过程，其特征在于，DSC图具有反映这一转变过程的放热峰，且同时具有两个或多个吸热峰，分别为转变前后的不同晶型的特征吸热峰。本发明化合物的晶型或无定形在适当条件下可发生晶型转变
热重分析(TGA)是在程序控制下，测定物质的质量随温度变化的一种技术，适用于检查晶体中溶剂的丧失或样品升华、分解的过程，可推测晶体中含结晶水或结晶溶剂的情况。TGA曲线显示的质量变化取决于样品制备和仪器等许多因素；不同仪器以及不同样品之间，TGA检测的质量变化略有差别。在一些实施例中，本发明所述的钙盐晶型A在温度150℃左右失重5.1％左右。根据本发明试验所用的仪器状况，质量变化存在±0.3％的误差容限。
在本发明的上下文中，X射线粉末衍射图中的2θ值均以度(°)为单位。
需要说明的是，“wt％”是指质量比(g/g)，例如在水合物中，晶型A的水分含量为3.0wt％，是指该晶型A中水的质量与该晶型A的质量的比例(g/g)为3.0；又例如在溶剂合物中，晶型C中1,4-二氧六环的含量为3.1wt％，是指该晶型C中1,4-二氧六环的质量与该晶型C的质量的比例(g/g)为3.1。
术语“基本上如图所示”是指X射线粉末衍射图或DSC图或TGA结果中至少50％，或至少60％，或至少70％，或至少80％，或至少90％，或至少95％，或至少99％的峰显示在其图中。
当提及谱图或/和出现在图中的数据时，“峰”指本领域技术人员能够识别的不会归属于背景噪音的一个特征。
“基本上纯净的”是指一种晶型基本上不含另外一种或多种晶型，即晶型的纯度至少80％，或至少85％，或至少90％，或至少93％，或至少95％，或至少98％，或至少99％，或至少99.5％，或至少99.6％，或至少99.7％，或至少99.8％，或至少99.9％，或晶型中含有其它晶型，所述其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于3％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“基本上不含”是指一种或多种其它晶型在晶型的总体积或总重量中的百分比少于20％，或少于10％，或少于5％，或少于4％，或少于3％，或少于2％，或少于1％，或少于0.5％，或少于0.1％，或少于0.01％。
“相对强度”是指X-射线粉末衍射图(XRPD)的所有衍射峰中第一强峰的强度为100％时，其它峰的强度与第一强峰的强度的比值。
在本发明的上下文中，当使用或者无论是否使用“大约”或“约”等字眼时，表示在给定的值或范围的10％以内，适当地在5％以内，特别是在1％以内。或者，对于本领域普通技术人员而言，术语“大约”或“约”表示在平均值的可接受的标准误差范围内。每当公开一个具有N值的数字时，任何具有N+/-1％，N+/-2％，N+/-3％，N+/-5％，N+/-7％，N+/-8％或N+/-10％值以内的数字会被明确地公开，其中“+/-”是指加或减。
术语“包含”为开放式表达，即包括本发明所指明的内容，但并不排除其他方面的内容。
附图说明
图1为晶型A的X射线粉末衍射(XRPD)图；
图2为晶型A的热重分析(TGA)图；
图3为晶型A的差示扫描量热(DSC)图；
图4为晶型B的X射线粉末衍射(XRPD)图；
图5为晶型B的热重分析(TGA)图；
图6为晶型B的差示扫描量热(DSC)图；
图7为晶型C的X射线粉末衍射(XRPD)图；
图8为晶型C的热重分析(TGA)图；
图9为晶型C的差示扫描量热(DSC)图；
图10为晶型D的X射线粉末衍射(XRPD)图；
图11为晶型D的热重分析(TGA)图；
图12为晶型D的差示扫描量热(DSC)图；
图13为晶型E的X射线粉末衍射(XRPD)图；
图14为晶型E的热重分析(TGA)图；
图15为晶型E的差示扫描量热(DSC)图；
图16为晶型F的X射线粉末衍射(XRPD)图；
图17为晶型F的热重分析(TGA)图；
图18为晶型F的差示扫描量热(DSC)图；
图19为晶型G的X射线粉末衍射(XRPD)图；
图20为晶型G的热重分析(TGA)图；
图21为晶型G的差示扫描量热(DSC)图；
图22为晶型B的 1H NMR图；
图23为晶型C的 1H NMR图；
图24为晶型E的 1H NMR图；
图25为晶型F的 1H NMR图；
图26为晶型G的 1H NMR图；
图27为混悬竞争后固体的XRPD叠图(I/III)；
图28为混悬竞争后固体的XRPD叠图(II/III)；
图29为混悬竞争后固体的XRPD叠图(III/III)。
具体实施方式
下面通过实施例对本申请进行详细描述，但并不意味着存在对本申请而言任何不利的限制。本文已经 详细地描述了本申请，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本申请精神和范围的情况下针对本申请具体实施方式进行各种变化和改进将是显而易见的。
本发明的XRPD结果是在PANalytical Empyrean和X’Pert3X射线粉末衍射分析仪上采集，扫描参数如下表8所示。
表8
Figure PCTCN2022080430-appb-000017
本发明TGA和DSC图分别在TA Q5000/Discovery 5500热重分析仪和TA Discovery 2500差示扫描量热仪上采集，表9列出了测试参数。
表9
参数 TGA DSC
方法 线性升温 线性升温
样品盘 铝盘，敞开 铝盘，压盖
温度范围 RT-350℃ RT-目标温度
加热速率 10℃/min 10℃/min
保护气体 氮气 氮气
本发明动态水分吸附(DVS)曲线在SMS(Surface Measurement Systems)的DVS Intrinsic上采集。在25℃时的相对湿度用LiCl、Mg(NO 3) 2和KCl的潮解点校正。DVS测试参数列于表10。
表10
Figure PCTCN2022080430-appb-000018
Figure PCTCN2022080430-appb-000019
本发明氢谱液态核磁谱图在Bruker 400M核磁共振仪上采集，以DMSO-d 6作为溶剂。
本发明所用高效液相色谱(HPLC)试验中稳定性试验由安捷伦1260高效液相色谱仪测试，分析条件如表11所示。
表11
Figure PCTCN2022080430-appb-000020
本发明采用的溶剂缩写或英文的中文含义如下表12所示：
表12
英文 中文 英文 中文
MeOH 甲醇 MTBE 甲基叔丁基醚
EtOH 乙醇 THF 四氢呋喃
IPA 异丙醇 2-MeTHF 2-甲基四氢呋喃
CHCl 3 氯仿 ACN 乙腈
MIBK 甲基异丁基酮 n-Heptane 正庚烷
EtOAc 乙酸乙酯 Toluene 甲苯
IPAc 乙酸异丙酯 H 2O 水
DMSO 二甲亚砜 DCM 二氯甲烷
Anisole 苯甲醚 1,4-Dioxane 1,4-二氧六环
MEK 甲基乙基酮 DMF 二甲基甲酰胺
Cumene 异丙基苯 n-Hexane 正己烷
本发明实施例公开了式(I)化合物的晶型以及它们的制备方法。本领域技术人员可以借鉴本发明内容，适当改进工艺参数来实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明中。本发明的方法已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。
实施例1：式(Ⅰ)化合物的制备
Figure PCTCN2022080430-appb-000021
参考WO2019014352中的方法合成制备中间体D5。向反应瓶中加入二氯甲烷200mL，在搅拌条件下，向反应瓶中分别加入D5 40g、HATU 53.8g、D6 19.1g，并继续搅拌。向反应瓶中缓慢滴加DIPEA 42.2g，在滴加过程中控制反应瓶内温不高于35℃，滴加完毕后，保持反应瓶内温30～35℃继续搅拌16小时。反应结束后，将反应体系降温至25～30℃，并补加二氯甲烷100mL，向体系中加入已经配制好的5％碳酸钾水溶液240mL，并搅拌0.5小时，静置分液。有机相依次用5％的柠檬酸水溶液7％的碳酸氢钠水溶液和纯净水洗涤后，减压浓缩，得式(Ⅰ)化合物。
LCMS:m/z 459.0(M+H) +； 1H NMR(400MHz,DMSO-d 6)δ10.83(s,1H),8.61(s,1H),8.03(s,1H),8.00–7.98(m,1H),7.47–7.44(m,2H),7.40–7.34(m,3H),7.21-7.16(m,2H).
实施例2：晶型A的制备及鉴定
通过将20.2mg式(I)所示化合物在0.3mL MTBE中室温打浆10天后获得晶型AXRPD结果如图1所示、TGA结果如图2所示、DSC结果如图3所示。TGA结果显示样品加热至150℃有3.9％的失重(一个结晶水的理论含量约为3.8％)。DSC结果显示，样品在86.3℃(起始温度)处有一个较宽的吸热峰。
实施例3：晶型B的制备及鉴定
通过将19.9mg式(I)所示化合物在0.3mL Acetone中室温打浆10天后获得晶型B。XRPD结果如图4所示、TGA结果如图5所示、DSC结果如图6所示。TGA结果显示升温至150℃有1.2％的失重。DSC结果显示，样品在146.6℃(起始温度)处有一个吸热峰。 1H NMR结果(图22)表明，该样品中仅观察到极少量(0.04wt％)的Acetone残留。
实施例4：晶型C的制备及鉴定
通过将20.0mg式(I)所示化合物在0.5mL 1,4-Dioxane/Toluene(1:4,v/v)中室温打浆10天后获得晶型C。XRPD结果如图7所示、TGA结果如图8所示、DSC结果如图9所示。TGA结果显示样品升温至 80℃有1.2％的失重，从80℃加热至150℃有7.0％的台阶式失重。DSC结果显示，样品在106.6℃和111.3℃(峰值温度)观察到重叠的吸热峰。 1H NMR结果显示(图23)检测到6.3wt％的1,4-dioxane。
实施例5：晶型D的制备及鉴定
通过将15.0mg式(I)所示化合物在4mL MEK中气固扩散一周后获得晶型D。XRPD结果如图10所示、TGA结果如图11所示、DSC结果如图12所示。TGA结果显示样品升温至80℃有0.9％的失重，从80℃加热至150℃有7.0％的失重。DSC结果显示，样品在97.8℃和149.2℃(峰值温度)处有两个吸热峰。
实施例6：晶型E的制备及鉴定
通过将15.0mg式(I)所示化合物在4mL THF中室温气固扩散一周后获得晶型E。XRPD结果如图13所示、TGA结果如图14所示、DSC结果如图15所示。TGA结果显示从室温升温至80℃，样品失重为1.9％，从80℃升温至150℃，样品失重为4.9％。DSC结果显示，样品在85.1℃(起始温度)处有一个较宽的吸热峰。 1H NMR结果显示(图24)检测到3.8wt％的THF。
实施例7：晶型F的制备及鉴定
通过将15.1mg式(I)所示化合物在4mL CHCl 3中室温气固扩散一周后获得晶型F。XRPD结果如图16所示、TGA结果如图17所示、DSC结果如图18所示。TGA结果显示升温至150℃有11.5％的失重。DSC结果显示，样品在95.7℃(起始温度)处有一个吸热峰。 1H NMR结果显示(图25)检测到11.1wt％的CHCl 3(与TGA失重一致)。
实施例8：晶型G的制备及鉴定
通过将约20mg式(I)所示化合物在DMSO中室温气固扩散约4天后，氮气保护下加热至100℃后降至室温获得晶型G。XRPD结果如图19所示、TGA结果如图20所示、DSC结果如图21所示。TGA结果显示将晶型G样品升温至160℃有2.3％的失重。DSC结果显示，样品在146.8℃(起始温度)处有一个吸热峰。 1H NMR结果显示(图26)，检测到1.0wt％的DMSO溶剂残留。
实施例9：固态稳定性实验
为了评估游离态无水晶型B的固态稳定性，分别称取适量样品在60℃条件下闭口放置24小时，25℃/60％RH及40℃/75％RH条件下敞口放置一周。将不同条件下放置后的固体样品，通过XRPD测试晶型变化，HPLC测试纯度评估化学稳定性。表征结果汇总于表13中，结果显示，晶型B样品在测试条件下HPLC纯度未见明显降低，且晶型未发生改变。
表13
Figure PCTCN2022080430-appb-000022
为了进一步研究游离态无水晶型及水合物晶型间的转化关系，对无水晶型B/G及水合物晶型A进行了混悬竞争试验。首先在ACN中5℃、室温和50℃以及EtOAc中室温设置了无水晶型B和G之间的混悬竞争试验。具体步骤如下：1)配制对应温度下游离态在不同溶剂体系中的饱和溶液；2)将相应游离态晶型样品加入到0.5mL的饱和溶液中形成悬浊液；3)分别在相应的温度条件下磁力搅拌；4)搅拌1～5天后分离固体测试XRPD。结果如表14所示，在测试条件下均仅得到游离态晶型B。
因此，设置了室温稳定的无水晶型B与水合物晶型A在ACN/H 2O室温不同水活度(a w＝0/0.2/0.4/0.6/.0.8/1.0)的混悬竞争试验。结果如表14显示，在a w＝0～0.4条件下得到无水晶型B，a w＝0.6～1(纯水)中得到水合物晶型A。试验中所得固体的XRPD图谱如图27至错误！未找到引用源。所示。
表14游离态不同晶型混悬竞争试验结果
Figure PCTCN2022080430-appb-000023
由上表可知，游离态无水晶型B可在一定水活度条件下稳定存在，且水合物晶型在后续开发中可能存在脱水风险，因而无水晶型B的稳定性及后续成药性更优。
效果实施例：
一.式(I)化合物对钠离子通道1.8(NaV1.8)的阻滞活性
1.测试方法：膜片钳技术检测化合物对电压门控钠离子通道(NaV)1.1～1.8亚型电流的影响
2.给药制剂的配制和分析
2.1给药制剂储液配制方法
对照：称量合适体积的DMSO作为储液。
测试化合物：称量合适质量的式(I)化合物(实际量＝理论浓度*体积×分子量/纯度)，根据公式，计算出所需的DMSO的体积，然后换算出最终所需的DMSO的质量。之后将粉末用称量的DMSO溶解。根据最终的DMSO使用量计算出实际的储液浓度，一般地实际储液浓度与理论浓度略有差异。
2.2给药制剂工作液配制方法及浓度
NaV通道电流测试之前，将对照和测试化合物储液稀释到10mL细胞外液中作为工作液，并超声20min。
3.实验系统
3.1.细胞培养
1)稳定表达Nav1.8通道的CHO细胞系具体信息如下：SCN10A:NM_006514
2)细胞在含有10％胎牛血清以及10μg/mL Blasticidin、200μg/mL Hygromycin B及100μg/mL Zeocin的HAM’S/F-12培养基中培养，培养温度为37℃，二氧化碳浓度为5％。
3)细胞传代：除去旧培养基并用PBS洗一次，然后加入1mL 0.25％-Trypsin-EDTA溶液，37℃孵育1.5min。当细胞从皿底脱离，加入5mL 37℃预热的完全培养基。将细胞悬液用吸管轻轻吹打使聚集的细胞分离。将细胞悬液转移至无菌的离心管中，1000rpm离心5min收集细胞。扩增或维持培养，将细胞接种于6厘米细胞培养皿，每个细胞培养皿接种细胞量为2.5*10 5cells(最终体积：5mL)。
4)为维持细胞的电生理活性，细胞密度必须不能超过80％。
5)膜片钳检测，实验之前细胞用0.25％-Trypsin-EDTA分离，以每孔8*10 3细胞的密度接种到预先放好盖玻片的24孔板中(最终体积：500μL)，加入四环素，第二天进行实验检测。
3.2.电生理溶液
1)细胞外液:140mM NaCl，3.5mM KCl，2mM CaCl 2，10mM HEPES，1.25mM NaH 2PO 4，1mM MgCl 2，10mM Glucose，pH＝7.4(NaOH)。
2)细胞内液:50mM CsCl，10mM NaCl，10mM HEPES，20mM EGTA，60mM CsF，pH＝7.2(CsOH)。
4.试验方法
4.1.仪器如下表15所示
表15：仪器供应商及型号
名称 供应商 型号
放大器 HEKA(Germany) EPC10
微操纵器 Sutter Instruments(USA) MP285
电极拉制仪 Sutter Instruments(USA) P97
显微镜 Olympus(Japan) IX71
毛皮玻璃管 Sutter Instruments(USA) BF150-86-10
数据采集和分析软件 HEKA(Germany) Patchmaster&IGOR
4.2膜片钳检测
全细胞膜片钳记录Nav通道电流的电压刺激方案如下：首先将细胞的膜电位钳制在-130mV,然后以10mv的阶跃间隔，将电压阶跃至-40mV或者-20mV，持续8s。钳制电压维持在-120mV，每隔20秒重复采集数据。测量其内向电流的峰值振幅，确定其半失活电压。
细胞钳制电位设定在-120mV。钠电流的静息和半失活抑制使用双脉冲模式来测量。双脉冲模式由两个持续50ms的0mV去极化测试脉(TP1以及TP2)完成。两个去极化脉冲之间的条件电压，设定在半失活电压附近(持续8s)。在给与第二个去极化脉冲之前，将细胞膜电位钳制到-120mv，持续20ms以使得未结合化合物，且处于失活状态的通道得到恢复。以20s的间隔重复采集数据，并测量两个测试脉冲处的电流峰值。
实验数据由EPC-10放大器(HEKA)进行采集并储存于PatchMaster(HEKA)软件中(软件版本：v2x73.2)。
用微电极拉制仪(P97，Sutter Instruments)将毛细玻璃管(BF150-86-10，Sutter Instruments)拉制成记录电极。在倒置显微镜(IX71)下操纵微电极操纵仪(MP285)将记录电极接触到细胞上，给予负压抽吸， 形成GΩ封接。形成GΩ封接后进行快速电容补偿，然后继续给予负压，吸破细胞膜，形成全细胞记录模式。然后进行慢速电容的补偿并记录膜电容及串联电阻，不给予漏电补偿。
当全细胞记录的Nav通道电流稳定后开始给药，每个药物浓度作用至5分钟(或者电流至稳定)后检测下一个浓度，每一个测试化合物检测多个浓度。将铺有细胞的盖玻片置于倒置显微中的记录浴槽中，测试化合物以及不含化合物的外液利用重力灌流的方法从低浓度到高浓度依次流经记录小室从而作用于细胞，在记录中利用真空泵进行液体交换。每一个细胞在不含化合物的外液中检测到的电流作为自己的对照组。独立重复检测多个细胞。所有电生理实验在室温下进行。
4.3数据分析
首先将每一个药物浓度作用后的电流和空白对照电流标准化，然后计算每一个药物浓度对应的阻滞率。对每一个浓度计算平均数和标准误差，以上所有数值利用Microsoft Excel 2013计算获得。此外通过IGOR软件运用以下的方程计算每种化合物的半抑制浓度：阻滞率＝1/【1+(IC 50/c) h】。
用以上方程对剂量依赖效应进行非线性拟合，其中c代表药物浓度，IC 50为半抑制浓度，h代表希尔系数。曲线拟合以及IC 50的计算利用IGOR软件完成(软件版本：6.0.1.0)。
在本实施例中测定了式(I)化合物对NaVl.8的半数阻滞活性(IC 50)如表16所示。其中：
表16：式(I)化合物对NaV1.8的阻滞活性IC 50值(nM)
编号 NaV1.8IC 50(nM)
式(I)化合物 6.2
式(I)化合物对NaV1.8通道活性具有明显的阻滞效果。
二.式(I)化合物的药代动力学实验结果
本实验例对大鼠通过单次静脉注射或灌胃口服给药进行了体内药代动力学评价。
实验方法和条件：雄性Sprague Dawley大鼠，动物均禁食过夜，分别单次给予待测化合物1mg/Kg(静脉注射，溶剂5％DMSO/10％Solutol/85％Saline)和10mg/Kg(灌胃给药)，给药后5,15,30min,1,2,4,6,8和24hr经颌下静脉采血，每个样品采集约0.20mL，肝素钠抗凝，采集后放置冰上，并于1小时之内离心分离血浆待测。血浆中血药浓度的检测采用液相串联质谱法(LC/MS/MS)，测得浓度用以计算药代动力学参数。结果如下表17和表18所示。
表17：静脉给药(1mg/kg)的药代动力学
Figure PCTCN2022080430-appb-000024
表18：灌胃注射给药(10mg/kg)的药代动力学
Figure PCTCN2022080430-appb-000025
式(I)化合物在大鼠内药代吸收良好，具有药代动力学优势。

Claims (32)

  1. 式(Ⅰ)所示化合物晶型A，
    Figure PCTCN2022080430-appb-100001
    其特征在于，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：16.63±0.2°、18.04±0.2°、20.59±0.2°、23.38±0.2°、23.96±0.2°、29.19±0.2°。
  2. 根据权利要求1所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.46±0.2°、13.11±0.2°、16.63±0.2°、18.04±0.2°、20.59±0.2°、23.38±0.2°、23.96±0.2°、27.66±0.2°、29.19±0.2°、29.82±0.2°。
  3. 根据权利要求2所述的晶型A，其特征在于，所述晶型A的X射线粉末衍射图谱具有基本上如图1所示的X射线粉末衍射图谱。
  4. 根据权利要求3所述的晶型A，其特征在于，所述晶型A为水合物，所述水合物的水分含量为3.0wt％-5.0wt％。
  5. 式(Ⅰ)所示化合物晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.28±0.2°、14.47±0.2°、18.86±0.2°、23.09±0.2°、25.50±0.2°、27.58±0.2°。
  6. 根据权利要求5所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：12.28±0.2°、14.47±0.2°、16.81±0.2°、18.86±0.2°、19.78±0.2°、23.09±0.2°、25.09±0.2°、25.50±0.2°、27.58±0.2°、28.19±0.2°。
  7. 根据权利要求6所述的晶型B，其特征在于，所述晶型B的X射线粉末衍射图谱具有基本上如图4所示的X射线粉末衍射图谱。
  8. 式(Ⅰ)所示化合物晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.22±0.2°、17.33±0.2°、19.55±0.2°、20.27±0.2°、21.99±0.2°、24.90±0.2°。
  9. 根据权利要求8所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：8.22±0.2°、13.80±0.2°、17.33±0.2°、19.55±0.2°、20.27±0.2°、21.99±0.2°、23.00±0.2°、23.95±0.2°、24.90±0.2°、26.10±0.2°。
  10. 根据权利要求9所述的晶型C，其特征在于，所述晶型C的X射线粉末衍射图谱具有基本上如图7所示的X射线粉末衍射图谱。
  11. 根据权利要求10所述的晶型C，其特征在于，所述晶型C为1,4-二氧六环溶剂合物，所述1,4-二氧六环的含量为3wt％-17wt％。
  12. 式(Ⅰ)所示化合物晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.2°、16.81±0.2°、20.40±0.2°、21.50±0.2°、22.23±0.2°、26.08±0.2°。
  13. 根据权利要求12所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.63±0.2°、11.02±0.2°、16.81±0.2°、19.58±0.2°、20.40±0.2°、21.50±0.2°、22.23±0.2°、24.17±0.2°、 26.08±0.2°、28.44±0.2°。
  14. 根据权利要求13所述的晶型D，其特征在于，所述晶型D的X射线粉末衍射图谱具有基本上如图10所示的X射线粉末衍射图谱。
  15. 根据权利要求14所述的晶型D，其特征在于，所述晶型D为甲基乙基酮溶剂合物，所述甲基乙基酮的含量为4wt％-14wt％。
  16. 式(Ⅰ)所示化合物晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.75±0.2°、13.71±0.2°、18.29±0.2°、20.18±0.2°、22.92±0.2°、23.96±0.2°。
  17. 根据权利要求16所述的晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.75±0.2°、13.71±0.2°、16.65±0.2°、17.17±0.2°、18.29±0.2°、20.18±0.2°、22.92±0.2°、23.96±0.2°、24.76±0.2°、29.18±0.2°。
  18. 根据权利要求17所述的晶型E，其特征在于，所述晶型E的X射线粉末衍射图谱具有基本上如图13所示的X射线粉末衍射图谱。
  19. 根据权利要求18所述的晶型E，其特征在于，所述晶型E为四氢呋喃溶剂合物，所述四氢呋喃的含量2wt％-14wt％。
  20. 式(Ⅰ)所示化合物晶型F，其特征在于，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：17.24±0.2°、20.28±0.2°、23.03±0.2°、23.96±0.2°、24.89±0.2°、28.96±0.2°。
  21. 根据权利要求20所述的晶型F，其特征在于，所述晶型F的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：5.78±0.2°、14.31±0.2°、17.24±0.2°、20.28±0.2°、22.06±0.2°、23.03±0.2°、23.96±0.2°、24.89±0.2°、26.27±0.2°、28.96±0.2°。
  22. 根据权利要求21所述的晶型F，其特征在于，所述晶型F的X射线粉末衍射图谱具有基本上如图16所示的X射线粉末衍射图谱。
  23. 根据权利要求22所述的晶型F，其特征在于，所述晶型F为氯仿溶剂合物，所述氯仿的含量5wt％-21wt％。
  24. 式(Ⅰ)所示化合物晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：15.53±0.2°、17.08±0.2°、21.41±0.2°、23.23±0.2°、26.00±0.2°、28.49±0.2°。
  25. 根据权利要求24所述的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱在下列2θ角处具有特征衍射峰：10.54±0.2°、13.02±0.2°、15.53±0.2°、17.08±0.2°、21.41±0.2°、23.23±0.2°、25.10±0.2°、26.00±0.2°、27.17±0.2°、28.49±0.2°。
  26. 根据权利要求25所述的晶型G，其特征在于，所述晶型G的X射线粉末衍射图谱具有基本上如图19所示的X射线粉末衍射图谱。
  27. 一种药物组合物，其特征在于，包含权利要求1-4任一项所述的晶型A或权利要求5-7任一项所述的晶型B或权利要求8-11任一项所述的晶型C或权利要求12-15任一项所述的晶型D或权利要求16-19任一项所述的晶型E或权利要求20-23任一项所述的晶型F或权利要求24-26任一项所述的晶型G。
  28. 根据权利要求27所述的药物组合物，其中，所述的药物组合物进一步包含药学上可接受的载体，赋形剂，稀释剂，辅剂，媒介物或它们的组合。
  29. 权利要求1-4任一项所述的晶型A或权利要求5-7任一项所述的晶型B或权利要求8-11任一项所述的晶型C或权利要求12-15任一项所述的晶型D或权利要求16-19任一项所述的晶型E或权利要求20-23任 一项所述的晶型F或权利要求24-26任一项所述的晶型G或权利要求27或28所述的药物组合物在制备用于抑制个体的电压门控型钠通道的药物中的用途。
  30. 根据权利要求29所述的用途，其中，所述电压门控型钠通道是Navl.8。
  31. 权利要求1-4任一项所述的晶型A或权利要求5-7任一项所述的晶型B或权利要求8-11任一项所述的晶型C或权利要求12-15任一项所述的晶型D或权利要求16-19任一项所述的晶型E或权利要求20-23任一项所述的晶型F或权利要求24-26任一项所述的晶型G或权利要求27或28所述的药物组合物在制备用于治疗和/或预防个体的疼痛、咳嗽或减轻其严重性的药物中的用途。
  32. 根据权利要求31所述的用途，其中，所述疼痛选自慢性疼痛、肠痛、神经性疼痛、肌肉骨骼痛、急性疼痛、炎性疼痛、癌症疼痛、原发性疼痛、手术后疼痛、内脏痛、多发性硬化症、夏-马-图三氏综合症、失禁和心律失常。
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