Pyridine n-oxide compound crystal form and uses thereof

Abstract

A crystalline form of a pyridine N-oxide compound and uses thereof, in particular, a crystalline form of a compound represented by formula (I), pharmaceutical compositions and uses thereof.

Description

[0001] The present application claims priority to:

[0002] Application No.: CN202110265997.3, filing date: March 11, 2021;

[0003] Application No.: CN202210195905.3, filing date: March 01, 2022. TECHNICAL FIELD

[0004] The present application relates to a crystalline form of a compound represented by Formula (I), a pharmaceutical composition, and use thereof as a voltage-gated sodium channels (NaV) blocker. BACKGROUND

[0005] Pain is one of the most common symptoms in clinical practice, and is the fifth vital sign after respiration, pulse, blood pressure and body temperature, which seriously affects the quality of life of patients. According to statistics, the global analgesic market was about $36 billion in 2018, and is expected to reach $56 billion in 2023. Among them, acute and severe pain mainly depends on opioid drugs, accounting for about two-thirds of the analgesic market share, and will grow steadily at a CAGR of 2.5% in the future. The number of patients with chronic pain, mainly neuropathic pain and arthritic pain, is increasing year by year, and the market is expected to show a CAGR of about 18%, which is the main driving force for the sustained growth of the global pain market in the next decade.

[0006] 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 harmless stimuli. Common causes of neuropathic pain include diabetes, shingles, spinal cord injury, stroke, multiple sclerosis, cancer, HIV infection, lumbar or cervical nerve root neuropathy, and postoperative nerve damage, etc. Osteoarthritis, also known as degenerative arthritis, is caused by various factors, leading to cartilage degeneration in the bone joint, which can cause the bone surface of the joint to be uneven and possibly form bone spurs. The main clinical manifestations are joint pain and joint stiffness. Long-term pain not only affects the patient's sleep, work and life ability, but also increases the incidence of emotional disorders such as depression or anxiety, thus causing heavy economic burden to the patient's family and society.

[0007] According to the NeuPSIG (Neuropathic Pain Special Interest Group) of the International Association for the Study of Pain, the prevalence of neuropathic pain is about 3.3%-8.2%. It is estimated that there are at least 50 million patients in China. In 2017, there were 30.5 million patients with neuropathic pain in the United States, Japan and the European Union (France, Germany, Italy, Spain and the United Kingdom), and the number is increasing year by year. Neuropathic pain is one of the most difficult diseases to treat, and most current treatment options still cannot achieve satisfactory results. It is reported that only 14.9% of outpatients can be treated by drugs to relieve pain in time, that is, about 85% of patients with pain have not received timely and effective drug treatment, so some patients have to seek surgical intervention. The first-line drugs for the treatment of neuropathic pain in clinical practice are mainly calcium channel modulators (such as pregabalin, gabapentin), tricyclic antidepressants and serotonin and norepinephrine reuptake inhibitors (such as duloxetine, venlafaxine, anticonvulsant and antidepressant drugs). 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, and the main side effects include gastrointestinal reactions, nausea, drowsiness, dry mouth, sweating and dizziness, which lead to a drug discontinuation rate of 15%-20%. Antiepileptic drugs gabapentin and pregabalin are the main drugs for the treatment of neuropathic pain, which can cause dizziness, drowsiness, peripheral edema, weight gain, weakness, headache and dry mouth and other adverse reactions. In recent years, it has also been found that pregabalin can cause suicidal ideation and self-injurious behavior related to drug use in a small number of patients.

[0008] The number of patients with osteoarthritis is huge, and it is estimated that there are more than 400 million patients worldwide, and more than 100 million patients in China. There is no effective treatment for osteoarthritis pain. Physical therapy, drug therapy and surgical treatment are available in clinical practice. Physical therapy includes heat therapy, hydrotherapy, ultrasound and massage, and in addition, auxiliary devices are used to reduce joint pressure and relieve pain, but the effect is limited, and most of them still need to rely on drug treatment. These drugs have varying degrees of side effects. Non-steroidal anti-inflammatory drugs are only suitable for mild to moderate pain, and have gastrointestinal side effects and cardiovascular risks. Opioid analgesics are used for severe pain, but have obvious side effects such as nausea, 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 drugs targeting new targets and new mechanisms that are safe and effective for analgesia to meet the unmet clinical needs.

[0009] Recent research results gradually reveal that sodium channel subtype 1.8 (NaV1.8) plays an important role in the generation and transmission of pain. NaV1.8 is a voltage-gated sodium channel, mainly expressed in afferent neurons including sensory neurons, which plays an important role in maintaining the excitability of nociceptive sensory neurons, the firing and persistence of action potentials, and the regulation of pain sensitivity by controlling the entry and exit of sodium ions into cells. Patients with NaV1.8 activating mutations develop paroxysmal pain caused by small fiber neuropathy (mainly responsible for pain transmission Aδ fiber and damaged C-type fiber without medulla). Chronic inflammation and diabetes can cause increased expression or altered properties of NaV1.8, thereby sensitizing nociceptive neurons and causing various pains. NaV1.8 knockout mice are insensitive to pain.

[0010] With the determination of the role of Nav1.8 in chronic pain, research on drugs based on this target has also become increasingly popular. Currently, there is a small molecule blocker in the international clinical phase 2, and other small molecule blockers and antibodies are in preclinical development. There is no other new drug development targeting this target in China. The small molecule NaV1.8 blocker VX-150 of the American Vertex company is at the forefront of research and development. It has been used in patients with osteoarthritis, acute pain and pain caused by small fiber neuropathy in the second phase of clinical trials, and all three studies have obtained positive results, indicating that inhibiting the activity of NaV1.8 can relieve various pains including neuropathic pain. VX-150 has obtained the breakthrough therapy designation of the US FDA for the treatment of moderate to severe pain, which once again proves that NaV1.8 is a very potential target for analgesia. In addition, the mechanism of action of NaV1.8 blockers and phase II clinical trials show that they are suitable for a wide range of applications, including neuropathic pain, osteoarthritis pain and acute injury pain; and the safety is relatively high, there is no addiction, and there are no gastrointestinal side effects and cardiovascular side effects of non-steroidal anti-inflammatory drugs; it can be used with other analgesics to enhance efficacy and reduce side effects.

[0011] Recent studies have shown that sodium channel subtype 1.8 (NaV1.8) has a certain regulatory effect on cough, and NaV1.8 blockers may be potential drugs for treating cough.

[0012] The application number PCT / CN2020 / 114700 (application date September 11, 2020) provides a NaV1.8 blocker, the structure of which is as follows: SUMMARY

[0013] In one aspect of the present application, the present application provides a crystalline form A of a compound represented by formula (I), which has an X-ray powder diffraction pattern with characteristic peaks at the following 2θ 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°.

[0014]

[0015] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form A described above has characteristic peaks at the following 2θ 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°.

[0016] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form A described above has an X-ray powder diffraction pattern substantially as shown in Figure 1 .

[0017] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form A described above has the following Table 1.

[0018] Table 1

[0019]

[0020]

[0021] In some embodiments of the present application, when the crystalline form A described above is subjected to thermogravimetric analysis (TGA), the crystalline form A has a weight loss of 3.9% when heated to 150°C, with an error tolerance of ±0.2%.

[0022] In some embodiments of the present application, the crystalline form A described above has a thermogravimetric analysis substantially as shown in Figure 2 .

[0023] In some embodiments of the present application, the crystalline form A described above has an endothermic peak at 101.1°C±3°C in differential scanning calorimetry (DSC).

[0024] In some embodiments of the present application, the crystalline form A described above has a DSC differential scanning calorimetry curve substantially as shown in Figure 3 .

[0025] In some embodiments of the present application, the crystalline form A described above is a hydrate, and the water content of the hydrate is 2.0wt%-6.0wt%, with an error tolerance of ±0.2%.

[0026] In some embodiments of the present application, the crystalline form A is a hydrate, and the water content of the hydrate is 3.0 wt% to 5.0 wt%, with an error tolerance of ±0.2%.

[0027] In some embodiments of the present application, the crystalline form A is a hydrate, and the water content of the hydrate is 2.1 wt%, 2.3 wt%, 2.5 wt%, 2.8 wt%, 3.1 wt%, 3.2 wt%, 3.5 wt%, 3.8 wt%, 4.1 wt%, 4.2 wt%, 4.5 wt%, 4.8 wt%, 5.1 wt%, 5.2 wt%, 5.5 wt%, 5.8 wt% or 6.1 wt%, with an error tolerance of ±0.02%.

[0028] In one aspect of the present application, the present application provides a crystalline form B of the compound represented by formula (I), which has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 12.28±0.2°, 14.47±0.2°, 18.86±0.2°, 23.09±0.2°, 25.50±0.2°, 27.58±0.2°.

[0029] In some embodiments of the present application, the crystalline form B has characteristic diffraction peaks at the following 2θ angles in its X-ray powder diffraction pattern: 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°.

[0030] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form B has substantially the X-ray powder diffraction pattern as shown in Figure 2. Figure 4

[0031] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline form B has substantially the X-ray powder diffraction pattern as shown in Figure 2.

[0032] Table 2

[0033]

[0034]

[0035]

[0036] In some embodiments of the present application, when the crystalline form B is subjected to thermogravimetric analysis (TGA), the crystalline form B has a weight loss of 1.2% when heated to 150°C, with an error tolerance of ±0.1%.

[0037] In some embodiments of the present application, the crystalline form B has substantially the X-ray powder diffraction pattern as shown in Figure 2.​Figure 5 Thermogravimetric analysis.

[0038] In some embodiments of the application, the crystalline Form B has a differential scanning calorimetry (DSC) with an endothermic peak at 148.4°C ± 3°C.

[0039] In some embodiments of the application, the crystalline Form B has a differential scanning calorimetry (DSC) with an endothermic peak at 148.4°C ± 3°C. Figure 6

[0040] In some embodiments of the application, the crystalline Form B is an anhydrous crystalline form.

[0041] In one aspect of the application, the present application provides a crystalline Form C of the compound of Formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°.

[0042] In some embodiments of the application, the crystalline Form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°.

[0043] In some embodiments of the application, the crystalline Form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°. Figure 7

[0044] In some embodiments of the application, the crystalline Form C has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°.

[0045] Table 3

[0046]

[0047]

[0048] In some embodiments of the application, when the crystalline Form C is subjected to thermogravimetric analysis (TGA), the crystalline Form C has a weight loss of 1.2% upon heating to 80°C, a stepwise weight loss of 7.0% upon heating from 80°C to 150°C, with an error tolerance of ± 0.1%.

[0049] In some embodiments of the application, the crystalline Form C has a thermogravimetric analysis with a weight loss of 1.2% upon heating to 80°C, a stepwise weight loss of 7.0% upon heating from 80°C to 150°C, with an error tolerance of ± 0.1%. Figure 8

[0050] ​​​In some embodiments of the application, the crystalline Form C has differential scanning calorimetry (DSC) profile with overlapping endothermic peaks at 106.6°C ± 3°C and 111.3°C ± 3°C.

[0051] In some embodiments of the application, the crystalline Form C has differential scanning calorimetry (DSC) profile with overlapping endothermic peaks at 106.6°C ± 3°C and 111.3°C ± 3°C. Figure 9

[0052] In some embodiments of the application, the crystalline Form C is a 1,4-dioxane solvate having a content of 1,4-dioxane of 3 wt% to 17 wt% with a tolerance of ± 0.2%.

[0053] In some embodiments of the application, the crystalline Form C is a 1,4-dioxane solvate having a content of 1,4-dioxane of 6 wt% to 16 wt% with a tolerance of ± 0.2%.

[0054] In some embodiments of the application, the crystalline Form C is a 1,4-dioxane solvate having a content of 1,4-dioxane of 3.1 wt%, 3.3 wt%, 3.5 wt%, 3.8 wt%, 4.1 wt%, 4.3 wt%, 4.5 wt%, 4.8 wt%, 5.1 wt%, 5.3 wt%, 5.5 wt%, 5.8 wt%, 6.1 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7.1 wt%, 7.3 wt%, 7.5 wt%, 7.8 wt%, 8.1 wt%, 8.3 wt%, 8.5 wt%, 8.8 wt%, 9.1 wt%, 9.3 wt%, 9.5 wt%, 9.7 wt%, 10.1 wt%, 10.3 wt%, 10.5 wt%, 10.8 wt%, 11.1 wt%, 11.3 wt%, 11.5 wt%, 11.8 wt%, 12.1 wt%, 12.3 wt%, 12.5 wt%, 12.8 wt%, 13.1 wt%, 13.3 wt%, 13.5 wt%, 13.8 wt%, 14.1 wt%, 14.3 wt%, 14.5 wt%, 14.8 wt%, 15.1 wt%, 15.3 wt%, 15.5 wt%, 15.8 wt%, 16.1 wt%, 16.3 wt%, 16.5 wt%, 16.8 wt%, or 17.1 wt% with a tolerance of ± 0.02%.

[0055] In one aspect of the application, the present application provides a crystalline Form D of the compound of Formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°.

[0056] ​In some embodiments of the application, the X-ray powder diffraction pattern of Form D has characteristic peaks at the following 2-theta 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°.

[0057] In some embodiments of the application, the X-ray powder diffraction pattern of Form D has substantially the X-ray powder diffraction pattern shown in Figure 2. Figure 10

[0058] In some embodiments of the application, the X-ray powder diffraction pattern of Form D has substantially the X-ray powder diffraction pattern shown in Figure 2.

[0059]

[0060]

[0061] In some embodiments of the application, when Form D is subjected to thermogravimetric analysis (TGA), Form D loses 0.9% of its weight when heated to 80°C, and loses 7.0% of its weight when heated from 80°C to 150°C, with a tolerance of ± 0.1%.

[0062] In some embodiments of the application, Form D has substantially the thermogravimetric analysis shown in Figure 3. Figure 11

[0063] In some embodiments of the application, Form D has two endothermic peaks at 97.8°C ± 3°C and 149.2°C ± 3°C when subjected to differential scanning calorimetry (DSC).

[0064] In some embodiments of the application, Form D has substantially the DSC differential scanning calorimetry curve shown in Figure 4. Figure 12

[0065] In some embodiments of the application, Form D is a methyl ethyl ketone solvate, and the content of methyl ethyl ketone is 4 wt% to 14 wt%, with a tolerance of ± 0.2%.

[0066] In some embodiments of the application, Form D is a methyl ethyl ketone solvate, and the content of methyl ethyl ketone is 6 wt% to 14 wt%, with a tolerance of ± 0.2%.

[0067] ​​​In some embodiments of the application, the crystalline form D described above is a 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%, 5.3 wt%, 5.5 wt%, 5.8 wt%, 6.1 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7.1 wt%, 7.3 wt%, 7.4 wt%, 7.5 wt%, 7.8 wt%, 8.1 wt%, 8.3 wt%, 8.5 wt%, 8.8 wt%, 9.1 wt%, 9.3 wt%, 9.5 wt%, 9.8 wt%, 10.1 wt%, 10.3 wt%, 10.5 wt%, 10.7 wt%, 10.9 wt%, 11.1 wt%, 11.3 wt%, 11.5 wt%, 11.8 wt%, 12.1 wt%, 12.3 wt%, 12.5 wt%, 12.8 wt%, 13.1 wt%, 13.3 wt%, 13.5 wt%, 13.6 wt%, 13.8 wt%, or 14.1 wt%, with an error tolerance of ±0.02%.

[0068] In one aspect of the application, the application provides a crystalline form E of the compound of formula (I), which has an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2θ 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°.

[0069] In some embodiments of the application, the X-ray powder diffraction pattern of the crystalline form E described above has characteristic diffraction peaks at the following 2θ 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°.

[0070] In some embodiments of the application, the X-ray powder diffraction pattern of the crystalline form E described above has an X-ray powder diffraction pattern substantially as shown in Figure 5. Figure 13

[0071] In some embodiments of the application, the X-ray powder diffraction pattern of the crystalline form E described above has an X-ray powder diffraction pattern substantially as shown in Figure 5.

[0072] Table 5

[0073]

[0074]

[0075] ​In some embodiments of the application, Form E has a weight loss of 1.9% when heated from 80 °C, a weight loss of 4.9% when heated from 80 °C to 150 °C, with a tolerance of ±0.1%.

[0076] In some embodiments of the application, Form E has a thermogravimetric analysis substantially as shown in Figure 14

[0077] In some embodiments of the application, Form E has a differential scanning calorimetry analysis (DSC) with a broad endothermic peak at 94.1 °C ± 3 °C.

[0078] In some embodiments of the application, Form E has a DSC differential scanning calorimetry curve substantially as shown in Figure 15

[0079] In some embodiments of the application, Form E is a tetrahydrofuran solvate having a content of tetrahydrofuran of 2 wt% to 14 wt%, with a tolerance of ±0.2%.

[0080] In some embodiments of the application, Form E is a tetrahydrofuran solvate having a content of tetrahydrofuran of 2.1 wt%, 2.3 wt%, 2.5 wt%, 2.8 wt%, 3.1 wt%, 3.3 wt%, 3.5 wt%, 3.8 wt%, 4.1 wt%, 4.3 wt%, 4.5 wt%, 4.8 wt%, 5.1 wt%, 5.3 wt%, 5.5 wt%, 5.8 wt%, 6.1 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7.1 wt%, 7.3 wt%, 7.4 wt%, 7.5 wt%, 7.8 wt%, 8.1 wt%, 8.3 wt%, 8.5 wt%, 8.8 wt%, 9.1 wt%, 9.3 wt%, 9.5 wt%, 9.8 wt%, 10.1 wt%, 10.3 wt%, 10.5 wt%, 10.7 wt%, 10.9 wt%, 11.1 wt%, 11.3 wt%, 11.5 wt%, 11.8 wt%, 12.1 wt%, 12.3 wt%, 12.5 wt%, 12.8 wt%, 13.1 wt%, 13.3 wt%, 13.5 wt%, 13.6 wt%, 13.8 wt%, or 14.1 wt%, with a tolerance of ±0.02%. In one aspect of the application, the application provides Form F of the compound of formula (I) having an X-ray powder diffraction pattern with characteristic diffraction peaks at the following 2Θ 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°.

[0081] ​​In some embodiments of the application, the X-ray powder diffraction pattern of Form F has characteristic peaks at the following 2-theta 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°.

[0082] In some embodiments of the application, the X-ray powder diffraction pattern of Form F has substantially the X-ray powder diffraction pattern shown in Figure 2. Figure 16

[0083] In some embodiments of the application, the X-ray powder diffraction pattern of Form F has substantially the X-ray powder diffraction pattern shown in Figure 2.

[0084] Table 6

[0085]

[0086]

[0087] In some embodiments of the application, when Form F is subjected to thermogravimetric analysis (TGA), Form F loses 11.5% of its weight when heated to 150°C, with an error tolerance of ± 0.1%.

[0088] In some embodiments of the application, Form F has substantially the thermogravimetric analysis shown in Figure 4. Figure 17

[0089] In some embodiments of the application, Form F has an endothermic peak at 105.2°C ± 3°C when subjected to differential scanning calorimetry (DSC).

[0090] In some embodiments of the application, Form F has substantially the DSC differential scanning calorimetry curve shown in Figure 6. Figure 18

[0091] In some embodiments of the application, Form F is a chloroform solvate, and the amount of chloroform present is 5 wt% to 21 wt%, with an error tolerance of ± 0.2%.

[0092] In some embodiments of the application, Form F is a chloroform solvate, and the amount of chloroform present is 11 wt% to 21 wt%, with an error tolerance of ± 0.2%.

[0093] ​​​In some embodiments of the application, the Form F is a chloroform solvate, and the chloroform content is 5.1 wt%, 5.3 wt%, 5.5 wt%, 5.8 wt%, 6.1 wt%, 6.3 wt%, 6.5 wt%, 6.8 wt%, 7.1 wt%, 7.3 wt%, 7.4 wt%, 7.5 wt%, 7.8 wt%, 8.1 wt%, 8.3 wt%, 8.5 wt%, 8.8 wt%, 9.1 wt%, 9.3 wt%, 9.5 wt%, 9.8 wt%, 10.1 wt%, 10.3 wt%, 10.5 wt%, 10.7 wt%, 10.9 wt%, 11.1 wt%, 11.3 wt%, 11.5 wt%, 11.8 wt%, 12.1 wt%, 12.3 wt%, 12.5 wt%, 12.8 wt%, 13.1 wt%, 13.3 wt%, 13.5 wt%, 13.6 wt%, 13.8 wt%, 14.1 wt%, 14.3 wt%, 14.5 wt%, 14.8 wt%, 15.1 wt%, 15.3 wt%, 15.5 wt%, 15.8 wt%, 16.1 wt%, 16.3 wt%, 16.5 wt%, 16.8 wt%, 17.1 wt%, 17.3 wt%, 17.5 wt%, 17.8 wt%, 18.1 wt%, 18.3 wt%, 18.5 wt%, 18.8 wt%, 19.1 wt%, 19.3 wt%, 19.5 wt%, 19.8 wt%, 20.1 wt%, 20.3 wt%, 20.5 wt%, 20.6 wt%, 20.7 wt%, 20.8 wt%, or 21.1 wt%, with an error tolerance of ±0.02%.

[0094] In one aspect of the application, the present application provides a compound of Formula (I) in crystalline Form G, having an X-ray powder diffraction pattern with characteristic peaks at the following 2θ 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°

[0095] In some embodiments of the application, the Form G has an X-ray powder diffraction pattern with characteristic peaks at the following 2θ 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°.

[0096] In some embodiments of the application, the Form G has an X-ray powder diffraction pattern substantially as shown in the X-ray powder diffraction pattern Figure 19 ​

[0097] In some embodiments of the present application, the X-ray powder diffraction pattern of the crystalline Form G described above is as shown in Table 7 below.

[0098] Table 7

[0099]

[0100] In some embodiments of the present application, when the crystalline Form G described above is subjected to thermogravimetric analysis (TGA), the crystalline Form G has a weight loss of 2.3% when heated to 160°C, with an error tolerance of ±0.1%.

[0101] In some embodiments of the present application, the crystalline Form G described above has a thermogravimetric analysis substantially as shown in Figure 2. Figure 20

[0102] In some embodiments of the present application, the crystalline Form G described above has a differential scanning calorimetry (DSC) endothermic peak at 149.0°C ± 3°C.

[0103] In some embodiments of the present application, the crystalline Form G described above has a DSC differential scanning calorimetry curve substantially as shown in Figure 3. Figure 21

[0104] In some embodiments of the present application, the crystalline Form G described above is an anhydrous crystalline form.

[0105] In yet another aspect of the present application, the present application also discloses a pharmaceutical composition. In some embodiments of the present application, the pharmaceutical composition described above comprises the crystalline Form A to G described above.

[0106] In some embodiments of the present application, the pharmaceutical composition described above further comprises a pharmaceutically acceptable carrier, excipient, diluent, adjuvant, vehicle or a combination thereof.

[0107] In yet another aspect of the present application, the present application also discloses the use of the crystalline Form A to G described above or the pharmaceutical composition described above in the manufacture of a medicament for inhibiting voltage-gated sodium channels in a subject.

[0108] In some embodiments of the present application, the voltage-gated sodium channels described above is Navl.8.

[0109] In yet another aspect of the present application, the present application also discloses the use of the crystalline Form A to G described above in the manufacture of a medicament for treating and / or preventing pain, cough or alleviating the severity of pain, cough in a subject.

[0110] In some embodiments of the present application, the pain described above is selected from the group consisting of chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Tooth syndrome, incontinence and arrhythmia. Figure 3 ​​​

[0111] In some embodiments of the application, the intestinal pain is selected from the group consisting of inflammatory bowel disease pain, Crohn's disease pain, and interstitial cystitis pain.

[0112] In some embodiments of the application, the neuropathic pain is selected from the group consisting of post-herpetic neuralgia, diabetic neuropathy, painful HIV-associated sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom pain, painful neuromas, traumatic neuromas, Morton's neuroma, entrapment injuries, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug therapy-induced neuropathic pain, cancer chemotherapy-induced neuropathic pain, antiretroviral therapy-induced neuropathic pain, post-spinal cord injury pain, idiopathic small-fiber neuropathy, idiopathic sensory neuropathy, and trigeminal autonomic cephalalgias.

[0113] In some embodiments of the application, the musculoskeletal pain is selected from the group consisting of osteoarthritic pain, back pain, cold pain, burn pain, and dental pain.

[0114] In some embodiments of the application, the inflammatory pain is selected from the group consisting of rheumatoid arthritis pain and vulvodynia.

[0115] In some embodiments of the application, the primary pain is selected from the group consisting of fibromyalgia.

[0116] In yet another aspect of the application, the present application also provides a method of treating or reducing pain in a subject.

[0117] In some embodiments of the application, the method comprises administering to the subject a therapeutically effective amount of the crystalline Form A-G described above or the pharmaceutical composition described above. In some embodiments of the application, the pain in the subject is as defined in the present application.

[0118] In yet another aspect of the application, the present application also provides a method of inhibiting voltage-gated sodium channels in a subject.

[0119] In some embodiments of the application, the method comprises administering to the subject a therapeutically effective amount of the crystalline Form A-G described above or the pharmaceutical composition described above. In some embodiments of the application, the voltage-gated sodium channel is Navl.8.

[0120] Definitions and Descriptions

[0121] Unless otherwise indicated, all technical and scientific terms used herein have the same meaning as those commonly understood by one of ordinary skill in the art to which the application pertains. All patents and publications referred to in this application are incorporated herein by reference in their entirety. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present application, the preferred methods, devices, and materials are described.

[0122] "Crystal form" or "crystalline form" refers to a solid having a highly regular chemical structure, including, but not limited to, single component or multi-component crystals, and / or polymorphs, solvates, hydrates, clathrates, co-crystals, salts, solvates of salts, hydrates of salts of a compound. Crystalline forms of a substance 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 in the presence of additives such as co-crystallizing counter-molecules, desolvation, dehydration, rapid evaporation, rapid cooling, slow cooling, vapor diffusion, sublimation, reactive crystallization, anti-solvent addition, milling, and solvent-drop grinding, and the like.

[0123] "Amorphous" or "amorphous form" refers to a substance in which the particles (molecules, atoms, ions) are arranged in three-dimensional space without periodicity, characterized by a diffuse, peakless X-ray powder diffraction pattern. Amorphous is a special physical form of a solid substance, whose locally ordered structural features suggest a close relationship to crystalline materials. Amorphous forms of a substance can be obtained by a number of methods known in the art. Such methods include, but are not limited to, quenching, anti-solvent flocculation, ball milling, spray drying, freeze-drying, wet granulation, and solid dispersion techniques, and the like.

[0124] "Solvent" refers to a substance (typically a liquid) that is capable of completely or partially dissolving another substance (typically a solid). Solvents useful in the practice of the present application 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, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, l-methyl-2-pyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, mixtures thereof, and the like.

[0125] "Anti-solvent" refers to a fluid that promotes precipitation of a product (or a precursor to a product) from a solvent. An anti-solvent can include a cold gas, or a fluid that promotes precipitation through a chemical reaction, or a fluid that decreases the solubility of a product in a solvent; it can be the same liquid as the solvent but at a different temperature, or it can be a different liquid from the solvent.

[0126] "Solvate" refers to a crystal having a solvent on the surface, or in the lattice, or both, wherein the solvent can be water, acetic acid, acetone, acetonitrile, benzene, chloroform, carbon tetrachloride, dichloromethane, dimethyl sulfoxide, 1,4-dioxane, ethanol, ethyl acetate, butanol, t-butanol, N,N-dimethylacetamide, N,N-dimethylformamide, formamide, formic acid, heptane, hexane, isopropanol, methanol, methyl ethyl ketone, methylpyrrolidinone, mesitylene, nitromethane, polyethylene glycol, propanol, 2-propanone, pyridine, tetrahydrofuran, toluene, xylene, and mixtures thereof, and the like. One particular example of a solvate is a hydrate, wherein the solvent on the surface, or in the lattice, or both, is water. A hydrate can or can not have other solvents in addition to water on the surface, or in the lattice, or both.

[0127] Crystal forms or amorphous can be identified by a variety of 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, solubility calorimetry, scanning electron microscopy (SEM), quantitative analysis, solubility and dissolution rate, and the like.

[0128] X-ray powder diffraction (XRPD) can detect information of crystal form change, crystallinity, crystal state, etc., and is a common means for identifying crystal forms. The peak position of XRPD pattern mainly depends on the structure of crystal form, and is relatively insensitive to experimental details, while the relative peak height depends on many factors related to sample preparation and instrument geometry. Therefore, in some embodiments, the crystal forms of the present application are characterized by XRPD patterns having certain peak positions, which are substantially as shown in the XRPD patterns provided in the drawings of the present application. Meanwhile, the measurement of 2Θ of XRPD pattern can have experimental errors, and the measurement of 2Θ of XRPD pattern can be slightly different between different instruments and different samples, so the numerical value of 2Θ cannot be considered as absolute. According to the condition of the instrument used in the experiment of the present application, there is an error tolerance of ±0.2° for the diffraction peak.

[0129] Differential scanning calorimetry (DSC) is a technique that measures the energy difference between a sample and an inert reference (commonly a-Al203) as a function of temperature under programmed heating or cooling. The height of the melting peak in a DSC curve depends on many factors related to sample preparation and instrument geometry, while the position of the peak is relatively insensitive to experimental details. Thus, in some embodiments, the crystalline forms described herein are characterized by DSC patterns having characteristic peak positions, as substantially shown in the DSC patterns provided in the figures herein. At the same time, DSC patterns can vary experimentally, and peak positions and peak values can vary slightly between different instruments and different samples, and thus the values of the peak positions or peak values of the DSC endothermic peaks described herein are not to be considered absolute. Depending on the instrument conditions used in the experiments described herein, there is a tolerance of ± 3 °C for the melting peak.

[0130] The glass transition refers to the transition between the high-elastic state and the glassy state of an amorphous substance, and is an inherent property of the substance; the transition temperature corresponding to the glass transition is the glass transition temperature (Tg), which is an important physical property of the amorphous substance. The glass transition is a phenomenon related to molecular motion, and thus the glass transition temperature (Tg) mainly depends on the structure of the substance and is relatively insensitive to experimental details. In some embodiments, the amorphous form described herein has a glass transition temperature (Tg) of 107.44 °C, as determined by differential scanning calorimetry (DSC). Depending on the instrument conditions used in the experiments described herein, there is a tolerance of ± 3 °C for the glass transition temperature.

[0131] Differential scanning calorimetry (DSC) can also be used to detect whether the crystalline form has a crystal transformation or a mixed crystal phenomenon.

[0132] Solids with the same chemical composition often form different isomorphs, or variants, with different crystal structures under different thermodynamic conditions, a phenomenon known as polymorphism or homomorphism. When the temperature and pressure conditions change, the variants will transform into each other, a phenomenon known as crystal transformation. Due to crystal transformation, the mechanical, electrical, magnetic, and other properties of the crystal will change greatly. When the temperature of the crystal transformation is within the measurable range, the transformation process can be observed on a differential scanning calorimetry (DSC) graph, which is characterized by an exothermic peak reflecting the transformation process, and at the same time having two or more endothermic peaks, which are the characteristic endothermic peaks of the different crystal forms before and after the transformation. The crystalline form or amorphous form of the compound described herein can undergo crystal transformation under appropriate conditions

[0133] Thermogravimetric analysis (TGA) is a technique that measures the mass of a substance as a function of temperature under programmed control and is suitable for examining the loss of solvent from a crystal or the process of sublimation, decomposition of a sample, and can be used to infer the presence of crystalline water or crystalline solvent in a crystal. The mass change shown in a TGA curve depends on many factors, including sample preparation and the instrument; there can be slight differences in the mass change detected by TGA between different instruments and between different samples. In some embodiments, the calcium salt Form A described herein loses about 5.1% of its mass at about 150 °C. Depending on the instrument conditions used in the experiments according to the present application, there can be an error tolerance of ± 0.3% in the mass change.

[0134] In the context of the present application, the 2-theta values in the X-ray powder diffractograms are given in degrees (°).

[0135] It is noted that "wt%" means mass ratio (g / g), for example, in a hydrate, the water content of Form A is 3.0 wt%, meaning that the ratio of the mass of water in the Form A to the mass of the Form A is 3.0 (g / g); for example, in a solvate, the content of 1,4-dioxane in Form C is 3.1 wt%, meaning that the ratio of the mass of 1,4-dioxane in the Form C to the mass of the Form C is 3.1 (g / g).

[0136] The term "substantially as shown" means that at least 50%, or at least 60%, or at least 70%, or at least 80%, or at least 90%, or at least 95%, or at least 99% of the peaks in the X-ray powder diffractogram or DSC plot or TGA results are shown in the plot thereof.

[0137] When referring to a spectrum or / and data appearing in a plot, "peak" means a feature recognizable by one of skill in the art that is not attributable to background noise.

[0138] "Substantially pure" means that a crystal form is substantially free of one or more other crystal forms, i.e., the purity of the crystal form is at least 80%, or at least 85%, or at least 90%, or at least 93%, 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 in a percentage of 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% of the total volume or total weight of the crystal form.

[0139] "Substantially free of" means that one or more other crystal forms are in a percentage of 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% of the total volume or total weight of the crystal form.

[0140] "Relative intensity" means the ratio of the intensity of a peak to the intensity of the first most intense peak in the X-ray powder diffraction pattern (XRPD) when the intensity of the first most intense peak is 100%.

[0141] In the context of the present application, when used or whether or not the words "about" or "approximately" are used, means within 10%, suitably within 5%, and particularly within 1% of a given value or range. Alternatively, for those skilled in the art, the terms "about" or "approximately" mean within an acceptable standard deviation from the mean. Whenever a number N is disclosed, any number within N + / - 1%, N + / - 2%, N + / - 3%, N + / - 5%, N + / - 7%, N + / - 8%, or N + / - 10% is also disclosed, where "+" or "-" means plus or minus.

[0142] The term "comprising" is to be construed as an open-ended term that means including, but not excluding, other steps or components. BRIEF DESCRIPTION OF DRAWINGS

[0143] Figure 1 X-ray powder diffraction (XRPD) pattern of Form A;

[0144] Figure 2 Thermogravimetric analysis (TGA) pattern of Form A;

[0145] Figure 3 Differential scanning calorimetry (DSC) pattern of Form A;

[0146] Figure 4 X-ray powder diffraction (XRPD) pattern of Form B;

[0147] Figure 5 Thermogravimetric analysis (TGA) pattern of Form B;

[0148] Figure 6 Differential scanning calorimetry (DSC) pattern of Form B;

[0149] Figure 7 X-ray powder diffraction (XRPD) pattern of Form C;

[0150] Figure 8 Thermogravimetric analysis (TGA) pattern of Form C;

[0151] Figure 9 Differential scanning calorimetry (DSC) pattern of Form C;

[0152] Figure 10 X-ray powder diffraction (XRPD) pattern of Form D;

[0153] Figure 11 Thermogravimetric analysis (TGA) pattern for Form D;

[0154] Figure 12 Differential scanning calorimetry (DSC) pattern for Form D;

[0155] Figure 13 X-ray powder diffraction (XRPD) pattern for Form E;

[0156] Figure 14 Thermogravimetric analysis (TGA) pattern for Form E;

[0157] Figure 15 Differential scanning calorimetry (DSC) pattern for Form E;

[0158] Figure 16 X-ray powder diffraction (XRPD) pattern for Form F;

[0159] Figure 17 Thermogravimetric analysis (TGA) pattern for Form F;

[0160] Figure 18 Differential scanning calorimetry (DSC) pattern for Form F;

[0161] Figure 19 X-ray powder diffraction (XRPD) pattern for Form G;

[0162] Figure 20 Thermogravimetric analysis (TGA) pattern for Form G;

[0163] Figure 21 Differential scanning calorimetry (DSC) pattern for Form G;

[0164] Figure 22 XRPD overlay (I / III) for suspension post-competition solid; 1 H NMR pattern for Form B;

[0165] Figure 23 H NMR pattern for Form C; 1

[0166] Figure 24 H NMR pattern for Form E; 1

[0167] Figure 25 H NMR pattern for Form F; 1

[0168] Figure 26 H NMR pattern for Form G; 1

[0169] Figure 27 XRPD overlay (I / III) for suspension post-competition solid; ​​​​

[0170] Figure 28 XRPD overlay of suspended solids after competition (II / III);

[0171] Figure 29 XRPD overlay of suspended solids after competition (III / III). DETAILED DESCRIPTION

[0172] The present application is described in detail below by way of Examples, but it is not meant to present any adverse limitations on the present application. The present application has been described in detail and specific embodiments thereof have been disclosed with particularity, but it is to be understood that various changes and modifications can be suggested to one skilled in the art, and it is intended that the present application encompass such changes and modifications as fall within the spirit and scope of the application.

[0173] XRPD results of the present application were collected on a PANalytical Empyrean and X’Pert3 X-ray powder diffractometer with the scan parameters shown in Table 8.

[0174] Table 8

[0175]

[0176] TGA and DSC plots of the present application were collected on a TA Q5000 / Discovery 5500 thermogravimetric analyzer and a TA Discovery 2500 differential scanning calorimeter, respectively, and the test parameters are listed in Table 9.

[0177] Table 9

[0178] Parameter TGA DSC Method Linear heating Linear heating Sample pan Aluminum pan, open Aluminum pan, crimped Temperature range RT - 350 °C RT - target temperature Heating rate 10 °C / min 10 °C / min Protective gas Nitrogen Nitrogen

[0179] Dynamic vapor sorption (DVS) curves of the present application were collected on a DVS Intrinsic from Surface Measurement Systems. The relative humidity at 25 °C was corrected using the deliquescence points of LiCl, Mg(N03)2, and KCl. The DVS test parameters are listed in Table 10.

[0180] Table 10

[0181]

[0182]

[0183] Proton NMR spectra of the present application were collected on a Bruker 400M NMR spectrometer with DMSO-d6 as solvent.

[0184] The stability test in the high performance liquid chromatography (HPLC) test used in the present application is tested by Agilent 1260 high performance liquid chromatograph, and the analysis conditions are shown in Table 11.

[0185] Table 11

[0186]

[0187] The solvent abbreviations or Chinese meanings of English used in the present application are shown in Table 12 as follows:

[0188] Table 12

[0189] English Chinese English Chinese MeOH Methanol MTBE Methyl tert-butyl ether EtOH Ethanol THF Tetrahydrofuran IPA Isopropanol 2-MeTHF 2-Methyltetrahydrofuran CHCl3 Chloroform ACN Acetonitrile MIBK Methyl isobutyl ketone n-Heptane n-Heptane EtOAc Ethyl acetate Toluene Toluene

[0190] IPAc Isopropyl acetate [H2O] Water DMSO Dimethyl sulfoxide DCM Methylene chloride Anisole Anisole 1,4-Dioxane 1,4-Dioxane MEK Methyl ethyl ketone DMF Dimethylformamide Cumene Cumene n-Hexane n-Hexane

[0191] The present application discloses a crystalline form of a compound of formula (I) and a preparation method thereof. Those skilled in the art can refer to the content of the present application and appropriately improve the process parameters to achieve it. In particular, it is pointed out that all similar substitutions and changes are obvious to those skilled in the art, and they are considered to be included in the present application. The method of the present application has been described by the preferred embodiments, and the relevant personnel can obviously modify or appropriately change and combine the methods described herein without departing from the content, spirit and scope of the present application, to realize and apply the present application technology.

[0192] In order to further understand the present application, the present application will be described in detail below in combination with examples.

[0193] Example 1: Preparation of a compound of formula (I)

[0194]

[0195] Reference is made to the method in WO2019014352 to synthesize the intermediate D5. Dichloromethane 200 mL is added to a reaction bottle, and under stirring conditions, D5 40 g, HATU 53.8 g, and D6 19.1 g are added to the reaction bottle, respectively, and continue to stir. DIPEA 42.2 g is slowly added dropwise to the reaction bottle, and the temperature in the reaction bottle is controlled not to be higher than 35°C during the dropping process. After the dropping is completed, the temperature in the reaction bottle is kept at 30-35°C to continue stirring for 16 hours. After the reaction is completed, the reaction system is cooled to 25-30°C, and dichloromethane 100 mL is supplemented, 5% potassium carbonate aqueous solution 240 mL which has been prepared is added to the system, and stirred for 0.5 hours, and then allowed to stand to separate. The organic phase is washed with 5% citric acid aqueous solution, 7% sodium bicarbonate aqueous solution and pure water, respectively, and then concentrated under reduced pressure to obtain a compound of formula (I).

[0196] LCMS: m / z 459.0 (M+H) + ;1 H NMR (400 MHz, DMSO-d6) δ 10.83 (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).

[0197] Example 2: Preparation and characterization of Form A

[0198] Form A was obtained by slurry 20.2 mg of the compound of Formula (I) in 0.3 mL of MTBE at room temperature for 10 days. The XRPD 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 showed a 3.9% weight loss upon heating to 150 °C (the theoretical content of one water of crystallization is about 3.8%). The DSC results showed a broad endothermic peak at 86.3 °C (onset temperature).

[0199] Example 3: Preparation and characterization of Form B

[0200] Form B was obtained by slurry 19.9 mg of the compound of 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 upon heating to 150 °C. The DSC results showed an endothermic peak at 146.6 °C (onset temperature). 1 H NMR results Figure 22 indicated that only a very small amount (0.04 wt%) of Acetone residue was observed in the sample.

[0201] Example 4: Preparation and characterization of Form C

[0202] Form C was obtained by slurry 20.0 mg of the compound of Formula (I) in 0.5 mL of 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 showed a 1.2% weight loss upon heating to 80 °C and a stepwise 7.0% weight loss upon heating from 80 °C to 150 °C. The DSC results showed overlapping endothermic peaks at 106.6 °C and 111.3 °C (peak temperatures). 1 H NMR resultsFigure 23 ) 6.3 wt% 1,4-dioxane was detected.

[0203] Example 5: Preparation and characterization of Form D

[0204] Form D was obtained by gas-solid diffusion of 15.0 mg of the compound of 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 , and the DSC results are shown in Figure 12 . The TGA results showed a 0.9% weight loss from room temperature to 80 °C and a 7.0% weight loss from 80 °C to 150 °C. The DSC results showed two endothermic peaks at 97.8 °C and 149.2 °C (peak temperature).

[0205] Example 6: Preparation and characterization of Form E

[0206] Form E was obtained by gas-solid diffusion of 15.0 mg of the compound of 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 a 1.9% weight loss from room temperature to 80 °C and a 4.9% weight loss from 80 °C to 150 °C. The DSC results showed one broad endothermic peak at 85.1 °C (onset temperature). 1 H NMR results showed Figure 24 ) 3.8 wt% THF was detected.

[0207] Example 7: Preparation and characterization of Form F

[0208] Form F was obtained by gas-solid diffusion of 15.1 mg of the compound of Formula (I) in 4 mL of CHCl3at 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 an 11.5% weight loss from room temperature to 150 °C. The DSC results showed one endothermic peak at 95.7 °C (onset temperature). 1 H NMR results showed Figure 25 ) 11.1 wt% CHCl3was detected (consistent with the TGA weight loss).

[0209] Example 8: Preparation and characterization of Form G

[0210] Form G was obtained by vapor diffusion of about 20 mg of the compound of Formula (I) in DMSO at room temperature for about 4 days, followed by 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 The DSC results are shown in Figure 21 The TGA results show that the sample of Form G loses 2.3% weight when heated to 160 °C. The DSC results show that the sample has an endothermic peak at 146.8 °C (onset temperature). 1 The H NMR results show that Figure 26 1.0 wt% of DMSO solvent remains.

[0211] Example 9: Solid-state stability experiment

[0212] To evaluate the solid-state stability of free anhydrous Form B, an appropriate amount of sample was placed in a closed container at 60 °C for 24 hours, and in an open container at 25 °C / 60% RH and 40 °C / 75% RH for one week, respectively. The solid samples after being placed under different conditions were tested for crystal form change by XRPD and chemical stability by HPLC. The characterization results are summarized in Table 13, which shows that the HPLC purity of the sample of Form B did not decrease significantly under the test conditions, and the crystal form did not change.

[0213] Table 13

[0214]

[0215] To further study the conversion relationship between free anhydrous forms and hydrate forms, suspension competition experiments were performed on anhydrous Forms B / G and hydrate Form A. First, suspension competition experiments between anhydrous Forms B and G were set up in ACN at 5 °C, room temperature and 50 °C, and in EtOAc at room temperature. The specific steps are as follows: 1) prepare a saturated solution of the free form at the corresponding temperature in different solvent systems; 2) add the corresponding free form sample to 0.5 mL of the saturated solution to form a suspension; 3) magnetically stir under the corresponding temperature conditions; 4) separate the solid after stirring for 1-5 days and test by XRPD. The results are shown in Table 14. Under the test conditions, only free Form B was obtained.

[0216] Therefore, suspension competition experiments of room temperature stable anhydrous Form B and hydrate Form A in ACN / H2O at room temperature with different water activities (a w = 0 / 0.2 / 0.4 / 0.6 / .0.8 / 1.0) were set up. The results are shown in Table 14. Under a w = 0-0.4, anhydrous Form B was obtained, and under a w = 0.6-1 (pure water), hydrate Form A was obtained. The XRPD patterns of the solids obtained in the experiments are as follows:Figure 27 To Error! Reference source not found..

[0217] Table 14 Suspension competition test results of different free state crystal forms

[0218]

[0219] From the above table, 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 subsequent development, so the stability and subsequent drug development of anhydrous crystal form B are better.

[0220] Effect implementation example:

[0221] I. Blocking activity of the compound of formula (I) on sodium ion channel 1.8 (NaV1.8)

[0222] 1. Test method: Patch clamp technique to detect the effect of compounds on voltage-gated sodium ion channel (NaV) 1.1-1.8 subtype current

[0223] 2. Preparation and analysis of administration preparation

[0224] 2.1 Preparation method of administration preparation stock solution

[0225] Control: Weigh the appropriate volume of DMSO as stock solution.

[0226] Test compound: Weigh the appropriate mass of the compound of formula (I) (actual amount = theoretical concentration * volume * molecular weight / purity), calculate the required volume of DMSO according to the formula, then convert the final required mass of DMSO. Then dissolve the powder with the weighed DMSO. Calculate the actual stock solution concentration according to the final DMSO usage amount. Generally, the actual stock solution concentration is slightly different from the theoretical concentration.

[0227] 2.2 Preparation method and concentration of administration preparation working solution

[0228] Before testing the NaV channel current, dilute the control and test compound stock solution to 10 mL of extracellular solution as working solution, and ultrasonic for 20 min.

[0229] 3. Experimental system

[0230] 3.1. Cell culture

[0231] 1) The specific information of CHO cell line stably expressing Nav1.8 channel is as follows: SCN10A: NM_006514

[0232] 2) Cells were cultured in HAM'S / F-12 medium containing 10% fetal bovine serum and 10 μg / mL Blasticidin, 200 μg / mL Hygromycin B and 100 μg / mL Zeocin at 37°C in 5% CO2.

[0233] 3) Cell passage: Remove old medium and wash once with PBS, then add 1 mL of 0.25% -Trypsin-EDTA solution, incubate at 37°C for 1.5 min. When cells are detached from the dish bottom, add 5 mL of 37°C pre-warmed complete medium. Gently pipette the cell suspension to dissociate the aggregated cells. Transfer the cell suspension to a sterile centrifuge tube and collect the cells by centrifugation at 1000 rpm for 5 min. Expand or maintain the culture by seeding the cells in 6 cm cell culture dishes at a cell density of 2.5*10 5 cells (final volume: 5 mL).

[0234] 4) To maintain the electrophysiological activity of the cells, the cell density must not exceed 80%.

[0235] 5) Patch-clamp recordings, cells were dissociated with 0.25% -Trypsin-EDTA before the experiment, seeded at a density of 8*10 3 Cells were seeded at a density of 2*10 cells per well (final volume: 500 μL) in 24-well plates pre-coated with coverslips and tetracycline was added. The experiment was performed the next day.

[0236] 3.2. Electrophysiological solutions

[0237] 1) Extracellular solution: 140 mM NaCl, 3.5 mM KCl, 2 mM CaCl2, 10 mM HEPES, 1.25 mM NaH2PO4, 1 mM MgCl2, 10 mM Glucose, pH=7.4 (NaOH).

[0238] 2) Intracellular solution: 50 mM CsCl, 10 mM NaCl, 10 mM HEPES, 20 mM EGTA, 60 mM CsF, pH=7.2 (CsOH).

[0239] 4. Test method

[0240] 4.1. Instruments The instruments are listed in Table 15 below.

[0241] Table 15: Instruments suppliers and models

[0242] Name Supplier Model Amplifier HEKA (Germany) EPC10 Micro manipulator Sutter Instruments (USA) MP285 Electrode puller Sutter Instruments (USA) P97 Microscope Olympus (Japan) IX71 Glass pipette Sutter Instruments (USA) BF150-86-10 Data acquisition and analysis software HEKA (Germany) Patchmaster & IGOR

[0243] 4.2 Patch-clamp recordings

[0244] The voltage stimulation protocol for recording Nav channel currents in whole-cell patch clamp recordings was as follows: the membrane potential of the cell was first clamped at -130 mV, then stepped to -40 mV or -20 mV in 10 mV steps for 8 s. The clamp voltage was maintained at -120 mV and data was collected every 20 s. The peak amplitude of the inward current was measured and the half-inactivation voltage was determined.

[0245] The cell was clamped at -120 mV. Resting and half-inactivation inhibition of sodium currents was measured using a double pulse protocol. The double pulse protocol was achieved by two 50 ms depolarizing test pulses at 0 mV (TP1 and TP2). The conditioning voltage between the two depolarizing pulses was set near the half-inactivation voltage (for 8 s). The membrane potential of the cell was clamped to -120 mV for 20 ms before the second depolarizing pulse was given to allow for recovery of unbound compound and channels in the inactivated state. Data was collected every 20 s and the peak current at both test pulses was measured.

[0246] Experimental data was collected by an EPC-10 amplifier (HEKA) and stored in PatchMaster (HEKA) software (software version: v2x73.2).

[0247] Capillary glass tubes (BF150-86-10, Sutter Instruments) were pulled into recording electrodes using a microelectrode puller (P97, Sutter Instruments). The recording electrodes were contacted to the cells using a micromanipulator (MP285) under an inverted microscope (IX71) and negative pressure was applied to form a GΩ seal. After a GΩ seal was formed, fast capacitance compensation was performed and then negative pressure was continuously applied to break the cell membrane and form a whole-cell recording mode. Slow capacitance compensation was then performed and the membrane capacitance and series resistance were recorded without leak compensation.

[0248] When the whole-cell recorded Nav channel currents were stable, drug application was started. Each drug concentration was applied for 5 minutes (or until the currents were stable) before the next concentration was tested. The coverslips with cells were placed in the recording bath of the inverted microscope and test compounds and compound-free external solution were gravity perfused through the recording chamber from low to high concentrations to act on the cells. The currents detected in each cell in the compound-free external solution were used as its own control. Multiple cells were independently and repeatedly tested. All electrophysiological experiments were performed at room temperature.

[0249] 4.3 Data analysis

[0250] Firstly, the current of each drug concentration and the blank control current were normalized, then the block rate of each drug concentration was calculated. The average and standard error of each concentration were calculated, and all the above values were calculated by Microsoft Excel 2013. In addition, the half-inhibitory concentration of each compound was calculated by the following equation using IGOR software: Block rate = 1 / 【1 + (IC 50 / c) h 】.

[0251] The above equation was used to perform nonlinear fitting of the dose-dependent effect, where c represents the drug concentration, IC 50 is the half-inhibitory concentration, and h represents the Hill coefficient. Curve fitting and IC 50 calculation were completed using IGOR software (software version: 6.0.1.0).

[0252] In this example, the half-block activity (IC 50 ) of the compound of formula (I) on NaV1.8 was determined, as shown in Table 16. Among them:

[0253] Table 16: Block activity IC 50 value (nM) of the compound of formula (I) on NaV1.8

[0254] Number NaV1.8 IC 50 (nM)]]> Compound of formula (I) 6.2

[0255] The compound of formula (I) has a significant blocking effect on the activity of NaV1.8 channel.

[0256] II. Pharmacokinetic experimental results of the compound of formula (I)

[0257] In this experimental example, in vivo pharmacokinetic evaluation was performed on rats by single intravenous injection or oral administration by gavage.

[0258] Experimental methods and conditions: Male Sprague Dawley rats, all animals were fasted overnight, and were respectively given a single dose of 1 mg / Kg (intravenous injection, solvent 5% DMSO / 10% Solutol / 85% Saline) and 10 mg / Kg (gavage administration) of the test compound. Blood was collected from the submandibular vein at 5, 15, 30 min, 1, 2, 4, 6, 8 and 24 hr after administration, with each sample collecting about 0.20 mL, and heparin sodium was used for anticoagulation. After collection, the samples were placed on ice and centrifuged to separate the plasma within 1 hour for testing. The plasma concentration was detected by liquid chromatography tandem mass spectrometry (LC / MS / MS), and the measured concentration was used to calculate the pharmacokinetic parameters. The results are shown in Tables 17 and 18 below.

[0259] Table 17: Pharmacokinetics of intravenous administration (1 mg / kg)

[0260]

[0261] Table 18: Pharmacokinetics of intragastric injection administration (10 mg / kg)

[0262]

[0263] The compound of formula (I) is well absorbed in rats, and has pharmacokinetic advantages.

Claims

1. The compound shown in formula (Ⅰ) has crystal form A. ， Its features are, The X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ angles: 16.63±0.2°, 18.04±0.2°, 20.59±0.2°, 23.38±0.2°, 23.96±0.2°, and 29.19±0.2°.

2. The crystal form A according to claim 1, characterized in that, The X-ray powder diffraction pattern of crystal form A has characteristic diffraction peaks at the following 2θ 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°, and 29.82±0.2°.

3. The crystal form A according to claim 2, characterized in that, The X-ray powder diffraction pattern of crystal form A is shown in Figure 1.

4. The crystal form A according to claim 3, characterized in that, The crystal form A is a hydrate, and the water content of the hydrate is 3.0wt%-5.0wt%.

5. The compound shown in formula (Ⅰ) has crystal form B. ， Its features are, The X-ray powder diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ angles: 12.28±0.2°, 14.47±0.2°, 18.86±0.2°, 23.09±0.2°, 25.50±0.2°, and 27.58±0.2°.

6. The crystal form B according to claim 5, characterized in that, The X-ray powder diffraction pattern of crystal form B has characteristic diffraction peaks at the following 2θ 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°, and 28.19±0.2°.

7. The crystal form B according to claim 6, characterized in that, The X-ray powder diffraction pattern of crystal form B is shown in Figure 4.

8. The compound shown in formula (Ⅰ) has crystal form C. ， Its features are, The X-ray powder diffraction pattern of the crystal form C has characteristic diffraction peaks at the following 2θ angles: 8.22±0.2°, 17.33±0.2°, 19.55±0.2°, 20.27±0.2°, 21.99±0.2°, and 24.90±0.2°.

9. The crystal form C according to claim 8, characterized in that, The X-ray powder diffraction pattern of crystal form C has characteristic diffraction peaks at the following 2θ 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°, and 26.10±0.2°.

10. The crystal form C according to claim 9, characterized in that, The X-ray powder diffraction pattern of crystal form C is shown in Figure 7.

11. The crystal form C according to claim 10, characterized in that, The crystal form C is a 1,4-dioxane solvate, and the content of the 1,4-dioxane is 3wt%-17wt%.

12. The compound shown in formula (Ⅰ) has crystal form D. ， Its features are, The X-ray powder diffraction pattern of crystal form D has characteristic diffraction peaks at the following 2θ angles: 5.63±0.2°, 16.81±0.2°, 20.40±0.2°, 21.50±0.2°, 22.23±0.2°, and 26.08±0.2°.

13. The crystal form D according to claim 12, characterized in that, The X-ray powder diffraction pattern of crystal form D has characteristic diffraction peaks at the following 2θ 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°, and 28.44±0.2°.

14. The crystal form D according to claim 13, characterized in that, The X-ray powder diffraction pattern of the crystal form D is shown in Figure 10.

15. The crystal form D according to claim 14, characterized in that, The crystal form D is a methyl ethyl ketone solvate, and the content of the methyl ethyl ketone is 4wt%-14wt%.

16. The compound shown in formula (Ⅰ) has crystal form E. ， Its features are, The X-ray powder diffraction pattern of crystal form E has characteristic diffraction peaks at the following 2θ angles: 5.75±0.2°, 13.71±0.2°, 18.29±0.2°, 20.18±0.2°, 22.92±0.2°, and 23.96±0.2°.

17. The crystal form E according to claim 16, characterized in that, The X-ray powder diffraction pattern of crystal form E has characteristic diffraction peaks at the following 2θ 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°, and 29.18±0.2°.

18. The crystal form E according to claim 17, characterized in that, The X-ray powder diffraction pattern of the crystal form E is shown in Figure 13.

19. The crystal form E according to claim 18, characterized in that, The crystal form E is a tetrahydrofuran solvate, and the content of the tetrahydrofuran is 2wt%-14wt%.

20. The compound shown in formula (Ⅰ) has crystal form F. ， Its features are, The X-ray powder diffraction pattern of the crystal form F has characteristic diffraction peaks at the following 2θ angles: 17.24±0.2°, 20.28±0.2°, 23.03±0.2°, 23.96±0.2°, 24.89±0.2°, and 28.96±0.2°.

21. The crystal form F according to claim 20, characterized in that, The X-ray powder diffraction pattern of crystal form F has characteristic diffraction peaks at the following 2θ 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°, and 28.96±0.2°.

22. The crystal form F according to claim 21, characterized in that, The X-ray powder diffraction pattern of the crystal form F is shown in Figure 16.

23. The crystal form F according to claim 22, characterized in that, The crystal form F is a chloroform solvate, and the content of chloroform is 5wt%-21wt%.

24. The compound shown in formula (Ⅰ) has crystal form G. ， Its features are, The X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ angles: 15.53±0.2°, 17.08±0.2°, 21.41±0.2°, 23.23±0.2°, 26.00±0.2°, and 28.49±0.2°.

25. The crystal form G according to claim 24, characterized in that, The X-ray powder diffraction pattern of the crystal form G has characteristic diffraction peaks at the following 2θ 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°, and 28.49±0.2°.

26. The crystal form G according to claim 25, characterized in that, The X-ray powder diffraction pattern of the crystal form G is shown in Figure 19.

27. A pharmaceutical composition, characterized in that, It includes crystal form A as described in any one of claims 1-4, crystal form B as described in any one of claims 5-7, crystal form C as described in any one of claims 8-11, crystal form D as described in any one of claims 12-15, crystal form E as described in any one of claims 16-19, crystal form F as described in any one of claims 20-23, or crystal form G as described in any one of claims 24-26.

28. Use of the crystal form A according to any one of claims 1-4, or the crystal form B according to any one of claims 5-7, or the crystal form C according to any one of claims 8-11, or the crystal form D according to any one of claims 12-15, or the crystal form E according to any one of claims 16-19, or the crystal form F according to any one of claims 20-23, or the crystal form G according to any one of claims 24-26, or the pharmaceutical composition according to claim 27 in the preparation of a medicament for inhibiting voltage-gated sodium channels in an individual.

29. The use according to claim 28, wherein, The voltage-gated sodium channel is Navl.

8.

30. Use of the crystal form A according to any one of claims 1-4, or the crystal form B according to any one of claims 5-7, or the crystal form C according to any one of claims 8-11, or the crystal form D according to any one of claims 12-15, or the crystal form E according to any one of claims 16-19, or the crystal form F according to any one of claims 20-23, or the crystal form G according to any one of claims 24-26, or the pharmaceutical composition according to claim 27 in the preparation of a medicament for treating an individual's chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, primary pain, postoperative pain, visceral pain, or to reduce its severity.

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