Use of fused tricyclic gamma-amino acid derivative in treating pathological central nervous pain

Abstract

The present invention relates to use of a compound represented by formula (I), or a stereoisomer, a tautomer, a deuterated form, a solvate, a prodrug, a metabolite, a pharmaceutically acceptable salt thereof, a cocrystal or a composition thereof in preparing a medicament for treating pathological central nervous pain. The present invention further relates to a method for treating pathological central nervous pain, comprising: administering an effective amount of the compound represented by formula (I), or the stereoisomer, the tautomer, the deuterated form, the solvate, the prodrug, the metabolite, the pharmaceutically acceptable salt, the cocrystal or the composition thereof.

Description

Use of a fused tricyclic γ-amino acid derivative in treating central nervous system pathological pain Technical Field

[0001] The present invention relates to the use of a compound of formula (I) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or compositions thereof in the preparation of drugs for treating central nervous system pathological pain. Background Art

[0002] Neuropathic pain is pain caused by damage to or pathology of the nervous system. The pathogenesis of neuropathic pain is complex, including anatomical changes and functional impairment, and is often caused by multiple mechanisms, including peripheral sensitization, central sensitization, dysfunction of the descending inhibitory system, activation of spinal glial cells, changes in ion channels, etc. Central neuropathic pain is a type of neuropathic pain based on the anatomical location of the injury or disease. The other type is peripheral neuropathic pain. Common types of central neuropathic pain include post-stroke pain, spinal cord injury pain, Parkinson's disease pain, and multiple sclerosis pain.

[0003] According to the 2013 edition of the "Expert Consensus on the Diagnosis and Treatment of Neuropathic Pain," calcium channel modulators (such as pregabalin and gabapentin), tricyclic antidepressants (such as amitriptyline), and serotonin-norepinephrine reuptake inhibitors (such as venlafaxine and duloxetine) are recommended as first-line treatments for neuropathic pain. The 2017 Chinese "Expert Consensus on the Assessment, Treatment, and Rehabilitation of Traumatic Spinal Cord Injury" recommends gabapentin and pregabalin as first-line treatments for pathological neuropathic pain after spinal cord injury. Other medications that can be used include tricyclic antidepressants, opioids, and local anesthetics. Medication is the mainstay of treatment for central nervous system pain after stroke. Drugs used to treat neuropathic pain are typically used as routine treatment for post-stroke pain. Drug options include antidepressants, antiepileptics, opioids, NMDA (N-methyl-D-aspartate) receptor antagonists, and antiarrhythmics. Clinical treatment for early-stage Parkinson's disease pain primarily involves interventions with nonsteroidal anti-inflammatory drugs, anxiolytics, and antidepressants, while dopaminergic drugs are often used to treat mid- to late-stage Parkinson's disease pain. However, due to the high incidence of Parkinson's disease pain and inadequate understanding of pain mechanisms, there is currently no consensus on clinical treatment. Clinically, for persistent pain caused by multiple sclerosis, baclofen, tizanidine, and gabapentin are first-line treatments, while diazepam and dantrolene are second-line medications. This indicates that calcium channel modulators, such as pregabalin or gabapentin, are recommended as first-line treatments for various types of central nervous system pain.

[0004] Currently, no regulatory agencies in China have approved drugs for the treatment of central nervous system pain. Internationally, pregabalin was approved by the US Food and Drug Administration (FDA) in 2012 for the treatment of spinal cord injury-related neuralgia. In a clinical study evaluating the safety and efficacy of pregabalin for the treatment of spinal cord injury-related neuralgia, which was registered with the FDA, pregabalin demonstrated significantly greater pain relief in patients with spinal cord injury-related neuralgia compared to placebo. Melogabalin is a novel oral GABA analog. As an α2δ ligand, it primarily targets the α2δ-1 subreceptor of the calcium channel, exhibiting high binding affinity and selectivity, and exhibits a slower dissociation rate from α2δ-1 than pregabalin. Melogabalin was approved by the Pharmaceuticals and Medical Devices Agency (PMDA) of Japan in 2022 for the treatment of central nervous system pain. Although pregabalin is already available in China, its indications only indicate its approval for the treatment of postherpetic neuralgia and fibromyalgia, and melogabalin has not yet been approved for marketing in China.

[0005] Furthermore, although a variety of drugs with different mechanisms of action are currently available for the treatment of central nervous system pain, the vast majority of patients still experience insufficient pain relief or are ineffective in responding to these drugs, often accompanied by severe adverse reactions. Therefore, there is an urgent need for drugs to treat central nervous system pain with better analgesic efficacy and fewer adverse reactions.

[0006] WO2018050046 describes a compound of formula (I) having a significant analgesic effect. Summary of the Invention

[0007] The present invention provides a compound of formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or combinations thereof, and its use in preparing a medicament for treating central nervous system pathological pain.

[0008] Among them, R 1 With R 4 Combined to form -(CR 9 R 9’ )n-or-CR 9 =CR 9’ -;

[0009] R 1’ 、R 2 、R 3 、R 3’ 、R 4’ 、R 5 、R 5’ 、R 6 、R 9 or R 9’Each independently selected from H, F, Cl, Br, I, hydroxyl, amino, carboxyl, carboxylate, amide, cyano, C 1-6 Alkyl, C 1-6 Alkoxy, C 1-6 Sulfanyl, C 2-6 Alkenyl, C 2-6 Alkynyl, 3 to 6 membered carbocyclic group or 3 to 6 membered heterocyclic group, wherein the alkyl, alkoxy, sulfanyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally further substituted by 0 to 6 groups selected from F, Cl, Br, I, hydroxyl, amino, carboxyl, C 1-6 alkyl, 3- to 6-membered carbocyclic group or 3- to 6-membered heterocyclic group, wherein the heterocyclic group contains 1 to 2 heteroatoms selected from N, O or S; n is selected from 1, 2 or 3;

[0010] The pharmaceutically acceptable salt is selected from benzenesulfonate, p-toluenesulfonate or methanesulfonate.

[0011] Furthermore, the structure of the compound described by general formula (I) is selected from one of the structures shown in Table S-1:

[0012] Table S-1 Compound Structure

[0013] In some embodiments, the structure of the compound of formula (I) is the compound shown in formula (II):

[0014] In some embodiments, the compound of formula (I) has a structure represented by formula (III):

[0015] In some embodiments, the compound of formula (I) has a structure represented by formula (IV):

[0016] In some embodiments, the compound of formula (I) has a structure represented by formula (V):

[0017] In some embodiments, the use is to administer to a mammal an effective dose of a compound of formula (IV) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or combinations thereof.

[0018] The present invention relates to central nervous system pathological pain selected from at least one of the following: post-stroke pain, spinal cord injury pain, Parkinson's disease pain, multiple sclerosis pain, and other pathological pain caused by central nervous system damage.

[0019] In some embodiments of the present invention, the use of a drug for treating central nervous system pathological pain and a method of treatment are provided, wherein an effective dose of a compound of formula (IV) or a stereoisomer, tautomer, deuterated substance, solvate, prodrug, metabolite, pharmaceutically acceptable salt, cocrystal or a combination thereof is administered to a mammal. When the amount is calculated based on the compound of structural formula (IV), the amount of the compound is 1-100 mg / day, preferably 5-20 mg / day.

[0020] The present invention relates to the use of a compound of formula (IV) in a drug for treating central neuropathic pain and in some embodiments of a method for treating central neuropathic pain, the route of administration of the compound of formula (IV) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or compositions thereof is selected from injection, instillation, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, transbuccal, nasal drops, inhalation, topical delivery, subcutaneous, intrafatty, intraarticular, intraperitoneal or intrathecal.

[0021] The present invention relates to the use of the compound of formula (IV) in drugs for treating central neuropathic pain and in some embodiments of the method for treating central neuropathic pain, the administration route of the compound of formula (IV) or its stereoisomers, tautomers, deuterated substances, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or compositions thereof is selected from intravenous injection, intravenous drip, arterial injection, intramuscular injection, subcutaneous injection, intraarticular injection, intraperitoneal injection, intrathecal injection or nasal drops.

[0022] Unless otherwise stated, the terms used in the specification and claims have the following meanings:

[0023] "Pharmaceutical composition" means a mixture of one or more compounds described herein or their physiologically / pharmaceutically acceptable salts or stereoisomers, solvates, pharmaceutically acceptable salts or cocrystals, and other ingredients, wherein the other ingredients include physiologically / pharmaceutically acceptable carriers and excipients.

[0024] "Stereoisomers" refer to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, and conformational isomers.

[0025] An "effective amount" refers to that amount of a compound that will elicit the physiological or medical response of a tissue, system, or subject that is being sought, and includes an amount of the compound that, when administered to a subject, is sufficient to prevent or alleviate to some extent one or more symptoms of the disorder or condition being treated.

[0026] "Solvate" refers to a compound of the present invention or a salt thereof, which further includes a stoichiometric or non-stoichiometric amount of a solvent bound by non-covalent intermolecular forces. When the solvent is water, it is a hydrate. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] FIG1 shows the mechanical pain thresholds of animals in each group before modeling (baseline) in Test Example 1 of the present invention;

[0028] FIG2 shows the mechanical pain thresholds of animals in each group before administration (0 hours) in Test Example 1 of the present invention;

[0029] FIG3 shows the analgesic effect of compound (V) in a central neuropathic pain model induced by spinal cord injury in mice 2 hours after administration of Test Example 1 of the present invention;

[0030] FIG4 shows the analgesic effect of compound (V) in a central neuropathic pain model induced by spinal cord injury in mice 4 hours after administration of Test Example 1 of the present invention;

[0031] FIG5 shows the analgesic effect of compound (V) in a central neuropathic pain model induced by spinal cord injury in mice 6 hours after administration of Test Example 1 of the present invention;

[0032] FIG6 is the area under the curve (AUC) of the mechanical pain threshold change of each group of animals in Test Example 1 of the present invention;

[0033] FIG7 is an overall design diagram of the clinical study of the present invention. DETAILED DESCRIPTION

[0034] The technical solutions of the present invention are described in detail below with reference to the accompanying drawings and embodiments, but the protection scope of the present invention includes but is not limited to them.

[0035] Synthesis Example:

[0036] The compounds of formula (IV) and (V) were prepared according to the method described in WO2018050046:

[0037] Biological test cases

[0038] Test Example 1: Study on the analgesic effect of compound (V) in a central neuropathic pain model induced by spinal cord injury in mice

[0039] Female C57BL / 6J mice from Zhejiang Weitonglihua Experimental Animal Technology Co., Ltd. were acclimated for one week before the experiment began. The specific experimental procedures are as follows:

[0040] (1) Three days before the experiment, the mice were stroked for 5 minutes every day to familiarize the experimental animals with the experimenter. The mice were then placed on a metal pain measuring frame for 60 minutes to adapt.

[0041] (2) The mechanical pain baseline value of all experimental animals was measured (Ascending test method). Each animal was measured twice and the average value was taken, with an interval of at least 5 minutes between each measurement. The Excel random function was used to divide the animals into groups (Sham group and model group) according to their numbers for the first time.

[0042] (3) The sham group underwent sham surgery, and the remaining animals underwent partial spinal cord injury (SCI) modeling, with the day of modeling being designated as Day 0.

[0043] (4) On Day 25 after modeling, all mice were evaluated for spinal cord injury BBB scores, and mice that failed the modeling were screened out (the qualified range was the mean ± standard deviation of the BBB score).

[0044] (5) Mechanical pain detection before drug administration: The mechanical pain threshold of mice was detected on the 26th day after model establishment (Day 26), i.e., the data at 0 hours (before drug administration).

[0045] (6) Animal grouping before administration: Based on the mechanical pain threshold (MPT) before administration, mice with no significant decrease in pain threshold (MPT>0.4g) were screened out, and the remaining modeled animals were evenly divided into experimental groups according to different pain thresholds using Excel random function.

[0046] (7) Administration and post-administration mechanical pain threshold detection: On Day 28 after model establishment, different doses (calculated as free base) of compound (V) or vehicle (0.5% methylcellulose) prepared with a solvent were administered by gavage, and the mechanical pain threshold of the mice was detected 2, 4, and 6 hours after a single administration.

[0047] The method for establishing a central neuropathic pain model induced by spinal cord injury in mice is as follows:

[0048] (1) Turn on the air pump of the respiratory anesthesia machine, rotate the oxygen flow adjustment knob counterclockwise and adjust it to 0.8L / min; place the animal in the induction box, turn the gas conversion switch to the "Chamber" direction, and the anesthetic gas will flow to the induction box; press the dial lock button, rotate the evaporator dial, and adjust the anesthetic gas concentration to 2L / min. After the induction of anesthesia is completed, rotate the evaporator dial, adjust the anesthetic gas concentration to 1L / min, and turn the gas conversion switch to the "Mask" direction, and the gas will flow to the anesthesia mask; remove the animal from the anesthesia induction box, place its head / nose in the anesthesia mask, and after confirming that the animal is in a good state of anesthesia, subsequent experimental operations can be carried out.

[0049] (2) Sterilize surgical instruments, remove the hair on the back, and disinfect with iodine.

[0050] (3) Identify the T9 vertebra along the 13th dorsal rib.

[0051] (4) Make a 1-2 cm midline skin incision on the back centered on the spinous process of the T9 vertebra.

[0052] (5) Bluntly separate the subcutaneous tissue and muscles to expose the spinous process and lamina of the T9 vertebra.

[0053] (6) Fix the T9 spinous process with a clamp and gently lift it to the upper left to open the intervertebral space. Use the right intervertebral space of T9 as the entry point, cut the yellow ligament, and cut the junction of the T9 transverse process and the two adjacent transverse processes in sequence. Use the middle finger of the left hand to lift the T9 spinous process upward from the abdomen as much as possible to increase the intervertebral space.

[0054] (7) Hold the ophthalmic surgical knife in the right hand, with the blade facing the transverse side. After the tip of the knife enters the intervertebral space parallel to the T9 spinous process, cut vertically downward to the vertebral body. At the same time, the handle of the knife tilts a certain angle toward the uncut side. Twitching of the hind limb on the cut side indicates that the model preparation is successful.

[0055] (8) Use sutures to suture the muscles and skin layer by layer and disinfect them.

[0056] (9) The sham group only underwent surgical steps (1) to (5), and then sutured the muscles and skin layer by layer with sutures and disinfected them.

[0057] (10) After the operation, rotate the evaporator dial, close the isoflurane valve and oxygen valve, turn the oxygen flow adjustment knob clockwise, turn off the air pump, and clean the anesthesia induction box.

[0058] The BBB scoring method for spinal cord injury is described in the following table:

[0059] The mechanical pain threshold (MPT) determination method (Ascending method) is as follows:

[0060] (1) Place the experimental animal on the metal grid for mechanical pain testing and let it rest for 1 hour. Start the test after the animal stops looking around, exploring, and becomes relatively quiet.

[0061] (2) After the experimental animal is quiet, use Von Frey fiber (North Coast, catalog number NC12775-99) to slowly and gently stimulate the sole of the hind limb to be tested vertically to bend the fiber. Continue for 2-3 seconds and observe the animal's paw withdrawal reaction. Stimulate the test animal one by one in the order of fiber weight from small to large. Each fiber weight is stimulated 5 times in a row, with an interval of at least 10 seconds between each stimulation. If there are less than 3 positive reactions, repeat the above operation with a larger fiber. When 3 or more positive reactions occur in the first test, the fiber is the pain threshold of the animal (each animal is tested twice and the average value is taken).

[0062] (3) If the animal raises its paw, avoids or licks its paw in response to stimulation, it is marked as positive (×). Paw withdrawal due to physical activity is not counted. If there is no such response, it is marked as negative (o).

[0063] (4) Fiber weight: 0.16g, 0.4g, 0.6g, 1.0g, 1.4g and 2.0g, with a cut-off value of 2.0g.

[0064] After the test is completed, the area under the curve (AUC) is calculated based on the mechanical pain threshold (MPT) at each time point before and after administration. The calculation formula is: AUC = MPT 0h +2×MPT 2h +2×MPT 4h +MPT 6h Statistical analysis and graph drawing were performed using GraphPad Prism 8 software.

[0065] The results are shown in Table 1, Table 2 and Figures 1 to 6 . At a dose of 30 mg / kg, compound (V) had a very significant analgesic effect, and the mechanical pain threshold of the animals in this group was comparable to that of the Sham group.

[0066] Table 1 summarizes the mechanical pain thresholds (mean ± standard error) of the animals in each group of Test Example 1 of the present invention.

[0067] Table 1

[0068] Table 2 summarizes the areas under the curve of mechanical pain threshold changes of the animals in each group of Test Example 1 of the present invention (mean ± standard error).

[0069] Table 2

[0070] Clinical trial: A multicenter, randomized, double-blind, placebo-controlled Phase III clinical trial to evaluate the efficacy and safety of Compound (V) capsules in the treatment of moderate to severe central nervous system pain in Chinese patients.

[0071] Duration of the trial: Each subject will participate in this trial for approximately 56 weeks, including a 2-week screening period (14 days before the run-in period), a 1-week run-in period [including baseline (D0)], a 12-week double-blind treatment period, a 40-week open-label extended treatment period, and a 1-week safety follow-up period.

[0072] Purpose of the test

[0073] Main Purpose

[0074] To evaluate the efficacy of Compound (V) capsules (hereinafter referred to as Compound (V)) in treating moderate to severe central neuropathic pain compared with placebo.

[0075] Secondary purpose

[0076] To evaluate the safety of compound (V) compared with placebo in the treatment of moderate to severe central neuropathic pain.

[0077] To evaluate the long-term safety and efficacy of compound (V) in the treatment of moderate to severe central neuropathic pain (52 weeks).

[0078] To evaluate the pharmacokinetic (PK) characteristics of compound (V) in Chinese patients with moderate to severe central neuropathic pain.

[0079] Test overall design

[0080] This study adopted a multicenter, randomized, double-blind, placebo-controlled, parallel-group design.

[0081] The test included a 2-week screening period (14 days before the lead-in period), a 1-week lead-in period [including baseline (D0)], a 12-week double-blind treatment period, a 40-week open-label extended treatment period, and a 1-week safety follow-up period.

[0082] After signing the informed consent form (ICF), the subjects will enter the screening period. Subjects who complete the screening examinations specified in the protocol during the screening period and meet the inclusion criteria and do not meet the exclusion criteria will enter the placebo run-in period, during which they will take a placebo once a day in the morning and evening (1 tablet / time, BID) for 1 week. Subjects will undergo randomization standard assessment at baseline (D0), and qualified subjects will be randomly assigned to the compound (V) group and the placebo group in a 1:1 ratio. Stratified randomization will be performed based on baseline ADPS score (<6 points and ≥6 points) and disease type (spinal cord lesion-related neuropathic pain, central neuropathic pain after stroke, Parkinson's disease pain, multiple sclerosis pain).

[0083] Drug treatment period: includes two stages: a 12-week double-blind treatment period and a 40-week open extended treatment period.

[0084] Double-blind treatment period: Subjects who meet the randomization criteria will receive Compound (V) capsules or placebo orally twice daily (BID). Randomization criteria will be assessed at baseline (D0). Eligible subjects will begin receiving the test treatment (20 mg dose) at Visit V3, the evening of the day of randomization (D0), and will receive 20 mg BID starting the following day. At Visit V4 (end of the second week of treatment), tolerability and efficacy response will be assessed. If the subject's PGIC score is "much improved," "much improved," or "slightly improved," the dose will be maintained at 20 mg BID. If the subject's PGIC score is "no change," "slightly worsened," "much worsened," or "much worsened" and the treatment is well tolerated (no Grade 3 or higher adverse drug reactions (ADRs)), the dose will be adjusted to 40 mg BID. Tolerability will be assessed at Visit V5 (end of the fourth week). Subjects whose dose has been adjusted to 40 mg BID and who experience intolerance (severe dizziness, somnolence, or Grade 3 or higher ADRs) may have their dose adjusted back to 20 mg BID. No dose adjustment is allowed from visit V5 to visit V7 (end of the double-blind treatment period), that is, from the beginning of week 5 to the end of week 12.

[0085] Open-label extension period: Subjects who complete the 12-week double-blind treatment phase and do not experience significant safety issues may voluntarily enter a 40-week open-label extension period. Subjects who voluntarily enter the open-label extension period will begin open-label extension treatment (at a dose of 20 mg of Compound (V)) on the evening of Visit V7, and begin receiving Compound (V) 40 mg / day (20 mg BID) the following day. During the open-label extension period, subjects may adjust their dose based on their response and tolerance, under the guidance of the investigator. For example, if a subject experiences an inadequate response at 20 mg BID, the dose may be adjusted to 40 mg BID. The investigator will then decide whether to adjust the dose back to 20 mg BID based on the subject's tolerance and pain relief. After completing 52 weeks of treatment, subjects will undergo a safety follow-up visit 7 days after the last dose of the study drug.

[0086] For subjects who are unwilling to participate in the open-label extended treatment period, after completing the 12-week double-blind treatment period, they will receive a safety follow-up on the 7th day after the last dose of the trial drug.

[0087] For subjects who did not complete the test treatment, an early termination visit was required.

[0088] No rescue medication should be used during the run-in period and 1 week before the end of the double-blind treatment period.

[0089] Dosage of remedial medication: once every 4 to 6 hours, 1 tablet each time, no more than 4 tablets per day, and should not be taken continuously for more than 5 days.

[0090] The overall design diagram of the test is shown in Figure 7.

[0091] Pharmacokinetic blood sampling

[0092] PK blood samples will be collected from all subjects. PK blood samples will be collected at the following times: V4 visit (D15-1 / +2) within 30 minutes before morning dosing; V5 visit (D29-1 / +2) within 30 minutes before morning dosing; V6 visit (D57-1 / +2) within 30 minutes before morning dosing, 30 minutes to 2 hours after morning dosing, and 4 to 12 hours after morning dosing (before evening dosing). Approximately 3 mL of whole blood will be collected at each blood collection point. The time of blood collection and medication administration must be recorded at all visits involving PK blood collection. Breakfast time on the day of blood collection must be recorded at visits V4, V5, and V6.

[0093] Number of subjects

[0094] A total of 204 subjects were enrolled in the single disease type group, 102 in the compound (V) group and 102 in the placebo group; enrollment was stopped when the number of subjects in both disease types was met.

[0095] Inclusion criteria (Subjects who meet all of the following criteria are eligible for this test)

[0096] 1) Voluntarily sign the informed consent form;

[0097] 2) be able to read and complete the questionnaire;

[0098] 3) Male or female patients aged ≥18 years;

[0099] 4) Subjects with a history and symptoms of central nervous system pathological pain, including spinal cord lesion-related neuralgia, post-stroke central nervous system pain, Parkinson's disease pain, and multiple sclerosis pain, and who meet the following requirements:

[0100] a) pain duration ≥ 3 months;

[0101] b) Meet the characteristics of neuropathic pain: Neuropathic Pain (DN4) Scale score ≥ 4 points;

[0102] At the screening visit, patients assessed their average pain visual analogue scale (VAS) score of ≥40 mm over the past 24 hours.

[0103] Exclusion criteria (Subjects who meet any of the following criteria are not eligible for this test)

[0104] 1) The presence of other pain that may affect the assessment of central neuropathic pain as assessed by the test subject, including but not limited to:

[0105] a) Pain caused by compression of nerve roots due to intervertebral disc herniation / bulging, spinal stenosis, vertebral degeneration / hyperplasia, etc. within 12 months before screening (except for patients with no nerve compression confirmed by imaging after treatment);

[0106] b) Pain caused by gouty arthritis, rheumatoid arthritis, osteoarthritis, soft tissue injury, etc. within 6 months before screening;

[0107] c) Pain caused by peripheral neuropathy due to other reasons or acquired peripheral neuropathy within 6 months before screening;

[0108] d) history of diabetic peripheral neuropathic pain;

[0109] e) Patients with a history of postherpetic neuralgia (except cured patients: patients whose herpes zoster has been cured at the time of screening and who have no postherpetic pain, skin lesions or other related symptoms and signs within 6 months before screening);

[0110] 2) Patients with unstable spinal cord lesions or stroke who are expected to require surgical treatment;

[0111] 3) The presence of chronic systemic diseases that may affect the subject's participation in the test as assessed by the tester, including but not limited to:

[0112] a) Severe cardiopulmonary disease, such as unstable angina, acute myocardial infarction within 6 months, severe arrhythmia, World Health Organization (WHO) heart function class III-IV at screening, hypertension that is poorly controlled despite active treatment, systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening; recurrent asthma attacks;

[0113] b) Suffering from chronic digestive system diseases, such as liver diseases such as liver fibrosis, recurrent indigestion or diarrhea, and peptic ulcers;

[0114] c) The presence of other neuropsychiatric diseases that may affect self-scoring as determined by the test-taker, including but not limited to moderate to severe cognitive impairment, somatoform disorders, epilepsy, recurrent dizziness, headaches, and memory impairment;

[0115] 4) diabetic patients with poor blood sugar control (fasting blood glucose ≥11.1mmol / l at screening);

[0116] 5) Known history of drug abuse or alcoholism within 1 year before screening [more than 14 drinks per week (1 drink is equivalent to 360 mL of beer, or 45 mL of liquor with 40% alcohol content, or 150 mL of wine)];

[0117] 6) Previous use of pregabalin ≥300 mg / day or gabapentin ≥1200 mg / day, and claim of lack of clinical efficacy;

[0118] 7) Severe abnormalities in hematology, liver, or kidney function, as indicated by any of the following clinical laboratory test results:

[0119] a) Hematology: WBC count <3 × 10 9 / L, neutrophils <1.5×10 9 / L, or platelets <75×10 9 / L, or hemoglobin <90g / L;

[0120] b) Liver function: alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN); or total bilirubin (TBIL) > 1.5 × ULN;

[0121] c) Estimated glomerular filtration rate (eGFR) <60 mL / min / 1.73 m 2 (calculated according to the simplified MDRD formula);

[0122] d) Creatine kinase >2.0×ULN.

[0123] 8) History of malignant tumors: Subjects with basal cell carcinoma, localized squamous cell carcinoma of the skin, or carcinoma in situ of the cervix may participate in this study if they have completed curative treatment for at least 12 months before signing the informed consent form; subjects with other malignant tumors may participate in this study if they have completed curative treatment for at least 5 years before signing the informed consent form;

[0124] 9) Hepatitis B surface antigen (HBsAg) positive or hepatitis C virus antibody (HCV Ab) positive at screening [further hepatitis B virus deoxyribonucleic acid (HBV DNA) titer test or hepatitis C virus ribonucleic acid (HCV RNA) test is required (exclusion is required if the test exceeds the lower limit of detection)], human immunodeficiency virus antibody (HIV Ab) positive, serum Treponema pallidum antibody (TP Ab) positive (further Treponema pallidum titer test is required, if positive, exclusion is required);

[0125] 10) Those who used prohibited drugs before screening, or changed the restricted concomitant medication within 30 days before screening (except those who stopped using restricted drugs for more than 5 half-lives before screening and planned not to use them during the test); If the subject used prohibited drugs before screening, they must stop taking the drugs for at least 5 half-lives before the screening visit (the specific half-life is subject to the instructions) before screening, and the drugs must be stopped during the entire test treatment period;

[0126] 11) Patients with a history of allergy to pregabalin, investigational drugs, acetaminophen, or other drugs or excipients with similar chemical structures;

[0127] 12) Those with a history of suicidal behavior or suicidal tendencies;

[0128] 13) Women who are pregnant, preparing to become pregnant, or breastfeeding during the test period; subjects who are unwilling to take reliable contraceptive measures (including condoms, spermicides, or intrauterine devices, etc.) from the signing of the ICF to the last administration of the trial drug within 28 days, or women who plan to use progestin-containing contraceptives during this period;

[0129] 14) Operators of dangerous machinery such as those engaged in high-altitude operations and motor vehicle driving during the test period;

[0130] 15) Participated in any other clinical tests within 30 days before screening;

[0131] 16) The tester determines that there are other circumstances that make it inappropriate to participate in the test.

[0132] Randomization criteria (after the completion of the lead-in period and before entering the double-blind treatment period, any of the following criteria must be met)

[0133] 1) Meet all inclusion criteria and do not meet any exclusion criteria;

[0134] 2) VAS pain score ≥40 mm during the run-in period and baseline visit;

[0135] 3) The daily pain numerical rating scale (NRS) score was ≥ 4 points during the 1-week run-in period, and the pain NRS assessment must have been completed for at least 4 days;

[0136] 4) subjects with less variability in daily NRS pain scores (the difference between any two NRS pain scores was less than 4 points) and a smaller placebo effect (the VAS score in V3 decreased by less than 30% compared with V1) during the 1-week run-in period;

[0137] 5) The compliance rate of the trial drugs during the lead-in period is 80-120%.

[0138] Test endpoint

[0139] Primary End Point

[0140] 1) Compare the change from baseline in ADPS at week 12 between compound (V) and placebo in the spinal cord lesion population;

[0141] 2) Compare the change from baseline in ADPS at week 12 between compound (V) and placebo in the overall population;

[0142] 3) Compare the changes in ADPS from baseline at week 12 between compound (V) and placebo in patients with central neuropathic pain after stroke.

[0143] Secondary End Points

[0144] 1) Evaluation of the ADPS response rate (proportion of subjects with a weekly ADPS decrease of ≥30% and ≥50% relative to baseline) between Compound (V) and placebo at Week 12 according to disease type and overall population;

[0145] 2) Compare the changes from baseline in weekly ADPS between Compound (V) and placebo from Weeks 1 to 12 by disease type and overall population;

[0146] 3) Evaluate the change from baseline in VAS score of Compound (V) compared with placebo at week 12 according to disease type and overall population;

[0147] 4) Evaluation of the change from baseline in the Short Form McGill Pain Questionnaire (SF-MPQ) score at Week 12 by compound (V) compared to placebo, according to disease type and overall population;

[0148] 5) Evaluation of the change from baseline in the Average Daily Sleep Disturbance Scale (ADSIS) score at Week 12 by disease type and overall population;

[0149] 6) Evaluate the effect of compound (V) compared with placebo on the quality of life of subjects as measured by the European 5-dimensional health scale, level 5 version (EQ-5D-5L) at week 12 according to disease type and overall population;

[0150] 7) Evaluation of the change from baseline in the Hospital Anxiety and Depression Scale (HADS) score at Week 12 for Compound (V) compared to placebo according to disease type and overall population;

[0151] 8) Changes from baseline in POMS-C scores for Compound (V) compared to placebo at week 12, according to disease type and overall population;

[0152] 9) Patient global impression of disease change (PGIC) at week 12, according to disease type and overall population;

[0153] 10) Changes from baseline in the SF-MPQ (including VAS) at week 52, evaluated by disease type and overall population;

[0154] 11) Changes in EQ-5D-5L scores compared to baseline at week 52, evaluated by disease type and overall population;

[0155] Pharmacokinetic indicators:

[0156] Plasma concentrations of compound (V) at specific time points (V4, V5, V6) within 12 weeks of oral administration in patients with central neuropathic pain.

[0157] Safety indicators:

[0158] To compare the AEs, laboratory tests, physical examinations, vital signs, and 12-lead ECG after 12 weeks of oral administration of Compound (V) and placebo, and to evaluate the safety and tolerability of Compound (V);

[0159] The safety and tolerability of Compound (V) were evaluated after oral administration for 52 weeks.

[0160] Test conclusion:

[0161] The above clinical test results show that compound (V) has good efficacy and safety in treating moderate to severe central nervous system pathological pain.

Claims

1. Use of a compound of formula (I) or its stereoisomers, tautomers, deuterated compounds, solvates, prodrugs, metabolites, pharmaceutically acceptable salts, cocrystals or combinations thereof in the preparation of a medicament for the treatment of central neuropathic pain, characterized in that Administering to a mammal an effective dose of a compound of formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, co-crystal or a combination thereof; The structure of formula (I) is as follows: Among them, R 1 combines with R 4 to form -(CR 9 R 9’ )n- or -CR 9 =CR 9’ -; R 1’ 、R 2 、R 3 、R 3’ 、R 4’ 、R 5 、R 5’ 、R 6 、R 9 or R 9’ each independently selected from H, F, Cl, Br, I, hydroxyl, amino, carboxyl, carboxylic acid ester group, amide group, cyano, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 thioalkyl, C 2-6 alkenyl, C 2-6 alkynyl, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the alkyl, alkoxy, thioalkyl, alkenyl, alkynyl, carbocyclic group or heterocyclic group is optionally further substituted by 0 to 6 substituents selected from F, Cl, Br, I, hydroxyl, amino, carboxyl, C 1-6 alkyl, a 3- to 6-membered carbocyclic group or a 3- to 6-membered heterocyclic group, and the heterocyclic group contains 1 to 2 heteroatoms selected from N, O or S; n is selected from 1, 2 or 3; The pharmaceutically acceptable salt is selected from benzenesulfonate, p-toluenesulfonate or mesylate.

2. The use according to claim 1, characterized in that, The compound of formula (I) is selected from one of the following structures:

3. The use according to claim 1 or 2, characterized in that, The central neuropathic pain includes post-stroke pain, spinal cord injury pain, Parkinson's disease pain and multiple sclerosis pain.

4. The use according to any one of claims 1-3, wherein the effective dose is calculated as the free base of formula (I), and the effective dose is 1-100 mg / day, preferably 5-20 mg / day.

5. The use according to claim 4, wherein the administration route of the compound of formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, co-crystal or a combination thereof is selected from injection, infusion, transdermal absorption, buccal absorption, parenteral intraperitoneal, rectal, buccal, intranasal, inhalation, topical delivery, subcutaneous, intralipid, intra-articular, intraperitoneal or intrathecal.

6. The use according to claim 5, wherein the administration route of the compound of formula (I) or a stereoisomer, tautomer, deuterated compound, solvate, prodrug, metabolite, pharmaceutically acceptable salt, co-crystal or a combination thereof is selected from intravenous injection, intravenous infusion, arterial injection, intramuscular injection, subcutaneous injection, intra-articular injection, intraperitoneal injection, intrathecal injection or intranasal.

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