Compound C2230 and pharmaceutical compositions and uses thereof

Abstract

The application discloses a compound C2230 and a pharmaceutical composition and use thereof, and belongs to the technical field of chemical medicine research and development. Specifically provided are a compound shown in formula I, a tautomer, a stereoisomer, a hydrate, a solvate, a pharmaceutically acceptable salt or a prodrug thereof, a preparation method thereof, and use thereof in the preparation of medicines.

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical drug research and development, and specifically relates to compound C2230 and its pharmaceutical composition and use. Background Art

[0002] Pain is a multifaceted, debilitating condition that significantly reduces quality of life and afflicts millions of people worldwide. In the United States, pain management relies primarily on nonsteroidal anti-inflammatory drugs, traditional opioids, and adjunctive medications such as antidepressants and anticonvulsants. However, achieving comprehensive pain relief has proven difficult given the numerous side effects often associated with these treatments. To address this ongoing challenge, researchers have explored a variety of molecular targets, among which the voltage-gated CaV2.2 (N-type) calcium channel is a clinically successful target for pain relief.

[0003] CaV2.2 channels are key in pain signaling pathways. These channels are primarily expressed in primary afferent neurons and spinal cord terminals and play a central role in mediating the transmission of pain signals from the periphery to the central nervous system. Overexpression and overactivity of these channels can lead to hyperexcitability and increased release of excitatory neurotransmitters. Conversely, blocking CaV2.2 can lead to reduced neurotransmitter release and pain signals. Multiple lines of evidence support the role of CaV2.2 in nociceptive pathways. Studies of CaV2.2 knockout mouse models have shown that CaV2.2-deficient mice exhibit reduced pain-like behaviors, while gene silencing and pharmacological blockade of these channels alleviate pain symptoms.

[0004] Ziconotide (Prialt®) is a synthetic peptide derived from the conopeptide ω-conotoxin MVIIA that functions as a selective CaV2.2 inhibitor. Discovered over 40 years ago, it is considered the first non-opioid intrathecal analgesic approved by the US Food and Drug Administration (FDA) for the treatment of intractable chronic pain. Its effectiveness is hampered by its limited ability to cross the blood-brain barrier, necessitating intrathecal administration. Systemic administration of ziconotide can cause dizziness and sedation, while systemic administration can have profound hemodynamic effects. While pore blockers have shown promise in pain management, recent research has focused on identifying state- and use-dependent CaV2.2 inhibitors. TROX-1 is an orally available state- and use-dependent inhibitor of CaV2.2 channels with the potential to reverse pain-like behaviors. However, its further development faces challenges due to potential impairments in motor and cardiovascular function. While TROX-1 demonstrates pain relief efficacy, these side effects raise significant concerns, potentially hindering its development and clinical use. Therefore, there is still a need in this field to develop new CaV2.2-specific inhibitors to reduce the side effects of this type of drugs. Summary of the Invention

[0005] The present invention addresses the aforementioned deficiencies in the prior art by providing compound C2230, a pharmaceutical composition thereof, and its uses. Compound C2230 inhibits CaV2.2 channels heterologously expressed in HEK293T cells and natively in rat dorsal root ganglion and trigeminal ganglion neurons, reducing the release of excitatory neurotransmitters and successfully alleviating pain-like behaviors induced by spinal nerve ligation, avoiding nerve damage and exhibiting no off-target effects. This CaV2.2 inhibitor can be used to prepare pharmaceuticals to provide alternative treatment options for chronic pain.

[0006] To achieve the above object, the present invention adopts the following technical solutions:

[0007] The first object of the present invention is to provide a compound represented by formula (I), its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs:

[0008] .

[0009] A second object of the present invention is to provide a pharmaceutical composition comprising the compound as claimed in claim 1, its tautomers, stereoisomers, hydrates, solvates, pharmaceutically acceptable salts or prodrugs and a pharmaceutically acceptable excipient.

[0010] In the pharmaceutical composition, the compound or its pharmaceutically acceptable salt may be used in a therapeutically effective amount.

[0011] The third object of the present invention is to provide the use of the above-mentioned compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition as claimed in claim 2 in the preparation of a drug for inhibiting voltage-gated sodium ion channels.

[0012] Furthermore, the voltage-gated sodium ion channel is CaV2.2.

[0013] Furthermore, at a holding voltage of -50 mV, the half-maximal inhibitory concentration of the compound on CaV2.2 current was 1.1±0.2 μM.

[0014] Furthermore, at a holding voltage of -80 mV, the half-maximal inhibitory concentration of the compound on CaV2.2 current was 9.5±1.5 μM.

[0015] The fourth object of the present invention is to provide a compound, its tautomer, stereoisomer, hydrate, solvate, pharmaceutically acceptable salt or prodrug, or the composition as claimed in claim 2 for use in the preparation of a drug for treating, relieving or preventing pain.

[0016] Furthermore, the pain includes chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

[0017] A fifth object of the present invention is to provide a method for preparing the aforementioned compound, comprising: using 2-(tert-butyl)-4-methoxyphenol and epichlorohydrin as starting materials, dechlorinating to obtain the intermediate 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane; and reacting 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane with cyclopentylamine in an organic solvent by heating to obtain the aforementioned compound, 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol.

[0018] Furthermore, the temperature of the heating reaction is 140-150°C.

[0019] Definitions and Explanations of Terms

[0020] Unless otherwise specified, the terms and definitions used in this application, including the specification and claims, are as follows.

[0021] The term "pharmaceutically acceptable salt" refers to salts prepared from pharmaceutically acceptable acids (including inorganic and organic acids). Such acids include acetic acid, benzenesulfonic acid, benzoic acid, camphorsulfonic acid, citric acid, ethanesulfonic acid, fumaric acid, gluconic acid, glutamic acid, hydrobromic acid, hydrochloric acid, isethionic acid, lactic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, mucic acid, nitric acid, pantothenic acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, p-toluenesulfonic acid, and the like.

[0022] Examples of pharmaceutically acceptable salts include those formed from maleic acid, fumaric acid, benzoic acid, ascorbic acid, succinic acid, hydrochloric acid, sulfuric acid, bismethylenesalicylic acid, methanesulfonic acid, ethanedisulfonic acid, propionic acid, tartaric acid, salicylic acid, citric acid, gluconic acid, aspartic acid, stearic acid, palmitic acid, itaconic acid, glycolic acid, p-aminobenzoic acid, glutamic acid, benzenesulfonic acid, cyclamic acid, phosphoric acid, and nitric acid.

[0023] The term "pharmaceutical composition" refers to a mixture of one or more compounds described herein, or their physiologically / pharmaceutically acceptable salts or prodrugs, with other chemical components, such as physiologically / pharmaceutically acceptable carriers and excipients. The purpose of a pharmaceutical composition is to facilitate administration of the compound to an organism.

[0024] The term "excipient" refers to a pharmaceutically acceptable inert ingredient. Examples of the term "excipient" include, but are not limited to, binders, disintegrants, lubricants, glidants, stabilizers, fillers, and diluents. Excipients enhance the handling properties of pharmaceutical formulations, i.e., by increasing flowability and / or cohesiveness, making the formulation more suitable for direct compression.

[0025] The pharmaceutical excipients described herein can be those widely used in the pharmaceutical production field. Excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition. They can also provide methods to dissolve the active ingredient at a desired rate after administration to a subject, or to promote effective absorption of the active ingredient after administration of the composition to a subject. The pharmaceutical excipients described herein can be inert fillers, or can provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredient. The pharmaceutical excipients described herein can include one or more of the following: binders, suspending agents, emulsifiers, diluents, fillers, granulating agents, adhesives, disintegrants, lubricants, anti-adherents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, enhancers, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.

[0026] The pharmaceutical compositions of the present invention can be prepared according to the disclosed content using any method known to those skilled in the art, such as conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0027] The pharmaceutical compositions of the present invention can be administered in any form, including intravenous, mucosal, oral (solid and liquid formulations), inhalation, ophthalmic, rectal, topical, or parenteral (infusion, injection, implant, subcutaneous, intravenous, intraarterial, intramuscular) administration. The pharmaceutical compositions of the present invention can also be in controlled-release or delayed-release dosage forms (e.g., liposomes or microspheres). Examples of solid oral formulations include, but are not limited to, powders, capsules, caplets, softgels, and tablets. Examples of liquid formulations for oral or mucosal administration include, but are not limited to, suspensions, emulsions, elixirs, and solutions. Examples of topical formulations include, but are not limited to, emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops, or serum formulations. Examples of formulations for parenteral administration include, but are not limited to, solutions for injection, dry formulations that can be dissolved or suspended in a pharmaceutically acceptable carrier, suspensions for injection, and emulsions for injection. Examples of other suitable formulations of the pharmaceutical composition include, but are not limited to, eye drops and other ophthalmic preparations; aerosols such as nasal sprays or inhalers; liquid dosage forms suitable for parenteral administration; suppositories; and lozenges.

[0028] The term "prodrug" refers to a compound of the present invention that can be converted to a biologically active compound under physiological conditions or by solvolysis. Prodrugs of the present invention are prepared by modifying functional groups within the compound. These modifications can be removed by conventional procedures or in vivo to yield the parent compound. Prodrugs include compounds in which a hydroxyl group or an amino group within a compound of the present invention is attached to any group. When a prodrug of a compound of the present invention is administered to a mammalian subject, the prodrug is cleaved to form a free hydroxyl group or a free amino group, respectively.

[0029] The term "stereoisomer" refers to isomers resulting from different spatial arrangements of atoms in a molecule, including cis-trans isomers, enantiomers, diastereomers and conformational isomers.

[0030] The term "tautomer" refers to functional group isomers resulting from the rapid shift of an atom between two positions in a molecule. Compounds of the present invention may exhibit tautomerism. Tautomeric compounds can exist as two or more interconvertible species. Prototropic tautomers result from the migration of a covalently bonded hydrogen atom between two atoms. Tautomers generally exist in equilibrium, and attempts to isolate a single tautomer usually result in a mixture with physical and chemical properties consistent with a mixture of compounds. The position of equilibrium depends on the chemical properties within the molecule. For example, in many aliphatic aldehydes and ketones, such as acetaldehyde, the keto form predominates, while in phenols, the enol form predominates. The present invention encompasses all tautomeric forms of the compounds.

[0031] Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all within the scope of the present invention.

[0032] The compounds of the present invention may exist in specific geometric or stereoisomeric forms. All such compounds, including cis- and trans-isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, D-isomers, L-isomers, and racemic and other mixtures thereof, such as enantiomerically or diastereomerically enriched mixtures, are contemplated by the present invention and are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers and mixtures thereof are encompassed by the present invention.

[0033] Optically active (R)- and (S)-isomers, as well as D- and L-isomers, can be prepared by chiral synthesis or chiral reagents, or other conventional techniques. If a single enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (e.g., amino) or an acidic functional group (e.g., carboxyl), diastereomeric salts are formed with an appropriate optically active acid or base, followed by diastereomeric resolution by fractional crystallization or chromatography as is known in the art, and the pure enantiomers are recovered. Furthermore, separation of enantiomers and diastereomers is typically accomplished by chromatography using a chiral stationary phase, optionally combined with chemical derivatization (e.g., formation of carbamates from amines).

[0034] Compounds of the Invention The present invention also includes isotope-labeled compounds which are identical to the compounds defined in aspects 1 to 4 except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, fluorine, e.g. 3 H. 11 C. 14 C and 18 F. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0035] With respect to a drug or pharmacologically active agent, the term "effective amount" or "therapeutically effective amount" refers to a non-toxic amount of the drug or agent sufficient to achieve the intended effect. For the oral dosage forms of the present invention, an "effective amount" of an active substance in the composition means the amount required to achieve the intended effect when used in combination with another active substance in the composition. The determination of an effective amount varies from person to person, depending on the age and general condition of the recipient, as well as the specific active substance. The appropriate effective amount in each individual case can be determined by those skilled in the art through routine experimentation.

[0036] The terms "active ingredient," "therapeutic agent," "active substance," or "active agent" refer to a chemical entity that is effective in treating a target disorder, disease, or condition.

[0037] Compared with the prior art, the technical solution provided by the present invention has the following beneficial effects:

[0038] (1) The present invention provides a novel structure, excellent pharmacokinetic properties, and good efficacy or drugability of CaV2.2 inhibitors. They inhibit CaV2.2 channels in rat dorsal root ganglion and trigeminal ganglion neurons in a G protein-coupled receptor-independent manner, reducing the release of excitatory neurotransmitters. At the same time, the compound has strong specificity and maintains the activity of other channels unaffected. It can be used to effectively treat CaV2.2-related diseases and conditions.

[0039] (2) The compounds of the present invention have strong inhibitory activity on CaV2.2 ion channels;

[0040] (3) Compound C2230 of the present invention successfully alleviated pain-like behaviors induced by spinal nerve ligation, avoided nerve damage, and had no off-target effects;

[0041] (4) The compound C2230 of the present invention is a promising analgesic development lead compound that can provide an alternative treatment option for chronic pain. BRIEF DESCRIPTION OF THE DRAWINGS

[0042] Figure 1 Schematic diagram of the synthetic route of compound C2230 provided by the present invention;

[0043] Figure 2 To verify the activity of compound C2230 and characterize its calcium channel mechanism of action;

[0044] Figure 3 The effect of compound C2230 on rat DRG neurons;

[0045] Figure 4 The results of a pain reversal study of compound C2230 in a spinal nerve ligation (SNL)-induced model in mice. DETAILED DESCRIPTION

[0046] To make the purpose, technical solutions and advantages of the present invention clearer, the specific embodiments of the present invention are described in further detail below in conjunction with specific examples and accompanying drawings. Where specific techniques or conditions are not specified in the examples, the techniques or conditions described in the literature in this field or the product specifications are used. Where the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be obtained commercially.

[0047] Example 1

[0048] This example provides a method for preparing compound C2230.

[0049] refer to Figure 1 The preparation is carried out according to the synthetic process route shown in the figure, and the specific steps are as follows:

[0050] Step 1: NaH (60% oil suspension, 8.32 mmol) was slowly added to a solution of 2-(tert-butyl)-4-methoxyphenol (5.55 mmol) in anhydrous THF. After stirring at room temperature for 30 minutes, epichlorohydrin (16.6 mmol) was added to the solution, and the mixture was refluxed. After 24 hours, the mixture was concentrated on a rotary evaporator. The residue was partitioned between Et2O and 5% aqueous citric acid. The ether layer was collected, washed with water and brine, and dried over anhydrous Na2SO4. Rotary evaporation of the Et2O yielded crude 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane as a light yellow oil, which was used in the next step without further purification.

[0051] Step 2: A mixture of 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane (0.899 mmol) and cyclopentylamine (1.35 mmol) in EtOH was heated to 140°C for 5 minutes using microwave irradiation. The solution was cooled to room temperature, and the solvent was evaporated under reduced pressure. The resulting residue was then purified by flash column chromatography (gradient elution from 0% to 10% MeOH in CHCl) to provide 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol as a white solid, designated C2230.

[0052] The purity and structure of C2230 obtained by chemical synthesis were analyzed by RP-HPLC and NMR. The results showed that the purity of C2230 obtained by chemical synthesis was greater than 95% and the structure was correct. The structure of compound C2230 is as follows: Figure 2 As shown in A.

[0053] According to the synthesis route, the -OH in compound C2230 has a stereo configuration, and the potential configurations are shown in the following formulas (II) and (III):

[0054] ;

[0055] .

[0056] Example 2

[0057] Activity verification of compound C2230 and characterization of its calcium channel action mechanism.

[0058] Experimental Materials: HEK293T cells used in this study (all purchased from the Cell Bank of the Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences) were cultured at 37°C in 5% CO2 using complete medium. The complete medium used was a mixture of 10% fetal bovine serum and 1% penicillin-streptomycin (100 U / mL penicillin, 100 μg / mL streptomycin) added to Dulbecco's Modified Eagle Medium (DMEM) and stored sealed at 4°C. DMEM, fetal bovine serum, and penicillin-streptomycin were all purchased from Invitrogen.

[0059] The CaV2.2 plasmid was deposited at Hunan Normal University. The vector construction method was performed according to the literature (Gao, S., Yao, X.&Yan, N. Structure of human Ca(v)2.2 channel blocked by the painkillerziconotide. Nature 596, 143-147, doi:10.1038 / s41586-021-03699-6 (2021).). Other conventional reagents were purchased from SIGMA.

[0060] Experimental Methods: Human embryonic kidney 293T (HEK293T) cells were transfected with the CaV2.2 plasmid. HEK293T cells were cultured in 6-well plates. When cells reached 60–80% confluency, transfection was performed using a transfection reagent. 2 μg of CaV2.2 plasmid was added to each well, with the same amount of blank vector used as a reference. Twenty-four hours after transfection, the cells were trypsinized and transferred to individual small culture dishes for 3 hours. One dish of cells was removed from the incubator and observed under a microscope. A well-maintained slide was removed and gently rinsed with room-temperature equilibrated extracellular solution. The slide was then placed in a 35 × 10 mm culture dish containing 1.5 ml of electrode external solution. Patch clamp experiments were performed at room temperature (20–25°C). The internal solution of the electrode is: CsCl 120 mM, HEPES 20 mM, EGTA 10 mM, Na2-GTP 0.4 mM, Mg-ATP 5 mM, pH 7.2; the external solution of the electrode is: TEA-Cl 160 mM, BaCl2 2 mM, TTX 200 nM, glucose 10 mM, HEPES 10 mM, pH 7.4.

[0061] First, under an inverted microscope, select cells with smooth, complete, clear plasma membranes, strong three-dimensional sense, and uniform cytoplasm. Apply a slight positive pressure to form an outward convex liquid surface at the tip of the electrode to ensure that the electrode is clean when entering the water. It is best when the resistance measured after the electrode enters the liquid is 4 to 6 MΩ. Then compensate and eliminate the potential difference between the liquid inside the electrode and the liquid outside the electrode (liquid junction potential (LJ)). Use a micromanipulation system to continuously move the electrode closer to the cell. When the electrode is close to the cell membrane, the electrode resistance will gradually increase. When it increases by 0.5 MΩ, stop moving the electrode to release the positive pressure and apply negative pressure, so that the glass microelectrode is tightly adsorbed on the cell surface, and a gigahertz (1 GΩ=10 9 Ω) seal. Compensate for electrode fast capacitance. Clamp the cell membrane potential at -50 mV, then apply a brief, strong negative voltage to disrupt the small patch of cell membrane clamped by the electrode. Compensate for cell slow capacitance. After establishing whole-cell recording mode, clamp the cell potential to -80 mV and stabilize for approximately 5 minutes to allow equilibrium between the electrode fluid and intracellular components. Then, apply a depolarizing pulse to measure current. Recorded current signals are filtered using an EPC-10 patch clamp amplifier at both 3 kHz and 10 kHz. System series resistance is generally compensated between 60% and 80% and should remain within the 5-10 MΩ range throughout the experiment. CaV2.2 channels are tested at a voltage of +10 mV and a stimulation duration of 200 ms.

[0062] The experimental results are as follows Figure 2 As shown in Figure B, compound C2230 rapidly inhibits CaV2.2 currents at 5 μM in a voltage-dependent manner. Figure C shows that at holding voltages of -80 mV and -50 mV, C2230 at the same concentration exhibits higher inhibitory potency at -50 mV. A nonlinear fit of the inhibitory effects of different C2230 concentrations on CaV2.2 currents revealed corresponding 50% inhibitory concentrations of 1.1±0.2 μM (-50 mV) and 9.5±1.5 μM (-80 mV). Figure D shows the time course of inhibition of CaV2.2 channel currents by 20 μM C2230, demonstrating that C2230 binds to CaV2.2 channels rapidly and is partially eluted. As shown in Figure E, selectivity analysis of Kv2.1, NaV1.5, CaV1.2, CaV3.1, CaV3.2, and CaV3.3 channels at the clamping voltages of -80 mV and -50 mV showed more stable selectivity at -50 mV.

[0063] Example 3

[0064] Study on the effects of compound C2230 on rat DRG neurons.

[0065] (1) Experimental animals: Male SD rats, 8-10 weeks old, weighing 160-200 g (all rats used in this experiment were purchased from Changsha Shrek Jingda Experimental Animal Company).

[0066] (2) Experimental reagents and equipment: Trypsin, purchased from Sigma; collagenase type I, purchased from Sigma; DMEM culture medium; complete culture medium; surgical scissors; ophthalmic scissors; ophthalmic forceps; Venus scissors.

[0067] (3) Experimental method: Adult SD rats were killed by cervical dislocation. The spinal column was removed and the surrounding muscle tissue was removed with surgical scissors. The spinal column was washed in DMEM culture medium. The surface liquid was blotted dry with filter paper. The spinal column was cut open along the midline with ophthalmic scissors and placed in DMEM culture medium again for washing. The surface liquid was then blotted dry with filter paper. The spinal cord in the spinal column was gently opened with ophthalmic forceps. The dorsal root nerves at the thoracic and lumbar ends were removed and placed in a culture dish containing DMEM culture medium. The dorsal root ganglia were then separated using Venus scissors under a stereomicroscope. The dorsal root ganglia were transferred to a small amount of DMEM culture medium and minced. Digestion solution (0.66 mg trypsin and 1.56 mg type I collagenase dissolved in 5 mL of DMEM culture medium) was added and digested at 37°C with shaking for 20 min. The mixture was gently pipetted every 5 min to mix. Complete culture medium was added to terminate the digestion and centrifuged at 800 rpm for 5 min at room temperature. Discard the supernatant and add an appropriate amount of complete culture medium to resuspend the cells. Evenly add the resuspended cells onto a 15 mm glass slide that has been pre-soaked with poly-lysine in a 12-well plate. After standing for about 45 minutes, add 1 mL of complete culture medium to each well and return to the incubator for 3-5 hours. Electrophysiological experiments can be performed after the cells have attached to the wall.

[0068] The results are as follows Figure 3 As shown in Figures A and B, at a clamping voltage of -50 mV, C2230 at 5 and 10 μM strongly attenuated CaV2.2 currents and current density, while 50 μM of C2230 almost eliminated these currents at depolarization voltages ranging from -20 mV to +50 mV. GPCR receptors interact with CaV2.2, and higher depolarization voltages can dissolve the interaction. Figure 3 As shown in Figures C and D, after depolarizing voltage, the inhibitory effect of C2230 on CaV2.2 activity was not changed, indicating that C2230 does not inhibit CaV2.2 activity in a G protein-coupled receptor-independent manner.

[0069] Example 4

[0070] Compound C2230 was investigated for pain reversal in a spinal nerve ligation (SNL)-induced model in male and female mice.

[0071] Experimental animals: 100 C57bl / 6j mice, 7-8 weeks old, weighing 16-20 g, half male and half female, were purchased from Changsha Shrek Jingda Laboratory Animal Company.

[0072] Experimental reagents and equipment: C2230; physiological saline; isoflurane, purchased from Shanghai Bioengineering; 4.0 silk thread, 1 / 2 round needle suture needle, scalpel, hemostatic forceps, ophthalmic scissors, ophthalmic forceps, Venus scissors.

[0073] Experimental Methods: C57bl / 6j mice were anesthetized with isoflurane and placed in the prone position on the operating table. The lumbar spine and hip bones were shaved and skin prepared. After disinfection with iodine, a 2 cm incision was made near the hip bone along the spine. The fascia and muscles were separated to expose the L5 transverse process. The L5 transverse process was carefully bitten off with forceps to expose the L5 nerve. The L5 nerve was then separated with a glass needle and ligated with a 5-0 ligature. The muscle and skin were sutured and disinfected. Fourteen days after surgery, plantar pain thresholds were measured in the model mice. Male mice were randomly divided into two groups of eight. Drugs were administered intrathecally in each group. Plantar pain thresholds were measured at 0, 1, 2, 3, 4, and 5 hours after drug administration. Statistical results are expressed as mean ± SEM. One-way ANOVA was used for statistical analysis. P < 0.05 was considered statistically significant.

[0074] The experimental results are as follows Figure 4 As shown in Figures A and B, SNL caused mechanical allodynia in mice 14 days after injury (time point 0). Intraperitoneal administration of C2230 (10 mg / kg) dose-dependently reduced SNL-induced mechanical allodynia in male mice and increased the area under the curve (AUC) compared to vehicle-treated mice.

[0075] In the absence of conflict, the above embodiments and features in the embodiments may be combined with each other.

[0076] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. Compounds represented by formula (I), enantiomers, and pharmaceutically acceptable salts: 。 2. A pharmaceutical composition, characterized in that The invention comprises the compound, enantiomers and pharmaceutically acceptable salts as claimed in claim 1.

3. Use of the compound, enantiomer, pharmaceutically acceptable salt of claim 1, or the composition of claim 2 in the preparation of a drug for inhibiting voltage-gated sodium ion channels.

4. The use according to claim 3, characterized in that The voltage-gated sodium ion channel is CaV2.

2.

5. The use according to claim 4, characterized in that At a holding voltage of -50 mV, the half-maximal inhibitory concentration of the compound on CaV2.2 current was 1.1±0.2 μM.

6. The use according to claim 4, wherein At a holding voltage of -80 mV, the half-maximal inhibitory concentration of the compound on CaV2.2 current was 9.5±1.5 μM.

7. Use of the compound, enantiomer, pharmaceutically acceptable salt according to any one of claims 1 or the composition according to claim 2 in the preparation of a drug for treating, alleviating or preventing pain.

8. The use according to claim 7, characterized in that The pain includes chronic pain, acute pain, inflammatory pain, cancer pain, neuropathic pain, musculoskeletal pain, primary pain, intestinal pain and idiopathic pain.

9. A method for preparing the compound according to claim 1, characterized in that: 2-(tert-butyl)-4-methoxyphenol and epichlorohydrin are used as starting materials, and dechlorination is performed to obtain the intermediate 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane. 2-((2-(tert-butyl)-4-methoxyphenoxy)methyl)oxirane is then reacted with cyclopentylamine in an organic solvent by heating to obtain the compound, 1-(2-(tert-butyl)-4-methoxyphenoxy)-3-(cyclopentylamino)propan-2-ol.

10. The preparation method according to claim 9, characterized in that The temperature of the heating reaction is 140-150°C.

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