Deuterated tetrahydrofuran nav1.8 inhibitor and use thereof

Abstract

The present invention belongs to the pharmaceutical field. Provided are a deuterated tetrahydrofuran NaV1.8 inhibitor and the use thereof. The NaV1.8 inhibitor comprises a compound as represented by formula I, or a pharmaceutically acceptable salt or solvate thereof, wherein R1 and R2 are each independently selected from H and a deuterated C1 - 3 alkyl. The deuterated tetrahydrofuran NaV1.8 inhibitor or a pharmaceutical composition containing same can significantly improve the pharmacokinetic properties of an NaV1.8 inhibitor, and can reduce the dosage and toxic side effects thereof. Specifically, the deuterated tetrahydrofuran NaV1.8 inhibitor exhibits an NaV1.8 channel activity IC50 of less than 0.1 nmol / L, an NaV1.8 inhibitory activity IC50 of less than 43 nmol / L, and an oral pharmacokinetic parameter t1 / 2 of 5.2±1.2 h. These pharmacodynamic and pharmacokinetic indices are all significantly superior to those of commercially available VX-548 preparations.

Description

Deuterated tetrahydrofuran NaV1.8 inhibitors and their uses Technical Field

[0001] This invention belongs to the pharmaceutical field, specifically relating to deuterated tetrahydrofuran NaV1.8 inhibitors and their uses. Background Technology

[0002] Electrical signals are the foundation for controlling a series of physiological processes, including pain signal transmission, and sodium ion channels are the main factor in initiating these signals. Voltage-gated sodium channels are multi-subunit transmembrane glycoproteins expressed on the cell membrane, composed of α and β subunits. The α subunit is a functional unit, consisting of four homologous transmembrane domains, each containing six transmembrane hydrophobic α-helices (S1-S6). S1-S4 constitute a voltage receptor, which can regulate the hydrophilicity of the sodium ion channel between S5 and S6, causing cell depolarization or hyperpolarization, thus completing the transmembrane signal transmission.

[0003] In the human body, there are nine different subtypes of the α subunit, designated NaV1.1–1.9. Their aberrant inactivation or activation is associated with various neurological, cardiovascular, and muscular diseases, with the four subtypes primarily related to pain being NaV1.3, NaV1.7, NaV1.8, and NaV1.9. NaV1.7 is present in sympathetic ganglion neurons and peripheral sensory neurons. NaV1.8 and NaV1.9 are expressed only in peripheral sensory neurons. Aberrant activation of these channels can cause analgesia or abnormal pain, providing potential targets for non-addictive analgesic mechanisms. NaV1.8, a tetrodotoxin-insensitive sodium channel primarily expressed on nociceptive neurons, plays a crucial role in pain signal transduction in the peripheral nervous system and is a major selective target for pain treatment. Because NaV1.8 is primarily distributed in pain-sensing neurons, the use of selective NaV1.8 inhibitors is unlikely to cause the adverse reactions common to non-selective NaV inhibitors. More importantly, NaV1.8 does not participate in central nervous system-related activities, so NaV1.8 inhibitors do not pose the addiction problems associated with opioids, nor do they affect motor function. VX-548 is an orally administered selective NaV1.8 inhibitor. Compared to other NaV ion channels, it exhibits high selectivity for NaV1.8 (approximately 30,000 times higher than other subtypes) and selectively produces an inhibitory effect. Compared to opioids, VX-548 provides better analgesia while avoiding side effects such as addiction. However, VX-548 has a short half-life in vivo, low bioavailability, and potential toxic side effects. Summary of the Invention

[0004] To overcome at least one technical problem existing in the prior art, one of the purposes of the present application is to provide a NaV1.8 inhibitor.

[0005] The second purpose of the present application is to provide a pharmaceutical composition.

[0006] The third purpose of the present application is to provide the use of the above-mentioned NaV1.8 inhibitor in the preparation of analgesic drugs.

[0007] To achieve the above-mentioned purposes, the technical solution adopted by the present application is:

[0008] The first aspect of the present application provides a NaV1.8 inhibitor, comprising a compound represented by Formula I or a pharmaceutically acceptable salt, solvate thereof;

[0009] wherein R1, R2 are each independently selected from H, deuterated C 1～3 alkyl.

[0010] Preferably, R1, R2 are each independently selected from H, deuterated C 1～2 alkyl.

[0011] Preferably, R1, R2 are each independently selected from H, -CD3, -CHD2, -CH2D, -CD2CD3, -CH2CD3 or -CD2CHD2, D is deuterium.

[0012] Preferably, R1, R2 are each independently selected from H, -CD3, -CHD2, -CH2D or -CD2CD3, D is deuterium.

[0013] Preferably, the compound represented by Formula I is selected from:

[0014] Preferably, the pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

[0015] The second aspect of the present application provides a pharmaceutical composition, comprising the NaV1.8 inhibitor of the first aspect of the present application and a pharmaceutically acceptable adjuvant.

[0016] Preferably, the dosage form of the pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalants, ointments, suppositories or patches.

[0017] Preferably, the amount of the NaV1.8 inhibitor is a therapeutically effective amount.

[0018] Preferably, the pharmaceutically acceptable excipients include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffering substances (such as phosphates, glycine, sorbic acid, or potassium sorbate), mixtures of saturated vegetable fatty acid metaglycerides, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene block polymers, lanolin, and sugars (such as lactose, glucose, and sucrose). Starch (such as corn starch and potato starch), cellulose and its derivatives (such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate), powdered tragacanth gum, malt, gelatin, talc, excipients (such as cocoa butter and suppository wax), oils (such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil), glycols (such as propylene glycol or polyethylene glycol), esters (such as ethyl oleate and ethyl laurate), agar, buffers (such as magnesium hydroxide and aluminum hydroxide), alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethanol, phosphate buffer solutions and other non-toxic and compatible lubricants (such as sodium lauryl sulfate and magnesium stearate), colorants, release agents, coating agents, sweeteners, flavorings, aromatics, preservatives and antioxidants, etc.

[0019] A third aspect of the present invention provides the use of the NaV1.8 inhibitor described in the first aspect of the present invention in the preparation of analgesic drugs.

[0020] Preferably, the analgesic drug is used to treat chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Toussaint syndrome, incontinence, pathological cough, or arrhythmia.

[0021] A fourth aspect of the invention provides a method for treating pain, the method comprising administering a therapeutically effective amount of the NaV1.8 inhibitor of the first aspect of the invention to a subject in need.

[0022] Preferably, the pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Toussaint syndrome, incontinence, pathological cough, or arrhythmia.

[0023] Preferably, the intestinal pain includes inflammatory bowel disease pain, Crohn's disease pain, or interstitial cystitis pain.

[0024] Preferably, the neuropathic pain includes postherpetic neuralgia, diabetic neuralgia, painful HIV-related sensory neuropathy, trigeminal neuralgia, burning mouth syndrome, post-amputation pain, phantom limb pain, painful neuroma, traumatic neuroma, Morton's neuroma, nerve entrapment injury, spinal stenosis, carpal tunnel syndrome, radicular pain, sciatica, nerve avulsion injury, brachial plexus avulsion injury, complex regional pain syndrome, drug-induced neuralgia, cancer chemotherapy-induced neuralgia, antiretroviral therapy-induced neuralgia, post-spinal cord injury pain, small fiber neuropathy, idiopathic small fiber neuropathy, idiopathic sensory neuropathy, or trigeminal autonomic headache.

[0025] Preferably, the musculoskeletal pain includes osteoarthritis pain, back pain, cold pain, burn pain, or toothache.

[0026] Preferably, the postoperative pain includes pain from joint replacement surgery, soft tissue surgery, hernia repair, bunion removal, or abdominoplasty.

[0027] The beneficial effects of this invention are: by using the deuterated tetrahydrofuran-based NaV1.8 inhibitor or a pharmaceutical composition containing it as described in this invention, the pharmacokinetic properties of the NaV1.8 inhibitor can be significantly improved, and the dosage and toxic side effects can be reduced. Specifically, the IC50 of the NaV1.8 channel activity is reduced. 50 Below 0.1 nmol / L, the inhibitory activity IC50 of NaV1.8 50 Below 43 nmol / L, oral pharmacokinetic parameter t 1 / 2 The efficacy and pharmacokinetic parameters were significantly better than those of the commercially available VX-548 formulation, with an efficacy of 5.2 ± 1.2 h. Detailed Implementation

[0028] The following examples provide a more detailed description of the specific implementation of the present invention, but the implementation and protection of the present invention are not limited thereto. It should be noted that any processes not specifically described below are methods that can be implemented or understood by those skilled in the art by referring to existing technology. Reagents or instruments whose manufacturers are not specified are all commercially available conventional products.

[0029] Example 1

[0030] This embodiment provides a NaV1.8 inhibitor, the structural formula of which is as follows:

[0031] The synthetic route of the NaV1.8 inhibitor in this embodiment is as follows:

[0032] The specific synthesis steps of the NaV1.8 inhibitor in this embodiment are as follows:

[0033] (1) Synthesis of intermediate 2

[0034] Intermediate 1 (5 mmol) and triethylamine (7.5 mmol) were dissolved in dichloromethane. Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 7.5 mmol) was added dropwise under ice bath conditions. After reacting for 0.5 h, dichloromethane was added again. The mixture was washed with saturated sodium bicarbonate solution and brine, and the organic phase was collected. The organic phase was dried with anhydrous sodium carbonate and concentrated to remove dichloromethane, yielding the intermediate to be used. Subsequently, 1,1,1-trifluoroprop-2-one-3,3,3-d3 (5 mmol) was dissolved in dichloromethane at -78 °C. A 1 mol / L solution of TiCl4 in dichloromethane (7.5 mmol) was added dropwise, followed by the dissolution of the intermediate to be used in dichloromethane and the addition of the solution. The reaction was continued for 2 h. After the reaction was confirmed to be complete by TLC, water was added to quench the reaction. After the reaction was heated to room temperature, dichloromethane was added for extraction. The organic phase was collected, dried, concentrated, and finally purified by column chromatography to obtain intermediate 2.

[0035] (2) Synthesis of intermediate 3

[0036] Intermediate 2 (5 mmol) was dissolved in toluene, and rhodium acetate (0.05 mmol) was added. The mixture was stirred at 100 °C for 2 h. After the reaction was confirmed to be complete by TLC, the mixture was filtered through diatomaceous earth, and the filtrate was concentrated to obtain intermediate 3.

[0037] (3) Synthesis of intermediate 4

[0038] Referring to the synthesis method of Example 3 in CN114945566A, the intermediate (4R,5R)-4,5-dimethyl-3-oxo-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid ethyl ester in the synthesis route of Example 3 in CN114945566A was replaced with intermediate 3 in this invention. Intermediate 4, namely (4S,5R)-3-(3,4-difluoro-2-methoxyphenyl)-4,5-bis(methyl-d3)-5-(trifluoromethyl)tetrahydrofuran-2-carboxylic acid, can be obtained through multiple steps of reaction.

[0039] (4) Synthesis of NaV1.8 inhibitors

[0040] Intermediate 4 (5 mmol) was dissolved in dichloromethane, and 0.5 mL of DMF was added. Oxaloyl chloride (8 mmol) was added dropwise under ice bath conditions, and the mixture was stirred for 0.5 h. The mixture was then brought to room temperature and reacted for another 1 h. The solvent was evaporated, dissolved in dichloromethane, and a solution of methyl 4-aminopyridine-2-carboxylate (5 mmol) and triethylamine (12 mmol) in dichloromethane was added dropwise. The reaction was allowed to proceed for 1 h. After the reaction was complete, the mixture was extracted with water, and the organic phase was collected, dried, and concentrated. It was then dissolved in methanol, and a methanol solution of 5 mol / L ammonia (10 mmol) was added. The reaction was allowed to proceed for 5 h at room temperature. After TLC detection to confirm the completeness of the reaction, the mixture was concentrated and separated by a chiral column to obtain the NaV1.8 inhibitor. The NMR data of the NaV1.8 inhibitor prepared in this example are as follows:

[0041] 1 ¹H NMR (400MHz, chloroform-d) δ 8.46 (d, J = 5.4 Hz, 1H), 8.32 (d, J = 2.1 Hz, 1H), 8.02–7.99 (m, 1H), 7.18 (d, J = 4.4 Hz, 1H), 7.00 (ddd, J = 8.3, 5.4, 2.1 Hz, 1H), 5.42 (d, J = 8.3 Hz, 1H), 4.78 (d, J = 5.7 Hz, 1H), 4.22 (d, J = 2.0 Hz, 1H), 3.97 (s, 3H), 2.98 (d, J = 2.0 Hz, 1H).

[0042] Example 2

[0043] This embodiment provides a NaV1.8 inhibitor, the structural formula of which is as follows:

[0044] The NaV1.8 inhibitor in this embodiment can be synthesized using the same method as in Example 1, except that ethyl 2-diazo-3-oxo-valerate is used as intermediate 1. The NMR data of the NaV1.8 inhibitor prepared in this embodiment are as follows:

[0045] 1 H NMR (400MHz, Chloroform-d) δ8.51(d,J=5.5Hz,1H),8.30(d,J=2.0Hz,1H),7.98(d,J=3.2Hz,1H),7.22(d,J=5.1Hz,1H),7.00–6.97( m,1H),5.45(d,J=7.6Hz,1H),4.74(d,J=5.2Hz,1H),4.21(d,J=2.0Hz,1H),3.96(s,3H),2.94(d,J=2.0Hz,1H),1.01(d,J=1.5Hz,3H).

[0046] Example 3

[0047] This embodiment provides a NaV1.8 inhibitor, the structural formula of which is as follows:

[0048] The NaV1.8 inhibitor in this embodiment can be synthesized using the same method as in Example 1, except that 1,1,1-trifluoroprop-2-one is used instead of 1,1,1-trifluoroprop-2-one-3,3,3-d3 in Example 1. The NMR data of the NaV1.8 inhibitor prepared in this embodiment are as follows:

[0049] 1 H NMR(400MHz,Chloroform-d)δ8.62(d,J=5.2Hz,1H),8.35(d,J=2.2Hz,1H),8.01–7.98(m,1H),7.21(d,J=5.0Hz,1H),7.00–6.98(m, 1H), 5.36 (d, J = 8.0Hz, 1H), 4.72 (d, J = 5.3Hz, 1H), 4.24 (d, J = 2.1Hz, 1H), 3.95 (s, 3H), 2.91 (d, J = 2.0Hz, 1H), 1.70 (d, J = 1.2Hz, 3H).

[0050] Performance testing:

[0051] (1) Navl.8 channel activity assay

[0052] The NaV1.8 inhibitors prepared in Examples 1-3 were dissolved in dimethyl sulfoxide (DMSO) to prepare a stock solution with a concentration of 30 mmol / L. An 11.5 logarithmic serial dilution was generated in DMSO, with a maximum concentration of 600 μmol / L. The test plate also included a positive control well, VX-548 (commercially available). The test plate was diluted 1:60 to ensure a final maximum concentration of the compound of 10 μmol / L and a DMSO content of 2%. The test sample and the control were added to the 384-well plate.

[0053] HEK293 cells stably expressing the human Nav1.8 sodium channel were used for testing. Nav1.8 sodium channel currents were recorded using whole-cell voltage-clamp technique at room temperature. Whole-cell voltage-clamp recording experiments were performed using an Axon patch 700B patch-clamp amplifier (Molecular Devices), a Digidata 1440A digital-to-analog converter (Molecular Devices), and glass microelectrodes were drawn from glass electrode blanks (World Precision Instruments) using a drawing machine (P97, Sutter). The tip resistance after perfusion with electrode fluid was approximately 1.5-2.5 MΩ. The glass microelectrodes were simply inserted into the amplifier probe to connect to the patch-clamp amplifier.

[0054] Electrophysiological stimulation protocol: After obtaining whole-cell recordings, wait 4-5 minutes at a -60mV clamp voltage until the intracellular fluid and electrode fluid reach equilibrium, then begin electrophysiological recording. Current stimulation and compound activity assay protocol: Clamp cells at -60mV, apply a depolarization voltage of +10mV for 20ms, then repolarize to -60mV at a stimulation frequency of 0.5Hz. Once the Nav1.8 sodium channel current has stabilized (approximately 1 minute), begin drug administration and continue until the cell current no longer changes (compound inhibition reaches steady state). Then calculate the inhibition rate using the following formula:

[0055] Inhibition rate (%) = [1 - magnitude of current after drug administration / magnitude of current before drug administration] × 100%

[0056] The IC50 values ​​of the NaV1.8 inhibitor and VX-548 prepared in Examples 1-3, calculated according to the above calculation method, were obtained. 50 The data is shown in Table 1 below.

[0057] Table 1 shows the IC50 values ​​of the NaV1.8 inhibitors and VX-548 prepared in Examples 1-3. 50 data

[0058] As shown in Table 1, the IC50 values ​​of the NaV1.8 inhibitors prepared in Examples 1-3 are... 50 The concentration was significantly lower than that of VX-548, and it exhibited better channel inhibitory activity of Navl.8 than VX-548.

[0059] (2) E-VIPR detection of Navl.8 inhibitory activity

[0060] HEK293 cells stably expressing the human Nav1.8 sodium channel were washed three times with 80 μL of buffer and added to each well, followed by 25 μL of hexyl dye solution. Cells were incubated at room temperature in the dark for 20 min. Then, 45 μL of stock solution (containing the NaV1.8 inhibitor or VX-548 prepared in Examples 1-3) was added to each well of the compound plate, and the cells were incubated at room temperature for 30 min. The cell plates containing the compound were read on an E-VIPR using a current-controlled amplifier, and stimulation pulses were applied using a symmetrical biphasic waveform. The electrical stimulation protocol was 1.25–4 amperes, delivered at 10 Hz with a 4 ms pulse width (depending on electrode composition), lasting 10 seconds. A 0.5-second pre-stimulation recording was performed on each well to obtain a baseline of unstimulated intensity. All E-VIPR responses were measured at a 200 Hz acquisition rate, and dose-response curves of the compound were plotted to calculate the IC50 of Nav1.8. 50 The values ​​are shown in Table 2 below.

[0061] Table 2 shows the NaV1.8 inhibitors and the NaV1.8 IC50 of VX-548 in Examples 1-3. 50 Value data

[0062] As shown in Table 2, the NaV1.8 inhibitors prepared in Examples 1-3 of this invention have lower NaV1.8 IC50 values ​​than VX-548. 50 The value indicates that the NaV1.8 inhibitors prepared in Examples 1-3 have higher NaV1.8 inhibitory activity.

[0063] (3) Pharmacokinetic experiments of the compound

[0064] Experimental instruments and materials:

[0065] High-speed refrigerated centrifuge, vortex shaker (Vortex Genius 3), high-speed centrifuge (Eppendorf 5415D), disposable syringes, pipettes (Eppendorf), male SD rats used in the experiment were all purchased from Yangzhou University, EDTA-K2 vacuum blood collection tubes, and physiological saline were used. All rats in the oral administration group were fasted for 12 hours before administration, but had free access to water and food during the administration period.

[0066] Experimental steps

[0067] The NaV1.8 inhibitor and VX-548 prepared in Example 1 were dissolved in a mixed solvent of DMSO, polyethylene glycol, and water (volume ratio 10:10:80) to prepare a clear solution. The oral administration dose of the compound was 10 mg / kg, and the tail vein administration dose was 2 mg / kg. At 2 min, 10 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after tail vein administration, 0.5 mL of blood was continuously collected from the fundus venous plexus and added to heparin tubes. At 5 min, 15 min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, and 24 h after oral administration, 0.5 mL of blood was continuously collected from the fundus venous plexus and added to heparin tubes. After centrifugation at 8000 rpm and 4 °C for 10 min, 0.15 mL of the supernatant plasma was collected and stored at -20 °C for LC-MS / MS analysis. The data were analyzed using the WinNolin non-compartmental model to obtain key pharmacokinetic parameters. The pharmacokinetic data of the NaV1.8 inhibitor and VX-548 in Example 1, obtained according to the above testing methods, are shown in Table 3 below.

[0068] Table 3 Pharmacokinetic Data

[0069] As shown in Table 3, compared with VX-548, the oral half-life of the NaV1.8 inhibitor prepared in Example 1 is significantly increased, which can effectively reduce the dosage and thus reduce the toxic side effects of high-dose administration. This indicates that the NaV1.8 inhibitor prepared in Example 1 has higher bioavailability.

[0070] The embodiments of the present invention have been described in detail above. However, the present invention is not limited to the above embodiments. Within the scope of knowledge possessed by those skilled in the art, various changes can be made without departing from the spirit of the present invention. Furthermore, the embodiments of the present invention and the features thereof can be combined with each other unless otherwise specified.

Claims

1. A NaV1.8 inhibitor, characterized in that: Including compounds represented by Formula I or pharmaceutically acceptable salts thereof; The compound represented by Formula I is selected from:

2. The NaV1.8 inhibitor according to claim 1, characterized in that: The pharmaceutically acceptable salt is selected from methanesulfonate, maleate, hydrochloride or phosphate.

3. A pharmaceutical composition, characterized in that: It includes the NaV1.8 inhibitor as described in any one of claims 1 to 2 and pharmaceutically acceptable excipients.

4. The pharmaceutical composition according to claim 3, characterized in that: The dosage form of the pharmaceutical composition is selected from capsules, powders, tablets, granules, pills, injections, syrups, oral liquids, inhalers, ointments, suppositories, or patches.

5. The use of the NaV1.8 inhibitor according to any one of claims 1 to 2 in the preparation of analgesic drugs.

6. The application according to claim 5, characterized in that: The analgesic is used to treat chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Toussy syndrome, incontinence, pathological cough, or arrhythmia.

7. A method for treating pain, characterized in that: This includes administering a therapeutically effective amount of the NaV1.8 inhibitor as described in any one of claims 1 to 2 to a subject in need.

8. The method according to claim 7, characterized in that: The pain includes chronic pain, intestinal pain, neuropathic pain, musculoskeletal pain, acute pain, inflammatory pain, cancer pain, idiopathic pain, postoperative pain, visceral pain, multiple sclerosis, Charcot-Marie-Toussaint syndrome, incontinence, pathological cough, or arrhythmia.

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