Twin medicine and composition and application thereof

Abstract

The invention discloses a twin drug with analgesic effect and application thereof, the twin drug is formed by connecting a drug A and a drug B through a chemical bond, the drug A is a TRPV1 agonist, and the drug B is lipoic acid, pregabalin, gabapentin, melogabalin or clinigabalin. Meanwhile, the invention also comprises a preparation method of the twin drug, and application of the twin drug or pharmaceutically acceptable salts and compositions thereof in preparation of drugs for preventing and treating pains or nervous system diseases. The twin drug can significantly improve the water solubility of the TRPV1 agonist, has a long-acting analgesic effect on different types of pains such as inflammatory pains and neuralgia, and has an analgesic effect superior to that of a composition of the two components and then superior to that of a single component. Meanwhile, twin drugs show a more lasting analgesic effect and have a good application prospect.

Description

Technical Field

[0001] The present invention belongs to the field of medicine, and relates to a class of twin drugs with therapeutic effects, a preparation method, a composition and their applications. Background Art

[0002] Pain is a public health problem that seriously affects the quality of life of patients. Therefore, actively and effectively treating pain is of great significance. With the increasing population and the accelerating trend of social aging, the incidence of pain has also increased. Currently, it affects approximately 20% of the global population, causing a huge social burden. In recent years, with the continuous clarification of the pain mechanism, it has been found that the occurrence and development of pain are characterized by multi-mechanism and multi-factor interactions, with different mechanisms influencing and regulating each other. Based on the above results, researchers have proposed the "multimodal analgesia" strategy. Twin drugs are one of the effective strategies for implementing multimodal analgesia programs. It refers to the covalent combination and connection of two identical or different lead compounds or drugs to form a new multifunctional molecule, which exerts its effects in the body, enhancing the drug efficacy, reducing side effects, improving pharmacokinetic properties, or increasing the selectivity of action. Compared with the combined use of multiple drugs and compound drugs, twin drugs can reduce the dosage, improve the treatment effect, have uniform pharmacokinetic characteristics, avoid drug interactions and the resulting toxic and side effects, and improve patient compliance.

[0003] The transient receptor potential vanilloid 1 (TRPV1) is a novel ion channel discovered by David Julius, the winner of the 2021 Nobel Prize in Physiology or Medicine. TRPV1 is mainly highly expressed on C and some Aδ nociceptive sensory nerves, especially those nerves (nociceptors) that detect pain or noxious sensations. Therefore, the activation of TRPV1 leads to the perception of pain, a process known as nociception. The TRPV1 receptor is a non-selective cation channel with a multimodal activation mechanism: temperature > 42°C, low pH < 6.5, osmotic pressure changes, arachidonic acid metabolites, etc. The TRPV1 channel is famous for mediating the perception of spicy compounds, and its activators include synthetic capsaicin (Nonivamide) and plant-derived components such as capsaicin, resiniferatoxin, piperine, gingerone, camphor, and eugenol. Synthetic capsaicin is structurally closely related to capsaicin and has a very similar effect on the target receptor TRPV1. Synthetic capsaicin has been shown to have similar desensitizing activity. Synthetic capsaicin can cause TRPV1 activation and Ca 2+ influx, leading to receptor desensitization of the TRPV1 ion channel and even ablation of peripheral nerve endings. TRPV1 receptor desensitization reduces the response of TRPV1 to endogenous ligands or inflammatory mediators, thereby reducing TRPV1-dependent hyperalgesia, and ablation of peripheral nerve endings is necessary for analgesia induced by mechanical hyperalgesia.

[0004]

[0005] α-lipoic acid (ALA) is mainly present in animal organs, such as muscle and liver tissues, and is present in very low levels in plant-based foods. ALA is a potent antioxidant with low toxicity and has been studied in randomized controlled trials for the treatment of pain symptoms in different diseases. The anti-nociceptive effects of ALA have been observed in multiple pain models, including cancer pain, chemotherapy-induced neuropathic pain, neuropathic pain observed in multiple sclerosis, and diabetic polyneuropathy. Previous studies on rats have shown that ALA has an inhibitory effect on the V3.2 type calcium channels of rat dorsal root ganglion sensory neurons, and it has been reported that local injection of ALA can reduce the sensation of heat and mechanical stimuli. ALA has a relieving effect on visceral pain in rats, and the analgesic mechanism is due to ALA inhibiting sodium channels, blocking sodium channels, and reducing their cellular synthesis, especially the V1.8 type sodium channels in the colonic sensory nerves of diabetic rats. In a study on paclitaxel-induced neuropathy in rats, ALA relieves pain by activating the nuclear erythroid 2-related factor pathway. In addition, although most randomized controlled trials have evaluated the population of diabetic polyneuropathy, some studies have verified the potential efficacy of ALA in other diseases, such as chemotherapy-induced neuropathy, burning mouth syndrome, migraine, and carpal tunnel syndrome.

[0006] Voltage-gated calcium channel blockers VGCCs are classified into subtypes such as L-type (regulating cardiovascular function), T-type (involved in epilepsy and heart rhythm), N / P / Q-type (mediating neurotransmitter release), etc. according to the α 1 subunit, and the α 2 -δ subunit, as a transmembrane regulatory element, can enhance the stability of channel inactivation through a conformational locking effect and inhibit its membrane trafficking. This subunit-specific binding avoids the cardiovascular side effects of traditional calcium channel blockers. As typical representatives of VGCCs, pregabalin [1-(aminomethyl)cyclohexaneacetic acid] and gabapentin [(S)-3-(aminomethyl)-5-methylhexanoic acid] were initially used for anti-convulsion and have now become first-line drugs for the treatment of neuropathic pain. Although both are structural analogs of γ-aminobutyric acid (GABA), they exert analgesic effects by specifically binding to the α 2 -δ subunit of voltage-gated calcium channels. By a steric hindrance effect, they inhibit calcium ion influx and reduce the release of excitatory neurotransmitters (such as glutamate, substance P, and calcitonin gene-related peptide) from the presynaptic membrane, thereby reducing the excessive excitability of central and peripheral neurons; at the same time, they inhibit central sensitization by regulating synaptic plasticity and block the transmission and amplification of pain signals. However, clinical data show that only 40%-60% of patients have obtained pain relief. In addition, pregabalin and gabapentin also have a series of side effects, such as shortness of breath and ataxia. Existing studies have confirmed that the combination drug strategy can effectively improve the efficacy and reduce the toxic and side reactions.

[0007] Summary of the Invention

[0008] Object of the Invention: The first object of the present invention is to provide a twin-drug small molecule compound with analgesic effect, the second object is to provide a pharmaceutical composition containing the compound, the third object is to provide a preparation method of the compound, and the fourth object is to provide the uses of the compound and its pharmaceutical composition.

[0009] To achieve the above objects, the present invention provides the following technical solutions: The twin-drug with analgesic effect of the present invention is formed by connecting drug A and drug B through a chemical bond. Drug A is a TRPV1 agonist, and drug B is lipoic acid or a voltage-gated calcium channel blocker.

[0010] Preferably, drug A is selected from capsaicin or synthetic capsaicin.

[0011] Preferably, the voltage-gated calcium channel blocker in drug B is selected from pregabalin, gabapentin, melegabalin, and clesgabalin.

[0012] Preferably, the chemical structure of the twin-drug shown in claim 4 of the present invention is as follows:

[0013]

[0014] Capsaicin or synthetic capsaicin is covalently linked to lipoic acid, pregabalin, and gabapentin through the hydroxyl terminus.

[0015] The present invention adopts a "multi-modal analgesia" strategy to prepare a twin-drug by covalently bonding a TRPV1 agonist with lipoic acid or a voltage-gated calcium channel blocker. The synthesized twin-drug releases the TRPV1 agonist and the single drug of lipoic acid or the voltage-gated calcium channel blocker through a hydrolysis process when entering the body, and produces an analgesic effect through multiple analgesic mechanisms to obtain a better analgesic effect, reduce dose-related side effects, and better meet the clinical medication needs. Therefore, the twin-drug of the analgesic drug TRPV1 agonist and lipoic acid or the voltage-gated calcium channel blocker has broad application prospects for the treatment of pain.

[0016] The pharmaceutical composition of the present invention contains the compound of the present invention, as well as a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier.

[0017] Preferably, the pharmaceutically acceptable carrier may be an excipient widely used in the field of drug production. Excipients are mainly used to provide a safe, stable and functional pharmaceutical composition, and can also provide methods to enable the active ingredient to dissolve at a desired rate after the subject receives the administration, or to promote the effective absorption of the active ingredient after the subject receives the composition administration. The pharmaceutical excipient may be an inert filler, or provide a certain function, such as stabilizing the overall pH value of the composition or preventing the degradation of the active ingredient of the composition. The pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesive agent, glidant, wetting agent, gelling agent, absorption retardant, dissolution inhibitor, enhancer, adsorbent, buffer, chelating agent, preservative, coloring agent, flavoring agent and sweetening agent.

[0018] The pharmaceutical composition of the present invention can be prepared by any method known to those skilled in the art according to the disclosed content. For example, conventional mixing, dissolving, granulating, emulsifying, grinding, encapsulating, embedding or freeze-drying processes.

[0019] The pharmaceutical composition of the present invention can be administered in any form, including injection (intravenous), mucosal, oral (solid and liquid preparations), inhalation, ocular, rectal, topical or parenteral (infusion, injection, implantation, subcutaneous, intravenous, intra-arterial, intramuscular) administration. The pharmaceutical composition of the present invention can also be a controlled-release or sustained-release dosage form (such as liposomes or microspheres). Examples of solid oral preparations include but are not limited to powders, capsules, caplets, soft gelatin capsules and tablets. Examples of liquid preparations for oral or mucosal administration include but are not limited to suspensions, emulsions, elixirs and solutions. Examples of topical preparations include but are not limited to emulsions, gels, ointments, creams, patches, pastes, foams, lotions, drops or serum preparations. Examples of preparations for parenteral administration include but are not limited to injection solutions, dry powder preparations that can be dissolved or suspended in a pharmaceutically acceptable carrier, injection suspensions and injection emulsions. Examples of other suitable preparations of the pharmaceutical composition include but are not limited to eye drops and other ophthalmic preparations: aerosols, such as nasal sprays or inhalants; liquid dosage forms suitable for parenteral administration; suppositories and lozenges.

[0020] The preparation method of compound 1-6 described in claim 4 of the present invention comprises the following steps:

[0021]

[0022] (1) Protect the amino group in the structure of gabapentin, pregabalin, melegabalin or cligabalin to obtain intermediate I;

[0023] (2) The intermediate I obtained in step (1) is subjected to a condensation reaction with a TRPV1 agonist under the action of a catalyst to obtain intermediate II;

[0024] (3) The protecting group of the intermediate II obtained in step (2) is removed under acidic, basic or neutral conditions to obtain the compound.

[0025] Wherein R 1 is selected from Boc, Cbz, Fomc, Alloc protecting groups, and is defined as described above.

[0026] Preferably, the amino protecting agent in step (1) is selected from di-tert-butyl dicarbonate (Boc2O), benzyl chloroformate (Cbz-Cl), 9-fluorenylmethyl chloroformate (Fmoc-Cl) or allyl chloroformate (Alloc-Cl), and the molar ratio of gabapentin, pregabalin, γ-aminobutyric acid, melegabalin or cligabalin to the amino protecting agent is 1:(1-10).

[0027] Preferably, the catalyst in step (2) is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI), 4-dimethylaminopyridine (DMAP), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HBTU), 6-chlorobenzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate (HCTU) or 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU), and the molar ratio of intermediate I, intermediate II and the catalyst is 1:(1-3):(0.01-10), and the reaction solvent is selected from dichloromethane, acetonitrile, acetone or tetrahydrofuran.

[0028] Preferably, the acidic, basic or neutral conditions in step (3) are selected from the conditions in the presence of ethyl acetate hydrogen chloride gas, trifluoroacetic acid, tetraethylammonium fluoride, tetramethylammonium fluoride, triethylamine, trimethylsilyl iodide or pyridine.

[0029] Use of a class of twin drugs, the use of a compound or a pharmaceutically acceptable salt thereof or a composition of twin drugs in the preparation of a drug for preventing or treating pain and / or nervous system diseases.

[0030] As a preferred technical solution of the present invention, the pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia and visceral pain.

[0031] As a preferred technical solution of the present invention, the neurological disease is pain, epilepsy, anxiety, depression, personality disorder, cognitive disorder, emotional disorder, neurodegenerative disease, convulsive disease, schizophrenia, head disease, neurodegenerative disease, insomnia and restless legs syndrome.

[0032] Beneficial effects: Compared with the prior art, the present invention has the following remarkable advantages:

[0033] TRPV1 and voltage-gated ion channels (especially VGCCs) form functional complementarity through calcium signal homeostasis, molecular interaction and pathway coordination in pain signal transmission. Therefore, based on the multimodal analgesia strategy, making TRPV1 agonists and lipoic acid or VGCCs into twin drugs provides a new strategy for the treatment of refractory pains such as neuropathic pain and chronic inflammatory pain. The present invention condenses capsaicin or synthetic capsaicin with lipoic acid, pregabalin or gabapentin to prepare twin drugs. While improving the water solubility of synthetic capsaicin, it can also produce analgesic effects through multiple analgesic mechanisms to obtain better analgesic effects, reduce dose-related side effects, and better meet the clinical medication needs. The compounds of the present invention can not only significantly improve various acute and chronic inflammatory pains, but also relieve paclitaxel-induced peripheral neuropathic pain. Since these in vivo pharmacological models are closely related to pain, the compounds or their compositions provided by the present invention have the potential to treat pain-related diseases. Description of the Drawings

[0034] Figure 1 Schematic diagram of the analgesic effect on mechanical pain of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), Compound 7, Compound 8 and Compound 7 in a carrageenan-induced acute inflammatory pain model; wherein A, C, E and G are the analgesic time-effect curves of carrageenan-treated mice for mechanical pain, and B, D, F and H are the time-effect relationships of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), Compound 7, Compound 8 and Compound 7 represented by AUC graphs, respectively.

[0035] Figure 2Schematic diagram of the analgesic effect on mechanical pain of capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 5), and synthetic capsaicin-gabapentin (Compound 6) in a carrageenan-induced acute inflammatory pain model; wherein A, C, and E are the analgesic time-effect curves of capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 5), and synthetic capsaicin-gabapentin (Compound 6) on mechanical pain in carrageenan-treated mice, respectively, and B, D, and F are the time-effect relationships of capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 5), and synthetic capsaicin-gabapentin (Compound 6) represented by AUC graphs, respectively.

[0036] Figure 3 Schematic diagram of the analgesic effect of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) in a paclitaxel-induced neuropathic pain model; wherein A, C, and E are the analgesic time-effect curves of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) on mechanical pain in paclitaxel-treated mice, respectively, and B, D, and F are the time-effect relationships of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) represented by AUC graphs, respectively.

[0037] Figure 4 Schematic diagram of the comparison of the pharmacodynamic effects of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) with equimolar amounts of synthetic capsaicin, lipoic acid, pregabalin, or gabapentin alone and in combination in a carrageenan-induced acute inflammatory pain model;

[0038] Figure 5 Schematic diagram of the comparison of the pharmacodynamic effects of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) with equimolar amounts of synthetic capsaicin, lipoic acid, pregabalin, or gabapentin alone and in combination in a paclitaxel-induced neuropathic pain model;

[0039] Figure 6 Schematic diagram of the analgesic effect on mechanical pain of synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) at high doses in a carrageenan-induced acute inflammatory pain model;

[0040] Figure 7Schematic diagram of the analgesic effect of synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) in a paclitaxel-induced neuropathic pain model;

[0041] Figure 8 Schematic diagram of the change in the number of times mice scratched their ears after applying synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) to the ears of mice in the ear scratching experiment;

[0042] Figure 9 Schematic diagram of the change in the number of times mice scratched their eyes after dropping synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) into the eyes of mice in the corneal irritation experiment; Detailed implementation mode

[0043] The embodiments of the present invention will be described in detail below in conjunction with the accompanying drawings, so that the advantages and features of the present invention can be more easily understood by those skilled in the art, thereby making a clearer and more definite definition of the protection scope of the present invention. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention.

[0044] The present invention provides a class of linked drugs with analgesic effects and their compositions. The linked drug is formed by connecting drug A and drug B through a chemical bond. Drug A is capsaicin and synthetic capsaicin, and drug B is lipoic acid, pregabalin or gabapentin.

[0045] The present invention also provides a method for preventing or treating diseases, which comprises administering a therapeutically effective amount of the compound of the present invention to a subject in need. The diseases include pain and / or nervous system diseases, wherein the pain-related diseases are acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia and visceral pain, and the nervous system diseases are pain syndrome, epilepsy, anxiety, cognitive impairment, emotional disorder and neurodegenerative diseases.

[0046] Example 1: Synthesis of 2-methoxy-4-(nonanoylaminomethyl)phenyl (R)-5-(1,2-dithiolan-3-yl)pentanoate (synthetic capsaicin-lipoic acid, Compound 1)

[0047] The synthesis route is as follows:

[0048]

[0049] In a 100 mL round-bottom flask, 20 mL of dichloromethane was added, along with capsaicin (0.59 g, 2 mmol, 1.0 eq), lipoic acid (0.50 g, 2.4 mmol, 1.2 eq), DMAP (0.024 g, 0.2 mmol, 0.1 eq). After stirring, EDCI (0.46 g, 2.4 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature. The reaction process was monitored by TLC. After 3 hours, the reaction of capsaicin was basically complete. The reaction solution was adjusted to pH 9 - 10 with saturated sodium bicarbonate. After extraction, the organic layer was adjusted to pH 5 - 6 with 1 mol / L hydrochloric acid and extracted again. The organic layer was washed once with water (10 mL) and once with saturated sodium chloride solution (10 mL), and finally dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain 1.1 g of a crude product as a white powder. The crude product was purified by a chromatographic column (DCM:MeOH = 15:1) to obtain capsaicin - lipoic acid (Compound 1) as a white powder, 0.68 g, with a yield of 70.6%.

[0050] 1 H NMR (500 MHz, Chloroform - d) δ6.94 (d, J = 8.0 Hz, 1H), 6.87 (d, J = 1.9 Hz, 1H), 6.81 (dd, J = 8.1, 1.9 Hz, 1H), 5.93 (s, 1H), 4.37 (d, J = 5.5 Hz, 2H), 3.79 (s, 3H), 3.62 - 3.55 (m, 1H), 3.20 - 3.08 (m, 2H), 2.58 (t, J = 7.4 Hz, 2H), 2.52 - 2.41 (m, 1H), 2.19 (t, J = 7.6 Hz, 2H), 1.96 - 1.86 (m, 1H), 1.83 - 1.67 (m, 4H), 1.67 - 1.47 (m, 4H), 1.34 - 1.20 (m, 10H), 0.86 (t, J = 6.9 Hz, 3H). (+)-ESI - MS: m / z 482.2395 (calcd. 482.2393 for C 25 H 40 NO 4 S 2 + [M + H] + )。

[0051] Example 2: Synthesis of (E)-2 - methoxy - 4 - ((8 - methylnon - 6 - enamido)methyl)phenyl (R)-5-(1,2 - dithiolan - 3 - yl)pentanoate (capsaicin - lipoic acid, Compound 2)

[0052] The synthetic route is as follows:

[0053]

[0054] In a 100 mL round-bottom flask, 20 mL of dichloromethane, capsaicin (0.61 g, 2 mmol, 1.0 eq), lipoic acid (0.50 g, 2.4 mmol, 1.2 eq), DMAP (0.024 g, 0.2 mmol, 0.1 eq) were added. After stirring, EDCI (0.46 g, 2.4 mmol, 1.2 eq) was added and the reaction was carried out at room temperature. The reaction process was monitored by TLC. After 3 hours, the reaction of capsaicin was basically complete. The reaction solution was adjusted to pH 9 - 10 with saturated sodium bicarbonate, and after extraction, the organic layer was adjusted to pH 5 - 6 with 1 mol / L hydrochloric acid, and then extracted again. The organic layer was washed once with water (10 mL) and once with saturated saline solution (10 mL), and finally dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain 1.1 g of a crude product as a white powder. The crude product was purified by a chromatographic column (DCM:MeOH = 15:1) to obtain 0.69 g of capsaicin-lipoic acid (Compound 2) as a white powder, with a yield of 69.9%.

[0055] 1 H NMR (500 MHz, Chloroform-d) δ 6.98 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 1.8 Hz, 1H), 6.85 (dt, J = 8.2, 1.3 Hz, 1H), 5.84 (s, 1H), 5.42 - 5.30 (m, 1H), 4.41 (d, J = 5.7 Hz, 2H), 3.82 (d, J = 1.5 Hz, 3H), 3.61 (dq, J = 8.5, 6.4 Hz, 1H), 3.24 - 3.11 (m, 2H), 2.61 (t, J = 7.3 Hz, 2H), 2.50 (m, 1H), 2.22 (td, J = 7.7, 2.1 Hz, 2H), 2.03 - 1.92 (m, 2H), 1.85 - 1.74 (m, 4H), 1.70 - 1.49 (m, 4H), 1.41 (tt, J = 9.7, 6.5 Hz, 2H), 1.33 - 1.21 (m, 2H), 1.20 - 1.11 (m, 1H), 0.97 (d, J = 6.7 Hz, 6H). (+)-ESI-MS: m / z 494.2395 (calcd. 494.2393 for C 26 H 40 NO 4 S 2 + [M + H] + )。

[0056] Example 3: Synthesis of 2-methoxy-4-(nonanoylaminomethyl)phenyl (R)-3-(aminomethyl)-5-methylhexanoate hydrochloride (synthesized capsaicin-pregabalin, Compound 3)

[0057] The synthetic route is as follows:

[0058]

[0059] Step 1: Synthesis of (S)-3-(((tert-butoxycarbonyl)amino)methyl)-5-methylhexanoic acid (1A)

[0060] In a 100 mL round-bottom flask, add pregabalin (1.6 g, 10 mmol, 1.0 eq), 1 mol / L aqueous sodium hydroxide solution (0.8 g, 20 mmol, 2.0 eq). While stirring, add a mixed solution of di-tert-butyl dicarbonate (2.65 g, 12 mmol, 1.2 eq) and 25 mL of dioxane dropwise. After stirring at room temperature for 2 hours, monitor the reaction by TLC until pregabalin has completely reacted. Cool the reaction solution to room temperature, add dichloromethane (3 × 15 mL) for extraction, combine the aqueous phases, add NaHCO 3 Adjust the pH to 4 - 5, add dichloromethane (3 × 20 mL) for extraction again, combine the organic layers. The organic layer is washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain 2.11 g of 1A as a white solid powder with a yield of 81.1%. 1 1H NMR (500 MHz, Chloroform-d) δ 4.80 (t, J = 6.5 Hz, 1H), 3.25 (dt, J = 14.0, 5.3 Hz, 1H), 3.08 (dt, J = 14.0, 6.9 Hz, 1H), 2.40 - 2.23 (m, 2H), 2.14 (dp, J = 19.3, 8.2, 6.4 Hz, 1H), 1.68 (dh, J = 13.1, 6.6 Hz, 1H), 1.47 (d, J = 12.7 Hz, 9H), 1.23 - 1.11 (m, 2H), 0.92 (dd, J = 8.8, 6.6 Hz, 6H). (+)-ESI-MS: m / z 260.1872 (calcd. 260.1856 for C 13 1H 26 NO 4 + [M + H] + ).

[0061] Step 2: Synthesis of 2-methoxy-4-(nonanoylaminomethyl)phenyl (S)-3-((tert-butoxycarbonyl)amino)-5-methylhexanoate (1B)

[0062] In a 100 mL round-bottom flask, 20 mL of dichloromethane was added, and capsaicin (0.59 g, 2 mmol, 1.0 eq), 1A (0.62 g, 2.4 mmol, 1.2 eq), DMAP (0.024 g, 0.2 mmol, 0.1 eq) were added. After stirring, EDCI (0.46 g, 2.4 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature. The reaction process was monitored by TLC. After 3 hours, the reaction of capsaicin was basically complete. The reaction solution was adjusted to pH 9 - 10 with saturated sodium bicarbonate, and after extraction, the organic layer was adjusted to pH 5 - 6 with 1 mol / L hydrochloric acid, and then extracted again. The organic layer was washed once with water (10 mL) and once with saturated sodium chloride solution (10 mL), and finally dried over anhydrous sodium sulfate, filtered, and rotary evaporated to obtain 1.3 g of a crude product as a white powder. The crude product was purified by a chromatographic column (DCM:MeOH = 15:1) to obtain 0.88 g of 1B as a white powder, and the yield was 84.5%. (+)-ESI-MS: m / z 521.3589 (calcd. 521.3585 for C 29 H 49 N 2 O 6 + [M+H] + ).

[0063] Step 3: Synthesis of 2-methoxy-4-(nonanoylaminomethyl)phenyl (R)-3-(aminomethyl)-5-methylhexanoate hydrochloride (Compound 3)

[0064] In a 100 mL round-bottom flask, 0.80 g of the product 1B from Step 3 was added, and it was dissolved with ethyl acetate (a small amount of methanol was added dropwise). While stirring, a saturated ethyl acetate / HCl (adjusted to pH 2 - 4) solution was added dropwise, and the mixture was stirred at room temperature. The reaction process was monitored by TLC. A large amount of white solid precipitated during the reaction process. After 2 hours, 1B was basically completely reacted. It was filtered by suction, and the filter cake was dried under reduced pressure to obtain 0.65 g of a white solid (Compound 3), and the yield was 81.25%. 1 H NMR (500 MHz, DMSO-d 6)δ 8.39 (t, J = 6.0 Hz, 1H), 8.19 (t, J = 5.9 Hz, 3H), 7.03 - 6.97 (m, 2H), 6.81 (d, J = 9.0 Hz, 1H), 4.24 (d, J = 5.9 Hz, 2H), 3.75 (s, 3H), 2.86 - 2.81 (m, 2H), 2.79 (d, J = 5.5 Hz, 1H), 2.55 (dd, J = 16.0, 7.4 Hz, 1H), 2.24 (p, J = 6.7 Hz, 1H), 2.13 (t, J = 7.4 Hz, 2H), 1.68 (dt, J = 13.3, 6.7 Hz, 1H), 1.51 (t, J = 7.2 Hz, 2H), 1.27 (m, 12H), 0.88 (dd, J = 6.5, 3.5 Hz, 6H), 0.85 (t, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, DMSO) δ 172.66, 170.47, 150.94, 139.40, 138.26, 122.80, 119.52, 112.14, 56.07, 42.24, 42.19, 40.55, 36.37, 35.81, 31.78, 31.72, 29.23, 29.16, 29.08, 25.81, 24.93, 22.99, 22.89, 22.55, 14.42. (+)-ESI-MS: m / z 435.3131 (calcd. 435.3127 for C 25 H 43 N 2 O 4 + [M + H] + )。

[0065] Example 4: Synthesis of 2-methoxy-4-(nonanamidomethyl)phenyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride (synthetic capsaicin-gabapentin, Compound 4)

[0066] The synthetic route is as follows:

[0067]

[0068] Step 1: Synthesis of 2-(1-((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetic acid (2A)

[0069] In a 100 mL round-bottom flask, gabapentin (1.7 g, 10 mmol, 1.0 eq) and 1 mol / L aqueous sodium hydroxide solution (0.8 g, 20 mmol, 2.0 eq) were added. While stirring, a mixed solution of di-tert-butyl dicarbonate (2.65 g, 12 mmol, 1.2 eq) and 25 mL of dioxane was added dropwise. After stirring at room temperature for 2 hours, TLC monitoring showed that pregabalin had completely reacted. The reaction solution was cooled to room temperature, and dichloromethane (3 × 15 mL) was added for extraction. The aqueous phases were combined, and NaHCO 3 was added to adjust the pH to 4 - 5. Dichloromethane (3 × 20 mL) was added again for extraction. The organic layers were combined, washed with 15 mL of saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain 2.21 g of 2A as a white solid powder, with a yield of 81.4%. (+)-ESI-MS: m / z 272.1866 (calcd. 272.1856 for C 14 H 26 NO 4 + [M + H] + ).

[0070] Step 2: Synthesis of 2-methoxy-4-(nonanoylaminomethyl)phenyl (S)-3-((tert-butoxycarbonyl)amino)-5-methylhexanoate (2B)

[0071] In a 100 mL round-bottom flask, 20 mL of dichloromethane, capsaicin (0.59 g, 2 mmol, 1.0 eq), 2A (0.62 g, 2.4 mmol, 1.2 eq), and DMAP (0.024 g, 0.2 mmol, 0.1 eq) were added. After stirring, EDCI (0.46 g, 2.4 mmol, 1.2 eq) was added, and the reaction was carried out at room temperature. The reaction process was monitored by TLC. After 3 hours, the reaction of capsaicin was basically complete. The pH of the reaction solution was adjusted to 9 - 10 with saturated sodium bicarbonate. After extraction, the pH of the organic layer was adjusted to 5 - 6 with 1 mol / L hydrochloric acid, and extraction was carried out again. The organic layer was washed once with water (10 mL) and once with saturated brine solution (10 mL), and finally dried over anhydrous sodium sulfate, filtered, and concentrated by rotary evaporation to obtain 1.3 g of the crude product as a white powder. The crude product was purified by a chromatographic column (DCM:MeOH = 15:1) to obtain 0.86 g of 2B as a white powder, with a yield of 69.6%. (+)-ESI-MS: m / z 547.3745 (calcd. 547.3742 for C 31 H 51 N 2 O 6 + [M + H] + ).

[0072] Step 3: Synthesis of 2-methoxy-4-((nonanamido)methyl)phenyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride (Compound 4)

[0073] In a 100 mL round-bottom flask, add 0.80 g of the product 2B from Step 3, dissolve it with ethyl acetate (a small amount of methanol was added dropwise), while stirring, dropwise add saturated ethyl acetate / HCl (adjust the pH to 2 - 4) solution, stir at room temperature, monitor the reaction process by TLC. A large amount of white solid precipitated during the reaction process. After 2 hours, 1B was basically completely reacted. Filter by suction, and after drying the filter cake under reduced pressure, 0.58 g of white solid (Compound 4) was obtained, with a yield of 72.5%.

[0074] 1 H NMR (500 MHz, DMSO-d 6 ) δ 8.43 (t, J = 6.0 Hz, 1H), 8.22 (t, J = 5.8 Hz, 3H), 7.00 (d, J = 8.4 Hz, 2H), 6.81 (d, J = 8.1 Hz, 1H), 4.24 (d, J = 5.8 Hz, 2H), 3.74 (s, 3H), 2.95 (q, J = 5.9 Hz, 2H), 2.75 (s, 2H), 2.13 (t, J = 7.4 Hz, 2H), 1.98 (s, 1H), 1.61 - 1.29 (m, 10H), 1.28 - 1.15 (m, 10H), 0.84 (t, J = 6.9 Hz, 3H). 13 C NMR (126 MHz, DMSO-d 6 ) δ 172.67, 169.59, 150.89, 139.44, 138.18, 122.87, 119.52, 112.14, 60.21, 56.09, 45.47, 42.18, 38.50, 35.82, 32.58, 31.72, 29.24, 29.16, 29.08, 25.81, 25.61, 22.56, 21.14, 14.41. (+)-ESI-MS: m / z 447.3219 (calcd. 447.3217 for C 26 H 43 N 2 O 4 + [M + H] + )。

[0075] Example 5: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl (R)-3-(aminomethyl)-5-methylhexanoate hydrochloride (Capsaicin-Pregabalin, Compound 5)

[0076] The synthesis route is as follows:

[0077]

[0078] Step 1: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl (S)-3-((tert-butoxycarbonyl)amino)-5-methylhexanoate (3B)

[0079] In a 100 mL round-bottom flask, add 20 mL of dichloromethane, capsaicin (0.61 g, 2 mmol, 1.0 eq), 1A (0.62 g, 2.4 mmol, 1.2 eq), DMAP (0.024 g, 0.2 mmol, 0.1 eq). After stirring, add EDCI (0.46 g, 2.4 mmol, 1.2 eq) and react at room temperature. Monitor the reaction process by TLC. After 3 hours, the capsaicin reaction is basically complete. Adjust the pH of the reaction solution to 9 - 10 with saturated sodium bicarbonate, extract, and then adjust the pH of the organic layer to 5 - 6 with 1 mol / L hydrochloric acid, extract again. Wash the organic layer once with water (10 mL) and once with saturated brine solution (10 mL), and finally dry with anhydrous sodium sulfate, filter, rotary evaporate to obtain 1.3 g of a crude product as a white powder. The crude product is purified by a chromatographic column (DCM:MeOH = 15:1) to obtain 0.81 g of 3B as a white powder, with a yield of 76.0%. (+)-ESI-MS: m / z 533.3589 (calcd. 533.3585 for C 30 H 49 N 2 O 6 + [M + H] + ).

[0080] Step 2: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl (R)-3-(aminomethyl)-5-methylhexanoate hydrochloride (Compound 5)

[0081] In a 100 mL round-bottom flask, add 0.79 g of the product 3B from Step 3, dissolve it with ethyl acetate (add a small amount of methanol dropwise), and while stirring, dropwise add a saturated ethyl acetate / HCl (adjust the pH to 2 - 4) solution. Stir at room temperature and monitor the reaction process by TLC. A large amount of white solid precipitates during the reaction process. After 2 hours, 3B is basically completely reacted. Filter by suction, and after drying the filter cake under reduced pressure, obtain 0.67 g of a white solid (Compound 5), with a yield of 69.3%. (+)-ESI-MS: m / z 447.3215 (calcd. 447.3217 for C 26 H 43 N 2 O 4 +[M+H] + )。

[0082] Example 6: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride (capsaicin-gabapentin, Compound 6)

[0083] The synthetic route is as follows:

[0084]

[0085] Step 1: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(1-(((tert-butoxycarbonyl)amino)methyl)cyclohexyl)acetate (4B)

[0086] In a 100 mL round-bottom flask, add 20 mL of dichloromethane, capsaicin (0.61 g, 2 mmol, 1.0 eq), 2A (0.62 g, 2.4 mmol, 1.2 eq), DMAP (0.024 g, 0.2 mmol, 0.1 eq). After stirring, add EDCI (0.46 g, 2.4 mmol, 1.2 eq) and react at room temperature. Monitor the reaction process by TLC. After 3 hours, the reaction of capsaicin is basically complete. Adjust the pH of the reaction solution to 9 - 10 with saturated sodium bicarbonate, extract, and then adjust the pH of the organic layer to 5 - 6 with 1 mol / L hydrochloric acid, extract again. Wash the organic layer with water (10 mL) once, saturated saline solution (10 mL) once, and finally dry with anhydrous sodium sulfate, filter, and rotary evaporate to obtain 1.3 g of a crude product as a white powder. The crude product is purified by a chromatographic column (DCM:MeOH = 15:1) to obtain 0.86 g of 4B as a white powder, with a yield of 77.0%. (+)-ESI-MS: m / z 559.3749 (calcd. 559.3742 for C 32 H 51 N 2 O 6 + [M+H] + )。

[0087] Step 2: Synthesis of (E)-2-methoxy-4-((8-methylnon-6-enamido)methyl)phenyl 2-(1-(aminomethyl)cyclohexyl)acetate hydrochloride (Compound 6)

[0088] In a 100 mL round-bottom flask, 0.86 g of the product 4B from Step 3 was added and dissolved in ethyl acetate (with a small amount of methanol added dropwise). While stirring, a saturated ethyl acetate / HCl solution (adjusted to pH 2 - 4) was added dropwise. Stirring was carried out at room temperature, and the reaction process was monitored by TLC. A large amount of white solid precipitated during the reaction. After 2 hours, 4B was basically completely reacted. Filtration was carried out by suction, and the filter cake was dried under reduced pressure to obtain 0.66 g of a white solid (Compound 6), with a yield of 66.7%. 1 H NMR(500MHz, Chloroform-d)δ6.99(d, J=7.9Hz, 1H), 6.94(s, 1H), 6.81(d, J=8.1Hz, 1H), 5.47 - 5.24(m, 2H), 4.75(brs, 3H), 4.37(s, 2H), 3.78(s, 3H), 3.11(s, 2H), 2.82(s, 2H), 2.40(t, J=7.5Hz, 2H), 2.25(q, J=6.6Hz, 1H), 2.09 - 1.93(m, 2H), 1.70 - 1.48(m, 10H), 1.39(t, J=7.3Hz, 2H), 1.27(h, J=3.3Hz, 2H), 0.96(dd, J=6.8Hz, 6H).(+)-ESI-MS: m / z 459.3275(calcd.459.3271 for C 27 H 43 N 2 O 4 + [M+H] + )。

[0089] Example 7: Synthesis of 2-(2-Methoxy-4-(nonanoylaminomethyl)phenoxy)-2-oxoethyl (R)-5-(1,2-dithiolan-3-yl)valerate (Compound 7)

[0090]

[0091] Step 1: Synthesis of 2-Methoxy-4-(nonanoylaminomethyl)phenyl 2-Chloroacetate (5B)

[0092] Add 0.88 g (3 mmol, 1.0 eq) of synthetic capsaicin, 0.9 g (9 mmol, 3.0 eq) of triethylamine, and 30 mL of DCM to a 100 mL round-bottom flask. After stirring, add 0.46 g (3.6 mmol, 1.2 eq) of chloroacetyl chloride and react at room temperature. Monitor the reaction process by TLC. The raw materials are basically reacted after twenty minutes. Quench the reaction with water. Adjust the pH of the reaction solution to 7 - 8 with 1 mol / L hydrochloric acid. Extract with dichloromethane (20 mL). Wash the organic layer with water (20 mL) once and saturated sodium chloride solution (10 mL) once. Finally, dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain 1.4 g of a brown solid. Elute through a chromatographic column. Remove the impurities at the solvent front with DCM in turn, and then elute the product with (DCM:MeOH = 150:1). After rotary evaporation and standing, 0.76 g of 5B is obtained as a white crystalline solid, and the yield is 68.45%. (+)-ESI-MS: m / z 370.1784 (calcd. 370.1780 for C 19 H 29 ClNO 4 + [M + H] + ).

[0093] Step 2: Synthesis of 2-(2-methoxy-4-(nonanoylaminomethyl)phenoxy)-2-oxoethyl (R)-5-(1,2-dithiolan-3-yl)pentanoate (Compound 7)

[0094] Add 0.74 g (2 mmol, 1.0 eq) of 5B, 0.413 g (2 mmol, 1.0 eq) of lipoic acid, 33.2 mg (0.2 mmol, 0.1 eq) of potassium iodide, 0.28 g (2.6 mmol, 1.3 eq) of sodium carbonate, and 20 mL of dimethyl sulfoxide to a 100 mL round-bottom flask. React at 75 °C. Monitor the reaction process by TLC. The raw materials are basically reacted after 3 hours. Wash away the dimethyl sulfoxide with water (200 mL), and extract three times with dichloromethane (30 mL). Wash the organic layer with saturated sodium chloride (20 mL), then dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain 0.86 g of a brown oil. Purify by eluting through a chromatographic column (DCM:MeOH = 250:1; 300 - 400 mesh silica gel) to obtain 0.78 g of Compound 7 as a pale yellow oil, and the yield is 72.46%. 11H NMR (500 MHz, Chloroform-d) δ 7.01 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.1, 1.9 Hz, 1H), 5.77 (s, 1H), 4.89 (s, 1H), 4.41 (d, J = 5.4 Hz, 2H), 3.81 (s, 3H), 3.60 - 3.47 (m, 1H), 3.19 - 3.06 (m, 1H), 2.46 (t, J = 7.4 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 1.93 - 1.81 (m, 2H), 1.68 (m, 6H), 1.55 - 1.41 (m, 2H), 1.36 - 1.18 (m, 12H), 0.89 - 0.85 (m, 3H). (+)-ESI-MS: m / z 539.2381 (calcd. 539.2375 for C 27 H 42 NO 6 S 2 + [M + H] + )。

[0095] Example 8: Synthesis of (((2-Methoxy-4-(nonanoylaminomethyl)phenoxy)carbonyl)oxy)methyl (R)-5-(1,2-dithiolan-3-yl)pentanoate (Compound 8)

[0096]

[0097] Step 1: Synthesis of Chloromethyl (2-methoxy-4-(nonanoylaminomethyl)phenyl) carbonate (6B)

[0098] Add 0.88 g (3 mmol, 1.0 eq) of synthetic capsaicin, 0.9 g (9 mmol, 3.0 eq) of triethylamine, and 30 mL of DCM to a 100 mL round-bottom flask. After stirring, add 0.46 g (3.6 mmol, 1.2 eq) of chloroformyl chloride and react at room temperature. Monitor the reaction process by TLC. The raw materials are basically reacted after 20 minutes. Quench the reaction with water, adjust the pH of the reaction solution to 7 - 8 with 1 mol / L hydrochloric acid, extract with dichloromethane (20 mL). Wash the organic layer with water (20 mL) once and saturated brine solution (10 mL) once, and finally dry with anhydrous sodium sulfate, filter, and rotary evaporate to obtain 1.4 g of a brown solid. Elute through a chromatographic column, remove the impurities at the solvent front with DCM in turn, and then elute the product with (DCM:MeOH = 150:1). Rotary evaporate and let stand to obtain 0.82 g of 6B as a white crystalline solid, with a yield of 70.59%. (+)-ESI-MS: m / z 386.1725 (calcd. 386.1729 for C19 H 29 ClNO 5 + [M+H] + )。

[0099] Step 2: Synthesis of (((2-methoxy-4-(nonanoylaminomethyl)phenoxy)carbonyl)oxy)methyl (R)-5-(1,2-dithiolan-3-yl)pentanoate (Compound 8)

[0100] Add 0.77 g (2 mmol, 1.0 eq) of 6B, 0.413 g (2 mmol, 1.0 eq) of lipoic acid, 33.2 mg (0.2 mmol, 0.1 eq) of potassium iodide, 0.28 g (2.6 mmol, 1.3 eq) of sodium carbonate, and 20 mL of dimethyl sulfoxide to a 100 mL round-bottom flask, and react at 75 °C. Monitor the reaction process by TLC. The raw materials are basically reacted after 3 hours. Wash off the dimethyl sulfoxide with water (200 mL), and extract three times with dichloromethane (30 mL). Wash the organic layer with saturated brine (20 mL), dry it over anhydrous sodium sulfate, filter, and rotary evaporate to obtain 0.85 g of a brown oil. Purify it by column chromatography elution (DCM:MeOH = 250:1; 300 - 400 mesh silica gel) to obtain 0.77 g of Compound 8 as a pale yellow oil, with a yield of 76.70%. 1 H NMR (500 MHz, Chloroform-d) δ 7.08 (d, J = 8.1 Hz, 1H), 6.91 (d, J = 1.9 Hz, 1H), 6.84 (dd, J = 8.1, 1.9 Hz, 1H), 5.85 (s, 2H), 5.79 (t, J = 7.3 Hz, 1H), 4.41 (d, J = 5.7 Hz, 2H), 3.83 (s, 3H), 3.60 - 3.52 (m, 1H), 3.22 - 3.05 (m, 2H), 2.42 (t, J = 7.4 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 1.90 (m, 1H), 1.74 - 1.61 (m, 7H), 1.56 - 1.41 (m, 2H), 1.27 (m, 10H), 0.87 (t, J = 6.9 Hz, 3H). (+)-ESI-MS: m / z 556.2393 (calcd. 556.2397 for C 27 H 42 NO 7 S 2 + [M+H] + )。

[0101] Example 9: Synthesis of 1-(((2-Methoxy-4-(nonanoylaminomethyl)phenoxy)carbonyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate (Compound 9)

[0102]

[0103] Step 1: Synthesis of 1-chloroethyl (2-methoxy-4-(nonanoylaminomethyl)phenyl) carbonate (7B)

[0104] Add 0.88 g (3 mmol, 1.0 eq) of synthetic capsaicin, 0.9 g (9 mmol, 3.0 eq) of triethylamine, and 30 mL of DCM to a 100 mL round-bottom flask. After stirring, add 0.46 g (3.6 mmol, 1.2 eq) of chloroethyl chloroformate and react at room temperature. Monitor the reaction process by TLC. The raw materials are basically reacted completely in twenty minutes. Quench the reaction with water. Adjust the pH of the reaction solution to 7 - 8 with 1 mol / L hydrochloric acid. Extract with dichloromethane (20 mL). Wash the organic layer with water (20 mL) once and saturated sodium chloride solution (10 mL) once. Finally, dry over anhydrous sodium sulfate, filter, and rotary evaporate to obtain 1.4 g of a brown solid. Elute through a chromatographic column. Remove the impurities at the solvent front with DCM in sequence, and then elute the product with (DCM:MeOH = 150:1). Rotary evaporate and let stand to obtain 0.91 g of 7B as a white crystalline solid, with a yield of 76.12%. (+)-ESI-MS: m / z 400.1890 (calcd. 400.1885 for C 20 H 31 ClNO 5 + [M + H] + ).

[0105] Step 2: Synthesis of 1-(((2-Methoxy-4-(nonanoylaminomethyl)phenoxy)carbonyl)oxy)ethyl 5-((R)-1,2-dithiolan-3-yl)pentanoate (Compound 9)

[0106] Add 0.80 g (2 mmol, 1.0 eq) of 7B, 0.413 g (2 mmol, 1.0 eq) of lipoic acid, 33.2 mg (0.2 mmol, 0.1 eq) of potassium iodide, 0.28 g (2.6 mmol, 1.3 eq) of sodium carbonate, and 20 mL of dimethyl sulfoxide into a 100 mL round-bottom flask and react at 75 °C. Monitor the reaction process by TLC. The raw materials are basically reacted after 3 hours. Wash off the dimethyl sulfoxide with water (200 mL) and extract three times with dichloromethane (30 mL). Wash the organic layer with saturated brine (20 mL), dry it over anhydrous sodium sulfate, filter, and rotary evaporate to obtain 0.96 g of a brown oil. Purify it by column chromatography elution (DCM:MeOH = 250:1; silica gel 300 - 400 mesh) to obtain 0.75 g of compound 7 as a pale yellow oil, with a yield of 65.49%. 1 H NMR(500MHz, Chloroform-d)δ6.95(d, J = 8.0Hz, 1H), 6.89(dd, J = 7.6, 1.9Hz, 1H), 6.83(dd, J = 8.0, 1.9Hz, 1H), 5.83(s, 1H), 4.40(d, J = 5.5Hz, 2H), 3.80(s, 3H), 3.63 - 3.55(m, 1H), 3.22 - 3.06(m, 2H), 2.58(t, J = 7.4Hz, 2H), 2.51 - 2.44(m, 1H), 2.20(t, J = 7.7Hz, 2H), 1.96 - 1.85(m, 2H), 1.83 - 1.70(m, 3H), 1.64(t, J = 7.2Hz, 3H), 1.62 - 1.46(m, 3H), 1.38 - 1.13(m, 12H), 0.87(t, J = 6.9Hz, 3H). (+)-ESI-MS: m / z 570.2559(calcd.570.2554 for C 28 H 44 NO 7 S 2 + [M + H] + )。

[0107] Example 10: Determination of the water solubility of compounds 3 - 6;

[0108] Solubility is one of the most important properties affecting the bioavailability of drugs, and the solubility of drugs is closely related to their oral absorption in the body. In this study, the solubilities of compounds 3 - 6 in pure water, 0.9% normal saline, and 5% glucose injection were tested.

[0109] Weigh approximately 3 mg of synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), and capsaicin-gabapentin (Compound 6) separately and place them in test tubes. Add 10 μL of purified water, 0.9% normal saline, and 5% glucose injection at intervals and vortex until dissolved. The results are shown in Table 1. Capsaicin and synthetic capsaicin are insoluble in water at room temperature.

[0110] Table 1 Equilibrium solubility values of Compounds 3-6

[0111]

[0112] Example 11: Evaluation of the analgesic effects of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), capsaicin-gabapentin (Compound 6), Compound 7, Compound 8, and Compound 9 in a carrageenan-induced acute inflammatory pain model

[0113] (1) Experimental method

[0114] Experimental animals: ICR mice (22-30 g), female, were housed in an environment with a constant temperature of (22 ± 3) °C and a relative humidity of 55 ± 5%, and were subjected to a 12-hour light / dark cycle.

[0115] Drug preparation method: Synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), Compound 7, Compound 8, and Compound 9 were dissolved in 5% DMSO solution; synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), and capsaicin-gabapentin (Compound 6) were dissolved in normal saline; carrageenan was prepared as a 1% solution in normal saline.

[0116] Drug administration method: Synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), and capsaicin-gabapentin (Compound 6) were administered subcutaneously into the plantar surface at a fixed administration volume of 20 μL; other compounds were administered by gavage at 0.1 mL / 10 g.

[0117] Inflammatory pain is one of the most common types of pathological pain in clinical practice. Carrageenan-induced inflammatory pain has high predictive value in the study of analgesics and is often used to evaluate the anti-inflammatory pain effects of drugs.

[0118] ICR mice were randomly divided into a negative control group, a model group, and each dose group of the compound, with 6 mice in each group. Before injecting carrageenan or normal saline, the baseline mechanical withdrawal thresholds (MWTs, expressed in g) of each mouse were measured. A ZH-ZKL type mechanical needle pain stimulator was used to evaluate mechanical allodynia. Briefly, the mice were unrestrainedly acclimated to the environment in an elevated metal grid under a transparent plastic chamber (21×27×15 cm). When the mice were acclimated for at least 30 minutes, a progressive force was applied to the left hind paw of the mice, and when the mice withdrew their hind paws, the pain stimulator automatically recorded the MWTs of the mice. Each test was repeated three times (test interval: 30 seconds). Three hours after injecting 20 μL of 1% carrageenan or normal saline, the compound or normal saline was administered by gavage. The MWTs were detected at 0, 30, 60, 90, and 120 minutes after administration. The percentage of maximum possible effect (%MPE) was calculated by the following formula: %MPE = (MWT 1 - MWT 2 ) / (MWT 3 - MWT 2 ) × 100%, where MWT 1 refers to the maximum threshold after drug treatment, MWT 2 refers to the threshold after modeling, and MWT 3 refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated by the area under the curve (AUC). The AUC describing the change of mechanical withdrawal threshold over time was calculated by the approximate trapezoidal rule using GraphPad Prism 10.0 software.

[0119] The experimental dose groups were set as shown in Table 2.

[0120] Table 2 Experimental grouping of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), capsaicin-gabapentin (Compound 6), Compound 7, Compound 8, and Compound 9 in a carrageenan-induced acute inflammatory pain model

[0121]

[0122] (2) Experimental results

[0123] The results are shown in Figure 1 and Figure 2As shown, 3 hours after injecting carrageenan, the mechanical threshold of mice decreased significantly. After administration of the twin drugs, the inflammatory pain induced by carrageenan could be alleviated in a dose-dependent manner. The analgesic inhibition rates of 1, 5, and 10 mg / kg of synthetic capsaicin-lipoic acid (Compound 1) in inflammatory pain were 26.79%, 51.34%, and 76.82% respectively, and its 50% maximum effective concentration (ED 50 ) value was 3.558 mg / kg. The analgesic inhibition rates of 1, 5, and 10 mg / kg of capsaicin-lipoic acid (Compound 2) in inflammatory pain were 17.63%, 58.34%, and 96.55% respectively, and its ED s0 was 3.28 mg / kg. In the carrageenan-induced acute inflammatory pain model, the maximum inhibition rates of synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin-pregabalin (Compound 5), and capsaicin-gabapentin (Compound 6) after administration were 66.34%, 57.14%, 70.21%, and 68.82% respectively. The maximum inhibition rates of Compound 7, Compound 8, and Compound 9 after administration were 47.78%, 57.13%, and 47.12% respectively. The analgesic activities of synthetic capsaicin-lipoic acid (Compound 1) and capsaicin-lipoic acid (Compound 2) in inflammatory pain were comparable. It can be seen from the maximum inhibition rate that the analgesic activities of synthetic capsaicin-lipoic acid (Compound 1) and capsaicin-lipoic acid (Compound 2) were better than those of Compound 7, Compound 8, and Compound 9. In addition, at the same dose, the analgesic effect of capsaicin-pregabalin (Compound 5) was the strongest, and the analgesic effect of synthetic capsaicin-gabapentin (Compound 4) was the weakest.

[0124] Example 12: Evaluation of the analgesic effects of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) in a paclitaxel-induced neuropathic pain model

[0125] (1) Experimental method

[0126] Experimental animals: The same as in Example 1.

[0127] Experimental materials: Synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), polyoxyethylene castor oil EL, paclitaxel, normal saline, absolute ethanol.

[0128] Preparation method: synthetic capsaicin-lipoic acid (compound 1) was dissolved in 5% DMSO solution, synthetic capsaicin-pregabalin (compound 3) and synthetic capsaicin-gabapentin (compound 4) were dissolved in normal saline as solvent; paclitaxel: dissolved in a solution consisting of 50% polyoxyethylene castor oil EL and 50% anhydrous ethanol at a concentration of 6 mg / mL (stored at -20°C for up to 14 days), and then diluted with normal saline (0.9% NaCl) to a final concentration of 0.2 mg / mL before administration.

[0129] Administration method: Synthetic capsaicin-lipoic acid (Compound 1) was administered orally at 0.1 mL / 10 g; synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) were administered subcutaneously at the sole of the foot at a fixed administration volume of 20 μL.

[0130] Paclitaxel can induce a peripheral neuropathic pain state characterized by allodynia and hyperalgesia induced by noxious or innocuous stimuli and is widely used to evaluate the anti-chemotherapeutic drug-induced neuropathic pain effects of drugs.

[0131] ICR mice were randomly divided into negative control group, model group and compound dose groups, with 6 mice in each group. MWTs of each mouse were measured before injection of paclitaxel or saline. Mechanical allodynia was assessed using a ZH-ZKL mechanical needle analgesia instrument. Briefly, mice were allowed to adapt to the environment in an elevated metal grid under a transparent plastic chamber (21×27, 15 cm) without restraint. When the mice had adapted for at least 30 minutes, a gradual force was applied to the left hind paw of the mouse, and the analgesia instrument automatically recorded the MWTs of the mouse when the mouse retracted its hind paw. Each test was repeated three times (inter-trial interval: 30 seconds). Paclitaxel stock solution (6.00 mg / mL) was prepared in a mixed solution of 50% polyoxyethylene castor oil and 50% ethanol, and diluted to a concentration of 0.2 mg / ml using saline. Mice were intraperitoneally injected with paclitaxel (2 mg / kg) at a dose of 0.1 mL / 10 g once a day for 5 consecutive days (days 1, 2, 3, 4, and 5). On the sixth day, the baseline mechanical threshold of each mouse was assessed, and intraperitoneal administration or saline was given. The mechanical withdrawal threshold of mice in each group was measured at 30, 60, 90, and 120 minutes after administration. The calculation formula of %MPE is as follows: %MPE = (MWT 1 -MWT 2 ) / (MWT 3 -MWT 2 )×100%, where MWT 1 Refers to the maximum threshold after drug treatment, MWT 2 Refers to the threshold after modeling, MWT 3Refers to the threshold of normal mice before modeling. The degree and duration of analgesia were estimated by the AUC value. The AUC describing the change of mechanical withdrawal threshold over time was calculated by the approximate trapezoidal rule using GraphPad Prism 10.0 software.

[0132] The experimental dose groups were set as shown in Table 3.

[0133] Table 3 Experimental groups of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) in a paclitaxel-induced neuropathic pain model

[0134]

[0135] (2) Experimental results

[0136] As Figure 3 shown, after five consecutive days of paclitaxel administration, the mechanical pain threshold of mice was significantly lower than the baseline level, indicating successful establishment of the neuralgia model. Among them, the analgesic inhibition rates of 1, 5, and 10 mg / kg synthetic capsaicin-lipoic acid (Compound 1) in paclitaxel-induced neuropathic pain were 4.57%, 36.52%, and 71.87% respectively, and the ED 50 value was 6.437 mg / kg. The analgesic inhibition rates of 60 μg and 100 μg synthetic capsaicin-pregabalin (Compound 3) in paclitaxel-induced neuropathic pain were 36.18% and 58.58% respectively. The analgesic inhibition rates of 30 μg, 60 μg, and 100 μg synthetic capsaicin-gabapentin (Compound 4) in paclitaxel-induced neuropathic pain were 5.71%, 27.49%, and 62.98% respectively.

[0137] From the ED s0 value, it can be seen that the analgesic effect of synthetic capsaicin-lipoic acid (Compound 1) in the inflammatory pain model is better than that in the neuropathic pain model. The analgesic activities of synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) in paclitaxel-induced neuropathic pain are comparable.

[0138] Example 13: Pharmacodynamic comparison experiment of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) with equimolar amounts of capsaicin, synthetic capsaicin, lipoic acid, pregabalin, or gabapentin alone and in combination in a carrageenan-induced inflammatory pain model

[0139] (1) Experimental method

[0140] The experimental animals were the same as those in Example 1.

[0141] Experimental materials: Synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), capsaicin, synthetic capsaicin, lipoic acid, pregabalin, gabapentin, and carrageenan.

[0142] Drug preparation method: Synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), and lipoic acid are dissolved in 5% DMSO solution; synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), pregabalin, and gabapentin use physiological saline as the solvent; synthetic capsaicin is dissolved in 5% dimethyl sulfoxide solution; carrageenan: A 1% solution is prepared with physiological saline as the solvent.

[0143] Drug administration method: Synthetic capsaicin-lipoic acid (Compound 1) and capsaicin-lipoic acid (Compound 2) and their equimolar single drugs are administered by gavage at 0.1 mL / 10 g; synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) and their equimolar single drugs are administered subcutaneously at the plantar surface with a fixed administration volume of 20 μL.

[0144] The experimental dose groups are set as shown in Table 4.

[0145] Table 4 Experimental grouping of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) in a carrageenan-induced acute inflammatory pain model

[0146]

[0147] (2) Experimental results

[0148] To further evaluate the pharmacodynamic advantages of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4), in this example, in a carrageenan-induced acute inflammatory pain model, the analgesic effect differences between synthetic capsaicin-lipoic acid (Compound 1) (5 mg / kg), capsaicin-lipoic acid (Compound 2) (5 mg / kg), synthetic capsaicin-pregabalin (Compound 3) (100 μg), and synthetic capsaicin-gabapentin (Compound 4) (100 μg) and their equimolar amounts of capsaicin, synthetic capsaicin, lipoic acid, pregabalin, and gabapentin as single drugs and in combination were compared.

[0149] In the carrageenan-induced acute inflammatory pain model, the inhibition rate of 5 mg / kg synthetic capsaicin-lipoic acid (Compound 1) at 90 min was 51.34%, and the inhibition rates of the corresponding equimolar synthetic capsaicin and physical mixture were 20.45% and 23.28% respectively, while lipoic acid at equimolar dose showed almost no analgesic activity. The inhibition rate of 5 mg / kg capsaicin-lipoic acid (Compound 2) at 90 min was 58.34%, while capsaicin and lipoic acid at equimolar dose showed almost no analgesic activity. The inhibition rate of 100 μg synthetic capsaicin-pregabalin (Compound 3) at 30 min was 66.34%, while synthetic capsaicin, pregabalin and physical mixture at equimolar dose showed almost no analgesic activity. The inhibition rate of 100 μg synthetic capsaicin-gabapentin (Compound 4) at 30 min was 57.14%, while the inhibition rates of gabapentin and physical mixture at equimolar dose were 10.58% and 21.58% respectively, and synthetic capsaicin at equimolar dose showed almost no analgesic activity. The results are shown in Figure 4 .

[0150] Therefore, in the carrageenan-induced acute inflammatory pain model, the analgesic activities of synthetic capsaicin-lipoic acid (Compound 1), capsaicin-lipoic acid (Compound 2), synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) were all superior to those of capsaicin, synthetic capsaicin, lipoic acid, pregabalin and gabapentin alone and in combination at equimolar doses.

[0151] Example 14: Pharmacodynamic comparison experiment of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) with equimolar amounts of synthetic capsaicin, lipoic acid, pregabalin or gabapentin alone and in combination in a paclitaxel-induced neuropathic pain model

[0152] (1) Experimental method

[0153] The experimental animals and implementation details were the same as those in Example 12.

[0154] Experimental materials: synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), synthetic capsaicin, lipoic acid, pregabalin, gabapentin and paclitaxel.

[0155] Drug preparation method: The same as that in Example 12.

[0156] Drug administration method: The same as that in Example 12.

[0157] The experimental dose groups were set as shown in Table 4.

[0158] (2) Experimental results

[0159] To further evaluate the pharmacodynamic advantages of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4), in this example, in a paclitaxel-induced neuropathic pain model, the analgesic effects of synthetic capsaicin-lipoic acid (Compound 1) (5 mg / kg), synthetic capsaicin-pregabalin (Compound 3) (100 μg), and synthetic capsaicin-gabapentin (Compound 4) (100 μg) were compared with those of equimolar amounts of synthetic capsaicin, lipoic acid, pregabalin, and gabapentin alone and in combination. The curative effects of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) were superior to those of combined use and single-drug treatment at equimolar doses.

[0160] In a paclitaxel-induced neuropathic pain model, the inhibition rate of 5 mg / kg synthetic capsaicin-lipoic acid (Compound 1) at 90 min was 36.52%, and the inhibition rates of the corresponding equimolar synthetic capsaicin and physical mixture were 24.18%, 11.17%, and 6.45%, respectively. The inhibition rate of 100 μg synthetic capsaicin-pregabalin (Compound 3) at 60 min was 58.58%, while synthetic capsaicin, pregabalin, and physical mixture at equimolar doses showed almost no analgesic activity. The inhibition rate of 100 μg synthetic capsaicin-gabapentin (Compound 4) at 30 min was 62.98%, while synthetic capsaicin, gabapentin, and physical mixture at equimolar doses showed almost no analgesic activity. The results are shown in Figure 5 。

[0161] Therefore, in a paclitaxel-induced neuropathic pain model, the analgesic activities of synthetic capsaicin-lipoic acid (Compound 1), synthetic capsaicin-pregabalin (Compound 3), and synthetic capsaicin-gabapentin (Compound 4) were superior to those of synthetic capsaicin, lipoic acid, pregabalin, and gabapentin alone and in combination at equimolar doses.

[0162] Example 15: Pharmacodynamic comparison experiment of high-dose synthetic capsaicin-pregabalin (Compound 3) and synthetic capsaicin-gabapentin (Compound 4) with equimolar amounts of synthetic capsaicin, pregabalin, or gabapentin alone and in combination in a carrageenan-induced inflammatory pain model

[0163] (1) Experimental method

[0164] The experimental animals and implementation details were the same as those in Example 1.

[0165] Experimental materials: synthetic capsaicin-pregabalin (Compound 3), synthetic capsaicin-gabapentin (Compound 4), synthetic capsaicin, pregabalin, gabapentin, and carrageenan.

[0166] Drug preparation method: Capsaicin - pregabalin (Compound 3), capsaicin - gabapentin (Compound 4), pregabalin and gabapentin use normal saline as the solvent; capsaicin is dissolved in a 5% dimethyl sulfoxide solution; carrageenan: is prepared into a 1% solution with normal saline as the solvent.

[0167] Drug administration method: Capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) and their equimolar single drugs are administered subcutaneously at the plantar surface with a fixed administration volume of 20 μL.

[0168] The experimental dose groups are set as shown in Table 5.

[0169] Table 5 Experimental grouping of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) in a carrageenan - induced acute inflammatory pain model

[0170]

[0171] (2) Experimental results

[0172] Since high - dose TRPV1 agonists can achieve the characteristic of long - acting analgesia, to further evaluate the pharmacodynamic advantages of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4), in this example, in a carrageenan - induced acute inflammatory pain model, the analgesic effect differences between capsaicin - pregabalin (Compound 3) (200 μg) and capsaicin - gabapentin (Compound 4) (200 μg) and equimolar amounts of capsaicin, pregabalin, gabapentin alone and in combination were compared respectively. It can be seen from the time - effect curve that the curative effects of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) are better than the combined use and single - drug treatment at equimolar doses. The results are shown in Figure 6 .

[0173] Example 16: Pharmacodynamic comparison experiment of high - dose capsaicin - pregabalin (Compound 3), capsaicin - gabapentin (Compound 4) and equimolar amounts of capsaicin, pregabalin or gabapentin alone and in combination in a paclitaxel - induced neuropathic pain model

[0174] (1) Experimental method

[0175] The experimental animals and implementation details are the same as in Example 14.

[0176] Experimental materials: Capsaicin - pregabalin (Compound 3), capsaicin - gabapentin (Compound 4), capsaicin, pregabalin, gabapentin and paclitaxel.

[0177] Drug dispensing method: Capsaicin - pregabalin (Compound 3), capsaicin - gabapentin (Compound 4), pregabalin and gabapentin are dissolved in normal saline as the solvent; capsaicin is dissolved in a 5% dimethyl sulfoxide solution; paclitaxel: dissolved in a solution composed of 50% polyoxyethylene castor oil EL and 50% absolute ethanol, with a concentration of 6 mg / mL (stored at -20 °C for a maximum of 14 days), and then diluted to a final concentration of 0.2 mg / mL with normal saline (0.9% NaCl) before administration.

[0178] Drug administration method: Capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) and their equimolar single drugs are administered subcutaneously into the plantar surface at a fixed administration volume of 20 μL.

[0179] The experimental dose groups are set as shown in Table 5.

[0180] (2) Experimental results

[0181] Since high doses of TRPV1 agonists can achieve the property of long - acting analgesia, to further evaluate the pharmacodynamic advantages of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4), in this example, in a paclitaxel - induced neuropathic pain model, the analgesic effect differences between capsaicin - pregabalin (Compound 3) (200 μg) and capsaicin - gabapentin (Compound 4) (200 μg) and their equimolar amounts of capsaicin, pregabalin, and gabapentin alone and in combination were compared respectively. It can be seen from the time - effect curve that the curative effects of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) are superior to the combined use and single - drug treatment at equimolar doses. The results are shown in Figure 7 .

[0182] Example 17: In the irritation experiment (ear wiping experiment), the irritation comparison experiment of capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4)

[0183] (1) Experimental method

[0184] Experimental animals: The same as in Example 1.

[0185] Experimental materials: Capsaicin - pregabalin (Compound 3), capsaicin - gabapentin (Compound 4), capsaicin.

[0186] Drug dispensing method: Capsaicin - pregabalin (Compound 3) and capsaicin - gabapentin (Compound 4) are dissolved in normal saline as the solvent; capsaicin is dissolved in a 5% dimethyl sulfoxide solution.

[0187] Experimental details: Capsaicin, capsaicin-pregabalin (Compound 3), and capsaicin-gabapentin (Compound 4) were formulated into solutions of different concentrations. Then, the solutions of capsaicin, capsaicin-pregabalin (Compound 3), and capsaicin-gabapentin (Compound 4) were applied to the ears of mice, and the number of times the ears were scratched was recorded during the subsequent 30 minutes.

[0188] (2) Experimental results

[0189] To study the safety of capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4) as topical drugs, a skin irritation test was conducted, comparing them with capsaicin to examine the toxicity associated with TRPV1 agonists. Similar to the general idea that all TRPV1 agonists cause skin irritation and edema, however, capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4) showed less skin irritation in the animal model, while capsaicin showed high irritation in a concentration-dependent manner. The results are shown in detail in Figure 8 .

[0190] Example 18: Comparative experiment on the irritation of capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4) in the irritation experiment (corneal irritation experiment)

[0191] (1) Experimental method

[0192] Experimental animals, experimental materials, and drug preparation method: The same as in Example 16.

[0193] Experimental details: Capsaicin, capsaicin-pregabalin (Compound 3), and capsaicin-gabapentin (Compound 4) were formulated into solutions with concentrations of 5 mg / mL and 10 mg / mL. Then, the solutions (10 μL) of capsaicin, capsaicin-pregabalin (Compound 3), and capsaicin-gabapentin (Compound 4) were applied to the right eyes of mice, and the number of eye rubs within 60 s was recorded.

[0194] (2) Experimental results

[0195] To study the safety of capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4) as topical drugs, a protective eye wipe test was conducted to examine the in vivo irritation of capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4). It can be seen from the figure that compared with the strong irritating effect of capsaicin, the wiping behavior caused by the instillation of capsaicin-pregabalin (Compound 3) and capsaicin-gabapentin (Compound 4) was significantly reduced. The results are shown in detail in Figure 9 .

[0196] Example 19: Preparation of a Tablet Containing Capsaicin - Lipoic Acid (Compound 1)

[0197] Table 8 Composition of the Prescription for Compound 1 Tablets

[0198]

[0199] Mix the raw and auxiliary materials by conventional methods, granulate, dry, and press into tablets.

[0200] The above examples only represent several implementation manners of this description. The description is relatively specific and detailed, but it should not be construed as a limitation on the scope of the patent of the description. It should be noted that for those of ordinary skill in the art, without departing from the concept of this description, several modifications and improvements can still be made, and these all belong to the protection scope of this description.

Claims

1. A type of analgesic drug, characterized in that: The anticonvulsant is formed by connecting drug A and drug B through a chemical bond, wherein drug A is a TRPV1 agonist, and drug B is lipoic acid or a voltage-gated calcium channel blocker.

2. The twin drug according to claim 1, characterized in that: The TRPV1 agonist is selected from capsaicin or synthetic capsaicin.

3. The twin drug according to claim 1, characterized in that: The voltage-gated calcium channel blocker is selected from pregabalin, gabapentin, melogabalin or cligabalin.

4. The twin drugs according to claims 1-3 are selected from the following structures:

5. A pharmaceutical composition, characterized in that Containing the compound according to any one of claims 1 to 4 or its isomer or salt and a pharmaceutically acceptable carrier.

6. A method for preparing compound 1-6 according to claim 4, characterized in that: R1 is selected from Boc, Cbz, Fomc, Alloc protecting groups, and is selected from gabapentin, pregabalin, melogabalin or cligabalin. The preparation method comprises the following steps: (1) protecting the amino group in the structure of gabapentin, pregabalin, melogabalin or cligabalin to obtain intermediate I; (2) subjecting the intermediate I obtained in step (1) to a condensation reaction with a TRPV1 agonist in the presence of a catalyst to obtain an intermediate II; (3) Removing the protecting group from the intermediate II obtained in step (2) under acidic, alkaline or neutral conditions to obtain the compound.

7. The preparation method according to claim 6, characterized in that: The molar ratio of gabapentin, pregabalin, melogababalin or clegabalin to the amino protecting agent in step (1) is 1:(1-10).

8. The preparation method according to claim 6, characterized in that: The catalyst described in step (2) is selected from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride, 4-dimethylaminopyridine, N,N′-dicyclohexylcarbodiimide or N,N′-diisopropylcarbodiimide, the molar ratio of intermediate I, TRPV1 agonist and catalyst is 1:(1-3):(0.01-10), and the reaction solvent is selected from dichloromethane, acetonitrile, acetone or tetrahydrofuran; In the preparation method described in claim 6, the acidic, alkaline or neutral conditions described in step (3) are selected from the conditions in the presence of ethyl acetate hydrochloric acid gas, trifluoroacetic acid, tetraethylammonium fluoride, tetramethylammonium fluoride, triethylamine, trimethylsilane iodide or pyridine.

9. Use of the spasticity medicine or the composition thereof according to claims 1-5 in the preparation of medicines for treating pain or nervous system diseases.

10. The use of the twin medicine or its combination according to claim 9, characterized in that: The pain is acute pain, chronic pain, neuropathic pain, inflammatory pain, nociceptive pain, cancer pain, hyperalgesia and visceral pain.

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